Effects of atrasentan on disease progression and biological markers in men with metastatic hormone-refractory prostate cancer: Phase 3 study

Abstract

4508 Background: In earlier trials, atrasentan, a potent, selective, oral endothelin A receptor antagonist, significantly delays time to disease progression (TTP) in a per-protocol group of hormone-refractory prostate cancer (HRPC) patients identified pre–blind break. We report the results from a phase 3 trial. Methods: 809 subjects with metastatic HRPC enrolled into a phase 3, randomized, double-blind, placebo-controlled study of 10 mg atrasentan were analyzed (401 placebo, 408 atrasentan). Kaplan-Meier and Cox proportional hazard methodologies were used to compare TTP (a composite of radiographic and clinical measures) between treatments. Analysis of covariance compared change from baseline to final value in PSA and bone and total alkaline phosphatase (BAP and ALP). Data from a protocol-compliant subset identified prior to blind break were analyzed as well. Results: Atrasentan exhibited a nonsignificant trend in delayed TTP (log-rank p=0.091; hazard ratio [HR] = 1.14, 95% CI = 0.98–1.34) and significantly delayed time to BAP progression (TTBAP, >50% increase from nadir) versus placebo (median: 254 vs 505 days; log-rank p<0.001; HR = 1.78, 95% CI = 1.34–2.37). The atrasentan group showed smaller mean increases than the placebo group in PSA (p=0.025), BAP (p=0.001), and ALP (p<0.001). In the protocol-compliant subset (329 placebo, 342 atrasentan), atrasentan significantly delayed TTP (log-rank p=0.007; HR = 1.26, 95% CI = 1.06–1.50) and TTBAP (log-rank p<0.001) and resulted in smaller mean changes from baseline to final in the 3 biological markers. Atrasentan was well tolerated. The most common associated adverse events, peripheral edema, rhinitis, and headache, resulted in few discontinuations. Conclusions: Atrasentan demonstrated a significant delay in TTP and attenuated increase in relevant bone and tumor markers in metastatic HRPC patients representative of the intended target population. The accumulating and consistent data for atrasentan demonstrates biologic and clinical activity of endothelin receptor blockade in metastatic HRPC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories Aventis Abbott Laboratories