Comprehensive genomic profiling in prostate cancer: Clinical relevance of BRCA1/2 pathogenic variants in the mCRPC.

Abstract

210 Background: To delineate the genomic landscape of prostate cancer (PCa) and evaluate clinical outcomes of the PARP inhibitor olaparib in patients with pathogenic BRCA1/2 variants using a nationwide Japanese database. Methods: We conducted a retrospective cohort study of 5,893 patients with PCa registered in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) between June 2019 and June 2025. Comprehensive genomic profiling (CGP) was performed using five nationally approved assays, and results were reviewed by a Molecular Tumor Board (MTB). Clinical data were longitudinally collected. Overall survival (OS) was assessed from the initiation of first-line systemic therapy or from the start of olaparib. OS was compared according to homologous recombination repair (HRR) status and BRCA1/2 variant subtype. Results: Among 5,893 patients, 2,202 (37.4%) harbored ≥1 pathogenic HRR variant and 791 (13.4%) carried BRCA1/2 pathogenic variants. Olaparib was recommended for 792 patients, of whom 389 (49.1%) received it. Patients with HRR alterations had significantly shorter OS than those without (P = .021). BRCA1 variants were associated with worse OS compared with BRCA2 (P = .007). In BRCA2-mutated cases, those with BRCA2 loss demonstrated the most favorable survival (P < .001), whereas the I1859fs*3 variant showed a trend toward poorer outcomes. Multivariate analysis confirmed BRCA1 variants as independent adverse prognostic factors and BRCA2 loss as an independent predictor of improved outcomes. Conclusions: This nationwide analysis represents the largest real-world genomic cohort of PCa in Japan. Outcomes of olaparib varied by BRCA subtype: BRCA1 pathogenic variants were linked to poor prognosis, while BRCA2 loss predicted favorable response. These findings highlight the clinical importance of detailed genomic annotation to optimize precision oncology strategies in metastatic castration-resistant prostate cancer.