Suppression of prostate cancer induced bone remodeling by the endothelin receptor A antagonist atrasentan.
OBJECTIVE
We examined the effects of atrasentan (endothelin-A receptor antagonist) on bone deposition and resorption markers and on bone scan index.


METHODS
This double-blind, randomized, placebo controlled clinical trial of hormone refractory prostate cancer patients was done at 74 medical centers in the United States and Europe. A total of 288 asymptomatic patients with hormone refractory prostate adenocarcinoma and evidence of metastatic disease were randomized to 1 of 3 treatment groups, namely 2.5 mg. atrasentan, 10 mg. atrasentan or placebo administered orally daily until disease progression. The main outcomes measures were changes in bone deposition markers (total alkaline phosphatase and bone alkaline phosphatase) and bone resorption (N-telopeptides, C-telopeptides and deoxypyridinoline), and in the bone scan index.


RESULTS
At baseline markers of bone deposition and resorption were elevated 1.4 to 2.7-fold above respective upper limits of normal. Subjects receiving placebo experienced a 58% elevation in mean total alkaline phosphatase and a 99% elevation in mean bone alkaline phosphatase (p < 0.001), whereas subjects receiving 10 mg. atrasentan maintained stable mean total alkaline phosphatase and bone alkaline phosphatase values compared with baseline. N-telopeptides, C-telopeptides and deoxypyridinoline elevation from baseline were consistently less in patients receiving 10 mg. atrasentan compared with placebo. Similar trends were observed in subjects who received 2.5 mg. atrasentan. Changes in clinical bone scan studies paralleled bone marker changes.


CONCLUSIONS
Atrasentan suppressed markers of biochemical and clinical prostate cancer progression in bone and demonstrates clinical activity for hormone refractory prostate cancer.
Nelson
Joel B
JB
Sidney Kimmel Comprehensive Cancer Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nabulsi
Azmi A
AA
Vogelzang
Nicholas J
NJ
Breul
Jurgen
J
Zonnenberg
Bernard A
BA
Daliani
Danai D
DD
Schulman
Claude C
CC
Carducci
Michael A
MA
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000503:physiopathology; D000368:Aged; D000469:Alkaline Phosphatase / Q000032:analysis; D000596:Amino Acids / Q000032:analysis; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077868:Atrasentan; D014408:Biomarkers, Tumor / Q000032:analysis; D016723:Bone Remodeling / Q000187:drug effects* / Q000502:physiology; D001862:Bone Resorption / Q000503:physiopathology; D003094:Collagen / Q000032:analysis / Q000652:urine; D024042:Collagen Type I; D004311:Double-Blind Method; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D008297:Male; D010455:Peptides / Q000032:analysis / Q000652:urine; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011759:Pyrrolidines
D000596:Amino Acids; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D024042:Collagen Type I; D019332:Endothelin-1; D010455:Peptides; D011759:Pyrrolidines; C052929:collagen type I trimeric cross-linked peptide; C036020:deoxypyridinoline; D003094:Collagen; D000469:Alkaline Phosphatase; D000077868:Atrasentan