Phase II, Multicenter, Randomized Trial of Docetaxel plus Prednisone with or Without Cediranib in Men with Chemotherapy-Naive Metastatic Castrate-Resistant Prostate Cancer

Elisabeth Heath, Lance Heilbrun, Heather Mannuel, Glenn Liu, Primo N Lara, J. Paul Monk, Thomas Flaig, Amado Zurita, Philip Mack, Ulka Vaishampayan, Philip Stella, Daryn Smith, Susan Bolton, Arif Hussain, Anas Al-Janadi, Daniel Silbiger, Muhammad Usman, S. Percy Ivy

Research output: Contribution to journalArticle

Abstract

Lessons Learned: The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC). The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. Background: Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). Methods: This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. Results: The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). Conclusion: Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.

Original languageEnglish (US)
JournalOncologist
DOIs
StatePublished - Jan 1 2019

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docetaxel
Prednisone
Multicenter Studies
Prostatic Neoplasms
Drug Therapy
Angiogenesis Inhibitors
Survival Rate
cediranib
Prostate-Specific Antigen
Disease-Free Survival
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase II, Multicenter, Randomized Trial of Docetaxel plus Prednisone with or Without Cediranib in Men with Chemotherapy-Naive Metastatic Castrate-Resistant Prostate Cancer. / Heath, Elisabeth; Heilbrun, Lance; Mannuel, Heather; Liu, Glenn; Lara, Primo N; Monk, J. Paul; Flaig, Thomas; Zurita, Amado; Mack, Philip; Vaishampayan, Ulka; Stella, Philip; Smith, Daryn; Bolton, Susan; Hussain, Arif; Al-Janadi, Anas; Silbiger, Daniel; Usman, Muhammad; Ivy, S. Percy.

In: Oncologist, 01.01.2019.

Research output: Contribution to journalArticle

Heath, E, Heilbrun, L, Mannuel, H, Liu, G, Lara, PN, Monk, JP, Flaig, T, Zurita, A, Mack, P, Vaishampayan, U, Stella, P, Smith, D, Bolton, S, Hussain, A, Al-Janadi, A, Silbiger, D, Usman, M & Ivy, SP 2019, 'Phase II, Multicenter, Randomized Trial of Docetaxel plus Prednisone with or Without Cediranib in Men with Chemotherapy-Naive Metastatic Castrate-Resistant Prostate Cancer', Oncologist. https://doi.org/10.1634/theoncologist.2019-0331
Heath, Elisabeth ; Heilbrun, Lance ; Mannuel, Heather ; Liu, Glenn ; Lara, Primo N ; Monk, J. Paul ; Flaig, Thomas ; Zurita, Amado ; Mack, Philip ; Vaishampayan, Ulka ; Stella, Philip ; Smith, Daryn ; Bolton, Susan ; Hussain, Arif ; Al-Janadi, Anas ; Silbiger, Daniel ; Usman, Muhammad ; Ivy, S. Percy. / Phase II, Multicenter, Randomized Trial of Docetaxel plus Prednisone with or Without Cediranib in Men with Chemotherapy-Naive Metastatic Castrate-Resistant Prostate Cancer. In: Oncologist. 2019.
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abstract = "Lessons Learned: The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC). The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. Background: Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). Methods: This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. Results: The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61{\%}) compared with the DP arm (57{\%}). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38{\%} in the DP+C arm vs. 18{\%} in the DP arm). Conclusion: Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.",
author = "Elisabeth Heath and Lance Heilbrun and Heather Mannuel and Glenn Liu and Lara, {Primo N} and Monk, {J. Paul} and Thomas Flaig and Amado Zurita and Philip Mack and Ulka Vaishampayan and Philip Stella and Daryn Smith and Susan Bolton and Arif Hussain and Anas Al-Janadi and Daniel Silbiger and Muhammad Usman and Ivy, {S. Percy}",
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T1 - Phase II, Multicenter, Randomized Trial of Docetaxel plus Prednisone with or Without Cediranib in Men with Chemotherapy-Naive Metastatic Castrate-Resistant Prostate Cancer

AU - Heath, Elisabeth

AU - Heilbrun, Lance

AU - Mannuel, Heather

AU - Liu, Glenn

AU - Lara, Primo N

AU - Monk, J. Paul

AU - Flaig, Thomas

AU - Zurita, Amado

AU - Mack, Philip

AU - Vaishampayan, Ulka

AU - Stella, Philip

AU - Smith, Daryn

AU - Bolton, Susan

AU - Hussain, Arif

AU - Al-Janadi, Anas

AU - Silbiger, Daniel

AU - Usman, Muhammad

AU - Ivy, S. Percy

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Lessons Learned: The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC). The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. Background: Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). Methods: This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. Results: The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). Conclusion: Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.

AB - Lessons Learned: The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC). The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. Background: Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). Methods: This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. Results: The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). Conclusion: Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.

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