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.