title: Clinical Outcomes and Survival Following Treatment of Metastatic Castrate-Refractory Prostate Cancer With Docetaxel Alone or With Strontium-89, Zoledronic Acid, or Both: The TRAPEZE Randomized Clinical Trial.
abstract: OBJECTIVE
  Bony metastatic castrate-refractory prostate cancer (CRPC) has a poor prognosis and high morbidity. Zoledronic acid (ZA) is commonly combined with docetaxel in practice but lacks evidence that combining is effective, and strontium-89 (Sr89) is generally used palliatively in patients unfit for chemotherapy. Phase 2 analysis of the TRAPEZE trial confirmed combining the agents was safe and feasible, and the objectives of phase 3 include assessment of the treatments on survival.
  
  
  OBJECTIVE
  To determine clinical effectiveness and cost-effectiveness of combining docetaxel, ZA, and Sr89, all having palliative benefits and used in bony metastatic CRPC to control bone symptoms and, for docetaxel, to prolong survival.
  
  
  METHODS
  The TRAPEZE trial is a 2 × 2 factorial trial comparing docetaxel alone or with ZA, Sr89, or both. A cohort of 757 participants were recruited between February 2005 and February 2012 from hospitals in the United Kingdom. Overall, 169 participants (45%) had received palliative radiotherapy, and the median (IQR) prostate-specific antigen level was 146 (51-354). Follow-ups were performed for at least 12 months.
  
  
  METHODS
  Up to 10 cycles of docetaxel alone; docetaxel with ZA; docetaxel with a single Sr89 dose after 6 cycles; or docetaxel with both ZA and Sr89.
  
  
  METHODS
  Primary outcomes included clinical progression-free survival (CPFS) (pain progression, skeletal-related events [SREs], or death) and cost-effectiveness. Secondary outcomes included SRE-free interval, pain progression-free interval, total SREs, and overall survival (OS).
  
  
  RESULTS
  Overall, of 757 participants, 349 (46%) completed docetaxel treatment. Median (IQR) age was 68 (63-73) years. Clinical progression-free survival did not reach statistical significance for either Sr89 or ZA. Cox regression analysis adjusted for all stratification variables showed benefit of Sr89 on CPFS (hazard ratio [HR], 0.85; 95% CI, 0.73-0.99; P = .03) and confirmed no effect of ZA (HR, 0.98; 95% CI, 0.85-1.14; P = .81); ZA had a significant effect on SRE-free interval (HR, 0.78; 95% CI, 0.65-0.95; P = .01). For OS, there was no effect of either Sr89 (HR, 0.92; 95% CI, 0.79-1.08; P = 0.34) or ZA (HR, 0.99; 95% CI, 0.84-1.16; P = 0.91).
  
  
  CONCLUSIONS
  Strontium-89 combined with docetaxel improved CPFS but did not improve OS, SRE-free interval, or total SREs; ZA did not improve CPFS or OS but did significantly improve median SRE-free interval and reduced total SREs by around one-third, suggesting a role as postchemotherapy maintenance therapy.
  
  
  BACKGROUND
  isrctn.com Identifier: ISRCTN12808747.
authors.affiliation: University Hospital Birmingham NHS Foundation Trust, Birmingham, England.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: James
authors.affiliation: Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, England.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Pirrie
authors.affiliation: Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, England.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Pope
authors.affiliation: Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, England.
authors.forename: Darren
authors.initials: D
authors.lastname: Barton
authors.affiliation: Health Economics Unit, University of Birmingham, England.
authors.forename: Lazaros
authors.initials: L
authors.lastname: Andronis
authors.affiliation: Health Economics Unit, University of Birmingham, England.
authors.forename: Ilias
authors.initials: I
authors.lastname: Goranitis
authors.affiliation: Cancer Research UK Clinical Trials Unit, Birmingham, England.
authors.forename: Stuart
authors.initials: S
authors.lastname: Collins
authors.affiliation: University Hospital Birmingham NHS Foundation Trust, Birmingham, England.
authors.forename: Adam
authors.initials: A
authors.lastname: Daunton
authors.affiliation: Department of Clinical Oncology, Western General Hospital, Edinburgh, Scotland.
authors.forename: Duncan
authors.initials: D
authors.lastname: McLaren
authors.affiliation: Northern Ireland Cancer Centre, Belfast City Hospital, Belfast, Northern Ireland.
authors.forename: Joe
authors.initials: J
authors.lastname: O'Sullivan
authors.affiliation: The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, Sutton, England.
authors.forename: Christopher
authors.initials: C
authors.lastname: Parker
authors.affiliation: University Hospital Birmingham NHS Foundation Trust, Birmingham, England.
authors.forename: Emilio
authors.initials: E
authors.lastname: Porfiri
authors.affiliation: Institute of Cancer and Genetics, Cardiff University, Cardiff, Wales.
authors.forename: John
authors.initials: J
authors.lastname: Staffurth
authors.affiliation: Department of Oncology Pharmacy, Birmingham City Hospital, Birmingham, England.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stanley
authors.affiliation: Department of Clinical Oncology, The Christie Hospital, Manchester, England.
authors.forename: James
authors.initials: J
authors.lastname: Wylie
authors.affiliation: Department of Clinical Oncology, Kent Oncology Centre, Maidstone, England.
authors.forename: Sharon
authors.initials: S
authors.lastname: Beesley
authors.affiliation: Rosemere Cancer Centre, Royal Preston Hospital, Lancashire, England.
authors.forename: Alison
authors.initials: A
authors.lastname: Birtle
authors.affiliation: Cancer Research UK Clinical Centre at Leeds, University of Leeds, St James' University Hospital, Leeds, England.
authors.forename: Janet
authors.initials: J
authors.lastname: Brown
authors.affiliation: Department of Oncology, Royal Derby Hospital, Derby, England.
authors.forename: Prabir
authors.initials: P
authors.lastname: Chakraborti
authors.affiliation: Institute of Translational Medicine, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, England.
authors.forename: Syed
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Beatson West of Scotland Cancer Centre, Glasgow, Scotland.
authors.forename: Martin
authors.initials: M
authors.lastname: Russell
authors.affiliation: Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, England.
authors.forename: Lucinda J
authors.initials: LJ
authors.lastname: Billingham
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D013324:Strontium / Q000008:administration & dosage / Q000009:adverse effects; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D043823:Taxoids; D000077143:Docetaxel; D000077211:Zoledronic Acid; C025700:strontium chloride; D013324:Strontium