The phase 3 PROpel trial provided the primary supporting data for the approval.
Olaparib (Lynparza) has been approved for use in combination with abiraterone acetate (Zytiga) and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test.1
The phase 3 PROpel trial (NCT03732820) provided the primary supporting data for the approval. The overall study results in the intent-to-treat (ITT) showed that adding olaparib to frontline abiraterone acetate and prednisone/prednisolone significantly improved radiographic progression-free survival (rPFS) compared with abiraterone and prednisone/prednisolone alone in patients with mCRPC.
The FDA decision to limit the approval to the BRCA mutation–positive population was based on a subanalysis that focused solely on the 11% (n = 85) of patients in the PROpel trial with confirmed BRCA mutations. In this subgroup, the addition of olaparib to abiraterone led to a 76% reduction in the risk of disease progression or death vs abiraterone alone (HR, 0.24) and a 70% reduction in the risk of death (HR, 0.3). The median rPFS was not reached in the olaparib with abiraterone arm compared to 8 months (95% CI, 6-15) for those receiving placebo with abiraterone.
In contrast, among patients without BRCA mutations (n = 711), the addition of olaparib only led to a 23% reduction in the risk of disease progression or death (HR, 0.77) and no reduction in the risk of death (HR, 0.96).
In the overall ITT population, the median investigator-assessed rPFS was 24.8 months with olaparib/abiraterone vs 16.6 months with placebo/abiraterone, translating to a 34% reduction in the risk of radiographic disease progression or death (HR, 0.66; 95% CI, 0.54-0.81; P <.0001).2
Data from the final prespecified overall survival (OS) analysis for the ITT population showed that the median OS was 42.1 months in the abiraterone/olaparib cohort vs 34.7 months in the abiraterone/placebo cohort, translating to a 19% reduction in the risk of death (HR, 0.81; 95% CI, 0.67-1.00; P = .0544). The maturity for survival was 47.9%. The results were not statistically significant.3
Overall PROpel trial
In the international, double-blind, phase 3 PROpel trial (NCT03732820), investigators randomized patients with mCRPC in the first-line setting 1:1 to receive olaparib at 300 mg twice daily plus abiraterone at 1000 mg daily (n = 399) or placebo and abiraterone at 1000 mg daily (n = 397). Patients could have received docetaxel in the metastatic hormone-sensitive prostate cancer (mHSPC) setting, but no prior abiraterone was allowed. Other NHAs were permitted if they were stopped at least 12 months prior to study enrollment. Patients also had ongoing androgen deprivation therapy and an ECOG performance status of 0 or 1.
Baseline characteristics were well-balanced between the 2 arms. The median age was 69.5 years (range, 43-91), and most patients had an ECOG performance status of 0 (70.1%). Of note, symptomatic patients (Brief Pain Inventory-Short Form ≥4 and/or opiate use) comprised 25.8% and 20.2% of olaparib- and placebo-treated patients, respectively; 22.5% of patients had received docetaxel at the mHSPC stage.
Regarding safety, adverse effects (AEs) occurred in 97.2% and 94.9% of olaparib/abiraterone- and placebo/abiraterone-treated patients, respectively; grade 3 or higher AEs occurred in 47.2% and 38.4% of patients, respectively. AE-related deaths occurred in 4.0% (n = 16) of those on the olaparib arm compared with 4.3% (n = 17) of patients on the placebo arm.
1. FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. Accessed May 31, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-prednisone-or-prednisolone-brca-mutated-metastatic-castration
2. Clarke NW, Armstrong AJ, Thiery Vuillemin A, et al; PROpel Investigators. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022;1(9). doi:10.1056/EVIDoa2200043
3. Clarke NW, Armstrong AJ, Thiery Vuillemin A, et al. Final overall survival (OS) in PROpel: abiraterone (abi) and olaparib (ola) versus abiraterone and placebo (pbo) as first-line (1L) therapy for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(suppl 6):LBA16. doi:10.1200/JCO.2023.41.6_suppl.LBA16