Background
Phase III, double-blind, placebo-controlled RCT. 805 patients with first-line mCRPC all-comers (unselected for HRR status), receiving enzalutamide as backbone. Talazoparib (potent PARP1/2 trapper) added to enzalutamide to test the PARP + ARPI combination using an enzalutamide backbone rather than abiraterone. HRR-mutated patients pre-enrolled in a first cohort; all-comers in a second cohort.
Interventions and follow up
Arm A: Talazoparib 0.5mg/day orally + enzalutamide 160mg/day
Arm B: Placebo + enzalutamide 160mg/day
Primary endpoint: Radiographic PFS (rPFS) in all-comers
mFollow up: 24.9 mo
Arm B: Placebo + enzalutamide 160mg/day
Primary endpoint: Radiographic PFS (rPFS) in all-comers
mFollow up: 24.9 mo
Results
rPFS (all-comers): Not reached vs 21.9 mo, HR 0.63, P<.001
rPFS (HRR-mutated): Not reached vs 13.8 mo, HR 0.45, P<.001
rPFS (HRR-wildtype): Not reached vs 22.5 mo, HR 0.77
PSA response (≥50% decline): 71.0% vs 57.4%
rPFS (HRR-mutated): Not reached vs 13.8 mo, HR 0.45, P<.001
rPFS (HRR-wildtype): Not reached vs 22.5 mo, HR 0.77
PSA response (≥50% decline): 71.0% vs 57.4%
Adverse events
Overall: Grade ≥3 AEs 71.7% vs 40.6%; discontinuation due to AEs 18.7% vs 7.2%
Hematologic: Anemia grade ≥3 46.5% vs 1.0%; neutropenia grade ≥3 12.5% vs 1.0%; thrombocytopenia grade ≥3 9.0% vs 0.4%
Constitutional: Fatigue grade ≥3 5.8% vs 3.8%
Hematologic: Anemia grade ≥3 46.5% vs 1.0%; neutropenia grade ≥3 12.5% vs 1.0%; thrombocytopenia grade ≥3 9.0% vs 0.4%
Constitutional: Fatigue grade ≥3 5.8% vs 3.8%
Conclusions
Talazoparib + enzalutamide significantly improved rPFS in first-line all-comer mCRPC, with substantially greater benefit in HRR-mutated patients. The combination provides activity in the HRR-wildtype population as well, though the clinical significance of an rPFS benefit without OS data remains uncertain for unselected patients.
Key Limitations
Key Limitations: OS data were immature at primary analysis. Anemia rate of 46.5% grade ≥3 is the highest among PARP + ARPI combination trials and represents a major clinical management concern requiring close hematologic monitoring. The rPFS benefit in HRR-wildtype patients (HR 0.77) must be weighed against this toxicity burden. Talazoparib is a potent PARP trapper and may have different off-target effects than other PARP inhibitors. The 0.5mg fixed dose was selected without weight adjustment.
Clinical Context
FDA approved talazoparib + enzalutamide for HRR-mutated first-line mCRPC in 2023 — the only PARP + ARPI combination using an enzalutamide backbone. Clinicians must weigh the substantial anemia risk against efficacy. For BRCA1/2-mutated patients, all three approved PARP + ARPI doublets (olaparib + abi, niraparib + abi, talazoparib + enza) are options; toxicity, cost, and comorbidities guide selection.
References
References: Agarwal N et al, Lancet 2023