Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial

Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators

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Abstract

Background: Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy. Methods: We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK. Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open-label in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use (from December, 2015), and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December, 2015. Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomisation. The primary outcome was overall survival, measured as the number of deaths; this analysis had 90% power with a one-sided α of 2·5% for a hazard ratio (HR) of 0·75. Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. This trial is registered with ClinicalTrials.gov, number NCT00268476. Findings: Between Jan 22, 2013, and Sept 2, 2016, 2061 men underwent randomisation, 1029 were allocated the control and 1032 radiotherapy. Allocated groups were balanced, with a median age of 68 years (IQR 63–73) and median amount of prostate-specific antigen of 97 ng/mL (33–315). 367 (18%) patients received early docetaxel. 1082 (52%) participants nominated the daily radiotherapy schedule before randomisation and 979 (48%) the weekly schedule. 819 (40%) men had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0·76, 95% CI 0·68–0·84; p<0·0001) but not overall survival (0·92, 0·80–1·06; p=0·266). Radiotherapy was well tolerated, with 48 (5%) adverse events (Radiation Therapy Oncology Group grade 3–4) reported during radiotherapy and 37 (4%) after radiotherapy. The proportion reporting at least one severe adverse event (Common Terminology Criteria for Adverse Events grade 3 or worse) was similar by treatment group in the safety population (398 [38%] with control and 380 [39%] with radiotherapy). Interpretation: Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer. Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis.

Original languageEnglish
Pages (from-to)2353-2366
Number of pages14
JournalThe Lancet
Volume392
Issue number10162
DOIs
Publication statusPublished - 1 Dec 2018

Bibliographical note

Funding Information:
GA reports personal fees from Veridex, Novartis, Millennium Pharmaceuticals, Takeda, and Sanofi-Aventis, outside the submitted work; personal fees and non-financial support from Roche/Ventana, Astellas, Medivation, Pfizer, Abbott Laboratories, Essa Pharmaceuticals, and Bayer Healthcare Pharmaceuticals, outside the submitted work; grants from AstraZeneca, Arno Therapeutics, and Innocrin Pharma, outside the submitted work; grants, personal fees, and non-financial support from Janssen, outside the submitted work; and personal fees and other from the Institute of Cancer Research, outside the submitted work. ABi reports advisory board fees from Astellas, during the conduct of the study; personal fees, speaker fees, and advisory board fees from Sanofi, during the conduct of the study; personal fees and advisory board fees from Janssen, during the conduct of the study; and advisory board fees from Bayer and AstraZeneca, outside the submitted work. SC reports personal fees from Janssen Pharmaceutical, outside the submitted work. NWC reports personal fees from Janssen, during the conduct of the study and outside the submitted work. WC reports personal fees from Janssen, outside the submitted work; and advisory board fees from Bayer, outside the submitted work. DPD reports grants and other from the National Institute for Health Research Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, during the conduct of the study; grants from Cancer Research UK (programme grant C46/A10588, C33589/A19727) , during the conduct of the study; personal fees from Amgen, Astellas, Takeda, Sandoz, Janssen, and the Institute of Cancer Research (share of royalties for abiraterone), outside the submitted work; and has a patent (EP1933709B1) issued. SG reports personal fees and honoraria to her hospital from AAA International, Roche, Orion, and Sanofi, outside the submitted work; honoraria to her hospital from Bayer, Clovis, CureVac, Astellas, Bristol-Myers Squibb, Janssen, Ferring, Innocrin Pharmaceuticals, Novartis, and Cell Search, outside the submitted work; uncompensated advisory role for Nectar Therapeutics and ProteoMediX, outside the submitted work; and personal fees from MaxiVax SA, outside the submitted work. CG reports grants from Clovis Oncology, outside the submitted work. NDJ reports advisory board fees from Sanofi and Novartis, outside the submitted work; and grants, personal fees, non-financial support, advisory board fees, speaker fees, and travel fees from Janssen, outside the submitted work. RJJ reports personal fees and non-financial support from Janssen, outside the submitted work; grants, personal fees, research funding, honoraria, speaker fees, and advisory board fees from Astellas, outside the submitted work; and personal fees and advisory board fees from Sanofi and Novartis, outside the submitted work. JFL reports personal fees, non-financial support, advisory board fees, and travel fees from Janssen, Astellas, and Sanofi, outside the submitted work. ZIM reports personal fees, consultancy, advisory board fees, honoraria, and travel fees from Janssen and Sanofi, outside the submitted work; advisory board fees, honoraria, and travel fees from Astellas, outside the submitted work; and travel fees from Bayer, outside the submitted work. MDM reports personal fees, speaker fees, and advisory board fees from Sanofi, outside the submitted work; and personal fees from Janssen and Bayer, outside the submitted work. JMO'S reports advisory board fees from Sanofi, outside the submitted work; personal fees, speaker fees, and advisory board fees from Janssen and Astellas, outside the submitted work; and speaker fees, advisory board fees, and research funding from Bayer, outside the submitted work. CCP reports a research grant, personal fees, and advisory board fees from Bayer, outside the submitted work; advisory board fees from AAA, outside the submitted work; and personal fees and speaker fees from Janssen, outside the submitted work. MKBP reports educational grants from Astellas, Clovis Oncology, Novartis, Pfizer, and Sanofi, outside the submitted work. DJS reports fees for meeting attendance from Astellas and Ipsen, outside the submitted work. NNS reports personal fees from Janssen, Pfizer, Sanofi, Merck Sharpe & Dohme, and Roche, outside the submitted work. MRS reports grants and non-financial support from Astellas, Clovis Oncology, Novartis, Pfizer, and Sanofi, outside the submitted work; personal fees from Eli Lilly, outside the submitted work; and grants, personal fees and non-financial support from Janssen, outside the submitted work. AA, RA, CLA, ABa, CDB, OD, HD, CE, JG, MRG, APH, SJ, SK, REL, DM, RM, OAP, IDP, DMP, AWSR, GNT, ATHT, and JMR declare no competing interests.

Funding Information:
This trial was funded by Cancer Research UK (CRUK_A12459), UK Medical Research Council (MRC_MC_UU_12023/25), and the Swiss Group for Clinical Cancer Research. Research support for the protocol was provided by Cancer Research UK (CRUK_A12459), UK Medical Research Council (MRC_MC_UU_12023/25), the Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis. This Article represents independent research part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research. The views expressed in this Article are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health. We thank Fiona Ingleby and Adrian Cook (Medical Research Council Clinical Trials Unit at University College London) for reviewing analyses.

Publisher Copyright:
© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

ASJC Scopus subject areas

  • Medicine(all)

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