Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 3 Trial with a Primary Pain Endpoint

Background: Bone metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) are associated with debilitating pain and functional compromise.

Objective: To compare pain palliation as the primary endpoint for cabozantinib versus mitoxantrone-prednisone in men with mCRPC and symptomatic bone metastases using patient-reported outcome measures. Design, setting, and participants: A randomized, double-blind phase 3 trial (COMET-2; NCT01522443) in men with mCRPC and narcotic-dependent pain from bone metastases who had progressed after treatment with docetaxel and either abiraterone or enzalutamide.

Intervention: Cabozantinib 60 mg once daily orally versus mitoxantrone 12 mg/m2 every 3 wk plus prednisone 5 mg twice daily orally.

Outcome measurements and statistical analysis: The primary endpoint was pain response at week 6 confirmed at week 12 (30% decrease from baseline in patient-reported average daily worst pain score via the Brief Pain Inventory without increased narcotic use). The planned sample size was 246 to achieve 90% power.

Results and limitations: Enrollment was terminated early because cabozantinib did not demonstrate any survival benefit in the companion COMET-1 trial. At study closure, 119 participants were randomized (cabozantinib: N = 61; mitoxantrone-prednisone: N = 58). Complete pain and narcotic use data were available at baseline, week 6, and week 12 for 73/106 (69%) patients. There was no significant difference in the pain response with cabozantinib versus mitoxantrone-prednisone: the proportions of responders were 15% versus 17%, a2% difference (95% confidence interval:16% to 11%,p = 0.8). Barriers to accrual included pretreatment requirements for a washout period of prior anticancer therapy and a narcotic optimization period to maximize analgesic dosing.

Conclusions: Cabozantinib treatment did not demonstrate better pain palliation than mitoxantrone-prednisone in heavily pretreated patients with mCRPC and symptomatic bone metastases. Future pain-palliation trials should incorporate briefer timelines from enrollment to treatment initiation.

Patient summary: Cabozantinib was not better than mitoxantrone-prednisone for pain relief in patients with castration-resistant prostate cancer and debilitating pain from bone metastases.

Authors: Ethan M. Basch,1 Mark Scholz,2 Johann S. de Bono,3 Nicholas Vogelzang,4 Paul de Souza,5 Gavin Marx,6 Ulka Vaishampayan,7 Saby George,8 James K. Schwarz,9 Emmanuel S. Antonarakis,10 Joseph M. O’Sullivan,11 Arash Rezazadeh Kalebasty,12 Kim N. Chi,13 Robert Dreicer,14 Thomas E. Hutson,15 Amylou C. Dueck,16 Antonia V. Bennett,17 Erica Dayan,18 Milan Mangeshkar,19 Jaymes Holland,19 Aaron L. Weitzman,19 Howard I. Scher18

Author Affiliations:
1. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; 
2. Prostate Oncology Specialists, Marina del Rey, CA, USA; 
3. Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, England, UK; 
4. Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA; 
5. Western Sydney University School of Medicine, Sydney, Australia; 
6. Sydney Medical School, University of Sydney and Sydney Adventist Hospital, Wahroonga, Australia; 
7. Karmanos Cancer Institute, Detroit, MI, USA; 
8. Roswell Park Cancer Institute, Buffalo, NY, USA; 
9. University of Nebraska Medical Center, Omaha, NE, USA; 
10. The Sidney Kimmel Comprehensive Cancer at John Hopkins, Baltimore, MD, USA; 
11. Belfast City Hospital, Belfast, Northern Ireland, UK; 
12. Norton Cancer Institute, Louisville, KY, USA; 
13. British Columbia Cancer Agency, Vancouver, BC, Canada; 
14. Emily Couric Clinical Cancer Center, University of Virginia, Charlottesville, VA, USA; 
15. Texas Oncology Sammons Cancer Center, Dallas, TX, USA; 
16. Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA; 
17. Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA; 
18. Department of Medicine, Genitourinary Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 
19. Exelixis, Inc., South San Francisco, CA, USA

Basch, Ethan M. et al. Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 3 Trial with a Primary Pain Endpoint" European Urology, Volume 75, Issue 6, 929 -
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