A randomized phase III international trial presented at the fourth annual Genitourinary Cancers Symposium, being held February 2-4, 2012, at the San Francisco Marriott Marquis in San Francisco, CA, USA, shows for the first time that an investigational oral drug that halts androgen signaling significantly improves overall survival in patients with metastatic castration-resistant prostate cancer (CRPC).

The drug, MDV3100, an experimental androgen receptor antagonist drug developed by Medivation, could become another key component in the oncologists? arsenal against this difficult-to-treat form of prostate cancer. ?MDV3100 works differently than other agents for metastatic castration-resistant prostate cancer,? said lead author Howard I. Scher, MD, Chief of the Genitourinary Oncology Service and D. Wayne Calloway Chair in Urologic Oncology at Memorial Sloan-Kettering Cancer Center in New York. ?This drug targets a unique aspect of the malignant process, blocking a biological mechanism that enables tumors to resist other therapies and grow ? and it worked far better than we expected when we set out.?

Prostate cancer is considered castration-resistant when tumor growth continues despite hormonal therapies that lower testosterone levels. Testosterone works through the androgen receptor to promote cell growth.

According to Scher, MDV3100, developed by Charles Sawyers and Michael Jung, was designed to interfere directly with androgen receptor signaling by preventing androgens ? or male sex hormones like testosterone ? from binding to androgen receptors in the tumor, a key step in promoting prostate cancer growth. The drug also limits the ability of the androgen receptor to get to the nucleus and bind to DNA, subsequent steps in androgen receptor function. The action of the drug blocks cell growth and results in prostate cancer cell death.

In the study, called AFFIRM (NCT00974311), 1,199 men with metastatic CRPC were randomized to receive either MDV3100 or placebo. All patients had cancers that continued to progress despite previous hormonal therapy and docetaxel chemotherapy. After a planned interim analysis, researchers found that median overall survival was 18.4 months for patients treated with MDV3100 and 13.6 months for those receiving placebo. Treatment with MDV3100 prolonged life by 4.8 months and reduced the risk of death by 37 percent compared to placebo. As a result, the trial was halted early, and patients in the placebo arm were offered the drug.

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Progression-free survival
The researchers also found the median radiographic progression-free survival was 8.3 months for those given MDV3100 versus 2.9 months for placebo. This means that MDV3100 significantly slowed the progression of bone metastases, the primary site of prostate cancer spread and a major cause of morbidity, and other metastases. Additionally, almost 30% of patients had complete or partial responses to MDV3100 treatment on imaging as compared to 1.3% in the placebo group.

Reduction in prostate-specific antigen
MDV3100 treatment also resulted in a substantial impact on level of prostate-specific antigen, or PSA. PSA reductions of 50% or greater from baseline were observed in 54.0 % of MDV3100 patients versus 1.5% of placebo patients and 90% or greater from baseline in 25% of patients vs. 1% of placebo patients. Finally, MDV3100 increased the time to PSA progression by 5.3 months, from ? 3.0 months in the placebo group to 8.3 months in the MDV3100 treated group.

Adverse events
Importantly, MDV3100 was well-tolerated in the AFFIRM study. The most common adverse events occurring more frequently in the MDV3100 group (?2%) than in the placebo group included fatigue, diarrhea and hot flushes. These were generally mild and did not result in dose-reduction. ?The next challenge is finding the best way to maximize how we use MDV3100, which may be in sequence or in combination with other treatments. But for now, we think this once-daily oral drug could be a valuable new option for certain patients with cancer that progresses, despite standard hormone therapy and chemotherapy ? a type of prostate cancer that has historically been extremely unresponsive to therapy,? Scher noted.

Treatment benefits
MDV3100 is also being evaluated in patients with CRPC who have not yet been treated with chemotherapy or hormonal therapy, the standard initial treatment to lower testosterone. The latter approach has the potential provide similar treatment benefits as traditional hormonal therapy but would not lower androgen levels. ?This would potentially be a more favorable option for patients? quality of life, enabling men to avoid hot flashes and other side effects typically experienced during hormonal therapy,? Scher said.

For more information:
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, De Wit R, Mulders P, Hirmand M, Selby B, De Bono JS. Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: Results from the phase III AFFIRM study. Abstract #LBA1

What: General Session II
Lead Author: Howard Scher, MD Memorial Sloan-Kettering Cancer Center, New York, NY)
When: Thursday, February 2, 2012 10:15-11:45 AM PT

Clinical trial:
Safety and Efficacy Study of MDV3100 in Patients With Castration-Resistant Prostate Cancer Who Have Been Previously Treated With Docetaxel-based Chemotherapy (AFFIRM)

Photo credit: 2012 Genitourinary Cancers Symposium – Howard I. Scher, MD discusses Abstract LBA#1 Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI) on overall survival in patients with prostate cancer post docetaxel: Results from the phase III AFFIRM study at the 2012 Genitourinary Cancers Symposium (GU) meeting at the Marriott Marquis on Thursday February 2, 2012. A record 2500 attendees from around the world were on hand to learn the latest treatment and research in Genitourinary cancers from fellow physicians, researchers, health care professionals, cancer survivors and patient advocates. Photo by ? ASCO/Todd Buchanan

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