TALAPRO-2 (NCT03395197) is an ongoing double-blind, randomized, placebo-controlled trial. Details of the trial design have been published23 and are in the protocol (Supplementary Protocol).

Eligibility criteria included ongoing androgen deprivation therapy; asymptomatic or mildly symptomatic mCRPC with HRR gene alterations; Eastern Cooperative Oncology Group performance status score of 0 or 1; progressive disease; adequate bone marrow function (hemoglobin ≥9 g dl−1); and no prior life-prolonging systemic therapy for castration-resistant disease23. Prior docetaxel and abiraterone or orteronel in the castration-sensitive setting were allowed. Patients were randomized in a 1:1 ratio (using a centralized, interactive web response system and a permuted block size of 4) to receive 0.5 mg talazoparib (moderate renal impairment, 0.35 mg) or placebo (all received enzalutamide, 160 mg) once daily. Randomization was stratified by prior second-generation androgen receptor pathway inhibitor (abiraterone or orteronel) or docetaxel (yes/no). Formal crossover from the placebo group to the talazoparib group was not part of the study design.

Before randomization, patients consented to provide solid tumor tissue (de novo or archival) and/or blood-based samples, for prospective assessment of HRR gene alterations (BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12) using FoundationOne® CDx and/or FoundationOne Liquid® CDx (Foundation Medicine). Historical FoundationOne® test results could also be used. Patients were considered HRR-deficient if they had one or more alteration(s) in at least one of these 12 genes. For prospective HRR status determination, test records generated after the randomization date were excluded. Alterations were defined as truncating short variants, selected inactivating short variants identified as known/likely pathogenic per FoundationOne® pipeline, inactivating rearrangements or homozygous deletion of one or more exons. The definition of HRR alterations was the same for FoundationOne® Liquid CDx, except homozygous deletion of one or more exons was limited to BRCA1/BRCA2 only. Notably, patients with heterozygous deletions of one or more exons alone were not enrolled in the HRR-deficient population.

Enrollment of patients with ATM and/or CDK12 gene alterations was paused between January and November 2021 as their observed prevalence exceeded expectations7 and was anticipated to suppress the representation of alterations in the remaining genes under study. The pause in enrollment of patients with ATM and/or CDK12 gene alterations was driven by expected prevalence numbers based on the largest and most comprehensive prospective assessment of prostate cancer tumor samples using the FoundationOne® assay7. This pause occurred in a blinded fashion regarding distribution of HRR alterations to the two treatment arms and allowed a rebalancing of the distribution across the 12-gene panel in an effort to best reflect the prevalence in mCRPC7.

Study treatment continued until radiographic progression, adverse event leading to permanent discontinuation, patient decision to discontinue or death. Treatment could continue after radiographic progression if the investigator determined benefit was still being derived.

The trial was conducted in accordance with the International Ethical Guidelines for Biomedical Research Involving Human Subjects, Good Clinical Practice guidelines, the principles of the Declaration of Helsinki and local laws. The protocol and amendments were approved by the institutional review board and independent ethics committee for each site. The following independent ethics committees or Institutional Review Boards provided study approval: Comite de Revision Institucional - Hospital Britanico de Buenos Aires, CABA, Argentina; Comite de Etica ‘Dr. Claude Bernard’, Rosario, Argentina; Comite de Etica en Investigacion - Centro de Educacion Medica e Investigaciones Clinicas ‘Norberto Quirno’ – CEMIC, CABA, Argentina; Comite de Etica en Investigacion de la Fundacion OncoSalud (CEIFOS), Pergamino, Argentina; Comite Independiente De Etica Para Ensayos En Farmacologia Clinica, CABA, Argentina; Comite Institucional de Etica de la Investigacion en Salud (C.I.E.I.S) de la Clinica Universitaria Reina Fabiola, Cordoba, Argentina; Comite Institucional de Etica de Investigacion en Salud del Hospital Privado Centro Medico de Cordoba, Cordoba, Argentina; St Vincent’s Hospital Human Research Ethics Committee, Darlinghurst, Australia; Bellberry Limited, Eastwood, Australia; Commissie Voor Medische Ethiek, Gent, Belgium; Comissao Nacional de Etica em Pesquisa/CONEP, Brasilia, Brazil; Comite de Etica em Pesquisa da Fundacao Pio XII - Hospital de Cancer de Barretos, Barretos, Brazil; Comite de Etica em Pesquisa da Universidade do Vale do Taquari – UNIVATES, Lajeado, Brazil; Comite de Etica em Pesquisa do Hospital Mae de Deus, Porto Alegre, Brazil; Comite de Etica em Pesquisa do Instituto D’Or de Pesquisa e Ensino, Rio de Janeiro, Brazil; Comite de Etica em Pesquisa-Hospital Universitario Pedro Ernesto, Rio de Janeiro, Brazil; Comite de Etica em Pesquisa da Universidade Regional do Noroeste do Estado do Rio Grande do Sul, Ijui, Brazil; Comite de Etica em Pesquisa - CEP do Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo - HCFMUSP, Sao Paulo, Brazil; Comite de Etica em Pesquisa da Faculdade de Medicina do ABC, Santo Andre, Brazil; Comitê de Ética em Pesquisa do Instituto Nacional de Câncer Jose Alencar Gomes da Silva – INCA, Rio de Janeiro, Brazil; Comite de Etica em Pesquisa do Hospital Nossa Senhora da Conceicao - Grupo Hospitalar Conceicao, Porto Alegre, Brazil; Comite de Etica em Pesquisa da Sociedade Beneficente de Senhoras Hospital Sirio Libanes, Sao Paulo, Brazil; Comitê de Ética em Pesquisa do Hospital Alemão Oswaldo Cruz – SP, Sao Paulo, Brazil; Comite de Etica em Pesquisa da Pontificia Universidade Catolica do Rio Grande do Sul-PUC/RS, Porto Alegre, Brazil; Comite d’ethique de la recherche du CHUM, Montreal, Canada; Health Research Ethics Board of Alberta - Cancer Committee, Edmonton, Canada; Ontario Cancer Research Ethics Board, Toronto, Canada; Comite de Etica Cientifico Servicio de Salud Metropolitano Oriente, Santiago, Chile; Comite Etico Cientifico Hospital Gustavo Fricke Servicio de Salud Vina del Mar – Quillota, Vina del Mar, Chile; Comite de Etica Cientifica Servicio Salud Araucania Sur, Temuco, Chile; Ethics Committee of Zhongshan Hospital Fudan University, Shanghai, China; Ethics Committee of The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China; Ethics committee of Zhejiang Cancer Hospital, Hangzhou, China; Ethics Committee of National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Ethics Committee of Chongqing University Cancer Hospital, Chongqing, China; Ethics Committee of Beijing Cancer Hospital, Beijing, China; Ethics Committee of The First Affiliated Hospital of Anhui Medical University, Hefei, China; Medical Ethics Committee of First Affiliated Hospital of Xiamen University, Xiamen, China; Wuxi People’s Hospital Ethics Committee, Wuxi, China; Ethics Committee of Nanjing Drum Tower Hospital, Nanjing, China; Ethics Committee of Shanghai Tenth People’s Hospital, Shanghai, China; Clinical Trial Ethics Committee of Huazhong University of Science and Technology, Wuhan, China; Ethics Committee of Huashan Hospital, Fudan University, Shanghai, China; Ethics Committee of Fudan University Cancer Hospital, Shanghai, China; Ethics Committee of Beijing Hospital, Beijing, China; Ethics Committee of Peking University First Hospital, Beijing, China; Peking University Third Hospital Medical Science Research Ethics Committee, Beijing, China; Ethics Committee for Clinical Trials of Drugs (Medical Apparatus) of Ningbo First Hospital, Ningbo, China; Ethics Committee of Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China; West China Hospital of Sichuan University Clinical Trial Ethics Committee, Chengdu, China; EC of Second Affiliated Hospital of Suzhou University, Suzhou, China; Shanghai General Hospital Medical Ethics Committee, Shanghai, China; Ethics Committee of Nanjing First Hospital, Nanjing, China; Clinical Trial Ethics Committee of Huazhong University of Science and Technology, Wuhan, China; Drug and Machinery Clinical trial Branch of EC of The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Ethics Committee of Yunnan Cancer Hospital, Kunming, China; The First Affiliated Hospital of Nanchang University Ethics Committee, Nanchang, China; Jilin Cancer Hospital Institutional Review Board, Changchun, China; Ethics Committee of The Second Hospital of Tianjin Medical University, Tianjin, China; Ethics Committee of Zhejiang Provincial People’s Hospital, Hangzhou, China; Ethics Committee of The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, China; Ethics Committee of Nantong Tumor Hospital, Nantong, China; Medical Ethics Committee of The First People’s Hospital of Lianyungang, Lianyungang, China; The Clinical Trial Ethics Committee of The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Eticka komise Krajska zdravotni a.s., Masarykova nemocnice v Usti nad Labem, Usti and Labem, Czech Republic; Eticka komise pro multicentricke klinicke hodnoceni Fakultni nemocnice Kralovske Vinohrady, Praha, Czech Republic; Eticka komise Fakultni Nemocnice Ostrava, Ostrava-Poruba, Czech Republic; Eticka komise Fakultni nemocnice Hradec Kralove, Hradec Kralove, Czech Republic; Helsingin ja Uudenmaan sairaanhoitopiiri, Helsinki, Finland; Comite De Protection Des Personnes (CPP) Sud-Ouest Et Outre-Mer III, Bordeaux, France; Ethikkommission der Aerztekammer Hamburg, Hamburg, Germany; Egészségügyi Tudományos Tanács Klinikai Farmakológiai Etikai Bizottsága, Budapest, Hungary; Bnai Zion Medical Center Helsinki Committee, Haifa, Israel; Rambam Health Care Campus Helsinki Committee, Haifa, Israel; Tel Aviv Sourasky Medical Center Helsinki Committee, Tel Aviv, Israel; Rabin Medical Center Helsinki Committee, Petah Tikva, Israel; Shaare Zedek Medical Center Helsinki Committee, Jerusalem, Israel; Comitato Etico Azienda Ospedaliero Universitaria San Luigi Gonzaga, Orbassano, Italy; Comitato Etico Val Padana, Cremona, Italy; Comitato Etico Regionale (CER) dell’Umbria, Perugia, Italy; Comitato Etico Cardarelli-Santobono, Napoli, Italy; Comitato Etico Per Le Sperimentazioni Cliniche Dell’Azienda Provinciale Per I Servizi Sanitari, Trento, Italy; Comitato Etico della Romagna (CEROM), Meldola, Italy; Comitato Etico di Brescia, Brescia, Italy; Comitato Etico di Area Vasta Emilia Centro, Bologna, Italy; Comitato Etico IRCCS Pascale, Napoli, Italy; National Hospital Organization Central Review Board, Meguro-ku, Tokyo, Japan; National Cancer Center Institutional Review Board, Chuo-ku, Tokyo, Japan; Kindai University Hospital Institutional Review Board, Osakasayama, Japan; Yokohama City University Medical Center Institutional Review Board, Yokohama, Japan; Keio University Hospital Institutional Review Board, Shinjuku-ku, Tokyo, Japan; Nagoya University Hospital Institutional Review Board, Nagoya, Japan; Hokkaido University Hospital Institutional Review Board, Sapporo, Japan; Tokushima University Hospital Institutional Review Board, Tokushima, Japan; Chiba Cancer Center Institutional Review Board, Chiba, Japan; Hirosaki University School of Medicine & Hospital Institutional Review Board, Hirosaki, Japan; Yamagata Prefectural Central Hospital Institutional Review Board, Yamagata, Japan; Yokosuka Kyosai Hospital Institutional Review Board, Yokosuka, Japan; Hamamatsu University School of Medicine, University hospital Institutional Review Board, Hamamatsu, Japan; Osaka International Cancer Institute Institutional Review Board, Osaka-shi, Japan; Osaka University Hospital Institutional Review Board, Suita, Japan; Kanazawa University Hospital Institutional Review Board, Kanazawa, Japan; Kagoshima University Hospital Institutional Review Board, Kagoshima, Japan; Yamagata University Hospital Institutional Review Board, Yamagata, Japan; Kyungpook National University Chilgok Hospital Institutional Review Board, Daegu, Republic of Korea; Samsung Medical Center Institutional Review Board, Seoul, Republic of Korea; Asan Medical Center Institutional Review Board, Seoul, Republic of Korea; Severance Hospital, Yonsei University Health System Institutional Review Board, Seoul, Republic of Korea; Pusan National University Hospital Institutional Review Board, Busan, Republic of Korea; Seoul National University Hospital Institutional Review Board, Seoul, Republic of Korea; National Cancer Center Institutional Review Board, Goyang-si, Republic of Korea; The Catholic University of Korea Seoul St. Mary’s Hospital Institutional Review Board, Seoul, Republic of Korea; Health and Disability Ethics Committee, Wellington, New Zealand; REK Sor-Ost, Oslo, Norway; Comite Institucional de Etica en Investigacion del INEN, Lima, Peru; Comite Institucional de Bioetica de Via Libre, Lima, Peru; Komisja Bioetyczna przy Okregowej Izbie Lekarskiej w Gdansku, Gdansk, Poland; Comissao de Etica para a Investigacao Clinica, Lisboa, Portugal; University of the Witwatersrand Human Research Ethics Committee (Medical), Johannesburg, South Africa; CEIm del Hospital Universitari Vall d’Hebron, Barcelona, Spain; Etikprovningsmyndigheten, Uppsala, Sweden; Health and Care Research Wales, Wales REC 3, Cardiff, United Kingdom; Advarra Institutional Review Board, Columbia, MD, United States; Vanderbilt Human Research Protection Program (VHRPP) Institutional Review Board, Nashville, TN, United States; University of Utah Institutional Review Board, Salt Lake City, UT, United States; Biomedical Research Alliance of New York, LLC/Institutional Review Board, Lake Success, NY, United States; Western Institutional Review Board, Puyallup, WA, United States; Sharp HealthCare Institutional Review Board, San Diego, CA, United States; Schulman Associates Institutional Review Board, Cincinnati, OH, United States; Loma Linda University Health - Institutional Review Board, Loma Linda, CA, United States; Administrative Panels on Human Subjects in Medical Research (‘Stanford Institutional Review Board’), Palo Alto, CA, United States; University of Maryland, Baltimore - Institutional Review Board, Baltimore, MD, United States; Cook County Health Office of Research and Regulatory Affairs, Chicago, IL, United States; Samaritan Health Services Regional Institutional Review Board, Corvallis, OR, United States; University of Iowa Institutional Review Board-01, Human Subjects Office, Iowa City, IA, United States; Lakeland Regional Medical Center, Inc. Institutional Review Board, Lakeland, FL, United States; VA Med Ctr, Long Beach CA Institutional Review Board #1, Long Beach, CA, United States; Rush University Medical Center Institutional Review Board, Chicago, IL, United States; UCLA Office of the Human Research Protection Program, Los Angeles, CA, United States; VA Saint Louis Healthcare System Institutional Review Board, St. Louis, MO, United States; Baylor Scott and White Research Institute Institutional Review Board-Gold, Temple, TX, United States; Providence St. Joseph Health Institutional Review Board, Renton, WA, United States; IntegReview, Austin, TX, United States; Kaiser Permanente Northwest Institutional Review Board, Portland, OR, United States; Ochsner Institutional Review Board, New Orleans, LA, United States; Eisenhower Medical Center, Institutional Review Board, Rancho Mirage, CA, United States. All patients provided written informed consent.

The primary endpoint was rPFS by blinded independent central review per Response Evaluation Criteria in Solid Tumors (version 1.1; soft tissue disease) and Prostate Cancer Clinical Trials Working Group 3 (bone disease)23. A full list of secondary endpoints is included in the Supplementary Methods, and these endpoints have been previously listed23. Planned secondary endpoints not reported in this article are: time to opiate use for prostate cancer pain, pharmacokinetics and patient-reported outcomes.

Exploratory subgroup analyses were conducted for rPFS by baseline characteristics (Supplementary Methods). A post hoc analysis of rPFS by BRCA1/BRCA2 alteration status (yes/no) and by single genes and hierarchical gene clusters (BRCA, PALB2, CDK12, ATM and any of all other HRR genes) was also performed (Supplementary Methods).

Approximately 380 patients with HRR gene alterations were to be enrolled. To maintain overall type I error at or below a one-sided alpha level of 0.025, alpha was split equally between the all-comers cohort and HRR-deficient population.

For the primary comparison in the HRR-deficient population, 224 PFS events based on a Lan DeMets α-spending function would provide 85% power to detect an HR of 0.64 using a one-sided stratified log-rank test at a significance level of 0.0125. A prespecified interim analysis of PFS was planned after approximately 70% of the expected events (157 events). The HRR-deficient cohort would be stopped if the efficacy boundary was crossed and an interim efficacy analysis of overall survival would be performed. As the efficacy boundary (P ≤ 0.0038) was crossed at this interim analysis, this became the final analysis. Other endpoints had no adjustment for multiplicity. Survival and safety follow-up continue.

Time-to-event endpoints were compared between treatment groups using a stratified log-rank test unless otherwise stated. HRs and associated 95% two-sided CIs were estimated by a Cox proportional hazards model. Median time-to-event endpoints were estimated by the Kaplan–Meier method, and 95% CIs based on the Brookmeyer–Crowley method. For subgroup analysis of rPFS (except by BRCA status), the HR was based on an unstratified Cox model with treatment as the only covariate due to small patient numbers in some subgroups. Missing/partial dates were imputed as specified per protocol. Other missing data were not imputed. Reported P values are two sided.

Oracle Clinical Remote Data Capture was used for data collection, and SAS version 9.4 was used for data analysis.

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.