Impact of BRCA alterations on androgen receptor pathway inhibition treatment outcome in advanced prostate cancer.

e17074 Background: Prostate cancer (PCa) is a heterogeneous disease at both molecular and clinical levels. Alterations in homologous recombination repair (HRR) pathways, found in approximately a quarter of metastatic PCas, are associated with adverse outcomes. We sought to understand how genomic alterations in HRR genes, particularly BRCA1/2, can impact Androgen Receptor Pathway Inhibitor (ARPI) treatment outcomes in advanced PCa. Methods: We conducted a retrospective analysis of pooled data from five randomized clinical trials investigating ARPIs (apalutamide (Apa) or abiraterone acetate (Abi) plus prednisone/prednisolone (Prd)) in metastatic castration sensitive (mCSPC), non-metastatic castration resistant (nmCRPC) or metastatic castration resistant (mCRPC) disease settings. All patients were treated with Abi and/or Apa based regimens or Androgen Deprivation Therapy (ADT) alone as in the table. A total of 878 patients with diagnostic biopsy tissue or blood plasma collected at screening or end of treatment were included in the analysis. Targeted panel sequencing or whole-exome-sequencing was performed to detect BRCA mutations. Patients with BRCA1/2 mutations in any longitudinal sample were considered BRCA altered. Radiographic progression-free survival and overall survival were compared between biomarker groups using Kaplan-Meier and Cox proportional-hazard models. Differences in subpopulations were controlled by trial as strata in the multivariate cox model. Results: Among 71 patients with diagnostic biopsy tissue and blood plasma samples, plasma testing showed positive percent agreement of 60% and negative percent agreement of 98.5% with tissue testing in calling BRCA alterations. With interpretation limited by sample size and other factors, in the full cohort of 878 patients, 4.3% (CI 2.3-7.7) nmCRPC, 6.1% (CI 3.6-10) mCSPC, and 6.4% (CI 4.2-9.5) mCRPC patients were BRCA altered. Among these 878 patients, BRCA altered patients were at increased risk of progression (HR=1.6 CI 1.1-2.4, p=0.01) and mortality (HR=1.7 CI 1.2-2.4, p=0.005) compared to BRCA wildtype. In 608 Apa and/or Abi treated patients, BRCA altered patients were at increased risk of progression (HR=1.8 CI 1.2-2.8, p-val=0.009) and mortality (HR=1.6 CI 1.02-2.35, p=0.04) compared to BRCA wildtype. Conclusions: These data show that poorer responses to treatment of BRCA altered patients are also seen when such patients are treated with ARPIs, which underlines the unmet need for new and targeted therapeutic approaches for these patients. Trial (ID) Disease Intervention Study patients SPARTAN (NCT01946204) nmCRPC Apa + ADT vs ADT 128 vs 129 TITAN (NCT02489318) mCSPC Apa + ADT vs ADT 84 vs 129 LATITUDE (NCT01715285) mCSPC Abi + Prd + ADT vs ADT 22 vs 12 ACIS (NCT02257736) mCRPC Apa + Abi + Prd vs Abi + Prd 124 vs 115 PCR2023 (NCT01867710) mCRPC Abi with 4 glucocorticoid regimes 135