Medical Officer’s Primary Review of Efficacy and Safety

Oncology Drugs Advisory Committee Meeting of December 18, 2002

NDA 20-498/s012

Applicant AstraZeneca Pharmaceuticals LP
PO Box 8355
Wilmington, DE 19803-8355

Submission Type Efficacy supplement

Drug

Established name Bicalutamide

Trade name CasodexÒ

Drug Class Nonsteroidal anti-androgen

Proposed Indication Original Indication (Submitted 20 December 2001 with NDA)
Immediate hormonal therapy or adjuvant therapy to treatment of curative intent in patients with non-metastatic prostate cancer

First Revision of Indication (Submitted 10 May 2002)
Part 1: Adjuvant therapy to radical prostatectomy and radiotherapy of curative intent in patients with locally advanced non-metastatic prostate cancer who have a high risk for disease recurrence or

Part 2: Immediate treatment of non-metastatic prostate cancer in patients for whom therapy of curative intent is not indicated

Second Revision of Indication (Submitted 22 October 2002)
Part 1: (Unchanged from 10 May 2002 submission)

Part 2: Immediate treatment of localized non-metastatic prostate cancer in patients for whom therapy of curative intent is not indicated

Dosing Regimen One 150 mg tablet daily

Medical Reviewer Scott E. Monroe MD
Division of Reproductive and
Urologic Drug Products

November 19, 2002

TABLE OF CONTENTS

EXECUTIVE SUMMARY

1 Brief Overview of Clinical Program *

1.1 Drug *

1.2 Design of the Clinical Program *

2 Efficacy *

2.1 Proposed Label Claim *

2.2 Primary Efficacy Endpoints *

2.3 Efficacy Population and Efficacy Results (Primary Endpoints and Analyses) *

2.3.1 Demographics *

2.3.2 Sponsor’s Preferred Endpoints and Analyses *

2.3.3 FDA Requested Endpoints and Analyses *

2.3.4 Deaths *

2.4 Unresolved Efficacy Issues *

3 Safety *

3.1 Adequacy of Safety Testing *

3.2 Overview of Safety Findings *

3.2.1 Common Adverse Events. *

3.2.2 Potentially Serious or Life-Threatening Adverse Events *

3.2.3 Deaths *

4 Dosing REgimen *

CLINICAL REVIEW

1 INTRODUCTION AND BACKGROUND *

1.1 General Information *

1.2 Carcinoma of the Prostate *

1.2.1 Epidemiology *

1.2.2 Treatment of Prostate Cancer *

1.2.3 Rationale for the Use of Androgen Ablation Therapy *

1.2.4 Pharmacology of Casodex and Other Nonsteroidal Anti-androgens *

1.3 Other Relevant Information *

1.3.1 Earlier Submission (NDA 20-498/s006) *

1.3.2 Regulatory and Marketing Status *

1.3.2.1 Casodex 50 mg Tablets *

1.3.2.2 Casodex 150 mg Monotherapy *

1.3.2.3 Postmarketing Experience *

1.4 Important Issues with Pharmacologically Related Agents *

2 HUMAN PHARMACOKINETICS AND PHARMACODYNAMICS *

2.1 Pharmacokinetics *

2.1.1 Pharmacokinetics *

2.1.2 Potential for Interactions as Substrate, Inhibitor, or Inducer *

2.1.3 Effects of Renal or Hepatic Insufficiency and Age *

2.2 Pharmacodynamics *

3 Description of clinical data and sources *

3.1 Sources of Clinical Data *

3.1.1 Clinical Trials *

3.2 Overview of Clinical Trials *

4 Integrated Review of Efficacy *

4.1 Brief Statement about Efficacy *

4.2 General Approach to the Review of the Efficacy of the Drug *

4.3 Clinical Trials to Support Sponsor’s Efficacy Claim *

4.3.1 Overall Study Design *

4.3.2 Study Objectives *

4.3.3 Study Patients and Enrollment Criteria *

4.3.4 Study Drugs *

4.3.4.1 Rationale for Choice of Comparator *

4.3.4.2 Rationale for Dose Selection of Casodex *

4.3.4.3 Assignment to Study Drug and Treatment Schedules *

4.4 Study Procedures and Study Conduct *

4.4.1 Schedule of Study Assessments and Procedures *

4.4.2 Efficacy Assessments *

4.4.2.1 Objective Progression *

4.4.2.2 Non-objective Progression *

4.4.2.3 Bone Scans *

4.5 Efficacy Endpoints and Analyses *

4.5.1 Primary Efficacy Endpoints and Analyses *

4.5.2 Secondary Efficacy Endpoints and Analyses *

4.5.3 Overview of Statistical Analyses *

4.5.3.1 Efficacy Population *

4.5.3.2 Sponsor’s Analyses of Primary Efficacy Endpoints *

4.5.3.3 FDA Requested Analyses *

4.6 Results *

4.6.1 Enrollment and Patient Disposition *

4.6.2 Demographics and Baseline Disease Characteristics *

4.6.2.1 Baseline Demographics *

4.6.2.2 Baseline Disease Characteristics *

4.6.3 Primary Efficacy Outcomes *

4.6.3.1 Objective Disease Progression or Death in Absence of Progression (Sponsor’s Preferred Endpoints and Analyses) *

4.6.3.2 Efficacy Outcomes (FDA-Requested Endpoints and Analyses) *

4.6.3.3 Additional Subset Analyses to Support Adjuvant Use of Casodex *

4.6.3.4 First Revision by Sponsor to Proposed Label Claims *

4.6.3.5 Additional Subset Analyses to Support Immediate or Monotherapy Indication *

4.6.3.6 Second Revision by Sponsor to Proposed Label Claims *

4.6.3.7 Additional Subset Analyses by Baseline Disease Characteristics *

4.6.3.8 Central Reread of Bone Scans *

4.6.3.9 Survival *

4.6.4 Secondary Efficacy Endpoints *

4.6.4.1 Time to Treatment Failure *

4.6.4.2 Time to PSA Doubling *

4.7 Consultations *

4.8 Conclusions Regarding Demonstrated Efficacy *

4.8.1 Achievement of Protocol-Defined Primary Efficacy Endpoints *

4.8.2 Support of Label Efficacy Claims *

4.9 Statistician’s Assessment of Efficacy *

4.10 Medical Reviewer’s Overall Assessment of Efficacy (Statistical and Clinical Significance) *

4.10.1 Demonstrated Efficacy of Casodex in Non-US Clinical Trials (Trials 24 and 25) *

4.10.2 Lack of Casodex Efficacy in US Clinical Trial (Trial 23) *

4.10.3 Relevance of Watchful Waiting (Immediate Therapy) Subgroups in Trials 24 and 25
to Prostate Cancer Patients in the US Managed by Watchful Waiting
*

4.10.4 Lack of Improved Survival in Casodex-Treated Patients *

5 Integrated Review of Safety *

5.1 Brief Statement of Conclusions *

5.2 Overview of Controlled Safety Studies (Trials 23, 24, and 25) *

5.3 Protocol Defined Safety Assessments *

5.3.1 Adverse Events and Survival *

5.3.2 Clinical Laboratory Tests *

5.3.3 Assessment of Sexual Function (Trial 25 Only) *

5.4 Demographics and Other Baseline Characteristics (Safety Population) *

5.4.1 Exposure and Duration of Treatment in the Controlled Clinical Trials *

5.5 Patient Disposition *

5.6 Adverse Events *

5.6.1 Overview of Adverse Events *

5.6.2 Adverse Events (All Intensities and All Relationships to Study Drug) *

5.6.3 Treatment-Related Adverse Events *

5.6.4 Adverse Events Resulting in Patient Withdrawal *

5.6.5 Serious Adverse Events during the Treatment Period *

5.7 Deaths *

5.8 Laboratory Assessments *

5.8.1 Mean LFT Values and Mean Changes from Baseline Values *

5.8.2 Shifts in LFT Laboratory Values to Above the Normal Range *

5.8.3 Clinically Relevant Changes in LFT Laboratory Values *

5.8.4 Non-hepatic Laboratory Safety Assessments *

5.9 Safety Issues of Special Interest or Concern *

5.9.1 Pharmacological Adverse Events *

5.9.1.1 Gynecomastia and Breast Pain during the Treatment Period *

5.9.1.2 Resolution of Breast Pain and Gynecomastia after Withdrawal of Treatment *

5.9.2 Sexual Dysfunction *

5.9.3 Liver Toxicity *

5.9.3.1 Abnormal Liver Function Test (LFT) Values Reported as Adverse Events *

5.9.3.2 Hepatic-related Adverse Events during the Treatment Period *

5.9.3.3 Deaths Related to Hepatic Failure or Primary Hepatic Neoplasms *

5.9.4 Cardiovascular Morbidity and Mortality *

5.9.4.1 Cardiovascular Adverse Events during the Treatment Period *

5.9.4.2 Cardiovascular Mortality *

5.9.5 Second Tumors *

5.9.5.1 Gastrointestinal Tumors *

5.9.5.2 Myelodysplasia and Leukemia *

5.10 Adequacy of Patient Exposure and Safety Assessments *

6 Dosing Regimen *

6.1 Dosing Regimen *

6.2 Effects of Renal or Hepatic Impairment on Casodex Pharmacokinetics *

 

7 Conclusions and Recommendations *

7.1 Conclusions *

7.1.1 Benefits of Treatment with Casodex *

7.1.2 Risks of Treatment with Casodex *

7.1.3 Summary of Risk-Benefit Analysis *

7.2 Recommendations *

7.2.1 Recommendations Regarding Approvability (Based on Indications Submitted on
10 May 2002)
*

8 References *

APPENDIX (Supplemental Efficacy Analyses) ……………………….……………119

 

TABLE OF TABLES

Table 1. Studies Supporting Safety and Efficacy of Casodex for Localized or Locally Advanced Prostate Cancer. *

Table 2 Overview of Phase III Clinical Trials (Similarities and Differences) *

Table 3 Primary and Secondary Objectives of the Clinical Trials *

Table 4 Schedule of Study Assessments and Procedures *

Table 5 Summary of Primary and Secondary Endpoints and Analyses *

Table 6 Patient Enrollment and Treatment Status as of June 2, 2000 1 *

Table 7 Patient Years of Exposure to Study Drug and Follow-up 1 *

Table 8 Baseline Demographic Characteristics (Trials 23, 24, and 25) *

Table 9 Disease Characteristics at Baseline *

Table 10 Serum PSA (Prior to Prostatectomy or Radiotherapy and/or at Randomization) *

Table 11 Objective Disease Progression or Death in Trials 23, 24, and 25 *

Table 12 Time to Objective Progression or Death in Absence of Progression *

Table 13 Objective Disease Progression or Death in Absence of Progression Based on Pre-randomization Treatment (Data for Trials 23, 24, and 25 Combined) *

Table 14 Time to Objective Progression or Death (Trials 23, 24, and 25 Combined) *

Table 15 Objective Disease Progression or Death in Absence of Progression in Subgroups Based on Pre-randomization Treatment (Trial 24) *

Table 16 Objective Disease Progression or Death in Absence of Progression in Subgroups Based on Pre-randomization Treatment (Trial 25) *

Table 17 Hazard Ratios for Objective Disease Progression or Death (Any Cause) in Subgroups based on Pre-randomization Treatment (Trials 24 and 25) *

Table 18 Bone Scan Confirmed Disease Progression or Death in the Absence of Progression within 2.5 Years after Randomization *

Table 19 Odds Ratios for Bone Scan Confirmed Progression or Death in Absence of Progression within 2.5 Years after Randomization *

Table 20 Bone Scan Confirmed Disease Progression or Death within 2.5 Years after Randomization (Trial 23: Prior Treatment Subgroups) *

Table 21 Bone Scan Confirmed Disease Progression or Death within 2.5 Years after Randomization (Trial 24: Prior Treatment Subgroups) *

Table 22 Bone Scan Confirmed Disease Progression or Death within 2.5 Years after Randomization (Trial 25: Prior Treatment Subgroups) *

Table 23 Odds Ratios for Bone Scan Confirmed Progression or Death from Any Cause within 2.5 Years after Randomization in Treatment Subgroups *

Table 24 Disease Progression in Patients with Locally Advanced (Stage T3/T4), M0 Prostate Cancer and Post Prostatectomy PSA Values > 0.2 ng/mL *

Table 25 Patients with Bone Scan Progression or Death from Any Cause within 2.5 Years of Randomization in Watchful Waiting Group (Trial 24) *

Table 26 Patients with Bone Scan Progression or Death from Any Cause within 2.5 Years of Randomization in Watchful Waiting Group (Trial 25) *

Table 27 Patients with Bone Scan Progression or Death from Prostate Cancer within 2.5 Years of Randomization in Watchful Waiting Group (Trials 24 and 25) *

Table 28 Comparison of Local Read and Central Reread (Data from Trials 23, 24, and 25 Combined) *

Table 29 Comparison of Results of Local Read and Central Reread including only Scans Reread as Positive or Negative *

Table 30 Number and Percentage of Deaths in Trials 23, 24, and 25 *

Table 31 Reasons for Treatment Failure (Trials 23, 24, and 25) *

Table 32 Analyses of Time to Treatment Failure (Trials 23, 24, and 25) *

Table 33 Number (%) of Patients with a PSA Doubling Event *

Table 34 Analyses of Time to a PSA Doubling Event in Trials 23, 24, and 25 *

Table 35 Years of Exposure to Study Drug (Trials 23, 24, and 25 Combined) *

Table 36 Duration of Treatment (Trials 23, 24, and 25 Combined) *

Table 37 Disposition of Patients in Trials 23, 24, and 25 as of 23 February 2001 *

Table 38 Overview of Adverse Events during Treatment (Trials 23, 24, and 25) *

Table 39 Overview of Adverse Events by Clinical Trial during Randomized
Treatment
*

Table 40 Adverse Events with an Incidence ³ 5% (Combined Data from Trials 23, 24, and 25) *

Table 41. Treatment-Related Adverse Events Occurring in ³  0.5% of Patients (Combined Data from Trials 23, 24, and 25) *

Table 42 Adverse Events with an Incidence ³  0.3% Leading to Withdrawal (Combined Data from Trials 23, 24, and 25) *

Table 43 Serious Adverse Events with Incidence ³  0.5% during Treatment Period *

Table 44 Number and Percentage of Deaths in Trials 23, 24, and 25 (Combined Data) *

Table 45 Number and percentages of Deaths in Each of Trials 23, 24, and 25 *

Table 46 Primary Causes of Death due to Drug-Related Adverse Events *

Table 47 Number (%) of Patients with Primary Cause of Death Classified by COSTART Body System Term and Treatment Period (All Trials) *

Table 48 Primary Causes of Death (Other than Prostate Cancer) during the Treatment Period (Trials 23, 24, and 25 Combined) *

Table 49 Mean Serum ALT Values (U/L) and Mean of Percent Changes from Baseline during Treatment (Data Combined from Trials 23, 24, and 25) *

Table 50 ALT Shifts from Within the Normal Range at Baseline to Above the Normal Range (High) during Treatment in Each of Trials 23, 24, and 25 *

Table 51 Bilirubin Shifts from Within the Normal Range at Baseline to Above the Normal Range (High) during Treatment in each of Trials 23, 24, and 25 *

Table 52 Clinically Relevant Changes in ALT, AST, and Total Bilirubin Values during Treatment in Trials 23, 24, and 25 (Combined Analysis) *

Table 53 Resolution of Clinically Relevant Changes in ALT, AST, and Total
Bilirubin Values in Trials 23, 23, and 25 (Combined Analyses)
*

Table 54 Adverse Events Reported as Anemia or Erythrocyte Disorder during the Treatment Period (Combined Data from Trials 23, 24, and 25) *

Table 55 Pharmacological-Related (Anti-androgenic and Estrogenic) Adverse Events (Combined Data from Trials 23, 24, and 25) *

Table 56 Incidence of and Withdrawals due to Gynecomastia and Breast Pain within the Treatment Period (Combined Data from Trials 23, 24, and 25) *

Table 57 Incidence of and Withdrawals due to Gynecomastia and Breast Pain within the Treatment Period in Each of Trials 23, 24, and 25 *

Table 58 Percentage of Patients with Resolution of Gynecomastia and Breast Pain after Withdrawal of Treatment *

Table 59 Maintenance of Sexual Function Relative to Baseline *

Table 60 Number (%) of Patients with Increased Liver Function Test Values Reported as Adverse Events (Trials 23, 24, and 25) *

Table 61 Hepatic-related Adverse Events during Treatment (Trials 23, 24, and 25) *

Table 62 Deaths Related to Hepatic Failure or Primary Hepatic Neoplasms *

Table 63 Serious Cardiovascular Adverse Events with Incidence ³  0.2% during Treatment Period (Combined Data from Trials 23, 24, and 25) *

Table 64 Patients with a Cardiovascular-related Primary Cause of Death (Combined Data from Trials 23, 24, and 25) *

Table 65 Primary Causes of Cardiovascular Deaths with Incidence ³ 0.05% (Combined Data from Trials 23, 24, and 25) *

Table 66 Solid Tumors Reported as Adverse Events within the Treatment Period in ³  0.2% Patients (Data Combined for Trials 23, 24, and 25) *

Table 67 Incidence of Gastrointestinal Tumors (Trials 23, 24, and 25) *

Table 68 Patients Who Developed Myelodysplasia Syndrome or Leukemia *

TABLE OF FIGURES

Figure 1 Efficacy Analysis Population and Treatment Status at Time of Data
Cutoff
*

Figure 2 Overview of Safety Patient Population *

Figure 3 Time to First Occurrence of Gynecomastia within the Treatment Period *

 

EXECUTIVE SUMMARY

  1. Brief Overview of Clinical Program
    1. Drug
    2. Casodex (bicalutamide) is a nonsteroidal anti-androgen with no other known endocrine activity. It competitively inhibits the action of androgens by binding to cytosol androgen receptors in the target tissue.

    3. Design of the Clinical Program

    The Sponsor submitted data from 3 placebo-controlled, randomized, double-blind, parallel-group clinical trials that enrolled men with local or locally advanced non-metastatic prostate cancer. The trials were conducted in (1) North America, predominantly the US [Trial 23], (2) Europe (other than Scandinavia), South Africa, Israel, Mexico, and Australia [Trial 24], and (3) Scandinavia [Trial 25]. Patients were randomized in a 1:1 ratio to treatment with either Casodex 150 mg per day or matching placebo. In all 3 trials, Casodex was investigated as adjuvant therapy in patients who had had previous therapy for their prostate cancer (i.e., radical prostatectomy or radiation therapy). In Trials 24 and 25 (but not Trial 23), Casodex also was investigated as monotherapy (i.e., in patients who had had no prior therapy and whose prostate cancer would otherwise be managed by watchful waiting or surveillance). In Trial 23, treatment was limited to a maximum of 2 years or until objective disease progression (whichever occurred first). In Trials 24 and 25, patients were to be treated for 5 years (adjuvant group in Trial 24) or indefinitely (all other groups) or until progression of disease (all patients).

  2. Efficacy
    1. Proposed Label Claim
    2. The Sponsor has proposed (revised indication of 10 May 2002) that Casodex 150 mg per day is indicated as (1) adjuvant therapy to radical prostatectomy and radiotherapy of curative intent in patients with locally advanced non-metastatic prostate cancer who have a high risk for disease recurrence and (2) immediate treatment of non-metastatic prostate cancer in patients for whom therapy of curative intent is not indicated.

    3. Primary Efficacy Endpoints
    4. The protocol-defined primary efficacy endpoints were (1) objective disease progression defined as local or distant progression of disease confirmed by bone scan, x-ray, CT scan, magnetic resonance imaging, ultrasonography, or biopsy and (2) death due to any cause in the absence of objectively confirmed progression. The protocol-defined primary efficacy analyses were time to objective progression or death. Because of the potential for assessment bias (the side effects of Casodex treatment were likely to unblind patient treatment assignments in many instances), the Division of Reproductive and Urologic Drug Products (DRUDP) requested that the primary efficacy endpoints be limited to (1) the events of (a) bone scan documented disease progression and (b) death due to any cause in the absence of bone scan confirmed progression and (2) events that occurred within 2 years of randomization.

    5. Efficacy Population and Efficacy Results (Primary Endpoints and Analyses)
      1. Demographics
      2. A total of 8,113 patients were randomized to therapy (the intent-to-treat population) with 3292, 3603, and 1218 patients randomized to Trials 23, 24, and 25, respectively. Median patient-years of follow up for disease progression and survival (efficacy analyses) were 3.2 years (Trial 23), 2.6 years (Trial 24) and 3.0 years (Trial 25). Within each of the individual trials, baseline demographic and disease characteristics were well balanced across the Casodex and placebo treatment groups. In general, baseline patient characteristics across Trials 24 and 25 were similar but differed somewhat from those in Trial 23 in that patients in Trial 23 tended to be younger by several years, weighed slightly more, and had lower serum PSA values.

      3. Sponsor’s Preferred Endpoints and Analyses
      4. The percentages of patients with disease progression or death in the absence of disease progression in each of the trials (based on the Sponsor’s preferred protocol-defined endpoints) are summarized in Table A. The percentage of patients with disease progression in each of Trials 24 and 25 was numerically lower in the Casodex-treated patients. Based on this endpoint and a time to event analysis, there was a statistically significant reduction in the time to disease progression in Trial 24 (hazard ratio [HR] = 0.574, 95% confidence interval [CI]: 0.477 to 0.692) and Trial 25 (HR = 0.430, 95% CI: 0.336 to 0.552). There was no evidence of benefit from Casodex treatment in Trial 23 (the only trial conducted in the US).

        Table A Disease Progression or Death (Based on Sponsor’s Preferred Endpoints)

         

        Number (per cent) of patients with event

        Event

        Study 23

        Study 24

        Study 25

        Casodex
        (N = 1647)

        Placebo
        (N = 1645)

        Casodex
        (N = 1798)

        Placebo
        (N = 1805)

        Casodex
        (N = 607)

        Placebo
        N = 611)

        Positive bone scan

        21

        (1.3)

        15

        (0.9)

        60

        (3.3)

        116

        (6.4)

        32

        (5.3)

        95

        (15.5)

        Other objective events 1

        10

        (0.6)

        17

        (1.0)

        25

        (1.4)

        85

        (4.7)

        19

        (3.1)

        40

        (6.5)

        Death in absence of progression

        52

        (3.2)

        55

        (3.3)

        96

        (5.3)

        92

        (5.1)

        48

        (7.9)

        44

        (7.2)

        Total (%) Patients

        83

        (5.0)

        87

        (5.3)

        181

        (10.1)

        293

        (16.2)

        99

        (16.3)

        179

        (29.3)

        1 Documented by magnetic resonance imaging, computerized tomography, sonography, or biopsy.

        Exploratory subset analyses for Trial 24 (based on the sponsor’s preferred endpoints) indicated a reduction in disease progression in the Casodex-treated patients in both the adjuvant therapy subgroups (patients treated by prior prostatectomy or radiotherapy) and the watchful waiting (immediate or monotherapy) subgroup. Results for the watchful waiting subgroup in Trial 25 (the only subgroup with more than 250 patients in this trial) also showed a numeric reduction in disease progression in Casodex-treated patients. The estimates of the hazard ratios and 95% CIs for the watchful waiting subgroups were 0.674 (Trial 24, 95% CI = 0.518 to 0.878) and 0.423 (Trial 25, 95% CI = 0.321 to 0.557).

      5. FDA Requested Endpoints and Analyses
      6. The percentages of patients with objective disease progression or death in the absence of objective progression within 2.5 years of randomization are presented in Table B. For Trials 24 and 25, the estimates of the odds ratios (OR) and 95% CIs were 0.645 (Trial 24, 95% CI = 0.500 to 0.832 and 0.515 (Trial 25, 95% CI = 0.365 to 0.729).

        Table B Disease Progression or Death (Based on FDA Requested Endpoints)

         

        Number (per cent) of patients with event within 2.5 yr. of randomization

        Event

        Study 23

        Study 24

        Study 25

        Casodex
        (N = 1647)

        Placebo
        (N = 1645)

        Casodex
        (N = 1798)

        Placebo
        (N = 1805)

        Casodex
        (N = 607)

        Placebo
        N = 611)

        Positive bone scan

        14

        (0.9)

        11

        (0.7)

        42

        (2.3)

        98

        (5.4)

        22

        (3.6)

        72

        (11.8)

        Death in absence of progression

        25

        (1.5)

        37

        (2.2)

        70

        (3.9)

        70

        (3.9)

        41

        (6.8)

        33

        (5.4)

        Total (%) of patients

        39

        (2.4)

        48

        (2.9)

        112

        (6.2)

        168

        (9.3)

        63

        (10.4)

        105

        (17.2)

        Exploratory subset analyses for Trial 24 indicated that the proportions of Casodex-treated patients with disease progression were numerically lower in both the adjuvant therapy subgroups (patients treated by prior prostatectomy or radiotherapy) and the watchful waiting subgroup (Table C). The estimates of the odds ratios and 95% CIs for the subgroups were 0.616 (radical prostatectomy, 95% CI = 0.379 to 1.003), 0.625 (radiotherapy, 95% CI = 0.361 to 1.081), and 0.674 (watchful waiting, 95% CI = 0.471 to 0.964).

        Table C Disease Progression or Death by Pre-randomization Treatment in Trial 24 (FDA Requested Endpoints)

         

        Number (per cent) of patients with event within 2.5 yr. of randomization

        Event

        Radical Prostatectomy

        Radiotherapy

        Watchful Waiting

        Casodex
        (N = 835)

        Placebo
        (N = 813)

        Casodex
        (N = 335)

        Placebo
        (N = 325)

        Casodex
        (N = 628)

        Placebo
        (N = 666)

        Positive bone scan

        12

        (1.4)

        27

        (3.3)

        11

        (3.3)

        28

        (8.6)

        19

        (3.0)

        43

        (6.5)

        Death (any cause) in absence of progression

        17

        (2.0)

        16

        (2.0)

        13

        (3.9)

        8

        (2.5)

        40

        (6.4)

        46

        (6.9)

        Total (%) Patients

        29

        (3.5)

        43

        (5.3)

        24

        (7.2)

        36

        (11.1)

        59

        (9.4)

        89

        (13.4)

        Results for the watchful waiting subgroup in Trial 25 (the only subgroup with more than 250 patients in this trial) also showed a numeric reduction in disease progression in Casodex-treated patients. The estimate of the odds ratio and 95% CI for this subgroup was 0.498, 95% CI = 0.338 to 0.734.

      7. Deaths

      The total number and percentage of deaths due to prostate cancer or other causes in each of the trials at the data cutoff for the efficacy analyses (2 June 2000) and the data cutoff for the safety update (28 September 2001) are listed in Table D. There were no significant differences in the percentage of patients who died, either of prostate cancer or of other causes, in the Casodex and placebo groups within each of the trials. There were, however, differences across the trials.

      Table D Total Number and (%) of Deaths due to Prostate Cancer or Other Causes

      Cause of
      Death

      Study 23

       

      Study 24

       

      Study 25

      Casodex
      N= 1647

      Placebo N=1645

       

      Casodex
      N= 1798

      Placebo N=1805

       

      Casodex
      N= 607

      Placebo
      N= 611

       

      n

      (%)

      n

      (%)

       

      n

      (%)

      n

      (%)

       

      n

      (%)

      n

      (%)

      Prostate cancer

      8

      (0.5)

      3

      (0.2)

       

      26

      (1.4)

      38

      (2.1)

       

      24

      (4.0)

      28

      (4.6)

      Other

      54

      (3.3)

      58

      (3.5)

       

      97

      (5.4)

      99

      (5.5)

       

      45

      (7.4)

      42

      (6.9)

      Total 1

      62

      (3.8)

      61

      (3.7)

       

      123

      (6.8)

      137

      (7.6)

       

      69

      (11.4)

      70

      (11.5)

      Prostate cancer

      14

      (0.9)

      6

      (0.4)

       

      56

      (3.1)

      66

      (3.7)

       

      49

      (8.1)

      56

      (9.2)

      Other

      91

      (5.6)

      93

      (5.7)

       

      168

      (9.4)

      161

      (9.0)

       

      67

      (11.1)

      50

      (8.2)

      Total 2

      105

      (6.5)

      99

      (6.1)

       

      224

      (12.5)

      227

      (12.7)

       

      116

      (19.2)

      106

      (17.4)

      1. Data cutoff of 2 June 2000 (efficacy population). 2. Data cutoff of 28 September 2001 (safety population).

    6. Unresolved Efficacy Issues

The relevance of the findings in Trials 24 and 25 to men with prostate cancer in the US who would be treated with Casodex (either adjuvant therapy or monotherapy) is unclear.

Adjuvant Therapy. Based on the data submitted by the Sponsor, patients similar to those enrolled in Trial 230 who are initially treated by radical prostatectomy or radiotherapy in the US would derive no benefit from Casodex adjuvant therapy. A supplemental analysis by the Sponsor, based on a subset of patients in Trial 23, also did not show convincing evidence of efficacy for Casodex adjuvant therapy. In addition, it was not possible (1) to adequately characterize the patients in Trials 24 and 25 because of lack of standardized Gleason scores and (2) to extrapolate the data from patients in Trials 24 and 25 to Trial 23 to identify US patients who might benefit from Casodex adjuvant therapy.

Immediate Treatment or Monotherapy. A watchful waiting subgroup was not included in Trial 23. The proposed indication does not adequately identify the population of prostate cancer patients in the US who might derive sufficient benefit from Casodex monotherapy to warrant the risks of treatment.

  1. Safety
    1. Adequacy of Safety Testing
    2. The database from Trials 23, 24, and 25 supporting the safety of Casodex 150 mg per day was large. It included 4,022 Casodex-treated patients, representing 9,387 patient-years of exposure. Patient exposure to Casodex in the controlled clinical trials was adequate to assess the likely safety profile of Casodex 150 mg per day in men with prostate cancer.

    3. Overview of Safety Findings
    4. Most patients in the controlled clinical trials (97.4% Casodex group, 88.2% placebo group) had at least 1 adverse event. The number of patients with at least 1 drug-related adverse event was approximately 3-fold higher in the Casodex group (90.5%) than the placebo group (31.4%). A greater number of patients in the Casodex group also were withdrawn from treatment as a result of an adverse event (27.7% compared with 9.2% of placebo-treated patients). The number of patients who had at least 1 serious adverse event was similar across the treatment groups (33.6% Casodex group, 32.5% placebo group). Much of the difference between the Casodex and placebo treatment groups in each of the categories of (a) any adverse event, (b) drug-related adverse events, and (c) adverse events leading to withdrawal was due to the pharmacological (anti-androgenic and compensatory estrogenic) actions of Casodex.

      Side effects associated with Casodex treatment can be classified for the most part into one of 2 categories: (1) those of a generally non-serious and non-life threatening nature that are due to the pharmacological actions of Casodex and which occur with a high incidence and (2) those that occur in a few percent of patients and which may be serious or life-threatening (primarily liver toxicity).

      1. Common Adverse Events.
      2. The most commonly reported adverse events that occurred more frequently in Casodex-treated patients and the percentage of Casodex-treated patients that experienced these adverse events were breast pain (73%), gynecomastia (67%), asthenia (11%), vasodilatation (9%), impotence (9%), alopecia (6%), and weight gain (6%). All of these adverse events (other than perhaps asthenia and weight gain) are likely to be due to the pharmacological actions of Casodex.

        Most Casodex-treated patients (86.2%) reported gynecomastia or breast pain. Of these patients, 16.1% withdrew from Casodex therapy because of these adverse events. Gynecomastia or breast pain was reported as severe in 8.6% of Casodex-treated patients. Breast pain was reversible in > 90% of patients after cessation of Casodex therapy. Gynecomastia, however, resolved in only 50% of patients after discontinuation of treatment. In the placebo-treated patients, only 12.4% patients reported gynecomastia or breast pain, and only 0.6% withdrew from treatment because of these adverse events.

      3. Potentially Serious or Life-Threatening Adverse Events
      4. Treatment with all nonsteroidal anti-androgens is associated with hepatotoxicity that can be serious and occasionally fatal. Hepatotoxicity appears to occur more frequently in patients being treated with flutamide than other nonsteroidal anti-androgens. In the combined findings from Trials 23, 24, and 25, patient withdrawals due to increased serum ALT and AST values or increased bilirubin values were higher in Casodex-treated patients (1.2% and 0.4%, respectively) than in placebo-treated patients (0.5% and 0.2%, respectively). Similarly, adverse events classified as serious due to increased serum ALT and AST values or increased bilirubin values were more frequent in Casodex-treated patients (0.3% and 0.2%, respectively) than in placebo-treated patients (0.0% and <0.1%, respectively). However, the number of patients reported to have died from hepatic failure or a primary hepatic neoplasm was similar in the 2 treatment groups (5 of 4,022 Casodex-treated patients and 5 or 6 of 4,031 placebo-treated patients).

        Twelve (12) Casodex-treated patients and 5 placebo-treated patients developed myelodysplasia syndrome or leukemia (relative incidence Casodex/placebo = 2.4). Of these patients, 8 of the Casodex-treated patients and 4 of the placebo-treated patients have died as a direct or indirect result of their underlying hematologic disorder. The significance of this numeric imbalance and its possible relationship to treatment with Casodex are not known at this time.

      5. Deaths

    As of the data cutoff date for the Safety Update (28 September 2001), 445 of 4,022 patients (11.1%) who received Casodex and 432 of 4,031 patients (10.7%) who received placebo had died. Prostate cancer was the listed cause of death in 2.96% and 3.18% of patients in the Casodex- and placebo-treatment groups, respectively. Among non-prostate cancer causes of death, cardiovascular events were the major cause of death with 77 cases reported in Casodex-treated patients and 66 cases reported in placebo-treated patients. Deaths that linked to the respiratory system were the second most frequent in both treatment groups, occurring in 29 Casodex-treated and 36 placebo-treated patients. Deaths that linked to the digestive system were the third most frequent, affecting 24 Casodex-treated patients and 17 placebo-treated patients. Among this group, gastrointestinal carcinoma was the most common single cause of death, affecting 18 Casodex-treated patients and 10 placebo-treated patients.

  2. Dosing REgimen
  3. The proposed dosing-regimen is Casodex 150 mg per day for at least 2 years or until disease progression. The proposed dose appears to be appropriate based on dose-ranging data concerning suppression of serum PSA values in men with prostate cancer that were provided in an earlier submission (NDA 20-498/s006). The basis for the recommendation that treatment should continue for at least 2 years is unclear since treatment in Trial 24 and Trial 25 was to be for at least 5 years or until disease progression.

    CLINICAL REVIEW

  4. INTRODUCTION AND BACKGROUND
    1. General Information

First Revision of Indication (Submitted 10 May 2002)
(1) Adjuvant therapy to radical prostatectomy and radiotherapy of curative intent in patients with locally advanced non-metastatic prostate cancer who have a high risk for disease recurrence or

(2) Immediate treatment of non-metastatic prostate cancer in patients for whom therapy of curative intent is not indicated

Second Revision of Indication (Submitted 22 October 2002)
(1) (Unchanged from 10 May 2002 submission).

(2) Immediate treatment of localized non-metastatic prostate cancer in patients for whom therapy of curative intent is not indicated

    1. Carcinoma of the Prostate
      1. Epidemiology
      2. Cancer of the prostate is the most frequent noncutaneous malignancy in men, and after lung cancer, the second most frequent cause of death from cancer in men over 50 years of age. It is estimated that approximately 200,000 new cases of prostate cancer were diagnosed and that 30,000 deaths occurred from the disease in the year 2001. Prostate cancer is a major social, economic, and health issue.

      3. Treatment of Prostate Cancer
      4. Treatment options for prostate cancer include radical prostatectomy, radiotherapy, androgen ablation or deprivation therapy (achieved by surgical castration, GnRH analogs, or nonsteroidal antiandrogens), and no active therapy (watchful waiting or surveillance). Selection of the most appropriate treatment depends on many factors that include the clinical stage of the tumor (localized to the prostate, local extension beyond the prostate, or distant or bony metastases), status of regional lymph nodes, degree of tumor differentiation (generally assessed as Gleason grade), serum prostate specific antigen (PSA) concentration, and the patient’s likely life expectancy due to the presence of other co-morbid conditions.

        Patients with tumors that are localized to the prostate gland may be cured of their disease by a radical prostatectomy or radiation therapy. Patients with local extension of their tumor beyond the prostate gland also may be candidates for a curative procedure (radical prostatectomy or radiotherapy) in some instances, particularly if the tumor is well- or moderately well-differentiated and is associated with a serum PSA of < 10 ng/mL at the time of diagnosis. Patients with extensive local disease generally are not candidates for a curative procedure, particularly if the tumor is poorly differentiated and the serum PSA is > 10 ng/mL. Such patients are often managed by androgen ablation therapy alone or androgen ablation therapy plus radiotherapy. Patients with bony metastases or non-local soft tissue metastases are generally treated with androgen ablation therapy alone.

        A minority of patients in the US (perhaps 10% of newly diagnosed cases) are initially managed by watchful waiting or surveillance. In the US, men who initially receive no active therapy tend to be older (generally > 75 years of age at diagnosis), have low grade and localized tumors, have no symptoms from their prostate cancer, and often have a life expectancy of < 10 years. The rationale for management by watchful waiting or surveillance is the expectation that prostate cancer will remain asymptomatic in the majority of these men, and they will likely die from a disorder unrelated to prostate cancer.

      5. Rationale for the Use of Androgen Ablation Therapy
      6. Growth of prostate glandular tissue is regulated by a complex of growth factors of which androgens play a pivotal role. In most men, prostate cancer is at least partially an androgen-dependent tumor at the time of initial presentation. Prostate cancer also is partially androgen-dependent in most men at the time of initial progression (either local or metastatic) if the patient has not been treated previously with androgen ablation or deprivation therapy.

        Because of the androgen-dependence of prostate cancer and the availability of GnRH analogs and nonsteroidal antiandrogens, androgen ablation therapy has been used as adjuvant therapy in conjunction with radical prostatectomy and radiation therapy. There are limited data on the benefits of androgen deprivation adjuvant therapy following radical prostatectomy, particularly in men with lymph node negative disease.1 A report demonstrating the benefit of androgen deprivation adjuvant therapy in men with positive lymph nodes was that of Messing et al.2 In this study, 98 men with positive lymph nodes at the time of radical prostatectomy were randomized to receive either immediate androgen deprivation therapy (with either a GnRH analog or surgical castration) or placebo therapy. After 7.1 median years of follow up, 7 of 47 men who received immediate androgen deprivation therapy had died as compared with 18 of 51 men in the placebo group (p < 0.02).

        The potential benefit of androgen ablation therapy in conjunction with radiotherapy, generally for locally advanced or high-grade prostate carcinoma, has been investigated in several clinical trials. In one such trial (Bolla et al 3), 415 men with locally advanced prostate cancer were treated with external beam radiotherapy alone or radiotherapy plus a GnRH analog. At a median follow up of 45 months, estimates of overall survival at 5 years were 79% and 62% for patients treated with adjuvant GnRH analog compared to placebo (p = 0.001). Other studies in which men were treated with radiotherapy and adjuvant androgen ablation therapy have shown improvement in local control of disease or improved survival in subgroups (Hellerstedt BA and Pienta KJ 4).

        Based in part on these findings in men with prostate cancer and the demonstrated benefits of adjuvant anti-estrogen therapy in women with carcinoma of the breast, AstraZeneca initiated 3 clinical trials (the pivotal trials in support this supplemental NDA) in men with non-metastatic prostate cancer. In each of the trials, the potential benefit of adjuvant therapy with Casodex immediately following either radical prostatectomy or radiotherapy was compared to placebo. In 2 of the trials, the potential benefit of Casodex monotherapy (compared to placebo) was investigated in men with non-metastatic prostate cancer who otherwise would be managed by watchful waiting or surveillance.

      7. Pharmacology of Casodex and Other Nonsteroidal Anti-androgens

      Nonsteroidal anti-androgens (NSAAs) currently available for clinical use in the US include flutamide (Eulexin), nilutamide (Nilandron), and bicalutamide (Casodex). All three are approved for use in the US in combined androgen blockade therapies: Casodex (50 mg per day ) and flutamide in combination with a GnRH agonist and nilutamide in combination with surgical castration are approved for the treatment of advanced prostate cancer. No NSAA is presently licensed in the US as single agent monotherapy.

      The mode of action of NSAAs such as Casodex differs from that of medical (i.e., GnRH-induced) or surgical castration. Whereas castration causes a reduction in circulating levels of androgens, Casodex is a competitive antagonist of testosterone and dihydrotestosterone action at the level of the intracellular androgen receptor. Casodex binds competitively and reversibly to the androgen receptor without activating gene expression, and thus inhibits the stimulatory effect of androgens. This action of Casodex and other NSAAs markedly reduces the effects of circulating androgens on prostate cancer cells.

    2. Other Relevant Information
      1. Earlier Submission (NDA 20-498/s006)
      2. In February 2000, AstraZeneca submitted an efficacy supplement (NDA 20-498/s006) for the treatment of locally advanced, non-metastatic (Stages T3-T4, NX, M0) prostate cancer with Casodex monotherapy (150 mg/d). Two pivotal trials (Trials 0306 and 0307) were submitted in support of the application. The trials were similar in design but conducted in different geographic locales. Neither study was conducted in North America. Both were open-label, active comparator trials that compared Casodex monotherapy to medical or surgical castration. The studies originally included patients with metastatic disease (Stage M1) as well as non-metastatic (M0) disease. Based on an interim analysis of survival, the Data Safety Monitoring Board (DSMB) recommended that Casodex treatment be discontinued in M1 patients. The data at the time of their recommendation indicated that the risk of death was 25% and 31% higher in the Casodex M1 groups compared to the castration M1 groups in Trails 0306 and 0307, respectively. The trials continued thereafter with only patients who had Stage M0 disease at the time of entry.

        Survival in the Casodex-treated MO patients, compared to that in the patients treated by castration, differed across Trials 0306 and 0307. In Trial 0306 (n = 140 M0 patients), the risk of death was calculated as 36% lower in the Casodex group while in Trial 0307 (n = 352 M0 patients), the risk of death was calculated as 25% higher in the Casodex group. Both the primary medical reviewer and statistical reviewer recommended that the application not be approved for several reasons that included (1) the conflicting trial results with the larger trial demonstrating a survival disadvantage in the Casodex treatment group for M0 patients, (2) a survival disadvantage for M1 patients treated with Casodex in both clinical trials, and (3) a combined statistical analysis that (a) did not fully meet the Sponsor’s original definition of noninferiority and (b) was considered to be statistically inappropriate. Upon learning that the application would not be approved, AstraZeneca withdrew the supplemental NDA in December 2000.

      3. Regulatory and Marketing Status
        1. Casodex 50 mg Tablets
        2. Casodex at a daily dose of 50 mg in combination with medical or surgical castration is registered world-wide for the treatment of advanced prostate cancer. In some markets, the mode of castration is limited to one or the other method. The product was approved in the US in 1995 for the treatment of metastatic prostate cancer (Stage D2) in combination with GnRH analog therapy.

        3. Casodex 150 mg Monotherapy

Casodex and other NSAAs are not approved as monotherapy in the US.

Locally advanced prostate cancer. The applicant stated that "Product Licences have been granted for the use of Casodex 150 mg monotherapy in the treatment of locally advanced, non-metastatic prostate cancer in 35 countries. Applications are currently under review in a number of other countries." Representative approved labeling for Casodex 150 mg monotherapy for locally advanced non-metastatic prostate cancer is presented below:

Sweden: Casodex 150 mg per day monotherapy is indicated for the treatment of patients with locally advanced, non-metastatic prostate cancer, for whom hormonal treatment is indicated, but surgical or medical castration is considered inappropriate.

UK:  Casodex 150 mg is also indicated for the management of patients with locally advanced, non-metastatic prostate cancer for whom surgical castration or other medical intervention is not appropriate or acceptable.

A supplemental NDA (20-498/s006) was submitted to the FDA in February 2000 seeking approval for Casodex monotherapy (150 mg per day) for the treatment of locally advanced non-metastatic prostate cancer. The application was withdrawn in December 2000 after the applicant learned that the sNDA would not be approved (see Section 1.3.1).

Localized or locally advanced prostate cancer. Following submission of additional data regarding the use of Casodex in men with early prostate cancer (Clinical Trials 7054IL/0023, 7054IL/0024, and 7054IL/0025 [the pivotal trials in sNDA 20-498/s012 as well]), the Product Licenses for Casodex monotherapy were broadened in several countries. As of 1 March 2002 according to the Sponsor, Casodex (150 mg per day) had been approved in 12 countries as therapy for men with localized or locally advanced prostate cancer, either alone as monotherapy or as adjuvant therapy to radical prostatectomy or radiation therapy of curative intent. These 12 countries are (in order of approval date) Slovakia, Italy, UK, Greece, Austria, Portugal, Belgium and Luxembourg, Czech Republic, Mexico, Norway, and Hungary.

Medical Officer’s Comments

        1. Postmarketing Experience

According to the Sponsor, the estimated postmarketing worldwide exposure to Casodex (50 mg or 150 mg) from 1995 until 28 September 2001 was approximately 687,000 patient years. Approximately 9,800 patient-years of the total exposure was to Casodex 150 mg.

    1. Important Issues with Pharmacologically Related Agents

Two other nonsteroidal anti-androgens, flutamide and nilutamide, are approved for use in men with prostate cancer. All of the nonsteroidal anti-androgens have similar pharmacologically-related side effects. Pharmacologically-related adverse events are secondary to either the direct anti-androgenic actions of the drugs (e, g, increased incidence of erectile dysfunction, decreased libido, and anemia) or indirect compensatory estrogenic effects of the drugs (increased incidence of breast pain and gynecomastia).

All nonsteroidal anti-androgens are hepatotoxic to varying degrees. Treatment with nilutamide (but not flutamide or Casodex ) also has been reported to be associated with an increased incidence of interstitial pneumonia.

Medical Officer’s Comment

  1. HUMAN PHARMACOKINETICS AND PHARMACODYNAMICS
    1. Pharmacokinetics
      1. Pharmacokinetics
      2. Casodex is a racemate with the anti-androgenic activity almost exclusively in the (R)-enantiomer; the (S)-enantiomer is essentially inactive. Casodex is well absorbed following oral administration, although the absolute bioavailability is unknown. The pharmacokinetics of Casodex were dose proportional over the range of 10 mg to 150 mg doses. Co-administration of Casodex with food had no clinically significant effect on rate or extent of absorption. Casodex is highly protein-bound (>90%) and may displace other highly protein bound drug substances, thus increasing their free plasma concentrations.

      3. Potential for Interactions as Substrate, Inhibitor, or Inducer
      4. R-Casodex significantly inhibited CYP 3A4, 2C9, 2C19, 2D6, and 1A2, in vitro, while no significant inhibition was noted with S-Casodex.

      5. Effects of Renal or Hepatic Insufficiency and Age

      Renal impairment (as measured by creatinine clearance) had no significant effect on the elimination of total bicalutamide or the active R-enantiomer in doses up to 450 mg. No clinically significant difference in the pharmacokinetics of either enantiomer of bicalutamide was noted in patients with mild-to-moderate hepatic disease as compared to healthy controls. However, the half-life of the R-enantiomer was increased approximately 76% (5.9 and 10.4 days for normal and impaired patients, respectively) in patients with severe liver disease (n=4). In studies in patients given up to 450 mg daily, no significant relationship between age and steady-state levels of total bicalutamide, or the active R-enantiomer has been shown.

    2. Pharmacodynamics

Casodex is a nonsteroidal anti-androgen with no other known endocrine activity. It competitively inhibits the action of androgens by binding to androgen receptors in the target tissue. No pharmacodynamic data were submitted with the present efficacy supplement. At the request of the medical reviewer, the Sponsor submitted information on the effects of treatment with Casodex on serum concentrations of testosterone, dihydrotestosterone (DHT), and estradiol obtained from a clinical study that was not included in the present application.

In this study, mean serum concentrations of testosterone during treatment with 150 mg Casodex increased from 3.15 nmol/L at baseline (n=23) to a maximum of 6.00 nmol/L at Month 2 (n=21). At Month 6 of treatment, mean serum concentrations of testosterone were 5.22 nmol/L (n=21). Mean serum concentrations of DHT in these patients were 0.29 ng/mL (baseline), 0.35 ng/mL (Month 2) and 0.34 ng/mL (Month 6). Mean serum concentrations of free testosterone in these patients were 8.77 [no units provided] at baseline, 13.47 at Month 2, and 13.55 at Month 6. Mean serum concentration of estradiol in these patients increased from 34.4 pmol/L at baseline to 55.8 pmol/L at Month 6.

Medical Officer's Comments

  1. Description of clinical data and sources
    1. Sources of Clinical Data
      1. Clinical Trials

      The sponsor submitted efficacy and safety data from 3 Phase III clinical trials (Trials 7054IL/0023, 7054IL/0024, and 7054IL/0025, hereafter referred to as Trials 23, 24, and 25, respectively) on 20 December 2001. The trials were conducted in (1) North America, predominantly the US [Trial 23], (2) Europe (other than Scandinavia), South Africa, Israel, Mexico, and Australia [Trial 24], and (3) Scandinavia [Trial 25]. On 18 April 2002, the sponsor provided an integrated, comprehensive 4-month Safety Update for Trials 23, 24, and 25. Throughout the review process, the sponsor submitted additional data and analyses in response to requests from DRUDP.

    2. Overview of Clinical Trials

Complete Final Study Reports for 3 Phase III clinical trials were submitted with NDA 20-498/s012 to support the safety and efficacy of Casodex 150 mg tablets for the treatment of men with localized and locally advanced prostate cancer. Enrollment in the 3 clinical trials was initiated in August 1995 (Trial 23), September 1995 (Trial 24), and October 1995 (Trial 25). The last patients were enrollment in August 1997 (Trial 23) and July 1998 (Trials 24 and 25). The data cutoff date for each of the Final Study Reports was 2 June 2000. The applicant also submitted a separate safety addendum for each of the clinical trials (data cut-off date of 23 February 2001 for each addendum). The study number and title of each of the trials are listed below.

  1. Trial Number 7054IL/0023. "A Randomized Double-Blind Comparative Trial of Bicalutamide (CASODEXÔ ) Versus Placebo in Patients with Early Prostate Cancer."
    (First patient recruited: 01 August 1995; last patient recruited: 29 August 1997).
  2. Trial Number 7054IL/0024. "A Randomised, Double-Blind, Parallel-Group Trial Comparing CASODEXÔ 150 mg Once Daily with Placebo in Patients with Non-metastatic Prostate Cancer." (First patient recruited: 21 September 1995; last patient recruited: 27 July 1998).
  3. Trial Number 7054IL/0025. "A Randomised, Double-Blind, Parallel-Group Trial Comparing CASODEXÔ 150 mg Once Daily with Placebo in Patients with Non-metastatic Prostate Cancer (SPCG-6)." (First patient recruited: 4 October 1995; last patient recruited: 30 July 1998).

Each of the clinical trials was a comparative, randomized, double blind, parallel-group, multicenter trial. In each trial, the efficacy and safety of Casodex (150 mg per day) was compared to that of placebo. Additional information concerning each of the clinical trials is provided in Table 1.

Table 1. Studies Supporting Safety and Efficacy of Casodex for Localized or Locally Advanced Prostate Cancer.


Study No.

Study Title


Study Design

Study Status


No. of Patients 1

Age of Pt.
Mean (range)

Racial Distribution


Total No. of Sites

Country and (No. Pt. per country)


Treatment
Study Drug: number patients 1 Duration of Treatment


7054IL/0023

"A Randomized Double-Blind Comparative Trial of Bicalutamide (CASODEXÔ ) Versus Placebo in Patients with Early Prostate Cancer


Phase 3, randomized, blinded, placebo controlled, and multicenter.

Treatment completed;
follow up for survival ongoing.


3292 men

64.5 years
(38-85 years)

White 2760
Black 379
Hispanic 106
Other 47


96 Sites

United States (n=2974),
Canada (n=318).


Treatment
Casodex: 1647 patients
Placebo: 1645 patients

Duration
All patients
2 years or until objective
progression

7054IL/0024

"A Randomized, Double-Blind, Parallel-Group Trial Comparing CASODEXÔ 150 mg Once Daily with Placebo in Patients with Non-metastatic Prostate Cancer."

Phase 3, randomized, blinded, placebo controlled, and multicenter.

Treatment ongoing.

3603 men

68.7 years
(42-93 years)

White 3423
Hispanic 62
Mixed 61
Afro-
Caribbean 30
Other 27

191 Sites

Australia (n=14), Austria (n=62), Belgium (n=236), Czech Rep (n=184), France (n=348), Germany (n=107), Holland (n=220), Hungary (n=70), Ireland (n=23), Israel (n=193),
Italy (n=94), Mexico (n=77),
Poland (n=7), Portugal (n=170),
South Africa (n=394), Spain (n=506), and UK (n=898).


Treatment
Casodex: 1798 patients
Placebo: 1805 patients

Duration
Adjuvant patients
5 years or until progression

Non-adjuvant patients
Until progression

7054IL/0025

"A Randomized, Double-Blind, Parallel-Group Trial Comparing CASODEXÔ 150 mg Once Daily with Placebo in Patients with Non-metastatic Prostate Cancer (SPCG-6)."

Phase 3, randomized, blinded, placebo controlled, and multicenter.

Treatment ongoing.

1218 men

68.5 years
(46-87 years)

White 1213
Hispanic 3
Other 2

62 Sites

Denmark (n=173), Finland (n=277), Norway (n=509), and Sweden (n=259).


Treatment
Casodex: 607 patients
Placebo: 611 patients

Duration
All patients
Until progression

1. Number of patients randomized (i.e., the efficacy population). Not all patients received study drug.
Source: Prepared by Medical Officer from various sources.

  1. Integrated Review of Efficacy
    1. Brief Statement about Efficacy
    2. The Sponsor has provided statistically significant evidence in two non-US clinical trials (Trials 24 and 25) that treatment with Casodex 150 mg per day, compared to treatment with placebo, in men with non-metastatic prostate cancer at entry delayed progression of disease as assessed by (1) bone scan confirmed metastases or (2) death from any cause in the absence of disease progression. In these trials, Casodex was studied as (1) adjuvant therapy in men previously treated by radical prostatectomy or radiotherapy or (2) monotherapy in men who would otherwise be managed by watchful waiting. In Trial 23 (the only trial conducted in the US and the trial most relevant to patients in the US), there was no evidence that treatment with Casodex delayed disease progression. The relevance of benefit from treatment with Casodex in the 2 non-US trials for men with prostate cancer in the US who might be treated with Casodex adjuvant therapy or Casodex monotherapy is unknown.

      There was no evidence that treatment with Casodex improved survival in any of the trials or in the combined analysis. Evidence of improved survival, however, was not anticipated by the cut-off date for efficacy data (2 June 2000) or the cut-off for the Safety Update (28 September 2001) as the survival data were expected to be immature.

    3. General Approach to the Review of the Efficacy of the Drug
    4. The clinical component of NDA 20-498/s012 consisted of 3 pivotal Phase III clinical trials (Trials 23, 24, and 25). Efficacy data from each of the Phase III clinical trials were reviewed separately and collectively. The 3 clinical trials were very similar in design. Efficacy assessments were identical across studies, and each trial had nearly identical primary and secondary efficacy endpoints; consequently, the 3 pivotal efficacy trials are presented, for the most part, in an integrated manner in the review that follows.

    5. Clinical Trials to Support Sponsor’s Efficacy Claim
      1. Overall Study Design
      2. The 3 Phase III clinical trials were comparative, multicenter, randomized, double-blind, parallel-group trials. Table 1 provides an overview of these trials. The trials were conducted in (1) North America (Trial 23), (2) Europe (other than Scandinavia), South Africa, Israel, Mexico, and Australia (Trial 24), and (3) Scandinavia (Trial 25). All patients who qualified for enrollment were randomized in a 1:1 ratio to treatment with either Casodex 150 mg per day or matching placebo. Table 2 provides a comparison of the similarities and differences across the 3 trials. All trials excluded the enrollment of patients with metastatic disease beyond that of positive regional lymph nodes; however, in Trial 23, patients with positive regional lymph nodes also were not eligible. All 3 trials investigated Casodex as adjuvant therapy in patients who had had previous therapy for their prostate cancer (i.e., radical prostatectomy or radiation therapy). Trials 24 and 25 (but not Trial 23) also investigated Casodex monotherapy (patients who had had no prior therapy and whose prostate cancer would otherwise be managed by watchful waiting or surveillance). The maximal period of treatment with study drug varied in each of the studies. In Trial 23, treatment was limited to a maximum of 2 years or until objective disease progression (whichever occurred first). In Trial 25, patients were to be treated indefinitely or until progression of disease. In Study 24, patients with prior therapy (adjuvant patients) were to be treated for a maximum of 5 years. Patients in each of the clinical trials were to have a bone scan at 2 years after enrollment unless objective progression of their disease had been confirmed prior to this time.

         

        Table 2 Overview of Phase III Clinical Trials (Similarities and Differences)

        Design Element

        Trial 23

        Trial 24

        Trial 25

        North America

        Europe, South Africa, Israel, Mexico, Australia

        Scandinavia

        Double-blind, placebo controlled

        Yes

        Yes

        Yes

        Number of patients randomized

        3292

        3603

        1218

        Tumor staging criteria

        T1b-T4, N0 or NX (N+ excluded), M0

        T1b-T4,
        any N, M0

        Same as 0024

        Permitted standard care

             

        Radical prostatectomy or radiotherapy

        Yes

        Yes

        Yes

        Watchful waiting

        No

        Yes

        Yes

        Intended period of randomized treatment

        2 yr.

        5 yr. for adjuvant patients

        Until progression for all patients

           

        Until progression in non adjuvant patients

         

        2-yr. bone scan to determine progression

        Yes

        Yes

        Yes

        Follow-up for progression and survival

        Yes 1

        Yes

        Yes

        1 Monitored only for survival and serum PSA. Bone scans to be obtained at discretion of Investigator.

      3. Study Objectives

The primary and secondary objectives of the 3 clinical trials are listed in Table 3. They were very similar across the 3 trials with some exceptions. Survival was a secondary objective in Trial 24 instead of a primary objective as in Trials 23 and 25. Sexual satisfaction was assessed only in Study 25.

Table 3 Primary and Secondary Objectives of the Clinical Trials

Primary Objectives:

  • To compare Casodex 150 mg once daily with placebo in terms of time to objective progression
  • To compare Casodex 150 mg once daily with placebo in terms of overall survival 1
  • To evaluate the tolerability of Casodex 150 mg compared with placebo 2

Secondary objectives:

  • To compare Casodex 150 mg once daily with placebo in terms of time to treatment failure
  • To compare Casodex 150 mg once daily with placebo in terms of the time for prostate specific antigen (PSA) to double
  • To assess sexual function using the Golombok Rust Inventory 3

1 Secondary objective in Study 24.
2 Secondary objective in Study 23.
3 Included only in Study 25.

      1. Study Patients and Enrollment Criteria

Only patients with non-metastatic prostate cancer (Stage M0) were potentially eligible for enrollment in the clinical trials. Entry criteria were generally similar across the 3 clinical trials although there were some significant differences, particularly in the entry criteria for Trial 23 compared to those for Trials 24 and 25. These differences included exclusion of patients from Trial 23 who (1) had positive local or regional lymph nodes and (2) had not undergone either a radical prostatectomy or radiation therapy with the expectation that the procedure would be curative. Thus patients who had not received active therapy for their prostate cancer (patients initially managed by watchful waiting) were excluded from Trial 23.

Inclusion Criteria Included

a radical prostatectomy (nerve or non-nerve sparing) defined as the total extirpation of the prostate including the seminal vesicles performed within 16 weeks before randomization

radiation to the prostate initiated within 16 weeks before randomization

Exclusion Criteria Included

Medical Officer’s Comments

      1. Study Drugs
        1. Rationale for Choice of Comparator

According to the Sponsor, it was not common clinical practice or established policy at the time that these trials were initiated, to use immediate rather than deferred therapy in patients with localized disease. There also was not a consensus of opinion on the use of hormonal therapy as adjuvant therapy following radical prostatectomy or radiation treatment for localized disease. The Sponsor therefore chose to compare the effects of treatment with Casodex to those of treatment with placebo.

Medical Officer’s Comments

        1. Rationale for Dose Selection of Casodex

The applicant had previously conducted a series of dose-ranging trials with Casodex (Trials 0002, 0003, and 0005) to identify the lowest dose of Casodex that appeared to exert maximal anti-androgenic effects. In these studies, the percentage inhibition of PSA was used as a measure of the anti-androgenic effect of Casodex. Following 3 months of administration, Casodex doses of 100 to 200 mg produced the maximal suppression of serum PSA. Doses of 100 mg and 150 mg were subsequently selected for comparison with castration in a Phase III clinical program (Trails 0306 and 0307) that were conducted in support of an earlier application (NDA 20-498/s006). Based on a planned, early evaluation of these 2 doses, Casodex 150 mg per day was selected for (1) continued evaluation in these latter 2 trials and (2) the early prostate cancer program (Trials 23, 24, and 25 in the present application).

Medical Officer’s Comments

        1. Assignment to Study Drug and Treatment Schedules

Randomized study drugs were administered in tablet form as a once daily oral dose and were supplied as white tablets containing either 150 mg of Casodex or placebo. Patients were randomly assigned in a 1:1 ratio to treatment with either Casodex or placebo. Treatment was to be initiated as soon as possible after randomization, but in no case was this period to exceed 2 weeks. Treatment with study drug initially was to be for 2 years in all 3 of the clinical trials. Prior to the first patient completing 2 years of treatment, the Data and Safety Monitoring Committee (DSMC) reviewed the blinded patient safety data across the whole program. The DSMC concluded that both treatments (Casodex and placebo) were well tolerated and that there were no safety concerns to prevent treatment of patients beyond 2 years (96 weeks) in any of the trials. However, the final decisions regarding extending treatment beyond 2 years differed for each of the 3 trials. These differences were based, according to the Sponsor, upon investigator preferences.

Trial 23. It was decided that treatment would not extend beyond 2 years as the investigators thought this treatment period was sufficient for the study population.

Trial 24. It was decided that adjuvant patients (patients who had initially received primary treatment by either radical prostatectomy or radiation therapy would continue to receive blinded treatment for a total of 5 years. However, therapy in these patients could continue treatment beyond 5 years based at the individual investigator’s discretion. For other patients (i.e., those initially managed by watchful waiting), there would be no limit on the duration of treatment. For both groups of patients, it also was recommended that treatment with study drug be discontinued if objective disease progression was documented or if a patient reached any treatment failure endpoint as defined in Section 4.5.2.

Study 25. It was decided that all patients would continue to receive randomized treatment until they had reached a treatment failure endpoint.

Until such time as objective disease progression had been documented, patients were not to receive any systemic treatment other than randomized study therapy. If the investigator considered that it was in the patient’s best interest to initiate alternative systemic therapy for prostate cancer before progression had been documented, this was considered a treatment failure, and the patient’s randomized therapy was to be discontinued.

Medical Officer’s Comment

    1. Study Procedures and Study Conduct
      1. Schedule of Study Assessments and Procedures

The schedule for study assessments and procedures is summarized in Table 4. During the baseline or screening period, a potential patient’s eligibility for participation was determined according to the inclusion and exclusion criteria described in Section 4.3.3). Baseline assessments included a physical examination and medical history, a bone scan if not previously performed within the prior 24 weeks (later amended to 30 weeks), measurements of serum PSA and liver transaminases, and completion of the Golombok Rust Inventory of Sexual Satisfaction (GRISS) questionnaire (Trial 25 only).

Study Weeks 1-96

During the first 96 weeks of each clinical trial, patients were to be assessed every 12 weeks for clinical evidence of disease progression and monitoring of liver function and adverse events. A bone scan to detect distant metastases of prostate cancer was to be performed at Week 96 in all patients (regardless of treatment status) unless the patient previously had had a positive on-treatment bone scan. Patients in Trial 25 also completed the GRISS questionnaire at Weeks 12, 24, 36, and 48. Patients who terminated treatment prior to Week 96 for a reason other than objective disease progression were to continue with clinical visits every 12 weeks for monitoring for clinical disease progression and measurement of serum PSA. Following documentation of objective disease progression, patients were to be assessed every 24 weeks for survival.

Table 4 Schedule of Study Assessments and Procedures

Procedure

Weeks after randomization

 

Baseline

Wk 12

Wk 24

Wk 36

Wk 48

Wk 60

Wk 72

Wk 84

Wk 96

After Early Termination 1

Post
Wk 96 1a

Physical examination

X 2

X

X

X

X

X

X

X

X

X

 

Bone scan

X 3

             

X 3a

 

X 4

PSA 5

X

X

X

X

X

X

X

X

X

X

X 5

ALT, AST, bilirubin

X

X

X

X

X

X

X

X

X

   

Assess for clinical progression 6

 

X

X

X

X

X

X

X

X

X

X

GRISS questionnaire 7

X

X

X

X

X

           

Adverse events

 

X

X

X

X

X

X

X

X

X

 

Concomitant therapy

X

X

X

X

X

X

X

X

X

   

Daily dosing with Study Drug 8

 

X

X

X

X

X

X

X

X

 

X

1. Patients were to be assessed every 12 weeks until progression irrespective of whether they had stopped randomized treatment; following progression, patients were to be assessed every 24 weeks.

1a In Trial 23, patients were to have clinical visits very 6 months through 4 years post randomization and annually thereafter until death. In Trials 24 and 25, patients were to continue to have a clinic visit every 12 weeks while continuing to receive randomized treatment. Following discontinuation of randomized treatment or documentation of disease progression, patients were to have a clinic visit every 6 months until death.

2. Included demographic and medical history at baseline visit.

3. To be performed within 24 weeks (Trials 24 and 25) or 30 weeks (Trail 23) before randomization.

3a. All patients were to have a bone scan at Week 96 unless they previously had had an on-treatment positive bone scan documenting progression of disease.

4. Additional assessments performed every 96 weeks thereafter for Trials 24 and 25 only.

5. PSA measurements were to be obtained (1) at each 12-week clinical visit until disease progression in Trials 24 and 25 or (2) at each 6-month or annual clinical visit until disease progression in Trial 23.

6. Patients were assessed, as warranted by clinical symptoms and findings, for local and regional disease and distant metastases at each clinical visit until objective progression was documented.

7. Golombok Rust Inventory of Sexual Satisfaction (GRISS). Performed only in Trial 25.

8. In all trials, dosing with blinded study drug was to continue through Week 96 or until objective progression of disease. Dosing in Trial 23 was limited to a maximum of 2 years. In Trials 24 and 25, dosing was to continue through 5 years (adjuvant group in Trial 24) or indefinitely (all other groups) or until objective disease progression.

After Study Week 96

Trial 23. Treatment with study drug was limited to 96 weeks in Trial 23. Subjects who completed 96 weeks of treatment without documented evidence of clinical progression were to be contacted every 3 months thereafter. In addition, they were to have a clinical visit every 6 months for a physical examination and PSA assessment, up to and including Month 48 and annually thereafter. A bone scan also was to be performed at the discretion of the investigator if progression was suspected. Subjects who had documented evidence of clinical progression were to be contacted every 3 months to determine their survival status.

Trials 24 and 25. Treatment with study drug was to continue for at least 5 years or until disease progression in Trials 24 and 25 (See Section 4.3.4.3 for further details). During treatment with randomized therapy, patients were to continue to have clinical visits every 12 weeks. At each visit, they were to be assessed for clinical progression of disease and adverse events. A blood specimen for the measurement of PSA, ALT, AST, and bilirubin concentrations was to be collected. In addition to the assessments performed every 12 weeks, a repeat bone scan was to be performed every 96 weeks, or earlier, if warranted by clinical findings until objective progression of disease was documented.

Following discontinuation of treatment with study drug, patients were to be seen in the clinic every 24 weeks until objective disease progression and/or death. Patients who had gynecomastia or breast pain at termination of treatment with study drug, were to be assessed for improvement or resolution of these signs or symptoms at each post treatment visit.

Medical Officer's Comment

      1. Efficacy Assessments
      2. At each clinical visit, patients were assessed for signs of disease progression. These assessments included a physical examination and measurement of serum PSA concentration. These assessments were performed every 12 to 24 weeks in accordance with the schedule of assessments listed in Table 4. In addition, bone scans were to be performed at Study Week 96 if objective disease progression (as defined below) had not been documented previously. Evidence of disease progression (either local or distant progression) was classified by the Sponsor as either objective or non-objective depending upon the clinical or laboratory method of documentation.

        1. Objective Progression

Imaging procedures or biopsy. Objective progression required confirmation of disease progression by either an imaging procedure (e.g., bone scan, x-ray, magnetic resonance imaging, computerized tomography, or ultrasonography) or biopsy.

Medical Officer’s Comment

        1. Non-objective Progression
        2. Signs and Symptoms. Non-objective progression included signs or symptoms that were compatible with disease progression (e.g., ureteral obstruction, lymphedema of the lower extremities, vesical obstruction) but which were not confirmed by an imaging procedure or biopsy. Investigators were instructed to confirm non-objective progressive events by an objective procedure whenever possible.

          Serum PSA. Increases in serum PSA values by themselves were not considered to be objective evidence of disease progression. PSA samples obtained at baseline (immediately prior to randomization) and following randomization were, for the most part, measured at one of two central laboratories using the HybritechÔ Assay. For Trial 23, PSA assays were performed at Quest Diagnostics (formerly SmithKline Beecham Laboratories), Clinical Trials Center, Van Nuys, CA. For Trials 24 and 25, PSA assays were performed at AstraZeneca’s Central Laboratory, Mereside, Alderley Park, Cheshire, UK. PSA samples obtained prior to radical prostatectomy or radiation therapy (i. e., prior to screening for enrollment into the clinical trials) may have been analyzed by other assay procedures at the respective study site.

        3. Bone Scans

In each of the clinical trials, a bone scan was to obtained at Study Week 96 or sooner if warranted by the patient’s symptoms or clinical findings. If a bone scan was obtained prior to Week 96 for clinical reasons and was found to be negative, the bone scan was to be repeated at Study Week 96. All bone scans were performed at the study sites and read locally.

Medical Officer’s Comments

    1. Efficacy Endpoints and Analyses
    2. The primary and secondary efficacy endpoints in each of the 3 clinical trials and in the sponsor’s combined analysis are listed in Table 5. They were identical in each of the trials with one exception, time to death was a secondary endpoint in Trial 24 but a primary endpoint in Trials 23 and 25 as well as in the combined analysis. Each of these endpoints is described further in Sections 4.5.1 and 4.5.2. The Sponsor chose a data cutoff date of 2 June 2000 for efficacy data, which allowed (according to the Sponsor) for at least 2 years of follow up after randomization for each patient in each clinical trial.

      Table 5 Summary of Primary and Secondary Endpoints and Analyses

      Endpoint

      Definition

      Trial

      Com-
      bined 1

         

      23

      24

      25

       
         

      Primary or Secondary 2

      Time to objective progression 3

      Time from randomization to:
      1. Objectively confirmed progression
      2. Death in the absence of objectively confirmed progression

      1°

      1°

      1°

      1°

      Time to death (overall survival)

      Time from randomization to death from any cause

      1°

      2°

      1°

      1°

      Time to treatment failure

      Time from randomization to the first of:
      1. Additional systemic therapy or radiotherapy 2. Withdrawal of trial therapy
      3. Objective progression
      4. Death from any cause

      2°

      2°

      2°

      2°

      Time to PSA doubling

      Time from randomization to the first of:
      1. An increase of serum PSA to twice that at randomization
      2. Objectively confirmed progression
      3. Death from any cause

      2°

      2°

      2°

      2°

      1 Sponsor’s combined analysis for Trials 23 + 24 + 25.

      2 1° = primary endpoint; 2° = secondary endpoint.

      3 Objectively confirmed progression = local or distant progression of disease confirmed by bone scan, x-ray, CT scan, magnetic resonance imaging, ultrasonography, or biopsy.

       

      1. Primary Efficacy Endpoints and Analyses

Objective progression. Objective progression, as defined previously in Section 4.4.2.1, was examined in each of the clinical trials and in the combined analyses. Time to objective progression (TTP) was defined as the number of days between randomization and the documented date of objective progression or death (by any cause in the absence of objective disease progression).

Overall survival (time to death). Time to death (TTD) was a primary efficacy endpoint in 2 of the 3 clinical trials (Trials 23 and 25) and in the Sponsor’s combined analysis. Time to death was defined as the number of days between randomization and the documented date of the patient’s death from any cause.

Medical Officer’s Comments

      1. Secondary Efficacy Endpoints and Analyses

Secondary efficacy endpoints were time to treatment failure and time to a PSA doubling event.

Time to treatment failure (TTF). Time to treatment failure was defined as the number of days from the date of randomization until the earliest of the following events:

  • death from any cause
  • objective progression of disease
  • withdrawal of trial therapy
  • administration of an additional systemic therapy or radiotherapy for prostate cancer

The reason for treatment failure was defined as the first of these events to occur.

Time to a PSA doubling event (TTPSAd). Time to a PSA doubling event was defined as the number of days from the date of randomization until the earliest of the following events:

      1. Overview of Statistical Analyses
        1. Efficacy Population
        2. Efficacy data were analyzed on an intent-to-treat (ITT) basis (analyzed as randomized). Therefore, all randomized patients with data were included in the efficacy analyses regardless of whether the patient had met all the entry criteria (protocol violations), had departed from the protocol design or procedures after entry into the trial (protocol deviations), had not received randomized therapy, or had received subsequent non-randomized prostate cancer therapy.

        3. Sponsor’s Analyses of Primary Efficacy Endpoints

Time to objective progression was analyzed for each individual trial and for pooled data from all 3 contributing trials. The analyses were achieved by fitting a Cox proportional hazards regression model to the data. Terms were fitted allowing for the effects of randomized treatment and the following covariates:

From the model including these main effects, the hazard ratio (Casodex/placebo) was estimated together with its associated 95% confidence interval and p-value. Data also were displayed graphically using Kaplan-Meier plots. For the purpose of the analyses, only patients with objectively confirmed disease progression (positive bone scan or other objective event) or who had died (from any cause) in the absence of objective progression were considered to have had disease progression.

Medical Officer’s Comments

        1. FDA Requested Analyses

The FDA requested that the primary analyses for disease progression utilize only the results of (1) bone scans obtained at the protocol-mandated 2-year time point and (2) death in the absence of progression within 2 years of randomization as these endpoints were least likely to be influenced by potential bias. The results the FDA-requested analyses (i.e., the proportion of patients with disease progression or death at 2 years after randomization) as well as analyses based on bone scan documented progression or death in the absence of objective progression within 2 years of randomization were provided. The Sponsor stated in the Application that the within 2 years of randomization was the more appropriate analysis. The rationale for the Sponsor’s position was that in accordance with the protocol, bone-scans could be taken at times prior to the 2-year time point if clinically indicated. If the bone scan was positive, these patients were not required to have another bone scan at the 2-year time point. Such patients would therefore be incorrectly classified in the analyses as not having had objective progression of disease if a strict definition of "at 2 years after randomization" was employed.

The results of these analyses were expressed in terms of an odds ratio of Casodex relative to placebo, together with the associated 95% confidence limits and p-value. Results also were expressed in terms of relative risk and simple incidence rates. Confidence intervals for relative risks also were calculated.

Medical Officer’s Comments

    1. Results
      1. Enrollment and Patient Disposition
      2. A total of 8113 patients were randomized to treatment in the 3 clinical trials that were submitted in support of this Application. Of these, 4052 patients were randomized to receive Casodex 150 mg per day and 4061 patients were randomized to receive placebo. The disposition of the patients at the time of the efficacy data cutoff (2 June 2000) is shown in Figure 1.

         

        Figure 1 Efficacy Analysis Population and Treatment Status at Time of Data Cutoff

        A total of 3292, 3603, and 1218 patients were randomized to treatment in Trial 23, Trial 24, and Trial 25, respectively. The first patients were enrolled in August 1995 (Trial 23), September 1995 (Trial 24), and October 1995 (Trial 25). The last patients were enrolled in August 1997 (Trial 23) and July 1998 (Trials 24 and 25). The clinical trials included a total of 349 investigative sites (Trial 23: 96 sites; Trial 24: 191 sites; and Trial 25: 62 sites). Each of the trials was conducted in a different geographic area. Trial 23 was conducted in North America, with approximately 90% of patients from the United States and the remainder from Canada. Trial 24 was conducted in Europe (other than Scandinavia), South Africa, Israel, Mexico, and Australia. Trial 25 was conducted in Scandinavia (Denmark, Finland, Norway, and Sweden). Table 1 lists the number of patients enrolled in each country in each of the clinical trials.

        Patient enrollment and patient status (i.e., terminated treatment prematurely, completed treatment, or continuing treatment) in each of the 3 trials as of 2 June 2000 (efficacy data cutoff date) is summarized in Table 6. In Trial 23, treatment was limited to a maximum of 2 years and the maximum treatment period for all patients had been reached by 2 June 2000. Thirty eight percent (38%) of patients in the Casodex group and 20.2% of patients in the placebo group terminated treatment before completing 2 years. In Trials 24 and 25, treatment was on going at the time of data cutoff. In Trial 24, 40.3% and 37.2% of the patients in the Casodex and placebo treatment groups had terminated treatment as of 2 June 2000. In Trial 25, 31.9% and 47.0% of the patients in the Casodex and placebo treatment groups had terminated treatment as of 2 June 2000.

        Table 6 Patient Enrollment and Treatment Status as of June 2, 2000 1

         

        Trial 23

        Trial 24

        Trial 25

         

        Casodex

        Placebo

        Casodex

        Placebo

        Casodex

        Placebo

        Number of patients randomized

        1647

        1645

        1798

        1805

        605

        611

        Number of patients treated

        1627

        1627

        1790

        1795

        605

        609

        Patient disposition

                   

        Terminated prematurely (% of pt.) 2, 4

        38.0%

        20.2%

        40.3%

        37.2%

        31.9%

        47.0%

        Completed treatment (Trial 23 only) or treatment ongoing (% of pt.) 3, 4

        62.0%

        79.8%

        59.7%

        62.8%

        68.1%

        53.0%

        1. June 2, 2000 was the efficacy data cutoff date.

        2. Includes patients withdrawn from treatment because of disease progression, adverse events, need for prohibited therapy and other reasons.

        3. Treatment period in Study 23 was up to a maximum of 2 years; treatment period in Trial 23 completed prior to June 2, 2000.

        4. Percentages based on number of patients treated (i.e., those who received study drug).

        Source: Text Table T3.8 (Final Study Reports for Trials 23, 24, and 25).

        Patient exposure to randomized study drugs and follow up times for disease progression in each of the clinical trials is summarized in Table 7. Median patient exposure to study drug ranged from 1.8 years in Trial 23 (Casodex and placebo treatment groups) to 2.5 years in Trial 25 (Casodex treatment group). Median patient years of follow up for disease progression and survival (efficacy analyses) were 3.2 years (Trial 23), 2.6 years (Trial 24) and 3.0 years (Trial 25).

        Table 7 Patient Years of Exposure to Study Drug and Follow-up 1

         

        Trial 23

         

        Trial 24

         

        Trial 25

         

        Casodex

        Placebo

         

        Casodex

        Placebo

         

        Casodex

        Placebo

        Patient exposure to study drug

                       

        Total pt yr.

        2276

        2660

         

        3820

        4024

         

        1531

        1419

        Median pt yr.

        1.8

        1.8

         

        2.2

        2.3

         

        2.5

        2.3

        Follow up for progression and survival

                     

        Total pt yr.

        5430

        5428

         

        4817

        4811

         

        1807

        1794

        Median pt yr.

        3.2

        3.2

         

        2.6

        2.6

         

        3.0

        3.0

        1. As of efficacy data cutoff date of June 2, 2000.

        Source: Tables T5.1.1 and T5.2.1 from Final Study Reports for Trials 23, 24, and 25.


      3. Demographics and Baseline Disease Characteristics
        1. Baseline Demographics

Baseline demographic characteristics for each of the 3 trials are summarized in Table 8. Mean treatment group ages at enrollment ranged from 64.4 and 64.5 years (Trial 23) to 68.6 and 68.7 years (Trial 24). Individual patient ages ranged from 38 years to 93 years. Mean treatment group weights ranged from 77.3 and 78.1 kg in Trial 24 to 85.4 and 84.6 kg in Trial 23.

Medical Officer's Comments

 

Table 8 Baseline Demographic Characteristics (Trials 23, 24, and 25)

Demographic Characteristic

Trial 23

Trial 24

Trial 25

Casodex
(N=1647)

Placebo
(N=1645)

Casodex
(N=1798)

Placebo
(N=1805)

Casodex
(N=607)

Placebo
(N=611)

Age (yr.)

           

Mean

64.5

64.4

68.6

68.7

68.5

68.5

Range

42 to 85

38 to 83

42 to 93

46 to 93

46 to 87

52 to 77

Age Distribution (n,%)

           

<55 yr.

151

(9.2)

155

(9.4)

62

(3.4)

51

(2.8)

10

(1.6)

4

(0.7)

55 to < 65 yr.

614

(37.3)

607

(36.9)

422

(23.5)

432

(23.9)

99

(16.3)

113

(18.5)

65 to <75 yr.

780

(47.4)

785

(47.7)

936

(52.1)

934

(51.7)

475

(78.3)

468

(76.6)

³ 75 yr.

102

(6.2)

98

(6.0)

378

(21.0)

388

(21.5)

23

(3.8)

26

(4.3)

Weight (kg)

     

Mean

85.38

84.60

77.28

78.08

79.31

80.61

Range

49 to 166

46 to 160

45 to 132

40 to 135

46 to 143

48 to 125

Race (n, %)

     

White

1369

(83.1)

1391

(84.6)

1714

(95.3)

1709

(94.7)

606

(99.8)

607

(99.3)

Black

191

(11.6)

188

(11.4)

17

(0.9)

13

(0.7)

0

 

0

 

Other

87

(5.3)

66

(4.0)

67

(3.7)

83

(4.6)

1

(0.2)

4

(0.7)

Source: Text table 4, pg. 29, ISE.

        1. Baseline Disease Characteristics

Baseline disease characteristics (other than serum PSA values) in each of the 3 trials are summarized in Table 9. The distribution of disease characteristics is expressed in terms of percentage of patients with the specific characteristic in each category. Within each of the individual trials, baseline disease characteristics were well balanced across the Casodex and placebo treatment groups. In each of the trials, more than 50% of patients had Stage T1/T2 disease (early or localized disease). A slightly greater percentage of patients in Trial 24 (approximately 35%) and Trial 25 (approximately 40%) had Stage T3/T4 disease (locally advanced disease) than in Trial 23 (less than 30%). Based on reported Gleason scores, a greater percentage of patients in Trial 23 (47-48%) had poorly differentiated tumors (Gleason scores of 7-10) than in either Trial 24 (26-27%) or Trial 25 (11-12%). In accordance with the inclusion criteria for Trial 23, all patients had received prior therapy of curative intent with approximately 80% of patients having had a radical prostatectomy. In contrast, 35-37% of patients in Trial 24 and 80-83% of patients in Trial 25 were being managed by watchful waiting (i.e., had not had therapy) prior to randomization.

Table 9 Disease Characteristics at Baseline

 

Percentage of patients within each category

Characteristic

Study 23

Study 24

Study 25

 

Casodex

Placebo

Casodex

Placebo

Casodex

Placebo

 

(N=1647)

(N=1645)

(N=1798)

(N=1805)

(N=607)

(N=611)

Tumor stage: T category

           

T1

9.6

9.7

25.5

25.2

19.8

22.4

T2

62.7

63.2

38.8

41.1

39.7

38.1

T3

27.4

26.9

33.2

31.2

38.9

37.0

T4

0.2

0.2

2.6

2.5

1.5

2.3

Gleason score

           

Well differentiated (2,3,4)

4.2

4.8

31.0

31.2

42.7

43.2

Moderately differentiated (5,6)

47.9

48.5

40.5

41.1

43.7

45.2

Poorly differentiated (7,8,9,10)

47.9

46.7

26.7

26.1

11.9

11.1

Lymph node category

           

N-

72.0

71.2

61.3

60.4

21.7

20.0

N+

0.1

0.0

2.6

2.7

4.6

4.3

NX

27.9

28.8

36.0

36.9

73.6

75.8

Previous therapy

           

Radical prostatectomy

80.3

80.5

46.4

45.0

13.0

13.1

Radiotherapy only

19.7

19.5

18.6

18.0

6.4

4.3

Watchful waiting

0.0

0.0

34.9

36.9

80.1

82.7

Source: Text table 5, pg. 30, ISE

Median serum PSA concentrations, both prior to prostatectomy or radiation therapy in patients who had had prior active therapy and at the time of randomization in all patients, are listed in Table 10 for each of the trials. Median serum PSA values prior to prostatectomy or radiation ranged from 7.1 m g/L in Trial 23 to 17.0 m g/L in Trial 25. Median pre-randomization serum PSA values were lowest in patients who had been treated by radical prostatectomy (median range: below the limit of detection [NQ, Trials 23 and 24] to 1.2 m g/L [Trial 25]) and highest in patients managed by watchful waiting (median range: 11.0 m g/L [Trial 24] to 17.8 m g/L [Trial 25]). Within each initial treatment group, median serum PSA concentrations at randomization tended to be lowest in Trial 23 (or Trial 24 for watchful waiting patients) and highest in Trial 25.

 

Table 10 Serum PSA (Prior to Prostatectomy or Radiotherapy and/or at Randomization)

Time of Measurement or Pre-randomization Group

Trial 23

Trial 24

Trial 25

Casodex

Placebo

Casodex

Placebo

Casodex

Placebo

PSA (m g/L) prior to prostatectomy or radiation therapy

Number patients 1

1578

1581

1152

1122

109

99

Median PSA

7.1

7.1

12.0

11.5

17.0

16.0

PSA (m g/L) at time of randomization

Prostatectomy patients

           

Number patients

1312

1316

800

795

78

78

Median PSA

NQ 2

NQ

NQ

NQ

1.2

1.1

Radiotherapy patients

           

Number patients

323

317

330

310

39

25

Median PSA

2.9

3.0

3.5

3.4

8.2

8.0

Watchful waiting patients

           

Number patients

0

0

604

642

483

497

Median PSA

--

--

11.0

11.6

16.6

17.8

All treatments (all patients)

           

Number patients

1635

1633

1734

1748

603

600

Median PSA

NQ

NQ

1.3

1.3

12.6

13.8

1. Number of patients for whom PSA values were available.

2. NQ = non quantifiable (i.e., below the minimal detectable value).

Source: Text table 7, pg. 32, ISE.

Medical Officer's Comments

      1. Primary Efficacy Outcomes
      2. In the following Section on primary efficacy outcomes, the Sponsor’s preferred endpoints and the outcomes related to these endpoints are first presented and reviewed. This is followed by presentation and review of the efficacy outcomes based on the FDA-requested endpoints and analyses. The FDA-requested analyses were performed, for the most part, by the Sponsor.

        1. Objective Disease Progression or Death in Absence of Progression (Sponsor’s Preferred Endpoints and Analyses)

Objective disease progression or death in the absence of objective progression in each of the clinical trials is summarized in Table 11. This Table lists by trial and treatment group the total number (%) of patients with (1) a positive bone, (2) other objective events classified as disease progression by the Sponsor, and (3) death in the absence of objective progression. The percentage of patients with bone scan confirmed objective evidence of disease progression was lowest in Trial 23, intermediate in Trial 24, and highest in Trial 25. In each of Trials 24 and 25, the percentage of patients with either (1) a positive bone scan or (2) other objective events of disease progression was numerically lower in the Casodex treatment group compared to the placebo group. In Trial 23, there were no differences between the Casodex and placebo treatment groups in the proportions of patients with disease progression.

Table 11 Objective Disease Progression or Death in Trials 23, 24, and 25

 

Number (per cent) of patients with event 1

Event

Study 23

Study 24

Study 25

Casodex
(N = 1647)

Placebo
(N = 1645)

Casodex
(N = 1798)

Placebo
(N = 1805)

Casodex
(N = 607)

Placebo
N = 611)

Positive bone scan

21

(1.3)

15

(0.9)

60

(3.3)

116

(6.4)

32

(5.3)

95

(15.5)

Other objective events 2

10

(0.6)

17

(1.0)

25

(1.4)

85

(4.7)

19

(3.1)

40

(6.5)

Death in absence of progression

52

(3.2)

55

(3.3)

96

(5.3)

92

(5.1)

48

(7.9)

44

(7.2)

Total (%) Patients

83

(5.0)

87

(5.3)

181

(10.1)

293

(16.2)

99

(16.3)

179

(29.3)

1. Based on Sponsor’s preferred endpoints.

2. Other objectively confirmed progression (documented by magnetic resonance imaging, computerized tomography, sonography, or biopsy).

Source: Table T4.1, ISE.

Medical Officer's Comments

The Sponsor’s primary analyses of time to disease progression (TTP) for each of the individual trials and the trials combined are presented in Table 12. Hazard ratios were 0.933 (Trial 23), 0.477 (Trial 24), 0.430 (Trial 25), and 0.509 (combined analysis). All hazard ratios, other than that for Trial 23 were highly statistically significant (p < 0.0001).

 

Table 12 Time to Objective Progression or Death in Absence of Progression

 

Study

Number (%) of patients with event
(objective progression or death)

Hazard ratio 1

95% confidence interval

P value

Casodex

Placebo

 

Number

(%)

Number

(%)

     

23

83/1647

(5.0)

87/1645

(5.3)

0.933

0.691 to 1.261

0.653

24

181/1798

(10.1)

293/1805

(16.2)

0.574

0.477 to 0.692

<0.0001

25

99/607

(16.3)

179/611

(29.3)

0.430

0.336 to 0.552

<0.0001

Combined Data
(Trials 23+24+25)

363/4052

(9.0)

559/4061

(13.8)

0.581

0.509 to 0.663

<0.0001

1. Based on Sponsor’s preferred endpoints and analyses.

Source: Table T4.2, ISE.

Medical Officer’s Comments

Objective disease progression or death in the absence of progression based on pre-randomization treatment (radical prostatectomy, radiation therapy, or watchful waiting) is summarized in Table 13. Data have been combined across the 3 clinical trials in the sponsor’s analysis that is presented in the Table. Based on this combined analysis, the proportions of patients exhibiting progression based on either a positive bone scan or other objective events were numerically lower both in patients who had had prior therapy and in those who had not had prior therapy (watchful waiting treatment group). There was no effect of treatment on the proportion of patients who experienced death in the absence of disease progression.

Table 13 Objective Disease Progression or Death in Absence of Progression Based on Pre-randomization Treatment (Data for Trials 23, 24, and 25 Combined)

 

Number (per cent) of patients with event 1

Event

Radical Prostatectomy

Radiotherapy

Watchful Waiting

Casodex
(N = 2236)

Placebo
(N = 2218)

Casodex
(N = 699)

Placebo
(N = 671)

Casodex
(N = 1114)

Placebo
N = 1171)

Positive bone scan

33

(1.5)

58

(2.6)

28

(4.0)

45

(6.7)

51

(4.6)

123

(10.5)

Other objective events 2

22

(1.0)

58

(2.6)

11

(1.6)

20

(3.0)

21

(1.9)

64

(5.5)

Death in absence of progression

60

(2.7)

54

(2.4)

36

(5.2)

38

(5.7)

100

(9.0)

99

(8.5)

Total (%) Patients

115

(5.1)

170

(7.7)

75

(10.7)

103

(15.4)

172

(15.4)

286

(24.4)

1. Based on Sponsor’s preferred endpoints.

2. Other objectively confirmed progression (documented by magnetic resonance imaging, computerized tomography, sonography, or biopsy).

Source: Table T4.4, ISE.

The Sponsor’s analyses of time to progression in the radical prostatectomy, radiation therapy, and watchful waiting treatment groups (data combined across the 3 trials) are summarized in Table 14. Hazard ratios ranged from 0.53 (watchful waiting group) to 0.63 (adjuvant treatment groups).

Table 14 Time to Objective Progression or Death (Trials 23, 24, and 25 Combined)

 

Patient Subgroup

Number (%) of patients with event
(objective progression or death)

Hazard ratio 1

95% confidence interval

Casodex

Placebo

 

Number

(%)

Number

(%)

   

All adjuvant patients

190/2935

(6.5)

273/2889

(9.4)

0.63

0.52 to 0.76

Radical prostatectomy patients

115/2236

(5.1)

170/2218

(7.7)

0.63

0.50 to 0.80

Radiotherapy patients

75/699

(10.7)

103/671

(15.4)

0.63

0.46 to 0.85

All watchful waiting patients2

172/1114

(15.4)

286/1171

(24.4)

0.53

0.44 to 0.64

1. Based on Sponsor’s preferred endpoints and analyses.

2. Includes only patients from Trials 24 and 25.

Source: Table T4.13, ISE.

Medical Officer’s Comments

At the request of the Medical Reviewer, the Sponsor provided additional subset analyses for Trial 24 (Table 15) and Trial 25 (Table 16). In each of the subgroups (radical prostatectomy, radiotherapy, and watchful waiting) in Trial 24 and Trial 25, the proportion of patients with disease progression was numerically lower in the Casodex-treated patients.

Table 15 Objective Disease Progression or Death in Absence of Progression in Subgroups Based on Pre-randomization Treatment (Trial 24)

 

Number (per cent) of patients with event 1

Event

Radical Prostatectomy

Radiotherapy

Watchful Waiting

Casodex
(N = 835)

Placebo
(N = 813)

Casodex
(N = 335)

Placebo
(N = 325)

Casodex
(N = 628)

Placebo
(N = 666)

Positive bone scan

17

(2.0)

36

(4.4)

17

(5.1)

32

(9.8)

26

(4.1)

48

(7.2)

Other objective events 2

14

(1.7)

42

(5.2)

4

(1.2)

15

(4.6)

7

(1.1)

28

(4.2)

Death in absence of progression

21

(2.5)

21

(2.6)

14

(4.2)

12

(3.7)

61

(9.7)

59

(8.9)

Total (%) Patients

52

(6.2)

99

(12.2)

35

(10.4)

59

(18.2)

94

(15.0)

135

(20.3)

1. Based on Sponsor’s preferred endpoints

2. Other objectively confirmed progression (documented by magnetic resonance imaging, computerized tomography, sonography, or biopsy).

Source: Submission of April 3, 2002, Appendix 1.

 

Table 16 Objective Disease Progression or Death in Absence of Progression in Subgroups Based on Pre-randomization Treatment (Trial 25)

 

Number (per cent) of patients with event 1

Event

Radical Prostatectomy

Radiotherapy

Watchful Waiting

Casodex
(N = 79)

Placebo
(N = 80)

Casodex
(N = 39)

Placebo
(N = 26)

Casodex
(N = 486)

Placebo
(N = 505)

Positive bone scan

2

(2.5)

11

(13.8)

4

(10.3)

9

(34.6)

25

(5.1)

75

(14.9)

Other objective events 2

1

(1.3)

3

(3.8)

4

(10.3)

1

(3.8)

14

(2.9)

36

(7.1)

Death in absence of progression

5

(6.3)

1

(1.3)

4

(10.3)

3

(11.5)

39

(8.0)

40

(7.9)

Total (%) Patients

8

(10.1)

15

(18.8)

12

(30.8)

13

(50.0)

78

(16.0)

151

(29.9)

1. Based on Sponsor’s preferred endpoints.

2. Other objectively confirmed progression (documented by magnetic resonance imaging, computerized tomography, sonography, or biopsy).

Source: Submission of April 3, 2002, Appendix 1.

Estimates of the hazard ratios (and 95% confidence limits) for the differences between the time to disease progression in the Casodex-treated and placebo-treated patients are provided in Table 17. Hazard ratios ranged from 0.423 (watchful waiting patients in Trial 25) to 0.674 (watchful waiting patients in Trial 24).

Table 17 Hazard Ratios for Objective Disease Progression or Death (Any Cause) in Subgroups based on Pre-randomization Treatment (Trials 24 and 25)

Trial Number

Previous Treatment

Randomized Treatment

Number of events

Number of patients

% patients with event

Estimate of hazard ratio 1

95%
confidence limits

24

Radical prostatectomy

Casodex

52

835

6.2%

   
 

Placebo

99

814

12.2%

0.463

0.331 to 0.649

 

Radiotherapy

Casodex

35

335

10.4%

   
 

Placebo

59

325

18.2%

0.564

0.370 to 0.860

 

Watchful waiting

Casodex

94

628

15.0%

   
 

Placebo

135

666

20.3%

0.674

0.518 to 0.878

25

Radical prostatectomy

Casodex

9

82

11.0%

   
 

Placebo

15

80

18.8%

0.530

0.230 to 1.220

 

Radiotherapy

Casodex

12

39

30.8%

   
 

Placebo

13

26

50.0%

0.436

0.194 to 0.979

 

Watchful waiting

Casodex

78

486

16.0%

   
 

Placebo

151

505

29.9%

0.423

0.321 to 0.557

1. Based on Sponsor’s preferred endpoints and analyses.

Source: Submission of 3 April 2002 Appendix 2.

Medical Officer's Comments

        1. Efficacy Outcomes (FDA-Requested Endpoints and Analyses)

As discussed earlier in Section 4.5.3.3, the Division of Reproductive and Urologic Drug Products (DRUDP) was concerned about the possibility of assessment bias in a time-to-event analysis because treatment blinding could not assured; consequently, DRUDP requested that the efficacy outcomes be evaluated by means of a binary analysis based on the proportion of patients with bone scan confirmed progression at 2 years or death in the absence of disease progression. The Sponsor provided the requested analyses as well as a slightly modified analysis - bone scan confirmed progression or death in the absence of progression within 2.5 years of randomization. Findings based on this latter analysis are presented in the remainder of this section.

Table 18 lists the number and percentage of patients with bone scan confirmed progression or death in the absence of progression within 2.5 years of randomization in each of the trials. In Trial 23, there was no evidence of a significant reduction in the proportion of patients with disease progression or death in the Casodex group (2.4%) compared to the placebo group (2.9%). In each of Trials 24 and 25, the proportion of patients with disease progression or death was lower in the Casodex group compared to the placebo group (Trial 24: 6.2% vs. 9.3%; Trial 25: 10.4% vs. 17.2%).

Table 18 Bone Scan Confirmed Disease Progression or Death in the Absence of Progression within 2.5 Years after Randomization

 

Number (per cent) of patients with event 1

Event

Study 23

Study 24

Study 25

Casodex
(N = 1647)

Placebo
(N = 1645)

Casodex
(N = 1798)

Placebo
(N = 1805)

Casodex
(N = 607)

Placebo
N = 611)

Positive bone scan

14

(0.9)

11

(0.7)

42

(2.3)

98

(5.4)

22

(3.6)

72

(11.8)

Death in absence of progression

25

(1.5)

37

(2.2)

70

(3.9)

70

(3.9)

41

(6.8)

33

(5.4)

Total (%) of patients

39

(2.4)

48

(2.9)

112

(6.2)

168

(9.3)

63

(10.4)

105

(17.2)

1. Based on FDA-requested endpoints.

Source: Table A4, pg. A56-A58, ISE.

Medical Officer's Comments

The estimates of the odds ratio (and 95% confidence limit) for disease progression in Casodex-treated patients compared to placebo-treated patients for each of Trials 23, 24, and 25, based on the requested FDA analysis, are listed in Table 19.

Table 19 Odds Ratios for Bone Scan Confirmed Progression or Death in
Absence of Progression within 2.5 Years after Randomization

Trial

Treatment

No. of events

No. of patients

% patients with event

Estimate of Odds Ratio1

95% confidence limit

23

Casodex

39

1647

2.4%

   
 

Placebo

48

1645

2.9%

0.81 2

0.52 to 1.24 1

24

Casodex

112

1798

6.2%

   
 

Placebo

168

1803

9.3%

0.645

0.500 to 0.832

25

Casodex

63

607

10.4%

   
 

Placebo

105

611

17.2%

0.515

0.365 to 0.729

1 Based in FDA-requested endpoints and analyses.

2 Values for Trial 23 calculated by FDA statistician. Values for Trials 24 and 25 calculated by Sponsor.

Source: Submission of 17 May 2002, Appendix 2.

Medical Officer's Comments

To obtain a more complete picture of which treatment subgroup(s) may have derived benefit from treatment with Casodex, the Sponsor was asked to provide additional subgroup analyses based on the patient’s treatment prior to randomization (i.e., radical prostatectomy, radiotherapy, or management by watchful waiting). The descriptive analyses for each of the trials are summarized in Table 20, Table 21, and Table 22. For each of the trials, the proportion of patients with bone scan confirmed disease progression or death from any cause in the absence of disease progression was numerically lower in Casodex-treated patients in each of the subgroups. For Trial 23, the reductions in total events in Casodex-treated patients compared to placebo-treated patients were (1) very small (0.3% in the prostatectomy subgroup; 1.6% in the radiotherapy subgroup group), (2) based on a very small number of events, and (3) were not related to a reduction in the proportion of patients with positive bone scans.

Table 20 Bone Scan Confirmed Disease Progression or Death within 2.5 Years
after Randomization (Trial 23: Prior Treatment Subgroups)

 

Number (per cent) of patients with event 1, 2

Event

Radical Prostatectomy

Radiotherapy

Casodex
(N = 1322)

Placebo
(N = 1325)

Casodex
(N = 325)

Placebo
(N = 320)

Positive bone scan

10

(0.8)

8

(0.6)

4

(1.2)

3

(0.9)

Death (any cause) in absence of progression

16

(1.2)

22

(1.7)

9

(2.8)

15

(4.7)

Total (%) Patients

26

(2.0)

30

(2.3)

13

(4.0)

18

(5.6)

1. Based on FDA-requested endpoints.

2. Patients previously managed by watchful waiting were not eligible for this Trial.

Source: Submission of 3 April 2002, Appendix 3.

 

Table 21 Bone Scan Confirmed Disease Progression or Death within 2.5 Years
after Randomization (Trial 24: Prior Treatment Subgroups)

 

Number (per cent) of patients with event 1

Event

Radical Prostatectomy

Radiotherapy

Watchful Waiting

Casodex
(N = 835)

Placebo
(N = 813)

Casodex
(N = 335)

Placebo
(N = 325)

Casodex
(N = 628)

Placebo
(N = 666)

Positive bone scan

12

(1.4)

27

(3.3)

11

(3.3)

28

(8.6)

19

(3.0)

43

(6.5)

Death (any cause) in absence of progression

17

(2.0)

16

(2.0)

13

(3.9)

8

(2.5)

40

(6.4)

46

(6.9)

Total (%) Patients

29

(3.5)

43

(5.3)

24

(7.2)

36

(11.1)

59

(9.4)

89

(13.4)

1. Based on FDA-requested endpoints.

Source: Submission of 3 April 2002, Appendix 3.

 

 

Table 22 Bone Scan Confirmed Disease Progression or Death within 2.5 Years
after Randomization (Trial 25: Prior Treatment Subgroups)

 

Number (per cent) of patients with event 1

Event

Radical Prostatectomy

Radiotherapy

Watchful Waiting

Casodex
(N = 79) 2

Placebo
(N = 80)

Casodex
(N = 39)

Placebo
(N = 26)

Casodex
(N = 486)

Placebo
(N = 505)

Positive bone scan

1

(1.3) 3

7

(8.8)

3

(7.7)

6

(23.1)

17

(3.5)

59

(11.7)

Death (any cause) in absence of progression

5

(6.3)

1

(1.3)

4

(10.3)

3

11.5)

32

(6.6)

29

(5.7)

Total (%) Patients

6

(7.6)

8

(10.0)

7

(17.9)

9

(34.6)

49

(10.1)

88

(17.4)

1. Based on FDA-requested endpoints.

2. Does not include 3 patients who were initially treated by radical prostatectomy followed by local radiotherapy.

3. Does not include 1 patient who was initially treated by radical prostatectomy followed by local radiotherapy.

Source: Submission of 3 April 2002, Appendix 3.

 

Medical Officer’s Comments

The estimate of the odds ratio (and 95% confidence interval) for the proportion of patients with bone scan confirmed disease progression or death in each of the subgroups is listed in Table 23. In all instances other than the subgroup of watchful waiting, the upper bound of the 95% confidence limit exceeded 1.000. In Trial 24, however, the upper bound of the 95% confidence limit for the radical prostatectomy and radiotherapy subgroups barely crossed 1.000 and was 1.003 and 1.081, respectively.

 

Table 23 Odds Ratios for Bone Scan Confirmed Progression or Death from Any Cause within 2.5 Years after Randomization in Treatment Subgroups

Trial Number

Previous Treatment

Randomized Treatment

Number of events

Number of patients

% patients with event

Estimate of Odds Ratio 1

95%
confidence limits

23

All treatments

Casodex

39

1647

2.4%

   
 

Placebo

48

1645

2.9%

0.81 2

0.52 to 1.24 2

 

Radical prostatectomy

Casodex

26

1322

2.0%

   
 

Placebo

30

1325

2.3%

0.862

0.506 to 1.467

 

Radiotherapy

Casodex

13

325

4.0%

   
 

Placebo

18

320

5.6%

0.672

0.321 to 1.408

24

All treatments

Casodex

112

1798

6.2%

   
 

Placebo

168

1805

9.3%

0.645

0.500 to 0.832

 

Radical prostatectomy

Casodex

29

835

3.5%

   
 

Placebo

43

814

5.3%

0.616

0.379 to 1.003

 

Radiotherapy

Casodex

24

335

7.2%

   
 

Placebo

36

325

11.1%

0.625

0.361 to 1.081

 

Prostatectomy or Radiotherapy

Casodex

53

1170

4.5%

   

Placebo

79

1139

6.9%

0.619

0.430 to 0.890

 

Watchful waiting

Casodex

59

628

9.4%

   
 

Placebo

89

666

13.4%

0.674

0.471 to 0.964

25

All treatments

Casodex

63

607

10.4%

   
 

Placebo

105

611

17.2%

0.515

0.365 to 0.729

 

Radical prostatectomy

Casodex

7

82

8.5%

   
 

Placebo

8

80

10.0%

0.836

0.282 to 2.480

 

Radiotherapy

Casodex

7

39

17.9%

   
 

Placebo

9

26

34.6%

0.397

0.123 to 1.285

 

Prostatectomy. or Radiotherapy

Casodex

14

121

11.6%

   

Placebo

17

106

16.0%

0.584

0.264 to 1.292

 

Watchful waiting

Casodex

49

486

10.1%

   
 

Placebo

88

505

17.4%

0.498

0.338 to 0.734

1. Based on FDA-requested endpoints and analyses.

2 Values calculated by FDA statistician. Other values calculated by Sponsor.

Source: Submission of 3 April 2002, Appendix 4 and Submission of 17 May 2002, Appendix 2.

Medical Officer’s Comments

        1. Additional Subset Analyses to Support Adjuvant Use of Casodex

On 25 April 2002, a teleconference between the Sponsor and DRUDP was held. The purpose of the teleconference was to provide the Sponsor with an update as to the status of the review and to inform the Sponsor that there were several unresolved review issues. Prior to the teleconference, the Sponsor was provided with a list of questions that included the following:

  1. How do you explain the disparity between the efficacy findings of Trial 23 (North American study) and those of Trials 24 and 25?
  2. Based on the findings in Trial 23 as of 2 June 2000 (data cutoff date), it appears that Casodex does not offer a significant benefit for men with early prostate cancer who initially are treated by radical prostatectomy or radiation therapy with a curative intent. In light of this observation, what population of patients with prostate cancer in the US, who are initially treated with radical prostatectomy or radiation therapy of curative intent, would benefit from adjuvant treatment with Casodex?
  3. Since there was not a watchful waiting group in Trial 23, can you tell us how men treated by watchful waiting in Trials 24 and 25 compare to those that are likely to be treated by watchful waiting in the US. In particular, how do we know that such patients in the US would respond in a similar fashion as patients in Trials 24 and 25?
  4. Please explain the criteria that were used to obtain Gleason scores for the tumors in each of the clinical trials. Did all pathologists use the same criteria?
  5. There appears to be a lack of correlation between Gleason scores and preprocedure PSA values. Patients in Trial 23 had higher Gleason scores (more severe disease) but lower PSA values. How do you explain this?

These questions initially were addressed by the Sponsor during the teleconference and subsequently more completely in a written response of 10 May 2002. The Sponsor’s written response included the following information and explanations regarding the 5 questions listed above.

  1. "The disparity in efficacy findings between Trial 23 and Trials 24 and 25 is related to the immaturity of Trial 23. At data cutoff, only 5.2% of patients had objective progression, with the majority of progression events being non-prostate cancer related deaths."
  2. "…. on closer examination of the data, by means of the multivariate analysis, several groups of patients were identified in which a clear and consistent benefit for Casodex was found. These patients were as follows:
  • patients who underwent prostatectomy with locally advanced disease and detectable postsurgical PSA levels and
  • patients who underwent radiotherapy with locally advanced disease and elevated preradiation PSA levels"

"AstraZeneca believes that patients with locally advanced non-metastatic prostate cancer who undergo radical prostatectomy but are at high risk for disease recurrence (e.g., patients with detectable postsurgical PSA levels) would benefit from adjuvant treatment with Casodex."

  1. "These data and guidelines [e.g., the American Urologic Association’s Prostate Cancer Clinical Guidelines Panel Report] clearly show that watchful waiting is a well-recognized and practiced treatment option in the US, with the guidelines also recognizing this treatment for the types of patients represented in the watchful waiting cohorts in Trials 24 and 25."
  2. "In the Casodex EPC program, the local pathologist assessed Gleason grade. In Trial 23, the actual numerical score was captured, but in Trials 24 and 25, the grade was captured only in terms of well, moderately, or poorly differentiated with guidance that ‘well’ represented a Gleason score of 2 to 4; moderate, a score of 5 or 6; and poorly, a grade of ³  7."
  3. "The reason for the lack of correlation between Gleason grade and PSA is unclear, but may relate to the fact that they measure different aspects of the tumor. Therefore, as noted in Question 2, AZ does not believe that conclusions can be drawn in this program on the basis of Gleason grade."

Medical Officer’s Comment

With the written response of 10 May 2002, the Sponsor provided addition information in support of their contention that patients who would benefit from adjuvant Casodex therapy included those with locally advanced disease (Stage T3/T4) prior to initial therapy and either (1) a serum PSA concentration > 0.2 ng/mL following radical prostatectomy or (2) a serum PSA concentrations > 10 ng/mL prior to radiotherapy. Table 24 summarizes objective disease progression or death in the absence of progression for the subset of patients with Stage T3/T4 tumors and post prostatectomy PSA values > 0.2 ng/mL. Events represented in Table 24 are based on the Sponsor’s preferred endpoints.

Table 24 Disease Progression in Patients with Locally Advanced (Stage T3/T4), M0 Prostate Cancer and Post Prostatectomy PSA Values > 0.2 ng/mL

Number (%) of patients with event 1, 2

Casodex

Placebo

Hazard Ratio

Event

Number (%)

Number (%)

(95% CL)

Trial 23

Total Pts Enrolled (158/2647 [6.0%])3

834

754

Number of Pts with Event

8

(9.6%)

12

(16.0%)

0.53 (0.21, 1.37)

Bone Scan Positive

5

4

Other Objective Events

2

4

Deaths 5, 6

1

4

Trial 24

Total Pts Enrolled (277/1648 [16.8%])3

1334

1444

Total Events

20

(15.0%)

35

(24.3%)

0.55 (0.32, 0.96)

Bone Scan Positive

11

15

Other Objective Events

4

16

Deaths 5

5

4

Trial 25

Total Pts Enrolled (74/159 [46.5%])3

334

414

Total Events

4

(12.1%)

11

(26.8%)

0.49 (0.15, 1.58)

Bone Scan Positive

2

8

Other Objective Events

1

2

Deaths 5

1

1

1. Based on Sponsor’s preferred endpoints of positive bone, other objective events, or death from any cause at any time post-randomization.

2. Values (other than for category of "Total Events") compiled by medical reviewer from Submission of 22 May 2002.

3. The value expressed as [%] represents the percentage of patients in the Trial previously treated by radical prostatectomy who were clinical stage T3 or T4 and had a postsurgical PSA value > 0.2 ng/mL relative to all patients previously treated by prostatectomy.

4. Total number of patients enrolled in the Casodex or placebo treatment group previously treated by radical prostatectomy who were clinical stage T3 or T4 and had a postsurgical PSA value > 0.2 ng/mL.

5. Death from any cause.

6. All deaths in Trial 23 (other than 1 case in the placebo group) were due to causes other than prostate cancer.

Source: Submission of 10 May 2002, Table 2; Submission of 22 May 2002, Appendix 3.

Medical Officer’s Comments

        1. First Revision by Sponsor to Proposed Label Claims

Based in part on the information provided in the written response of 10 May 2002, the Sponsor also submitted revised wording for the Casodex 150 mg label. The revised indication (also submitted on 10 May 2002) was:

Casodex 150 mg is indicated as

Medical Officer's Comment

        1. Additional Subset Analyses to Support Immediate or Monotherapy Indication

AstraZeneca was asked to provide additional information about the disease characteristics of the watchful waiting patients in Trials 24 and 25 to allow DRUDP to assess further the relevance of these findings in non-US patients to patients in the US who would otherwise be managed by watchful waiting or surveillance. The Sponsor was asked to provide the requested data in a manner that would allow DRUDP to determine if the benefit of treatment with Casodex in the watchful waiting (immediate treatment) subgroup also was observed in patients with minimal or early disease. These data are summarized in Table 25 (Trial 24) and Table 26 (Trial 25). In these tables, patients with bone scan confirmed progression or death from any cause in the absence of progression within 2.5 years after randomization (FDA-requested endpoints) are presented in terms of baseline disease characteristics (clinical stage, Gleason category, and pre-randomization serum PSA value).

Table 25 Patients with Bone Scan Progression or Death from Any Cause within 2.5 Years of Randomization in Watchful Waiting Group (Trial 24)

 

All patients in category 2

 

Number (%) of patients with event 1

Subgroup

 

Casodex

 

Placebo

 

N

%

 

N

%

 

N

%

All Patients

1294

(100)

 

59/628

(9.4)

 

89/666

(13.4)

Tumor Stage

               

Localized (T1/T2)

996

(77)

 

35/475

(7.4)

 

52/521

(10.0)

Locally advanced

298

(23)

 

24/153

(15.7)

 

37/145

(25.5)

                 

Gleason category

               

Well differentiated

560

(43)

 

22/272

(8.1)

 

22/288

(7.6)

Moderately differentiated

463

(36)

 

19/226

(8.4)

 

33/237

(13.9)

Poorly differentiated

239

(19)

 

18/115

(15.7)

 

31/124

(25.0)

                 

Prerandomization PSA

               

£ 0.2 ng/mL

8

(<1)

 

0/4

(0.0)

 

0/4

(0.0)

> 0.2 to 4 ng/mL

252

(20)

 

6/122

(4.9)

 

10/130

(7.7)

> 4 to 10 ng/mL

298

(24)

 

8/156

(5.1)

 

16/142

(11.3)

> 10 to 20 ng/mL

316

(26)

 

20/150

(13.3)

 

16/166

(9.6)

>20 ng/mL

370

(30)

 

20/170

(11.8)

 

44/200

(22.0)

1. Based on FDA-requested endpoints for disease progression.

2. Includes all patients (both those who did and did not have disease progression.

Source: Submission of 17 May 2002, Appendix 3.

 

Table 26 Patients with Bone Scan Progression or Death from Any Cause within 2.5 Years of Randomization in Watchful Waiting Group (Trial 25)

 

All patients in category 2

 

Number (%) of patients with event 1

Subgroup

 

Casodex

 

Placebo

 

N

%

 

N

%

 

N

%

All patients

991

(100)

 

49/486

(10.1)

 

88/505

(17.4)

Tumor Stage

               

Localized (T1/T2)

631

(64)

 

29/304

(9.5)

 

39/327

(11.9)

Locally advanced

360

(36)

 

20/182

(11.0)

 

49/178

(27.5)

                 

Gleason category

               

Well differentiated

462

(47)

 

16/229

(7.0)

 

24/233

(10.3)

Moderately differentiated

415

(42)

 

15/198

(7.6)

 

44/217

(20.3)

Poorly differentiated

101

(10)

 

17/49

(34.7)

 

18/52

(34.6)

                 

Prerandomization PSA

               

£ 0.2 ng/mL

2

(<1)

 

1/2

(50.0)

 

0/0

(0.0)

> 0.2 to 4 ng/mL

98

(10)

 

4/39

(10.3)

 

3/59

(5.1)

> 4 to 10 ng/mL

209

(21)

 

11/111

(9.9)

 

10/98

(10.2)

> 10 to 20 ng/mL

237

(24)

 

7/125

(5.6)

 

12/112

(10.7)

> 20 ng/mL

434

(44)

 

26/206

(12.6)

 

61/228

(26.8)

1. Based on FDA-requested endpoints for disease progression.

2. Includes all patients (both those who did and did not have disease progression.

Source: Submission of 17 May 2002, Appendix 3.

Medical Officer's Comments

        1. Second Revision by Sponsor to Proposed Label Claims

After receiving comments from DRUDP concerning the reasons for the non-approval of NDA 20-498/s012, AstraZeneca revised the claim for the immediate use of Casodex. The modification limited the target population to patients with localized disease, defined by the Sponsor as patients with T1/T2, NX, M0 prostate cancer. According to this modification, patients with locally advanced disease (i.e., T3/T4) would no longer be appropriate candidates for Casodex immediate therapy.

Medical Officer's Comments

Many elderly patients with prostate cancer die of causes unrelated to their prostate disease. The sponsor was therefore asked to provide information on the number of patients in the watchful waiting groups in Trials 24 and 25 who had objective disease progression (i.e., a positive bone scan) or death due only to prostate cancer in the absence of objective progression. This information is presented in Table 27. For patients with no prior treatment and localized disease in the placebo treatment groups, only 3.6% of patients (Trial 24) and 7.3% of patients (Trial 25) experienced disease progression.

Table 27 Patients with Bone Scan Progression or Death from Prostate Cancer within 2.5 Years of Randomization in Watchful Waiting Group (Trials 24 and 25)

 

All patients in category 2

 

Number (%) of patients with event 1

Subgroup

 

Casodex

 

Placebo

 

N

%

 

N

%

 

N

%

Trial 24

               

All patients

1294

(100)

 

23/628

(3.7)

 

48/666

(7.2)

Tumor Stage

               

Localized (T1/T2)

996

(77)

 

10/475

(2.1)

 

19/521

(3.6)

Locally advanced

298

(23)

 

13/153

(8.5)

 

29/145

(20.0)

                 

Trial 25

               

All patients

991

(100)

 

22/486

(4.5)

 

64/505

(12.7)

Tumor Stage

               

Localized (T1/T2)

631

(64)

 

9/304

(3.0)

 

24/327

(7.3)

Locally advanced

360

(36)

 

13/182

(7.1)

 

40/178

(22.5)

1. Only deaths from prostate cancer or a positive bone scan are considered to be an event.

2. Includes all patients (both those who did and did not have disease progression.

Source: Submission of 17 May 2002, Appendix 3.

Medical Officer's Comments

        1. Additional Subset Analyses by Baseline Disease Characteristics
        2. Although there were some differences in the inclusion and exclusion criteria of each the 3 pivotal clinical trials (see Section 4.3.3), patients with all stages of non-metastatic (M0) prostate disease (i.e., stages T1-T4) were eligible for enrollment. In addition, patients may have undergone active therapy (radical prostatectomy or radiotherapy) or no therapy (except in Trial 23) prior to enrollment. To allow DRUDP to investigate the effects of Casodex treatment in each of these subgroups, the Sponsor was asked to provide additional descriptive subset analyses based on patient disease characteristics prior to enrollment. In these analyses, the proportions of patients with disease progression in each Trial are presented based on (1) clinical stage (T1-T4), (2) Gleason score, (3) PSA value at randomization, and (4) PSA value prior to prostatectomy or radiotherapy for adjuvant patients. Data for adjuvant patients are presented separately for the prostatectomy and radiotherapy groups in the Appendix (Appendix Tables 1a-1c, pg. 120-123). Data for the "immediate therapy patients" (i.e., watchful waiting group) are presented in Table 25 and Table 26 in the main body of this review. In these descriptive analyses, disease progression is defined as (1) a positive bone scan or (2) death from any cause in the absence of a positive bone scan, both within 2.5 years of randomization (FDA-preferred endpoints). A second set of descriptive subset analyses for adjuvant patients is presented in Appendix Tables 2a-2c (pg. 124-127). In these later analyses, disease progression is defined as (1) a positive bone scan or (2) death due to prostate cancer in the absence of a positive bone scan, both within 2.5 years of randomization (a modification of the FDA-preferred endpoints).

        3. Central Reread of Bone Scans

The use of a binary primary efficacy endpoint, instead of a time-to-event analysis, reduced one potential source of assessment bias due to the likely unblinding of treatment assignments in some patients. Another possible source of bias resulting from this unblinding of treatment assignments concerned the reading of bone scans at the local study centers. It was possible that bone scans from patients thought to be on placebo therapy would be more likely to be read as positive than scans from patients on Casodex therapy. To investigate this possible source of bias, it was recommended by DRUDP that bone scans be reread by blinded reviewers at a central facility. In response to this request, the Sponsor designed and conducted a substudy in which all positive bone scans and a representative sample of negative scans were to be reread by at least 2 blinded reviewers at a central facility. The design and outcome of this substudy are described in detail in the separate review of Robert Yaes MD, Division of Medical Imaging and Radiopharmaceutical Drug Products (DMIRDP), FDA. The following is a brief summary of the findings from this substudy.

A total of 1,259 scans from among the 3 trials were identified for review at the central facility. Of these, 1,032 were available for review. Table 28 summarizes the comparative results from the original local read and the central reread. Scans that were available for reread were classified as positive, negative, or indeterminate. Approximately 15% of scans were not available for reread.

Table 28 Comparison of Local Read and Central Reread (Data from
Trials 23, 24, and 25 Combined)


Treatment Group


Local Result

Central Reread Result

Number (%) of scans in each category

Positive

Negative

Indeterminate

Not Available

Casodex

Positive

73

(65%)

22

(19%)

5

(4%)

13

(12%)

                   
 

Negative

31

(5%)

443

(72%)

34

(6%)

107

(17%)

                   

Placebo

Positive

144

(63%)

36

(16%)

18

(8%)

28

(12%)

                   
 

Negative

22

(4%)

359

(71%)

45

(9%)

79

(16%)

Source: Report on Bone Scan Reread Study, Table T9.2, pg. ST-66.

Medical Officer's Comments

Table 29 summarizes the comparative results from the original local read and the central reread for each trial, considering only those scans reread as positive or negative and excluding those that were reread as indeterminate or those that were not available for reread.

Table 29 Comparison of Results of Local Read and Central Reread
including only Scans Reread as Positive or Negative

     

Central Reread Result

Trial

Treatment Group

Local
Result

Number (%) of scans in each category

 

Positive

Negative

23

Casodex

Positive

13

(72%)

5

(23%)

   

Negative

10

(6%)

150

(94%)

 

Placebo

Positive

8

(67%)

4

(33%)

   

Negative

7

(5%)

136

(95%)

24

Casodex

Positive

33

(69%)

15

(31%)

   

Negative

12

(7%)

153

(93%)

 

Placebo

Positive

70

(76%)

22

(24%)

   

Negative

10

(8%)

122

(92%)

25

Casodex

Positive

27

(93%)

2

(7%)

   

Negative

9

(6%)

140

(94%)

 

Placebo

Positive

66

(87%)

10

(13%)

   

Negative

5

(5%)

101

(95%)

Source: Report on Bone Scan Reread Study, Table T9.3, pg. ST-67 to ST-69.

Medical Officer’s Comments

        1. Survival

At the time of the efficacy data cutoff date of 2 June 2000, the median follow-up time for patients in each treatment group was 3.0 years, which was equivalent to 12,053 and 12,033 total patient-years of follow-up for the Casodex and placebo groups, respectively. Additional data on survival were provided in the Safety Addendum Reports for each trial and the 4-Month Safety Update. The cumulative numbers and percentages of deaths due to prostate cancer or other causes in each of the trials at data cutoff dates of 2 June 2000, 23 February 2001 (Safety Addendum Reports), and 28 September 2001 (4-Month Safety Update) are listed in Table 30. At each of the data cutoff dates, there were no significant differences in the percentage of patients who had died, either of prostate cancer or of other causes, in the Casodex or placebo groups within each of the trials. There were, however, significant differences in the proportion of deaths across the trials, particularly for deaths due to prostate cancer. The percentages of patients who died from all causes was approximately 2-fold and 3-fold greater in Trial 24 and Trial 25, respectively, than in Trial 23 at each of the data cutoff times.

Table 30 Number and Percentage of Deaths in Trials 23, 24, and 25

Cause of
Death

Study 23

 

Study 24

 

Study 25

Casodex
N= 1647

Placebo N=1645

 

Casodex
N= 1798

Placebo N=1805

 

Casodex
N= 607

Placebo
N= 611

 

n

(%)

n

(%)

 

n

(%)

n

(%)

 

n

(%)

n

(%)

Prostate cancer

8

(0.5)

3

(0.2)

 

26

(1.4)

38

(2.1)

 

24

(4.0)

28

(4.6)

Other

54

(3.3)

58

(3.5)

 

97

(5.4)

99

(5.5)

 

45

(7.4)

42

(6.9)

Total 1

62

(3.8)

61

(3.7)

 

123

(6.8)

137

(7.6)

 

69

(11.4)

70

(11.5)

Prostate cancer

9

(0.6)

4

(0.2)

 

47

(2.6)

53

(2.9)

 

35

(5.8)

42

(6.9)

Other

74

(4.6)

83

(5.1)

 

132

(7.3)

131

(7.3)

 

54

(8.9)

43

(7.1)

Total 2

83

(5.1)

87

(5.3)

 

179

(10.0)

184

(10.3)

 

89

(14.7)

85

(14.0)

Prostate cancer

14

(0.9)

6

(0.4)

 

56

(3.1)

66

(3.7)

 

49

(8.1)

56

(9.2)

Other

91

(5.6)

93

(5.7)

 

168

(9.4)

161

(9.0)

 

67

(11.1)

50

(8.2)

Total 3

105

(6.5)

99

(6.1)

 

224

(12.5)

227

(12.7)

 

116

(19.2)

106

(17.4)

1. Data cutoff date of 2 June 2000. Data based on efficacy population.

2. Data cutoff date of 23 February 2001. Data based on safety population. (Calculated by medical reviewer).

3. Data cutoff date of 28 September 2001. Data based on safety population. (Calculated by medical reviewer).

Source: Table T5.1, ISE; Table T8.2 Safety Addendum for each of Trials 23, 24, and 25; Submission of 17 May 2002, Appendix 1.

Medical Officer’s Comments

      1. Secondary Efficacy Endpoints
        1. Time to Treatment Failure

The number and percentage of patients who failed treatment in each of the trials, categorized by the reason for treatment failure, are presented in Table 31. The proportion of patients who had a treatment failure event ranged from 21.1% (Trial 23, placebo group) to 48.0% (Trial 25, placebo group). The most common reason for treatment failure in each of the trials was "withdrawal of therapy" in the absence of objective disease progression or death. Withdrawal of therapy, as the reason for treatment failure ranged from 18.5% of patients (Trial 23, placebo group) to 36.5% (Trial 23, Casodex group). In Trial 23, virtually all patients who failed treatment did so because of withdrawal of therapy in the absence of objective disease progression or death. Additional information as to the reasons for "withdrawal of therapy" in the absence of disease progression is provided in Section 5.5 (Patient Disposition).

Table 31 Reasons for Treatment Failure (Trials 23, 24, and 25)

 

Number (per cent) of patients with event

Reason for

Study 23

Study 24

Study 25

treatment failure 1

Casodex
(N = 1647)

Placebo
(N = 1645)

Casodex
(N = 1798)

Placebo
(N = 1805)

Casodex
(N = 607)

Placebo
N = 611)

Objective disease
progression

5

(0.3)

8

(0.5)

47

(2.6)

151

(8.4)

32

(5.3)

103

(16.9)

Withdrawal of therapy2

601

(36.5)

304

(18.5)

620

(34.5)

468

(25.9)

133

(21.9)

163

(26.7)

Death

9

(0.5)

13

(0.8)

48

(2.7)

36

(2.0)

26

(4.3)

18

(2.9)

Additional systemic
therapy given

3

(0.2)

4

(0.2)

12

(0.7)

25

(1.4)

3

(0.5)

7

(1.1)

No trial therapy
received

20

(1.2)

18

(1.1)

8

(0.4)

10

(0.6)

2

(0.3)

2

(0.3)

Total (%) Patients

638

(38.7)

347

(21.1)

735

(40.9)

690

(38.2)

196

(32.3)

293

(48.0)

1. Categories are mutually exclusive and hierarchical; the event that occurred first was assigned as the reason for treatment failure.

2. Withdrawal of therapy in the absence of disease progression or death.

Source: Text Table 16, pg. 48, ISE.

The Sponsor’s analyses of time to treatment failure are summarized in Table 32. The hazard ratios for the time to treatment failure in the Casodex versus placebo treatment groups showed statistical significance in both Trial 23 and Trial 25 (albeit in opposite directions) with no statistical significance for Trial 24.

Table 32 Analyses of Time to Treatment Failure (Trials 23, 24, and 25)

Trial

Number (%) of patients with event of treatment failure

Hazard ratio

95% confidence interval

p-value

 

Casodex group

Placebo group

     

23

638

(38.7)

347

(21.1)

2.083

1.827 to 2.374

<0.001

24

735

(40.9)

690

(38.2)

1.095

0.986 to 1.215

0.089

25

196

(32.3)

293

(48.0)

0.565

0.471 to 0.679

<0.001

Source: Table T6.2, ISE.

Medical Officer’s Comment

        1. Time to PSA Doubling

A PSA doubling event was the earliest of (1) a doubling of serum PSA concentrations relative to baseline, (2) objective progression of disease, or (3) death from any cause. The number and proportion of patients with a PSA doubling event in each of the trials is summarized in Table 33. In each of the trials, the proportion of patients in whom PSA doubled or with a PSA doubling event was lower in the Casodex-treated patients compared to placebo-treated patients.

Table 33 Number (%) of Patients with a PSA Doubling Event

 

Number (per cent) of patients with event

Earliest Event 1

Study 23

Study 24

Study 25

Casodex
(N = 1647)

Placebo
(N = 1645)

Casodex
(N = 1798)

Placebo
(N = 1805)

Casodex
(N = 607)

Placebo
N = 611)

PSA doubled

211

(12.8)

333

(20.2)

126

(7.0)

440

(24.4)

48

(7.9)

243

(39.8)

Objective progression

12

(0.7)

9

(0.5)

53

(2.9)

80

(4.4)

37

(6.1)

56

(9.2)

Death

47

(2.9)

52

(3.2)

93

(5.2)

80

(4.4)

46

(7.6)

36

(5.9)

Total (%) of patients

270

(16.4)

394

(24.0)

272

(15.1)

600

(33.2)

131

(21.6)

335

(54.8)

1. Categories are mutually exclusive and hierarchical; the event that occurred first was assigned as the reason for PSA doubling.

Source: Text Table 19, pg. 51, ISE.

Medical Officer's Comment

The results of the sponsor’s analyses of time to PSA doubling (TTPSAd) are presented in Table 34. Treatment with Casodex increased the time to a PSA doubling event in each of the trials.

Table 34 Analyses of Time to a PSA Doubling Event in Trials 23, 24, and 25

 

Trial

Number (%) of patients with PSA
doubling event

Hazard ratio

95% confidence interval

P value

Casodex Group

Placebo Group

 

Number

(%)

Number

(%)

     

23

270/1647

(16.4)

394/1645

(24.0)

0.619

0.530 to 0.722

<0.0001

24

272/1798

(15.1)

600/1805

(33.2)

0.369

0.320 to 0.426

<0.0001

25

131/607

(21.6)

335/611

(54.8)

0.243

0.197 to 0.299

<0.0001

Source: Text Table 20, pg. 54, ISE.

Medical Officer’s Comment

    1. Consultations

The findings from Clinical Trials 23, 24, and 25 were presented to the Oncology Coordinating Committee (OCC), FDA on 28 March 2002. Recommendations from the OCC regarding the approvability of Casodex 150 mg for the Sponsor’s originally proposed indication included the following:

    1. Conclusions Regarding Demonstrated Efficacy
      1. Achievement of Protocol-Defined Primary Efficacy Endpoints
      2. Time to objective disease progression (Trials 23, 24, and 25) and time to death (Trials 23 and 25 and the Sponsor’s combined analysis) were the protocol-defined primary efficacy endpoints. For two of the 3 clinical trials (Trials 24 and 25), the Sponsor provided statistically significant evidence that treatment with Casodex 150 mg per day, compared to treatment with placebo, delayed disease progression as assessed by the appearance of new bone metastases or death in the absence disease progression. In Trial 23 (the only trial conducted in the US and the trial most relevant to patients in the US), there was no evidence that treatment with Casodex delayed disease progression.

        There was no evidence that treatment with Casodex improved survival in any of the trials or in the combined analysis. Evidence of improved survival, however, was not anticipated by the cutoff date for efficacy data (2 June 2000) as the data were expected to be immature.

      3. Support of Label Efficacy Claims

The Sponsor originally proposed the following efficacy claim:

CASODEX 150 mg tablets are indicated as immediate hormonal therapy or as adjuvant therapy to treatment of curative intent in patients with non-metastatic prostate cancer.

On 10 May 2002, the Sponsor submitted the following revised efficacy claim:

CASODEX 150 mg is indicated as (1) adjuvant therapy to radical prostatectomy and radiotherapy of curative intent in patients with locally advanced non-metastatic prostate cancer who have a high risk for disease recurrence or (2) immediate treatment of non-metastatic prostate cancer in patients for whom therapy of curative intent is not indicated.

The revised efficacy claim was submitted in response to questions submitted to the Sponsor by the Division (DRUDP) concerning the relevance of the non-US data to patients in the US, particularly in light of the negative outcome of Trial 23 (see Section 4.6.3.3). An exploratory subset analyses submitted by the Sponsor on 10 May 2002 from Trials 24 and 25 was somewhat supportive of the revised indication. However, a similar subset analysis for Trial 23, which included only adjuvant treated patients, provided at best only minimal support for the revised indication. Other data submitted by the Sponsor on 17 May 2002 were inconclusive as to the relevance of the efficacy findings for patients in the immediate therapy groups in Trials 24 and 25 to patients in the US presently managed by watchful waiting or surveillance (see Section 4.6.3.5)

Medical Officer’s Comment

On 22 October 2002, the Sponsor revised the proposed claim for immediate treatment with Casodex. The revised claim limited immediate treatment to patients with localized (T1, T2), NX, M0 disease. This change was made, according to the Sponsor, to address concerns by DRUDP regarding the appropriateness of Casodex monotherapy for patients with locally advanced (T3, T4) disease (see Section 1.3.1).

Medical Officer's Comments

    1. Statistician’s Assessment of Efficacy
    2. The following statements are the conclusion of Dr. Hoberman’s statistical review of the efficacy findings in NDA 20-498/s012. Dr. Hoberman was the primary statistical reviewer for this application.

      "Each European trial provides statistically significant evidence that Casodex 150 mg delays or possibly prevents objective progression of early prostate cancer as measured by bone scans positive for metastases. However, the inclusion of disparate patient groups which received different background therapy (or lack thereof), complicates inference by inviting examination of treatment comparisons within subgroups of patients. Nevertheless, there is evidence in each European trial that patients who either underwent previous therapy (radiation and/or radical prostatectomy) or who underwent ‘watchful waiting‘ derived some benefit from Casodex therapy. This evidence takes the form of (1) consistent direction of effect for Casodex in clinically relevant subgroups in both trials and of (although not rigorous statistical evidence) and (2) nominally low p-values in both trials separately comparing Casodex to placebo in each of these clinically relevant subgroups. However, based on Casodex labeling in other countries and the recent data searching by the sponsor, the revised version of the sponsor’s indication now excludes patients who underwent RP with T1/T2 disease.

      However, there is no evidence that Casodex would be beneficial to patients who underwent previous therapy in the US (the only class of patients who were studied in the US). Moreover, the sponsor has not provided evidence that ‘watchful waiting’ patients would benefit from Casodex 150 mg in the US. In fact, there is reason to believe that patients who got ‘watchful waiting ‘ in Europe are not the same patients who would receive ‘watchful waiting’ in the US. Although the sponsor claims that the patient population undergoing previous therapy in Europe and the US were quite different, adjusting for clinically relevant factors at baseline does not seem to account for the difference in incidence, a sign that baseline measurements may not be calibrated between the two regions, associations with progression are weak, and/or that there are some unrecorded factors which depressed "objectively confirmed progression" in the US. It is also possible that differences in clinical practice rendered the US study such that the prostatectomy patients were fated to get no benefit from Casodex. Only monitoring the current US trial can answer that question. Given the lack of sufficient information in the US at this time, one course is to request further data from the Trial 23 so that a decision does not rest solely on an extrapolation of results from Europe."

    3. Medical Reviewer’s Overall Assessment of Efficacy (Statistical and Clinical Significance)

Interpretation of the overall body of data submitted by the Sponsor in support of the efficacy of Casodex in delaying progression of disease in men with non-metastatic prostate cancer and the relevance of these data to US patients is problematic for several reasons.

  1. Each of the trials enrolled patients who had undergone different therapies prior to treatment with Casodex or placebo. Each of the trials, however, was powered only to show an overall treatment effect and the protocol-defined primary efficacy analysis for each study did not address the issue of varying degrees of efficacy in the different subsets of patients based on prior therapy.
  2. Although the enrollment criteria for the 3 pivotal trials were similar for the most part, there were significant differences. More importantly, review of the baseline disease characteristics of the patients enrolled into each of the 3 trials suggested that the extent or severity of disease at the time of randomization differed significantly in each of the trials.
  3. The Sponsor’s protocol-defined primary efficacy assessments, endpoints, and analyses were never entirely accepted by DRUDP.
  1. Whereas DRUDP felt that objective disease progression should be limited to the events of bone scan confirmed evidence of metastases or death in the absence of a positive bone scan, the Sponsor preferred a broader definition of objective disease progression. The Sponsor’s protocol defined events of objective disease progression included not only events confirmed by bone scan but events (both local and distant) that were documented by magnetic resonance imaging, computerized tomography, sonography, or biopsy.
  2. The Sponsor preferred a time to event analysis in which all post-randomization "objective" events would be included in the analyses. Because of the potential for investigator assessment bias due to lack of adequate treatment blinding, DRUDP preferred an alternative binary analysis. DRUDP preferred an analysis based entirely on the proportion of patients with bone scan confirmed progress or death within 2 years of randomization. The 2-year time point was selected because all patients were to have a protocol mandated bone scan at Year 2 if objective disease progression had not been previously documented.
  1. The outcomes of the 2 non-US trials (both supportive of efficacy) differed from the outcome of the single US trial (no evidence of efficacy).

Items 1 to 3 would have been less problematic to interpretation of the overall body of efficacy data if the outcome of Trial 23 had not differed from that of Trials 24 and 25 (Item 4).

In spite of the study design issues listed above, the Sponsor has provided and statistically significant evidence in two of 3 clinical trials (Trials 24 and 25) that treatment with Casodex 150 mg per day, compared to treatment with placebo, delayed progression of prostate cancer as assessed by the appearance of new bone scan documented metastases or death in the absence of disease progression. The relevance of these findings to US patients with prostate cancer, who might receive Casodex as (1) adjuvant therapy following radical prostatectomy or radiotherapy or (2) monotherapy instead of management by watchful waiting or surveillance, is not clear.

      1. Demonstrated Efficacy of Casodex in Non-US Clinical Trials (Trials 24 and 25)
      2. Efficacy analyses of the data in each of Trials 24 and 25 provided statistically significant evidence that treatment with Casodex, compared to treatment with placebo, delayed progression of prostate cancer. Evidence of efficacy was provided using either (1) the Sponsor’s preferred endpoint of all "objective progressions" or death in the absence of objective progression and a time-to-event analysis or (2) the FDA-preferred endpoint of bone scan confirmed progression or death in the absence of objective progression and a binary analysis based on events within 2.0 years (or 2.5 years) of randomization.

        Although none of the trials was designed or powered to demonstrate statistically significant improvement within a subgroup, estimates of the odds ratio for each subgroup in Trials 24 and 25 with a total of at least 500 patients suggested a benefit of Casodex treatment based on the FDA-requested endpoints and analyses. For the watchful waiting subgroups in Trials 24 and 25, the estimates of the odds ratios (Casodex vs. placebo) and the associated 95% confidence intervals were 0.674 (95% CI: 0.471 to 0.964; Trial 24) and 0.498 (95% CI: 0.338 to 0.734; Trial 25). For adjuvant-treated patients in Trial 24, the estimates of the odds ratios (Casodex vs. placebo) and the associated 95% confidence intervals were 0.616 (95% CI: 0.379 to 1.003; radical prostatectomy subgroup) and 0.625 (95% CI: 0.361 to 1.081; radiotherapy subgroup). Too few adjuvant-treated patients were studied in Trial 25 to draw any conclusions about the efficacy of Casodex treatment.

      3. Lack of Casodex Efficacy in US Clinical Trial (Trial 23)

Data presented by the Sponsor from Trial 23 showed no evidence of efficacy for adjuvant treatment with Casodex in patients previously treated by radical prostatectomy or radiotherapy. Patients previously managed by watchful waiting were not enrolled into Trial 23. Because the incidence of objective disease progression (i.e., positive bone scans) was very low in placebo-treated patients in Trial 23 (<1.5%), there was no opportunity for Casodex to demonstrate efficacy in the study population. The Sponsor’s explanation for the low incidence of disease progression in this Trial, relative to that in Trial 24 and Trial 25, was that patients enrolled into Trial 23 had less advanced disease at entry and had derived greater benefit from their initial therapy. To support this position, the Sponsor presented data from 2 subset analyses across the 3 trials. These subsets consisted of:

  • patients who underwent prostatectomy with locally advanced disease (Stage T3/T4) and detectable postsurgical PSA levels (PSA > 0.20 ng/mL) and
  • patients who underwent radiotherapy with locally advanced disease (Stage T3/T4) and elevated preradiation PSA levels (PSA > 10 ng/mL).

The subset analysis for Casodex adjuvant treatment of patients initially treated by radical prostatectomy appeared to be somewhat supportive of the Sponsor’s position. Upon further review of the of the analysis for Trial 23, however, it was learned that the numeric difference in support of the efficacy of Casodex was a result primarily of (1) objective events other than bone metastases and (2) deaths unrelated to prostate cancer. The subset analysis for Casodex adjuvant treatment of patients initially treated by radiotherapy included very few patients from Trial 23 and was not supportive of the sponsor’s position. Based on the results from Trial 23, it is not possible to determine which patients who are initially treated by radical prostatectomy or radiotherapy in the US might derive benefit from adjuvant treatment with Casodex.

      1. Relevance of Watchful Waiting (Immediate Therapy) Subgroups in Trials 24 and 25 to Prostate Cancer Patients in the US Managed by Watchful Waiting
      2. Patients managed by watchful waiting in the US generally are elderly men (³  75 years of age), have low grade (i.e., low Gleason Score), and localized (stage T1/T2) tumors with serum PSA levels < 20 ng/mL. It is anticipated that most of these men will remain free of clinically significant prostate cancer symptoms during their lifetime and will die from causes other than prostate cancer. Based on demographic data, baseline disease characteristics, and outcomes in the watchful waiting patients, it appeared that many of the patients in Trials 24 and 25 would likely have received active therapy (radiotherapy or castration [medical or surgical]) in the US in accordance with present standards of care. It cannot be determined with a reasonable level of assurance from the non-US data if patients in the US who are generally managed by watchful waiting would have experienced a sufficient number of bone scan confirmed events in the time frame of the clinical trials to have derived clinically significant benefit from Casodex monotherapy.

        The originally proposed indications and the first revision of the proposed indications for Casodex 150 mg therapy indicated that the Sponsor also was seeking approval for treatment of patients with locally advanced, non-metastatic prostate cancer. This was a concern since the efficacy of Casodex monotherapy in such patients was not compared to that of castration (the generally accepted standard of care in the US) in the trials submitted in support of this application. Data previously submitted by the Sponsor from Trials 0306 and 0307 did not adequately support the Sponsor’s contention that Casodex treatment and castration (medical or surgical) were equally efficacious (based on survival) for the treatment of locally advanced non-metastatic prostate cancer. Survival in the Casodex-treated MO patients, compared to that in the patients treated by castration, differed across the 2 trials. In Trial 0306 (n = 140 M0 patients), the risk of death was calculated as 36% lower in the Casodex group while in Trial 0307 (n = 352 M0 patients), the risk of death was calculated as 25% higher in the Casodex group. This concern has been addressed in part by the Sponsor’s second revision to the proposed indication for Casodex immediate therapy. The second revision states that Casodex immediate treatment is indicated for the treatment of "localized non-metastatic prostate cancer in patients for whom therapy of curative intent is not indicated."

      3. Lack of Improved Survival in Casodex-Treated Patients

Treatment with Casodex had no demonstrable effect on either disease-specific or overall survival. This finding was anticipated because of the short period of patient follow up subsequent to entry into the trials (median of 3 years follow up) and immaturity of the data.

  1. Integrated Review of Safety
    1. Brief Statement of Conclusions
    2. The database from Trials 23, 24, and 25 supporting the safety of Casodex 150 mg per day was large. It included 4,022 Casodex-treated patients, representing 9,387 patient years of exposure. Overall, most patients (97.4% Casodex group, 88.2% placebo group) had at least one adverse event. The number of patients with at least 1 drug-related adverse event was approximately 3-fold higher in the Casodex group (90.5%) than the placebo group (31.4%). A greater number of patients in the Casodex group also were withdrawn from treatment because of an adverse event (27.7% compared with 9.2% of placebo-treated patients). The number of patients who had at least 1 serious adverse event was similar across the treatment groups (33.6% Casodex group, 32.5% placebo group). Much of the difference between the Casodex and placebo treatment groups in each of the categories of (1) any adverse event, (2) drug-related adverse events, and (3) adverse events leading to withdrawal was due to the pharmacological (anti-androgenic and compensatory estrogenic) actions of Casodex.

      Adverse events associated with Casodex treatment can be classified for the most part into one of 2 categories: (1) those of a non-life threatening nature that are due to the pharmacological actions of Casodex and which occur with a high incidence (e.g., breast pain and gynecomastia) and (2) those that occur in a few percent of patients and which may be severe and rarely fatal (primarily hepatotoxicity). The risks of treatment with Casodex 150 mg per day appear to be justified and acceptable for patients who would derive significant benefit from treatment with Casodex.

    3. Overview of Controlled Safety Studies (Trials 23, 24, and 25)
    4. The sponsor submitted data from 3 randomized, double blind, placebo controlled clinical trials that enrolled men with non-metastatic prostate cancer. Enrollment criteria (with some exceptions), efficacy assessments, and safety assessments were similar across the 3 trials. Trial 23 (n = 3,254 safety patients) was conducted in North America, primarily the United States. Trial 24 (n = 3,585 safety patients) was conducted in Europe (other than Scandinavia), Israel, South Africa, Mexico, and Australia. Trial 25 (n = 1,214 safety patients) was conducted in Scandinavia. Of these patients, 4,022 received Casodex 150 mg per day and 4,031 received placebo tablets (Table 1 and Figure 2).

       

      Figure 2 Overview of Safety Patient Population

       

    5. Protocol Defined Safety Assessments
    6. Safety assessments in the controlled clinical trials consisted primarily of (a) monitoring for and recording of adverse events and deaths and (b) clinical laboratory measurements for signs of liver toxicity or dysfunction. Table 4 lists the times at which the protocol-required safety assessments were to be performed.

      1. Adverse Events and Survival
      2. Collection of adverse event data

        An adverse event was defined by the Sponsor as "any detrimental change in the condition of the patient unrelated to prostate cancer, irrespective of whether the investigator considered that this reported change was related to trial therapy." Adverse events were identified by spontaneous reporting by the patient and in response to a non-leading question asked by the investigator. In addition, any clinical finding or laboratory data considered by the investigator to be clinically significant or warranting treatment also was to be reported as an adverse event. All adverse events were to be reported if (1) they had an onset date or worsened while a patients was on randomized treatment or (2) they occurred within 28 days after termination of treatment or within 28 days of the onset of initiating additional systemic therapy for prostate therapy. On occasion, serious adverse events that had an onset date outside of the 28-day follow-up period also were reported.

        During the first 96 weeks after treatment onset in each of the clinical trial, patients were to be monitored for adverse events and changes in liver function every 12 weeks while receiving study drug. In Trial 23, randomized treatment was limited to 96 weeks or until disease progression, whichever occurred first. In Trials 24 and 25, treatment with study drug was to continue for at least 5 years or until disease progression. Following completion of, or withdrawal from randomized treatment, patients were to be contacted every 3-12 months to collect survival data. Progression of prostate cancer and the symptoms thereof were not routinely recorded as adverse events.

        Analysis and presentation of adverse event data

        All patients receiving trial therapy were included in the assessment of safety. Investigator’s descriptions of adverse events were categorized using an in-house dictionary of terms, based on the Food and Drug Administration’s Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) system. Consolidated COSTART terms were created to pool together common COSTART preferred terms for descriptive analyses. Adverse events were summarized by consolidated COSTART-preferred term.

        Deaths were attributed to either prostate cancer alone or to other causes. In contrast to adverse event data that was limited to on-treatment events, deaths that occurred from any cause, either during or after withdrawal of trial therapy, were included in the submission.

      3. Clinical Laboratory Tests
      4. Protocol-required clinical laboratory tests were limited to the assessment of liver toxicity and liver function and consisted of (1) SGOT/AST, (2) SGPT/ALT, and (3) total bilirubin. Blood samples for these measurements were collected at screening and every 12 weeks after the start of treatment with study drug.

        For the most part, all samples from the clinical trials were analyzed at a central laboratory at either AstraZeneca Pharmaceuticals, Macclesfield (Trials 24 and 25, European sites only) or Quest Diagnostics, Van Nuys, CA (Trial 23) (formerly SmithKline Beecham Diagnostics). For Trial 24, samples from Australia, Israeli, Mexican, and South African centers were sent to a local laboratory in each country.

      5. Assessment of Sexual Function (Trial 25 Only)

In Trial 25, sexual function during the first 48 weeks of treatment was monitored by a patient-completed shortened version of the Golombok Rust Inventory of Sexual Satisfaction (GRISS) questionnaire. The questionnaire was completed at the baseline (pre-randomization) visit and at Weeks 12, 24, 36, and 48. The questionnaire consisted of the following 6 questions:

  1. Do you have sexual intercourse more than twice a week?
  2. Do you become easily sexually aroused?
  3. Do you fail to get an erection?
  4. Do you get an erection during foreplay with your partner?
  5. Are there weeks in which you don’t have sex at all?
  6. Do you lose your erection during intercourse?

From the scores obtained for the 6 questions, 2 measures (domains) of sexual function were calculated: infrequency (based on the sum of the scores of Questions 1 and 5) and impotence (based on the sum of the scores of Questions 2, 3, 4 and 6).

    1. Demographics and Other Baseline Characteristics (Safety Population)

Virtually all (>99%) of the patients randomized to treatment (the efficacy population) received one or more doses of study drug. Baseline demographic data and baseline disease characteristics for the efficacy population were reviewed earlier in Section 4.6.2. Baseline demographic data are summarized in Table 8 and baseline disease characteristics are summarized in Table 9 and Table 10.

Medical Officer’s Comment

 

      1. Exposure and Duration of Treatment in the Controlled Clinical Trials

For the controlled trials, exposure was defined as the time from starting therapy to the earlier of either withdrawal of study therapy or addition of other systemic therapy for treatment of prostate cancer. If a patient had not discontinued randomized study therapy or had not received additional systemic therapy as of the date of the safety data cutoff, the time of exposure was calculated up to the last time that the patient was known to have taken study therapy.

Table 35 presents combined patient-years of exposure in the 3 controlled trials as of the 4-Month Safety Update data cutoff date of 28 September 2001. The mean and median duration of exposure to study drug was slightly higher for placebo-treated patients than for Casodex-treated patients.

 

Table 35 Years of Exposure to Study Drug (Trials 23, 24, and 25 Combined)

 

Years of exposure

 

Casodex

Placebo

 

(N=4022)

(N=4031)

Total patient-years

9387

9778

Mean patient years

2.33

2.43

Median patient years

1.85

1.86

Range (year)

<0.01 to 5.98

<0.01 to 5.80

N = Number of patients who received randomized treatment

Source: Safety Update, Table T2.2.1.

Table 36 summarizes exposure to treatment by duration of treatment across the 3 controlled trials. Approximately 42% of patients who received Casodex (1680/4022) and placebo (1690/4031) remained on therapy for at least 2 years. At the time of data cutoff for the Safety Update, more than 50% of the patients in Trials 24 and 25 had received at least 3 years of Casodex therapy. Unlike Trials 24 and 25, the treatment period in Trial 23 did not extend beyond 2 years.

Table 36 Duration of Treatment (Trials 23, 24, and 25 Combined)

 

Number (%) of patients

Duration of exposure

Casodex

Placebo

 

(N=4022)

(N=4031)

<6 months

573

(14.2)

324

(8.0)

6 months to <12 months

384

(9.5)

309

(7.7)

12 months to <18 months

230

(5.7)

217

(5.4)

18 months to <24 months

1155

(28.7)

1491

(37.0)

24 months to <36 months

248

(6.2)

303

(7.5)

36 months to <48 months

706

(17.6)

708

(17.6)

48 months +

726

(18.1)

679

(16.8)

Source: Safety Update, Table T2.1.1.

Medical Officer's Comments

    1. Patient Disposition

At the time of data cutoff for the ISS (23 February 2001), 1,532 of 4,022 patients (38.1%) in the Casodex-treated patients and 1,282 of 4,031 patients (31.8%) in the placebo-treated patients had withdrawn prematurely from treatment with study drug. Patient disposition in each of the clinical trials is summarized in Table 37.

In Trial 23, a total of 618 (38.0%) patients in the Casodex group and 329 (20.2%) patients in the placebo group were withdrawn from the trial. Of patients withdrawing from Casodex treatment, 31.0% withdrew due to adverse events, most notably gynecomastia and breast pain. In the placebo group, 9.0% withdrew from treatment due to adverse events. In Trial 24, 841 (47.0%) patients treated with Casodex and 801 (44.6%) patients treated with placebo were withdrawn from the trial. The most common reason for withdrawal from Casodex treatment was an adverse event (27.0% of patients compared with 9.4% of placebo-treated patients). Disease progression, either subjectively or objectively confirmed, was the most common reason for withdrawal in placebo-treated patients (12.6% compared with 3.7% of Casodex-treated patients). In Trial 25, 225 (37.2%) patients were withdrawn from Casodex treatment and 328 (53.9%) were withdrawn from placebo treatment. The most common reason for withdrawal from Casodex treatment was an adverse event (17.2% of patients compared with 7.4% of placebo-treated patients). Disease progression, either subjectively or objectively confirmed, was the most common reason for withdrawal in placebo-treated patients (32.3% compared with 10.7% of Casodex-treated patients).

Table 37 Disposition of Patients in Trials 23, 24, and 25 as of 23 February 2001

 

Percentage of Patients

Disposition

Trial 23

 

Trial 24

 

Trial 25

 

Casodex
(N=1627)

Placebo
(N=1627)

 

Casodex
(N=1790)

Placebo
(N=1795)

 

Casodex
(N=605)

Placebo
(N=609)

Treatment completed or ongoing 1

62.0%

79.8%

 

53.0%

55.4%

 

62.8%

46.1%

Premature termination of treatment

38.0%

20.2%

 

47.0%

44.6%

 

37.2%

53.9%

Death

0.6%

0.8%

 

3.4%

2.6%

 

4.6%

3.3%

Disease progression 2

0.3%

0.7%

 

3.7%

12.6%

 

10.7%

32.3%

Adverse event

31.0%

9.0%

 

27.0%

9.4%

 

17.2%

7.4%

Non-compliance

0.4%

0.6%

 

0.8%

0.9%

 

0.2%

0.2%

Patient’s decision

5.0%

5.4%

 

9.0%

7.6%

 

3.6%

5.3%

Investigator decision

0.6%

3.6%

 

--

--

 

--

--

Lost to follow up

--

--

 

0.8%

1.2%

 

0.2%

0.7%

Other 3

0.1%

0.1%

 

2.1%

10.3%

 

0.7%

4.8%

1. Treatment period in Trial 23 ended prior to 23 February 2001. Treatment in Trials 24 and 25 is ongoing.

2. Includes objective and subjective progression but not an increase in PSA alone.

3. Includes increase in PSA, need for other systemic therapy, and investigator’s decision (Trials 24 and 25).

Source: Text Table 2, Safety Addendum Report for each of Trials 23, 24, and 25.

Medical Officer's Comments

  • In each of the clinical trials, the most common cause for premature termination of treatment with Casodex was an adverse event. Adverse events were responsible for premature termination in 31.0%, 27.0%, and 17.2% of Casodex-treated patients in Trials 23, 24, and 25, respectively. In each of the trials, the percentage of patients terminating prematurely due to an adverse event was higher in the Casodex-treated patients. In each of the trials, breast pain or gynecomastia was the most common adverse event leading to premature termination of treatment in these patients.
  • In placebo-treated patients, the most common cause for premature termination of treatment was either an adverse event (Trial 23) or disease progression (Trial 24 and Trial 25).
    1. Adverse Events
    2. In this review, adverse events for Trials 23, 24, and 25 are presented and discussed in the following manner. An overview of reported adverse events, based on the numbers of patients reporting adverse events summarized into broad categories, is first presented (Section 5.6.1). This is followed by a summary and discussion of (1) the most commonly reported adverse events (all degrees of severity and all relationships to study drugs, Section 5.6.2), (2) the most commonly reported adverse events possibly related to treatment with study drugs (Section 5.6.3), (3) adverse events that resulted in withdrawal of patients from the clinical trials (Section 5.6.4), and (4) serious adverse events reported during the treatment period (Section 5.6.5). In these trials, clinical signs or symptoms that were related to progression of prostate cancer were not considered as adverse events and were not in general reported or included in data summaries or listings.

      Deaths from all causes other than prostate cancer are discussed in Section 5.7. Adverse events of particular interest (e.g., pharmacological adverse events such as gynecomastia) or adverse events of particular concern based on the reported safety data (e.g., liver toxicity and blood dyscrasias) are reviewed separately in Section 5.9.

      1. Overview of Adverse Events

Table 38 provides an overview of the proportion of patients who experienced adverse events across the 3 clinical trials during treatment with study drug. Overall, most patients (97.4% Casodex group, 88.2% placebo group) had at least one adverse event. The number of patients with at least 1 drug-related adverse event was approximately 3-fold higher in the Casodex group (90.5%) than the placebo group (31.4%). A greater number of patients in the Casodex group also were withdrawn from treatment because of an adverse event (27.7% compared with 9.2% of placebo-treated patients). The number of patients who had at least 1 serious adverse event was similar across the treatment groups (33.6% Casodex group, 32.5% placebo group). The percentage of patients with an adverse event leading to death (a non-prostate cancer related death that occurred within the treatment period) was slightly higher in the Casodex group (4.2% compared to 3.6% in placebo-treated patients).

Table 38 Overview of Adverse Events during Treatment (Trials 23, 24, and 25)

 

Number (%) of patients

Category 1

Casodex

Placebo

 

(N=4022)2

(N=4031)

Patients with at least 1 adverse event

3916

(97.4)

3555

(88.2)

Drug-related adverse events

3641

(90.5)

1267

(31.4)

Adverse events leading to withdrawal

1116

(27.7)

369

(9.2)

Serious adverse events

1350

(33.6)

1310

(32.5)

Adverse events leading to death 3

168

(4.2)

145

(3.6)

1. Patients may appear in more than 1 category.

2. N = number of patients who received randomized treatment.

3. Does not include deaths attributed to prostate cancer.

Source: Safety Update. Data derived from Table T3.1.1.

Medical Officer’s Comments

 

Number (%) of patients

Category

Casodex (N=4022)

Placebo (N=4031)

Any adverse event

       

All Causes

3916

(97.4)

3555

(88.2)

Gynecomastia and breast pain excluded

3583

(89.1)

3517

(87.2)

Drug-related adverse events

       

All Causes

3641

(90.5)

1267

(31.4)

Gynecomastia and breast pain excluded

1700

(42.3)

962

(23.9)

Adverse events leading to withdrawal

       

All Causes

1116

(27.7)

369

(9.2)

Gynecomastia and breast pain excluded

579

(14.4)

350

(8.7)

Source: Tables T3.1.1 and T3.1.8 from Safety Update.

 

Table 39 provides an overview of the proportion of patients who experienced adverse events within each of Trials 23, 24, and 25 during treatment with study drug.

Table 39 Overview of Adverse Events by Clinical Trial during Randomized Treatment

 

Percentage of Patients with Event

Category 1

Trial 23

 

Trial 24

 

Trial 25

   

Casodex

Placebo

 

Casodex

Placebo

 

Casodex

Placebo

   

N=1627

N=1627

 

N=1790

N=1795

 

N=605

N=609

Patients with ³ 1 adverse event

98.1

90.4

 

95.9

85.7

 

98.7

87.4

Drug related adverse event

92.8

31.8

 

87.5

32.0

 

92.7

26.3

AE leading to withdrawal

31.0

9.0

 

27.3

9.4

 

17.2

7.1

Serious adverse event

17.8

18.6

 

38.2

37.3

 

50.4

44.3

AE leading to death 2

1.2

1.5

 

4.7

4.3

 

6.9

4.4

1. Patients may appear in more than 1 category.

2. Does not include deaths attributed to prostate cancer.

N = number of patients who received randomized treatment.

Source: ISS, Table T3.1.2.

Medical Officer’s Comments

  • In the Casodex-treatment groups, adverse events leading to withdrawal occurred most frequently in Trial 23 (31.0% of patients) and least frequently in Trial 25 (17.2% of patients).
  • The proportion of patients with serious adverse events was approximately 2-fold and 2.5-fold greater in Trials 24 and 25, respectively, compared to Trial 23.
  • The proportion of patients with adverse events leading to death was highest in Trial 25 and lowest in Trial 23.
      1. Adverse Events (All Intensities and All Relationships to Study Drug)

The majority of patients enrolled in the clinical trials had at least 1 adverse event. In the Casodex treatment group, 3,916 of 4,022 patients (97.4%) reported one or more adverse events compared with 3,555 of 4,031 patients (88.2%) in the placebo treatment group. Adverse events that occurred in 5% or more of the patients in either of the treatment groups are listed in Table 40 by decreasing incidence in the Casodex-treated patients. Adverse events more common in the Casodex-treatment group than in the placebo group included breast pain, gynecomastia, alopecia, weight gain, vasodilatation, impotence, and asthenia. The majority of these latter adverse events were considered by the investigator to be related to study drug.

Medical Officer’s Comments

Table 40 Adverse Events with an Incidence ³ 5% (Combined Data from
Trials 23, 24, and 25)

 

Adverse Event

Number of patients reporting adverse event

 

Relative Incidence

Casodex
placebo

Casodex
(N = 4022)

 

Placebo
(N = 4031)

 
 

n 1

(%)

 

n 1

(%)

 

Breast pain

2937

(73.0)

296

(7.3)

9.94

Gynecomastia

2700

(67.1)

325

(8.1)

8.33

Asthenia

427

(10.6)

303

(7.5)

1.41

Pharyngitis

415

(10.3)

441

(10.9)

0.94

Rash

390

(9.7)

324

(8.0)

1.21

Back pain

367

(9.1)

442

(11.0)

0.83

Vasodilatation

364

(9.1)

211

(5.2)

1.73

Impotence

362

(9.0)

250

(6.2)

1.45

Constipation

344

(8.6)

283

(7.0)

1.22

Arthralgia

314

(7.8)

378

(9.4)

0.83

Urinary tract infection

299

(7.4)

259

(6.4)

1.16

Flu syndrome

295

(7.3)

296

(7.3)

1.00

Abdominal pain

275

(6.8)

278

(6.9)

0.99

Hypertension

271

(6.7)

303

(7.5)

0.90

Diarrhea

263

(6.5)

268

(6.7)

0.98

Urinary incontinence

261

(6.5)

237

(5.9)

1.10

Pain

258

(6.4)

286

(7.1)

0.90

Pelvic pain

258

(6.4)

261

(6.5)

0.99

Alopecia

239

(5.9)

31

(0.8)

7.73

Urinary tract disorder

234

(5.8)

277

(6.9)

0.85

Weight gain

231

(5.7)

115

(2.9)

2.01

Edema

226

(5.6)

206

(5.1)

1.10

Hernia

195

(4.9)

242

(6.0)

0.81

Headache

191

(4.8)

204

(5.1)

0.94

Hematuria

183

(4.6)

235

(5.8)

0.78

Accidental injury

171

(4.3)

225

(5.6)

0.76

1 Number of patients reporting the respective adverse event.
Source: Modified from Text Table 12, ISS, pg. 32.

      1. Treatment-Related Adverse Events

Treatment-related adverse events were reported for 3,641 of 4,022 patients (90.5%) in the Casodex treatment group and 1,267 of 4,031 patients (31.4%) in the placebo treatment group. Treatment-related adverse events that occurred in ³  0.5% of the patients in either of the treatment groups are listed in Table 41 by decreasing incidence in the Casodex-treated patients. Of the treatment-related adverse events listed in Table 41, 28 of 29 occurred more frequently in Casodex-treated patients. The most commonly reported treatment-related adverse events in the Casodex treatment group were breast pain (72.3% of patients), gynecomastia (66.7%), vasodilatation (8.5%), impotence (5.8%), asthenia (5.1%), alopecia (4.7%), and weight gain (4.0%).

Medical Officer’s Comments

 

Table 41. Treatment-Related Adverse Events Occurring in ³  0.5% of Patients (Combined Data from Trials 23, 24, and 25)

Adverse Event

 

Number of patients reporting adverse event

 

Relative Incidence

Casodex
placebo

Casodex
(N = 4022)

 

Placebo
(N = 4031)

 

n 1

Percentage

 

n 1

Percentage

 

Breast pain

2906

72.3%

 

282

7.0%

10.33

Gynecomastia

2681

66.7%

 

320

7.9%

8.40

Vasodilatation

342

8.5%

 

185

4.6%

1.85

Impotence

233

5.8%

 

112

2.8%

2.09

Asthenia

206

5.1%

 

105

2.6%

1.97

Alopecia

190

4.7%

 

19

0.5%

10.02

Weight gain

161

4.0%

 

61

1.5%

2.65

Rash

141

3.5%

 

66

1.6%

2.14

Libido decreased

122

3.0%

 

35

0.9%

3.49

Constipation

103

2.6%

 

49

1.2%

2.11

Diarrhea

103

2.6%

 

82

2.0%

1.26

Liver function tests abnormal

99

2.5%

 

39

1.0%

2.54

Nausea

88

2.2%

 

42

1.0%

2.10

Somnolence

78

1.9%

 

39

1.0%

2.00

Pruritus

76

1.9%

 

30

0.7%

2.54

Hirsutism

46

1.1%

 

6

0.1%

7.68

Abdominal pain

45

1.1%

 

24

0.6%

1.88

Dizziness

39

1.0%

 

18

0.4%

2.17

Headache

37

0.9%

 

26

0.6%

1.43

Edema

37

0.9%

 

13

0.3%

2.85

Sweating

36

0.9%

 

28

0.7%

1.29

Dyspepsia

31

0.8%

 

33

0.8%

0.94

Jaundice

31

0.8%

 

16

0.4%

1.94

Depression

29

0.7%

 

8

0.2%

3.63

Pelvic pain

27

0.7%

 

8

0.2%

3.38

Chest pain

24

0.6%

 

5

0.1%

4.81

Sleep disorder

24

0.6%

 

8

0.2%

3.01

Emotional lability

21

0.5%

 

2

<0.1%

10.52

Anxiety

20

0.5%

 

5

0.1%

4.01

1 Number of patients reporting the event.
Source: Modified from ISS, Text Table 16, pg. 40.

 

      1. Adverse Events Resulting in Patient Withdrawal

Adverse events resulting in patient withdrawal were reported for 1,116 of 4,022 patients (27.7%) in the Casodex treatment group and 369 of 4,031 patients (9.2%) in the placebo treatment group. Adverse events resulting in patient withdrawal that occurred in ³  0.3% of patients in either of the treatment groups are listed in Table 42 by decreasing incidence in the Casodex-treated patients. The most frequently reported adverse events leading to withdrawal in the Casodex-treated patients were breast pain (12.5% of patients), gynecomastia (10.6%), asthenia (1.4%), abnormal liver function tests (1.2%), vasodilatation (0.9%), and impotence (0.7%).

 

Table 42 Adverse Events with an Incidence ³  0.3% Leading to Withdrawal (Combined Data from Trials 23, 24, and 25)

 

 

Adverse Event

Number of patients reporting adverse event

 

Relative Incidence

Casodex
placebo

Casodex
(N = 4022)

 

Placebo
(N = 4031)

 
   

n 1

Percentage

n 1

Percentage

 

Breast pain

504

12.5%

15

0.4%

33.68

Gynecomastia

425

10.6%

16

0.4%

26.62

Asthenia

56

1.4%

18

0.5%

3.12

Liver function tests abnormal

47

1.2%

18

0.5%

2.62

Vasodilatation

36

0.9%

14

0.4%

2.58

Impotence

29

0.7%

6

0.2%

4.84

Myocardial infarction

27

0.7%

33

0.8%

0.82

Nausea

26

0.7%

14

0.4%

1.86

Rash

26

0.7%

14

0.4%

1.86

Libido decreased

25

0.6%

9

0.2%

2.78

Abdominal pain

23

0.6%

14

0.4%

1.65

Gastrointestinal carcinoma

22

0.6%

18

0.5%

1.22

Weight gain

22

0.6%

6

0.2%

3.67

Diarrhea

21

0.5%

20

0.5%

1.05

Somnolence

20

0.5%

5

0.1%

4.01

Heart failure

17

0.4%

3

0.1%

5.68

Jaundice

17

0.4%

6

0.2%

2.84

Carcinoma of lung

17

0.4%

20

0.5%

0.85

Depression

15

0.4%

6

0.2%

2.51

Cerebrovascular accident

14

0.4%

30

0.7%

0.47

Constipation

14

0.4%

6

0.2%

2.34

Dizziness

14

0.4%

10

0.3%

1.40

Heart arrest

13

0.3%

6

0.2%

2.17

Pruritus

13

0.3%

3

0.1%

4.34

Headache

11

0.3%

4

0.1%

2.76

Chest pain

10

0.3%

4

0.1%

2.51

Angina pectoris

10

0.3%

8

0.2%

1.25

Anxiety

10

0.3%

3

0.1%

3.34

Dyspnea

10

0.3%

6

0.2%

1.67

Pneumonia

5

0.1%

11

0.3%

0.46

Source: Safety Update, Text Table 20, pg. 47.

Medical Officer's Comments

 

      1. Serious Adverse Events during the Treatment Period

Adverse events classified as serious were reported for 1,350 of 4,022 patients (33.6%) in the Casodex treatment group and 1,310 of 4,031 patients (32.5%) in the placebo treatment group. Serious adverse events that occurred in ³  0.5% of the patients during the treatment period in either of the treatment groups are listed in Table 43, arranged by decreasing incidence in the Casodex-treated patients.

Medical Officer’s Comments

Table 43 Serious Adverse Events with Incidence ³  0.5% during Treatment Period

 

 

Adverse Event

Number of patients reporting adverse event

 

Relative Incidence

Casodex
placebo

Casodex
(N = 4022)

 

Placebo
(N = 4031
)

   

n 1

Percentage

n 1

Percentage

Gynecomastia

109

2.7%

1

<0.1%

109.24

Urinary tract disorder

103

2.6%

109

2.7%

0.95

Hernia

87

2.2%

108

2.7%

0.81

Myocardial infarct

72

1.8%

97

2.4%

0.74

Angina pectoris

71

1.8%

66

1.6%

1.08

Heart failure

61

1.5%

36

0.9%

1.70

Pneumonia

60

1.5%

61

1.5%

0.99

Chest pain

56

1.4%

29

0.7%

1.94

Myocardial ischemia

54

1.3%

64

1.6%

0.85

Infection

52

1.3%

30

0.7%

1.74

Gastrointestinal carcinoma

45

1.1%

37

0.9%

1.22

Accidental injury

41

1.0%

65

1.6%

0.63

Urinary retention

38

0.9%

68

1.7%

0.56

Cerebrovascular accident

37

0.9%

71

1.8%

0.52

Dyspnea

33

0.8%

39

1.0%

0.85

Breast pain

30

0.7%

1

<0.1%

30.07

Abdominal pain

29

0.7%

19

0.5%

1.53

Urinary tract infection

29

0.7%

21

0.5%

1.38

Cardiovascular disorder

28

0.7%

37

0.9%

0.76

Skin carcinoma

28

0.7%

24

0.6%

1.17

Arthritis

26

0.6%

19

0.5%

1.37

Arthrosis

26

0.6%

25

0.6%

1.04

Atrial arrhythmia

25

0.6%

35

0.9%

0.72

Cholelithiasis

25

0.6%

11

0.3%

2.28

Carcinoma of lung

23

0.6%

27

0.7%

0.85

Hematuria

23

0.6%

33

0.8%

0.70

Anemia

22

0.5%

16

0.4%

1.38

Cholecystitis

20

0.5%

15

0.4%

1.34

Kidney calculus

20

0.5%

31

0.8%

0.65

Urinary incontinence

20

0.5%

11

0.3%

1.82

Pain

19

0.5%

15

0.4%

1.27

Heart arrest

19

0.5%

7

0.2%

2.72

Cataract specified

19

0.5%

32

0.8%

0.60

Back pain

18

0.4%

21

0.5%

0.86

Syncope

18

0.4%

14

0.3%

1.29

Hypertension

15

0.4%

24

0.6%

0.63

Sepsis

13

0.3%

19

0.5%

0.69

Rectal hemorrhage

13

0.3%

19

0.5%

0.69

Pathological fracture

13

0.3%

21

0.5%

0.62

Vascular disorder

11

0.3%

27

0.7%

0.41

Urination impaired

7

0.2%

19

0.5%

0.37

Source: Safety Update, Text Table 22, pg. 51, and Table T5.2.3.

 

    1. Deaths

The number (and percentage) of patients in each treatment group who died in Trials 23, 24, and 25 (data combined across trials) are listed in Table 44. As of the data cutoff date for the Safety Update (28 September 2001), 445 of 4,022 patients (11.1%) who received Casodex and 432 of 4,031 patients (10.7%) who received placebo had died. The majority of deaths in each of the treatment groups was due to reasons other than prostate cancer.

Table 44 Number and Percentage of Deaths in Trials 23, 24, and 25 (Combined Data)

Category

Number (%) of patients

 

Casodex

Placebo

 

(N=4022)

(N=4031)

Total deaths (number [%]) 1

445

(11.1)

432

(10.7)

Deaths due to prostate cancer alone

119

(3.0)

128

(3.2)

Deaths not due to prostate cancer

326

(8.1)

304

(7.5)

Deaths due to adverse events 2

177

(4.4)

150

(3.7)

Deaths due to drug-related adverse event

7

(0.2)

1

(<0.1)

Deaths outside of treatment period

149

(3.7)

154

(3.8)

N = number of patients who received randomized treatment.

1 Two patients who received no therapy also died.

2 Includes deaths during the treatment period and deaths due to an adverse event that started during the treatment period.

Source: Data derived from Tables T4.1 and T4.5 of Safety Update.

Medical Officer’s Comment

The number (and percentage) of patients in each treatment group who died in each of Trials 23, 24, and 25 are listed in Table 45. Within each of the trials, the number of deaths in the Casodex and placebo treatment groups were similar. However, the proportions of patients who died from prostate cancer or other causes varied across the 3 trials. Total deaths across the trials ranged from approximately 6% (Trial 23) to 18% (Trial 25).

Table 45 Number and percentages of Deaths in Each of Trials 23, 24, and 25

Cause of
Death

Study 23

 

Study 24

 

Study 25

Casodex
N= 1647

Placebo N=1645

 

Casodex
N= 1798

Placebo N=1805

 

Casodex
N= 607

Placebo
N= 611

 

n

(%)

n

(%)

 

n

(%)

n

(%)

 

n

(%)

n

(%)

Prostate cancer

14

(0.9)

6

(0.4)

 

56

(3.1)

66

(3.7)

 

49

(8.1)

56

(9.2)

Other

91

(5.6)

93

(5.7)

 

168

(9.4)

161

(9.0)

 

67

(11.1)

50

(8.2)

Total

105

(6.5)

99

(6.1)

 

224

(12.5)

227

(12.7)

 

116

(19.2)

106

(17.4)

Sources: Safety Update (SAS files) and submission of 17 May 2002.

Medical Officer’s Comments

There were 8 instances in which a death was considered by the investigator to be possibly related to treatment with study drug (Table 46). Seven (7) of these 8 deaths occurred in patients treated with Casodex.

Table 46 Primary Causes of Death due to Drug-Related Adverse Events

Body system

Number (%) of patients who died

Consolidated COSTART term

Casodex

Placebo

 

(N=4022)

(N=4031)

Cardiovascular system

       

Cerebrovascular accident

1

(<0.1)

0

 

Myocardial infarction

1

(<0.1)

0

 

Myocardial ischemia

1

(<0.1)

0

 

Pulmonary embolus

1

(<0.1)

0

 

Digestive system

       

Pancreas disorder

1

(<0.1)

0

 

Hemic/lymphatic system

       

Blood dyscrasia

2

(0.1)

0

 

Urogenital system

       

Kidney failure

0

 

1

(<0.1)

Total

7

(0.2)

1

(<0.1)

Source: Safety Update, Text Table 18, pg. 43.

Medical Officer’s Comments

The number (and percentage) of patients whose primary cause of death was classified within each of the COSTART body systems are listed in Table 47. Deaths are further classified in terms of time of occurrence, i.e., during treatment with study drug or posttreatment. Patients whose primary cause of death was prostate cancer are not included in the Table. The body systems associated with the highest number of total deaths (those occurring either during or following treatment) in the Casodex treated patients were cardiovascular (n=143), respiratory (n=62), digestive (n=42) and body as a whole (n=42). These 4 body systems accounted for 289 of 326 (88.7%) of the non-prostate cancer deaths. Total deaths in the placebo treated patients followed a similar pattern with the cardiovascular (n=122), respiratory (n=72), digestive (n=36) and body as a whole (n=44) body systems accounting for 274 of 304 (90.1%) of deaths.

Table 47 Number (%) of Patients with Primary Cause of Death Classified by COSTART Body System Term and Treatment Period (All Trials)

     

Number (%) of patients with cause of death 1

 

Relative Incidence

Casodex
placebo

Body
System

Treatment
Period

 

Casodex
(N = 4022)

 

Placebo
(N = 4031
)

     

n

Percentage

n

Percentage

Body as a whole

During Treatment

18

0.45

11

0.27

1.64

 

Post Treatment

24

0.60

33

0.82

0.73

 

Total

42

1.04

44

1.09

0.96

Cardiovascular

During Treatment

77

1.91

66

1.64

1.17

 

Post Treatment

66

1.64

56

1.39

1.18

 

Total

143

3.56

122

3.03

1.17

Digestive

During Treatment

24

0.60

17

0.42

1.41

 

Post Treatment

18

0.45

19

0.47

0.95

 

Total

42

1.04

36

0.89

1.17

Endocrine

Post Treatment

1

0.02

1

0.02

1.00

 

Total

1

0.02

1

0.02

1.00

Hematopoietic/
lymphatic

During Treatment

10

0.25

4

0.10

2.51

Post Treatment

3

0.07

2

0.05

1.50

 

Total

13

0.32

6

0.15

2.17

Metabolic and nutritional

During Treatment

2

0.05

2

0.05

1.00

Post Treatment

1

0.02

2

0.05

0.50

 

Total

3

0.07

4

0.10

0.75

Musculoskeletal

During Treatment

0

0.00

2

0.05

0.00

 

Post Treatment

1

0.02

1

0.02

1.00

 

Total

1

0.02

3

0.07

0.33

Nervous

During Treatment

4

0.10

4

0.10

1.00

 

Post Treatment

3

0.07

3

0.07

1.00

 

Total

7

0.17

7

0.17

1.00

Respiratory

During Treatment

29

0.72

36

0.89

0.81

 

Post Treatment

33

0.82

36

0.89

0.92

 

Total

62

1.54

72

1.79

0.86

Skin/appendages

During Treatment

1

0.02

2

0.05

0.50

 

Post Treatment

1

0.02

0

0.00

NC

 

Total

2

0.05

2

0.05

1.00

Urogenital

During Treatment

3

0.07

2

0.05

1.50

 

Post Treatment

4

0.10

5

0.12

0.80

 

Total

7

0.17

7

0.17

1.00

1 Patients whose primary cause of death was prostate cancer are NOT included in the listing.

Source: Safety Update, Table T4.4.

Medical Officer’s Comment

  • A greater percentage of patients treated with Casodex, compared to placebo-treated patients, died of primary causes that linked to the hematopoietic/lymphatic (0.32% vs. 0.15%; relative incidence 2.17), cardiovascular (3.56% vs. 3.03%; relative incidence 1.17), and digestive (1.04% vs. 0.89%; relative incidence 1.17) body systems. For the most part, these imbalances were a result of increased numbers of deaths that occurred during the period of treatment with study drug and not during the post treatment period.

The primary causes of death (other than that of prostate cancer) and the number (%) of patients who died of these causes during the treatment period are listed by COSTART body system and COSTART preferred term in Table 48. Cardiovascular events were the major cause of death with 77 cases reported in Casodex-treated patients and 66 cases reported in placebo-treated patients (relative incidence, Casodex/placebo: 1.17). Of the cardiac-related deaths in Casodex-treated patients, deaths due to myocardial infarction (n=24), heart failure (n=15), and heart arrest (n=12) were the most commonly reported events. In the placebo-treated patients, deaths due to myocardial infarction, heart failure, and heart arrest were reported for 31, 1, and 5 patients, respectively.

Deaths that linked to the respiratory system were the second most frequent in both treatment groups, occurring in 29 Casodex–treated and 36 placebo-treated patients.

Deaths that linked to the digestive system were the third most frequent, affecting 24 Casodex-treated patients and 17 placebo-treated patients (relative incidence, Casodex/placebo: 1.41). Among this group, gastrointestinal carcinoma was the most common single cause of death, affecting 18 Casodex-treated patients and 10 placebo-treated patients.

Medical Officer’s Comments

  • As would be expected in a population of elderly men, cardiovascular events were the major cause of death unrelated to prostate cancer in both treatment groups. There was an excess of cardiovascular deaths due to myocardial infarction, heart failure, and heart arrest in the Casodex-treated patients (n=51) compared to the number of similarly classified deaths in the placebo-treated patients (n=37). This imbalance was partially offset by other causes of cardiovascular death in the placebo-treated patients and is discussed further in Section 5.9.4.1.
  • The imbalance in deaths related to the digestive system (greater in Casodex-treated patients) was due largely to the increased number of patients who died from a gastrointestinal malignancy in the Casodex-treated patients (n=18) compared to the number of similar deaths in the placebo-treated patients (n=10).
  • Deaths that linked to the hematopoietic/lymphatic body were 2.5-fold more common in Casodex-treated patients. These are discussed in Section 5.9.5.2.

 

Table 48 Primary Causes of Death (Other than Prostate Cancer) during the
Treatment Period (Trials 23, 24, and 25 Combined)

Body System

Number (%) of patients with cause of death

 

Relative Incidence

Casodex
placebo

Cause of Death
(COSTART term)

 

Casodex
(N = 4022)

 

Placebo
(N = 4031
)

 

n

Percentage

n

Percentage

Body as a whole

18

0.45

11

0.27

1.64

Accidental injury

2

0.05

2

0.05

1.00

Ascites

1

0.02

0

0.00

NC 2

Carcinoma

2

0.05

1

0.02

2.00

Death 1

7

0.17

0

0.00

NC

Gangrene

1

0.02

0

0.00

NC

Neoplasm

1

0.02

3

0.07

0.33

Peritonitis

0

0.00

1

0.02

0.00

Sarcoma

2

0.05

1

0.02

2.00

Sepsis

1

0.02

1

0.02

1.00

Suicide

1

0.02

2

0.05

0.50

Cardiovascular

77

1.91

66

1.64

1.17

Arrhythmia

0

0.00

2

0.05

0.00

Arteriosclerosis

2

0.05

0

0.00

NC

Cardiomegaly

1

0.02

0

0.00

NC

Cardiomyopathy

1

0.02

2

0.05

0.50

Cardiovascular disorder

2

0.05

2

0.05

1.00

Cerebrovascular accident

11

0.27

15

0.37

0.73

Embolus

0

0.00

1

0.02

0.00

Heart arrest

12

0.30

5

0.12

2.41

Heart failure

15

0.37

1

0.02

15.03

Intracranial hemorrhage

1

0.02

0

0.00

NC

Myocardial infarction

24

0.60

31

0.77

0.78

Myocardial ischemia

4

0.10

5

0.12

0.80

Pulmonary embolus

4

0.10

2

0.05

2.00

Digestive

24

0.60

17

0.42

1.41

Cirrhosis of liver

0

0.00

1

0.02

0.00

Gastrointestinal carcinoma

18

0.45

10

0.25

1.80

Gastrointestinal hemorrhage

1

0.02

2

0.05

0.50

GI neoplasia

2

0.05

1

0.02

2.00

Hepatoma

1

0.02

2

0.05

0.50

Intestinal obstruction

1

0.02

0

0.00

NC

Pancreas disorder

1

0.02

0

0.00

NC

Rectal hemorrhage

0

0.00

1

0.02

0.00

1 Not otherwise specified. (Continued)
2 Not calculated.

Source: Safety Update. Text Table 17, pg. 39 and Table T4.3.

 

 

Table 47 Primary Cause of Death (other than Prostate Cancer) during the
Treatment Period (Trials 23, 24, and 25 Combined)

Body System

Number (%) of patients with cause of death

 

Relative Incidence

Casodex
placebo

Cause of Death
(COSTART term)

 

Casodex
(N = 4022)

 

Placebo
(N = 4031
)

n

Percentage

n

Percentage

Hematopoietic/lymphatic

10

0.25

4

0.10

2.50

Acute leukemia

2

0.05

1

0.02

2.00

Blood dyscrasia

2

0.05

0

0.00

NC 2

Chronic myelocytic leukemia

1

0.02

1

0.02

1.00

Leukemia

1

0.02

0

0.00

NC

Lymphoma like reaction

4

0.10

1

0.02

4.01

Myeloma

0

0.00

1

0.02

0.00

Metabolic and nutritional

2

0.05

2

0.05

1.00

Hypoxia

1

0.02

0

0.00

NC

Uremia

0

0.00

1

0.02

0.00

Weight loss

1

0.02

1

0.02

1.00

Musculoskeletal

 

0.00

 

0.00

NC

Muscle atrophy

0

0.00

2

0.05

0.00

Nervous

4

0.10

4

0.10

1.00

CNS neoplasia

1

0.02

3

0.07

0.33

Dementia

2

0.05

0

0.00

NC

Extrapyramidal syndrome

0

0.00

1

0.02

0.00

Meningitis

1

0.02

0

0.00

NC

Respiratory

29

0.72

36

0.89

0.81

Apnea

3

0.07

4

0.10

0.75

Bronchitis

1

0.02

2

0.05

0.50

Carcinoma of larynx

0

0.00

1

0.02

0.00

Carcinoma of lung

16

0.40

14

0.35

1.15

Emphysema

1

0.02

2

0.05

0.50

Lung disorder

2

0.05

3

0.07

0.67

Pneumonia

4

0.10

10

0.25

0.40

Respiratory disorder

2

0.05

0

0.00

NC

Skin/appendages

1

0.02

2

0.05

0.50

Skin carcinoma

0

0.00

2

0.05

0.00

Skin melanoma

1

0.02

0

0.00

NC

Urogenital

3

0.07

2

0.05

1.50

Bladder carcinoma

2

0.05

1

0.02

2.00

Kidney failure

1

0.02

1

0.02

1.00

2 Not calculated.

Source: Safety Update. Text Table 17, pg. 39 and Table T4.3.

 

 

    1. Laboratory Assessments

Protocol required laboratory assessments for safety were limited to measurements of hepatic toxicity (ALT/SGPT, AST/SGOT) or hepatic function (total bilirubin). Laboratory data for these assessments (referred to as LFTs in this review) are presented as follows:

  • Mean values and mean changes from baseline values for each laboratory test at selected protocol-designated assessment times.
  • Percentages of patients with laboratory values that shifted from within the normal range at baseline to above the normal range at selected protocol-designated assessment times.
  • Clinically relevant laboratory values (values outside of the normal range that were considered to be of particular concern, based on the Sponsor’s predefined criteria) that were observed during treatment.
      1. Mean LFT Values and Mean Changes from Baseline Values

Data for mean serum ALT values and mean of the percent changes from baseline at 12-week intervals during the first year of treatment and every 24 weeks thereafter through Week 144 in the Casodex-and placebo-treatment groups are presented in Table 49. At baseline, the treatment groups in each of the trials were well matched for mean and median serum hepatic biochemistry values. During the first 6 months of treatment, mean ALT values and the means of the changes from baseline were numerically higher in the Casodex-treated patients. Thereafter, mean serum ALT values and mean changes from baseline in the Casodex-treated patients were comparable to or lower than those observed in the placebo-treated patients.

Table 49 Mean Serum ALT Values (U/L) and Mean of Percent Changes from Baseline
during Treatment (Data Combined from Trials 23, 24, and 25)

 

Casodex
(N=4022) 1

 

Placebo
(N=4031)

Study Week


n 2

Mean
ALT (U/L)

Mean of % change from baseline

 

Mean
ALT (U/L)

Mean of % change
from baseline

Baseline

3942

21.5

   

21.2

 

12

3817

22.8

25.9%

 

20.5

6.7%

24

3589

22.4

22.8%

 

20.7

9.0%

36

3422

20.8

14.7%

 

20.8

9.6%

48

3256

19.1

5.6%

 

20.9

10.5%

72

3001

18.5

1.2%

 

20.9

12.5%

96

2905

18.0

-2.5%

 

21.8

16.9%

120

1811 3

19.0

-1.5%

 

22.1

16.1%

144

1580

18.6

-2.8%

 

23.0

15.6%

1 Number of patients who received at least one dose of study drug.

2 Number of patients upon which mean absolute values in Casodex treatment group are based. The number of observations at each assessment time is lower for the category of "mean of % change from baseline."

3 Decreased number of patients after Week 96 largely a result of maximum 2-year treatment period in Trial 23.

Source: Table T7.2, ISS and Table 2, Appendix B of 3 May 2002 Submission.

Medical Officer's Comments

  • AST values (i.e., mean serum values and mean changes from baseline) in the Casodex- and placebo-treated patients showed a pattern of relative changes similar to that for ALT values.
  • There were no notable differences in mean serum bilirubin values or mean changes from baseline in the Casodex-treated patients compared to the placebo-treated patients.
  • In summary, although there were instances of large, clinically significant changes in LFT values in individual patients in both treatment groups, changes in mean and median serum values for ALT, AST, and total bilirubin were relatively small and did not appear to be of clinical significance.
      1. Shifts in LFT Laboratory Values to Above the Normal Range

The number and proportion of Casodex- and placebo-treated patients with a normal ALT value at baseline and an ALT value above the normal range at representative protocol-designated clinical visits are listed in Table 50 for each of the 3 clinical trials. Similar data for changes in bilirubin values in each of the trials are listed in Table 51.

 

Table 50 ALT Shifts from Within the Normal Range at Baseline to Above the Normal Range (High) during Treatment in Each of Trials 23, 24, and 25

   

Number (%) of patients with shift to above the normal range

   

Trial 23

 

Trial 24

 

Trial 25

Study Week

 

Casodex
N=1627

Placebo
N=1627

 

Casodex
N=1790

Placebo
N=1795

 

Casodex
N=605

Placebo
N=609

   

n

(%) 2

n

(%)

 

n

(%)

n

(%)

 

n

(%)

n

(%)

12

 

38

(2.6)

23

(1.5)

 

32

(2.2)

8

(0.5)

 

24

(4.3)

5

(0.9)

24

 

48

(3.6)

16

(1.1)

 

39

(2.7)

14

(0.9)

 

24

(4.4)

5

(0.9)

36

 

24

(2.0)

18

(1.3)

 

26

(1.8)

9

(0.6)

 

23

(4.3)

4

(0.8)

48

 

14

(1.2)

15

(1.1)

 

22

(1.6)

14

(1.0)

 

13

(2.5)

2

(0.4)

72

 

8

(0.8)

26

(2.0)

 

15

(1.2)

17

(1.3)

 

6

(1.2)

1

(0.2)

96

 

8

(0.9)

26

(2.1)

 

15

(1.2)

18

(1.5)

 

5

(1.0)

7

(1.6)

120

 

-- 1

 

--

   

18

(1.5)

18

(1.5)

 

5

(1.1)

2

(0.5)

144

 

--

 

--

   

18

(1.7)

20

(2.0)

 

1

(0.2)

9

(2.6)

1. Treatment period was limited to 96 weeks.

2. Percentages based on both number of values above the normal range and the total number of samples evaluate at each of the respective study weeks.

Source: Safety Addendum for each of Trials 23, 24, and 25. Table T9.2.2.

Medical Officer's Comments

  • In both treatment groups, the proportion of patients who shifted to above the normal range for serum ALT values was relatively small and did not exceed 4.4% (Casodex-treatment group, Trial 25). However, a greater proportion of patients in the Casodex treatment groups shifted to above the normal range, most noticeable during the first 36 weeks (Trial 23), first 48 weeks (Trial 24), and first 72 weeks (Trial 25) of treatment.
  • The largest numeric disparity between the Casodex and placebo treatment groups was observed in Trial 25.
  • Changes in AST values (not listed) were similar to those observed for ALT values.

Table 51 Bilirubin Shifts from Within the Normal Range at Baseline to Above the Normal Range (High) during Treatment in each of Trials 23, 24, and 25

   

Number (%) of patients with shift

   

Trial 23

 

Trial 24

 

Trial 25

Study Week

 

Casodex
N=1627

Placebo
N=1627

 

Casodex
N=1790

Placebo
N=1795

 

Casodex
N=605

Placebo
N=609

   

n

(%)2

n

(%)

 

n

(%)

n

(%)

 

n

(%)

n

(%)

12

 

27

(1.8)

30

(1.9)

 

24

(1.7)

31

(2.2)

 

4

(0.7)

8

(1.5)

24

 

28

(2.0)

30

(2.0)

 

13

(1.0)

24

(1.8)

 

5

(1.0)

2

(0.4)

36

 

21

(1.7)

28

(1.9)

 

14

(1.1)

28

(2.2)

 

5

(1.0)

4

(0.8)

48

 

21

(1.8)

26

(1.9)

 

11

(0.9)

18

(1.4)

 

4

(0.8)

1

(0.2)

72

 

20

(1.9)

27

(2.1)

 

15

(1.3)

20

(1.7)

 

3

(0.6)

4

(0.9)

96

 

18

(1.9)

21

(1.7)

 

9

(0.8)

20

(1.8)

 

4

(0.9)

2

(0.5)

120

 

-- 1

 

--

   

9

(0.8)

18

(1.7)

 

2

(0.5)

1

(0.3)

144

 

--

 

--

   

17

(1.8)

11

(1.2)

 

2

(0.5)

2

(0.6)

1. Treatment period was limited to 96 weeks.

2. Percentages based on both number of values above the normal range and the total number of samples evaluate at each of the respective study weeks.

Source: Safety Addendum for each of Trials 23, 24, and 25, Table T9.2.1.

Medical Officer's Comment

  • In both treatment groups, the proportion of patients who shifted to above the normal range for serum total bilirubin values was relatively small and did not exceed 2.2% at any specific assessment time. Within each trial, the proportion of patients in the Casodex and placebo treatment groups who shifted to above the normal range appeared to be comparable during the 96-week and 144-week treatment periods represented in the above Table.
      1. Clinically Relevant Changes in LFT Laboratory Values

Definitions for clinically relevant changes in hepatic laboratory values (changes that were considered to be of particular concern) were established by the Sponsor. For ALT and AST values, a clinically relevant change was defined as an increase of (1) greater than or equal to 3 times the upper reference range for that laboratory variable or (2) greater than or equal to twice the upper reference range for that laboratory variable on 2 or more consecutive occasions. For total bilirubin values, a clinically relevant change was defined as an increase from the pre-randomization value by greater than or equal to 100% of the upper reference range for that laboratory variable.

The number and percentage of patients with one or more clinically relevant changes in each of ALT, AST, or total bilirubin values in Trials 23, 24, and 25 (combined analysis) are listed in Table 52. For each biochemistry variable, data are presented separately for patients who had normal or abnormal baseline values. Among patients with normal baseline values, a higher proportion of Casodex-treated patients showed clinically relevant changes from baseline for AST (1.7%), ALT (1.6%), and bilirubin (0.8%) than placebo-treated patients (0.7%, 0.4%, and 0.5%, respectively).

 

Table 52 Clinically Relevant Changes in ALT, AST, and Total Bilirubin Values during Treatment in Trials 23, 24, and 25 (Combined Analysis)

     

Casodex (N=4022)

 

Placebo (N=4031)

Parameter

Baseline
Value 1

 

Baseline

Patients with clinically relevant change

 

Baseline

Patients with clinically relevant change

     

N 2

n 3

(%)

 

N 2

n 3

(%)

AST

Normal

 

3745

65

(1.7)

 

3770

27

(0.7)

 

Abnormal

 

100

3

(3.0)

 

93

4

(4.3)

                   

ALT

Normal

 

3660

60

(1.6)

 

3685

13

(0.4)

 

Abnormal

 

186

9

(4.8)

 

179

8

(4.5)

                   

Total bilirubin

Normal

 

3530

29

(0.8)

 

3558

18

(0.5)

 

Abnormal

 

314

7

(2.2)

 

305

1

(0.3)

1 Baseline value: normal = within reference range; abnormal = outside reference range

2 N = number of patients with a baseline value and at least one non-missing laboratory assessment post dose.

3 n = number of patients with a clinically relevant change in the laboratory value.

Source: ISS, Text Table 24, pg. 62.

Medical Officer’s Comments

  • The number of patients with normal baseline values that had clinically relevant changes in hepatic biochemistry values was generally very low. However, more patients treated with Casodex had clinically relevant changes from a baseline value of normal than placebo-treated patients.
  • In patients with abnormal baseline ALT or AST values, the proportion with clinically relevant changes during treatment was similar in both treatment groups. However, for patients with an abnormal bilirubin value at baseline, the proportion of patients with a clinically relevant change during treatment was greater in Casodex-treated patients.

The number of patients with resolution of their clinically relevant change(s) in ALT, AST, or total bilirubin, either within the treatment or post treatment period, is listed in Table 53. Resolution is presented either as (1) return of the parameters to within the normal range or (2) parameter no longer clinically relevant but not within the normal range.

Table 53 Resolution of Clinically Relevant Changes in ALT, AST, and Total Bilirubin Values in Trials 23, 23, and 25 (Combined Analyses)

 

AST

 

ALT

 

Bilirubin

Status of clinically
relevant (CR) change

Casodex
N=68 1

Placebo
N=31

 

Casodex
N=69

Placebo
N=21

 

Casodex
N=36

Placebo
N=19

Time of Resolution

 

n

(%)

n

(%)

 

n

(%)

n

(%)

 

n

(%)

n

(%)

Parameter within normal range

                           

Within treatment period

18

(26)

12

(39)

 

21

(30)

7

(33)

 

11

(31)

5

(26)

Post treatment period

23

(34)

7

(23)

 

23

(33)

5

(24)

 

3

(8)

0

(0)

Parameter no longer CR

                           

Within treatment period

5

(7)

3

(10)

 

4

(6)

1

(5)

 

3

(8)

8

(42)

Post treatment period

2

(3)

0

(0)

 

1

(1)

0

(0)

 

5

(14)

0

(0)

Not resolved

3

(4)

4

(13)

 

5

(7)

4

(19)

 

1

(3)

0

(0)

No further information

17

(25)

5

(16)

 

15

(22)

4

(19)

 

13

(36)

6

(32)

1 Total number of patients with the clinically relevant change.

Source: ISS, Tables T7.5.1, T7.5.2, and T7.5.3.

Medical Officer’s Comments

  • For those patients with follow up laboratory data (64-75% of patients in the Casodex group), more than 90% had resolution (complete or partial) of their clinically relevant changes. Among Casodex-treated patients with follow up data, 4% (AST), 7% (AST), and 3% (bilirubin) showed no improvement.
  • Overall, these changes in hepatic laboratory values do not raise concerns of sufficient magnitude to preclude the use of Casodex in the proposed population (men with prostate cancer) and are adequately addressed in proposed labeling. Previous labeling appears to have provided adequate guidance to physicians for the safe use of Casodex 50 mg per day in men with prostate cancer, based on post marketing safety reports.
  • The potential clinical significance of these changes in biochemistry measurements of hepatic toxicity or function is discussed further in Section 5.9.3.

 

      1. Non-hepatic Laboratory Safety Assessments

Protocol required laboratory assessments for safety were limited to measurements of hepatic toxicity (ALT/SGPT, AST/SGOT) and hepatic function (total bilirubin). Androgens are known to affect erythropoiesis; consequently, an increase in the number of Casodex-treated patients, relative to placebo-treated patients, who experienced reduced concentrations of hemoglobin and anemia, was not unexpected. Since collection of hematological laboratory data was not a component of these clinical trials, assessment of the effect of Casodex on blood indices in these clinical trials is limited to reports of hematological adverse events (see Table 54). A higher proportion of Casodex-treated patients reported an adverse event classified as anemia or erythrocyte disorder (2.9% vs. 1.9%). Adverse events of these types classified as serious also occurred more frequently in Casodex-treated patients (25 of 4022, 0.62%) than in placebo-treated patient s (19 of 4031, 0.47%).

Table 54 Adverse Events Reported as Anemia or Erythrocyte Disorder during the Treatment Period (Combined Data from Trials 23, 24, and 25)

 

Number (%) of patients

Treatment group

All
Adverse events 1


Deaths


Withdrawals 2

Serious
Adverse Events 3

 

n

%

n

%

n

%

n

%

Casodex (N=4022)

115

(2.9)

0

--

4

(0.10)

25

(0.62)

Placebo (N=4031)

77

(1.9)

0

--

2

(0.05)

19

(0.47)

1. All adverse events reported as anemia or erythrocyte disorder.
2. All withdrawals due to an adverse event reported as anemia or erythrocyte disorder.
3. All serious adverse events reported as anemia or erythrocyte disorder.

Source: ISS, Table T12.2

Medical Officer's Comment

  • The differences in the proportion of Casodex-treated and placebo-treated patients who experienced adverse events classified as anemia or erythrocyte disorders was to be expected. The magnitude of the differences, particularly for serious adverse events, was very small.
    1. Safety Issues of Special Interest or Concern
      1. Pharmacological Adverse Events

Adverse events that may have been a result of the anti-androgenic or compensatory estrogenic activity of Casodex (i.e., pharmacological adverse events) and the number of patients who experienced them are summarized in Table 55. All occurred more frequently in Casodex-treated patients than in placebo-treated patients. The most frequently reported adverse events, occurring in 73% and 67% of patients in the Casodex group were breast pain and gynecomastia, respectively. Other adverse events occurring in 5-10% of Casodex treated patients were vasodilatation, impotence, and alopecia.

Table 55 Pharmacological-Related (Anti-androgenic and Estrogenic)
Adverse Events (Combined Data from Trials 23, 24, and 25)

 

Adverse Event

Number (%) of patients

Casodex

Placebo

(N=4022)

(N=4031)

n

%

n

%

Breast pain

2937

73.0%

296

7.3%

Gynecomastia

2700

67.1%

325

8.1%

Vasodilatation

364

9.1%

211

5.2%

Impotence

362

9.0%

250

6.2%

Alopecia

239

5.9%

31

0.8%

Libido decreased

145

3.6%

45

1.1%

Source: Modified from ISS, Text Table 30, pg. 74.

Medical Officer’s Comment

  • The high incidence of gynecomastia and breast pain may be a direct consequence of the anti-androgenic activity of Casodex, a consequence of the compensatory increase in serum concentrations of estradiol that are observed during treatment with Casodex, or a combination of both.
        1. Gynecomastia and Breast Pain during the Treatment Period

Most Casodex-treated patients (86.2%) reported gynecomastia or breast pain. Of these, 649/4022 (16.1%) patients withdrew from Casodex therapy. A total of 345/4,022 (8.6%) of these patients reported severe gynecomastia or severe breast pain. In the placebo-treated patients, only 12.4% patients reported gynecomastia or breast pain, and only 0.6% withdrew from treatment because of these adverse events (Table 56).

Table 56 Incidence of and Withdrawals due to Gynecomastia and Breast Pain within the Treatment Period (Combined Data from Trials 23, 24, and 25)

 

Number (%) of patients

Category

Casodex

Placebo

 

(N=4022)

(N=4031)

 

n

(%)

n

(%)

Number of patients with:

       

Gynecomastia alone

2700

(67.1)

325

(8.1)

Male breast pain alone

2937

(73.0)

296

(7.3)

Both gynecomastia and male breast pain

2170

(54.0)

120

(3.0)

Either gynecomastia or male breast pain

3467

(86.2)

501

(12.4)

Number of patients with withdrawal due to:

       

Gynecomastia

418

(10.4)

15

(0.4)

Male breast pain

498

(12.4)

15

(0.4)

Both gynecomastia and male breast pain

267

(6.6)

5

(0.1)

Either gynecomastia or male breast pain

649

(16.1)

25

(0.6)

Source: Text Table 31, pg. 75 of the ISS.

The time to occurrence of gynecomastia was estimated from Kaplan-Meier plots (Figure 3). More than 50% of Casodex-treated patients who developed gynecomastia did so within 200 days of treatment onset. Most who developed gynecomastia did so within 24 months of starting treatment.

Figure 3 Time to First Occurrence of Gynecomastia within the Treatment Period

Source: Figure 2, pg 76 of the ISS.

Table 57 summarizes the percentage of patients with gynecomastia and/or breast pain within the treatment period and the percentage of patients who withdrew because of these adverse events in each of Trials 23, 24, and 25. The percentage of Casodex-treated patients reporting gynecomastia was highest in Trial 23 (72.6%) and lowest in Trial 25 (55%). The percentage of Casodex-treated patients reporting either gynecomastia or breast pain differed slightly across the 3 trials and ranged from 90.1% (Trial 23) to 82.9% (Trial 24). The percentage of patients reporting either of these adverse events was considerably lower in the placebo treatment groups and ranged from 16.1% (Trial 23) to 6.6% (Trial 25). The percentage of Casodex-treated patients who withdrew from treatment because of either gynecomastia or breast pain also was highest in Trial 23 (20.0%) and lowest in Trial 25 (4.5%). Less than 1% of patients in any of the placebo groups withdrew because of either gynecomastia or breast pain.

Medical Officer’s Comments

  • Gynecomastia and/or breast pain are by far the most frequently reported adverse events in men treated with Casodex, occurring in 86% of patients in the combined trials. In 8.6% of the patients, these adverse events were reported as severe. Across the 3 trials, 16.1% of Casodex-treated patients withdrew because of these adverse events.
  • Patients in Trial 23 (primarily US patients) tolerated gynecomastia and/or breast pain least well. Twenty (20) percent of Casodex-treated patients in Trial 23 withdrew from treatment because of these adverse events while only 4.5% of Casodex-treated patients in Trial 25 withdrew for this reason. The high withdrawal rate because of gynecomastia and/or breast pain was clearly related to treatment with Casodex per se and not study participation in general in that < 1% of patients in the placebo group in Trial 23 withdrew because of these adverse events.
  • The Sponsor performed subset analyses to determine if there were any associations other than Casodex that were related to the development of gynecomastia or breast pain. According to the Sponsor, there was no obvious relationship between age, race (Trial 23 only), tumor stage, weight, or body mass index and the incidence of gynecomastia or breast pain.
  • In Trial 25, some patients were offered breast irradiation prior to initiation of randomized therapy; however, the number of patients was too small to draw any conclusions about the benefit of the procedure.

Table 57 Incidence of and Withdrawals due to Gynecomastia and Breast Pain within the Treatment Period in Each of Trials 23, 24, and 25

 

Number (per cent) of patients with event

Category

Study 23

Study 24

Study 25

Casodex
(N = 1627)

Placebo
(N = 1627)

Casodex
(N = 1790)

Placebo
(N = 1795)

Casodex
(N = 605)

Placebo
N = 609)

n

(%)

n

(%)

n

(%)

n

(%)

n

(%)

n

(%)

Number of patients with adverse event

                 

Gynecomastia

1182

(72.6)

165

(10.1)

1185

(66.2)

141

(7.9)

333

(55.0)

19

(3.1)

Breast pain

1390

(85.4)

173

(10.6)

1173

(65.5)

98

(5.5)

374

(61.8)

25

(4.1)

Either gynecomastia or breast pain

1466

(90.1)

262

(16.1)

1484

(82.9)

199

(11.1)

517

(85.5)

40

(6.6)

Number of patients withdrawing because of adverse event

           

Gynecomastia

190

(11.7)

6

(0.4)

212

(11.8)

8

(0.4)

16

(2.6)

1

(0.2)

Breast pain

285

(17.5)

8

(0.5)

195

(10.9)

7

(0.4)

18

(3.0)

0

(0.0)

Either gynecomastia or breast pain

326

(20.0)

12

(0.7)

296

(16.5)

12

(0.7)

27

(4.5)

1

(0.2)

Source: ISS, Tables 9.3.2 and 9.3.3

 

        1. Resolution of Breast Pain and Gynecomastia after Withdrawal of Treatment

Approximately 10% of all patients who withdrew from trial therapy with ongoing gynecomastia or breast pain did not have any follow-up information. For Casodex-treated patients who had gynecomastia ongoing at the time of withdrawal and had at least 1 follow-up assessment as of the 23 February 2001 data cutoff, 50.7% had resolution of their gynecomastia (Table 58). The median time from withdrawal of trial therapy to resolution of gynecomastia was approximately 101 weeks. According to the Sponsor, the time to resolution of gynecomastia appeared to be longer with increasing duration of trial therapy.

For Casodex-treated patients who had breast pain ongoing at the time of withdrawal and had at least 1 follow-up assessment, 92.2% of patients had resolution of breast pain by the date of data cutoff. The median time from withdrawal of trial therapy to resolution of breast pain was approximately 24 weeks.

Table 58 Percentage of Patients with Resolution of Gynecomastia and Breast
Pain after Withdrawal of Treatment

 

Number (%) of patients

Category

Casodex (N=4022) 1

 

n 2

(%)

Gynecomastia:

   

Patients with event ongoing at withdrawal and follow up information

1572

(100.0)

Patients with event ongoing at withdrawal and follow up information and resolution

787

(50.7)

Breast pain

   

Patients with event ongoing at withdrawal and follow up information

1729

(100.0)

Patients with event ongoing at withdrawal and follow up information and resolution

1595

(92.2)

1. Total number of patients treated with Casodex.

2. Number of patients with condition.

Source: ISS, Summary Table T9.2.2.

Medical Officer’s Comments

  • The high percentage of patients who developed gynecomastia during treatment (67%) and persistence of gynecomastia after discontinuation of Casodex treatment are significant problems and of concern. According to the Sponsor, only 50.7% of Casodex-treated patients with post treatment follow up data had resolution of gynecomastia by the date of data cutoff. For many men, particularly those with localized prostate disease who had undergone radical prostatectomy or radiation therapy of curative intent, permanent gynecomastia may be a significant quality of life consideration.
  • GnRH analogs were not compared to Casodex in the clinical trials included in this submission. However, in a prior submission (NDA 20-498/s006), GnRH analogs were show to be at least as effective as Casodex in terms of a survival endpoint in men with locally advanced non-metastatic prostate cancer and superior to Casodex in men with metastatic (M1) prostate cancer. In the present application, the Sponsor argues that Casodex is likely to be better tolerated than GnRH analogs that induce a complete medical castration and more severe symptoms of androgen deprivation. GnRH analogs, however, do not induce gynecomastia or breast pain. It is therefore unclear as to which therapy would be associated with a better quality of life, particularly if long-term survival is anticipated.
      1. Sexual Dysfunction

In Trial 25, sexual function was assessed during the first 48 weeks of treatment by a patient-completed shortened version of the GRISS questionnaire. The questionnaire was completed and the responses were collected at baseline and then at 12-week intervals until Week 48. Maintenance of sexual function based on the GRISS questionnaire relative to baseline during the first 48 weeks of treatment is summarized in Table 59. Maintenance of sexual function was considered to be no loss of potency or frequency. The findings summarized in Table 59 indicate that Casodex therapy was associated with a reduction in the frequency of sexual intercourse and an increase in impotence compared to treatment with placebo. At Week 48, 31.4% of Casodex-treated patients and 47.6% of placebo-treated patients were assessed as having had no significant change in sexual frequency. Also at Week 48, 34.9% of Casodex-treated patients and 53.4% of placebo-treated patients were assessed as having had no significant change in sexual potency.

Table 59 Maintenance of Sexual Function Relative to Baseline

Sexual function domain

 

Weeks post-randomization

Wk 12

 

Wk 24

 

Wk 36

 

Wk 48

Percentage of patients who maintained baseline function

Frequency

       

Casodex

44.9%

41.9%

36.1%

31.4%

Placebo

61.5%

55.1%

47.1%

47.6%

Potency

       

Casodex

49.8%

43.7%

39.7%

34.9%

Placebo

62.1%

58.4%

60.1%

53.4%

Source: Table 25, pg. 65, ISS.

Medical Officer's Comments

  • It is of interest that almost 40% of patients were assessed as having had a decrease in either sexual frequency or potency at 12 weeks after the onset of placebo therapy.
  • Changes in sexual function based on the GRISS questionnaire were qualitatively consistent with the pattern of adverse events for decreased libido and impotence reported in Trial 25. Based on reported adverse events, Casodex-treated patients had higher rates of decreased libido (23/605 [3.8%]) and impotence (97/605 [16.0%]) than placebo-treated patients (decreased libido: 7/609 [1.2%] and impotence: 41/609 [6.7%]). These adverse events, however, appear to have been underreported since the proportion of patients with decreased sexual function based on the GRISS questionnaire was much higher.
      1. Liver Toxicity
        1. Abnormal Liver Function Test (LFT) Values Reported as Adverse Events

Laboratory values outside of the normal range were not to be routinely reported as adverse events unless the investigator believed that they were clinically significant or required clinical intervention. The number and proportion of patients for whom an increase in serum concentrations of ALT, AST, or total bilirubin were reported as an adverse event in each of the trials is listed in Table 60. Across the 3 trials, 138 of 4022 (3.4%) patients in the Casodex group and 94 of 4031 (2.3%) patients in the placebo group had one or more increased liver function test values reported as an adverse event. In each of the trials, the proportion of patients with a LFT-related adverse event (any type) was numerically higher in the Casodex treatment group.

Table 60 Number (%) of Patients with Increased Liver Function Test Values Reported as Adverse Events (Trials 23, 24, and 25)

 

Number (per cent) of patients with event

Test Reported as Adverse Event

Study 23

Study 24

Study 25

Casodex
(N = 1627)

Placebo
(N = 1627)

Casodex
(N = 1790)

Placebo
(N = 1795)

Casodex
(N = 605)

Placebo
N = 609)

n

(%)

n

(%)

n

(%)

n

(%)

n

(%)

n

(%)

Any Increased Test 1

68

(4.2)

60

(3.7)

50

(2.8)

14

(0.8)

20

(3.3)

6

(1.0)

Increased ALT

52

(3.2)

44

(2.7)

41

(2.3)

11

(0.6)

19

(3.1)

2

(0.3)

Increased AST

43

(2.6)

25

(1.5)

39

(2.2)

12

(0.7)

18

(3.0)

3

(0.5)

Increased bilirubin

20

(1.2)

19

(1.2)

8

(0.4)

3

(0.2)

4

(0.7)

3

(0.5)

1. Total number (%) of patients with an increased ALT, AST, or bilirubin value reported as an adverse event.

Source: Table 12, Safety Addendum Trial 23; Table 1 and Table 2 (Pg. 7) of submission of May 3, 2002.

Medical Officer’s Comments

  • For each of the 3 tests of liver toxicity or liver function, higher numbers of adverse events were reported for Casodex-treated patients in each of the trials with 2 exceptions (bilirubin values in Trials 23 and 25). The absolute differences between the proportion of Casodex-treated and placebo-treated patients were in general small, particularly in Trial 23 ("any increased tests") and in all trials for "increased bilirubin."
  • Clinically relevant changes in LFT values and their likely clinical significance were previously reviewed (see Table 52 and Table 53).
        1. Hepatic-related Adverse Events during the Treatment Period

All adverse events. A total of 220 (5.3%) of Casodex-treated patients and 139 (3.3%) placebo-treated patients had at least one hepatic-related adverse event. Table 61 summarizes all hepatic-related adverse events reported during the treatment period in Trials 23, 24, and 25 combined. In this Table, the category of Abnormal Liver Function Test includes the COSTART preferred terms of "liver function tests abnormal, AST/SGOT increased, and ALT/SGPT increased." The category of jaundice includes the COSTART preferred terms of "cholestatic jaundice, jaundice, bilirubinemia, and gamma glutamyl transpeptidase increased." The incidence of hepatic-related adverse events was numerically greater in the Casodex group for 7 of the 10 categories represented in Table 61. However, only 3 categories of hepatic-related adverse events were reported by 1% or more of the patients in either treatment group. These were abnormal liver function test (3.0% Casodex group; 1.6% placebo group), jaundice (1.0% Casodex group, 0.7% placebo group), and cholelithiasis (1.0% Casodex group, 0.7% placebo group).

Serious adverse events other than deaths. The most frequently reported serious hepatic-related adverse events were cholelithiasis (0.6% Casodex-treated patients, 0.3% placebo-treated patients) and cholecystitis (0.5% Casodex-treated patients; 0.4% placebo-treated patients). Other categories in which the incidence of serious hepatic-related adverse events exceeded 0.1% in Casodex-treated patients were abnormal liver function tests (0.3%) and jaundice (0.2%).

Table 61 Hepatic-related Adverse Events during Treatment (Trials 23, 24, and 25)

Adverse Event

Number (%) of patients 1, 2

Treatment group

All
Adverse events 3


Deaths 3


Withdrawals 3

Serious
Adverse Events 3

 

n

%

n

%

n

%

n

%

Abnormal Liver Function Test 4

               

Casodex

120

(3.0)

0

 

47

(1.2)

10

(0.3)

Placebo

63

(1.6)

0

 

18

(0.5)

0

 

Jaundice 5

               

Casodex

42

(1.0)

0

 

17

(0.4)

6

(0.2)

Placebo

30

(0.7)

0

 

6

(0.2)

1

(<0.1)

Cholelithiasis

               

Casodex

40

(1.0)

0

 

1

(<0.1)

23

(0.6)

Placebo

28

(0.7)

0

 

1

(<0.1)

10

(0.3)

Cholecystitis

               

Casodex

22

(0.6)

0

 

1

(<0.1)

20

(0.5)

Placebo

16

(0.4)

0

 

1

(<0.1)

14

(0.4)

Hepatitis

               

Casodex

8

(0.2)

0

 

4

(0.1)

4

(0.1)

Placebo

1

(<0.1)

0

 

0

 

0

 

Hepatic Neoplasia

               

Casodex

6

(0.2)

1

(<0.1)

1

(<0.1)

3

(0.1)

Placebo

5

(0.1)

0

 

1

(<0.1)

4

(0.1)

Biliary Pain

               

Casodex

3

(0.1)

0

 

0

 

0

 

Placebo

2

(0.1)

0

 

0

 

1

(<0.1)

Cirrhosis of Liver

               

Casodex

1

(<0.1)

0

 

0

 

0

 

Placebo

1

(<0.1)

1

(<0.1)

1

(<0.1)

1

(<0.1)

Liver Fatty Deposit

               

Casodex

1

(<0.1)

0

 

0

 

0

 

Placebo

6

(0.2)

0

 

0

 

0

 

Hepatomegaly

               

Casodex

0

 

0

 

0

 

0

 

Placebo

3

(0.1)

0

 

1

(<0.1)

0

 

1. Individual patients may have had more than 1 event and may be represented in > 1 category.

2. 220 of 4022 (5.3%) Casodex-treated patients and 139 of 4031 (3.3%) placebo-treated patients experienced one or more hepatic adverse events during treatment.

3. Includes all adverse events, deaths, withdrawals, or serious adverse events in the respective category.

4. Includes COSTART preferred terms of "liver function tests abnormal, SGOT increased, and SGPT increased."

5. Includes COSTART preferred terms of "cholestatic jaundice, jaundice, bilirubinemia, and gamma glutamyl transpeptidase increased."

Source: Safety Update, Table T8.1.

Medical Officer’s Comments

  • The majority of adverse events related to increased AST and ALT values appeared to have occurred within the first year of trial therapy in both treatment groups.
  • The incidences of abnormal LFTs and jaundice that led to withdrawal were higher in Casodex-treated patients (1.2% and 0.4%, respectively) than placebo-treated patients (0.5% and 0.2%, respectively). Of the patients with abnormal liver function tests, 10 cases in Casodex-treated patients and 0 cases (none) in the placebo-treated patients were classified as serious.
        1. Deaths Related to Hepatic Failure or Primary Hepatic Neoplasms

Deaths classified as related to hepatic failure or primary hepatic neoplasms that occurred either during the treatment period or during the post treatment follow up period are listed in Table 62. Five (5) Casodex-treated patients and 6 placebo-treated patients were reported to have died from one of these causes. One of the deaths in the placebo group may have been associated with metastatic cancer to the liver and not due to a primary hepatic tumor. One case in the Casodex treatment group was classified by the investigator as possibly related to treatment with study drug.

Table 62 Deaths Related to Hepatic Failure or Primary Hepatic Neoplasms

Trial No.

Patient No.

Age

Cause of Death

(Actual Wording of Investigator)

Length of Tx (Days)

Study Day of Death

Comment

CASODEX

23

---

61

Hepatic Coma 1

673

1641

24

---

76

Hepatocarcinoma

1713

1858

Poss. related to Tx per Investigator

24

---

75

Hepatic Cancer Death

1702

1749

24

---

57

Liver Failure

1268

1389

Pt received open label Casodex 2

25

---

67

Hepatocellular Cancer 1

248

1849

PLACEBO

23

---

62

End Stage Liver Disease 1

505

547

23

---

56

End-Stage Cirrhosis (Liver)

361

1729

24

---

72

Hepatic Cancer 1

646

787

25

---

71

Cirrhases Hepates 1

371

974

25

---

71

Carcinoma Hepatocellulare

194

194

25

---

71

Carcinoma Of Liver

1326

1326

May be metastatic cancer to liver

1. Patient narrative not provided for review.

2. Patient assigned to placebo treatment. Received open label Casodex after code break.

Source: Prepared by medical reviewer from Sponsor’s SAS transport file for all deaths and Table G2, both in Safety Update.

Medical Officer’s Comments

  • The distribution and causes of hepatic-related deaths appeared to be similar in the Casodex and placebo treatment groups.
  • There were 2 and 3 deaths in the Casodex and placebo treatment groups, respectively that were related to hepatic failure that was not associated with a primary hepatic tumor. Deaths due to a primary hepatic tumor were reported for 2 and 2 or 3 patients in the Casodex and placebo treatment groups, respectively.

Medical Officer’s Summary Comments Regarding Hepatotoxicity

  • The potential for drug-induced liver toxicity with all nonsteroidal anti-androgens is a concern, particularly if they are intended for long-term use. The safety data provided in this supplemental NDA includes 9,387 and 9,778 total patient-years of treatment in the Casodex and placebo treatment groups. This is an adequate sample size to assess the likely toxicity of Casodex 150 mg per day in men with localized and locally advanced non-metastatic cancer of the prostate. Since the 3 clinical trials that were conducted in support of this supplemental NDA were placebo controlled, safety comparisons across treatment groups are particularly useful.
  • The safety data provided in NDA 20-498/s012 indicate that treatment with Casodex is associated with an increase in the incidence of liver toxicity compared to treatment with placebo. The increase in liver-related toxicity is manifested primarily by an increase in the proportion of patients with an increase in serum transaminases and to a lesser extent an increase in serum total bilirubin levels. Patients withdrawals due to increased serum ALT or AST values and increased bilirubin values were higher in Casodex-treated patients (1.2% and 0.4%, respectively) than in placebo-treated patients (0.5% and 0.2%, respectively). Similarly, adverse events classified as serious due to increased serum ALT or AST values and increased bilirubin values were more frequent in Casodex-treated patients (0.3% and 0.2%, respectively) than in placebo-treated patients (0.0% and <0.1%, respectively). However, the number of patients reported to have died from hepatic failure or a primary hepatic neoplasm was similar in the 2 treatment groups (5 of 4,022 Casodex-treated patients and 5 or 6 of 4,031 placebo-treated patients.
  • The current labeling for Casodex 50 mg and the proposed labeling for Casodex 150 mg indicate (under Warnings Section) that "serum transaminase levels should be measured prior to starting treatment with CASODEX, at regular intervals for the first 4 months of treatment, and periodically thereafter. If clinical symptoms or signs suggestive of liver dysfunction occur, (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, jaundice, or upper right quadrant tenderness), serum transaminases, in particular the serum ALT, should be measured immediately. If at any time a patient has jaundice, or the ALT level rises above 2 times the upper limit of normal, CASODEX should be discontinued, with appropriate follow-up of liver function."
  • The Sponsor also provided an analysis of liver toxicity for both flutamide and Casodex (50 mg per day) based on US post marketing safety data. According to the Sponsor, the incidence of significant flutamide-related hepatotoxicity has been estimated to be 2.5 per 100,000 prescriptions in the US (Wysowski 1996 5) against a background incidence in a similar US population of 0.2 per 100,000 prescriptions in patients not exposed to drugs. Using the same criteria as Wysowski (cases from the USA only and number of prescriptions filled in the US), the Sponsor claims that the incidence of significant hepatic toxicity for Casodex using those US post-marketing cases considered by AstraZeneca Pharmaceuticals to be even possibly related to Casodex was 0.1 per 100,000 prescriptions. The estimated number of prescriptions for Casodex in the US since launch to May 2000 was 1,714,000 per the Sponsor. It is possible, however, that hepatotoxicity will be increased in patients receiving 150 mg Casodex per day compared to those receiving 50 mg per day.
      1. Cardiovascular Morbidity and Mortality
        1. Cardiovascular Adverse Events during the Treatment Period
        2. Serious cardiovascular adverse events were reported less frequently in Casodex-treated patients (351 of 4,022 patients [8.73%]) than placebo-treated patients (386 of 4,031 patients [9.58%]) (Table 5.4, submission of 3 May 2002). As noted earlier in this review, however, some types of serious cardiovascular adverse events and deaths due to cardiovascular causes (both based on COSTART preferred terms) were reported more frequently in Casodex-treated patients. Serious cardiovascular adverse events reported for ³ 0.2% of patients in either treatment group are listed in Table 63. Events are listed by decreasing incidence in the Casodex-treated patients. Cardiac events of note that occurred more frequently in Casodex-treated patients (relative incidence of ³ 1.2, Casodex/placebo) included heart failure, heart arrest, syncope, and arrhythmia. Cardiac events that occurred more frequently in placebo-treated patients (relative incidence of £ 0.85 included myocardial infarction, myocardial ischemia, and atrial arrhythmia.

          Table 63 Serious Cardiovascular Adverse Events with Incidence ³  0.2% during Treatment Period (Combined Data from Trials 23, 24, and 25)

           

           

          Adverse Event

          Number of patients reporting adverse event

           

          Relative Incidence

          Casodex
          placebo

          Casodex
          (N = 4022)

           

          Placebo
          (N = 4031
          )

             

          n

          Percentage

          n

          Percentage

          Myocardial infarct

          72

          1.8%

          97

          2.4%

          0.74

          Angina pectoris

          71

          1.8%

          66

          1.6%

          1.08

          Heart failure

          61

          1.5%

          36

          0.9%

          1.70

          Chest pain

          56

          1.4%

          29

          0.7%

          1.94

          Myocardial ischemia

          54

          1.3%

          64

          1.6%

          0.85

          Cerebrovascular accident

          37

          0.9%

          71

          1.8%

          0.52

          Cardiovascular disorder

          28

          0.7%

          37

          0.9%

          0.76

          Atrial arrhythmia

          25

          0.6%

          35

          0.9%

          0.72

          Heart arrest

          19

          0.5%

          7

          0.2%

          2.72

          Syncope

          18

          0.4%

          14

          0.3%

          1.29

          Cerebral Ischemia

          16

          0.4%

          17

          0.4%

          0.94

          Hypertension

          15

          0.4%

          24

          0.6%

          0.63

          Arrhythmia

          15

          0.4%

          11

          0.3%

          1.37

          Vascular disorder

          11

          0.3%

          27

          0.7%

          0.41

          Carotid occlusion

          11

          0.3%

          14

          0.4%

          0.97

          Arteriosclerosis

          9

          0.2%

          8

          0.2%

          1.13

          Thrombosis

          5

          0.1%

          9

          0.2%

          0.56

          Source: Safety Update, Text Table 22, pg. 51, and Table T5.2.3.

        3. Cardiovascular Mortality

Cardiovascular-related events were the most common single cause of death (other than prostate cancer), both during and following treatment with study drug. The numbers (%) of patients whose primary cause of death was classified as cardiovascular-related are listed in Table 64. A numerically greater proportion of Casodex-treated patients was classified as having died of a cardiovascular event, either during or following treatment. Overall, the primary cause of death was considered to be cardiovascular-related in 143 of 4,022 (3.56%) of Casodex-treated patients and 122 of 4,031 (3.03%) of placebo-treated patients.

Table 64 Patients with a Cardiovascular-related Primary Cause of Death
(Combined Data from Trials 23, 24, and 25)

 

Number (%) of patients

 

Relative Incidence

Casodex
placebo

Treatment Period

 

Casodex
(N = 4022)

 

Placebo
(N = 4031
)

 
 

n

Percentage

 

n

Percentage

 

During Treatment

77

1.91%

66

1.64%

1.17

Post Treatment

66

1.64%

56

1.39%

1.18

Total

143

3.56

122

3.03

1.17

Source: Safety Update, Table T4.3.

The primary causes of cardiovascular-related deaths in each of the treatment groups, both during and following treatment, are listed in Table 65. The most common causes of deaths (treatment and post treatment periods combined) in the Casodex-treated patients were myocardial infarction (n=42), cerebrovascular accident (n=25), heart arrest (n=23), and heart failure (n=21). In the placebo-treated patients, the most common causes of death were myocardial infarction (n=52), cerebrovascular accident (n=22), and heart arrest (n=12).

Medical Officer’s Comments

  • Overall, there were 21 more deaths attributed to cardiovascular causes in the Casodex-treated patients than in the placebo treated patients. This difference can be accounted for almost entirely by the excess number of deaths due to heart arrest (D = 11) and heart failure (D = 16) in the Casodex-treated patient partially offset by an excess number of deaths due to myocardial infarction (D = 10) in the placebo-treated patients.
  • The Sponsor states the following in their analysis of cardiac-related deaths in the Integrated Summary of Efficacy.
    • "Across all 3 controlled studies, only 5 patients (3 CASODEX, 2 placebo) experienced heart arrest in association with a cardiac condition which was not pre-existing at trial entry. These numbers of heart arrest events are too small to causally implicate CASODEX."
    • "CASODEX does not cause heart failure in animals. Only 2 patients had unconfounded cases of heart failure (1 of which was deemed related to trial therapy by the investigator), a finding not unexpected in an elderly male population of 4,022 patients treated with CASODEX."

Table 65 Primary Causes of Cardiovascular Deaths with Incidence ³ 0.05% (Combined Data from Trials 23, 24, and 25)

 

Number (%) of patients with cause of death

 

Relative Incidence

Casodex
placebo

Cause of Death
(COSTART term)

 

Casodex
(N = 4022)

 

Placebo
(N = 4031
)

 

n

Percentage

n

Percentage

Arrhythmia

         

On treatment

0

0.00

2

0.05

0.00

Post treatment

0

0.00

0

0.00

NC 1

Total

0

0.00

2

0.05

0.00

Arteriosclerosis

         

On treatment

2

0.05

0

0.00

NC

Post treatment

5

0.12

3

0.07

1.67

Total

7

0.17

3

0.07

2.34

Cardiomyopathy

         

On treatment

1

0.02

2

0.05

0.50

Post treatment

0

0.00

2

0.05

0.00

Total

1

0.02

4

0.10

0.25

Cardiovascular disorder

         

On treatment

2

0.05

2

0.05

1.00

Post treatment

2

0.05

2

0.05

1.00

Total

4

0.10

4

0.10

1.00

Cerebrovascular accident

         

On treatment

11

0.27

15

0.37

0.73

Post treatment

14

0.35

7

0.17

2.00

Total

25

0.62

22

0.55

1.14

Heart arrest

         

On treatment

12

0.30

5

0.12

2.41

Post treatment

11

0.27

7

0.17

1.57

Total

23

0.57

12

0.30

1.92

Heart failure

         

On treatment

15

0.37

1

0.02

15.03

Post treatment

6

0.15

4

0.10

1.50

Total

21

0.52

5

0.12

4.21

Myocardial infarction

         

On treatment

24

0.60

31

0.77

0.78

Post treatment

18

0.45

21

0.52

0.86

Total

42

1.04

52

1.29

0.81

Myocardial ischemia

         

On treatment

4

0.10

5

0.12

0.80

Post treatment

4

0.20

3

0.07

1.33

Total

8

0.20

8

0.20

1.00

Pulmonary embolus

         

On treatment

4

0.10

2

0.05

2.00

Post treatment

1

0.12

4

0.10

0.25

Total

5

0.12

6

0.15

0.84

1. Unable to calculated as no events occurred in placebo group.

Source: Safety Update, Table T4.3.

 

      1. Second Tumors

The proportion of patients with solid second tumors during the treatment period was similar in both treatment groups (312 of 4,022 [7.76%] Casodex-treated patients; 315 of 4,031 [7.81%] placebo-treated patients). Solid second tumors reported as an adverse event in ³  0.2% of patients during the treatment period are summarized by body system and COSTART preferred term in Table 66. The most common solid tumors in both treatment groups were neoplasm (body as a whole), skin cancer, GI neoplasia, gastrointestinal carcinoma, and carcinoma of the lung.

Table 66 Solid Tumors Reported as Adverse Events within the Treatment
Period in ³  0.2% Patients (Data Combined for Trials 23, 24, and 25)

   

Number (%) of patients with event

COSTART
body system

COSTART preferred
term

Casodex
(N=4022)

 

Placebo
(N=4031)

   

No. Pt

Percent

No. Pt

Percent

Body as a whole

Adenoma

9

0.22

14

0.35

 

Carcinoma

17

0.42

11

0.27

 

Neoplasm

67

1.67

60

1.49

Digestive

Gastrointestinal carcinoma

48

1.19

39

0.97

 

Gastrointestinal neoplasm

65

1.62

75

1.86

Respiratory

Carcinoma of lung

24

0.60

28

0.69

Skin

Skin cancer

58

1.44

61

1.51

 

Skin melanoma

9

0.22

9

0.22

Urogenital system

Bladder carcinoma

13

0.32

9

0.22

 

Bladder neoplasm

9

0.22

7

0.17

Source: SAS File aeaf1 (calculated by medical reviewer) and Table T14.4, both from Safety Update.

Medical Officer's Comments

  • Tumors listed as carcinoma under "body system as a whole" included a diverse number of tumor types for which descriptions were often vague, thus making more precise classification impossible in many instances. Included in this category were 5 cases of renal cell carcinoma or renal cancer (3 and 2 cases in the Casodex and placebo groups, respectively). Tumors listed as neoplasm under "body system as a whole" were predominantly benign neoplasms, often lipomas or merely described as ‘lumps."
  • Tumors classified under the digestive body system included a greater number of tumors classified as gastrointestinal carcinoma in the Casodex-treated patients (n=48) than in placebo-treated patients (n=39). Conversely, tumors classified as gastrointestinal neoplasm were more common the placebo-treated patients (n=75) than in the Casodex-treated patients (n=65).
        1. Gastrointestinal Tumors

The Sponsor provided a more detailed analysis of the incidence of gastrointestinal tumors based on a somewhat broader review of the data from the 3 clinical trials. The result of this analysis is presented in Table 67.

Table 67 Incidence of Gastrointestinal Tumors (Trials 23, 24, and 25)

 

Number of patients with event

Gastrointestinal
tumor site

Casodex (N=4022)

Placebo
(N=4031)

Incidence
ratio 1

Colorectal

30

27

1.11

Colon

21

23

0.91

Rectal

9

4

2.25

CUP-abdominal 2

3

2

1.50

Esophageal

5

3

1.67

Gastric

5

7

0.71

Hepatic

4

2

2.00

Mouth

1

2

0.50

Pancreatic

5

5

1.00

Parotid

1

0

 

Small intestine

2

1

2.00

Total

56

49

1.14

1 Casodex/placebo

2 CUP = cancer unknown primary

Source: Text Table 36 of Safety Update, pg. 80.

Medical Officer's Comments

  • Although the number of patients with a gastrointestinal tumor continued to be numerically higher in the Casodex-treated patients, the difference was relatively small (56 of 4,022 [1.4%] Casodex-treated patients; 49 of 4,031 [1.2%] placebo-treated patients.
        1. Myelodysplasia and Leukemia

There was an increase in the number of Casodex-treated patients who developed myelodysplasia syndrome or leukemia. The patients who were identified by the Sponsor as having developed myelodysplasia syndrome or leukemia or whose underlying cause of death was related to these disorders are listed in Table 68. Twelve (12) Casodex-treated patients and 5 placebo-treated patients are represented in the Table (relative incidence Casodex/placebo = 2.4). Of these patients, 8 of 12 Casodex-treated patients and 4 of 5 placebo-treated patients have died as a direct or indirect result of their underlying hematologic disorder.

 

Table 68 Patients Who Developed Myelodysplasia Syndrome or Leukemia

 

Patient number

Age at
Study Entry

Diagnosis 1

Duration of Treatment
(Days)

Time to Diagnosis
(Days)

Death (Y/N)

Casodex treatment group

-----

72

AML

321

1012

N

-----

56

MDS

126

139

N

-----

60

AML

666

1167

Y

-----

68

MDS

658

496

Y

-----

65

AML

283

1444

N

-----

82

MDS

581

627

Y

-----

70

AML

90

166

Y

-----

74

AML

482

483

Y

-----

64

AML

1084

1019

Y

-----

73

MDS

1096

1024

N

-----

74

MDS

90

113

Y

-----

65

AML

1190

1168

Y

Placebo treatment group

-----

59

MDS

92

1012

Y

-----

76

MDS

755

1335

Y

-----

75

MDS

1776

1248

Y

-----

662

AML

1090

1139

N

-----

72

AML

1253

1037

Y

1 AML = acute myelogenous leukemia; MDS = myelodysplasia syndrome.

2 This patient was withdrawn from placebo therapy and began open-label treatment with Casodex. AML was diagnosed 6-7 weeks after staring Casodex.

Source: Text Table 35, pg. 78, of Safety Update.

Medical Officer’s Comments

  • The basis for this numeric imbalance is unclear. Based on the preclinical toxicology of Casodex, one would not anticipate that treatment with this drug would cause the development of either myelodysplasia syndrome or leukemia.
  • The numeric imbalance (12 of 4022 Casodex-treated patients [0.30%]; and 5 of 4031 placebo-treated patients [0.12%]) was not statistically significant (p-value = 0.24, Fisher’s exact test for a 2-sided hypothesis, FDA calculation).
  • The significance of this numeric imbalance and its possible relationship to treatment with Casodex are not known at this time.
    1. Adequacy of Patient Exposure and Safety Assessments

The safety database for this application was large and included 4022 Casodex-treated patients and 4031 placebo-treated patients. At the time of the data cutoff for the Safety Update, total exposure to study drug was 9,387 patient-years in the Casodex treatment group and 9,778 patient-years in the placebo treatment group. Total patient exposure to Casodex and safety monitoring in Trials 23, 24, and 25 was adequate to assess the likely safety profile of Casodex 150 per day in men with prostate cancer.

  1. Dosing Regimen
    1. Dosing Regimen
    2. The proposed dosing-regimen is Casodex 150 mg per day for at least 2 years or until disease progression. The proposed dose appears to be appropriate based on dose-ranging data provided in an earlier submission (NDA 20-498/s006). The basis for the recommendation that treatment should continue for at least 2 years is unclear since the protocols for Trial 24 and Trial 25 recommended that treatment should continue for at least 5 years or until disease progression.

    3. Effects of Renal or Hepatic Impairment on Casodex Pharmacokinetics

    According to the Sponsor, renal impairment (as measured by creatinine clearance) had no significant effect on the elimination of total bicalutamide or the active R-enantiomer in doses up to 450 mg.

    Casodex is extensively metabolized by the liver. Limited data in subjects with severe hepatic impairment suggest that excretion of Casodex may be delayed and could lead to further accumulation.

  2. Conclusions and Recommendations
    1. Conclusions
      1. Benefits of Treatment with Casodex
      2. The Sponsor has provided statistically significant findings from 2 non-US clinical trials in men with non-metastatic prostate cancer (Clinical Trials 24 and 25) that treatment with Casodex 150 mg per day, compared to treatment with placebo, delayed progression of disease. Progression of disease was defined as (a) the appearance of new bone scan confirmed metastases, (b) other objectively confirmed progression of prostate cancer (as documented by magnetic resonance imaging, computerized tomography, sonography, or biopsy), or (c) death due to any cause in the absence of objectively documented progression of prostate cancer. In these trials, Casodex was studied as (1) adjuvant therapy in men previously treated by radical prostatectomy or radiotherapy or (2) immediate therapy (monotherapy) in patients who otherwise were to be managed by watchful waiting. In a third trial (Trial 23) that was conducted primarily within the US, there was no evidence that treatment with Casodex delayed disease progression. In this trial, Casodex was studies only as an adjuvant therapy following radical prostatectomy or radiotherapy. The relevance of the findings in the 2 non-US trials for men with prostate cancer in the US who might be treated with Casodex adjuvant therapy or Casodex monotherapy is uncertain at this time.

        The actual reduction in the incidence of (a) objective disease progression (based only on new bone scan confirmed metastases) and (b) death from any cause in the absence of disease progression within 2.5 years after entry into Trial 24 or Trial 25 was modest. In Trial 24, the proportion of patients with objective disease progression within 2.5 years of study entry decreased from 9.3% (placebo group) to 6.2% (Casodex group). In Trial 25, the proportion of patients with objective disease progression within 2.5 years of study entry decreased from 17.2% (placebo group) to 10.4% (Casodex group). Based on the information presented by the Sponsor, the short term clinical significance of this decrease in disease progression in Casodex-treated patients is not known as quality of life data (e.g., the proportion of symptomatic versus asymptomatic bone metastases) and other assessments of quality of life were not provided.

        The long-term clinical benefit of treatment with Casodex is unknown. There was no evidence of increased disease-specific survival or overall survival for Casodex-treated men in any of the 3 clinical trials. Median follow up time for disease progression was approximately 3 years, a short period for assessing the long-term benefits of a medical therapy for men with non-metastatic prostate cancer. It is possible, but entirely unproved at this time, that treatment with Casodex might improve disease-specific survival compared to placebo treatment.

        Medical therapy for early or locally advanced, non-metastatic prostate cancer. No medical therapy is presently approved by the FDA as monotherapy for early or locally advanced, non-metastatic prostate cancer. However, the present standard of care for patients with locally advanced, non-metastatic prostate cancer generally includes androgen deprivation therapy by medical or surgical castration.

        Casodex adjuvant therapy or Casodex monotherapy for men with non-metastatic prostate cancer may be equivalent to, but not superior to, treatment with a GnRH analog in terms of reducing disease progression. Both classes of drug (nonsteroidal anti-androgens and GnRH analogs) are thought to be effective in the management of prostate cancer by reducing androgen stimulation of cancer cells. However, nonsteroidal anti-androgens compared to GnRH analogs are likely to be less effective in vivo in blocking the effects of testosterone as there is a compensatory increase in serum testosterone concentrations during treatment with nonsteroidal anti-androgens. In some situation, (e.g., men with metastatic prostate cancer), this difference in pharmacological activity has important clinical consequences such as reduced survival as was shown in Trials 0306 and 0307 (NDA 20-498/s006) for patients with stage M1 disease. In other situations, efficacy may be similar and the difference in side effect profiles may be an important consideration in the choice of drug. Men treated with a GnRH analog are likely to have more severe and more frequent vasomotor symptoms (e.g., hot flashes), bone loss, and possibly more sexual dysfunction (impotence and decreased libido). Conversely, a very high proportion of men receiving 150 mg Casodex per day will develop gynecomastia and/or breast pain and are at a slightly greater risk for clinically significant hepatotoxicity.

      3. Risks of Treatment with Casodex

Adverse events associated with Casodex treatment can be classified for the most part into one of 2 categories:

  • Those of a non-life threatening nature that are due to the pharmacological actions of Casodex and which occur with a high incidence (i.e., gynecomastia and breast pain)
  • Those that occur in a few percent of patients and which may be severe or life threatening (primarily hepatotoxicity)

Gynecomastia and Breast Pain. In Trials 23, 24, and 25, gynecomastia alone was reported in 67.1% and 8.1% of Casodex-treated and placebo-treated patients, respectively. Gynecomastia or breast pain was reported to occur in 86.2% and 12.4% of Casodex-treated and placebo-treated patients, respectively. Breast pain was reversible in > 90% of patients after cessation of Casodex therapy. Gynecomastia, however, resolved in only 50% of patients with at least 1 or more follow up visits.

Hepatotoxicity. The safety data provided in NDA 20-498/s012 indicate that treatment with Casodex is associated with an increase in the incidence of liver toxicity compared to treatment with placebo. Liver-related toxicity is manifested primarily by an increase in the proportion of Casodex-treated patients with elevated serum transaminase levels, and to a lesser, elevated serum total bilirubin levels. Patient withdrawals due to increased serum ALT or AST values or increased bilirubin values were higher in Casodex-treated patients (1.2% and 0.4%, respectively) than in placebo-treated patients (0.5% and 0.2%, respectively). Similarly, adverse events due to increased serum ALT or AST values or increased bilirubin values classified as serious were more frequent in Casodex-treated patients (0.3% and 0.2%, respectively) than in placebo-treated patients (0.0% and <0.1%, respectively). However, the number of patients reported to have died from hepatic failure or a primary hepatic neoplasm was similar in the 2 treatment groups (5 of 4,022 Casodex-treated patients and 5 or 6 of 4,031 placebo-treated patients.

The current labeling for Casodex 50 mg and the proposed labeling for Casodex 150 mg state under the Warnings Section that "serum transaminase levels should be measured prior to starting treatment with CASODEX, at regular intervals for the first 4 months of treatment, and periodically thereafter..…If at any time a patient has jaundice, or the ALT level rises above 2 times the upper limit of normal, CASODEX should be discontinued."

The risk of serious hepatotoxicity in Casodex-treated patients with prostate cancer does not appear to be sufficient to preclude approval of the drug if the benefits of therapy are clinically and statistical significant.

      1. Summary of Risk-Benefit Analysis

The relevance of the findings in Trials 24 and 25 supporting the efficacy of adjuvant treatment and monotherapy with Casodex 150 mg per day to men with prostate cancer in the US is uncertain. Based on the data submitted by the Sponsor, patients similar to those enrolled in Trial 23 who are initially treated by radical prostatectomy or radiotherapy, would derive no benefit from Casodex adjuvant therapy. Such patients exhibited too few events of disease progression to warrant treatment with Casodex. Whether patients who would be treated by Casodex monotherapy, instead of watchful waiting in accordance with current medical practices in the US, would derive significant benefit also is uncertain. A watchful waiting subgroup was not included in Trial 23. Review of the baseline disease characteristics of the watchful waiting subgroups in Trials 24 and 25 indicated that many of these patients had more advanced prostate cancer than patients likely to be managed by watchful waiting alone in the US. The Sponsor has not show that patients presently managed by watchful waiting in the US would experience disease progression of sufficient magnitude to warrant treatment with Casodex and the side effects associated with such treatment. The Sponsor also has not shown that patients with locally advanced, non-metastatic prostate cancer treated by Casodex monotherapy would derive comparable benefit as patients treated by medical or surgical castration, the present standard of care in the US. Data previously submitted by the Sponsor from Trials 0306 and 0307 did not adequately support the Sponsor’s contention that Casodex treatment and castration (medical or surgical) were equally efficacious (based on survival) for the treatment of locally advanced non-metastatic prostate cancer. Patients with locally advanced prostate cancer who are treated with Casodex monotherapy may be at a slight survival disadvantage compared to men treated by medical or surgical castration.

In summary, the risks of treatment with Casodex 150 mg per day are justified and acceptable for patients who would derive significant clinical benefit from treatment. Such patients may be similar to those enrolled in Trials 24 and 25. However, based on data submitted to date by the Sponsor, it is not clear as to which patients in the US would derive significant clinical benefit from either adjuvant therapy or immediate monotherapy with Casodex. In the absence of such data, the risks of Casodex treatment for men in the US with non-metastatic prostate cancer are not warranted.

    1. Recommendations
      1. Recommendations Regarding Approvability (Based on Indications Submitted on 10 May 2002)

Indication No. 1: "CASODEX 150 mg is indicated as adjuvant therapy to radical prostatectomy and radiotherapy of curative intent in patients with locally advanced non-metastatic prostate cancer who have a high risk for disease recurrence."

  • Approval for Indication No. 1 is not recommended at this time

The Sponsor has not provided sufficient evidence (1) of efficacy for the adjuvant use of Casodex in men with prostate cancer initially treated by radical prostatectomy or radiotherapy in the US and (2) that the findings in Trials 24 and 25 are relevant to prostate cancer patients in the US. In particular, the data in the present application do not identify the subset of men with prostate cancer in the US who are most likely to benefit from Casodex adjuvant therapy.

Indication No. 2: "CASODEX 150 mg is indicated as immediate treatment of non-metastatic prostate cancer in patients for whom therapy of curative intent is not indicated."

  • Approval for Indication No. 2 is not recommended at this time.

The proposed indication does not adequately identify the population of prostate cancer patients in the US who might derive sufficient benefit from Casodex monotherapy to warrant the risks of treatment.

For local or early disease. The Sponsor has not provided sufficient evidence that the findings in Trials 24 and 25 are relevant to prostate cancer patients in the US who are currently managed by watchful waiting. In addition, the Sponsor will need to provide data demonstrating that prostate cancer-related morbidity or mortality in patients with localized prostate cancer occurs with a sufficiently high incidence that the potential benefits of Casodex treatment will out weight the adverse effects of treatment (e.g., gynecomastia, breast pain, and possible liver toxicity).

For locally advanced disease. Trials 24 and 25 were not conducted in accordance with present standards of care for patients with locally advanced, non-metastatic prostate cancer in the US. Since the comparator in these trials was placebo and not active therapy (i.e., medical or surgical castration), it is not possible to adequately address the efficacy of Casodex monotherapy. This is a critical issue since survival may be shortened in patients with locally advanced prostate cancer treated with Casodex monotherapy instead of by medical or surgical castration (the present standard of care in the US for such patients).

This concern has been addressed in part by the Sponsor’s second revision to the proposed indication for Casodex immediate therapy that was submitted on 22 October 2002. The second revision states that Casodex immediate treatment is indicated for the treatment of "localized non-metastatic prostate cancer in patients for whom therapy of curative intent is not indicated."

  1. References
  1. Wirth MP and Froehner M. Perspectives in adjuvant treatment of prostate cancer. Urologia Internationalis 2002;68:1-5.
  2. Messing EM et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999;341:1781-1788.
  3. Bolla M et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337:295-300.
  4. Hellerstedt BA and Pienta KJ. The current state of hormonal therapy for prostate cancer. CA: A Cancer Journal for Clinicians 2002;52:154-179.
  5. Wysowski DK and Fourcroy JL. Flutamide hepatotoxicity. J Urol 1996;155:209-212.

 

Appendix

(Supplemental Efficacy Analyses)

 

 

 

 

 

Supplemental Efficacy Analyses (Set No. 1)

  • Proportion of Patients with (1) Bone Scan Documented Progression or (2) Death from Any Cause in the Absence of Progress within 2.5 Years of Randomization as a Function of Baseline Disease Characteristics

Appendix Table 1a. Trial 23 ………………………………………………….. 121

Appendix Table 1b. Trial 24 ………………………………………………….. 122

Appendix Table 1c. Trial 25 ………………………………………………….. 123

 

Appendix Table 1a. Proportion of Patients with (1) Bone Scan Documented Progression or (2) Death from Any Cause in the Absence of Progress within 2.5 Years of Randomization as a Function of Baseline Disease Characteristics

(Trial 23)

 

Appendix Table 1b. Proportion of Patients with (1) Bone Scan Documented Progression or (2) Death from Any Cause in the Absence of Progress within 2.5 Years of Randomization as a Function of Baseline Disease Characteristics

(Trial 24)

Appendix Table 1c. Proportion of Patients with (1) Bone Scan Documented Progression or (2) Death from Any Cause in the Absence of Progress within 2.5 Years of Randomization as a Function of Baseline Disease Characteristics

(Trial 25)

 

 

 

 

 

 

 

 

 

 

Supplemental Efficacy Analyses (Set No. 2)

  • Proportion of Patients with (1) Bone Scan Documented Progression or (2) Death only from Prostate Cancer in the Absence of Progress within 2.5 Years of Randomization as a Function of Baseline Disease Characteristics

Appendix Table 2a. Trial 23 ………………………………………………….. 125

Appendix Table 2b. Trial 24 ………………………………………………….. 126

Appendix Table 2c. Trial 25 ………………………………………………….. 127

 

 

 

 

Appendix Table 2a Proportion of Patients with (1) Bone Scan Documented Progression or (2) Death only from Prostate Cancer in the Absence of Progress within 2.5 Years of Randomization as a Function of Baseline Disease Characteristics

(Trial 23)

 

Appendix Table 2b Proportion of Patients with (1) Bone Scan Documented Progression or (2) Death only from Prostate Cancer in the Absence of Progress within 2.5 Years of Randomization as a Function of Baseline Disease Characteristics

(Trial 24)

 

Appendix Table 2c Proportion of Patients with (1) Bone Scan Documented Progression or (2) Death only from Prostate Cancer in the Absence of Progress within 2.5 Years of Randomization as a Function of Baseline Disease Characteristics

(Trial 25)