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 60mg once daily orally versus mitoxantrone 12mg/m every 3wk plus prednisone 5mg 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 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.

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.