The US Food and Drug Administration announced today that the drug enzalutamide, formerly known as MDV 3100, has been approved for the treatment of men with metastatic prostate cancer (prostate cancer that has spread beyond the primary tumor to other parts of the body).
Recently, the results of a large, multicenter phase III study showed that enzalutamide significantly increased survival in men with advanced disease. Investigators led by Howard I. Scher, Chief of Memorial Sloan Kettering’s Genitourinary Oncology Service, first presented their findings at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium in February 2012. The findings were reported online on August 15, 2012 in the New England Journal of Medicine.
Laboratory work conducted by Memorial Sloan Kettering’s Charles L. Sawyers, Chair of the Human Oncology and Pathogenesis Program, and colleagues was instrumental in the development of this novel therapy.
“Prostate cancers that progress after standard hormone therapy and chemotherapy are notoriously difficult to treat,” Dr. Scher says. “We now have a new FDA-approved treatment that can prolong the lives of men with this disease.”
The Path to Approval
The trial that led to FDA approval, called AFFIRM, was an international phase III randomized, double-blind, placebo-controlled study of enzalutamide in men with prostate cancer who had been previously treated with one to two different types of chemotherapy, one of which contained docetaxel (Taxotere®).
Nearly 1,200 men were randomized to receive either enzalutamide or a placebo. On average, treatment with enzalutamide prolonged the lives of the men by nearly five months and reduced their risk of death by 37 percent when compared to the placebo group. As a result, the study was halted in November 2011 so patients in the placebo arm of the trial could be offered the drug.
“The results of the trial exceeded our expectations,” Dr. Scher comments. “It is extremely gratifying to see how the close integration of clinical studies and fundamental laboratory discoveries have come together to bring this new and effective therapy to patients.”
Enzalutamide: Blocking the Action
The male hormone testosterone and other androgens fuel the growth of prostate tumors, and some of the standard treatments for metastatic disease are drugs that stop the production or block the action of androgens – the equivalent of castration. Initially, most men respond to this treatment. But eventually the cancer progresses despite continued treatment, and they develop a more aggressive form of the disease called castration-resistant prostate cancer.
Earlier work by Dr. Sawyers and his enzalutamide co-inventor, chemist Michael Jung of the University of California, Los Angeles, determined that the reason for drug resistance was an increase in the tumor’s production of androgen receptors.
Enzalutamide is an oral androgen receptor-signaling inhibitor that targets multiple steps in the androgen receptor-signaling pathway, binding tightly to the androgen receptor and at the same time inhibiting it.
“The results of the AFFIRM trial – and now the FDA approval – represent a significant milestone for me personally and professionally,” Dr. Sawyers says. “The basic research that led to the development of the drug, and the collaborative efforts to bring that discovery into a clinical setting, should serve as a model for future drug development by investigators at academic institutions. The pride in knowing that one’s work will have an impact on patients’ lives is impossible to describe.”