title: Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer.
abstract: BACKGROUND
  Atrasentan is a potent, oral, selective endothelin-A (ET(A)) receptor antagonist that has clinical activity in patients with hormone-refractory prostate cancer (HRPC). In this article, the authors report the results from a phase 3, randomized, double-blind, placebo-controlled trial of atrasentan in patients with nonmetastatic HRPC.
  
  
  METHODS
  Of 941 patients who had adequate androgen suppression and no radiographic evidence of metastases but rising prostate-specific antigen (PSA) levels, 467 patients were randomized to receive atrasentan at a dose of 10 mg, and 474 patients were randomized to receive placebo daily. The primary endpoint was the time to disease progression (TTP), which was defined as the onset of metastases. Secondary endpoints were the time to PSA progression, change in bone alkaline phosphatase (BALP) levels, PSA doubling time, and overall survival.
  
  
  RESULTS
  There was a 93-day delay in the median TTP with atrasentan, but the difference from placebo in TTP was not statistically significant (P= .288). Large geographic differences in the median TTP were noted: in the US: The difference was 81 days longer with placebo; whereas, in non-US sites, the difference was 180 days longer with atrasentan. Atrasentan lengthened the PSA doubling time (P= .031) and slowed the increase in BALP (P< .001). The 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 ET(A) receptor antagonists.
  
  
  CONCLUSIONS
  Although the primary endpoint was not achieved, large regional differences in TTP were noted, suggesting that trial conduct may have influenced the results. The biologic activity was consistent with findings from other clinical trials of atrasentan in HRPC.
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15232, USA. nelsonjb@upmc.edu
authors.forename: Joel B
authors.initials: JB
authors.lastname: Nelson
authors.forename: William
authors.initials: W
authors.lastname: Love
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Chin
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.forename: Claude C
authors.initials: CC
authors.lastname: Schulman
authors.forename: Darryl J
authors.initials: DJ
authors.lastname: Sleep
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.forename: Joyce
authors.initials: J
authors.lastname: Steinberg
authors.forename: Michael
authors.initials: M
authors.lastname: Carducci
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000378:metabolism; D000077868:Atrasentan; D018450:Disease Progression; D004311:Double-Blind Method; D019332:Endothelin-1 / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000473:pathology; D010919:Placebos; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011759:Pyrrolidines / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D019332:Endothelin-1; D010919:Placebos; D011759:Pyrrolidines; D000469:Alkaline Phosphatase; D000077868:Atrasentan
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