Neal D. Shore, MD
Since the phase III AFFIRM trial of enzalutamide (formerly MDV3100) was halted early in November 2011 after meeting its endpoint of improved overall survival, physicians have remained hopeful about its potential as a treatment for prostate cancer.
Among them is Neal D. Shore, MD, of Atlantic Urology Clinics in Myrtle Beach, South Carolina, and its independent clinical research arm, the Carolina Urologic Research Center. As medical director of the research center, Shore has participated in more than 200 clinical trials, including studies of sipuleucel-T (Provenge) and abiraterone (Zytiga).
His center was a high-enrolling site in the AFFIRM trial, which tested the androgen receptor signaling inhibitor enzalutamide in patients with metastatic castrate-resistant prostate cancer (mCRPC) who had failed docetaxel. Now, Shore is serving as global primary investigator for the phase II TERRAIN trial investigating the drug in the prechemotherapy setting in patients with mCRPC.
Medivation, Inc, which is developing enzalutamide in partnership with Astellas Pharma, Inc, said a new drug application and request for priority review were submitted to the FDA in May.
Shore presented the results of the AFFIRM study on May 22 during the American Urological Association Annual Meeting in Atlanta, Georgia. In an interview with OncologyLive
, Shore said the drug is noteworthy because it is orally administered once a day, drove a significant improvement in overall survival in trial participants, has an excellent safety profile, and works through three distinct mechanisms of action.
“Its overall favorability profile,” he said, “makes it rather unique.”OncologyLive: What are enzalutamide’s mechanisms of action?
First, it impacts at the level of the androgen receptor by inhibiting binding of androgens to the androgen receptor on the prostate cancer cell. Second, it inhibits nuclear translocation of the androgen receptor from the cellular membrane as it then is transported through the cell cytoplasm to the nucleus. And third, it inhibits the association of the androgen receptor with DNA within the nucleus.
To understand the drug’s multiple mechanisms of action is to fully appreciate that it should be complementary to all currently approved therapies, and potentially could be given in combination. But we have to do combinatorial studies to prove that efficacy and safety.What were the parameters of the AFFIRM trial?
The trial was specifically designed for patients with mCRPC who had received at least one course of docetaxel and progressed. There were 1199 patients in this multinational trial that took place at 156 sites in 15 countries. Patients were randomized in a double-blind, prospective fashion; two out of three got enzalutamide 160 mg once a day, and the rest got placebo. The primary endpoint was overall survival.1
What were the trial’s main findings?
This study boasts the largest overall survival benefit ever recorded in a postchemotherapy setting for mCRPC. ”
–Neal D. Shore, MD
This study boasts the largest overall survival benefit ever recorded in a postchemotherapy setting for mCRPC.
At the end of the day, it showed that there was a 4.8-month improvement in overall survival at the median. There was a hazard ratio of 0.631, which translates to a 37% reduction in risk of death for patients taking enzalutamide compared with those getting placebo. The P
value was highly statistically significant, less than 0.0001, compared with getting the placebo.
Once patients progressed, they were allowed to go on to additional approved treatments such as cabazitaxel [Jevtana], abiraterone, or docetaxel, and what’s interesting is that the patients on the enzalutamide arm stayed on their drug therapy more than five months longer. The median was 8.3 months on enzalutamide versus three months on placebo.
Also really interesting was the fact that, in the enzalutamide arm, 54% of patients had greater than a 50% decrease in their baseline PSA [prostate-specific antigen], and approximately 25% had a greater than 90% decrease in their PSA from baseline.What were the findings regarding the drug’s side-effect profile?