Global Real-World Outcomes of Olaparib in Metastatic Castration-Resistant Prostate Cancer Patients With Homologous Recombination Repair Alterations

: Evidence to guide the treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) and Homologous Recombination Repair (HRR) gene alterations outside of clinical trials remains limited. This was an observational, cohort study, including mCRPC patients with tumor harboring HRR alterations, progressed on a prior androgen receptor pathway inhibitor, and treated with olaparib monotherapy from January 1, 2020, to April 30, 2025. Primary objectives were time on treatment (ToT) and overall survival (OS). Secondary objective was to explore the role of gene and type and location of pathogenic variant (PVs) as potential molecular predictors of olaparib benefit. We included 201 patients in the analysis. No significant differences in OS across distinct HRR gene subgroups were observed (median OS BRCA1/2 vs. non-BRCA HRR: 16.3 months [95% CI, 13.0-69.6] vs. 14.2 [95% CI, 12.0-22.9; p = 0.681]). Primary refractoriness to olaparib occurred in 36 (18%) patients and was associated with poor survival (1 year-OS rate of primary vs. non-primary refractory: 20% vs. 77%; p < 0.001). The 1 year-ToT rate of BRCA1 versus BRCA2 was 23% versus 39%, respectively (p = 0.021). Frameshift PVs in the BRCA2 gene were a prognostic factor for shorter OS. Differences in OS according to the PV location in the BRCA2 functional domains were also significant. Olaparib demonstrated clinical activity in this global, real world, population of mCRPC patients with HRR-altered tumors. Accurately detecting the multitude of variables associated with BRCA genetic variants represents a key area of research potentially affecting the patient's clinical outcomes.