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Background: Poly(ADP-ribose) polymerase (PARP) inhibitors have antitumour activity against metastatic castration-resistant prostate cancers with DNA damage response (DDR) alterations in genes involved directly or indirectly in homologous recombination repair (HRR). In this study, we assessed the PARP inhibitor talazoparib in metastatic castration-resistant prostate cancers with DDR-HRR alterations., Methods: In this open-label, phase 2 trial (TALAPRO-1), participants were recruited from 43 hospitals, cancer centres, and medical centres in Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA. Patients were eligible if they were men aged 18 years or older with progressive, metastatic, castration-resistant prostate cancers of adenocarcinoma histology, measurable soft-tissue disease (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]), an Eastern Cooperative Oncology Group performance status of 0-2, DDR-HRR gene alterations reported to sensitise to PARP inhibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received one or two taxane-based chemotherapy regimens for metastatic disease, and progressed on enzalutamide or abiraterone, or both, for metastatic castration-resistant prostate cancers. Eligible patients were given oral talazoparib (1 mg per day; or 0·75 mg per day in patients with moderate renal impairment) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1, by blinded independent central review. The primary endpoint was assessed in patients who received study drug, had measurable soft-tissue disease, and had a gene alteration in one of the predefined DDR-HRR genes. Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT03148795, and is ongoing., Findings: Between Oct 18, 2017, and March 20, 2020, 128 patients were enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumour activity population). Data cutoff for this analysis was Sept 4, 2020. After a median follow-up of 16·4 months (IQR 11·1-22·1), the objective response rate was 29·8% (31 of 104 patients; 95% CI 21·2-39·6). The most common grade 3-4 treatment-emergent adverse events were anaemia (39 [31%] of 127 patients), thrombocytopenia (11 [9%]), and neutropenia (ten [8%]). Serious treatment-emergent adverse events were reported in 43 (34%) patients. There were no treatment-related deaths., Interpretation: Talazoparib showed durable antitumour activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favourable benefit-risk profile supports the study of talazoparib in larger, randomised clinical trials, including in patients with non-BRCA alterations., Funding: Pfizer/Medivation., Competing Interests: Declaration of interests JSdB reports consulting fees from Astellas Pharma, AstraZeneca, Bayer, BioXcel Therapeutics, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Genmab, GSK, Janssen Oncology, Menarini Silicon Biosystems, Merck Serono, MSD, Orion Pharma GmbH, Pfizer, Roche/Genentech, Sanofi, Sierra Oncology, and Taiho Pharmaceutical; funding or support to his institution for laboratory and clinical work from Astex Pharmaceuticals, AstraZeneca, Bayer, Celgene, Cellcentric, Daiichi Sankyo, Genentech, GSK, MedImmune, Medivation, Merck Serono, MSD, Orion Pharma GmbH, Sanofi, Sierra Oncology, and Taiho Pharmaceutical; honoraria from Astellas Pharma, AstraZeneca, BioXcel Therapeutics, Daiichi Sankyo, Janssen Oncology, Menarini Silicon Biosystems, Pfizer, Roche/Genentech, Sanofi, and Sierra Oncology; travel, accommodation, and expenses from Astellas Pharma, AstraZeneca, Genmab, GSK, Orion Pharma GmbH, Qiagen, Sanofi, Taiho Pharmaceutical, and Vertex; and is named as an inventor, with no financial interest, on a patent (number 8,822,438). NM reports consulting fees from Astellas Pharma, Bristol-Myers Squibb, Genzyme, Janssen-Cilag, MSD Oncology, and Roche; funding or clinical trial and laboratory research support to his institution from Astellas Pharma, Janssen-Cilag, Pfizer, Roche/Genentech, and Sanofi; and accommodation and expenses from Astellas Pharma, Bristol-Myers Squibb, MSD Oncology, and Roche. GVS reports payment or honoraria from AstraZeneca, Eli Lilly, MSD, Pfizer, Roche, Johnson & Johnson, and Takeda; consulting fees from Eli Lilly, BeiGene, and AstraZeneca; institutional grants or contracts from MSD and Tesaro; support for attending meetings and travel from Bayer; and is a past president of the International Association for the Study of Lung Cancer. EC reports consulting fees to her institution from Astellas Pharma, AstraZeneca, Bayer, Clovis, Janssen, MSD, and Pfizer; payment or honoraria to herself from Astellas Pharma, AstraZeneca, Bayer, Clovis, Janssen, Pfizer, and Roche; grants or contracts to her institution from AstraZeneca, Bayer, Janssen, and Synlab; support for attending meetings and travel from AstraZeneca, Bayer, and Janssen; and is an unpaid member of the European Society for Medical Oncology faculty. TD reports participation on a Data Monitoring Safety Board or Advisory Board for Advanced Accelerator Applications, Bayer, Bristol-Myers Squibb, Exelixis, and Janssen. ASte reports consulting fees (personal) from Ipsen Pharma, Janssen, and Roche; participation on a Data Safety Monitoring Board or Advisory Board for Astellas Pharma, AstraZeneca, Ferring, and Synergo; and research grant funding from Amgen, Ipsen Pharma, and Karl Storz AG. CSH reports consulting fees from AstraZeneca, Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring, Hinova Pharmaceuticals, Janssen, and Pfizer; funding for research work to her institution from Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, eFFECTOR Therapeutics, Emergent BioSolutions, Ferring, Medivation, Pfizer, and Roche; honoraria from Astellas Pharma; and accommodation and expenses from Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring, Hinova Pharmaceuticals, Janssen Oncology, and Pfizer. FS reports consulting fees to himself from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Myovant, Novartis, Pfizer, and Sanofi; grants or contracts to his institution from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Myovant, Novartis, Pfizer, and Sanofi; and payment or honoraria from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Myovant, Novartis, Janssen, Pfizer, and Sanofi. CB reports consulting fees from Astellas Pharma, Janssen, Merck, and Pfizer. IMvO reports consulting fees from Astellas Pharma, Bayer, Janssen, and MSD/AstraZeneca; grants or contracts from Astellas Pharma, Bayer, Janssen, and MSD/AstraZeneca; payment or honoraria from Astellas Pharma, Bayer, Janssen, and MSD/AstraZeneca; and support for attending meetings and travel from Astellas Pharma. ADL, MM, H-CC, CGH, and AC are employees of Pfizer and hold Pfizer stock and stock options. KF reports payment or honoraria to his institution from Astellas Pharma, Bayer, Janssen, and Sanofi, and participation on a Data Monitoring Safety Board or Advisory Board to his institution for Amgen, Astellas Pharma, AstraZeneca, Bayer, Clovis, Janssen, Pfizer, and Sanofi. ASti and MTF declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)