Background Atrasentan is a potent, oral, selective endothelin-A (ETA) receptor antagonist with clinical activity in patients with hormone-refractory prostate cancer (HRPC). This reports the results of a Phase 3, randomized, double-blind, placebo-controlled trial of atrasentan in patients with nonmetastatic HRPC. Methods Of 941 patients with adequate androgen suppression, no radiographic evidence of metastases but rising prostate-specific antigen (PSA) levels 467 received atrasentan 10 mg daily and 474 received placebo daily. The primary endpoint was time to disease progression (TTP) defined as the onset of metastases. Secondary endpoints were time to PSA progression, change in bone alkaline phosphatase (BALP), PSA doubling time, and overall survival. Results Atrasentan delayed median TTP by 93 days but the difference from placebo was not statistically significant (P = .288). Large geographical differences in median TTP were noted: in the United States (US), the difference was 81 days longer with placebo, whereas in non-US sites, the difference was 180 days longer with atrasentan. Atrasentan lengthened PSA doubling time (P = .031) and slowed the increase in BALP (P < .001). Median survival was 1477 days with atrasentan and 1403 days with placebo. The most common adverse events associated with atrasentan were peripheral edema, nasal congestion, and headache, consistent with the vasodilatory properties of ETA receptor antagonists. Conclusions While the primary endpoint was not achieved, large regional differences in TTP were noted, suggesting that trial conduct might have influenced the results. The biological activity is consistent with findings from other clinical trials of atrasentan in HRPC.

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. Cancer 2007. © 2007 American Cancer Society.

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The models developed have good predictive validity. These algorithms enable researchers to translate cancer-specific HRQoL measures to preference-adjusted health status in metastatic HRPCA patients. The findings will help perform health status adjustments in cost-utility analyses.

These data demonstrate that patients with metastatic HRPC experience rapid, significant deterioration in HRQL, highlighting the need for effective palliative therapy for men with HRPC.