Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial.
Neeraj Agarwal, Arun Azad, Joan Carles, André P. Fay, Nobuaki Matsubara, Cezary Szczylik, Ugo De Giorgi, Jae Young Joung, Peter C.C. Fong, Éric Voog, Robert Jones Jones, Neal D. Shore, Curtis Dunshee, Stefanie Zschaebitz, Jan Oldenburg, Xun Lin, Cynthia G. Healy, Matko Kalac, Dana A. Kennedy, Karim Fizazi
Abstract
LBA18 Background: The Phase 3 TALAPRO-2 trial met its primary endpoint, showing improved radiographic progression-free survival (rPFS) for TALA + ENZA vs placebo (PBO) + ENZA as 1L treatment in pts with mCRPC unselected for homologous recombination repair (HRR) gene alterations (all-comers; cohort 1). Here we report final OS data, a descriptive update of rPFS, and extended safety follow-up in cohort 1. Methods: In cohort 1, pts were randomized 1:1 to ENZA 160 mg + either TALA 0.5 mg (0.35 mg if moderate renal impairment) or PBO once daily and stratified by prior abiraterone or docetaxel (yes/no) for castration-sensitive PC 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 rPFS by blinded independent central review. OS was an alpha-protected key secondary endpoint. For statistical significance at the final OS 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. Results: Overall, 805 pts were randomized, 402 to TALA+ENZA and 403 to PBO+ENZA. At data cutoff (Sept 3, 2024), 211 pts (52%) in the TALA + ENZA arm and 243 pts (60%) in the PBO + ENZA arm had died; median follow-up was 52.5 and 53.0 months, respectively. Hazard ratio (HR) for OS with TALA + ENZA vs PBO + ENZA was 0.796 (95% CI, 0.661–0.958; 2-sided P =0.0155); median OS (95% CI), 45.8 months (39.4–50.8) vs 37.0 months (34.1–40.4 months), respectively. In prespecified subgroup analyses, OS favored TALA + ENZA vs PBO + ENZA in pts who were HRR-deficient (n=169; HR, 0.549; 95% CI, 0.364–0.826; P =0.0035) or HRR–non-deficient/unknown (n=636; HR, 0.878; 95% CI, 0.713–1.080; P =0.218). In exploratory analyses of pts with results available for both circulating tumor DNA and tumor tissue, OS favored TALA + ENZA vs PBO + ENZA in pts without BRCA1/2 alterations (n=439; HR, 0.749; 95% CI, 0.582–0.963; P =0.024) and in pts without HRR alterations (n=314; HR, 0.782; 95% CI, 0.582–1.050; P=0.101). Consistent with the primary analysis, updated rPFS data favored TALA + ENZA vs PBO + ENZA (HR, 0.667; 95% CI, 0.551–0.807; P <0.0001); median rPFS, 33.1 vs 19.5 months, respectively. Consistent with primary results, the most common grade ≥3 TEAEs with TALA + ENZA were anemia (49%) and neutropenia (19%). TEAEs were generally manageable; 86 pts (22%) discontinued TALA due to TEAEs. Conclusions: TALA + ENZA demonstrated a statistically significant and clinically meaningful improvement in OS vs standard-of-care ENZA as 1L treatment in pts with mCRPC unselected for HRR gene alterations. rPFS continued to favor TALA + ENZA. No new safety signals were identified with extended follow-up. Clinical trial information: NCT03395197 .