Zibotentan for the treatment of castrate-resistant prostate cancer.
BACKGROUND
Patients with prostate cancer who have progression of their disease while on androgen deprivation therapy have limited therapeutic options. Docetaxel is currently the only agent that increases overall survival in patients with metastatic, castration-resistant prostate cancer; additional agents are needed.


METHODS
This review will describe the importance of endothelin-1 (ET-1) for growth of prostate cancer cells, development of bone metastases, and pain responses; the preclinical data for zibotentan, a specific inhibitor of the ET(A) receptor; and the clinical development of atrasentan, a first-generation ET receptor inhibitor, and zibotentan, a more selective inhibitor of the ET(A) receptor.


RESULTS
Readers will understand the importance of ET-1 as a novel pathway to target for patients with castration-resistant prostate cancer due to its association with prostate cancer growth, metastases to bone, and pain. Readers will learn about the preclinical and clinical development of zibotentan, including the promising Phase II results that have resulted in an extensive Phase III clinical trials program.


CONCLUSIONS
Modulating the activity of ET-1 through the ET(A) receptor is a novel target for treating patients with metastatic, castration-resistant prostate cancer. There are currently three ongoing Phase III trials with zibotentan, a selective ET(A) inhibitor, to determine the effect of this agent on overall survival in these patients.
Shepard
Dale R
DR
Cleveland Clinic, Taussig Cancer Institute, Department of Solid Tumor Oncology, Cleveland, OH 44195, USA.
Dreicer
Robert
R
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D004353:Drug Evaluation, Preclinical; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011759:Pyrrolidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; C511404:ZD4054