Exploratory analyses of homologous recombination repair alterations (HRRm) by gene subgroup and potential associations with efficacy in the HRR-deficient population from TALAPRO-2.

Abstract

5019 Background: In TALAPRO-2, talazoparib (TALA) + enzalutamide (ENZA) significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) vs ENZA + placebo (PBO) in patients (pts) with mCRPC harboring HRRm assessed prospectively. Here we report exploratory biomarker analyses which assessed HRR by gene subgroup and potential associations with efficacy in pts enrolled in the HRR-deficient cohort from TALAPRO-2. Methods: Pts were randomized 1:1 to TALA 0.5 mg (N=200) or PBO (N=199) + ENZA 160 mg QD. HRRm testing used a 12-gene HRR panel (HRR12; clinical trial assays based on FoundationOne CDx and FoundationOne Liquid CDx). HRRm status categorization by gene incorporated all available tumor and prescreening/screening ctDNA records using an algorithm similar to that previously used by others (Fallah et al, JCO 2024 PMID: 38484203). For non- BRCA gene analyses, pts with co-occurring BRCA1/2 alterations were excluded. For BRCA1 , pts with co-occurring BRCA2 alterations were excluded. The efficacy endpoints assessed were overall response rate (ORR), rPFS, and OS. Data cutoff Sept 3, 2024. Results: For all HRRm pts, TALA + ENZA was superior to ENZA + PBO across all efficacy endpoints: ORR, 69.4% vs 39.1% (odds ratio [OR], 0.28 [95% CI, 0.13–0.61]); rPFS, median 30.7 vs 12.3 months (mo) (hazard ratio [HR]=0.47 [0.36–0.62]); OS, median 45.1 vs 30.8 mo (HR=0.60 [0.46–0.78]). TALA + ENZA vs ENZA + PBO demonstrated benefit for BRCA2m across endpoints: ORR, 86.4% vs 31.0% (OR, 0.07 [95% CI, 0.01–0.35]); rPFS, median not reached (NR) vs 10.9 mo (HR=0.25 [0.15–0.42]); OS, median NR vs 28.5 mo (HR=0.47 [0.29–0.76]). Similar rPFS and OS benefit was seen for BRCA1m and PALB2m (allowing for small n in the groups); for ORR, evaluable n of 8 across arms for each gene was too low to meaningfully assess ORR differences. Benefit for TALA + ENZA was also evident for CDK12m : ORR, 63.6% vs 22.2% (OR, 0.16 [95% CI, 0.01–1.61]); rPFS, 19.3 vs 13.8 mo (HR=0.36 [0.19–0.70]); OS, 36.4 vs 22.8 mo (HR=0.41 [0.23–0.74]). ATMm also showed benefit for TALA + ENZA: ORR, 75.0% vs 33.3% (OR, 0.17 [95% CI, 0.02–1.32]); rPFS, 30.4 vs 18.3 mo (HR=0.66 [0.37–1.18]); OS, 45.1 vs 39.5 mo (HR=0.70 [0.38–1.29]). CHEK2m showed modest overall benefit for TALA + ENZA: ORR, 53.3% vs 42.9% (OR, 0.66 [95% CI, 0.07–5.59]); rPFS, 24.8 vs 18.3 mo (HR=0.65 [0.34–1.22]); OS, 34.2 vs 39.5 mo (HR=0.96 [0.51–1.81]). The remaining six HRR12 genes could not be meaningfully assessed for efficacy benefit by gene with TALA + ENZA vs ENZA + PBO due to low mutational prevalence. Conclusions: An efficacy benefit was evident for TALA + ENZA vs PBO + ENZA across multiple mutational subgroups assessed by gene, and was most pronounced for the BRCA1-PALB2-BRCA2 axis and CDK12 , with benefit also apparent for ATM . Analyses of additional efficacy endpoints are planned and will be presented. Clinical trial information: NCT03395197 .