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Original Investigation
April 2016

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

Author Affiliations
  • 1University Hospital Birmingham NHS Foundation Trust, Birmingham, England
  • 2Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, England
  • 3Health Economics Unit, University of Birmingham, England
  • 4Cancer Research UK Clinical Trials Unit, Birmingham, England
  • 5Department of Clinical Oncology, Western General Hospital, Edinburgh, Scotland
  • 6Northern Ireland Cancer Centre, Belfast City Hospital, Belfast, Northern Ireland
  • 7The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, Sutton, England
  • 8Institute of Cancer and Genetics, Cardiff University, Cardiff, Wales
  • 9Department of Oncology Pharmacy, Birmingham City Hospital, Birmingham, England
  • 10Department of Clinical Oncology, The Christie Hospital, Manchester, England
  • 11Department of Clinical Oncology, Kent Oncology Centre, Maidstone, England
  • 12Rosemere Cancer Centre, Royal Preston Hospital, Lancashire, England
  • 13Cancer Research UK Clinical Centre at Leeds, University of Leeds, St James’ University Hospital, Leeds, England
  • 14Department of Oncology, Royal Derby Hospital, Derby, England
  • 15Institute of Translational Medicine, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, England
  • 16Beatson West of Scotland Cancer Centre, Glasgow, Scotland
    † Deceased.
JAMA Oncol. 2016;2(4):493-499. doi:10.1001/jamaoncol.2015.5570

Importance  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.

Design, Setting, and Participants  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.

Interventions  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.

Main Outcomes and Measures  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 and Relevance  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.

Trial Registration  isrctn.com Identifier: ISRCTN12808747