title: Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data.
abstract: BACKGROUND
  Results from large randomised controlled trials combining docetaxel or bisphosphonates with standard of care in hormone-sensitive prostate cancer have emerged. In order to investigate the effects of these therapies and to respond to emerging evidence, we aimed to systematically review all relevant trials using a framework for adaptive meta-analysis.
  
  
  METHODS
  For this systematic review and meta-analysis, we searched MEDLINE, Embase, LILACS, and the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomised controlled trials (published, unpublished, and ongoing) comparing either standard of care with or without docetaxel or standard of care with or without bisphosphonates for men with high-risk localised or metastatic hormone-sensitive prostate cancer. For each trial, we extracted hazard ratios (HRs) of the effects of docetaxel or bisphosphonates on survival (time from randomisation until death from any cause) and failure-free survival (time from randomisation to biochemical or clinical failure or death from any cause) from published trial reports or presentations or obtained them directly from trial investigators. HRs were combined using the fixed-effect model (Mantel-Haenzsel).
  
  
  RESULTS
  We identified five eligible randomised controlled trials of docetaxel in men with metastatic (M1) disease. Results from three (CHAARTED, GETUG-15, STAMPEDE) of these trials (2992 [93%] of 3206 men randomised) showed that the addition of docetaxel to standard of care improved survival. The HR of 0·77 (95% CI 0·68-0·87; p<0·0001) translates to an absolute improvement in 4-year survival of 9% (95% CI 5-14). Docetaxel in addition to standard of care also improved failure-free survival, with the HR of 0·64 (0·58-0·70; p<0·0001) translating into a reduction in absolute 4-year failure rates of 16% (95% CI 12-19). We identified 11 trials of docetaxel for men with locally advanced disease (M0). Survival results from three (GETUG-12, RTOG 0521, STAMPEDE) of these trials (2121 [53%] of 3978 men) showed no evidence of a benefit from the addition of docetaxel (HR 0·87 [95% CI 0·69-1·09]; p=0·218), whereas failure-free survival data from four (GETUG-12, RTOG 0521, STAMPEDE, TAX 3501) of these trials (2348 [59%] of 3978 men) showed that docetaxel improved failure-free survival (0·70 [0·61-0·81]; p<0·0001), which translates into a reduced absolute 4-year failure rate of 8% (5-10). We identified seven eligible randomised controlled trials of bisphosphonates for men with M1 disease. Survival results from three of these trials (2740 [88%] of 3109 men) showed that addition of bisphosphonates improved survival (0·88 [0·79-0·98]; p=0·025), which translates to 5% (1-8) absolute improvement, but this result was influenced by the positive result of one trial of sodium clodronate, and we found no evidence of a benefit from the addition of zoledronic acid (0·94 [0·83-1·07]; p=0·323), which translates to an absolute improvement in survival of 2% (-3 to 7). Of 17 trials of bisphosphonates for men with M0 disease, survival results from four trials (4079 [66%] of 6220 men) showed no evidence of benefit from the addition of bisphosphonates (1·03 [0·89-1·18]; p=0·724) or zoledronic acid (0·98 [0·82-1·16]; p=0·782). Failure-free survival definitions were too inconsistent for formal meta-analyses for the bisphosphonate trials.
  
  
  CONCLUSIONS
  The addition of docetaxel to standard of care should be considered standard care for men with M1 hormone-sensitive prostate cancer who are starting treatment for the first time. More evidence on the effects of docetaxel on survival is needed in the M0 disease setting. No evidence exists to suggest that zoledronic acid improves survival in men with M1 or M0 disease, and any potential benefit is probably small.
  
  
  BACKGROUND
  Medical Research Council UK.
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK. Electronic address: claire.vale@ucl.ac.uk.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Vale
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Burdett
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK.
authors.forename: Larysa H M
authors.initials: LHM
authors.lastname: Rydzewska
authors.affiliation: Institut Gustave Roussy, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Albiges
authors.affiliation: Department of Urology, The Christie and Salford Royal NHS Foundation Trusts, Manchester, UK.
authors.forename: Noel W
authors.initials: NW
authors.lastname: Clarke
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Fisher
authors.affiliation: Institut Gustave Roussy, Paris, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: Department of Medical Oncology, Institut Paoli Calmettes, Marseille, France.
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Gravis
authors.affiliation: Warwick Cancer Research Unit, University of Warwick, Coventry, UK; University Hospitals Birmingham NHS Foundation Trust, The Medical School, University of Birmingham, Birmingham, UK.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: James
authors.affiliation: Cardiff University School of Medicine, Velindre Hospital, Cardiff, UK.
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Mason
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK.
authors.forename: Mahesh K B
authors.initials: MKB
authors.lastname: Parmar
authors.affiliation: Lank Center for Genitourinary Cancer, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sweeney
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sydes
authors.affiliation: Cliniques Universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Tombal
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK.
authors.forename: Jayne F
authors.initials: JF
authors.lastname: Tierney
mesh_terms: D000726:Androgen Antagonists / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D004164:Diphosphonates / Q000008:administration & dosage*; D018572:Disease-Free Survival; D000077143:Docetaxel; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000628:therapy*; D016032:Randomized Controlled Trials as Topic; D059039:Standard of Care; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage*; D000077211:Zoledronic Acid
chemical_list: D000726:Androgen Antagonists; D004164:Diphosphonates; D007093:Imidazoles; D043823:Taxoids; D000077143:Docetaxel; D000077211:Zoledronic Acid