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May 09, 2013
 |  BC Innovations  |  Cover Story

Rational approach to Xtandi resistance

A group led by researchers at the Memorial Sloan-Kettering Cancer Center has identified a mutation in the androgen receptor that could drive resistance to second-generation antiandrogen drugs such as

Medivation Inc.'s Xtandi enzalutamide. The team's subsequent rational drug design studies yielded a series of molecules that could overcome the resistance mechanism.1

The researchers now are testing their lead molecule in mouse xenograft models for prostate cancer. If the results are promising, MSKCC could consider running a clinical trial.

Antiandrogen drugs are one of the standard treatment options for prostate cancer, but many patients progress to castration-resistant disease in 12-18 months.2

Acquired mutations in the androgen receptor (AR) are one of the key events that can cause resistance to antiandrogen drugs.3-5

Xtandi is a second-generation oral androgen receptor antagonist that received FDA approval in August 2012 to treat metastatic castration-resistant prostate cancer (CRPC) in patients who previously received docetaxel. Last month, the EMA's Committee for Medicinal Products for Human Use recommended approval of an MAA for Xtandi.

In the U.S., clinicians already are seeing patients whose tumors initially respond to Xtandi but then develop resistance.

"We wanted to know how this could happen," said Charles Sawyers, chair of the Human Oncology and Pathogenesis Program at MSKCC and an investigator at the Howard Hughes Medical Institute. "We suspected that mutations in the androgen receptor might be one mechanism and designed...

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