February 1, 2012 — Results from a large phase 3 study of the investigational agent MDV3100 (Medivation) in advanced prostate cancer "exceeded our expectations," said principal investigator Howard Scher, MD, chief of the genitourinary oncology service at the Memorial Sloan-Kettering Cancer Center in New York City.
The phase 3 study, known as AFFIRM (NCT00974311), was conducted in men with metastatic castration-resistant prostate cancer (CRPC) who had progressed after treatment with docetaxel-based chemotherapy. The trial was stopped in November 2011 after a planned interim analysis showed a 37% reduction in the risk for death with MDV3100 over placebo (median, 18.4 vs 13.6 months; hazard ratio [HR], 0.631; P < .0001).
More results from this trial were released ahead of their presentation at the 2012 Genitourinary Cancers Symposium in San Francisco, California, at a presscast organized by the American Society of Clinical Oncology, one of the sponsors of the meeting.
"Wow! Very impressive!" said Nicholas Vogelzang, MD, from US Oncology Research, who moderated the presscast. "The 18.4-month median survival is unprecedented," he said.
The results from AFFIRM are part of the approval application that the manufacturer, Medivation, has already files with the US Food and Drug Administration (FDA). The FDA has granted fast-track designation for this postchemotherapy indication.
This is a therapeutic niche that has been filled with new agents over the past year or so. In addition to MDV3100 for use in postdocetaxel CRPC, the radiopharmaceutical radium-233 chloride (Alpharadin, Medivation) — also highlighted during the presscast — will soon be submitted for FDA approval for use in CRPC patients with bone metastases. In addition, 3 other products have recently been approved for use in this patient population — abiraterone (Zytiga, Cougar Biotechnology), carbazitaxel (Jevtana, sanofi-aventis), and the vaccine sipuleucel-T (Provenge, Dendreon).
During the presscast, prostate cancer expert Oliver Sartor, MD, medical director of the Tulane Cancer Center in New Orleans, Louisiana, noted that although each of these products has shown significant improvement in overall survival in CRPC, research on combinations or sequential use of these agents "may add even more value" and lead to even more important steps forward.
Currently, there are no clear guidelines about which agent should be used when, but there is plenty of discussion.
Dr. Scher reported that the benefit/risk profile of MDV3100 will likely position MDV3100 as the front-line agent for postdocetaxel CRPC.
Blocks Receptor-Signaling Pathway
MDV3100 acts as a very potent antagonist of androgen receptors, and binds to the receptor very tightly, Dr. Scher previously told Medscape Medical News. It is more potent and more specific than older antiandrogens, some of which had agonist and antagonist activity, he explained; this has led to MDV3100 being called a "super antiandrogen."
It is also unique in that it inhibits androgen-receptor signaling, which is a key driver of prostate cancer growth, Dr. Scher explained at the presscast. It has several sites of action: it inhibits the binding of androgens to the androgen receptor, it inhibits nuclear translocation of the androgen receptor, and it inhibits the association of the androgen receptor and DNA inside the cell nucleus.
It was specifically designed to block the androgen receptor and the androgen-receptor signaling that is considered to be a driver of this disease by 2 researchers working in academia: Charles Sawyers, MD, chair of human oncology and pathogenesis at the Memorial Sloan-Kettering Cancer; and Michael Jung, PhD, professor of chemistry at the University of California, Los Angeles.
"The basic research that led to the development of the drug and the collaborative efforts to bring that discovery into a clinical setting should serve as a model for future drug development by academia," Dr. Sawyers said in a statement.
Details of Results
The AFFIRM study was conducted in 1199 men with progressive CRPC who had failed on docetaxel; they were randomized in a 2:1 ratio to receive oral MDL3100 160 mg once daily or placebo.
The survival benefit that led to the early termination of the trial was supported by favorable changes in several secondary end points, Dr. Scher reported.
A significantly higher proportion of patients on MDV3100 showed tumor shrinkage on computed tomography or magnetic resonance imaging and had a decline of 50% or more in prostate-specific antigen (PSA), he said.
Time to disease progression, assessed by either imaging or PSA decline, was 5 months longer, on average, in the MDV3100 than in the placebo group, he noted.
Median radiographic progression-free survival was 8.3 months with MDV3100 and 2.9 months with placebo (HR, 0.404; P < .0001). Median time to confirmed PSA progression was 8.3 months with MDV3100 and 3.0 with placebo (HR, 0.248; P < .0001).
MDV3100 is "extremely well tolerated," Dr. Scher reported. The data on adverse events he presented showed slightly fewer events, numerically, in patients in the MV3100 group than in the placebo group, but individual adverse events were not specified. In answer to a question from a journalist, Dr. Scher noted that seizures were reported in 5 patients in the MV3100 group and 0 in the placebo group, but he also explained that this was not a concern because these were patients who were very sick and were taking other medications. Overall, the frequency of the adverse events reported with MV3100 was less than with placebo, he emphasized.
Other studies are ongoing. A second phase 3 trial is being conducted in patients with metastatic CRPC who are chemotherapy naive (NCT01212991).
2012 Genitourinary Cancers Symposium (GUCS): Abstract LBA1. To be presented February 2, 2012.
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Cite this: MDV3100 in Prostate Cancer 'Exceeded Expectations' - Medscape - Feb 01, 2012.