Dataset Information

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

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.

SUBMITTER: Basch EM

PROVIDER: S-EPMC6876845 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Basch Ethan M EM Scholz Mark M de Bono Johann S JS Vogelzang Nicholas N de Souza Paul P Marx Gavin G Vaishampayan Ulka U George Saby S Schwarz James K JK Antonarakis Emmanuel S ES O'Sullivan Joseph M JM Kalebasty Arash Rezazadeh AR Chi Kim N KN Dreicer Robert R Hutson Thomas E TE Dueck Amylou C AC Bennett Antonia V AV Dayan Erica E Mangeshkar Milan M Holland Jaymes J Weitzman Aaron L AL Scher Howard I HI

European urology 20181204 6

<h4>Background</h4>Bone metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) are associated with debilitating pain and functional compromise.<h4>Objective</h4>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.<h4>Design, setting, and participants</h4>A randomized, double-blind phase 3 trial (COMET-2; NCT01522443) in men with mCR ...[more]

PMID: 30528222

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Project description:IntroductionScant evidence reveals whether the use of weekly versus daily pain ratings leads to meaningful differences when measuring pain as a clinical trial outcome. We compared the ability of weekly ratings and descriptors of daily ratings to evaluate pain as an endpoint in a randomized phase 3 drug trial.MethodsParticipants (n = 119) with metastatic castration-resistant prostate cancer were randomized to treatment arms and rated their pain on the average and at its worst during a baseline week and at weeks 3, 6, and 12 of study treatment. For each reporting period, participants rated their pain daily for 7 days. On day 7, participants rated their pain over the prior 7 days. We estimated mean differences and intraclass correlation coefficients of the weekly ratings and the mean and the maximum daily ratings. We compared the ability of the weekly ratings and the daily rating descriptors to detect change in pain and evaluated the agreement of the weekly rating and the mean daily rating of pain at its worst to detect treatment response.ResultsFor both pain constructs, the weekly rating was consistently higher than the mean daily rating and lower than the maximum daily rating yet was moderately to highly correlated with both daily rating descriptors (intraclass correlation coefficient range = 0.55-0.94). The weekly rating and the daily rating descriptors consistently detected change in pain for the study sample and participant subgroups. Substantial agreement existed between the weekly rating and the mean daily rating of pain at its worst when used with trial protocol opioid criteria to detect treatment response (Cohen's κ = 0.71).ConclusionUse of daily over weekly ratings delivered no added benefit in evaluating pain in this clinical trial. This study is the first to compare weekly and daily recall to measure pain as an endpoint in a randomized phase 3 drug trial, and the pattern of differences in ratings that we observed is consistent with other recent evaluations of weekly and daily symptom reporting.

Dataset Information

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

Publications

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

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