James, N. D., Pirrie, S. J., Pope, A. M., Barton, D., Andronis, L., Goranitis, I., Collins, S., Daunton, A., McLaren, D., O'Sullivan, J., Parker, C., Porfiri, E., Staffurth, J., Stanley, A., Wylie, J., Beesley, S., Birtle, A., Brown, J., Chakraborti, P., Hussain, S., Russell, M., Billingham, L. J. (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. Jama Oncology, 2 (4). pp. 493-499. ISSN 2374-2445

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Abstract

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 x 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.

Item Type:	Article
Authors (ICR Faculty only):	Parker, Chris
All Authors:	James, N. D., Pirrie, S. J., Pope, A. M., Barton, D., Andronis, L., Goranitis, I., Collins, S., Daunton, A., McLaren, D., O'Sullivan, J., Parker, C., Porfiri, E., Staffurth, J., Stanley, A., Wylie, J., Beesley, S., Birtle, A., Brown, J., Chakraborti, P., Hussain, S., Russell, M., Billingham, L. J.
Additional Information:	ISI Document Delivery No.: DW5KJ Times Cited: 2 Cited Reference Count: 17 James, Nicholas D. Pirrie, Sarah J. Pope, Ann M. Barton, Darren Andronis, Lazaros Goranitis, Ilias Collins, Stuart Daunton, Adam McLaren, Duncan O'Sullivan, Joe Parker, Christopher Porfiri, Emilio Staffurth, John Stanley, Andrew Wylie, James Beesley, Sharon Birtle, Alison Brown, Janet Chakraborti, Prabir Hussain, Syed Russell, Martin Billingham, Lucinda J. Sanofi Aventis; Novartis Pharmaceuticals; UK National Institute for Health Research Health Technology Assessment Programme (NIHR HTA) [06/303/205] Sanofi Aventis and Novartis Pharmaceuticals supported the trial with educational grants and support for drug costs or trial discount for sites, respectively, and GE Healthcare also offered a trial discount to sites purchasing strontium-89. The TRAPEZE trial was an independent research project commissioned and funded by the UK National Institute for Health Research Health Technology Assessment Programme (NIHR HTA No. 06/303/205). The NIHR HTA will publish the full trial results in the Health Technology Assessment journal later in 2015; the NIHR HTA encourages publication of trial results journals but was not involved in the decision to do so here. 2 0 AMER MEDICAL ASSOC CHICAGO JAMA ONCOL
Uncontrolled Keywords:	EXTERNAL-BEAM RADIOTHERAPY SKELETAL COMPLICATIONS MITOXANTRONE PREDNISONE PREVENTION CARCINOMA
Research teams:	Clinical Units > Urology Unit
Depositing User:	Barry Jenkins
Date Deposited:	04 Jan 2017 13:41
Last Modified:	04 Jan 2017 13:41
URI:	http://publications.icr.ac.uk/id/eprint/15564

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