As reported in The Lancet by Neeraj Agarwal, MD, FASCO, and colleagues, the phase III TALAPRO-2 trial has shown that the addition of talazoparib to enzalutamide improved radiographic progression–free survival vs enzalutamide alone in the first-line treatment of patients with metastatic castration-resistant prostate cancer.

Findings from the trial in patients with homologous recombination repair (HRR) gene–mutated disease supported the June 2023 approval of talazoparib plus enzalutamide in HRR gene–mutated metastatic castration-resistant prostate cancer.

Neeraj Agarwal, MD, FASCO

Study Details

In the double-blind trial, 805 patients from sites in 26 countries were randomly assigned between January 2019 and September 2020 to receive talazoparib at 0.5 mg once daily (n = 402) or placebo (n = 403); both groups also received enzalutamide at 160 mg once daily. Treatment continued until radiographic progression or unacceptable toxicity. The primary endpoint was radiographic progression–free survival on blinded independent central review in the intention-to-treat population.

Progression-Free Survival

Median follow-up for radiographic progression–free survival was 24.9 months in the talazoparib group and 24.6 months in the control group. Median radiographic progression–free survival was not reached (95% confidence interval [CI] = 27.5 months to not reached) in the talazoparib group vs 21.9 months (95% CI = 16.6–25.1 months) in the control group (hazard ratio [HR] = 0.63, 95% CI = 0.51–0.78, P < .0001). In subgroup analysis by HRR gene alteration status, hazard ratios for radiographic progression–free survival were 0.46 (95% CI = 0.30–0.70, P = .0003) among patients with a status of deficient and 0.70 (95% CI = 0.54–0.89, P = .0039) among those with a status of nondeficient or unknown.

Overall survival data were immature. At data cutoff, death had occurred in 31% of patients in the talazoparib group and 32% of those in the control group (HR = 0.89, 95% CI = 0.69–1.14, P = .35). Confirmed objective response rates among patients with measurable disease at baseline were 62% vs 44%, with complete response in 38% vs 18%.  Median response durations were 20.4 months (95% CI = 16.1 months to not reached) vs 19.8 months (95% CI = 12.9 months to not reached).

Adverse Events

Grade ≥ 3 adverse events occurred in 75% of those in the talazoparib group vs 45% of those in the control group; the most common events in the talazoparib group were anemia (46%) and neutropenia (18%). Serious adverse events occurred in 39% vs 27% of patients. Adverse events led to discontinuation of talazoparib in 19% and placebo in 12% of patients, and to discontinuation of enzalutamide in 11% in each group. Myelodysplastic syndrome and acute myeloid leukemia occurred in one patient each in the talazoparib group. Treatment-related death occurred in no patients in the talazoparib group and in two patients in the control group.

The investigators concluded: “Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in radiographic progression–free survival vs standard of care enzalutamide as first-line treatment for patients with metastatic castration-resistant prostate cancer. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumor HRR gene alterations.”

Dr. Agarwal, of Huntsman Cancer Institute, University of Utah, Salt Lake City, and Karim Fizazi, MD, of Institut Gustave Roussy, University of Paris-Saclay, Villejuif, France, are the corresponding authors for The Lancet article.

Disclosure: The study was funded by Pfizer. For full disclosures of the study authors, visit thelancet.com.