Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial.
OBJECTIVE
To evaluate the efficacy and safety of atrasentan (ABT-627), an endothelin-A receptor antagonist, in the treatment of asymptomatic, hormone-refractory prostatic adenocarcinoma.


METHODS
A double-blind, randomized, placebo-controlled clinical trial of hormone-refractory prostate cancer (HRPCa) patients was conducted in the United States and Europe. Two hundred eighty-eight asymptomatic patients with HRPCa and evidence of metastatic disease were randomly assigned to one of three study groups receiving a once-daily oral dose of placebo, 2.5 mg atrasentan, or 10 mg atrasentan, respectively. Primary end point was time to progression; secondary end points included time to prostate-specific antigen (PSA) progression, bone scan changes, and changes in bone and tumor markers.


RESULTS
The three treatment groups were similar in all baseline characteristics. Median time to progression in intent-to-treat (ITT) patients (n = 288) was longer in the 10-mg atrasentan group compared with the placebo group: 183 v 137 days, respectively; (P =.13). Median time to progression in evaluable patients (n = 244) was significantly prolonged, from 129 days (placebo group) to 196 days (10-mg atrasentan group; P =.021). For both ITT and evaluable populations in the 10-mg atrasentan group, median time to PSA progression was twice that of the placebo group (155 v 71 days; P =.002). Patients who received placebo continued to have significant increases from baseline in serum (lactate dehydrogenase [LDH]), a marker of disease burden; elevations in LDH were uniformly attenuated by atrasentan in the ITT population. Headache, peripheral edema, and rhinitis were primary side effects, typically of mild to moderate severity. Quality of life was not adversely affected by atrasentan.


CONCLUSIONS
Atrasentan is an oral, targeted therapy with favorable tolerability and the potential to delay progression of HRPCa.
Carducci
Michael A
MA
Sidney Kimmel Comprehensive Cancer Center, the Johns Hopkins University School of Medicine, Baltimore, MD.
Padley
Robert J
RJ
Breul
Jurgen
J
Vogelzang
Nicholas J
NJ
Zonnenberg
Bernard A
BA
Daliani
Danai D
DD
Schulman
Claude C
CC
Nabulsi
Azmi A
AA
Humerickhouse
Rod A
RA
Weinberg
Mark A
MA
Schmitt
Jennifer L
JL
Nelson
Joel B
JB
D000135:Acid Phosphatase / Q000097:blood; D000230:Adenocarcinoma / Q000188:drug therapy*; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000077868:Atrasentan; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D007770:L-Lactate Dehydrogenase; D000135:Acid Phosphatase; D000077868:Atrasentan