The final overall survival results from cohort 1 of the phase III TALAPRO-2 trial showed a statistically significant and clinically meaningful improvement with the PARP inhibitor talazoparib plus the androgen receptor inhibitor enzalutamide vs standard-of-care enzalutamide in treatment-naive patients with metastatic castration-resistant prostate cancer who were unselected for homologous recombination repair (HRR) gene alterations. The findings were presented by Agarwal et al at the 2025 ASCO Genitourinary Cancers Symposium, held February 13 to 15 in San Francisco (Abstract LBA18).

The trial previously met its primary endpoint, showing improved radiographic progression-free survival with talazoparib plus enzalutamide in cohort 1 and in those from cohort 2 with HRR-deficient disease.

“These data support talazoparib plus enzalutamide as a standard-of-care initial treatment option for patients with metastatic castration-resistant prostate cancer,” commented Dr. Agarwal.

Study Details

Patients who met the following criteria were eligible to enroll in the study:

• Asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer;
• Eastern Cooperative Oncology Group performance status score of up to 1;
• Ongoing androgen-deprivation therapy;
• No prior life-prolonging therapy for castration-resistant prostate cancer.

In cohort 1, 805 patients were randomly assigned in a 1:1 ratio to receive 160 mg of enzalutamide in combination with either 0.5 mg of talazoparib (0.35 mg if moderate renal impairment; n = 402) or a placebo (n = 403) once daily. Stratification factors included prior abiraterone or docetaxel for castration-sensitive prostate cancer (yes vs no) and HRR gene alteration status (deficient vs nondeficient or unknown).

The primary endpoint was blinded independent central review–assessed radiographic progression-free survival. Overall survival was evaluated as an alpha-protected key secondary endpoint. The final overall survival analysis required a stratified log-rank two-sided P value of less than or equal to .022 for statistical significance, following a group sequential design with the O'Brien-Fleming spending function.

Overall Survival

At data cutoff, 211 patients (52%) treated with talazoparib plus enzalutamide had died, with a median follow-up of 52.5 months. In the placebo plus enzalutamide group, 243 patients (60%) had died, with a median follow-up of 53.0 months.

The hazard ratio (HR) for overall survival for the talazoparib plus enzalutamide vs placebo plus enzalutamide group was 0.796 (95% confidence interval [CI] = 0.661–0.958, two-sided P = .0155); the median durations were 45.8 (95% CI = 39.4–50.8) and 37.0 (95% CI = 34.1–40.4) months, respectively. Based on prespecified subgroup analyses, overall survival favored talazoparib plus enzalutamide in patients who were HRR-deficient (n = 169; HR = 0.542, 95% CI = 0.361–0.814) or HRR-nondeficient/unknown (n = 636; HR = 0.874, 95% CI = 0.711–1.076). Exploratory analyses revealed that, in patients with both circulating tumor DNA and tumor tissue results, overall survival favored talazoparib plus enzalutamide in those without BRCA1/2 alterations (n = 439; HR = 0.749, 95% CI = 0.582–0.963, P = .0237) and in those without HRR alterations (n = 314; HR = 0.782, 95% CI = 0.582–1.050, P = .1008)

Other Updates

Updated radiographic progression-free survival data appeared to continue to favor enzalutamide in combination with talazoparib vs placebo (HR = 0.667, 95% CI = 0.551–0.807, P < .0001); the median durations were 33.1 and 19.5 months, respectively. Consistent with primary results, anemia (67.8%; grade 3–4: 49.0%) and neutropenia (37.7%; grade 3–4: 19.3%) were the most frequently reported all-cause treatment-emergent adverse events with talazoparib plus enzalutamide. A total of 21.6% of patients discontinued talazoparib because of treatment-emergent adverse events.

Results from cohort 2, which showed a significant overall survival benefit with the addition of talazoparib to enzalutamide in patients with HRR gene alterations, were also presented at the 2025 ASCO GU Cancers Symposium. “TALAPRO-2 is the first PARP inhibitor plus androgen receptor pathway inhibitor combination study to show a statistically significant and clinically meaningful improvement in overall survival vs [a] standard-of-care androgen receptor pathway inhibitor in metastatic castration-resistant prostate cancer in patients unselected and selected for HRR gene alterations,” Dr. Agarwal concluded.

Disclosure: Funding for this study was provided by Pfizer. For full disclosures of the study authors, visit meetings.asco.org.