Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer.
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.
Nelson
Joel B
JB
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15232, USA. nelsonjb@upmc.edu
Love
William
W
Chin
Joseph L
JL
Saad
Fred
F
Schulman
Claude C
CC
Sleep
Darryl J
DJ
Qian
Jiang
J
Steinberg
Joyce
J
Carducci
Michael
M
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
D019332:Endothelin-1; D010919:Placebos; D011759:Pyrrolidines; D000469:Alkaline Phosphatase; D000077868:Atrasentan
J Natl Cancer Inst. 2002 Oct 2;94(19):1458-68
12359855
J Clin Oncol. 2003 Feb 15;21(4):679-89
12586806
Cancer. 2007 Nov 1;110(9):1959-66
17886253
Cancer. 2003 Feb 1;97(3 Suppl):779-84
12548575
Neoplasia. 2006 Sep;8(9):725-32
16984730
N Engl J Med. 2004 Oct 7;351(15):1513-20
15470214
CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
15761078
N Engl J Med. 2004 Oct 7;351(15):1502-12
15470213
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10954-9
12941866
J Urol. 2003 Mar;169(3):1143-9
12576870
Urology. 2007 Jul;70(1):209-15
17656249
Cancer Res. 1996 Feb 15;56(4):663-8
8630991
Semin Oncol. 1994 Oct;21(5):630-56
7939753
Nat Med. 1995 Sep;1(9):944-9
7585222
J Transl Med. 2004 May 27;2(1):16
15165288
Biometrics. 1999 Sep;55(3):874-82
11315020
J Urol. 2001 Mar;165(3):1033-6
11176535
Nat Rev Cancer. 2003 Feb;3(2):110-6
12563310
CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66
17237035
Eur Urol. 2006 May;49(5):781-9
16458417