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

Ethan M Basch, Mark Scholz, Johann S de Bono, Nicholas Vogelzang, Paul de Souza, Gavin Marx, Ulka Vaishampayan, Saby George, James K Schwarz, Emmanuel S Antonarakis, Joseph M O'Sullivan, Arash Rezazadeh Kalebasty, Kim N Chi, Robert Dreicer, Thomas E Hutson, Amylou C Dueck, Antonia V Bennett, Erica Dayan, Milan Mangeshkar, Jaymes HollandAaron L Weitzman, Howard I Scher

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Abstract

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/m2 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.

Original languageEnglish
JournalEuropean Urology
Early online date04 Dec 2018
DOIs
Publication statusEarly online date - 04 Dec 2018
Externally publishedYes

Bibliographical note

Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

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    Basch, E. M., Scholz, M., de Bono, J. S., Vogelzang, N., de Souza, P., Marx, G., Vaishampayan, U., George, S., Schwarz, J. K., Antonarakis, E. S., O'Sullivan, J. M., Kalebasty, A. R., Chi, K. N., Dreicer, R., Hutson, T. E., Dueck, A. C., Bennett, A. V., Dayan, E., Mangeshkar, M., ... Scher, H. I. (2018). Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer ; A Randomized Phase 3 Trial with a Primary Pain Endpoint. European Urology. https://doi.org/10.1016/j.eururo.2018.11.033