ZIBOTENTAN AND SUNITINIB FAILED IN PROSTATE CANCER

September 29, 2010 — In separate announcements, 2 phase 3 trials in prostate cancer have been stopped because of a lack of benefit. One of the trials was testing the investigational agent zibotentan (AstraZeneca) and the other was testing the already marketed product sunitinib (Sutent, Pfizer).

In contrast, a phase 3 trial of the investigational agent abiraterone (Ortho Biotech) in prostate cancer was recently unblinded because the results were so good. As well as unblinding the results, the trial's Data Monitoring Committee decreed that all patients who had been taking placebo should be put on the drug.

Honing in on a Novel Target

The stopped zibotentan trial is 1 of a program of 3 studies being carried out in men with castration-resistant prostate cancer (CRCP), involving more than 3000 patients in total. The other 2 trials are continuing.

The stopped trial involved 594 patients with metastatic CRCP; it compared zibotentan with placebo when added to standard care. It was stopped because the drug did not show a significant improvement in the primary end point of overall survival, the company said.

The 2 trials that are continuing are exploring the drug in different settings. One is comparing zibotentan plus chemotherapy with chemotherapy alone, and is also being conducted in men with metastatic CRPC; the other is comparing zibotentan with placebo in men with CRPC whose tumors have not yet metastasized.

Zibotentan constitutes a novel approach to the treatment of prostate cancer. It acts by blocking the endothelin pathway, which becomes uncontrolled as prostate cancer advances, allowing the cancer to grow and spread. The hope is that by blocking the endothelin A receptor in this pathway, the drug can slow tumor growth and spread, the manufacturer explained. Hope has faded a little now that 1 of 3 large trials has failed.

Sunitinib Showed No Benefit

The other stopped trial involved an anticancer drug marketed for other indications. Sunitinib is licensed for advanced/metastatic renal cell carcinoma and for gastrointestinal tumors after disease progression on or intolerance to imatinib (Gleevec, Novartis).

It is also being investigated in other cancers, but the latest announcement shows no benefit in prostate cancer. The trial was stopped because a planned interim analysis suggested that sunitinib with prednisolone would "not ultimately improve the overall survival of men with advanced stage, castration-resistant prostate cancer," the company stated.

Great Results With Abiraterone?

In contrast to the 2 failures, a phase 3 trial with abiraterone looks to be a great success, although the results have not yet been released — they are due to be presented next week at the European Society of Medical Oncology meeting in Milan, Italy, and will be reported in detail by Medscape Medical News journalists attending that meeting.

But the results must be good and must have shown a significant benefit for the Data Monitoring Committee to have taken the step of unblinding the study and proposing a crossover from placebo to active drug.

Abiraterone is an androgen-synthesis inhibitor that offers a new approach to hormonal manipulation in prostate cancer, and results so far have been positive and welcomed by specialists in the field, as previously reported by Medscape Medical News.

Another investigational drug in late clinical development, also offering a new approach to hormonal manipulation, is MDV3100 (Medivation). This drug has a different mechanism of action, acting as an androgen-receptor antagonist, but it has also shown positive results in CRPC.

"Both of these drugs look promising," William Dahut, MD, clinical director of the National Cancer Institute in Bethesda, Maryland, told Medscape Medical News earlier this year. He predicted that — if and when they reach the market — these drugs will be used in men who have progressed on hormonal therapy before they consider chemotherapy, pointing out that these new drugs are oral and are better tolerated.

A new chemotherapy — carbazitaxel (Sanofi-Aventis) — is also in the late stages of clinical development for use in prostate cancer. This would not compete, and might even complement, the new hormone-manipulating drugs under development.