First results from ZZFIRST: A randomized phase II trial of enzalutamide (EZ) with or without talazoparib (TALA) in metastatic hormone-naïve prostate cancer (mHNPC)

BackgroundCo-targeting the androgen receptor (AR) and DNA damage repair (DDR) pathways has shown potential for clinical synergy in phase III trials in mCRPC, but the optimal target population for this therapeutic approach remains unclear. This study assesses the safety and efficacy of combining TALA –a PARP inhibitor– and EZ –an AR inhibitor– in non-molecularly selected patients (pts) with mHNPC.MethodsZZFIRST (NCT04332744) is an investigator-initiated randomized phase 2 study in men with high-volume mHNPC, ECOG PS 0-1, and PSA≥4 ng/mL conducted across 8 hospitals in Spain. Pts receive ADT + EZ 160 mg/day for two 28-day cycles, to be randomized 1:2 on C3D1 to continue ADT+EZ or add TALA 0.5 mg/day (ADT+EZ+TALA) until progressive disease, unacceptable toxicity, or consent withdrawal. Randomization was stratified based on DDR mutation status. Primary endpoint is PSA-complete response (CR) rate for the EZ+TALA arm at C13D1. Key secondary endpoints include radiographic progression-free survival (rPFS) as per RECIST v.1.1/PCWG3 and safety and tolerability (CTCAE v.5.0). Sample size aimed for 80% power to detect improved PSA-CR rate (H0: 20%; H1≥40%) with one-sided alpha 5%, 10% dropout rate, using exact binomial test.Results54 pts were enrolled (37 EZ+TALA, 17 EZ). At data cutoff (Feb 15, 2024), median follow-up was 30.6 mo (range 4.2-40.1); 9 (52.9%) pts in the EZ arm and 19 (51.4%) pts in the EZ+TALA arm remained on therapy. C13D1 PSA-CR in EZ+TALA arm was 73% meeting the primary endpoint (95% CI, 55.9%-86.2%, p<0.001), and 64.7% in the control arm. Median rPFS was not reached for EZ+TALA arm vs 31.1 mo for EZ (hazard ratio 0.5, 95% CI 0.2–1.4). The 2-years rPFS rate was 78.5% for EZ+TALA vs 58.8% for EZ. In the TALA+EZ arm, fatigue (any grade: 83.8%; G≥3: 13.5%) and anemia (any grade: 67.6%; G≥3: 37.8%) were the most common treatment emergent adverse event. Two patients in the EZ+TALA arm developed acute leukemia after 26.0 and 32.8 mo on treatment.ConclusionsIn this interim analysis, TALA+EZ shows promising antitumor activity and predictable toxicity in high volume mHNPC, to be confirmed with longer follow-up; correlative biomarker studies are ongoing.Clinical trial identificationNCT04332744, EudraCT 2019-003096-20.Legal entity responsible for the studyMEDSIR.FundingPfizer S.L. and Astellas Pharma Europe Ltd.DisclosureJ. Mateo: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Janssen, Roche, Amunix, Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Guardant Health; Financial Interests, Institutional, Advisory Board, Scientific Advisory Board Member for the company: Nuage Therapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca, Pfizer Oncology, Amgen; Non-Financial Interests, Institutional, Product Samples, Access to drugs in early development for preclinical testing: AstraZeneca. E. Castro: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Janssen, MSD, Bayer, Pfizer, Daiichi Sankyo, Lilly, Medscape, Novartis; Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Janssen, Clovis, Pfizer, Medscaoe; Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Research Grant: Janssen, Bayer, Pfizer; Financial Interests, Institutional, Local PI: Janssen, Pfizer, MSD. A. Rodriguez-Vida: Financial Interests, Personal, Invited Speaker: Roche, BMS, Janssen, AstraZeneca, Ipsen; Financial Interests, Personal, Advisory Board: MSD, Pfizer, Astellas, Bayer, Merck. B. Mellado Gonzalez: Financial Interests, Research Funding: Roche, Bayer, Janssen; Financial Interests, Expert Testimony: Roche, Sanofi, Janssen, Astellas, Pfizer, Novartis, Bristol Myers Squibb, Ipse; Financial Interests, Other, Travel Accommodation/Expenses: Pfizer, Janssen. D.E. Castellano Gauna: Financial Interests, Personal, Advisory Board: Pfizer, Roche, BMS, Janssen, Astellas, MSD, Ipsen, AstraZeneca, Novartis, GSK; Financial Interests, Institutional, Local PI: Pfizer, Roche, MSD, BMS, AstraZeneca, Janssen, Astellas, Ipsen, Exelisis, Eisai, Lilly, Bayer, GSK, Clovis, QED Therapeutics; Non-Financial Interests, Other, any: Associate Professor of Medical Oncology/Internal Medicine department; Non-Financial Interests, Personal, Other, Executive member: SOGUG (Spanish Oncology Genito-Urinary Group) Foundation; Non-Financial Interests, Personal, Training, Head of GU Alliance for Research and Development Consortium: GUARD Consortium; Other, any: Member of the Internal/local Pharmacy Commission at the Hospital Universitario 12 de Octubre. M.A. Climent Duran: Financial Interests, Personal, Advisory Board: Roche, BMS, EUSA, Pfizer, Sanofi, Janssen, Astellas, Merck, Ipsen, MSD; Financial Interests, Personal, Invited Speaker: EUSA, Pfizer, Sanofi, Janssen, Astellas, Merck, Ipsen, BMS, Roche, MSD. A. Borque Fernando: Financial Interests, Invited Speaker: Alter, Asofarma, Astellas, AstraZeneca, Bayer, GP Pharm, Janssen, Lacer, MSD; Financial Interests, Advisory Role: Astellas, AstraZeneca, Bayer, Janssen, MSD. M.I. Sáez: Financial Interests, Advisory Role: Sanofi, Pfizer, Merck, Novartis; Financial Interests, Invited Speaker: BMS. B. Herrera Imbroda: Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, Astellas, Bayer; Financial Interests, Personal, Invited Speaker: Ipsen. A. Font Pous: Financial Interests, Institutional, Advisory Board: Pfizer, Bayer, Astellas. D. Lorente: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, Bayer, Sanofi, Bristol Myers Squibb, AstraZeneca, MSD; Financial Interests, Personal, Advisory Board: Janssen, Sanofi, Pfizer, AstraZeneca; Financial Interests, Personal, Other, Travel: Bayer, Pfizer. A. Vivancos: Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb, Guardant Health, Bayer, Incyte; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Bristol Myers Squibb, Roche, Incyte. J. Cardona: Financial Interests, Institutional, Full or part-time Employment: MEDSIR. J.A. Guerrero: Financial Interests, Institutional, Full or part-time Employment: MEDSIR. J. Perez-Escuredo: Financial Interests, Institutional, Full or part-time Employment: MEDSIR. A.J. Zurita Saavedra: Financial Interests, Advisory Role: Pfizer; Financial Interests, Advisory Board: Astellas, Incyte, Bayer, Exelixis, Dendreon, Janssen, HIKMA; Financial Interests, Research Funding: Pfizer, AstraZeneca, Astellas, X4 Pharma, Infinity, Merck, ABX, Curium, Clarity, Fusion. J.C. Galceran: Financial Interests, Personal, Advisory Board: Astellas Pharma, AstraZeneca, Bayer, Johnson & Johnson, MSD Oncology, Novartis (AAA), Roche, Sanofi; Financial Interests, Institutional, Local PI: Janssen-Cilag International NV, Lilly, S.A, MedImmune, Novartis Farmacéutica, S.A, Sanofi-Aventis, S.A; Other, Member of the Comission: Catalan Program of Ambulatory Medication Comission (CAHMDA). All other authors have declared no conflicts of interest.