Background
Phase III, open-label RCT. 387 patients with mCRPC and HRR gene alterations (Cohort A: BRCA1/2 or ATM mutations; Cohort B: 12 other HRR genes) who had progressed on prior abiraterone or enzalutamide. Tested olaparib as the first targeted therapy in molecularly selected mCRPC. HRR mutations present in ~28% of mCRPC patients by tumor testing.
Interventions and follow up
Arm A: Olaparib 300mg twice daily orally
Arm B: Investigator's choice: abiraterone 1000mg/day + prednisone OR enzalutamide 160mg/day (ARPI switch)
Primary endpoint: Radiographic PFS (rPFS) in Cohort A (BRCA1/2 + ATM)
mFollow up: 11.1 mo (primary rPFS); 21.9 mo (OS update)
Arm B: Investigator's choice: abiraterone 1000mg/day + prednisone OR enzalutamide 160mg/day (ARPI switch)
Primary endpoint: Radiographic PFS (rPFS) in Cohort A (BRCA1/2 + ATM)
mFollow up: 11.1 mo (primary rPFS); 21.9 mo (OS update)
Results
rPFS (Cohort A): 7.4 vs 3.6 mo, HR 0.34, P<.001
OS (Cohort A): 19.1 vs 14.7 mo, HR 0.69, P=.02
rPFS (BRCA1/2 subset): 7.4 vs 3.6 mo, HR 0.22
rPFS (Cohort A+B): 5.8 vs 3.5 mo, HR 0.49
OS (Cohort A): 19.1 vs 14.7 mo, HR 0.69, P=.02
rPFS (BRCA1/2 subset): 7.4 vs 3.6 mo, HR 0.22
rPFS (Cohort A+B): 5.8 vs 3.5 mo, HR 0.49
Adverse events
Overall: Grade ≥3 AEs 51% (olaparib) vs 37%; discontinuation 16% vs 9%
Hematologic: Anemia grade ≥3 21% vs 5%; thrombocytopenia grade ≥3 4% vs 0%
GI/constitutional: Nausea (any) 40% vs 19%; decreased appetite (any) 20% vs 9%; fatigue grade ≥3 9% vs 4%
Hematologic: Anemia grade ≥3 21% vs 5%; thrombocytopenia grade ≥3 4% vs 0%
GI/constitutional: Nausea (any) 40% vs 19%; decreased appetite (any) 20% vs 9%; fatigue grade ≥3 9% vs 4%
Conclusions
Olaparib significantly prolonged rPFS and OS in BRCA1/2- or ATM-mutated mCRPC after ARPI progression, establishing HRR-mutation testing as essential in mCRPC and olaparib as the first precision medicine approach in this disease. The largest benefit was seen in BRCA1/2-mutated patients (HR 0.22 for rPFS).
Key Limitations
Key Limitations: Open-label design with ARPI comparator that has limited efficacy in the post-ARPI setting (CARD showed ~14% PSA response with ARPI switch), potentially inflating the olaparib benefit. The ATM-mutated subgroup showed smaller benefit (HR 0.67 in Cohort A analysis excluding BRCA), raising debate about whether ATM truly predicts olaparib response. Crossover from control to olaparib was permitted, confounding OS. Anemia and hematologic toxicity require monitoring and dose modifications.
Clinical Context
PROfound led to FDA approval of olaparib for BRCA1/2-mutated mCRPC in 2020 (later updated to all HRR gene alterations). It established tumor biomarker testing (HRR panel) as standard in mCRPC. PARP inhibitors are now also tested in combination with ARPIs in first-line mCRPC (PROpel, MAGNITUDE, TALAPRO-2), expanding the PARP inhibitor-eligible population beyond the post-ARPI setting. ESMO-MCBS: 4.
References
References: de Bono J et al, NEJM 2020