Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone.
BACKGROUND
Endothelin-1 and the endothelin A (ET(A) ) receptor have been implicated in prostate cancer progression in bone. This study aimed to determine whether the specific ET(A) receptor antagonist, zibotentan, prolonged overall survival (OS) in patients with castration-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic for pain.


METHODS
Patients were randomized 1:1 to zibotentan 10 mg/day or placebo, plus standard prostate cancer treatment. The primary endpoint was OS. Secondary endpoints included times to pain progression, chemotherapy use, new bone metastases, and safety. Efficacy endpoints were analyzed using a log-rank test.


RESULTS
A total of 594 patients were randomized (zibotentan, n = 299; placebo, n = 295). Median OS was 24.5 months in zibotentan-treated patients versus 22.5 months for placebo, but the difference did not reach statistical significance (hazard ratio, 0.87; 95.2% confidence interval, 0.69-1.10; P = .240). No statistically significant differences were observed for any secondary efficacy endpoints. Peripheral edema (44%) and headache (31%) were the most commonly reported adverse events in the zibotentan group. Cardiac failure events were higher in the zibotentan group than placebo (any grade, 5.7% and 1.7%; Common Terminology Criteria for Adverse Events grade ≥3, 3.0% and 1.0%, respectively); these were manageable and reversible.


CONCLUSIONS
In this large, randomized, placebo-controlled phase 3 trial, treatment with zibotentan 10 mg/day did not lead to a statistically significant improvement in OS in this patient population. Zibotentan had an acceptable safety profile.
Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. nelsonjb@upmc.edu
Joel B
JB
Nelson
Karim
K
Fizazi
Kurt
K
Miller
Celestia
C
Higano
Judd W
JW
Moul
Hideyuki
H
Akaza
Thomas
T
Morris
Stuart
S
McIntosh
Kristine
K
Pemberton
Martin
M
Gleave
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D018572:Disease-Free Survival; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D009919:Orchiectomy; D010919:Placebos; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011759:Pyrrolidines / Q000009:adverse effects / Q000627:therapeutic use*; D013534:Survival; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010919:Placebos; D011759:Pyrrolidines; C511404:ZD4054