Background: PROpel (NCT03732820) met its primary endpoint and showed a significant investigator-assessed radiographic progression-free survival (rPFS) benefit with O + A vs P + A in first-line mCRPC (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P<0.001). At final prespecified analysis, median overall survival (OS) with O + A vs P + A was 42.1 vs 34.7 months (HR 0.81, 95% CI 0.67–1.00; P=0.0544). We report gene-by-gene efficacy of O + A vs P + A for pts from PROpel with a HRRm. Methods: PROpel was a Phase 3 randomized (1:1), double-blind trial. Pts were enrolled irrespective of biomarker status and received O (300 mg twice daily [bid]) or P, plus A (1000 mg once daily) and prednisone/prednisolone (5 mg bid). rPFS by investigator assessment was the primary endpoint (data cutoff [DCO]: 7/30/2021). OS was a key secondary endpoint (DCO: 10/12/2022). Following randomization and before primary analysis, HRRm status was assessed by tumor tissue (FoundationOne CDx) and ctDNA (FoundationOne Liquid CDx) tests and is reported using aggregated results from both tests. Genes assessed were ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. HR and CIs are not reported in subgroups with <5 events in either arm for both rPFS and OS. Results: 28.4% pts had an HRRm.For most pts with a single gene HRRm, there was a lower proportion of rPFS events and deaths in the O + A arm relative to the P + A arm (Table). The most prevalent gene mutations were BRCA2, ATM and CDK12; HRs for rPFS and OS numerically favored O + A (rPFS: BRCA2, HR 0.20, 95% CI 0.08–0.44; ATM, HR 0.55, 95% CI 0.20–1.38; CDK12, HR 0.51, 95% CI 0.20–1.18. OS: BRCA2, HR 0.20, 95% CI 0.07–0.48; ATM, HR 0.79, 95% CI 0.33–1.77; CDK12, HR 0.57, 95% CI 0.24–1.27). Conclusions:BRCA2, ATM and CDK12 were the most prevalent single gene mutations and clinical benefit was observed with O + A. Other single gene mutations were rare, limiting interpretation. The greatest treatment benefit was observed in pts with BRCA mutations. Clinical trial information: NCT03732820.

NR, not reached; BRIP1, RAD51B, RAD51D n=1; CHEK1, RAD51C n=0.