Detection of previously unidentified metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic, castration resistant prostate cancer.

Abstract

PURPOSE:

Understanding the extent of disease in asymptomatic patients with castration resistant prostate cancer is important when making treatment decisions and designing clinical trials. The ENTHUSE M0 (ENdoTHelin A USE) trial (NCT00626548) was a large phase III study comparing the endothelin A receptor antagonist zibotentan with placebo in patients with nonmetastatic, castration resistant prostate cancer. The study was stopped prematurely after early efficacy review indicated that it was unlikely to meet its co-primary objectives of improved overall and progression-free survival vs placebo. Screening failed in an unexpectedly high number of patients. We investigated this screening failure rate to promote better classification of patients thought to have nonmetastatic castration resistant prostate cancer and inform the design of future clinical trials in this setting.

MATERIALS AND METHODS:

The number of patients enrolled in and subsequently excluded from study was analyzed by geographic region and by the specialty of the investigating clinician (oncology or urology) who enrolled the study patients.

RESULTS:

Of 2,577 patients enrolled in a total of 350 hospital based centers in 39 countries screening failed in 1,155 (45%). The most common reason for screening failure was the detection of metastatic disease in 32% of all screened patients and in 71% of those in whom screening failed. The leading reasons for failed screening did not differ between investigator specialties overall or by geographic region.

CONCLUSIONS:

The high frequency of asymptomatic metastasis in men thought to have nonmetastatic, castration resistant prostate cancer highlights the importance of periodic staging assessments for the condition. Optimal treatment modalities may differ for metastatic and nonmetastatic disease.

• Authors: Evan Y Yu, Kurt Miller, Joel Nelson, Martin Gleave, Karim Fizazi, Judd W Moul, Faith E Nathan, Celestia S Higano
• Journal: The Journal of urology (J Urol) Vol. 188 Issue 1 Pg. 103-9 (Jul 2012) ISSN: 1527-3792 [Electronic] United States
• PMID: 22583636 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Chemical References

• Endothelin A Receptor Antagonists
• Pyrrolidines
• ZD4054
• Prostate-Specific Antigen

Topics

• Adult
• Aged
• Aged, 80 and over
• Disease Progression
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Double-Blind Method
• Endothelin A Receptor Antagonists
• Follow-Up Studies
• Humans
• Male
• Mass Screening
• Middle Aged
• Neoplasm Metastasis
• Orchiectomy
• Prostate (pathology)
• Prostate-Specific Antigen (blood)
• Prostatic Neoplasms (epidemiology, secondary, therapy)
• Pyrrolidines (administration & dosage)
• Survival Rate (trends)