Abstract
Enzalutamide (formerly MDV3100; Medivation and Astellas) appears poised to become the fourth drug approved by the U.S. Food and Drug Administration for castration-resistant prostate cancer after chemotherapy, based on a phase III trial reported in the New England Journal of Medicine in August.
Until recent years, men who developed castration-resistant prostate cancer after chemotherapy lacked life-prolonging treatment options. Now enzalutamide (formerly MDV3100; Medivation and Astellas) appears poised to become the fourth drug approved by the U.S. Food and Drug Administration (FDA) for the condition, based on a phase III trial reported in the New England Journal of Medicine in August.
Enzalutamide attacks multiple targets in the androgen-receptor signaling pathway. The AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) trial among 1,199 men with advanced prostate cancer was halted in November 2011 after a planned interim analysis showed median overall survival of 18.4 months in a group given the drug compared to 13.5 months in a group given a placebo. The survival benefit appeared across all subgroups of patients. The enzalutamide group also performed markedly better in all secondary endpoints, including quality of life and reduction in prostate-specific antigen level and soft-tissue response rate.
“Advanced prostate cancer is extremely difficult to treat, and it's taken a massive coordinated effort to finally bring new drugs into the pipeline, after decades when there were no options once old-style hormone treatment stopped working,” comments Alan Ashworth, PhD, chief executive of the Institute of Cancer Research (ICR), which jointly led the trial with the Royal Marsden NHS Foundation Trust, both of London. “What we're seeing now is an unprecedented period of success for prostate cancer research.”
The FDA is scheduled to decide on enzalutamide for treating castration-resistant prostate cancer in November. If approved, the drug will join the androgen production blocker abiraterone (Zytiga; Janssen Biotech), the chemotherapeutic agent cabazitaxel (Jevtana; Sanofi), and the immunotherapeutic sipuleucel-T (Provenge; Dendreon) in the arsenal for the disease. Several other agents, including radium-223 chloride, also have generated promising interim clinical trial results.
This wealth of new options raises a challenge in the clinic: “Currently, oncologists have no reliable way of selecting between treatments,” says Gerhardt Attard, MD, PhD, assistant professor at ICR and Royal Marsden.
Attard's lab is working alongside the lab of Johann de Bono, MD, PhD, head of the drug development unit at the ICR and Royal Marsden, to identify biomarkers that can help physicians select the best treatment for each patient. The ICR investigators and their international colleagues also are studying the mechanisms and clinical efficacy of combining therapies such as abiraterone and enzalutamide.
Additionally, these drugs may treat the disease earlier in its course, Attard notes. “We believe that novel hormone therapies such as enzalutamide-which were initially developed for patients previously treated with chemotherapy–will play an important role in earlier-stage prostate cancer, for the treatment of patients before the use of chemotherapy,” he says. “Moreover, enzalutamide could have a role as an adjunct to first-line hormone treatment to prolong the initial period free of disease.”
