Background
Phase 3 RCT; N=270 metastatic castration-resistant prostate cancer (mCRPC) with BRCA1, BRCA2, or ATM alteration and progression after a second-generation androgen-receptor pathway inhibitor (ARPI); rucaparib vs physician's choice.
Interventions and follow up
Arm A: Rucaparib 600 mg PO BID
Arm B: Physician's choice control (docetaxel, or a second-generation ARPI [abiraterone or enzalutamide])
Primary endpoint: Imaging-based progression-free survival (mPFS)
mFollow up: 62 mo
Arm B: Physician's choice control (docetaxel, or a second-generation ARPI [abiraterone or enzalutamide])
Primary endpoint: Imaging-based progression-free survival (mPFS)
mFollow up: 62 mo
Results
Imaging mPFS (BRCA subgroup): 11.2 mo vs 6.4 mo, HR 0.50, 95% CI 0.36–0.69, P<.001.
Imaging mPFS (ATM subgroup): 8.1 mo vs 6.8 mo, HR 0.95, 95% CI 0.59–1.52 (NS).
mOS: 24.3 mo vs 20.8 mo, HR 0.81, 95% CI 0.58–1.12, P=.21 (NS, log-rank).
Imaging mPFS (ATM subgroup): 8.1 mo vs 6.8 mo, HR 0.95, 95% CI 0.59–1.52 (NS).
mOS: 24.3 mo vs 20.8 mo, HR 0.81, 95% CI 0.58–1.12, P=.21 (NS, log-rank).
Adverse events
Grade 3–4 overall: 60% vs 44% (A vs B).
Rucaparib most common (G3+): anemia, neutropenia, fatigue.
Control most common: fatigue, neutropenia.
Discontinuation: 15% vs 22%.
Rucaparib most common (G3+): anemia, neutropenia, fatigue.
Control most common: fatigue, neutropenia.
Discontinuation: 15% vs 22%.
Conclusions
Rucaparib significantly prolonged imaging-based PFS vs physician's choice in BRCA-altered mCRPC after ARPI; benefit was driven by the BRCA subgroup, with no clear effect in ATM-altered disease.
Key Limitations
PFS surrogate primary endpoint; OS not significantly improved (confounded by crossover); benefit limited to BRCA, not ATM; control arm allowed an ARPI switch (a known inferior strategy) which may inflate relative benefit; biomarker-selected population.
Clinical Context
FDA approved rucaparib for BRCA-mutated (germline/somatic) mCRPC after ARPI and a taxane (2020, accelerated), with TRITON3 as confirmatory; EMA approved. ASCO/ESMO recommend PARP inhibitors for BRCA-altered mCRPC and support germline/somatic HRR testing; reinforces molecular profiling in mCRPC.