TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations.

Karim Fizazi Institut Gustave Roussy, University of Paris-Saclay, Villejuif, France info_outline Karim Fizazi, Arun Azad, Nobuaki Matsubara, Joan Carles, Andre P. Fay, Ugo De Giorgi, Jae Young Joung, Peter C.C. Fong, Eric Voog, Robert J. Jones, Neal D. Shore, Curtis Dunshee, Stefanie Zschaebitz, Jan Oldenburg, Xun Lin, Cynthia G. Healy, Nicola Di Santo, Fabian Zohren, Neeraj Agarwal

Authors Karim Fizazi Institut Gustave Roussy, University of Paris-Saclay, Villejuif, France info_outline Karim Fizazi, Arun Azad, Nobuaki Matsubara, Joan Carles, Andre P. Fay, Ugo De Giorgi, Jae Young Joung, Peter C.C. Fong, Eric Voog, Robert J. Jones, Neal D. Shore, Curtis Dunshee, Stefanie Zschaebitz, Jan Oldenburg, Xun Lin, Cynthia G. Healy, Nicola Di Santo, Fabian Zohren, Neeraj Agarwal Organizations Institut Gustave Roussy, University of Paris-Saclay, Villejuif, France, Peter MacCallum Cancer Centre, Melbourne, Australia, National Cancer Center Hospital East, Chiba, Japan, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, PUCRS School of Medicine, Porto Alegre, Brazil, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, Meldola, Italy, National Cancer Center, Goyang-Si, South Korea, Auckland City Hospital and University of Auckland, Auckland, New Zealand, Clinique Victor Hugo Centre Jean Bernard, Le Mans, France, School of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom, Carolina Urologic Research Center, Myrtle Beach, SC, Arizona Urology Specialists, Tucson, AZ, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany, Akershus University Hospital (Ahus), Lørenskog, Norway, Pfizer Inc., La Jolla, CA, Pfizer Inc., Collegeville, PA, Pfizer Inc., Durham, NC, Huntsman Cancer Institute (NCI-CCC), University of Utah, Salt Lake City, UT Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Pfizer Inc., Astellas Pharma Inc. provided enzalutamide Background: TALAPRO-2 is the first phase 3 study to combine the poly(ADP-ribose) polymerase inhibitor TALA with the androgen receptor inhibitor ENZA in pts with 1L mCRPC unselected (Cohort 1—previously reported) or selected (Cohort 2) for HRR gene alterations. Here, we report results of the prespecified, independently powered analysis of pts with mCRPC with HRR gene alterations from Cohorts 1 and 2. Methods: From February 2019 to January 2022, 399 pts (169 from Cohort 1) were randomized 1:1 to receive TALA 0.5 mg or PBO (all received ENZA 160 mg) once daily. Randomization was stratified by prior abiraterone or docetaxel for castration-sensitive PC (yes vs no). Key eligibility criteria: mildly or asymptomatic mCRPC with disease progression at study entry, HRR-deficient status prospectively confirmed by tumor tissue and/or ctDNA testing (genes tested: ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), ECOG PS ≤1, ongoing androgen deprivation therapy, no prior life-prolonging therapy for CRPC. Primary endpoint: radiographic progression-free survival (rPFS) by BICR per RECIST 1.1 and PCWG3. Results: 200 pts received TALA + ENZA and 199 PBO + ENZA. TALA + ENZA significantly improved rPFS by BICR (HR 0.45; 95% CI, 0.33–0.61; 2-sided P< 0.001; median PFS not reached vs 13.8 months). The HR for rPFS by BICR was 0.20 (95% CI, 0.11–0.36; P< 0.001) for the BRCA1/2 subgroup (n=155) and 0.68 (95% CI, 0.46–1.02; P = 0.06) in those without a BRCA1/2 alteration (n=240). The first interim analysis of OS was immature: 21.5% (TALA + ENZA) and 26.6% (PBO + ENZA) pts had died; HR 0.69 (95% CI, 0.46–1.03; P = 0.07). TALA + ENZA delayed time to PSA progression, cytotoxic chemotherapy, and antineoplastic therapy, and improved ORR, PSA response, and investigator-assessed PFS2. Grade (G) 3–4 treatment-emergent adverse events (TEAEs) were reported for 66.2% (TALA + ENZA) vs 37.2% (PBO + ENZA). There were more G≥3 hematologic TEAEs (anemia, neutropenia, thrombocytopenia, and leukopenia) with TALA + ENZA vs PBO + ENZA. TEAEs led to discontinuation of TALA in 10.1% vs PBO in 7.0%; discontinuation rates of ENZA were 7.6% (TALA + ENZA) vs 7.0% (PBO + ENZA). Time to definitive clinically meaningful deterioration in global health status/quality of life (GHS/QoL) was significantly longer with TALA + ENZA vs PBO + ENZA (HR 0.69; 95% CI, 0.49–0.97; P = 0.03; median 27.1 vs 19.3 months). Conclusions: TALA + ENZA demonstrated a statistically significant and clinically meaningful improvement in rPFS over standard of care ENZA as 1L treatment for pts with mCRPC and HRR gene alterations, while delaying time to definitive clinically meaningful deterioration in GHS/QoL. Toxicity was generally manageable and consistent with known safety profiles of TALA and ENZA. Clinical trial information: NCT03395197.