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Background: At the first interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, the addition of pembrolizumab to chemoradiotherapy provided a statistically significant and clinically meaningful improvement in progression-free survival in patients with locally advanced cervical cancer. We report the overall survival results from the second interim analysis of this study., Methods: Eligible patients with newly diagnosed, high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of nodal status), locally advanced, histologically confirmed, squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer were randomly assigned 1:1 to receive five cycles of pembrolizumab (200 mg) or placebo every 3 weeks with concurrent chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Pembrolizumab or placebo and cisplatin were administered intravenously. Patients were stratified at randomisation by planned external beam radiotherapy type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cervical cancer stage at screening (FIGO 2014 stage IB2-IIB node positive vs III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy [equivalent dose of 2 Gy]). Primary endpoints were progression-free survival per RECIST 1.1 by investigator or by histopathological confirmation of suspected disease progression and overall survival defined as the time from randomisation to death due to any cause. Safety was a secondary endpoint., Findings: Between June 9, 2020, and Dec 15, 2022, 1060 patients at 176 sites in 30 countries across Asia, Australia, Europe, North America, and South America were randomly assigned to treatment, with 529 patients in the pembrolizumab-chemoradiotherapy group and 531 patients in the placebo-chemoradiotherapy group. At the protocol-specified second interim analysis (data cutoff Jan 8, 2024), median follow-up was 29·9 months (IQR 23·3-34·3). Median overall survival was not reached in either group; 36-month overall survival was 82·6% (95% CI 78·4-86·1) in the pembrolizumab-chemoradiotherapy group and 74·8% (70·1-78·8) in the placebo-chemoradiotherapy group. The hazard ratio for death was 0·67 (95% CI 0·50-0·90; p=0·0040), meeting the protocol-specified primary objective. 413 (78%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 371 (70%) of 530 in the placebo-chemoradiotherapy group had a grade 3 or higher adverse event, with anaemia, white blood cell count decreased, and neutrophil count decreased being the most common adverse events. Potentially immune-mediated adverse events occurred in 206 (39%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 90 (17%) of 530 patients in the placebo-chemoradiotherapy group. This study is registered with ClinicalTrials.gov, NCT04221945., Interpretation: Pembrolizumab plus chemoradiotherapy significantly improved overall survival in patients with locally advanced cervical cancer These data, together with results from the first interim analysis, support this immuno-chemoradiotherapy strategy as a new standard of care for this population., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co., Competing Interests: Declaration of interests DL, YX, KH, GS, ML, PR-E, AA, JC, LR, AJPdSG, FCM, LH, HA, J-YL, VS, FZ, LG, JS, ET, KL, NC, C-LC, MB, HZ, AO, MC, EP, TU, SP, and LRD received funding to their institutions from Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA (MSD) to support the study. DL reports grants or contracts from AstraZeneca, Clovis Oncology, Pharma&, Genmab, GSK, Immunogen, MSD, Pharmamar, Novartis, Seagen, Alkermes, Incyte, Roche, and Corcept; consulting fees from AstraZeneca, Corcept, Clovis Oncology, Daiichi Sankyo, Genmab, GSK, Immunogen, MSD, Novartis, Oncoinvest, Novocure, Seagen, and Sutro; speaker fees from AstraZeneca, Corcept, Genmab, GSK, Immunogen, MSD, and Seagen; travel grants from AstraZeneca, Menarini, GSK, and MSD; advisory board participation for AstraZeneca, Corcept, Clovis Oncology, Daiichi Sankyo, Genmab, GSK, Immunogen, MSD, Oncoinvest, Novocure, Seagen, and Sutro; and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for GCIG, MITO, and ENGOT. YX reports study funding, paid to the Peking Union Medical College Hospital, and support for attending meetings or travel from MSD. KH reports research contracts from Daiichi Sankyo, Eisai, MSD, and Takeda; advisory board fees from Chugai, Eisai, Takeda, MSD, Roche, Genmab, Sanofi, GSK, and Zymeworks; honoraria from Daiichi Sankyo, AstraZeneca, Chugai, Eisai, Genmab, MSD, Takeda, Sanofi, Kyowa Kirin, Kaken, and GSK; and travel support from Regeneron and Seagen. GS reports consulting fees from AstraZeneca, MSD, Coviden AG (a Medtronic company), Johnson & Johnson, and TESARO Bio Italy; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events from Baxter Healthcare, Olympus Europa, Intuitive Surgical, GSK, and Clovis Oncology Italy. ML reports payment for expert testimony from MSD, support for attending meetings or travel from MSD and AstraZeneca; and other financial or non-financial interests from MSD, AstraZeneca, and Roche. PR-E reports honoraria for educational events from MSD, AstraZeneca, Novartis, Asofarma, Pfizer, and Roche; support for attending ESMO and ASCO meetings from AstraZeneca, Pfizer, and Asofarma; and honoraria for advisory boards from MSD, Roche, AstraZeneca, Asofarma, BMS and Novartis. LR reports medical writing support from Merck, institutional grants from Merck, Zentalis, Karyopharn, GOG Foundation, Regeneron, ImmunoGen, Acrivon, CanariaBio, Corcept Therapeutics, and Seagen; consulting fees from AstraZeneca, Merck, GSK, Genmab, Seagen, GOG Foundation, Zentalis, ImmunoGen, Semline, Eisai, Caris, Nykode, and Clovis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Seagen and Genmab; and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, from GOG Foundation. AJPdSG reports consulting fees and payment for expert testimony from Bayer, Astellas, and Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for expert testimony from Astellas, AstraZeneca, Bayer, and Janssen; and participation on a data safety monitoring board or advisory board for Astellas, Bayer, and Janssen. FCM reports honoraria for presentations from MSD and BMS; support for attending meetings or travel from AstraZeneca and MSD; and advisory board participation from Janssen and MSD. J-YL reports support for the present manuscript from MSD; grants or contracts from Advenchen, Ascendis Pharma, Alkermes, AstraZeneca, Beigene, BergenBio, BMS, CanariaBio, Corcept, Cellid, CKD, Clovis Oncology, Eisai, Genmab, Genemedicine, GII, GSK, ImmunoGen, Janssen, Kelun, Merck, Mersana, MSD, Novartis, Onconic Therapeutics, ONO, Regeneron, Roche, Seagen, Sutro, Synthon, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Janssen, MSD, Roche, Takeda, and ONO; and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, for AstraZeneca, CanariaBio, Genmab, GII, ImmunoGen, Seagen, Merck, Sutro, Regeneron, and MSD. FZ reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, consulting fees, support for attending meetings or travel, and data safety monitoring board and advisory board participation for AstraZeneca, Daiichi, Eli-Lilly, Merck, Novartis, MSD, Pfizer, Genesis-Pharma, and Roche. LG reports institutional grants from IMV, Pfizer, Sutro Bio, Pharma, Merck Sharpe Dohme, Corcept Therapeutics, ImmunoGen, Shattuck Labs, Roche, Tesaro, K-Group, Beta Inc., GOG Foundation, GSK, AstraZeneca, OncoQuest Pharmaceuticals, Novocure, Alkermes, Espersas, and Mersana; consulting fees from Merck and GSK; payment or honoraria for lectures and presentations from Merck and GSK; support for attending meetings or travel from GSK, Merck, EndomERA, and Zentalis; and participation on advisory board meetings for GSK, Merck, Eisai, Novocure, Kora Health, Corcept, ImmunoGen, Canariabio, and Repare Therapeutics. JS reports grants or contracts from Roche, MSD, GSK, Tesaro, AstraZeneca, Eisai, Merck, and Novocure; consulting fees from Immunogen, Incyte, GSK, AstraZeneca, Clovis, Novocure, MSD, Eisai, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Immunogen, Incyte, GSK, AstraZeneca, Clovis, Novocure, BMS, Eisai, and Novartis; support for attending meetings or travel from GSK, Astra Zeneca, Roche, Novocure, Immunogen, Incyte, MSD, and Eisei; participation on a data safety monitoring board or advisory board for Immunogen, Incyte, GSK, AstraZeneca, Clovis, Novocure, Bristol Myers Squibb, MSD, Merck, Bayer, and PharmaMar; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, for ENGAGE, ESGO, ASCO, ESGO, GCIG, Deutsche Stiftung Eierstockkrebs, and AGO; and medical writing assistance from MSD. ET reports honoraria for presentations and meeting travel support from Elektra. KL reports study funding from MSD; grants or contracts from GSK; lecture honoraria from Eisai and AstraZeneca; participation on a data safety monitoring board for Karyopharm; participation on an advisory board for Eisai, MSD, Nykode, AstraZeneca, and GSK; and serving as deputy medical director for the Nordic Society of Gynecological Oncology Clinical Trial Unit. NC reports institutional grants from AstraZeneca and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK and MSD; payment for participation on a data safety monitoring board or advisory board for AstraZeneca, Clovis Oncology, Eisai, GSK, ImmunoGen, Mersana, MSD, Merck, Nuvation Bio, Onxerna, Pfizer, PharmaMar, Pieris, Roche, and Novocure; and non-remunerated leadership role as Chair of the Alleanza Contro il Tumore Ovarico Scientific Committee. MB reports honoraria for lectures and educational events from Roche, AstraZeneca, and GSK; and support for attending meetings from Roche, AstraZeneca, and Viatris. AO reports consulting fees from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Daïichi Sankyo, Debiopharm International, Eisai, Exelisis, F. Hoffmann-La Roche, Genmab, GSK, ImmunoGen, Itheos, MSD, Mersana Therapeutics, Myriad Genetics, Novocure, OncoXerna Therapeutics, PharmaMar, Regeneron, Sattucklabs, Seagen–Pfizer, Sutro Biopharma, TORL Therapuetics, Zentalis, and Zymeworks; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from NSGO, Peerview, Peervoice, Medscape, Asociación Colombiada de Ginecológos Oncólogos, ESO, AstraZeneca, and GSK; support for attending meetings or travel from AstraZeneca, PharmaMar, and Roche; participation on a data safety monitoring board or advisory board from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Daïichi Sankyo, Debiopharm International, Eisai, Exelisis, F Hoffmann-La Roche, Genmab, GSK, ImmunoGen, Itheos, MSD, Mersana Therapeutics, Myriad Genetics, Novocure, OncoXerna Therapeutics, PharmaMar, Regeneron, Sattucklabs, Seagen–Pfizer, Sutro Biopharma, TORL Therapuetics, Zentalis, and Zymeworks; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, for Gynecologic Cancer Intergroup and European Society for Medical Oncology; and other financial or non-financial interests in Gynecologic Cancer Intergroup, European Society for Medical Oncology, American Society of Clinical Oncology, Spanish Society of Medical Oncology, and GOG Foundation. EP reports provision of study material from MSD; honoraria for lectures, presentations, and educational events from MSD, Roche, GSK, and AstraZeneca; and receipt of investigational drug for study treatment from MSD. PL, KY, ST, and SMK are current or former full-time employees of MSD and hold stock or restricted stock units in the company. SP reports research funding from Roche, MSD, GSK, Pfizer, and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, MSD, Roche, Pfizer, Novartis, and GSK; and participation on a Data Safety Monitoring Board or Advisory Board for GSK, MSD, Eisai, Biontech, and AstraZeneca. LRD reports institutional grants from Merck, Genentech, Roche, AbbVie, Acrivon, Advaxis, Aduro BioTech, Alkermes, Blueprint, Constellation, Eisai, GSK, Novartis, Immunogen, Inovio, Iovance, Karyopharm, KSQ Therapeutics, Lycera, Morab, MorphoTek, Naveris, Nurix, OncoQuest, Pfizer, Syndax, Tesaro, and Zentalis; royalties or licenses from UpToDate, Wiley, and ASCO; editing for ASCO Connection; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Advance Medical, CEA Group, and Clinical Care Options; participation on a data safety monitoring board for Innovia and Aegenus (payment to institution); and roles as Secretary Treasurer for SGO (unpaid) and on the Editorial Board of the British Journal of Obstetrics and Gynaecology., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: For patients with metastatic hormone-sensitive prostate cancer (mHSPC), delaying progression to castration-resistant disease is important not only for overall survival (OS) but also for patients' quality of life. Darolutamide plus androgen-deprivation therapy (ADT) with docetaxel improved OS versus ADT and docetaxel in patients with mHSPC. The ARANOTE trial evaluated darolutamide and ADT without chemotherapy in patients with mHSPC., Methods: In this global phase III trial, patients were randomly assigned 2:1 to receive darolutamide 600 mg twice daily or placebo, with concomitant ADT. The primary end point was radiological progression-free survival (rPFS)., Results: From March 2021 to August 2022, 669 patients were randomly assigned (darolutamide n = 446; placebo n = 223). At the primary cutoff date (June 7, 2024), darolutamide plus ADT significantly improved rPFS, reducing the risk of radiological progression or death by 46% versus placebo plus ADT (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.71]; P < .0001), with consistent benefits across subgroups, including high- and low-volume disease. OS results were suggestive of benefit with darolutamide versus placebo (HR, 0.81 [95% CI, 0.59 to 1.12]), and clinical benefits were seen across all other secondary end points, including delayed time to metastatic castration-resistant prostate cancer (HR, 0.40 [95% CI, 0.32 to 0.51]) and time to pain progression (HR, 0.72 [95% CI, 0.54 to 0.96]). Adverse events were similar in the two groups. Notably, the incidence of fatigue was lower in patients receiving darolutamide (5.6%) versus those receiving placebo (8.1%), and fewer patients receiving darolutamide (6.1%) versus placebo (9.0%) discontinued treatment because of adverse events., Conclusion: These results confirm the efficacy and tolerability of darolutamide plus ADT in patients with mHSPC, demonstrating clinically and statistically significant improvement in rPFS and a favorable safety profile consistent with prior phase III darolutamide trials.

Background: Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer., Methods: In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB node positive vs stage III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1-by investigator or by histopathologic confirmation of suspected disease progression-and overall survival. Primary analysis was conducted in the intention-to-treat population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants., Findings: Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab-chemoradiotherapy group and 531 to the placebo-chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3-22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab-chemoradiotherapy group versus 57% in the placebo-chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55-0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab-chemoradiotherapy group and 81% in the placebo-chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49-1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab-chemoradiotherapy group and 69% in the placebo-chemoradiotherapy group., Interpretation: Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD)., Competing Interests: Declaration of interests DL, YX, KH, GS, ML, PR-E, AAc, VSu, NC, AJPdSG, FCM, AR, AAy, J-YL, VSa, FZ, LG, JS, ET, KLin, RLaz, C-LC, RLam, HZ, AO, MC, SPo, TU, SPi, and LRD received funding to their institutions from MSD to support the study. DL reports consulting fees from AstraZeneca, Clovis Oncology, GSK, MSD, ImmunoGen, Genmab, Seagen, Novartis, and PharmaMar; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, ImmunoGen, GSK, Seagen, and Genmab; support for attending meetings or travel from AstraZeneca, Clovis Oncology, and GSK; participation on a data safety monitoring board or advisory board for Oncoinvest, Corcept, Sutro, AstraZeneca, ImmunoGen, GSK, Seagen, Genmab, Clovis Oncology, GSK, MSD, and PharmaMar; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for GCIG; receipt of equipment, materials, drugs, medical writing, gifts, or other services from Clovis Oncology, GSK, MSD, and PharmaMar; and other financial or non-financial interests in AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Incyte, MSD, Roche, Seagen, and Novartis. YX reports participation on a data safety monitoring board or advisory board for MSD. KH reports research contracts from Daiichi Sankyo, Eisai, MSD, and Takeda; advisory board fees from Chugai, Eisai, Takeda, MSD, Roche, Genmab, and Sanofi; honoraria from Daiichi Sankyo, AstraZeneca, Chugai, Eisai, Genmab, MSD, Takeda, Sanofi, Kyowa Kirin, and Kaken; and support for attending meetings or travel from Regeneron. GS reports grants or contracts from MSD Italia; consulting fees from Tesaro and Johnson & Johnson; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Clovis Oncology Italy. ML reports grants or contracts from MSD, AstraZeneca, and Roche; speaker fees from AstraZeneca and Roche; and meeting support from Roche. PR-E reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from MSD, Asofarma, Novartis, Janssen, and AstraZeneca; support for attending meetings or travel from Roche, Novartis, Asofarma, and AstraZeneca; and participation on a data safety monitoring board or advisory board for Pfizer, Asofarma, Bristol Myers Squibb, and AstraZeneca. NC reports participation on a data safety monitoring board or advisory board for GSK, Toray, Tarveda Therapeutics, Umoja, Kartos, Zentalis, Profound, and Novita Pharmaceuticals. AJPdSG reports consulting fees, payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events, and participation on a data safety monitoring board or advisory board for AstraZeneca, Astellas, Bayer, and Janssen; payment for expert testimony from Janssen; and support for attending meetings or travel from Janssen, MSD, and Bayer. FCM reports speaker fees from MSD, Bristol Myers Squibb, GSK, Eli Lilly, and BMS; payment for expert testimony from MSD, Janssen, GSK, Eli Lilly, and Bristol Myers Squibb; and meeting and travel support from MSD and Amgen. AR reports advisory board fees from MSD Israel. J-YL reports grants or contracts from Advenchen, Ascendis Pharma, Alkermes, AstraZeneca, BeiGene, BerGenBio, Bristol Myers Squibb, Cellid, Clovis Oncology, Eisai, Genmab, GII, GSK, ImmunoGen, Janssen, Merck, Mersana, MSD, Novartis, Onconic Therapeutics, OncoQuest, Ono, Regeneron, Roche, Seagen, Sutro, Synthon, and Takeda; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, Janssen, MSD, Roche, Takeda, and Ono. FZ reports grants or contracts, consulting fees, payment for expert testimony, support for attending meetings or travel, participation on a data safety monitoring board or advisory board, and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, from AstraZeneca, Eli Lilly, MSD, Pfizer, Roche, Daiichi Sankyo, Merck, Novartis, Genesis Pharma, and Gilead. LG reports institutional grants from GSK, Pfizer, MSD, Karyopharm, Tesaro, IMV, Alkermes, Clovis Oncology, ImmunoGen, Roche, Mersana, and AstraZeneca; consulting fees from GSK, Merck, Eisai, and Novocure; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from GSK, Merck, Eisai, Novocure, and Corcept; and support for attending meetings or travel from Corcept, GSK, AstraZeneca, and Merck. JS reports grants or contracts from Roche, MSD, GSK, Tesaro, AstraZeneca, Eisai, Merck, and Novocure; consulting fees from ImmunoGen, Incyte, GSK, AstraZeneca, Clovis Oncology, Novocure, MSD, Eisai, and Merck; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from ImmunoGen, Incyte, GSK, AstraZeneca, Clovis Oncology, Novocure, Bristol Myers Squibb, Eisai, and Novartis; support for attending meetings or travel from GSK, AstraZeneca, Roche, Novocure, ImmunoGen, Incyte, MSD, and Eisei; participation on a data safety monitoring board or advisory board for ImmunoGen, Incyte, GSK, AstraZeneca, Clovis Oncology, Novocure, Bristol Myers Squibb, MSD, Merck, Bayer, and PharmaMar; and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for ENGAGE, ESGO, ASCO, ESGO, GCIG, Deutsche Stiftung Eierstockkrebs, and AGO. KLin reports grants or contracts from GSK (paid to institution); payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Eisai; and participation on a data safety monitoring board or advisory board for Eisai, MSD, Nykode, AstraZeneca, and GSK. HZ reports contracted research and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events for MSD. AO reports grants or contracts from AbbVie Deutschland, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics, Bristol Myers Squibb, Clovis Oncology, Eisai, Roche, ImmunoGen, MSD de España, Millennium Pharmaceuticals, PharmaMar, Regeneron, and Tesaro (paid to institution); consulting fees and participation on a data safety monitoring board or advisory board from Agenus, AstraZeneca, Clovis Oncology, Corcept, Deciphera Pharmaceuticals, Eisai, Exelixis, EMD Serono, Roche, Genmab, GSK, ImmunoGen, iTeos, MSD de España, Mersana, Novocure, OncXerna Therapeutics, PharmaMar, Regeneron, Sattucklabs, Seagen, and Sutro; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from NSGO, Peerview, Peervoice, Medscape, Asociación Colombiana de Ginecológos Oncólogos, ESO, AstraZeneca, and GSK; and support for attending meetings or travel from AstraZeneca, PharmaMar, and Roche. SPo reports consulting fees from MSD, AstraZeneca, GSK, and Eisai; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events, support for attending meetings or travel, and advisory board fees from MSD, AstraZeneca, and GSK; and leadership or fiduciary role in other board, society, committee, or advocacy group for the Austrian Association of Gynecologic Oncology (unpaid). SPi reports research funding from Roche, MSD, AZ, Pfizer, and GSK; and honoraria from AZ, Roche, MSD, GSK, and PharmaMar. LRD reports research funding (paid to institution) from and acting as an expert advisor (unpaid) for Merck & Co; writing fees for expert content for UpToDate; participation on a scientific advisory board for Aadi Bioscience; and serving on the Editorial Board of the British Journal of Obstetrics and Gynaecology. KLi, KY, ST, and SMK are full-time employees of MSD and hold stock or restricted stock units in the company., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

What Is This Summary About?: This summary describes the results from an additional (or post hoc) analysis of the TITAN study. The TITAN study looked at whether the prostate cancer treatment apalutamide could be used to treat individuals with metastatic castration-sensitive prostate cancer (or mCSPC). A total of 1052 participants with mCSPC were included in the TITAN study. Treatment with apalutamide was compared with treatment with placebo. All participants received androgen deprivation therapy (or ADT), which is a type of hormone therapy that has been part of the main treatment for mCSPC for many years. The results showed that apalutamide plus ADT increased the length of time that participants remained alive compared with placebo plus ADT. Apalutamide plus ADT also controlled the growth of the cancer for a longer length of time compared with placebo plus ADT. Additionally, participants who received apalutamide plus ADT experienced a greater reduction in the blood levels of prostate-specific antigen (or PSA), called a deep PSA decline, compared with those who received placebo plus ADT. An additional (or post hoc) analysis was carried out to understand whether a decrease in blood PSA levels, in response to treatment, was associated with improved outcomes, including longer survival time., What Were the Results of the Additional Analysis?: In participants who received apalutamide plus ADT, a deep PSA decline in response to treatment was associated with longer survival time and improved outcomes., What Do These Results Mean for Individuals With Mcspc?: These results demonstrate that individuals with mCSPC can benefit from treatment with apalutamide plus ADT. The association seen between deep PSA decline and the longer survival time and improved outcomes highlights how PSA measurements can be used to help monitor cancer disease evolution in response to treatment. Monitoring PSA levels will assist doctors and other healthcare professionals to understand how effectively a treatment is working for a patient and to tailor their treatment approach to improve PSA decline.

Background: Whether disease burden in patients with metastatic castration-sensitive prostate cancer (mCSPC) predicts treatment outcomes is unknown. We assessed apalutamide treatment effect in TITAN patients with mCSPC by disease volume, metastasis number and timing of metastasis presentation., Methods: These protocol-defined and post hoc analyses of the phase III randomised TITAN study evaluated clinical outcomes in patients receiving 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy (ADT). Subgroups were defined by volume (high: visceral and ≥1 bone metastases or ≥4 bone lesions with ≥1 beyond vertebral column/pelvis), development of metastases per conventional imaging (synchronous: at initial diagnosis; metachronous: after localised disease) and oligometastases (≤5 bone-only metastases) or polymetastases (>5 in bone ± other locations or ≤5 in bone plus other locations). Overall survival (OS), radiographic or second progression-free survival, and time to prostate-specific antigen progression or castration resistance were assessed using Cox proportional hazards models., Results: Of 1052 patients, 63%, 81%, 54%, 27%, 5.7%, and 8.0% had high-volume, synchronous, synchronous/high-volume, synchronous/low-volume, metachronous/high-volume, and metachronous/low-volume disease, respectively. The OS benefit favoured apalutamide plus ADT versus ADT alone in synchronous/high-volume (hazard ratio = 0.68 [95% confidence interval: 0.53-0.87]; p = 0.002), synchronous/low-volume (0.65 [0.40-1.05]; p = 0.08), metachronous/high-volume (0.69 [0.33-1.44]; p = 0.32) and metachronous/low-volume (0.22 [0.09-0.55]; p = 0.001) subgroups. Apalutamide improved other clinical outcomes regardless of subgroup, with similar safety profiles. Most favourable outcomes were observed in oligometastatic disease., Conclusion: TITAN patients derived a robust benefit with apalutamide plus ADT regardless of disease volume and timing of metastasis presentation without differences in safety, supporting early apalutamide intensification in mCSPC., Clinical Trial Registration: NCT02489318., Competing Interests: Declaration of Competing Interest Dr. Axel Merseburger reports consulting and advisory role for Astellas, AstraZeneca, Bristol-Myers Squibb, EUSAPharm, Ipsen, Janssen, Merck Serono, MSD, Novartis, Teva, Pfizer, Roche and Takeda; lectures/speaker/honoraria for/from Astellas, AstraZeneca, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck Serono, MSD, Novartis, Pfizer, Roche, Takeda and Teva; research and clinical studies for Astellas, AstraZeneca, Bristol-Myers Squibb, EUSAPharm, Ipsen, Janssen, Merck Serono, MSD, Novartis, Pfizer, Roche, Takeda and Teva. Dr. Neeraj Agarwal reports consulting and advisory role for Astellas, 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; and research funding to institution from Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda and Tracon. Dr. Laurence Karsh reports consulting or advisory role for 3D Biopsy, Astellas, AstraZeneca, Bayer, Dendreon, Ferring, Janssen, Pfizer and Vaxiion; speakers’ bureau for Astellas, Bayer, Janssen, Pfizer and Clovis; honoraria from Astellas, Bayer, Janssen, Pfizer and Dendreon; stock or other ownership from Swan Valley Medical; research funding from Astellas, AstraZeneca, Bayer, BioXcel Therapeutics, Bristol Meyers Squibb, BU Optics, CUSP, Dendreon, Epizyme, Exact Sciences, Ferring, FKD, Genetech/Roche, GenomeDX, Genomic Health, Janssen, Merck, Myovant, Nucleix, OncoCell MDx, Pfizer, Pharmtech/Very, Precision Med and QED; and travel, accommodations and expenses from Astellas, Bayer, Dendreon, Janssen and Pfizer. Dr. Andrea Juliana Pereira de Santana Gomes reports consulting and advisory role for Janssen Oncology; speakers’ bureau for Astellas Pharma, Bayer and Janssen Oncology; research funding from Bayer, Janssen Oncology, MSD Oncology and Roche. Dr. Alvaro Juarez Soto reports consulting and advisory role for Astellas, Bayer and Janssen; meeting participation/lecturer for Astellas, Bayer and Janssen; investigator for Bayer and Janssen; meeting participation/lecturer for Astellas, Bayer and Janssen; clinical study participation for Janssen. Dr. Robert Given reports speakers’ bureau for Bayer, Janssen and Myovant; clinical study participation for Bayer and Janssen. Dr. Hirotsugu Uemura reports consulting and advisory role for AstraZeneca, Bayer, Janssen, MSD, Ono/BMS and Sanofi; meeting participation/lecturer for Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis, Ono/BMS, Pfizer and Takeda; investigator for Astellas, AstraZeneca, Bayer, Janssen, MSD, Ono/BMS, Pfizer, Sanofi, Taiho and Takeda; clinical study participation for Bayer, Janssen, MSD and Ono/BMS. Dr. Simon Chowdhury reports consulting and advisory role to Astellas Pharma, Bayer, Beigene, Clovis, Janssen-Cilag, Johnson & Johnson, Novartis and Sanofi; research funding (self) from Clovis; and honoraria from Astellas Pharma, Bayer, Beigene, Clovis, Janssen-Cilag, Johnson & Johnson, Novartis and Sanofi. Dr. Kim Chi reports consulting and advisory role to Janssen, Astellas, Essa, Sanofi, Bayer, Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Merck, Bristol Myers Squibb and Point Pharma; research funding to institution from Janssen, Astellas and Sanofi; and honoraria from Janssen, Astellas, Bayer, AstraZeneca, Merck and Pfizer. Dr. Anders Bjartell reports consulting and advisory role for Astellas and Bayer; board membership/officer/trustee for Glactone Pharma and LIDDS Pharma; meeting participation/lecturer for Astellas, AstraZeneca, Bayer, Incyte, Ipsen, Janssen and Merk; clinical study participation for Astellas, Ferring and Janssen; stock ownership in Glactone Pharma, LIDDS Pharma and WntResearch. Dr. Amitabha Bhaumik, Dr. Florence Lefresne, Dr. Sabine Brookman-May, Dr. Suneel Mundle and Ms. Sharon McCarthy are employees of Janssen Research & Development and may hold stock in Johnson & Johnson. Dr. Amitabha Bhaumik also reports stock ownership of AbbVie., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2)., Patients and Methods: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed., Results: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed., Conclusions: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients., Competing Interests: Disclosure KNC received consulting fees from Amgen, Astellas, AstraZeneca, Bayer, Janssen, Merck, Pfizer, POINT Biopharma, and Roche; and grants (to institution) from Amgen, AstraZeneca, Bayer, ESSA, Janssen, Merck, POINT Biopharma, and Roche. SS received honoraria from AstraZeneca, Bristol Myers Squibb, Janssen, Merck, and Novartis (DSM Committee Chair); and grants from AstraZeneca, Genentech, Merck, Novartis, and Pfizer. MRS received consulting or advisory fees from Amgen, Astellas, Bayer, Janssen, Eli Lilly, Novartis, and Pfizer; research funding from Bayer, ESSA, Janssen, Eli Lilly, and ORIC Pharmaceuticals; and travel, accommodations, and expense reimbursements from Amgen, Bayer, Janssen, and Eli Lilly. GA received honoraria from Astellas and Janssen; consulting or advisory fees from Abbott Laboratories, Astellas, AstraZeneca, Bayer, ESSA, Ferring, Janssen, Medivation, Millennium Pharmaceuticals, Novartis, Pfizer, Ventana Medical Systems, and Veridex; speakers’ bureau fees from Astellas, AstraZeneca, Ferring, Ipsen, Janssen, Sanofi, Takeda, and Ventana Medical Systems; research funding from Arno Therapeutics, Innocrin Pharma, and Janssen; has patents or other intellectual property or received royalties for abiraterone acetate; received travel, accommodations, or expense reimbursements from Abbott Laboratories, Astellas, Bayer, ESSA, Ferring, Janssen, Medivation, Pfizer, and Ventana Medical Systems; and is affiliated with the Institute of Cancer Research. MS received honoraria and consulting or advisory role fees from AstraZeneca, Astellas, Amgen, Ipsen, Johnson & Johnson, Merck, and Pfizer; grants (to institution) from Johnson & Johnson and Merck; and travel, accommodations, and expense reimbursements from Cipla, Ipsen, and Pfizer. DO received honoraria from Astellas, Bayer, and Janssen; consulting or advisory role fees from AstraZeneca, Bayer, Clovis Oncology, Daiichi Sankyo, Janssen, and Merck; research funding from Astellas, AstraZeneca, Bayer, Genentech/Roche, Janssen, Medivation, Merck, and Pfizer; and travel, accommodations, or expense reimbursements from Astellas, AstraZeneca, Bayer, Ipsen, Janssen, and Roche. EC received honoraria from Astellas, AstraZeneca, Bayer, Janssen, Merck, Pfizer, and Telix Pharmaceuticals; consulting or advisory fees from Astellas, AstraZeneca, Bayer, Daiichi Sankyo, Janssen, Merck, and Pfizer; grants (to institution) from AstraZeneca, Bayer, and Janssen; and travel, accommodations, or expense reimbursements from AstraZeneca, Bayer, Janssen, and Pfizer. GR received consulting or advisory role fees from Astellas, AstraZeneca (to institution), Bayer, Gilead (to institution), Janssen, Ipsen, and Pfizer; research funding from Bayer (to institution); honoraria for lectures/speakers’ bureau fees from AstraZeneca (to institution), Bayer, and Janssen; and travel, accommodations, or expense reimbursements from AstraZeneca, Bayer, and Janssen. AJPdSG received honoraria for lectures/speakers’ bureau fees from Adium Pharma, Astellas, AstraZeneca, Bayer, and Janssen; and travel, accommodations, and expense reimbursements from Astellas and Janssen. EJS has stock or other ownership of Fortis and Teon Therapeutics; received honoraria from Janssen and Johnson & Johnson; and received consulting or advisory role fees from Fortis and Janssen. DER received grants (to institution) from AstraZeneca, Bayer, Bristol Myers Squibb/Celgene, Promontory Therapeutics, and Taiho Pharma; consulting or advisory fees from AstraZeneca, Bayer, Bristol Myers Squibb/Celgene, Genentech, Myovant, and Promontory Therapeutics; and medical writing assistance from Genentech and Janssen. HG received consulting or advisory fees from Astellas, AstraZeneca, Ipsen, Janssen, Merck, Merck-Serono, and Pfizer; honoraria for lectures/speakers’ bureau fees from Ipsen and Merck; and received travel, accommodations, and expense reimbursements from AstraZeneca. EE received consulting or advisory fees, speakers’ bureau fees, and research funding from Astellas, AstraZeneca, Merck, Myovant Sciences, Novartis, Pfizer, and Sanofi. GEM, SD, DW, BD, KU, AdC, PF, and WK are employed by Janssen Research & Development, LLC. WJ has declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies. Homologous recombination repair (HRR) gene alterations, including BRCA1/2 alterations, can sensitize cancer cells to poly (ADP-ribose) polymerase inhibition, which may improve outcomes in treatment-naïve mCRPC when combined with androgen receptor signaling inhibition., Methods: MAGNITUDE (ClinicalTrials.gov identifier: NCT03748641) is a phase III, randomized, double-blinded study that evaluates niraparib and abiraterone acetate plus prednisone (niraparib + AAP) in patients with (HRR+, n = 423) or without (HRR-, n = 247) HRR-associated gene alterations, as prospectively determined by tissue/plasma-based assays. Patients were assigned 1:1 to receive niraparib + AAP or placebo + AAP. The primary end point, radiographic progression-free survival (rPFS) assessed by central review, was evaluated first in the BRCA1/2 subgroup and then in the full HRR+ cohort, with secondary end points analyzed for the full HRR+ cohort if rPFS was statistically significant. A futility analysis was preplanned in the HRR- cohort., Results: Median rPFS in the BRCA1/2 subgroup was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.6 v 10.9 months; hazard ratio [HR], 0.53; 95% CI, 0.36 to 0.79; P = .001). In the overall HRR+ cohort, rPFS was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.5 v 13.7 months; HR, 0.73; 95% CI, 0.56 to 0.96; P = .022). These findings were supported by improvement in the secondary end points of time to symptomatic progression and time to initiation of cytotoxic chemotherapy. In the HRR- cohort, futility was declared per the prespecified criteria. Treatment with niraparib + AAP was tolerable, with anemia and hypertension as the most reported grade ≥ 3 adverse events., Conclusion: Combination treatment with niraparib + AAP significantly lengthened rPFS in patients with HRR+ mCRPC compared with standard-of-care AAP., [Media: see text].

Background: The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN., Patients and Methods: Patients received apalutamide (240 mg/day) or placebo plus ADT (1 : 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months' follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months' follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan-Meier method, and Cox proportional hazards model., Results: One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.25-0.48), rPFS (HR 0.44; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% CI 0.27-0.52) compared with no decline (P < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of apalutamide treatment., Conclusions: Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We performed an exploratory analysis of prostate cancer-related pain and fatigue on health-related quality of life in patients with metastatic castration-sensitive prostate cancer receiving apalutamide (240 mg/day) or placebo, with continuous androgen deprivation therapy (ADT), in the phase 3, randomized, double-blind, placebo controlled TITAN trial (NCT02489318)., Materials and Methods: Patient-reported outcomes for pain and fatigue were evaluated using the Brief Pain Inventory-Short Form and Brief Fatigue Inventory. Time to deterioration (TTD) was estimated by Kaplan-Meier method; hazard ratios and 95% confidence intervals were calculated using Cox proportional hazards model. General estimating equations for logistic regression estimated treatment-related differences in the likelihood of worsening pain or fatigue., Results: Compliance for completing the Brief Pain Inventory-Short Form and Brief Fatigue Inventory was high (96% to 97%) in the first year. Median followup times were similar between treatments (19 to 22 months). Median pain TTD was longer with apalutamide than placebo for "pain at its least in the last 24 hours" (28.7 vs 21.8 months, respectively; p=0.0146), "pain interfered with mood" (not estimable vs 22.4 months; p=0.0017), "pain interfered with walking ability" (28.7 vs 20.2 months; p=0.0027), "pain interfered with relations" (not estimable vs 23.0 months; p=0.0139) and "pain interfered with sleep" (28.7 vs 20.9 months; p=0.0167). Likelihood for fatigue and worsening fatigue were similar between groups., Conclusions: Patients with metastatic castration-sensitive prostate cancer receiving apalutamide plus ADT vs placebo plus ADT reported consistently favorable TTD of pain. No difference for change in fatigue was observed with apalutamide vs placebo.

Purpose: The first interim analysis of the phase III, randomized, placebo-controlled TITAN study showed that apalutamide significantly improved overall survival (OS) and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving ongoing androgen deprivation therapy (ADT). Herein, we report final efficacy and safety results after unblinding and placebo-to-apalutamide crossover., Methods: Patients with mCSPC (N = 1,052) were randomly assigned 1:1 to receive apalutamide (240 mg QD) or placebo plus ADT. After unblinding in January 2019, placebo-treated patients were allowed to receive apalutamide. Efficacy end points were updated using the Kaplan-Meier method and Cox proportional-hazards model without formal statistical retesting and adjustment for multiplicity. Change from baseline in Functional Assessment of Cancer Therapy-Prostate total score was assessed., Results: With a median follow-up of 44.0 months, 405 OS events had occurred and 208 placebo-treated patients (39.5%) had crossed over to apalutamide. The median treatment duration was 39.3 (apalutamide), 20.2 (placebo), and 15.4 months (crossover). Compared with placebo, apalutamide plus ADT significantly reduced the risk of death by 35% (median OS not reached v 52.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P < .0001) and by 48% after adjustment for crossover (hazard ratio, 0.52; 95% CI, 0.42 to 0.64; P < .0001). Apalutamide plus ADT delayed second progression-free survival and castration resistance ( P < .0001 for both). Health-related quality of life, per total Functional Assessment of Cancer Therapy-Prostate, in both groups was maintained through the study. Safety was consistent with previous reports., Conclusion: The final analysis of TITAN confirmed that, despite crossover, apalutamide plus ADT improved OS, delayed castration resistance, maintained health-related quality of life, and had a consistent safety profile in a broad population of patients with mCSPC., Competing Interests: Kim N. ChiHonoraria: Janssen, Astellas Pharma, Bayer, AstraZeneca, Roche, MerckConsulting or Advisory Role: ESSA, Astellas Pharma, Janssen, Sanofi, Amgen, Bayer, AstraZeneca, Roche, POINT Biopharma, Daiichi Sankyo, Merck, Constellation PharmaceuticalsResearch Funding: Janssen, Astellas Pharma, Bayer, Sanofi, Bristol Myers Squibb, Merck, Roche, AstraZeneca, Novartis, Pfizer, ESSA Simon ChowdhuryHonoraria: Clovis Oncology, NovartisConsulting or Advisory Role: Clovis Oncology, Astellas Pharma, Bayer, Pfizer, Janssen-Cilag, BeiGene, NovartisSpeakers' Bureau: Pfizer, Janssen-CilagResearch Funding: Sanofi-Aventis Anders BjartellConsulting or Advisory Role: Astellas Pharma, Bayer, Janssen-Cilag, AstraZeneca, Merck, SandozSpeakers' Bureau: Astellas Pharma, Bayer, Janssen-CilagResearch Funding: Ferring, Astellas Pharma, BayerTravel, Accommodations, Expenses: Astellas Pharma, Bayer, Janssen-Cilag Byung Ha ChungHonoraria: Astellas Pharma, Ipsen, JW Pharmaceutical, TakedaConsulting or Advisory Role: Janssen, Bayer, Pfizer, AstraZeneca, Roche, Myovant Sciences Robert GivenConsulting or Advisory Role: Janssen OncologySpeakers' Bureau: Janssen Oncology, Bayer Schering Pharma, Myovant Sciences Alvaro Juárez SotoHonoraria: Astellas Pharma, Janssen Oncology, Pfizer, BayerConsulting or Advisory Role: Janssen OncologyResearch Funding: Janssen Oncology, Bayer, Exelixis Axel S. MerseburgerHonoraria: Janssen-Cilag, Astellas Pharma, Ipsen, Roche, Bristol Myers Squibb, Eisai, Takeda, Pfizer, NovartisConsulting or Advisory Role: MSD Oncology, Bristol Myers Squibb, Janssen-Cilag, Astellas Pharma, Ipsen, Clovis OncologySpeakers' Bureau: IpsenResearch Funding: Novartis, AstraZeneca, Janssen-Cilag, Bristol Myers Squibb, Clovis OncologyTravel, Accommodations, Expenses: Janssen-Cilag, Astellas Pharma, Ipsen Mustafa ÖzgüroğluHonoraria: Astellas Pharma, Novartis, Janssen OncologyConsulting or Advisory Role: MSD Oncology, AstraZenecaSpeakers' Bureau: AstraZenecaTravel, Accommodations, Expenses: AstraZeneca Hirotsugu UemuraConsulting or Advisory Role: Sanofi, Pfizer, JanssenSpeakers' Bureau: Pfizer, Bristol Myers Squibb, Janssen, BayerResearch Funding: Astellas Pharma, Takeda, AstraZeneca, Sanofi, Ono Pharmaceutical, Daiichi Sankyo/UCB Japan, Kissei Pharmaceutical Sabine Brookman-MayEmployment: Janssen Research & DevelopmentLeadership: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson & Johnson Suneel D. MundleEmployment: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson & Johnson Sharon A. McCarthyEmployment: Janssen OncologyStock and Other Ownership Interests: Johnson and Johnson Julie S. LarsenEmployment: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson and Johnson Weili SunEmployment: Janssen OncologyStock and Other Ownership Interests: Johnson and Johnson Katherine B. BevansEmployment: JanssenStock and Other Ownership Interests: Johnson and Johnson Ke ZhangEmployment: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson and Johnson Nebita BandyopadhyayEmployment: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson and Johnson Neeraj AgarwalConsulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Foundation One Inc, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, GenentechResearch Funding: Bayer, Bristol Myers Squibb, GlaxoSmithKline, Takeda, Novartis, Pfizer, BN ImmunoTherapeutics, Exelixis, TRACON Pharmaceuticals, Rexahn Pharmaceuticals, Amgen, AstraZeneca, Active Biotech, Bavarian Nordic, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Newlink Genetics, Prometheus, SanofiNo other potential conflicts of interest were reported.

Background: In the phase 3 TITAN study, the addition of apalutamide to androgen deprivation therapy (ADT) significantly improved the primary endpoints of overall survival and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer. We aimed to assess health-related quality of life (HRQOL) in TITAN, including pain and fatigue., Methods: In this randomised, placebo-controlled, double-blind, phase 3 study, patients with metastatic castration-sensitive prostate cancer (defined as not receiving ADT at the time of metastatic disease progression) aged 18 years and older, receiving continuous ADT (selected at the investigator's discretion), and with an Eastern Cooperative Oncology Group performance status score of 0 or 1 were randomly assigned (1:1), using an interactive web response system, to receive oral apalutamide (four 60 mg tablets, once daily) or matching placebo. Previous localised disease treatment or previous docetaxel for metastatic castration-sensitive prostate cancer were allowed. Randomisation was stratified by Gleason score at diagnosis, region, and previous docetaxel treatment. Randomisation was done using randomly permuted blocks (block size of four). Investigators, research staff, sponsor study team, and patients were masked to the identities of test and control treatments. Patient-reported outcomes were prespecified exploratory endpoints and were the Brief Pain Inventory-Short Form (BPI-SF), Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and EuroQoL 5D questionnaire 5 level (EQ-5D-5L). BPI and BFI were completed for 7 consecutive days (days -6 to 1 inclusive of each cycle visit), then at months 4, 8, and 12 in follow-up. FACT-P and EQ-5D-5L were completed during cycles 1-7, then every other cycle until the end of treatment, and at months 4, 8, and 12 in follow-up. Analyses were based on the intention-to-treat population. Missing patient-reported outcome assessments were calculated as the expected number of assessments for a visit minus the actual number of assessments received for that visit. For time-to-event endpoints, when median values could not be calculated because less than 50% of patients had degradation, 25th percentiles were compared. This study is registered with ClinicalTrials.gov, number NCT02489318, and is ongoing., Findings: Between Dec 9, 2015, and July 25, 2017, 1052 eligible patients were enrolled randomly assigned to apalutamide (n=525) or placebo (n=527). Data cutoff for this analysis of patient-reported outcomes was Nov 23, 2018. Median follow-up for time to pain-related endpoints ranged from 19·4 to 22·1 months. Patients were mostly asymptomatic at baseline: on the BPI-SF pain severity scale of 0-10, median pain scores (indicating worst pain in the past 24 h) were 1·14 (IQR 0-3·17) in the apalutamide group and 1·00 (0-2·86) in the placebo group, and median worst fatigue scores on the BFI were 1·29 (IQR 0-3·29) in the apalutamide group and 1·43 (0·14-3·14) in the placebo group. Patient experience of pain and fatigue (intensity and interference) did not differ between the groups for the duration of treatment. Median time to worst pain intensity progression was 19·09 months (95% CI 11·04-not reached) in the apalutamide group versus 11·99 months (8·28-18·46) in the placebo group (HR 0·89 [95% CI 0·75-1·06]; p=0·20). Median time to pain interference progression was not reached in either group (95% CI 28·58-not reached in the apalutamide group; not reached-not reached in the placebo group). 25th percentiles for time to pain interference progression were 9·17 months (5·55-11·96) in the apalutamide group and 6·24 months (4·63-7·43) in the placebo group (HR 0·90 [95% CI 0·73-1·10]; p=0·29). FACT-P total scores and EQ-5D-5L data showed preservation of HRQOL in both groups. The median time to deterioration as determined by FACT-P total score was 8·87 months (95% CI 4·70-11·10) in the apalutamide group and 9·23 months (7·39-12·91) in the placebo group (HR 1·02 [95% CI 0·85-1·22]; p=0·85)., Interpretation: Apalutamide with ADT is a well-tolerated and effective option for men with metastatic castration-sensitive prostate cancer. The combination significantly improves survival outcomes compared with ADT alone while maintaining HRQOL despite additive androgen blockade., Funding: Janssen Research & Development., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Apalutamide is an inhibitor of the ligand-binding domain of the androgen receptor. Whether the addition of apalutamide to androgen-deprivation therapy (ADT) would prolong radiographic progression-free survival and overall survival as compared with placebo plus ADT among patients with metastatic, castration-sensitive prostate cancer has not been determined., Methods: In this double-blind, phase 3 trial, we randomly assigned patients with metastatic, castration-sensitive prostate cancer to receive apalutamide (240 mg per day) or placebo, added to ADT. Previous treatment for localized disease and previous docetaxel therapy were allowed. The primary end points were radiographic progression-free survival and overall survival., Results: A total of 525 patients were assigned to receive apalutamide plus ADT and 527 to receive placebo plus ADT. The median age was 68 years. A total of 16.4% of the patients had undergone prostatectomy or received radiotherapy for localized disease, and 10.7% had received previous docetaxel therapy; 62.7% had high-volume disease, and 37.3% had low-volume disease. At the first interim analysis, with a median of 22.7 months of follow-up, the percentage of patients with radiographic progression-free survival at 24 months was 68.2% in the apalutamide group and 47.5% in the placebo group (hazard ratio for radiographic progression or death, 0.48; 95% confidence interval [CI], 0.39 to 0.60; P<0.001). Overall survival at 24 months was also greater with apalutamide than with placebo (82.4% in the apalutamide group vs. 73.5% in the placebo group; hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P = 0.005). The frequency of grade 3 or 4 adverse events was 42.2% in the apalutamide group and 40.8% in the placebo group; rash was more common in the apalutamide group., Conclusions: In this trial involving patients with metastatic, castration-sensitive prostate cancer, overall survival and radiographic progression-free survival were significantly longer with the addition of apalutamide to ADT than with placebo plus ADT, and the side-effect profile did not differ substantially between the two groups. (Funded by Janssen Research and Development; TITAN ClinicalTrials.gov number, NCT02489318.)., (Copyright © 2019 Massachusetts Medical Society.)