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

• Published in: European urology 2019-06, Vol.75 (6), p.929-937
• Main Authors: Basch, Ethan M., Scholz, Mark, de Bono, Johann S., Vogelzang, Nicholas, de Souza, Paul, Marx, Gavin, Vaishampayan, Ulka, George, Saby, Schwarz, James K., Antonarakis, Emmanuel S., O'Sullivan, Joseph M., Kalebasty, Arash Rezazadeh, Chi, Kim N., Dreicer, Robert, Hutson, Thomas E., Dueck, Amylou C., Bennett, Antonia V., Dayan, Erica, Mangeshkar, Milan, Holland, Jaymes, Weitzman, Aaron L., Scher, Howard I.
• Format: Article
• Language: English
• Subjects: Aged; Analgesics - administration & dosage; Anilides - therapeutic use; Bone Neoplasms - complications; Bone Neoplasms - secondary; Cabozantinib; Cancer Pain - drug therapy; Cancer Pain - etiology; Clinical trial; Double-Blind Method; Drug Combinations; Humans; Male; Middle Aged; Mitoxantrone - administration & dosage; Pain assessment; Pain Management - methods; Pain Measurement; Prednisone - administration & dosage; Prospective Studies; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - pathology; Pyridines - therapeutic use
• ISSN: 0302-2838; 1873-7560; 1873-7560
• DOI: 10.1016/j.eururo.2018.11.033

Bone metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) are associated with debilitating pain and functional compromise. 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. 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. Cabozantinib 60mg once daily orally versus mitoxantrone 12mg/m2 every 3wk plus prednisone 5mg twice daily orally. 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. Enrollment was terminated early because cabozantinib did not demonstrate a 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%, a −2% 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. 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. Cabozantinib was not better than mitoxantrone-prednisone for pain relief in patients with castration-resistant prostate cancer and debilitating pain from bone metastases. Control of debilitating pain is an unmet need for men with metastatic castration-resistant prostate cancer (mCRPC). This phase 3 trial failed to show an improved pain response for cabozantinib compared with mitoxantrone-prednisone in patients with previously treated, symptomatic mCRPC.