Prostate Cancer Trial Stopped as MDV3100 Improves Survival

Nick Mulcahy

November 03, 2011

November 3, 2011 — The experimental oral agent for metastatic castration-resistant prostate cancer, MDV3100 (Medivation), improved survival by 4.8 months, compared with placebo, in a phase 3 trial, the company announced.

A planned interim analysis of the AFFIRM trial revealed that estimated median survival was 18.4 months for men treated with MDV3100, compared with 13.6 months for men treated with placebo (P < .0001). This translates into a 37% reduction in the risk for death with MDV3100 (hazard ratio, 0.631).

As a result, the trial's Independent Data Monitoring Committee recommended that AFFIRM be stopped early and that men who were receiving placebo be offered MDV3100.

The recommendation was based on the fact that the study's prespecified interim efficacy stopping criteria were successfully met. The committee also examined the safety profile to date and determined that MDV3100 demonstrated a risk/benefit ratio that was favorable enough to stop the study, according to a company press statement.

"MDV3100 was rationally designed to target androgen-receptor signaling, a key driver of prostate cancer growth," said Howard I. Scher, MD, coprincipal investigator of the AFFIRM study, in a press statement. He is chief of the genitourinary oncology service at the Memorial-Sloan Kettering Cancer Center in New York City. "If approved, MDV3100 will be a welcome option for men with prostate cancers who have progressed on hormones and after initial chemotherapy."

The full results from AFFIRM, including safety data, will be presented at an upcoming scientific congress, according to the company.

The study is a randomized, double-blind, multinational trial comparing MDV3100 (160 mg/day) with placebo in 1199 men with advanced prostate cancer who were previously treated with docetaxel-based chemotherapy. Enrollment was completed in November 2010, and the interim analysis was triggered at 520 events.

If approved by the US Food and Drug Administration, MDV3100 will move into an increasingly crowded marketplace of products for the treatment of castration-resistant prostate cancer.

In phase 3 clinical trials in this setting, the immunotherapy sipuleucel-T (Provenge, Dendreon) has demonstrated a 4.1-month median survival benefit, and abiraterone (Zytiga, Johnson & Johnson) has shown a 3.9-month benefit. In addition, the chemotherapy cabazitaxel (Jevtana, sanofi-aventis) demonstrated a 2.4-month overall survival advantage over standard therapy.

MDV3100 and Abiraterone

MDV3100 was codeveloped by Charles Sawyers, MD, chair of human oncology and pathogenesis at Memorial Sloan-Kettering, and Michael Jung, PhD, professor of chemistry at the University of California, Los Angeles.

They theorized that androgen-receptor signaling is a driver in prostate cancer and that blocking the signaling would stop its growth. MDV3100 was designed to do just that.

In an earlier report on MDV3100, Dr. Scher told Medscape Medical News that it is a very potent antagonist of androgen receptors, and binds to the receptor very tightly.

MDV3100 is more potent and more specific than the older antiandrogens, such as flutamide (Drogenil) and bicalutamide (Casodex), which have been and are still being used in prostate cancer, usually with gonadotropin-releasing hormone agonists/antagonists, such as leuprolide (Lupron) and goserelin (Zoladex), said Dr. Scher. These older antiandrogen compounds also have some agonist activity, and have been found to stimulate prostate cancer growth in some men, Dr. Scher explained. This has not been seen with MDV3100, he noted at the time.

The mechanism of action of MDV3100 is very different from that of abiraterone, which is an inhibitor of androgen synthesis but does not block androgen binding, Dr. Scher said.

Because they act in different ways, there might be benefits from using the drugs together, he added.

Dr. Scher reports receiving research funding from Medivation. Coauthor Dr. Sawyers is a codeveloper of MDV3100, and is entitled to royalties that could result from its commercial success.