1805P Efficacy of olaparib (ola) + abiraterone (abi) vs placebo (pbo) + abi in the non-BRCA mutation (non-BRCAm) subgroup of patients (pts) with metastatic castration-resistant prostate cancer (mCPRC) in the PROpel trial

PROpel (NCT03732820) met its primary endpoint with a significant investigator-assessed radiographic progression-free survival (IA rPFS) benefit with ola + abi vs pbo + abi in the intention-to-treat (ITT) population in first-line mCRPC (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P<0.001). At final pre-specified analysis there was a trend to improved overall survival (OS) with ola + abi vs pbo + abi (median 42.1 vs 34.7 months [m]; HR 0.81, 95% CI 0.67–1.00; P=0.0544). The greatest magnitude of benefits was seen in the BRCAm subgroup. Post hoc exploratory analyses were conducted to further investigate outcomes in non-BRCAm pts. PROpel was a phase 3 double-blind trial. Pts were enrolled irrespective of biomarker status and randomized 1:1 to receive ola (300 mg twice daily [bid]) or pbo, and abi (1000 mg once daily) + prednisone/prednisolone (5 mg bid). Treatment continued until radiographic disease progression, unacceptable toxicity or withdrawal of consent. Aggregated tumour tissue (FoundationOne®CDx) and ctDNA (FoundationOne®Liquid CDx) test results, performed after randomization and before primary analysis, were used to classify pt mutation status. Non-BRCAm pts had no positive BRCAm test result and at least 1 negative BRCAm tissue or ctDNA result. In the non-BRCAm subgroup (n=693), there was a meaningful clinical benefit across endpoints for pts treated with ola + abi (Table). Safety profile of the combination was consistent with the ITT population. Within the non-BRCAm subgroup, analyses by baseline clinical characteristics showed consistent effect and will be presented.Table: 1805PNon-BRCAmOla + abi (n=343)Pbo + abi (n=350)HR (95% CI)Median (m):IA rPFS*24.119.00.76 (0.61–0.94)BICR rPFS*27.616.60.72 (0.58–0.90)OS†39.638.00.91 (0.73–1.13)Median time to (m):PSA progression*22.113.10.63 (0.50–0.79)First subsequent therapy†24.019.90.84 (0.70–1.01)First cytotoxic chemotherapy†30.122.70.80 (0.66–0.97)Second progression or death†NCNC0.86 (0.65–1.14)PSA 50 response,* %78.671.4ORR,* %51.145.4FACT-P change from baseline†-6.3-5.3Any AE of CTCAE Grade ≥3,† %57.043.7Any AE with outcome of death, † %7.04.9*DCO1; 30/7/21 †DCO3; 12/10/22 AE, adverse event; DCO, data cutoff; NC, not calculable; ORR, objective response rate; PSA, prostate-specific antigen Open table in a new tab *DCO1; 30/7/21 †DCO3; 12/10/22 AE, adverse event; DCO, data cutoff; NC, not calculable; ORR, objective response rate; PSA, prostate-specific antigen Exploratory analyses across multiple endpoints support a clinically meaningful benefit with ola + abi vs pbo + abi in non-BRCAm pts and a safety profile consistent with the overall ITT population.