The indication is restricted from the indication in the FDA supplemental New Drug Application for olaparib/abiraterone, which is for the population at-large in the BRCA–mutation positive setting.
The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 11 to 1 recommending approval of olaparib (Lynparza) for use in combination with abiraterone acetate (Zytiga) and prednisone or prednisolone for the first-treatment of adult patients with BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC).1,2
If the FDA decides to follow the panel’s recommendation, it would be approving the combination regimen for a restricted indication compared with the indication outlined in the original supplemental New Drug Application (sNDA) the FDA accepted from Merck and AstraZeneca in August 22.
The sNDA is for the use of the combination in the full frontline mCRPC population, without a restriction to only the BRCA–mutation positive sub-population.
“Today’s recommendation by the ODAC is disappointing news for clinicians and prostate cancer patients alike. Preventing or delaying radiographic progression is an important clinical endpoint in assessing oncologic treatment and is very relevant to patients, their caregivers and their families. It is essential that physicians and their patients have an opportunity to choose treatment with the goal of optimizing cancer care outcomes,” Neal Shore, MD, chief medical officer of urology and surgical oncology for GenesisCare, US and PROpel trial investigator, stated in a press release.2
The phase 3 PROpel trial (NCT03732820) provided the primary supporting data for the sNDA. Results from the study 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 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).3
Data from the final prespecified overall survival (OS) analysis showed that the median OS was 42.1 months in the abiraterone/olaparib cohort vs 34.7 months in the abiraterone/placebo cohort for 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.4
The ODAC panel reviewed these data but also conducted an analysis focused solely on the 11% of patients in the PROpel trial with confirmed BRCA mutations. In the briefing document for its meeting on the sNDA, the FDA reported that its analysis showed that patients with confirmed BRCA mutations accounted for much of the benefit observed with olaparib in the PROpel trial.
Specifically, the data showed that among patients with BRCA mutations, 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). In contrast, among patients without BRCA mutations, the addition of olaparib led to a 15% reduction in the risk of disease progression or death (HR, 0.85) and no reduction in the risk of death (HR, 1.06).
It was the results of this analysis that led ODAC to recommend a restricted, BRCA-focused indication for olaparib/abiraterone in this setting.
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.
The FDA will now make a final decision on the sNDA and if it decides to approve the application, it is not required to follow the ODAC recommendation; it can approve either a BRCA-restricted indication for olaparib/abiraterone or an indication for use in the overall frontline mCRPC population.
1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. April 28, 2023. Accessed April 28, 2023. https://www.youtube.com/live/KPyIswlHGPM
2. Update on FDA Advisory Committee Vote on LYNPARZA® (olaparib) Plus Abiraterone and Prednisone or Prednisolone in First-Line Metastatic Castration-Resistant Prostate Cancer. Published online April 28, 2023. https://bit.ly/3p52Bhe
3. 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
4. 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