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.

Figure 1

Geographic distribution of enrolled patients

Figure 2

Leading reasons for screening failure by investigator specialty. Values indicate number of patients for whom reason was cited for failure. Values in parentheses indicate percent of total enrolled population. Some patients had more than 1 reason for failure. Pink bars indicate serum bilirubin greater than 1.5 ULN. Light blue bars indicate hemoglobin less than 9 gm/dl. Orange bars indicate no biochemical progression. Blue-green bars indicate alanine aminotransferase or aspartate aminotransferase greater than 2.5 ULN. Purple bars indicate testosterone greater than 70 ng/dl or noncastrate. Green bars indicate QTc interval greater than 470 milliseconds. Red bars indicate creatinine clearance less than 50 ml per minute. Dark blue bars indicate metastatic disease detected.

Figure 3

Leading reasons for screening failure by region. Values indicate number of patients for whom reason was cited for failure. Values in parentheses indicate total enrolled population. Some patients had more than 1 reason for failure. Pink bars indicate serum bilirubin greater than 1.5 ULN. Light blue bars indicate hemoglobin less than 9 gm/dl. Orange bars indicate no biochemical progression. Blue-green bars indicate alanine aminotransferase or aspartate aminotransferase greater than 2.5 ULN. Purple bars indicate testosterone greater than 70 ng/dl or noncastrate. Green bars indicate QTc interval greater than 470 milliseconds. Red bars indicate creatinine clearance less than 50 ml per minute. Dark blue bars indicate metastatic disease detected.