In the phase III TALAPRO-3 trial, adding talazoparib to enzalutamide significantly improved imaging-based progression-free survival in patients with metastatic androgen pathway modulation–sensitive prostate cancer—also known as metastatic castration-sensitive prostate cancer—harboring homologous recombination repair (HRR) gene alterations. Agarwal et al reported the findings in The New England Journal of Medicine.
TALAPRO-3
The ongoing, international, double-blind trial enrolled patients with metastatic prostate adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, and an alteration in at least 1 of 12 homologous recombination repair genes.
Between June 2021 and May 2023, 599 patients were randomly assigned to receive once-daily talazoparib plus enzalutamide or placebo plus enzalutamide. All patients continued androgen-deprivation therapy unless they had undergone bilateral orchiectomy. The primary endpoint was investigator-assessed imaging-based progression-free survival; the key secondary endpoint was overall survival.
Baseline characteristics were similar between the treatment groups. Overall, 35% of patients had a BRCA1 or BRCA2 alteration, 71% had high-volume disease, and 84% had newly diagnosed metastatic disease.
Key Findings
After a median follow-up of about 38 months, the 3-year imaging-based progression-free survival rate was 77% with talazoparib plus enzalutamide vs 56% with placebo plus enzalutamide (hazard ratio [HR] = 0.48, P < .001). Median progression-free survival had not yet been reached with talazoparib and was 45.8 months with placebo.
Benefit from talazoparib plus enzalutamide was observed in both prespecified genomic subgroups. Among patients with BRCA1 or BRCA2 alterations, the 3-year imaging-based progression-free survival rate was 77% with talazoparib plus enzalutamide vs 49% with placebo plus enzalutamide. Among patients with non-BRCA alterations, 3-year rates were 76% with talazoparib plus enzalutamide and 60% with placebo plus enzalutamide.
In the interim overall survival analysis, the 3-year overall survival rate was 78% with talazoparib plus enzalutamide and 72% with placebo plus enzalutamide (HR = 0.77). The interim overall survival analysis did not meet the prespecified threshold for statistical significance, and follow-up is continuing.
At 3 years, 78% of patients in the talazoparib group and 63% of those in the control group were free from confirmed prostate-specific antigen progression; 79% and 62%, respectively, had not yet initiated subsequent anticancer therapy.
Grade 3 or higher adverse events occurred in 81% of patients receiving talazoparib plus enzalutamide and 44% of those receiving placebo plus enzalutamide; serious adverse events occurred in 42% and 32%, respectively. The most common adverse events with talazoparib were anemia, fatigue, and decreased neutrophil count. Grade 3 or higher anemia occurred in 51% of patients receiving talazoparib, and packed red-cell transfusions were given to 40% of patients in the talazoparib group vs 2% of those in the control group. Two treatment-related deaths occurred in the talazoparib group.
The investigators noted that talazoparib plus enzalutamide improved imaging-based progression-free survival, although treatment was associated with more serious adverse events.
“These findings highlight the importance of molecular testing in men with metastatic APMS prostate cancer,” the investigators wrote, noting that testing could enable biomarker-driven treatment strategies to be used earlier in the course of metastatic disease.
Neeraj Agarwal, MD, of Huntsman Cancer Institute, University of Utah, Salt Lake City, is the corresponding author of the article in The New England Journal of Medicine.
DISCLOSURE: The study was supported by Pfizer. For full disclosures of the study authors, visit www.nejm.org.
