Talazoparib Combo Significantly Improves Overall Survival in Metastatic CRPC

Findings from the phase 3 TALAPRO-2 trial showed that the safety profile of talazoparib was consistent with its known profile in metastatic CRPC.

The addition of talazoparib (Talzenna) to enzalutamide (Xtandi) exhibited enhanced overall survival (OS) vs enzalutamide plus placebo in patients with metastatic castration-resistant prostate cancer (CRPC) receiving ongoing androgen deprivation therapy, and naive to previous life-prolonging systemic therapy, according to findings from the phase 3 TALAPRO-2 trial (NCT03395197) published in The Lancet.1

Efficacy data revealed after a median follow up of 52.5 months (IQR, 48.6-56.0), the median OS in the talazoparib arm (n = 402) was 45.8 months (95% CI, 39.4-50.8) vs 37.0 months (95% CI, 34.1-40.4) with placebo (n = 403), with respective 4-year survival rates of 48% vs 38% (HR, 0.80; 95% CI, 0.66-0.96; P = .016). Additionally, the median radiographic progression-free survival (PFS) assessed by blinded independent review committee (BICR) was 33.1 months (95% CI, 27.4-39.0) vs 19.5 months (95% CI, 16.6-24.7), consistent with the primary analysis (HR, 0.67; 95% CI, 0.55-0.81; P <.0001).

In a prespecified exploratory subgroup analysis based on HRR gene alteration status, OS favored talazoparib in a subgroup of patients who were HRR-deficient (n = 169), with an HR of 0.55 (95% CI, 0.36-0.83; P = .0035). Additionally, among patients who have received previous androgen receptor pathway inhibitors (ARPIs; n = 50) and those who received prior docetaxel (n = 180), the respective HRs were 0.79 (95% CI, 0.40-1.55; P = .49) and 0.63 (95% CI, 0.42-0.94; P = .024).

“In conclusion, combining talazoparib with enzalutamide resulted in a statistically significant and clinically meaningful improvement in OS vs standard-of-care enzalutamide in the unselected cohort of TALAPRO-2,” primary investigator, Neeraj Agarwal, FASCO, MD, professor of medicine and Presidential Endowed Chair of Cancer Research at the Huntsman Cancer Institute at the University of Utah, wrote in the publication with study coinvestigators. “There were no new safety signals with extended follow-up. These results support the rationale for the combination and further support talazoparib plus enzalutamide as a standard-of-care initial treatment option for men with metastatic CRPC.”

Adult men 18 years and older with metastatic CRPC were randomly assigned 1:1 to receive talazoparib plus enzalutamide or enzalutamide plus placebo. Talazoparib was given orally once daily as two 0.25 mg capsules totaling 0.5 mg, or 0.35 mg daily as a 0.25 mg and 0.1 mg capsule in those with moderate renal impairment. Enzalutamide was given at 160 mg daily as four 40 mg capsules given at the same time as talazoparib or a matching placebo.

Treatment continued until radiographic progression, an adverse effect (AE)-related discontinuation, patient decision, or death. Those experiencing progression could continue treatment until the absence of clinical benefit.

Patients in the investigational or control arms had a median age of 71 years (IQR, 66-76) vs 71 years (IQR, 65-76), 60% vs 63% were White, 86% vs 86% had mild or no renal impairment, and 70% vs 70% had a Gleason score of 8 or greater. The baseline serum prostate-specific antigen (PSA) in the respective arms was 18.2 µg/L (IQR, 6.9-59.4) vs 16.2 µg/L (IQR, 6.4-53.4), and the baseline circulating tumor cell count was 1 (IQR, 0-7) vs 1 (IQR, 0-6) cell per 7.5 mL of blood.

The most common disease sites in the talazoparib and placebo arms included bone (87% vs 85%) and lymph nodes (37% vs 41%). Most patients had an ECOG performance score of 0 (64% vs. 67%), and the majority were HRR non-deficient (51% vs. 54%).

The primary end point of the study was radiographic PFS by BICR per RECIST v 1.1. The key α-protected secondary end point included OS. Other secondary end points included objective response rate, duration of soft tissue response, PSA response, time to PSA progression, and safety.

Treatment-related AEs (TRAEs) occurred in 90% vs 61% of the investigational and control arms, with 61% vs 19% of patients experiencing grade 3 or higher TRAEs. Serious AEs occurred in 46% vs 31% of the respective arms, including 42% vs 28% at a severity of grade 3 or higher. Grade 5 AEs were reported in 4% vs 5% of the respective arms.

The most common any-grade AEs in the talazoparib and placebo arms included anemia (68% vs 20%), neutropenia (38% vs 7%), and fatigue (35% vs 30%). The most common grade 3 to 4 AEs included anemia (49% vs 4%) and neutropenia (19% vs 1%). Discontinuations of talazoparib due to AEs occurred in 22% of patients, with 9% discontinuing due to anemia.

Reference

Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with metastatic castration-resistant prostate cancer: final overall survival results from the randomised, placebo-controlled, phase 3 TALAPRO-2 trial. Lancet. Published online July 16, 2025. doi:10.1016/S0140-6736(25)00684-1