MDV3100 VERSUS ABIRATERONE OR COMBINATION OF BOTH DRUGS?

April 15, 2010 — Encouraging results with the investigational drug MDV3100 (Medivation) in patients with metastatic castration-resistant prostate cancer were published online April 15 in The Lancet.

These results show that the drug has "substantial antitumor activity" in men who have and who have not had previous exposure to chemotherapy, say the authors, headed by Howard Scher, MD, chief of genitourinary oncology at the Memorial Sloan-Kettering Cancer Center in New York City.

"MDV3100 could have the potential to significantly change the treatment options in metastatic disease," they conclude.

The results come from a phase 1/2 trial of 140 men, 65 of whom were chemotherapy-naïve. The drug was associated with tumor regression and stable disease in soft tissue, and stable disease in bone. Preliminary data from this trial were released last year. These results with MDV3100 are similar to those seen with another investigational agent, abiraterone.

Although the 2 drugs have different mechanisms of action — MDV3100 is an androgen-receptor antagonist and abiraterone is an androgen-synthesis inhibitor — both offer new options for hormonal manipulation.

"Both of these drugs look promising," said William Dahut, MD, clinical director of the National Cancer Institute in Bethesda, Maryland, who cowrote an accompanying editorial. In an interview with Medscape Oncology, he predicted that — if and when they reach the market — these drugs will be used in men who have progressed on hormonal therapy before they consider chemotherapy, pointing out that these new drugs are oral and are better tolerated.

"Most men would rather take a pill than move onto chemotherapy," he said.

Activity So Far Similar to Docetaxel

Until recently, prostate cancer that progressed despite hormonal treatment was considered to be "hormone refractory," Dr. Dahut explained. However, this term has been changed to "hormone resistant," or castration-resistant, because there are men who respond to further hormone manipulation. But for those who are not responding, often the only remaining option has been chemotherapy with docetaxel, which has been shown to improve survival.

So far, there are no survival data for the new drugs, but results seen so far related to prostate-specific antigen (PSA) levels and time to progression compare favorably with those seen in older trials with docetaxel, Dr. Dahut said.

Both new drugs are now in phase 3 trials with a survival end point, and the hope is that they will show an increase in survival. These trials are being conducted in men who have progressed on chemotherapy — the patient population with the greatest medical need, Dr. Dahut explained. This is also the population in which an impact on survival — needed for regulatory approval — can be shown most quickly.

However, these are not the patients in whom these drugs are likely to be used in clinical practice, or in whom "they will work the best," Dr. Dahut said.

The new agents are more likely to be used as an option in men who have progressed on hormonal therapy, before chemotherapy, he said. Dr. Scher agreed, and pointed out that a trial in this chemotherapy-naïve population is already underway with abiraterone, and one with MDV3100 is planned to start soon.

This is also where the greatest benefit is seen, Dr. Dahut said. In the MDV3100 trial, the PSA decline was similar in chemotherapy-naïve and chemotherapy-treated men, but the time to progression was greater in the chemotherapy-naïve group (41 vs 21 weeks).

The editorial makes the point, however, that even this 21-week time to progression after chemotherapy is "clinically meaningful, particularly for a class of agents believed, until recently, to have no rationale whatsoever in this patient population."

Validation of Hypothesis

The results with both MDV3100 and abiraterone "seem to validate the hypothesis that androgens and the androgen receptor are vital to progression of metastatic castration-resistant prostate cancer," the editorialists write.

This echoes the researchers' comment that the "encouraging antitumor activity" they saw with MDV3100 in castration-resistant prostate cancer validates preclinical studies that have implicated androgen-receptor signaling as a driver of this disease.

Because androgen-receptor signaling appears to drive this cancer, blocking this signaling should stop its growth, the researchers theorized, and they went on to develop a drug that would do just that. MDL3100 was coinvented by Charles Sawyers, MD, chair of human oncology and pathogenesis at Memorial Sloan-Kettering (and a coauthor on this study), and Michael Jung, PhD, professor of chemistry at the University of California, Los Angeles.

New Drug Is Potent Antagonist

MDV3100 is a very potent antagonist of androgen receptors, lead author Dr. Scher told Medscape Oncology. It binds to the receptor very tightly, and is a potent inhibitor of the process by which the receptor-hormone complex is transported to the nucleus to interact with genes, he explained.

MDV3100 is more potent and is also more specific than the older antiandrogens, such as flutamide (Drogenil) and bicalutamide (Casodex), which have been and still are used in prostate cancer, usually with gonadotrophin-releasing hormone agonists/antagonists, such as leuprolide (Lupron) and goserelin (Zoladex). However, these older antiandrogen compounds also have some agonist activity and have been found to stimulate prostate cancer growth in some men, Dr. Scher explained. This has not been seen with MDV3100, he noted.

The mechanism of action of MDV3100 is also very different from that of abiraterone, which is an inhibitor of androgen synthesis, but does not block androgen binding, Dr. Scher said. Although they act in different ways, overall, the 2 drugs "have produced similar effects," he said.

Because they act in different ways, there may be benefits from using the drugs together, he added. However, currently, there is no information on how one drug influences the response to the other, and there are also not enough data to suggest which drug should be used first. "These are questions that need to be studied," he added.

Dr. Scher and several coauthors report receiving research funding from Medivation (the manufacturer of MDV3100), and 3 coauthors are company employees. Coauthor Dr. Sawyer is a coinventor of MDV3100, and is entitled to royalties that could result from its commercial success. The editorialists have disclosed no relevant financial relationships.

Lancet. Published online April 15, 2010.