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Zibotentan/docetaxel failed to improve OS in metastatic castration-resistant prostate cancer
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Docetaxel plus zibotentan failed to significantly improve OS in men with metastatic castration-resistant prostate cancer, according to final phase 3 data from the ENTHUSE clinical trial program.
Zibotentan, a novel once-daily tablet, works to block the endothelin pathway and slow tumor growth and the spread of cancer cells.
Karim Fizazi
Karim Fizazi, MD, PhD, of the department of cancer medicine at the Institut Gustave Roussy at the University of Paris, and colleagues conducted the phase 3 trial to assess the efficacy and safety of docetaxel plus zibotentan 10 mg/daily in 1,052 men with metastatic castrate-resistant prostate cancer.
The researchers observed no differences in OS between patients assigned docetaxel and zibotentan or docetaxel plus placebo (HR=1.00; 95% CI, 0.84-1.18; P = 0.963).
In addition, there were no significant differences observed in pain response (OR=0.84; 95% CI, 0.61-1.16; P=.283) or time to progression among those assigned to the combination regimen or placebo (median 9.3 months vs. 10 months).
Median time to death was 20 months for patients in the zibotentan group and 19.2 months for patients in the placebo group. Researchers reported 277 deaths in the zibotentan group and 280 in the placebo group at data cutoff.
The most common adverse events in the zibotentan group were peripheral edema (52.7%), diarrhea (35.4%), alopecia (33.9%) and nausea (33.3%).
“In conclusion, docetaxel plus zibotentan did not result in a significant improvement in OS vs. docetaxel plus placebo in patients with metastatic castration-resistant prostate cancer,” the researchers wrote. “In addition to the current study, the ENTHUSE M1 study failed to demonstrate a clinical benefit for zibotentan monotherapy in patients with metastatic castration-resistant prostate cancer, and ENTHUSEM0 — which evaluated zibotentan monotherapy in patients with nonmetastatic castration-resistant prostate cancer — was terminated after the results of an early efficacy review. As a result, zibotentan is no longer being investigated as a potential treatment for patients with prostate cancer, and we believe that this class of agent is no longer being considered as a treatment in this setting.”
Phase 1 and 2 trials were conducted as part of the ENTHUSE program that assessed docetaxel plus zibotentan in 37 patients with metastatic castration-resistant prostate cancer.
In an accompanying editorial, Emmanuel S. Antonarakis, MD, and Mario A. Eisenberger, MD, both of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, wrote: “The prespecified primary endpoints for the phase 2 expansion component were overall response rate and PSA response rate. There were no differences observed between arms in either of these endpoints. Despite these findings, and perhaps encouraged by a separate randomized phase 2 trial of single-agent zibotentan versus placebo in asymptomatic patients with metastatic castration-resistant prostate cancer, the authors of the phase 1 and 2 trial commented that ‘sufficient preliminary activity was seen with this combination to merit continued development.’ On the basis of the available clinical data, we do not believe that compelling evidence existed to justify proceeding with a phase 3 trial.”
Eight additional phase 3 trials with mature results also failed to meet OS rates, Antonarakis and Eisenberger wrote.
“Indeed, no docetaxel-based combination reported to date, to our knowledge, has been shown to extend survival compared with docetaxel alone,” they wrote.
For more information:
Antonarakis ES. J Clin Oncol. 2013;doi:10.1200/JCO.2013.48.8825.
Fizazi K. J Clin Oncol. 2013;doi:10.1200/JCO.2012.46.4149.
Disclosure: Fizazi reports consultant fees from AstraZeneca. Antonarakis reports consultant fees and honoraria from Denderon, Janssen and Sanofi-Aventis, and research funding from Denderon and Sanofi-Aventis. Eisenberger reports consultant fees from Sanofi-Aventis and research funding from Agensys, Genentech, Oncology Trials Insights and Sanofi-Aventis.