Talazoparib plus enzalutamide in men with HRR-deficient metastatic castration-resistant prostate cancer: final overall survival results from the randomised, placebo-controlled, phase 3 TALAPRO-2 trial
- PMID: 40683287
- DOI: 10.1016/S0140-6736(25)00683-X
Talazoparib plus enzalutamide in men with HRR-deficient metastatic castration-resistant prostate cancer: final overall survival results from the randomised, placebo-controlled, phase 3 TALAPRO-2 trial
Abstract
Background: Metastatic castration-resistant prostate cancer remains incurable and is particularly aggressive in patients with alterations in DNA damage repair genes involved directly or indirectly in homologous recombination repair (HRR). In the primary analysis of TALAPRO-2, talazoparib plus enzalutamide significantly improved radiographic progression-free survival (rPFS) versus enzalutamide plus placebo in patients with metastatic castration-resistant prostate cancer harbouring HRR gene alterations. At primary analysis, overall survival was immature. Here we report final prespecified overall survival analysis, updated rPFS, safety, and patient-reported outcomes in the HRR-deficient cohort of TALAPRO-2.
Methods: TALAPRO-2 is an ongoing international, randomised, double-blind, placebo-controlled phase 3 trial. The HRR-deficient cohort included randomly assigned patients from 142 hospitals, cancer centres, and medical centres in 26 countries; the study included men aged at least 18 years (≥20 years in Japan) with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer, progressive disease at study entry, and no previous life-prolonging systemic therapy for castration-resistant prostate cancer, but were receiving ongoing androgen deprivation therapy. Patients were prospectively assessed for tumour HRR gene alterations and randomly assigned (1:1) to once-daily oral talazoparib 0·5 mg plus enzalutamide 160 mg or enzalutamide plus placebo stratified by prior treatment (yes vs no) for castration-sensitive disease. The sponsor, patients, and investigators were masked to talazoparib or placebo, whereas enzalutamide was open label. The primary endpoint was rPFS (time from randomisation to radiographic progression or death, whichever occurred first) by blinded independent central review, and overall survival (time from randomisation to death due to any cause) was a key alpha-protected secondary endpoint, both assessed in the intention-to-treat population. Follow-up for overall survival was intended to continue until the planned final analysis. For statistical significance at the final overall survival analysis, the two-sided p value from the stratified log-rank test needed to be 0·024 or less based on a group sequential design with O'Brien-Fleming spending function. Safety was assessed in patients who had received at least one study drug dose. The trial is registered with ClinicalTrials.gov, NCT03395197.
Findings: Between Dec 18, 2018, and Jan 20, 2022, 399 patients with HRR-deficient metastatic castration-resistant prostate cancer were randomly assigned (200 [50%] to talazoparib plus enzalutamide and 199 [50%] to enzalutamide plus placebo). At a median follow-up of 44·2 months (IQR 36·0-50·8), treatment with talazoparib plus enzalutamide resulted in a statistically significant improvement in overall survival versus enzalutamide (hazard ratio [HR] 0·62 [95% CI 0·48-0·81]; two-sided p=0·0005); median overall survival 45·1 months (95% CI 35·4-not reached) in the talazoparib group versus 31·1 months (27·3-35·4) in the control group. In the subgroup of patients with BRCA1/2 alterations (n=155 [39%]), median overall survival was not reached for talazoparib plus enzalutamide versus 28·5 months for enzalutamide (HR 0·50 [95% CI 0·32-0·78]; p=0·0017); 4-year overall survival rates were 53% in the talazoparib group versus 23% in the control group. In patients without BRCA1/2 alterations (n=244 [61%]), median overall survival was 42·4 months for talazoparib plus enzalutamide versus 32·6 months for enzalutamide (HR 0·73 [95% CI 0·52-1·02]; p=0·066). Updated rPFS favoured talazoparib plus enzalutamide versus enzalutamide (HR 0·47 [95% CI 0·36-0·61]; p<0·0001; median rPFS 30·7 vs 12·3 months). No new safety signals were identified; most common adverse events of grade 3 or higher with talazoparib plus enzalutamide were anaemia (86 [43%] patients) and neutropenia (39 [20%] patients).
Interpretation: Talazoparib plus enzalutamide resulted in statistically significant and clinically meaningful improvement in survival versus enzalutamide plus placebo, further supporting this combination as a standard of care in HRR-deficient metastatic castration-resistant prostate cancer.
Funding: Pfizer.
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Conflict of interest statement
Declaration of interests KF reports honoraria (institution) for participation in advisory boards and talks from Advanced Accelerator Applications/Novartis, Amgen, Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Daiichi Sankyo, Janssen, MSD, Novartis, Pfizer, and Sanofi; and honoraria (personal) for participation in advisory boards from Arvinas, CureVac, MacroGenics, and Orion. AAA reports honoraria from Aculeus Therapeutics, Amgen, Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Ipsen, Janssen, Merck Serono, MSD, Novartis, Noxopharm, Pfizer, Sanofi, Telix Pharmaceuticals, and Tolmar; consulting fees from Aculeus Therapeutics, Astellas Pharma, Janssen, and Novartis; participation on advisory boards for Amgen, Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Ipsen, Janssen, Merck Serono, MSD, Novartis, Noxopharm, Pfizer, Sanofi, Telix, and Tolmar; participation on a data safety monitoring board for OncoSec; research funding (institution unless stated otherwise) from Aptevo Therapeutics, Astellas Pharma (investigator), AstraZeneca (investigator), Bionomics, Bristol Myers Squibb, Exelixis, Gilead Sciences, GlaxoSmithKline, Hinova Pharmaceuticals, Ipsen, Janssen, Lilly, MedImmune, Merck Serono (investigator), Merck Serono (institutional), MSD, Novartis, Pfizer, Sanofi, and Synthorx; travel, accommodation, or expenses from Amgen, Astellas Pharma, Bayer, Hinova Pharmaceuticals, Janssen, Merck Serono, Novartis, Pfizer, and Tolmar; and medical writing services support from Astellas Pharma, Exelixis, and Pfizer; he is Chair of the Urologic Oncology Group for the Clinical Oncology Society of Australia, and Chair of the Translational Research Subcommittee and on the Scientific Advisory Committee for the ANZUP Cancer Trials Group. NM reports honoraria (personal) from Sanofi; research funding (institution) from Amgen, Astellas Pharma, AstraZeneca, Bayer, Chugai Pharma, Eisai, Janssen, Lilly, MSD, Pfizer, PRA Health Science, Roche, Seagen, Taiho, and Takeda; and travel, accommodations, or expenses (personal) from Pfizer. JC has received personal fees for serving as a consultant to Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Ipsen, Johnson & Johnson, MSD Oncology, Novartis (AAA), Pfizer, Roche, and Sanofi; has participated in a speakers bureau for Astellas Pharma, Bayer, and Johnson & Johnson; has received research funding for their institution from AB Science, Aragon Pharmaceuticals, AROG Pharmaceuticals, Astellas Pharma, AstraZeneca AB, AVEO Pharmaceuticals, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics, Boehringer Ingelheim España, Bristol Myers Squibb, Clovis Oncology, Cougar Biotechnology, Deciphera Pharmaceuticals, Exelixis, F Hoffmann-La Roche, Genentech, GlaxoSmithKline, Incyte Corporation, Janssen-Cilag International NV, Karyopharm Therapeutics, Laboratoires Leurquin Mediolanum, Lilly, MedImmune, Millennium Pharmaceuticals, Nanobiotix, Novartis Farmacéutica, Pfizer, Puma Biotechnology, Sanofi-Aventis, SFJ Pharma, and Teva Pharma; and has received travel or accommodation expenses from AstraZeneca, Bristol Myers Squibb, Ipsen, and Roche. APF reports honoraria from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; a consulting or advisory role for Bayer, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; stock or stock options in Brazilian Information Oncology; research funding from AstraZeneca, Bristol Myers Squibb, CAPES – CNPq, Foundation Medicine, Ipsen, MSD, and Roche; and travel, accommodation, or expenses from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche. UDG reports a consulting or advisory role for Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Dompé Farmaceutici, Eisai, Ipsen, Janssen, Merck KGaA, MSD, Novartis, and Pfizer; research funding (institution) from AstraZeneca, Roche, and Sanofi; and travel, accommodation, or expenses from AstraZeneca, Ipsen, and Pfizer. PCCF reports a consulting or advisory role for MSD and travel, accommodation, or expenses from Pfizer. RJJ reports honoraria from Astellas Pharma, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, MSD, Pfizer, and Roche; a consulting or advisory role for Astellas Pharma, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, MSD, Novartis, Pfizer, and Roche; research funding from Astellas Pharma, Bayer, Clovis Oncology, Exelixis, and Roche; and travel, accommodations, or expenses from Bayer and Janssen. NDS reports a consulting or advisory role for AbbVie, Alessa Therapeutics, Akido, Amgen, Arquer, Asieris, Astellas Pharma, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, CG Oncology, Clarity Pharmaceuticals, Clovis Oncology, Dendreon, Exact Imaging, Exact Sciences, FerGene, Ferring, FIZE Medical, Foundation Medicine, GenesisCare, Genentech, Guardant Health, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, Mdxhealth, Merck, Minomic, Myovant Sciences, Myriad Genetics, Nymox, Pacific Edge Biotechnology, Pfizer, Photocure, PlatformQ, Profound, Promaxo, Propella Therapeutics, Protara, Sanofi, Sesen Bio, Speciality Networks, Telix Pharmaceuticals, Tolmar, UroGen Pharma, Vaxiion, and Vessi; providing expert testimony for Ferring; and leadership or other fiduciary role in another board, society, committee, or advocacy group with Photocure. CD reports participation on advisory boards for Astellas Pharma, Bayer, Janssen, and Pfizer; and research funding from AstraZeneca, Bayer, Dendreon, Hengrui Pharmaceuticals, Janssen, Laekna Therapeutics, Myovant Sciences, and Pfizer. SZ reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, and consulting fees (all personal), from Astellas Pharma, AstraZeneca, Bayer, Janssen, Merck, Novartis, and Pfizer; and grants or contracts (institution) from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck, Novartis, Pfizer, and Sanofi. JO reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb Norway, Eisai, Ipsen, Janssen-Cilag, Merck, and Roche; participation on a data safety monitoring board or advisory board for Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen-Cilag, Merck, and Roche; and travel, accommodation, or expenses from Astellas Pharma. XL, MK, ADL, and DK are employees of Pfizer and might hold Pfizer stock or stock options. NA reports no personal competing interests since April 15, 2021. NA reports consultancy fees for Astellas Pharma, AstraZeneca, AVEO, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. All other authors declare no competing interests.
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