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A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer.
Carducci, Michael A. MD 1,*; Saad, Fred MD 2; Abrahamsson, Per-Anders MD 3; Dearnaley, David P. MD 4; Schulman, Claude C. MD 5; North, Scott A. MD 6; Sleep, Darryl J. MD 7; Isaacson, Jeffrey D. PhD 7; Nelson, Joel B. MD 8; for the Atrasentan Phase III Study Group Institutions. 8
[Article] Cancer. 110(9):1959-1966, November 1, 2007.

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BACKGROUND. The objective of this study was to evaluate the efficacy and safety of atrasentan (Xinlay), a selective endothelin-A receptor antagonist, in patients with metastatic hormone-refractory prostate cancer (HRPC).

METHODS. This multinational, double-blind, placebo-controlled trial enrolled 809 men with metastatic HRPC. Patients were randomized 1:1 to receive either atrasentan 10 mg per day or placebo. The primary endpoint was time to disease progression (TTP), which was determined according to radiographic and clinical measures. Analyses of overall survival and changes in biomarkers also were performed.

RESULTS. Atrasentan did not reduce the risk of disease progression relative to placebo (hazards ratio, 0.89; 95% confidence interval, 0.76-1.04; P = .136). Most patients progressed radiographically at the first 12-week bone scan without concomitant clinical progression. In exploratory analyses, increases from baseline to final bone alkaline phosphatase (BAP) and prostate-specific antigen (PSA) levels were significantly lower with atrasentan treatment (P < .05 for each). The median time to BAP progression (>=50% increase from nadir) was twice as long with atrasentan treatment (505 days vs 254 days; P < .01). The delay in time to PSA progression did not reach statistical significance. Atrasentan generally was tolerated well, and the most common adverse events associated with treatment were headache, rhinitis, and peripheral edema, reflecting the vasodilatory and fluid-retention properties of endothelin-A receptor antagonism.

CONCLUSIONS. Atrasentan did not delay disease progression in men with metastatic HRPC despite evidence of biologic effects on PSA and BAP as markers of disease burden.

Despite evidence of the biologic effect of atrasentan on prostate-specific antigen and bone alkaline phosphatase as markers of disease burden, in a large, randomized, placebo-controlled Phase 3 trial, atrasentan did not delay disease progression in men with metastatic hormone-refractory prostate cancer.