Emma Hitt, PhD

May 25, 2012

May 25, 2012 (Atlanta) — A first-in-class drug, the androgen-receptor signaling inhibitor enzalutamide (MDV3100), has shown a survival benefit in men with postdocetaxel prostate cancer. The risk for death decreased by 37% relative to placebo, extending survival by more than 4 months, according to findings from the phase 3 AFFIRM study.

Neal Shore, MD, from the Carolina Urologic Research Center, in Myrtle Beach, South Carolina, and colleagues presented the findings in an oral podium poster session here at the American Urological Association 2012 Annual Scientific Meeting.

According to the researchers, enzalutamide, an oral hormonal agent, competitively inhibits the binding of androgens to the androgen receptor. It also inhibits androgen receptor nuclear translocation and the association of the receptor with DNA. Enzalutamide displayed activity during phase 1 and 2 trials in pre- and postchemotherapy patients with progressive castration-resistant prostate cancer.

In this double-blind placebo-controlled multinational study, researchers randomized patients with castration-resistant prostate cancer who had received at least 1 regimen of docetaxel-based chemotherapy to enzalutamide 160 mg/day or placebo (2:1 ratio). Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status and Brief Pain Inventory scores.

The study involved 1199 patients from 15 countries, recruited from September 2009 to November 2010. About three quarters of the patients had received at least 1 docetaxel-containing chemotherapy regimen, and 37.8% had more than 20 bone lesions.

The primary end point was overall survival; secondary end points included radiographic progression-free survival, time to first skeletal-related event, and time to prostate-specific antigen progression.

Overall Survival Benefit

The study was unblinded on the recommendation of the Independent Data Monitoring Committee after a planned interim analysis at 520 death events showed a significant 4.8-month overall survival benefit for enzalutamide, compared with placebo (18.4 vs 13.6 months; hazard ratio, 0.631; < .0001), indicating a 37% reduction in the risk for death.

A survival benefit was observed across all subgroups, Dr. Shore pointed out. Patients in the enzalutamide group received therapy for longer than those in the placebo group, and more patients in the enzalutamide group remained on study (28.9% vs 4.8%).

Good Tolerability, Although Seizures a Question

Overall, enzalutamide was well tolerated. According to Dr. Shore, there were no differences between the enzalutamide and placebo groups with respect to lab abnormalities or cardiovascular events. In terms of serious adverse events, the only difference was that in the enzalutamide group, 5 of more than 800 patients had seizures (incidence rate, 0.6%).

"This is the first once-a-day agent that doesn't require concomitant steroids, and you can take it with or without meals," Dr. Shore told Medscape Medical News.

This is a game-changing agent.

Trials in earlier-stage disease with this agent are ongoing. One large multicenter trial will evaluate this agent in patients who have not received docetaxel. There are also plans to evaluate it in M0 castrate-resistant prostate cancer and in the androgen-sensitive disease state, Dr. Shore said.

"This is a game-changing agent because of its tolerability and, more important, its efficacy and ease of administration," he said. "I think this is an exceptionally optimistic and exciting time for both clinicians and patients."

Benefits Apparent Early On

Celestia Higano, MD, from the University of Washington in Seattle, said her institution participated in the phase 1/2 trial of enzalutamide. "We gave the first dose ever given to a human," she told Medscape Medical News. "It was apparent very early on in the phase 1 trial that this is a very active oral compound in castration-resistant prostate cancer when given either before or after chemotherapy, and that it is very well tolerated," she said.

"Abiraterone and cabazitaxel have already been approved by regulatory authorities, based on the survival benefit seen in men who have already been treated with docetaxel," she said, adding that "the anticipated approval of enzalutamide will add to the options."

Yet another option, radium-223 (Alpharadin), is likely to be approved for use in this setting, according to Dr. Higano. Data from a study led by Oliver A. Sartor, MD, from the Departments of Medicine and Urology at Tulane University School of Medicine in New Orleans, Louisiana, show an overall survival benefit, as previously reported by Medscape Medical News.

Dr. Higano noted that, to date, there are no comparative trial results that confirm how these drugs should be sequenced or combined. "Clinicians need to consider the numerous options in the context of the individual patient until further information is available," she said.

New Drug Application Filed

According to Medivation and Astellas, the US Food and Drug Administration (FDA) has received a New Drug Application for enzalutamide. "I anticipate that the FDA will review the data favorably, given the combination of efficacy and safety from the AFFIRM clinical trial," Dr. Sartor told Medscape Medical News. "Several patients had seizures in the enzalutamide arm; this will likely be a discussion item," he said.

"This agent compares favorably to abiraterone," he added. However, "we still need to know how this agent will work in abiraterone failures, and how abiraterone will work in enzalutamide failures."

The study was funded by Medivation and Astellas. Dr. Shore reports financial relationships with Medication, Astellas, Dendreon, Ferring, Watson, Amgen, sanofi, and Janssen. Dr. Higano reports receiving clinical research support from multiple commercial interests, including Medivation. Dr. Sartor reports receiving financial support from multiple commercial interests, including consulting fees from Medivation.

American Urological Association (AUA) 2012 Annual Scientific Meeting: Abstract LBA1. Presented May 22, 2012.

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