Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer.
BACKGROUND
Metastatic prostate cancer is characterized by the presence of osteoblastic bone metastases. Bone metastases account for most of the morbidity from this disease. Inhibition of osteoclast activity with the potent bisphosphonate zoledronic acid reduces skeletal complications and decreases serum levels of biochemical bone turnover markers compared with placebo. Atrasentan is an investigational agent that inhibits endothelin-1 receptor, resulting in decreased osteoblast activity.


METHODS
The effects of atrasentan alone versus combination therapy with atrasentan and zoledronic acid were investigated on bone turnover markers in men with bone metastases from prostate cancer. Forty-four men were randomized to receive either atrasentan alone or combination therapy, and 33 completed at least 12 weeks of treatment and were included in the primary analysis.


RESULTS
Treatment with the combination resulted in significantly lower serum levels of N-telopeptide, a marker of bone resorption, compared with treatment with atrasentan alone. There was no difference between groups in serum levels of bone-specific alkaline phosphatase, a marker of bone formation, at 12 weeks. Commonly observed adverse effects were edema, rhinitis, fatigue, and shortness of breath, most of which were NCI CTC (version 3.0) Grade 1. No Grade 4 or 5 treatment-related toxicities were observed. There was minimal clinical efficacy, with no objective responses and only 1 prostate-specific antigen (PSA) response.


CONCLUSIONS
There is no evidence for additive or synergistic effects of combination therapy with atrasentan and zoledronic acid on bone turnover markers in men with metastatic prostate cancer.
Michaelson
M Dror
MD
Department of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. dmichaelson1@partners.org
Kaufman
Donald S
DS
Kantoff
Philip
P
Oh
William K
WK
Smith
Matthew R
MR
D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077868:Atrasentan; D014408:Biomarkers, Tumor / Q000032:analysis; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary; D001842:Bone and Bones / Q000201:enzymology / Q000378:metabolism; D004164:Diphosphonates / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D004417:Dyspnea / Q000150:complications; D004487:Edema / Q000150:complications; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000150:complications / Q000188:drug therapy*; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D000077211:Zoledronic Acid
D014408:Biomarkers, Tumor; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D011759:Pyrrolidines; D000077211:Zoledronic Acid; D000469:Alkaline Phosphatase; D000077868:Atrasentan