First-line talazoparib plus enzalutamide versus placebo plus enzalutamide for metastatic castration-resistant prostate cancer: patient-reported outcomes from the randomised, double-blind, placebo-controlled, phase 3 TALAPRO-2 trial
- PMID: 40179906
- DOI: 10.1016/S1470-2045(25)00030-0
First-line talazoparib plus enzalutamide versus placebo plus enzalutamide for metastatic castration-resistant prostate cancer: patient-reported outcomes from the randomised, double-blind, placebo-controlled, phase 3 TALAPRO-2 trial
Abstract
Background: Patients with metastatic castration-resistant prostate cancer have poor prognoses, underscoring the need for novel therapeutic strategies. First-line talazoparib plus enzalutamide significantly improved radiographic progression-free survival compared with placebo plus enzalutamide in men with metastatic castration-resistant prostate cancer in the phase 3 TALAPRO-2 study. We aimed to evaluate patient-reported outcomes in the all-comers cohort of TALAPRO-2, which included patients with and without alterations in homologous recombination repair (HRR) genes.
Methods: TALAPRO-2 is a randomised, double-blind, placebo-controlled, phase 3 trial conducted at 223 hospitals, cancer centres, and medical centres in 26 countries worldwide. Eligible participants were male patients aged 18 years or older (≥20 years in Japan) who were receiving ongoing androgen deprivation therapy, had asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, and had not received previous life-prolonging systemic therapy for castration-resistant prostate cancer or metastatic castration-resistant prostate cancer. Patients were randomly assigned (1:1) using a centralised interactive web response system and a permuted block size of 4 to oral talazoparib 0·5 mg once daily or placebo, plus oral enzalutamide 160 mg once daily. The funder, patients, and investigators were masked to allocation of talazoparib or placebo; enzalutamide was open-label. Stratification factors were HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with docetaxel or abiraterone, or both (yes vs no) in the castration-sensitive setting. The primary endpoint was radiographic progression-free survival by blinded independent central review and has been reported previously. Patient-reported outcomes were assessed as secondary endpoints in the patient-reported outcomes population, which comprised patients from the intention-to-treat population with a baseline patient-reported outcome assessment followed by at least one post-baseline patient-reported outcome assessment. Patient-reported outcomes included mean change from baseline in patient-reported pain symptoms (per Brief Pain Inventory-Short Form [BPI-SF]); global health status/quality of life (GHS/QoL), overall cancer and prostate cancer-specific functioning and symptoms (per European Organisation for Research and Treatment of Cancer [EORTC] Core Quality of Life Questionnaire [QLQ-C30] and Quality of Life Questionnaire-Prostate [QLQ-PR25]); and general health status (per EQ-5D-5L). Time to deterioration in patient-reported pain symptoms (per BPI-SF), and time to definitive deterioration in patient-reported GHS/QoL (per EORTC QLQ-C30) and prostate cancer-specific urinary symptoms (per EORTC-QLQ-PR25) were the other secondary endpoints. This study is registered with ClinicalTrials.gov, NCT03395197, and is ongoing.
Findings: Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned to treatment irrespective of HRR gene alteration status. 395 patients assigned to talazoparib plus enzalutamide and 398 assigned to placebo plus enzalutamide were included in the patient-reported outcome population. Median follow-up was 28·0 months (IQR 23·9-31·7) for talazoparib plus enzalutamide and 26·8 months (23·4-30·6) for placebo plus enzalutamide. Time to definitive deterioration in GHS/QoL was longer with talazoparib plus enzalutamide versus placebo plus enzalutamide (median 30·8 months [95% CI 27·0-non-estimable] vs 25·0 months [22·9-30·7]; hazard ratio [HR] 0·78 [95% CI 0·62-0·99]; two-sided p=0·038). Median time to definitive deterioration in urinary symptoms was non-estimable (95% CI non-estimable-non-estimable) in the talazoparib plus enzalutamide group and was 35·9 months (95% CI 32·3-non-estimable) in the placebo plus enzalutamide group (HR 0·76 [95% CI 0·54-1·06]; two-sided p=0·11). No clinically meaningful differences (≥10 points) in mean changes from baseline were observed in GHS/QoL, symptom, and functional scales between the treatment groups. No differences were observed between the groups in time to deterioration of pain as measured by the BPI-SF (HR 0·98 [95% CI 0·69-1·40]; two-sided p=0·93), mean pain scores (estimated mean difference in value of worst pain in the past 24 h between treatment groups was -0·1 [95% CI -0·3 to 0·1]; two-sided p=0·27), or general health status as measured by the EQ-5D-5L (estimated mean difference 0·0 [95% CI 0·0-0·0]; two-sided p=0·37).
Interpretation: Talazoparib plus enzalutamide prolonged time to definitive deterioration in GHS/QoL versus placebo plus enzalutamide. Together with clinical efficacy and safety data, these results inform the risk-benefit assessment of talazoparib plus enzalutamide in patients with metastatic castration-resistant prostate cancer in TALAPRO-2.
Funding: Pfizer.
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Conflict of interest statement
Declaration of interests 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, accommodation, or expenses (personal) from Pfizer. AAA reports honoraria from Aculeus Therapeutics, Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Ipsen, Janssen, Merck Serono, MSD, Novartis, Noxopharm, Pfizer, Sanofi, Telix, and Tolmar; consulting fees from Aculeus Therapeutics, Astellas Pharma, Janssen, and Novartis; participation on advisory boards for Amgen, Astellas Pharma, AstraZeneca, Arvinas, 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 Astellas Pharma (investigator), AstraZeneca (investigator), Merck Serono (investigator), Astellas Pharma, Aptevo Therapeutics, AstraZeneca, Bionomics, Bristol Myers Squibb, Eli Lilly, Exelixis, GlaxoSmithKline, Gilead Sciences, Hinova, Ipsen, Janssen, MedImmune, Merck Serono, MSD, Novartis, Pfizer, Sanofi Aventis, and SYNthorx; receiving medical writing services support from Astellas Pharma, Exelixis, and Pfizer; travel and accommodation fees from Amgen, Astellas Pharma, Bayer, Janssen, Merck Serono, Novartis, Pfizer, and Tolmar; speakers bureau activities for Amgen, Astellas Pharma, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, and Novartis; being a member of steering committees for Astellas Pharma, AstraZeneca, Exelixis, Janssen, and Pfizer; and 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. NA has received honorarium before May, 2021, and during his lifetime for consulting to Astellas Pharma, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, MEI Pharma, Merck, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics; and has received research funding during his lifetime (to his institution) from Arvinas, Astellas Pharma, AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, CRISPR Therapeutics, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, GlaxoSmithKline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. FS reports honoraria from Astellas Pharma, AstraZeneca, Bayer, Janssen Oncology, and Sanofi; a consulting role for Astellas Pharma, AstraZeneca/MedImmune, Janssen Oncology, and Sanofi; and institutional funding from Astellas Pharma, AstraZeneca, Bayer, Janssen Oncology, and Sanofi. UDG reports a consulting or advisory role for Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Dompé Farmaceutici, Eisai, Ipsen, Janssen, Merck KGaA, MSD, Novartis, Pfizer, and PharmaMar; research funding (institution) from AstraZeneca, Roche, and Sanofi; and travel, accommodation, or expenses from Ipsen, AstraZeneca, 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, accommodation, or expenses from Bayer and Janssen. SZ reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen (personal and institution), Astellas Pharma (personal and institution), Bayer (personal and institution), Bristol Myers Squibb (personal and institution), Eisai (personal), Janssen (personal), Merck Serono (personal and institution), MSD (institution), Novartis (personal), and Pfizer (personal and institution); participation on a data safety monitoring board or advisory board for Amgen (personal and institution), Bayer (personal and institution), Bristol Myers Squibb (institution), Eisai (personal), Ipsen (personal), Janssen (personal), Merck Serono (personal and institution), MSD (institution), Novartis (personal), and Pfizer (institution); research funding (institution) from Eisai; and travel, accommodation, or expenses from Amgen, Astellas Pharma, AstraZeneca, Ipsen, Janssen, Merck Serono, MSD, and Pfizer. JO reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas Pharma, AstraZeneca, Bayer, BMS 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. 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, FIZE Medical, Foundation Medicine, GenesisCare, Genentech, Guardant Ferring, 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 other 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. JC reports a consulting or advisory role for Advanced Accelerator Applications/Novartis, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Johnson & Johnson, MSD Oncology, Pfizer, Roche, and Sanofi; participation in speakers bureaus for Astellas Pharma, Bayer, and Johnson & Johnson; research funding (institution) from AB Science, Aragon Pharmaceuticals, AROG Pharmaceuticals, Astellas Pharma, AstraZeneca, AVEO Pharmaceuticals, Bayer, Blueprint Medicines, BN ImmunoTherapeutics, Boehringer Ingelheim España, Bristol Myers Squibb International Corporation, Clovis Oncology, Cougar Biotechnology, Deciphera, Exelixis, Genentech, GlaxoSmithKline, Incyte, Janssen–Cilag International, Karyopharm Therapeutics, Laboratoires Leurquin Mediolanum, Lilly, MedImmune, Millennium Pharmaceuticals, Nanobiotix, Novartis Farmacéutica, Pfizer, Puma Biotechnology, Roche, Sanofi Aventis, SFJ Pharmaceuticals Group, and Teva; and travel, accommodation, or 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; and 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. PC and CGH are employees of Pfizer. JC and AN are employees and shareholders of Pfizer. 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. JYJ declares no competing interests.
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