Abstract
Summary Background Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. Methods Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m2) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). Findings 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. Interpretation Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. Funding Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.
| Original language | English |
|---|---|
| Pages (from-to) | 1163-1177 |
| Number of pages | 15 |
| Journal | The Lancet |
| Volume | 387 |
| Issue number | 10024 |
| DOIs | |
| Publication status | Published - 19 Mar 2016 |
Bibliographical note
Funding Information:DPD, CCP, GA, and JdB acknowledge support from the National Institute for Health Research to the Royal Marsden NHS Trust and The Institute of Cancer Research Biomedical Research Centre. Support for the STAMPEDE trial has been provided by Novartis Pharmaceuticals UK Limited (educational grant, free drug, distribution costs) and Sanofi-Aventis (education grant, free and discounted drug). Affiliations and full details of contributions made by STAMPEDE investigators are provided in the appendix page 11 .
Funding Information:
Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research. GA reports personal fees from Sanofi-Aventis; personal fees and non-fi nancial support from Astellas; personal fees from Novartis; grants, personal fees, and non-fi nancial support from Janssen, personal fees and non-fi nancial support from Roche/Ventana, personal fees and nonfi nancial support from Medivation, personal fees from Millennium Pharmaceuticals, personal fees and non-fi nancial support from Abbott Laboratories, personal fees from Essa Pharmaceuticals, personal fees and non-fi nancial support from Bayer Healthcare Pharmaceuticals, personal fees from Takeda, and grants from AstraZeneca. AJB reports other support from Janssen, Sanofi , and Astellas, outside the submitted work. RC reports personal fees as a Consultant for Sanofi-Aventis, outside the submitted work. SC reports grants and personal fees from Sanofi - Aventis, outside the submitted work. JdB reports advisory boards and paid participation for Sanofi-Aventis. DPD reports grants from Cancer Research UK, during the conduct of the study; personal fees from Takeda Pharmaceuticals, outside the submitted work. TE reports that patients entering this study received docetaxel free of charge (Sanofi ) and has previously received per-patient payment for entering patients in other commercial trials investigating docetaxel. JDG reports other support as a local principal investigator for a study of radium-223 in prostate cancer funded by Bayer, and other support as a local principal investigator for a study of LHRH antagonist in prostate cancer funded by Millennium Pharmaceuticals, outside the submitted work. NDJ reports grants and personal fees from Sanofi , and grants and personal fees from Novartis, during the conduct of the study; grants and personal fees from Janssen, grants and personal fees from Astellas, and grants and personal fees from Bayer, outside the submitted work. RJJ reports grants from Sanofi , and grants and non-fi nancial support from Novartis, during the conduct of the study; grants, personal fees, and non-fi nancial support from Sanofi , grants, personal fees, and non-fi nancial support from Novartis, outside the submitted work. MDM reports personal fees from Sanofi , personal fees from Bayer, personal fees from Dendreon, personal fees from Bristol-Myers, and personal fees from Janssen, outside the submitted work. CCP reports personal fees from Sanofi-Aventis, research funding and speaker''s honoraria from Bayer, and Bavarian Nordic and Janssen, outside the submitted work. MKBP reports funding from Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfi zer, Janssen, Astellas, NIHR Clinical Research Network (formerly National Cancer Research Network), and SAKK-Swiss Group for Clinical Cancer Research, during the conduct of the study. JMR reports personal fees from Janssen (lecture fee), outside the submitted work. MRSp reports grants and non-fi nancial support from Sanofi-Aventis, grants and non-fi nancial support from Novartis, grants and non-fi nancial support from Pfi zer, grants and non-fi nancial support from Janssen, and grants and non-fi nancial support from Astellas, during the conduct of the study. JS reports support for travel and speakers fees for the following companies in the fi eld of prostate cancer, not related to this paper: Janssen Bayer and Astellas. SS reports personal fees and non-fi nancial support from Sanofi-Aventis, outside the submitted work. MRSy reports grants and non-fi nancial support from Sanofi-Aventis, grants and nonfi nancial support from Novartis, grants and non-fi nancial support from Pfi zer, grants and non-fi nancial support from Janssen, grants and nonfi nancial support from Astellas, during the conduct of the study; and personal fees from Eli-Lilly, outside the submitted work. ST reports other from Sanofi , other support from Astellas, personal fees from Astellas, and other support from Janssen, outside the submitted work. JW reports a paid consultancy for Janssen. Abiraterone acetate was developed at The Institute of Cancer Research, which therefore has a commercial interest in the development of this agent. All other authors declare no competing interests. DPD, CCP, GA, and JdB acknowledge support from the National Institute for Health Research to the Royal Marsden NHS Trust and The Institute of Cancer Research Biomedical Research Centre. Support for the STAMPEDE trial has been provided by Novartis Pharmaceuticals UK Limited (educational grant, free drug, distribution costs) and Sanofi - Aventis (education grant, free and discounted drug). Affi liations and full details of contributions made by STAMPEDE investigators are provided in the appendix page 11.
Funding Information:
GA reports personal fees from Sanofi-Aventis; personal fees and non-financial support from Astellas; personal fees from Novartis; grants, personal fees, and non-financial support from Janssen, personal fees and non-financial support from Roche/Ventana, personal fees and non-financial support from Medivation, personal fees from Millennium Pharmaceuticals, personal fees and non-financial support from Abbott Laboratories, personal fees from Essa Pharmaceuticals, personal fees and non-financial support from Bayer Healthcare Pharmaceuticals, personal fees from Takeda, and grants from AstraZeneca. AJB reports other support from Janssen, Sanofi, and Astellas, outside the submitted work. RC reports personal fees as a Consultant for Sanofi-Aventis, outside the submitted work. SC reports grants and personal fees from Sanofi-Aventis, outside the submitted work. JdB reports advisory boards and paid participation for Sanofi-Aventis. DPD reports grants from Cancer Research UK, during the conduct of the study; personal fees from Takeda Pharmaceuticals, outside the submitted work. TE reports that patients entering this study received docetaxel free of charge (Sanofi) and has previously received per-patient payment for entering patients in other commercial trials investigating docetaxel. JDG reports other support as a local principal investigator for a study of radium-223 in prostate cancer funded by Bayer, and other support as a local principal investigator for a study of LHRH antagonist in prostate cancer funded by Millennium Pharmaceuticals, outside the submitted work. NDJ reports grants and personal fees from Sanofi, and grants and personal fees from Novartis, during the conduct of the study; grants and personal fees from Janssen, grants and personal fees from Astellas, and grants and personal fees from Bayer, outside the submitted work. RJJ reports grants from Sanofi, and grants and non-financial support from Novartis, during the conduct of the study; grants, personal fees, and non-financial support from Sanofi, grants, personal fees, and non-financial support from Novartis, outside the submitted work. MDM reports personal fees from Sanofi, personal fees from Bayer, personal fees from Dendreon, personal fees from Bristol-Myers, and personal fees from Janssen, outside the submitted work. CCP reports personal fees from Sanofi-Aventis, research funding and speaker's honoraria from Bayer, and Bavarian Nordic and Janssen, outside the submitted work. MKBP reports funding from Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network (formerly National Cancer Research Network), and SAKK—Swiss Group for Clinical Cancer Research, during the conduct of the study. JMR reports personal fees from Janssen (lecture fee), outside the submitted work. MRSp reports grants and non-financial support from Sanofi-Aventis, grants and non-financial support from Novartis, grants and non-financial support from Pfizer, grants and non-financial support from Janssen, and grants and non-financial support from Astellas, during the conduct of the study. JS reports support for travel and speakers fees for the following companies in the field of prostate cancer, not related to this paper: Janssen Bayer and Astellas. SS reports personal fees and non-financial support from Sanofi-Aventis, outside the submitted work. MRSy reports grants and non-financial support from Sanofi-Aventis, grants and non-financial support from Novartis, grants and non-financial support from Pfizer, grants and non-financial support from Janssen, grants and non-financial support from Astellas, during the conduct of the study; and personal fees from Eli-Lilly, outside the submitted work. ST reports other from Sanofi, other support from Astellas, personal fees from Astellas, and other support from Janssen, outside the submitted work. JW reports a paid consultancy for Janssen. Abiraterone acetate was developed at The Institute of Cancer Research, which therefore has a commercial interest in the development of this agent. All other authors declare no competing interests.
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ASJC Scopus subject areas
- General Medicine
