Final TALAPRO-2 Analysis: Talazoparib Plus Enzalutamide Significantly Improves Survival in HRR-Deficient mCRPC

The final overall survival (OS) analysis from the phase III TALAPRO-2 trial confirms that the combination of talazoparib (TALA) and enzalutamide (ENZA) provides a statistically significant and clinically meaningful survival benefit for patients with homologous recombination repair (HRR)-deficient metastatic castration-resistant prostate cancer (mCRPC). Karim Fizazi, MD, Institut Gustave Roussy, presented the findings at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium.

The TALAPRO-2 trial previously demonstrated that TALA + ENZA significantly improved radiographic progression-free survival (rPFS) in HRR-deficient mCRPC patients. However, the data were immature at the first interim OS analysis, though early trends favored TALA + ENZA over enzalutamide alone. The latest analysis now provides final OS data, an update on rPFS, and extended safety follow-up.

The trial enrolled 399 patients with HRR-deficient tumors, who were randomized 1:1 to receive enzalutamide 160 mg plus either talazoparib 0.5 mg or placebo once daily. The study team stratified patients based on prior treatment with abiraterone or docetaxel for castration-sensitive prostate cancer. Eligible participants had asymptomatic or mildly symptomatic mCRPC, an ECOG performance status of 0–1, and had not received prior life-prolonging therapy for CRPC.

At a median follow-up of over 44 months, the OS hazard ratio (HR) was 0.622 (95% CI, 0.475-0.814; P<0.001) in favor of TALA + ENZA, representing a 38% reduction in the risk of death compared with enzalutamide alone. The median OS was 45.1 months (95% CI, 35.4-not reached) with TALA + ENZA, compared with 31.1 months (95% CI, 27.3-35.4) with placebo + ENZA.

Exploratory subgroup analyses indicated that the OS benefit was particularly pronounced in patients with BRCA1/2 alterations (HR, 0.497; 95% CI, 0.318-0.776; P=0.0017). Patients without BRCA1/2 alterations also trended toward improved survival (HR, 0.727; 95% CI, 0.516-1.024; P=0.0665), though statistical significance was not reached.

Updated rPFS data remained consistent with prior findings, further confirming the clinical benefit of the combination. TALA + ENZA reduced the risk of radiographic progression or death by 53% compared to enzalutamide alone (HR, 0.468; 95% CI, 0.359-0.612; P<0.0001). The median rPFS was 30.7 months for the combination therapy versus 12.3 months for enzalutamide alone.

The researchers found the safety profile of TALA + ENZA consistent with prior reports, with no new safety signals identified. The most common grade 3-4 treatment-emergent adverse events (TEAEs) in the TALA + ENZA arm were anemia (43%) and neutropenia (20%), both of which were manageable with supportive care. Only 13% (26 patients) discontinued talazoparib due to TEAEs, indicating that the combination was generally well tolerated.

According to Dr. Fizazi, the final OS analysis from TALAPRO-2 establishes TALA + ENZA as a new standard of care for patients with HRR-deficient mCRPC. The combination therapy significantly improves OS and rPFS, particularly in patients with BRCA1/2 alterations, while maintaining a manageable safety profile.