Journal: NPJ precision oncology
This retrospective Japanese cohort study evaluated 5,893 men with metastatic castration-resistant prostate cancer to characterize homologous recombination repair (HRR) gene alterations and their impact on prognosis and response to PARP inhibition.
Key findings:
- HRR alterations were common: 2,203 patients (∼37%) had at least one pathogenic HRR variant; 792 had BRCA1/2 pathogenic variants.
- Adverse prognostic impact of HRR alterations: Across the entire cohort, patients with HRR gene alterations had significantly shorter overall survival than those without HRR alterations (P = 0.023), underscoring their adverse prognostic impact.
- Olaparib use in BRCA1/2 variants: Olaparib was recommended for all patients with BRCA1/2 pathogenic variants; 389 actually received olaparib.
- Differences between BRCA1 and BRCA2 in olaparib-treated patients:
- BRCA1 pathogenic variants: Associated with significantly worse overall survival than BRCA2 pathogenic variants (P = 0.008) and emerged as an independent adverse prognostic factor in multivariable analysis.
- BRCA2 loss: Within BRCA2-altered cases, BRCA2 loss (presumably biallelic or clear loss events) was associated with the most favorable overall survival (P < 0.001) and was an independent favorable factor on multivariable analysis.
Clinical implications:
- Heterogeneity of HRR and BRCA1/2 alterations: Not all HRR or BRCA1/2 alterations carry the same prognostic or predictive weight in mCRPC.
- Value of detailed genomic annotation: Detailed genomic annotation (including distinguishing BRCA1 vs BRCA2, and characterizing BRCA2 loss specifically) refines prognostication and helps anticipate benefit from olaparib.
- Need for granular molecular profiling: The data support more granular molecular profiling beyond a simple “HRR altered” or “BRCA1/2 mutated” label when making treatment decisions in mCRPC.