Atrasentan

Atrasentan is a selective endothelin A receptor antagonist developed by Abbott. It reached phase 3 in prostate cancer twice: alone in men with non-metastatic and metastatic disease, where the results did not support approval and the FDA declined it in 2005, and then in combination with docetaxel.

SWOG S0421 randomised 994 men with metastatic castration-resistant prostate cancer and bone metastases 1:1 to docetaxel 75 mg/m2 every 21 days with atrasentan 10 mg daily or placebo, for up to 12 cycles, stratified by progression type, baseline pain, extraskeletal metastases and bisphosphonate use. The trial was halted early for futility in April 2011.

Median progression-free survival was 9.2 months (95 percent confidence interval 8.5 to 9.9) with atrasentan and 9.1 months (8.4 to 10.2) with placebo, hazard ratio 1.02 (0.89 to 1.16, p=0.81). Median overall survival was 17.8 months (16.4 to 19.8) against 17.6 (16.4 to 20.1), hazard ratio 1.04 (0.90 to 1.19, p=0.64). Grade 3 or worse toxicity occurred in 57 percent against 60 percent. The separately published patient-reported outcomes found no clinically meaningful difference in pain palliation (41.7 against 44.0 percent) or functional status.

The endothelin axis is the largest completely negative target hypothesis in prostate cancer: two drugs, five phase 3 trials, no effect.