(UroToday.com) The 2025 GU ASCO annual meeting featured a prostate cancer session and a presentation by Dr. Neeraj Agarwal discussing final overall survival with talazoparib + enzalutamide as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial.
Real world median overall survival for mCRPC is generally <3 years, with nearly half of the patients only receiving one systemic therapy. Preclinical evidence for PARP inhibitors + an androgen receptor pathway inhibitor combination has been shown to extend benefit to patients with mCRPC without homologous recombination repair (HRR) gene alterations. The phase 3 TALAPRO-2 trial met its primary endpoint, showing improved radiographic progression free survival for talazoparib + enzalutamide versus placebo + enzalutamide as first line treatment in patients with mCRPC unselected for HRR gene alterations (all-comers; cohort 1).1 At GU ASCO 2025, Dr. Agarwal and colleagues reported the final overall survival data, a descriptive update of radiographic progression free survival, and extended safety follow-up in cohort 1.
In cohort 1, patients were randomized 1:1 to enzalutamide 160 mg + either talazoparib 0.5 mg (0.35 mg if moderate renal impairment) or placebo once daily and stratified by prior abiraterone or docetaxel (yes/no) for castration-sensitive prostate cancer and HRR gene alteration status. Key eligibility criteria included asymptomatic or mildly symptomatic mCRPC, ECOG PS ≤1, ongoing androgen deprivation therapy, and no prior life-prolonging therapy for CRPC:
The primary endpoint was radiographic progression free survival by blinded independent central review. Overall survival was an alpha-protected key secondary endpoint. For statistical significance in the final overall survival analysis, the stratified log-rank 2-sided p value needed to be ≤0.022 using a group sequential design with O’Brien-Fleming spending function.
Overall, 805 patients were randomized, 402 to talazoparib + enzalutamide and 403 to placebo + enzalutamide. The baseline characteristics are as follows:
At the data cutoff (September 3, 2024), 211 patients (52%) in the talazoparib + enzalutamide arm and 243 patients (60%) in the placebo + enzalutamide arm had died, with a median follow-up of 52.5 and 53.0 months, respectively. Consistent with the primary analysis, updated radiographic progression free survival data favored talazoparib + enzalutamide versus placebo + enzalutamide (HR 0.667, 95% CI 0.551–0.807) with a median radiographic progression free survival of 33.1 versus 19.5 months, respectively:
The hazard ratio for overall survival with talazoparib + enzalutamide versus placebo + enzalutamide was 0.796 (95% CI, 0.661–0.958; 2-sided p = 0.0155), with a median overall survival of 45.8 months (95% CI 39.4–50.8) versus 37.0 months (95% CI 34.1–40.4 months), respectively:
In all prespecified subgroup analyses, overall survival generally favored talazoparib + enzalutamide versus placebo + enzalutamide, as highlighted in the following forest plot:
In exploratory analyses of patients with results available for both circulating tumor DNA and tumor tissue, overall survival favored talazoparib + enzalutamide versus placebo + enzalutamide in patients without BRCA1/2 alterations (n = 439; HR 0.749, 95% CI 0.582–0.963) and in patients without HRR alterations (n = 314; HR 0.782, 95% CI 0.582–1.050; p = 0.101):
Among patients treated with talazoparib + enzalutamide, 37.4% received subsequently antineoplastic systemic therapies, compared to 52.6% for those receiving placebo + enzalutamide, most commonly docetaxel for both groups. Consistent with primary results, there were no new safety signals after an additional two years of follow-up. The most common grade ≥3 treatment emergent adverse events with talazoparib + enzalutamide were anemia (49%) and neutropenia (19%):
Treatment emergent adverse events were generally manageable, with 86 patients (22%) discontinuing talazoparib due to treatment emergent adverse events. Quality of life was maintained with talazoparib + enzalutamide, with a median time to deterioration of 41.5 months versus 34.1 months with placebo + enzalutamide (HR 0.878, 95% CI 0.704-1.096, p = 0.2487):
Dr. Agarwal concluded his presentation discussing final overall survival with talazoparib + enzalutamide as first-line treatment in unselected patients with mCRPC in the phase 3 TALAPRO-2 trial with the following take-home points:
- TALAPRO-2 is the first PARP inhibitor + androgen receptor pathway inhibitor combination study to show a statistically significant and clinically meaningful improvement in overall survival versus standard of care androgen receptor pathway inhibitor in mCRPC among patients in an unselected (Cohort 1) and selected for HRR gene alterations (Cohort 2 – poster presented at GU ASCO 2025)
- Median overall survival with talazoparib + enzalutamide was similar across the ITT and HRR-non-deficient and HRR-deficient subgroup populations, ranging from 46-47 months.
- The median radiographic progression free survival in the talazoparib group was 33.1 months, which was 13.6 months longer than the active control group.
- There were no new safety signals with extended follow-up
- These data support talazoparib + enzalutamide as a standard of care initial treatment options for mCRPC
Presented by: Neeraj Agarwal, FASCO, MD, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.
Related content: Talazoparib and Enzalutamide in Unselected mCRPC Patients - Neeraj Agarwal
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