Metastatic prostate cancer responds to cytostatic agent

Nicholas J. Vogelzang, MD, director of the Nevada Cancer Institute, reached this conclusion following a meta-analysis of two placebo-controlled trials involving 1,002 patients. One was a randomized phase II trial and the other, a randomized phase III trial, both with time to disease progression as the primary endpoint. Data were presented at the American Society of Clinical Oncology 2005 annual meeting here.

Atrasentan is a selective endothelin-A receptor antagonist, originally investigated as a potential antihypertensive drug. But the preclinical models suggested this molecule has a potent ability to inhibit osteoblastic metastases in a variety of animal models, so it was deliberately designed for use in prostate cancer.

"In combining the two randomized trials, we get robust statistical significance showing a delay in time to disease progression," Dr. Vogelzang explained. "That is a composite endpoint composed of five elements: bone scan changes, changes to non-bone metastases, prostate cancer pain, skeletal events, and events requiring new treatment. In addition, bone alkaline phosphatase, PSA, and quality-of-life measures were used to test the effect of the drug in these patients."

The drug does not stop PSA from rising, although it slows the rate that PSA rises. It reduces the likelihood of developing bone pain and increases the time to bone pain and time to opioid use, improves quality of life, and lengthens time to disease progression, the primary endpoint, Dr. Vogelzang said.

Other endpoints improve

Compared with patients receiving placebo, patients treated with atrasentan, 10 mg, were 14% less likely to experience disease progression, had 18% less likelihood of experiencing bone pain and 22% less chance of PSA progression, and were 46% less likely to experience bone alkaline phosphatase progression. The relative probability of remaining progression-free was 10% greater at 3 months and 22% greater at 6 months among patients treated with atrasentan, 10 mg, than among those receiving placebo. The probability of remaining progression-free on placebo was 49% at 3 and 27% at 6 months, Dr. Vogelzang reported.

The side effect profile of atrasentan reflects that of a drug that dilates blood vessels: fluid retention accompanied by slight weight gain, slight vasodilation, and a slight drop in hemoglobin levels. Some patients with pre-existing heart disease may experience heart failure.

The average survival of patients in these trials was 17 to 18 months from the beginning of the trial, not from the date of diagnosis, which is consistent with what has been seen in a concurrent trial of docetaxel (Taxotere), Dr. Vogelzang said.