A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer.
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.
Carducci
Michael A
MA
Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA. carducci@jhmi.edu
Saad
Fred
F
Abrahamsson
Per-Anders
PA
Dearnaley
David P
DP
Schulman
Claude C
CC
North
Scott A
SA
Sleep
Darryl J
DJ
Isaacson
Jeffrey D
JD
Nelson
Joel B
JB
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood / Q000187:drug effects; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077868:Atrasentan; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D018450:Disease Progression; D004311:Double-Blind Method; D019008:Drug Resistance, Neoplasm; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D011759:Pyrrolidines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011759:Pyrrolidines; D000469:Alkaline Phosphatase; D017430:Prostate-Specific Antigen; D000077868:Atrasentan