Drug Trials Snapshots: TRUQAP
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the TRUQAP Prescribing Information for all the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
TRUQAP (capivasertib)
(TRUE-cap)
AstraZeneca
Approval date: November 16, 2023
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
TRUQAP is an oral kinase inhibitor approved for use in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations as detected by an FDA-approved test following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.
How is this drug used?
TRUQAP is an oral tablet given 400 mg orally twice daily (approximately 12 hours apart) with or without food, for four days followed by three days off treatment.
Who participated in the clinical trials?
The FDA approved TRUQAP based on safety and efficacy evidence from CAPItello-291, a study of 708 patients with advanced or metastatic HR-positive, HER2-negative breast cancer. This study was conducted at 181 sites in 19 countries in three different geographic regions worldwide: Region 1 includes the United States, Canada, Western Europe, Australia, and Israel; Region 2 includes Latin America, Eastern Europe, and Russia; and Region 3 includes Asia.
There were 44 patients enrolled in the United States, 21 in the TRUQAP arm and 23 in the placebo arm. The remaining 664 patients (94%) were enrolled outside the United States.
How were the trials designed?
TRUQAP was evaluated in a trial of 708 patients with locally advanced or metastatic HR-positive, HER2-negative breast cancer following recurrence or progression on or after initial therapy. Patients were randomized to receive either TRUQAP or placebo, given orally twice daily for four days followed by three days off treatment each week of 28-day treatment cycle.
Efficacy was based on 289 patients with PIK3CA/AKT1/PTEN-alterations. The major efficacy outcomes were investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Additional efficacy outcome measures were overall survival (OS), investigator-assessed objective response rate (ORR), and duration of response (DoR).
How were the trials designed?
TRUQAP was evaluated in CAPItello-291, a randomized, placebo-controlled trial of 708 patients with locally advanced or metastatic HR-positive, HER2-negative breast cancer following recurrence or progression on or after initial therapy. Eligible PIK3CA/AKT1 activating mutations or PTEN loss of function alterations were identified in the majority of formalin-fixed paraffin-embedded (FFPE) tumor specimens using FoundationOne®CDx next-generation sequencing (N=686). All patients were required to have progression on an aromatase inhibitor (AI)-based treatment in the metastatic setting or recurrence on or within 12 months of completing (neo)adjuvant treatment with an AI. Patients could have received up to two prior lines of endocrine therapy and up to one line of chemotherapy for locally advanced (inoperable) or metastatic disease. Patients were excluded if they had clinically significant abnormalities of glucose metabolism (defined as patients with diabetes mellitus Type 1, Type 2, requiring insulin treatment, or HbA1c ≥8% [63.9 mmol/mol]). Patients were randomized (1:1) to receive either 400 mg of TRUQAP (n=355) or placebo (n=353), given orally twice daily for four days followed by three days off treatment each week of 28-day treatment cycle. Fulvestrant 500 mg intramuscular injection was administered on Cycle 1 Days 1 and 15, and then at Day 1 of each subsequent 28-day cycle. Patients were treated until disease progression, or unacceptable toxicity. Randomization was stratified by presence of liver metastases (yes versus no), prior treatment with CDK4/6 inhibitors (yes versus no) and geographical region (as listed previously). The major efficacy outcomes were investigator-assessed PFS in the overall population, and in the population of patients whose tumors have PIK3CA/AKT1/PTEN-alterations (efficacy population) evaluated according to RECIST version 1.1. Additional efficacy outcome measures were OS, investigator-assessed ORR, and DoR.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes how many male and female patients were enrolled in the clinical trial used to evaluate the efficacy of TRUQAP.
Figure 1. Baseline Demographics by Sex, Efficacy Population
Source: Adapted from FDA Review
Figure 2 summarizes how many patients by race were enrolled in the clinical trial used to evaluate the efficacy of TRUQAP.
Figure 2. Baseline Demographics by Race, Efficacy Population
Source: Adapted from FDA Review
Figure 3 summarizes how many patients by age were enrolled in the clinical trial used to evaluate the efficacy of TRUQAP.
Figure 3. Baseline Demographics by Age, Efficacy Population
Source: Adapted from FDA Review
Figure 4 summarizes how many patients by ethnicity were enrolled in the clinical trial used to evaluate the efficacy of TRUQAP.
Figure 4. Baseline Demographics by Ethnicity, Efficacy Population
Source: Adapted from FDA Review
Who participated in the trials?
Table 1. Baseline Demographics of Patients in CAPItello-291
Demographic |
Overall Population | Efficacy Population1 | ||||
---|---|---|---|---|---|---|
TRUQAP N=355 n (%) |
Placebo N=353 n (%) |
Total N=708 n (%) |
TRUQAP N=155 n (%) |
Placebo N=134 n (%) |
Total N=289 n (%) |
|
Sex | ||||||
Male | 3 (0.8) | 4 (1.1) | 7 (1.0) | 2 (1.3) | 0 | 2 (0.7) |
Female | 352 (99) | 349 (99) | 701 (99) | 153 (99) | 134 (100) | 287 (99) |
Age group, years | ||||||
<50 | 76 (21) | 99 (28) | 175 (25) | 27 (17) | 29 (22) | 56 (19) |
≥50 to <65 | 164 (46) | 152 (43) | 316 (45) | 83 (54) | 60 (45) | 143 (50) |
≥65 to <75 | 91 (26) | 76 (23) | 167 (24) | 37 (24) | 28 (21) | 65 (23) |
≥75 | 24 (7) | 26 (7) | 50 (7) | 8 (5) | 17 (13) | 25 (9) |
Race | ||||||
Black or African American | 4 (1.1) | 4 (1.1) | 8 (1.1) | 2 (1.3) | 1 (0.7) | 3 (1.0) |
Native Hawaiian or other Pacific Islander | 1 (0.3) | 0 | 1 (0.1) | 0 | 0 | 0 |
American Indian or Alaska Native | 2 (0.6) | 2 (0.6) | 4 (0.6) | 1 (0.6) | 1 (0.7) | 2 (0.7) |
Asian | 95 (27) | 94 (27) | 189 (27) | 48 (31) | 35 (26) | 83 (29) |
White | 201 (57) | 206 (58) | 407 (57) | 75 (48) | 76 (57) | 151 (52) |
Other2 | 52 (15) | 47 (13) | 99 (14) | 29 (19) | 21 (16) | 50 (17) |
Ethnicity | ||||||
Hispanic or Latino | 31 (9) | 31 (9) | 62 (9) | 14 (9) | 10 (8) | 24 (8) |
Not Hispanic or Latino | 323 (91) | 322 (91) | 645 (91) | 141 (91) | 124 (92) | 265 (92) |
Source: Adapted from FDA Review
1 Efficacy population defined as patients with PIK3CA/AKT1/PTEN-altered tumors
2 FDA recommends not using the term “Other” when categorizing race and ethnicity. However, this category was included in the Applicant’s datasets.
What are the benefits of this drug?
A statistically significant difference in PFS was observed in the overall population and the efficacy population. An exploratory analysis of PFS in the 313 (44%) patients whose tumors did not have a PIK3CA/AKT1/PTEN-alteration showed a hazard ratio of 0.79 (95% CI:0.61, 1.02), indicating that the difference in the overall population was primarily attributed to the results seen in the efficacy population.
What are the benefits of this drug (results of trials used to assess efficacy)?
Efficacy results for PIK3CA/AKT1/PTEN-altered subgroup are presented in Table 2. Results from the blinded independent review committee assessment were consistent with the investigator-assessed PFS results. Overall survival results were immature at the time of the PFS analysis (30% of the patients died).
Table 2. Efficacy Results for CAPItello-291, Efficacy Population
Parameter |
TRUQAP N=155 |
Placebo N=134 |
|
---|---|---|---|
Investigator-assessed PFS | |||
Number of events (%) | 121 (78) | 115 (86) | |
Median, months (95% CI) | 7.3 (5.5, 9.0) | 3.1 (2.0, 3.7) | |
Hazard ratio (95% CI)a | 0.50 (0.38, 0.65) | ||
p-valueb | <0.0001 | ||
Investigator-assessed confirmed ORR | |||
Patients with measurable disease | 132 | 124 | |
ORR, % (95% CI) | 26 (19, 34) | 8 (4, 14) | |
Complete response, % | 2.3 | 0 | |
Partial response, % | 23 | 8 | |
Median DoR, months (95% CI) | 10.2 (7.7, NC) | 8.6 (3.8, 9.2) |
Source: Adapted from TRUQAP Prescribing Information
a Stratified Cox proportional hazards model stratified by presence of liver metastases (yes versus no), and prior use of CDK/6 inhibitors (yes versus no)
b Stratified log-rank test stratified by presence of liver metastases (yes versus no), and prior use of CDK4/6 inhibitors (yes versus no)
Abbreviations: CI, confidence interval; DoR, duration of response; NC, not calculable; ORR, objective response rate; PFS, progression free survival
Were there any differences in how well the drug worked in clinical trials among sex, race, and age?
- Sex: There was no biological rationale for a differential effect TRUQAP based on sex; however, there is not enough data to explore the efficacy results specifically in male patients.
- Race: TRUQAP worked similarly in White, Asian, and Black or African American or other patients.
- Age: TRUQAP worked similarly in patients younger and older than 65 years of age.
- Ethnicity: TRUQAP showed a hazard ratio above 1 for the Hispanic or Latino patients while the hazard ratio was below 1 for the non-Hispanic patients; however, there were only 24 Hispanic patients enrolled (n=14 for the TRUQAP arm versus n=10 for the placebo arm) making the data difficult to interpret and no conclusions can be drawn.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Table 3. Efficacy Results by Subgroup, Efficacy Population
Subgroup |
Efficacy Population, N=289 | |
---|---|---|
n | PFS Hazard ratio | |
Sex | ||
Male | 2 | NA |
Female | 287 | 0.55 (0.43, 0.72) |
Age, years | ||
<65 | 199 | 0.58 (0.43, 0.79) |
≥65 | 90 | 0.53 (0.33, 0.86) |
Race | ||
White | 151 | 0.59 (0.42, 0.85) |
Asian | 83 | 0.59 (0.36, 0.96) |
Black or African American and others | 55 | 0.41 (0.22, 0.75) |
Ethnicity | ||
Hispanic or Latino | 24 | 1.63 (0.63, 4.20) |
Not Hispanic or Latino | 265 | 0.51 (0.39, 0.67) |
Source: Adapted from FDA Review
Abbreviations: NA, not applicable; PFS, progression free survival
What are the possible side effects?
TRUQAP carries Warnings and Precautions for high blood sugar, diarrhea, and skin reactions.
The most common side effects were diarrhea, skin reactions, fatigue, nausea, mouth sores, and vomiting.
What are the possible side effects (results of trials used to assess safety)?
Overall, patients receiving TRUQAP experienced more side effects than patients receiving placebo, as well as more side effects that were severe. Patients receiving TRUQAP more often needed to change or discontinue dosing. Common toxicities in patients for whom TRUQAP is approved are described in Table 4
Table 4. Adverse Reactions ≥10% in Patients Who Received TRUQAP With a Difference Between Arms of ≥3% in CAPItello-291, Efficacy Population
Adverse Reaction |
TRUQAP, N=155 | Placebo, N=133 | ||
---|---|---|---|---|
All Grades % |
Grade 3 or 4 % |
All Grades % |
Grade 3 or 4 % |
|
Gastrointestinal disorders | ||||
Diarrhea | 77 | 12 | 19 | 0.8 |
Nausea | 35 | 1.3 | 14 | 0.8 |
Stomatitisa | 25 | 1.9 | 5 | 0 |
Vomiting | 21 | 1.9 | 7 | 0.8 |
Skin and subcutaneous tissue disorders | ||||
Cutaneous adverse reactionsb | 56 | 15 | 16 | 0.8 |
General disorders and administration site conditions | ||||
Fatiguea | 38 | 1.9 | 27 | 1.5 |
Metabolism and nutrition disorders | ||||
Hyperglycemiac | 19 | 1.9 | 4.5 | 0 |
Decreased appetite | 17 | 0 | 8 | 0.8 |
Nervous system disorders | ||||
Headachea | 17 | 0 | 13 | 0.8 |
Infections and infestations | ||||
Urinary tract infectiona | 14 | 0.6 | 5 | 0 |
Renal and urinary disorders | ||||
Renal injuryd | 11 | 2.6 | 1.5 | 0.8 |
Source: TRUQAP Prescribing Information
a Includes other related terms.
b Cutaneousadverse reaction includes butterfly rash, dermatitis, allergic dermatitis, dry skin, eczema, erythema multiforme, hand dermatitis, palmar-plantar erythrodysesthesia syndrome, pruritus, rash, erythematous rash, maculo-papular rash, papular rash, skin discoloration, skin fissures, skin reaction, skin ulcer, urticaria, purpura, erythema, and drug eruption.
c Hyperglycemia includes hyperglycemia, blood glucose increased, glycosylated hemoglobin increased, glucose tolerance impaired, and diabetes mellitus.
d Renal injury includes acute kidney injury, renal failure, renal impairment, glomerular filtration rate decreased, increased creatinine, and proteinuria.
Were there any differences in side effects among sex, race and age?
- Sex: There is no biological rationale for a differential safety profile for TRUQAP based on sex; however, there is not enough data to explore the safety results specifically in male patients.
- Race: There is no biological rationale for a differential safety profile for TRUQAP based on race; the safety of TRUQAP in patients with reported race of White (n=201), Asian (n=95), and all other races (n=59) was generally similar.
- Age: The occurrence of side effects that were severe or led to changes in dosing was higher in patients 65 years of age or older. FDA’s independent analysis of the safety of TRUQAP comparing patients ≥65 years of age (n=115) to younger patients (n=240) receiving TRUQAP suggests a higher incidence of Grade 3 to 5 adverse reactions (57% versus 36%), dose reductions (30% versus 15%), dose interruptions (57% versus 30%), and permanent discontinuations (23% versus 8%), respectively.
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.