Zibotentan

Endothelin-1 and the endothelin A receptor are implicated in the growth of prostate cancer in bone, and for most of the 2000s the endothelin axis was one of the most attractive non-hormonal targets in the disease. Zibotentan is a specific endothelin A receptor antagonist.

The ENTHUSE programme tested it in three settings. In ENTHUSE M1, 594 men with castration-resistant prostate cancer, bone metastases and no or mild pain were randomised 1:1 to zibotentan 10 mg daily or placebo with standard treatment. Median overall survival was 24.5 months with zibotentan against 22.5 with placebo, hazard ratio 0.87 (95.2 percent confidence interval 0.69 to 1.10, p=0.240), not significant, and no secondary endpoint reached significance either. Peripheral oedema (44 percent) and headache (31 percent) were the commonest adverse events, and cardiac failure of any grade occurred in 5.7 percent against 1.7 percent.

The other two ENTHUSE trials, in combination with docetaxel and in non-metastatic disease, were also negative, and AstraZeneca discontinued zibotentan in prostate cancer. Atrasentan, the other endothelin A antagonist, failed in SWOG S0421 in the same years. Both drugs have since been revived for kidney disease, where the target behaves differently.