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MDV3100 extended OS, PFS in men with castration-resistant prostate cancer

Issue: March 10, 2012

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The investigational androgen receptor signaling inhibitor MDV3100 extended OS and PFS compared with placebo for men with castration-resistant prostate cancer, according to phase 3 results from the international AFFIRM trial.

Researchers stopped the study early after a planned interim analysis at 520 death events showed that oral MDV3100 (Medivation) extended OS by 4.8 months and reduced the risk for death by 37% compared with placebo. At that point, the study was unblended, and patients in the placebo arm were offered the drug.

“Seeing this kind of survival advantage and this kind of safety profile in a population of men for whom there was no standard of care when the trial started is just overwhelming,” Howard I. Scher, MD, chief of the genitourinary oncology service at Memorial Sloan-Kettering Cancer Center, said in an interview with HemOnc Today. “This is changing the paradigm of how we think about this disease.”

Scher discussed the results during a press briefing in advance of the 2012 Genitourinary Cancers Symposium.

MDV3100 is the first in a class of agents that targets androgen receptor signaling, a mechanism that is unique from the currently available drugs. It also binds the receptor more tightly, inhibits the localization of the receptor to the nucleus and inhibits the binding to DNA.

“We’re inhibiting the downstream effects after binding,” Scher said. “These two mechanisms are unique from any drug currently approved.”

In this randomized, double blind, placebo-controlled, multinational trial, 1,199 men were assigned to 160 mg daily MDV3100 (n=800) or placebo (n=399).

MDV3100 was associated with a median OS of 18.4 months compared with 13.6 months for patients assigned to placebo (HR=0.631). Median PFS also favored MDV3100, 8.3 months vs. 2.9 months. Almost 30% of patients assigned to MDV3100 had complete or partial response compared with 1.3% in the placebo group, Scher said.

The drug also was associated with a PSA reduction of at least 50% from baseline in 54% of MDV3100 patients compared with 1.5% of placebo patients, and at least a 90% reduction from baseline in 25% of MDV3100 patients vs. 1% of placebo patients. Median time to PSA progression was 8.3 months in the experimental group compared with 3 months in the placebo group.

MDV3100 was well tolerated, Scher said. The most common adverse events that occurred more frequent in the MDV3100 group (≥2%) than in the placebo group included fatigue, diarrhea and hot flushes.

“If you look at the total adverse events, there was a slightly higher percentage of [acute diarrhea] in the placebo arm,” Scher said. “If you look at specific adverse events, there was slightly higher incidence of mild fatigue, mild diarrhea and mild hot flushes in the MDV3100 patients but otherwise no significant differences.”

Daniel A. Barocas, MD, MPH, a urologic oncologist at Vanderbilt-Ingram Cancer Center, called MDV3100 “exciting and important” but said referring to the drug as paradigm-shifting is an overstatement.

“There is a gain in median OS, but it’s only a 5-month gain. Many of the new medicines we’ve seen have created 4- or 5-month gains, and if we can find the right combination of medications, we’re going to find substantial gains. This is not a disease where one drug or one trial is going to change the whole thing.

“We’re making incremental gains and good ones,” Barocas added. “This is a novel approach to hormonal therapy. In the sense that it opens up a new way of blocking the androgen receptor, this is a big shift.” – by Jason Harris

For more information:

• Scher HI. Abstract #LBA1. Presented at: the 2012 Genitourinary Cancers Symposium; Feb. 2-4, 2012; San Francisco.

Disclosure: Dr. Barocas has served on advisory boards for Bayer, Dendreon and Jannsen Pharmaceuticals. Dr. Scher has served as a consultant for and received research funding from Medivation.

That is very impressive. An 18.4-month median survival with 25% of patients having a 90% decline in PSA is unprecedented. The OS in the post-docetaxel space exceeds the ABI-008 and the RaDIUM 223 survival data. MDV3100 has minimal toxicity, a high response rate and it’s an oral agent. What’s not to like? This is definitely going to change the way we take care of patients every day.

– Nicholas J. Vogelzang, MD

HemOnc Today Editorial Board member

Disclosure: Dr. Vogelzang has received research funding from Algeta.