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FDA decision on enzalutamide (MDV3100, Medivation) likely 22 Nov 2012

Bruce Kynaston

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As we reported back in May (http://forums.jimjim...rostate-cancer/) MDV3100 (Enzalutamide) can extend life after Docetaxel (Taxotere) chemotherapy failure.

The next step is approval by the USA Federal Drugs Administration (FDA).

The article below tells us that a decision is to be made on 22 November 2012.

From Medscape Medical News > Oncology

Enzalutamide: Next New Drug for Prostate Cancer?

Zosia Chustecka

August 15, 2012 —The investigational drug enzalutamide (formerly known as MDV3100, Medivation) looks set to be the next new treatment for prostate cancer.

A pivotal phase 3 trial, known as AFFIRM (A Study Evaluating the Efficacy of the Investigational Drug MDV3100), showed a survival advantage and therefore was stopped early. Results were published onlineAugust 15 in the New England Journal of Medicine.

The manufacturer announced recently that its approval application was accepted by the US Food and Drug Administration; the agency granted it a Priority Review designation, and a decision is expected by November 22. The drug is also under review in Europe.

The approval covers the use of enzalutamide in the treatment of castration-resistant prostate cancer (CRPC) in men previously treated with docetaxel-based chemotherapy.

This is the indication explored in AFFIRM. The study of 1199 patients showed that enzalutamide significantly prolonged median overall survival, compared with placebo (18.4 vs 13.6 months; hazard ratio, 0.63; P < .0001).

This difference became apparent after a planned interim analysis, and led to the trial being halted early (in November 2011) so that the men taking placebo could cross over to the active drug.

The AFFIRM results were presented earlier this year at the Genitourinary Cancers Symposium, as reported byMedscape Medical News, when Nicholas Vogelzang, MD, from US Oncology Research, said: "Wow! Very Impressive!" The 18.4-month median survival seen with enzalutamide is "unprecedented," he noted during a meeting presscast that he moderated.

AFFIRM coauthor Howard Scher, MD, chief of the genitourinary oncology service at Memorial Sloan-Kettering Cancer Center, New York City, said that "the results of the trial have exceeded our expectations."

The product was coinvented by Charles Sawyers, MD, also from Sloan-Kettering, and Michael Jung, PhD, professor of chemistry at the University of California, Los Angeles. They had observed that men with CRPC often build up resistance to hormone therapy because the tumor increases its production of androgen receptors. Therefore, they designed the drug to specifically target and bind to androgen receptors in tumor cells.

Enzalutamide acts as a very potent antagonist of androgen receptors, and binds to the receptors very tightly, Dr. Scher previously told Medscape Medical News. This makes it both more potent and more specific than older antiandrogens, some of which have both agonist and antagonist activity, he explained. It also led to the "super antiandrogen" nickname.

"This is an important new drug," said Marc Garnick, MD, clinical professor of medicine at Harvard Medical School, with an oncology practice at Beth Israel Deaconess Medical Center in Boston, Massachusetts. "It will add greatly to the treatments that can be offered to our patients with advanced prostate cancer," he toldMedscape Medical News.

Notoriously Difficult-to-Treat Population

"Prostate cancers that progress after standard hormones and chemotherapy are notoriously difficult to treat," Dr. Scher said in a statement.

"It is extremely gratifying to see how the close integration of clinical observations and fundamental laboratory discoveries have come together to provide a new and effective potential treatment that can prolong the lives of men with this disease," he added.

"These results validate androgen-receptor signaling as a key therapeutic target throughout the clinical spectrum of prostate cancer, including in men who have received previous chemotherapy," the study authors write. Clinical trials of the drug in earlier-stage disease are ongoing, they note.

It is anticipated that this novel agent will "join the therapeutic armamentarium of anticancer drugs with diverse mechanisms of action that confer a survival benefit in men with CRPC," the authors add.

Therein lies the big question: Where will this new drug fit among the already-available therapies?

Where Will it Fit?

The prostate cancer market has exploded in the past couple of years. Three new drugs for use in the CRPC patient population have recently been launched: cabazitaxel (Jevtana, sanofi-aventis), a new chemotherapy; sipuleucel-T (Provenge, Dendreon), an immunotherapeutic vaccine; and abiraterone (Zytiga, Johnson & Johnson), an androgen-synthesis inhibitor.

All of these products have been shown to improve survival in CRPC, but there are no clear guidelines — yet — on which product should be used when.

There is, however, plenty of discussion on this topic. Pharmaceutical business analysts have tipped abiraterone and enzalutamide as having blockbuster potential (with sales of more than $1 billion) and expect these 2 drugs to compete closely with one another. Both target androgen, but by different mechanisms. Another difference is that abiraterone needs to be used in combination with prednisolone, whereas enzalutamide does not.

There is also interest in seeing how enzalutamide and abiraterone, with their different approaches to androgen inhibition, will fare when they are used in combination with one another.

Dr. Garnick, who was not involved in the enzalutamide trial, told Medscape Medical News that "the sequencing of drug choices in the CRPC patient population is now challenging."

"But it's a nice challenge to have, since options now exist that did not in the past," he added.

"The exciting aspect of having another agent that effects meaningful anticancer responses, with a defined mechanism of action and acceptable safety features, will greatly enhance the design of future studies that will hopefully provide even greater improvements," Dr. Garnick noted.

N Engl J Med. Published online August 15, 2012.

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