Efficacy of Olaparib Plus Abiraterone for Patients with Metastatic Castration-resistant Prostate Cancer and Single Homologous Recombination Repair Gene Mutations in PROpel.

Synthetic lethality between PARP inhibition by olaparib and homologous recombination repair deficiency due to BRCA2, ATM or CDK12 mutations, combined with androgen pathway blockade by abiraterone.

PROpel (phase 3 randomised 1:1 double-blind trial, NCT03732820) had met its primary endpoint, with improved radiographic progression-free survival for olaparib plus abiraterone versus placebo plus abiraterone in biomarker-unselected first-line metastatic castration-resistant prostate cancer (HR 0.66; 95% CI 0.54-0.81; p < 0.0001) and a median overall survival of 42.1 months, a 7.4-month improvement. This analysis reports efficacy in patients with single homologous recombination repair gene mutations, status determined before the primary analysis by aggregating tumour tissue (FoundationOne CDx) and circulating tumour DNA (FoundationOne Liquid CDx) assay results. Overall, 28.4% of patients harboured an HRR mutation, predominantly BRCA2 (7.3%), ATM (6.2%) and CDK12 (5.0%). Hazard ratios numerically favoured the combination for radiographic progression-free survival (BRCA2 HR 0.20; 95% CI 0.08-0.44) and overall survival (BRCA2 HR 0.20; 95% CI 0.07-0.48), with more modest, inconclusive effects for ATM and CDK12. Other single-gene mutations were too rare (fewer than 5 events per arm) for interpretation.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The useful message for the tumour board is the hierarchy among HRR genes: the striking effect is concentrated on BRCA2, whereas ATM and CDK12 still yield confidence intervals crossing 1, which argues against treating HRR deficiency as a single block. Note the scope limitation for the cancer geneticist: HRR status here is aggregated from tumour tissue and circulating tumour DNA, so germline and somatic events are conflated, and these data are not sufficient to extrapolate management for a germline carrier identified in clinic. These subgroup analyses are exploratory and unadjusted for multiplicity: they inform discussion, they do not define a gene-by-gene indication.

Analysis by Dr Thibaut Benquey