Effect of type and location of BRCA2 deleterious variant on prognosis and survival in metastatic prostate cancer: A longitudinal, international, cohort study from hormone-sensitive to castration-resistant settings.

10503 Background: Emerging evidence suggests that BRCA -altered prostate cancer (PC) is not a unique molecular subtype. However, the prognostic and therapeutic relevance of specific pathogenic/likely pathogenic variant (PV) in metastatic PC (mPC) remains poorly defined. We investigated the impact of BRCA2 PV type and position on clinical outcomes across across different metastatic settings. Methods: This international, hospital-based cohort study (Jan 2020–Apr 2025) included mPC patients (pts) across 29 centers who underwent germline, somatic, and/or ctDNA BRCA testing. Analysis included three settings: 1) mHSPC (ADT+docetaxel vs. ADT+ARPi); 2) mCRPC (ARPi vs. taxanes); 3) mCRPC treated with PARP inhibitors (PARPi). Outcomes Time on Treatment (ToT); Overall Survival (OS) were analyzed by PV type (frameshift, missense, nonsense, splicing; indels, SNV, CNV) and position: 1) Functional Domains (FDs) (RAD51-BD AA 900-2000 vs. DBD AA 2459-3190 vs. Others); 2) The recently identified Prostate Cancer Cluster Regions (PCCR) (c.756-c.1000 and 3' of c.7914 vs. Others). Results: Of 2.119 pts included, 401 harbored Homologous Recombination Repair PVs. In the cohort of 1.411 mHSPC pts, BRCA2 -mutated (n = 201) showed significantly shorter OS vs. wild-type (mOS 63 vs 76 months; HR 1.2, p = 0.02), regardless of first-line therapy. Contrary to previous reports, BRCA2 -mutated mHSPC pts had superior ToT from ADT+ARPi vs. ADT+docetaxel (55 vs 15 mos; HR 3.5, p < 0.001). Within the BRCA2 subgroup, PV location was highly prognostic for OS. In mHSPC, PCCR-outside variants (c.756-c.1000/3'of c.7914) and non-FD variants (RAD51-BD/DBD-outside) were associated with shorter OS (PCCR: 57 vs 97 mos, HR 4.0, p = 0.006; FD: 47 vs 88 mos, HR 3.0, p < 0.001). Similar prognostic impacts were confirmed in 684 mCRPC pts (PCCR: 78.0 vs 38.0 mos, HR 3.3, p = 0.01; FD: 64.0 vs 34.0 mos, HR 2.7; p = 0.009). Among 201 pts treated with olaparib, those with RAD51-BD PVs achieved significantly longer ToT (20.0 vs 7.0 mos; p = 0.01) and longer OS. Furthermore, frameshift deletions were associated with shorter OS compared to other PV types (15.9 vs 26.0 mos; p = 0.04). Conclusions: This is the largest longitudinal study to demonstrate that BRCA2 PV type and location are critical determinants of survival and treatment response in mPC. Our findings identify a "high-risk" molecular subgroup (PCCR and RAD51-BD/DBD-outside and frameshift deletions) with significantly poorer outcomes. These results provide a rationale for refined risk-stratification and personalized treatment selection, including early PARPi integration, in BRCA2 -mutated patients.