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.
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/m(2)) 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).
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.
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.
Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.
Lancet (London, England). 2015 Dec 21 [Epub]
Nicholas D James, Matthew R Sydes, Noel W Clarke, Malcolm D Mason, David P Dearnaley, Melissa R Spears, Alastair W S Ritchie, Christopher C Parker, J Martin Russell, Gerhardt Attard, Johann de Bono, William Cross, Rob J Jones, George Thalmann, Claire Amos, David Matheson, Robin Millman, Mymoona Alzouebi, Sharon Beesley, Alison J Birtle, Susannah Brock, Richard Cathomas, Prabir Chakraborti, Simon Chowdhury, Audrey Cook, Tony Elliott, Joanna Gale, Stephanie Gibbs, John D Graham, John Hetherington, Robert Hughes, Robert Laing, Fiona McKinna, Duncan B McLaren, Joe M O’Sullivan, Omi Parikh, Clive Peedell, Andrew Protheroe, Angus J Robinson, Narayanan Srihari, Rajaguru Srinivasan, John Staffurth, Santhanam Sundar, Shaun Tolan, David Tsang, John Wagstaff, Mahesh K B Parmar, STAMPEDE investigators
Warwick Medical School, University of Warwick, Coventry, UK; University Hospitals Birmingham NHS Foundation Trust, The Medical School, University of Birmingham, Birmingham, UK., MRC Clinical Trials Unit at UCL, London, UK. Electronic address: ., Department of Urology, The Christie and Salford Royal NHS Foundation Trusts, Manchester, UK., Cardiff University School of Medicine, Velindre Hospital, Cardiff, UK., The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK., MRC Clinical Trials Unit at UCL, London, UK., Institute of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK., Department of Urology, Leeds Teaching Hospitals NHS Trust, Leeds., Department of Urology, University Hospital, Bern, Switzerland., Patient rep, MRC Clinical Trials Unit at UCL, London, UK., Department of Oncology, Weston Park Hospital, Sheffield & Doncaster, UK., Kent Oncology Centre, Maidstone Hospital, Maidstone, UK., Department of Oncology, Rosemere Cancer Centre, Royal Preston Hospital, Preston, UK., Department of Oncology, Poole Hospital NHS Foundation Trust and Royal Bournemouth Hospital NHS Foundation Trust, Chur, Switzerland., Kantonsspital Graubünden, Chur, Switzerland., Department of Oncology, Derby Hospitals NHS Foundation Trust, Royal Derby Hospital, Derby, UK., Department of Medical Oncology, Guy’s Hospital, London, UK., Department of Oncology, Cheltenham General Hospital & Hereford County Hospital, UK., Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK., Oncology and Haematology Clinical Trials Unit, Queen Alexandra Hospital, Portsmouth, UK., Department of Oncology, Queen’s Hospital, Romford, UK., Beacon Centre, Musgrove Park Hospital, Taunton, UK., Department of Urology, Hull & East Yorkshire Hospitals NHS Trust, Hull, UK., Mount Vernon Group, Mount Vernon Hospital, Middlesex, UK., Department of Oncology, Royal Surrey County Hospital, Guildford, UK., Department of Oncology, East Sussex Hospitals Trust, East Sussex, UK., Department of Oncology, Western General Hospital, Edinburgh, UK., Centre for Cancer Research and Cell Biology, Queens University Belfast/Belfast City Hospital, Belfast, UK., Department of Oncology, East Lancashire Hospitals NHS Trust, East Lancashire, UK., Department of Oncology & Radiotherapy, South Tees NHS Trust, Middlesbrough, UK., Department of Oncology, Churchill Hospital, Oxford, UK., Department of Oncology, Sussex Cancer Centre, Brighton, UK., Department of Oncology, Shrewsbury & Telford Hospitals NHS Trust, Shrewsbury, UK., Department of Oncology, Royal Devon & Exeter Hospital, Exeter, UK/Torbay Hospital, Torquay, UK., Department of Oncology, Nottingham University Hospitals NHS trust, Nottingham, UK., Department of Oncology & Radiotherapy, Clatterbridge Cancer Centre, Wirral, UK., Department of Oncology, Southend & Basildon Hospitals, Essex, UK., The South West Wales Cancer Institute and Swansea University College of Medicine, Swansea, UK.