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 Dueck, Antonia V. Bennett, Erica Dayan, Milan Mangeshkar, Jaymes Holland & 2 others Aaron L. Weitzman, Howard I. Scher

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 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 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. 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.

Original languageEnglish (US)
JournalEuropean Urology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Mitoxantrone
Castration
Prednisone
Prostatic Neoplasms
Pain
Narcotics
Neoplasm Metastasis
Bone Neoplasms
docetaxel
Bone and Bones
cabozantinib
Therapeutics
Sample Size
Analgesics

Keywords

  • Cabozantinib
  • Clinical trial
  • Pain assessment
  • Prostate cancer

ASJC Scopus subject areas

  • Urology

Cite this

Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer : A Randomized Phase 3 Trial with a Primary Pain Endpoint. / 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; Bennett, Antonia V.; Dayan, Erica; Mangeshkar, Milan; Holland, Jaymes; Weitzman, Aaron L.; Scher, Howard I.

In: European Urology, 01.01.2018.

Research output: Contribution to journalArticle

Basch, EM, Scholz, M, de Bono, JS, Vogelzang, N, de Souza, P, Marx, G, Vaishampayan, U, George, S, Schwarz, JK, Antonarakis, ES, O'Sullivan, JM, Kalebasty, AR, Chi, KN, Dreicer, R, Hutson, TE, Dueck, A, Bennett, AV, Dayan, E, Mangeshkar, M, Holland, J, Weitzman, AL & Scher, HI 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
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 ; Bennett, Antonia V. ; Dayan, Erica ; Mangeshkar, Milan ; Holland, Jaymes ; Weitzman, Aaron L. ; Scher, Howard I. / Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer : A Randomized Phase 3 Trial with a Primary Pain Endpoint. In: European Urology. 2018.
@article{16ed33eebb10469c8827e839afd8cce4,
title = "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 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 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. 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.",
keywords = "Cabozantinib, Clinical trial, Pain assessment, Prostate cancer",
author = "Basch, {Ethan M.} and Mark Scholz and {de Bono}, {Johann S.} and Nicholas Vogelzang and {de Souza}, Paul and Gavin Marx and Ulka Vaishampayan and Saby George and Schwarz, {James K.} and Antonarakis, {Emmanuel S.} and O'Sullivan, {Joseph M.} and Kalebasty, {Arash Rezazadeh} and Chi, {Kim N.} and Robert Dreicer and Hutson, {Thomas E.} and Amylou Dueck and Bennett, {Antonia V.} and Erica Dayan and Milan Mangeshkar and Jaymes Holland and Weitzman, {Aaron L.} and Scher, {Howard I.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.eururo.2018.11.033",
language = "English (US)",
journal = "European Urology",
issn = "0302-2838",
publisher = "Elsevier",

}

TY - JOUR

T1 - Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer

T2 - A Randomized Phase 3 Trial with a Primary Pain Endpoint

AU - Basch, Ethan M.

AU - Scholz, Mark

AU - de Bono, Johann S.

AU - Vogelzang, Nicholas

AU - de Souza, Paul

AU - Marx, Gavin

AU - Vaishampayan, Ulka

AU - George, Saby

AU - Schwarz, James K.

AU - Antonarakis, Emmanuel S.

AU - O'Sullivan, Joseph M.

AU - Kalebasty, Arash Rezazadeh

AU - Chi, Kim N.

AU - Dreicer, Robert

AU - Hutson, Thomas E.

AU - Dueck, Amylou

AU - Bennett, Antonia V.

AU - Dayan, Erica

AU - Mangeshkar, Milan

AU - Holland, Jaymes

AU - Weitzman, Aaron L.

AU - Scher, Howard I.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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 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. 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.

AB - 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 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. 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.

KW - Cabozantinib

KW - Clinical trial

KW - Pain assessment

KW - Prostate cancer

UR - http://www.scopus.com/inward/record.url?scp=85057838941&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057838941&partnerID=8YFLogxK

U2 - 10.1016/j.eururo.2018.11.033

DO - 10.1016/j.eururo.2018.11.033

M3 - Article

JO - European Urology

JF - European Urology

SN - 0302-2838

ER -