Genomic landscape and clinical impact of BRCA1/2 pathogenic variants in metastatic castration-resistant prostate cancer

Poly (ADP-ribose) polymerase (PARP) inhibitors provide clinical benefit for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 pathogenic variants. This study aimed to investigate the genomic landscape of mCRPC and evaluate the prognostic and therapeutic impact of pathogenic BRCA1/2 variants. We conducted a retrospective cohort study of 5893 patients with mCRPC registered in Japan. Overall survival (OS) was compared according to homologous recombination repair (HRR) gene alteration status and specific BRCA1/2 pathogenic variants. Of 5893 patients, 2203 carried at least one pathogenic variant in HRR genes, and 792 had BRCA1/2 pathogenic variants. Olaparib was recommended for all patients with BRCA1/2 pathogenic variants, of whom 389 received the treatment. Patients with HRR gene alterations had significantly shorter OS than those without (P = 0.023). Among olaparib-treated patients, BRCA1 pathogenic variants were significantly associated with worse OS compared with BRCA2 pathogenic variants (P = 0.008). Within BRCA2-altered cases, BRCA2 loss was associated with the most favorable OS (P < 0.001). Multivariate analysis confirmed BRCA1 pathogenic variants as an independent adverse prognostic factor and BRCA2 loss as an independent favorable factor in patients treated with olaparib. These findings highlight the clinical importance of detailed genomic annotation for precision oncology in mCRPC.