Olaparib Boosts Survival in BRCA-Mutated mCRPC, PROpel Analysis Shows

A post hoc analysis of the phase 3 PROpel trial (NCT03732820) presented at the 2025 Genitourinary Cancers Symposium found that adding olaparib (Lynparza) to abiraterone (Zytiga) improved radiographic progression-free (rPFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC)with BRCA mutations.

Regarding rPFS in patients with a germline BRCA mutation (n = 25), events occurred in 33.3% vs 100% of those in the olaparib/abiraterone (n = 15) and placebo/abiraterone (n = 10) arms, respectively.; the median rPFS was not reached (NR) vs 6.9 months (HR, 0.13; 95% CI, 0.04-0.38). In patients with a somatic BRCA mutation (n = 52), events occurred in 25.9% vs 68.0% of those in the olaparib/abiraterone (n = 27) and placebo/abiraterone (n = 25) arms, respectively; the median rPFS was NR vs 11.1 months (HR, 0.19; 95% CI, 0.07-0.45).

Additionally, OS events occurred in 33.3% vs 90.0% of patients with germline BRCA mutations in the olaparib/abiraterone and placebo/abiraterone arms, respectively; the median OS was NR vs 18.4 months (HR, 0.23; 95% CI, 0.07-0.67). In patients with a somatic BRCA mutation, OS events occurred in 22.2% vs 60.0% of those in the olaparib/abiraterone and placebo/abiraterone arms, respectively; the median OS was NR vs 27.5 months (HR, 0.26; 95% CI, 0.09-0.65).

“First-line use of olaparib plus abiraterone resulted in clinical benefit for rPFS and OS in patients with mCRPC and a germline or somatic BRCA mutation,” said Fred Saad, CQ, MD, FRCS, FCAHS, in a poster presentation at the meeting. “[Therefore,] our results highlight the importance of comprehensive biomarker testing, including tumor tissue and circulating tumor DNA [ctDNA] testing to inform treatment options, such as intensification of therapy with the combination of olaparib plus abiraterone.”

Saad is a full professor in the Department of Surgery at the Université de Montréal, uro-oncologist and the Raymond Garneau Chair in Prostate Cancer at the University of Montréal Hospital Center (CHUM) Research Center (CRCHUM), head of Urology at CHUM, and director of Prostate Cancer Research at the Montréal Cancer Institute/CRCHUM in Canada.

PROpel Background and Trial Design

In May 2023, the FDA approved olaparib/abiraterone for the treatment of patients with deleterious or suspected deleterious BRCA-mutated mCRPC, as determined by an FDA-approved companion diagnostic test.²

At the primary analysis data cutoff of July 30, 2021, the trial met its primary end point of rPFS, demonstrating significantly prolonged rPFS with olaparib/abiraterone vs placebo/abiraterone HR, 0.66; 95% CI, 0.54-0.81; P <.001).³

The multicenter, randomized, double-blind, placebo-controlled PROpel study evaluated the efficacy, safety, and tolerability of first-line olaparib/abiraterone compared with placebo/abiraterone in patients with mCRPC who did not previously receive chemotherapy or new hormonal agents (NHAs) for mCRPC.⁴ Patients were randomly assigned to the olaparib/abiraterone (n = 399) or placebo/abiraterone arms (n = 397).¹ Those in the olaparib/abiraterone arm were treated with olaparib at 300 mg twice daily plus abiraterone at 1000 mg once daily in combination with prednisone or prednisolone at 5 mg twice daily; those in the placebo/abiraterone arm received placebo plus abiraterone at 1000 mg once daily with prednisone or prednisolone at 5 mg twice daily.

Eligibility criteria included being 18 years of age or older; having histologically or cytologically confirmed prostate adenocarcinoma; an ECOG performance status of 0 or 1; metastatic status with at least 1 documented metastatic lesion via bone scan or CT/MRI scan; and mCRPC in the first line.⁴ Additionally, patients needed to be asymptomatic, mildly symptomatic, or symptomatic with no prior exposure to abiraterone. Other NHAs were allowed if they were discontinued at least 12 months before enrollment.¹ Stratification factors included site of distant metastases (bone only vs visceral vs other), and receipt of prior taxane therapy for metastatic hormone-sensitive prostate cancer (yes vs no).¹

In addition to investigator-assessed rPFS and OS, which served as the primary and key secondary end points, respectively, additional planned analyses included time to first subsequent therapy or death; prostate-specific antigen (PSA) progression; time to second progression or death; confirmed decrease in PSA from baseline by 50% or greater; health-related quality of life; objective response rate; homologous recombination repair (HRR) mutation status; and safety and tolerability.

Baseline Characteristics of the Entire Study Population

Patients in the olaparib/abiraterone arm had a median age of 69.0 years (range, 63-74), and the majority were White (71%) and not Hispanic or Latinx (78%).⁵ The majority of patients had a Gleason score of 8 or greater (66%) and an ECOG performance status of 0 (72%). A total of 26% of patients in this arm were symptomatic, and 24% were treated with docetaxel prior to mCRPC. Most patients had their site of disease in the bone (87%), and did not have HRR gene mutations (aggregate, 70%; ctDNA testing, 67%; tumor tissue testing, 52%) or BRCA mutations (86%).

In the placebo/abiraterone arm, the median age was 70.0 years (range, 65-76), and the majority were White (69%) and not Hispanic or Latinx (77%). Most patients had a Gleason score of 8 or greater (65%) and an ECOG performance status of 0 (69%). A total of 20% of patients in this arm were symptomatic and 25% were treated with docetaxel prior to mCRPC. Most patients had their site of disease in the bone (85%), and did not have HRR gene mutations (aggregate, 69%; ctDNA testing, 67%; tumor tissue testing, 53%) or BRCA mutations (88%).

Previously Reported Trial Data

At the data cutoff of July 30, 2021, in the intent-to-treat (ITT) population the median rPFS per investigator assessment was 24.8 months vs 16.6 months in the olaparib/abiraterone arm vs the placebo/abiraterone arm, with a two-sided boundary for significance of 0.0324 (HR, 0.66; 95% CI, 0.54-0.81; P = .0001). Of note, the greatest effect size was demonstrated in the subgroup of patients with BRCA mutations, with a median investigator-assessed rPFS that was NR vs 8.4 months in the olaparib/abiraterone (n = 47) vs placebo/abiraterone arms (n = 38; HR, 0.23; 95% CI, 0.12-0.43), according to post hoc analyses published in Lancet Oncology.⁵

At the data cutoff of October 12, 2022, the median OS among patients from the ITT population was 42.1 months vs 34.7 months in the olaparib/abiraterone and placebo/abiraterone arms, respectively, with a two-sided boundary for significance of 0.0377 (HR, 0.81; 95% CI, 0.67-1.00; P = .0544).¹ Patients in the BRCA mutation subgroup had a median OS that was NR vs 23.0 months in the olaparib/abiraterone vs placebo/abiraterone arms (HR, 0.29; 95% CI, 0.14-0.56).

References

• Saad F, Armstrong A, Oya M, et al. Efficacy of olaparib (ola) plus abiraterone (abi) versus placebo (pbo) plus abi in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with a germline or somatic BRCA mutation in the PROpel trial. J Clin Oncol. 2025;43(suppl 5):219. doi:10.1200/JCO.2025.43.5_suppl.219

• FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. FDA. May 31, 2023. Accessed February 13, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-prednisone-or-prednisolone-brca-mutated-metastatic-castration

• Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022;1(9):EVIDoa2200043. doi:10.1056/EVIDoa2200043

• Study on olaparib plus abiraterone as first-line therapy in men with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated October 8, 2024. Accessed February 13, 2025. https://clinicaltrials.gov/study/NCT03732820

• Saad F, Clarke NW, Oya M, et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2024;25(5):e180. doi:10.1016/S1470-2045(24)00209-2