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

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.

• Authors: Elisabeth Heath, Lance Heilbrun, Heather Mannuel, Glenn Liu, Primo 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
• Journal: The oncologist (Oncologist) Vol. 24 Issue 9 Pg. 1149-e807 (09 2019) ISSN: 1549-490X [Electronic] England
• PMID: 31152080 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial)
• Copyright: © AlphaMed Press; the data published online to support this summary are the property of the authors.

Chemical References

• Quinazolines
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Docetaxel
• KLK3 protein, human
• Kallikreins
• Prostate-Specific Antigen
• cediranib
• Prednisone

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Docetaxel (administration & dosage)
• Humans
• Kallikreins (blood)
• Male
• Middle Aged
• Neoplasm Metastasis
• Prednisone (administration & dosage)
• Prostate-Specific Antigen (blood)
• Prostatic Neoplasms, Castration-Resistant (blood, drug therapy, pathology)
• Quinazolines (administration & dosage)
• Survival Rate
• Treatment Outcome
• Vascular Endothelial Growth Factor A (blood)