This pre-specified subgroup analysis of PROpel (phase 3, double-blind RCT) examined efficacy of olaparib plus abiraterone vs. placebo plus abiraterone as first-line therapy in patients with mCRPC harboring single homologous recombination repair gene mutations (HRRm), determined via tumor tissue and ctDNA assays.
Among the 28.4% of patients with an HRRm, BRCA2-mutated patients showed the strongest benefit: rPFS HR 0.20 (95% CI 0.08–0.44) and OS HR 0.20 (95% CI 0.07–0.48). ATM and CDK12 single-gene mutations showed numerically favorable but non-significant rPFS and OS HRs. Overall (biomarker-unselected), olaparib plus abiraterone improved rPFS (HR 0.66; p<0.0001) and median OS by 7.4 months (42.1 vs. ~34.7 mo).
- Subgroups for most single HRRm genes other than BRCA2, ATM, and CDK12 had fewer than 5 events per arm, severely limiting interpretation. - HRRm status was determined by aggregating two assay platforms (tumor tissue + ctDNA), which may introduce heterogeneity in mutation detection. - ATM and CDK12 confidence intervals were wide and crossed 1.0, so benefit in these subgroups remains uncertain.
Olaparib plus abiraterone provides a strong first-line benefit in mCRPC patients with BRCA2 mutations (rPFS and OS HR ~0.20) and should be prioritized in this group. For ATM and CDK12 single-gene mutations, benefit is numerically present but not statistically confirmed, so clinical judgment is needed.
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