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Global Real-World Outcomes of Olaparib in Metastatic Castration-Resistant Prostate Cancer Patients With Homologous
Lorena Incorvaia1, Daniele Santini2, Marc R Matrana3
1Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), Section of Medical Oncology, University of Palermo, Palermo, Italy.
Abstract:
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.
Insights
Olaparib shows clinical activity in metastatic castration-resistant prostate cancer (mCRPC) with HRR alterations. Specific BRCA2 variants impact overall survival, highlighting the need for precise genetic analysis in treatment selection.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Limited evidence exists for treating metastatic castration-resistant prostate cancer (mCRPC) with Homologous Recombination Repair (HRR) gene alterations outside clinical trials.
- Androgen receptor pathway inhibitors are standard, but resistance necessitates alternative therapies.
- HRR gene alterations are increasingly recognized as therapeutic targets in mCRPC.
Purpose of the Study:
- To evaluate the real-world effectiveness of olaparib monotherapy in mCRPC patients with HRR alterations.
- To explore the role of specific HRR gene alterations and variant types/locations as predictors of olaparib benefit.
- To assess time on treatment (ToT) and overall survival (OS) as primary objectives.
Main Methods:
- Observational cohort study of 201 mCRPC patients with HRR alterations, treated with olaparib monotherapy.
- Data collected from January 1, 2020, to April 30, 2025.
- Analysis included time on treatment, overall survival, and exploration of gene-specific and variant-specific factors.
Main Results:
- Olaparib demonstrated clinical activity in this mCRPC population.
- No significant differences in OS were observed across distinct HRR gene subgroups (BRCA1/2 vs. non-BRCA HRR).
- Primary refractoriness to olaparib was associated with significantly poorer survival (1-year OS rate: 20% vs. 77%).
- Frameshift pathogenic variants (PVs) in BRCA2 and PV location within BRCA2 functional domains were prognostic for OS.
- Time on treatment differed between BRCA1 and BRCA2 alterations (1-year ToT: 23% vs. 39%).
Conclusions:
- Olaparib is a viable treatment option for mCRPC patients with HRR-altered tumors in a real-world setting.
- Precise characterization of BRCA genetic variants, including type and location, is crucial for predicting olaparib response and patient outcomes.
- Further research is needed to refine the understanding of molecular predictors for optimizing treatment strategies.
