Exploratory analyses of homologous recombination repair (HRR) gene subgroups and potential associations with secondary efficacy endpoints in the HRR-deficient population from TALAPRO-2.
Authors: Zschaebitz Stefanie , Fizazi Karim , Matsubara Nobuaki , Laird Douglas , Azad Arun , Shore Neal D. , ButtIgliero Consuelo , Szczylik Cezary , Fay Andre P. , Carles Joan , Jones Robert J , Voog Eric , Van Bruwaene Siska , De Giorgi Ugo , Yip Steven M. , Di Santo Nicola , Lin Xun , Healy Cynthia G. , Agarwal Neeraj 
Published: January 2024

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Background: TALAPRO-2 demonstrated statistically significant improvement in radiographic PFS with 1L talazoparib (TALA) + enzalutamide (ENZA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without HRR gene alterations (HRRm). Tumors were prospectively determined to harbor HRRm. Pts were randomized 1:1 to TALA 0.5 mg (N=200) or placebo (PBO; N=199) + ENZA 160 mg QD. Exploratory biomarker analyses assessed HRR gene subgroups and potential associations with secondary efficacy endpoints in pts with HRRm tumors. Methods: Prospective testing used a 12-gene HRR panel (HRR12) of FoundationOne CDx/FoundationOne Liquid CDx.For single gene groups, only pts bearing alteration(s) in that gene and no other HRR12 genes were analyzed. Gene cluster alteration dominance hierarchy: any BRCA1/2 alteration ( BRCA cluster); any PALB2 ( PALB2 cluster); any CDK12 ( CDK12 cluster); any ATM ( ATM cluster); all other HRR12 genes (each pt counted once). Endpoints: ORR, time to progression or death on first subsequent antineoplastic therapy (PFS2), PSA response ≥50%, time to PSA progression (TTPP), and time to initiation of cytotoxic chemotherapy (TTCC). Results: TALA + ENZA demonstrated differential benefit for BRCA2 single gene group across endpoints: ORR, 78.9% vs 33.3% (odds ratio [OR], 0.13 [95% CI, 0.03–0.63]); PFS2, median not reached (NR) vs 26.1 mo (HR, 0.44 [0.20–0.97]); PSA response >50%, 87.0% vs 58.3%; TTPP, NR vs 9.2 mo (HR, 0.20 [0.10–0.41]); TTCC, NR vs 17.0 mo (HR, 0.27 [0.13–0.57]). Similar broad benefit was seen for BRCA cluster and BRCA1 single gene groups and to a lesser extent PALB2 single gene and cluster groups (allowing for small n in the latter 3 groupings). Broad differential benefit was evident for CDK12 single gene group : ORR 70.0% vs 28.6% (OR 0.17 [0.01–2.03]); PFS2, 36.4 vs 18.8 mo (HR, 0.29 [0.11–0.75]); PSA response ≥50%, 85.7% vs 53.3%; TTPP, 13.8 vs 11.1 mo (HR 0.61 [0.29–1.26]); the exception was TTCC, NR vs NR (HR 1.32 [0.43–4.06]). Similar benefit was seen for CDK12 cluster. For ATM single gene group, differential numerical benefit was seen for ORR, 81.8% vs 20.0% (OR 0.06 [0.00–1.17]); TTPP, 26.8 vs 15.9 mo (HR, 0.61 [0.25–1.47]); TTCC, NR vs NR (HR 0.60 [0.18–1.96]); no differential benefit was seen in other endpoints (similar for ATM cluster). The CHEK2 single gene group showed numerically differential benefit for PSA endpoints and TTCC. The other HRR12 gene cluster typically showed comparable efficacy between arms with potential exception of TTPP, 28.6 vs 14.0 mo (HR 0.65 [0.33–1.31]), and TTCC, NR vs NR (HR 0.65 [0.26–1.62]). Conclusions: Broad differential efficacy benefit was evident for TALA + ENZA vs PBO + ENZA across multiple molecular subgroups and was most pronounced for the BRCA1- PALB2- BRCA2 axis and CDK12. Additional analyses are warranted. Clinical trial information: NCT03395197 .