TALAPRO-3: Talazoparib (TALA) + enzalutamide (ENZA) compared with placebo (PBO) + ENZA for the treatment of patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) harboring homologous recombination repair (HRR) gene alterations.

Abstract

LBA5007 Background: In the Phase 3 TALAPRO-2 trial, adding the poly(ADP-ribose) polymerase inhibitor TALA to the androgen-receptor pathway inhibitor (ARPI) ENZA significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) in pts with metastatic castration-resistant prostate cancer (mCRPC), with the HRR-deficient cohort experiencing the greatest benefit. The TALAPRO-3 trial investigates the efficacy and safety of TALA + ENZA in men with mCSPC bearing HRR gene alterations. Methods: In the Phase 3, double-blind TALAPRO-3 trial, pts were randomized 1:1 to TALA 0.5 mg (0.35 mg if moderate renal impairment) or PBO plus ENZA 160 mg once daily, stratified by de novo vs relapsed mCSPC, high- vs low-volume disease, and BRCA vs non- BRCA mutational status. Key eligibility criteria are ECOG PS 0 or 1, presence of HRR gene alteration(s) ( ATM , ATR , BRCA1 , BRCA2 , CDK12 , CHEK2 , FANCA , MLH1 , MRE11A , NBN , PALB2 , RAD51C ) confirmed by tumor tissue and/or circulating tumor DNA testing, ongoing androgen deprivation therapy (ADT), no prior treatment with docetaxel (protocol amendment in Sept 2021), and ≤3 mo of ADT with or without an approved ARPI for mCSPC. Primary endpoint is investigator-assessed rPFS; OS is the alpha-protected key secondary endpoint. Results: 599 pts were randomized (300 to TALA + ENZA; 299 to PBO + ENZA). At a median follow-up of 37.6 mo (TALA + ENZA) and 37.7 mo (PBO + ENZA) at data cutoff (Feb 18, 2026), TALA + ENZA significantly improved rPFS vs PBO + ENZA (HR, 0.481; 95% CI, 0.357–0.647; 2-sided P <0.0001; median rPFS not reached vs 45.8 mo). The HR for rPFS was 0.368 (95% CI, 0.222–0.609) in the BRCA -mutated subgroup (n=207; 34.6%) and 0.567 (95% CI, 0.392–0.819) in the non- BRCA -mutated subgroup (n=392; 65.4%). Interim analysis of OS favored TALA + ENZA but has not reached statistical significance (74 deaths TALA + ENZA, 91 deaths PBO + ENZA; HR, 0.767; 95% CI, 0.564–1.044). The most common all-grade TEAEs in the TALA + ENZA group were anemia (71.2%), fatigue (28.4%), neutrophil count decreased (27.1%), neutropenia (22.1%), asthenia (21.4%) and white blood cell count decreased (21.4%), with no new safety signals identified. TEAEs were generally manageable with dose modifications; 56 pts (18.7%) discontinued TALA due to TEAEs. Conclusions: Treatment with TALA+ENZA led to a statistically significant and clinically meaningful improvement in the primary endpoint of rPFS with a trend towards improved OS vs standard-of-care ENZA in pts with HRR-deficient mCSPC. The safety profile was generally manageable and consistent with those for TALA and ENZA. Clinical trial information: NCT04821622 .