Beyond BRCA : Real-world outcomes with poly(ADP-ribose) polymerase inhibitors among patients with metastatic castration-resistant prostate cancer and homologous recombination repair mutations.

89 Background: Poly(ADP-ribose) polymerase inhibitors (PARPi) are established therapies for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair mutations(m) (HRRm), with the greatest benefit in pts with BRCA mutation ( BRCA m). However, the real-world (rw) distribution of HRRm and outcomes following PARPi therapy, especially among those with non- BRCA HRRm, are not well defined. Methods: This retrospective cohort study selected from the US-based, EHR-derived deidentified Flatiron Health Research Database containing data from 373,536 pts with prostate cancer. Pts diagnosed with mCRPC between May 1, 2020 and June 30, 2025 and with evidence of an HRRm at any time were included. The PARPi treated subgroup included pts who received a PARPi-containing regimen on or after their mCRPC diagnosis and had an HRRm confirmed before or within the 30 days after PARPi initiation. rw overall survival (rwOS) and rw time to next treatment (rwTTNT) were measured from the start of the earliest PARPi line of therapy in the mCRPC setting using Kaplan-Meier curves and Cox proportional-hazards models adjusted for age, race, ethnicity, and the line (1L-3L+) of the PARPi therapy. Results: Of 27,771 pts diagnosed with mCRPC, 51% (n=14,046) were HRR tested, and 28% (n=3919) of those tested had HRRm. Of pts with HRRm, 34% had BRCA m and 66% had non- BRCA HRRm. ATM (32%), CHEK2 (20%), CDK12 (14%) were the most prevalent non- BRCA HRRm. Among pts with HRRm, PARPi receipt was higher in those with BRCA m 48% (n=636/1330) vs 29% in non- BRCA HRRm (n=739/2589). Of the PARPi treated subgroup (n=1343), 47% had a BRCA m and 53% were non- BRCA HRRm. Overall, PARPi was initiated 39% in 1L, 34% 2L and 27% 3L+; distributions were similar by BRCA status. Most pts in both groups received PARPi monotherapy. Baseline characteristics were similar across BRCA m/non- BRCA HRRm subgroups. Overall, median rwOS (months, 95% CI) was 15.19 (13.12-16.34) in pts with BRCA m vs 12.26 (11.01-13.87) in those with non- BRCA HRRm. Overall, rwTTNT (months, 95% CI) was longer in pts with BRCA m: 7.30 (6.61-7.92) vs 5.69 (5.33-6.25). In the adjusted Cox models, BRCA m was associated with lower hazard of death (0.83; 95% CI 0.71-0.96; p=0.013) and longer rwTTNT (0.78; 95% CI 0.69-0.89; p<0.001). Conclusions: In this large rw-mCRPC cohort, non- BRCA HRRm were more common than BRCA m; yet pts with non- BRCA HRRm were less likely to receive PARPi and experienced shorter survival and treatment duration. Variability in outcomes across HRR subgroups highlights biological and clinical heterogeneity among pts with mCRPC and HRRm and the need for better access to PARPi.