SAN FRANCISCO – MDV3100, new oral inhibitor of androgen receptor signaling, reduces the risk of death by more than a third after a failure of docetaxel chemotherapy in men with progressive castration-resistant prostate cancer, according to results of the randomized AFFIRM trial.
Interim data for the trial, which was conducted in nearly 1,200 men, showed that those given the investigational drug lived 4.8 months longer than their counterparts who had been given a placebo, corresponding to a 37% reduced risk of death, lead investigator Dr. Howard I. Scher reported at the Genitourinary Cancers Symposium. This positive finding triggered early trial closure.
Dr. Howard I. Scher
Additional analyses revealed that men treated with the drug were significantly more likely to have a soft tissue response and to have at least a halving of their prostate-specific antigen (PSA) level. At the same time, there was no increase in the rate of higher-grade adverse events; seizures (a potential concern from earlier research) occurred at low frequency.
"MDV3100 now joins the list of drugs demonstrating a survival benefit in a phase III trial post docetaxel," adding to abiraterone (Zytiga) and cabazitaxel (Jevtana), Dr. Scher maintained. "The risk-benefit ratio will likely position this as the frontline agent post docetaxel therapy."
"I’m not the [Food and Drug Administration], but I would say that when you see this kind of survival benefit and safety profile – and looking at a prior drug [investigation] that I had a privilege of leading – I would say that this should be approved relatively quickly," he commented in a press briefing.
"I have only one comment: wow! That’s very impressive," said Dr. Nicholas J. Vogelzang, the moderator of the briefing and the chair and medical director of the Developmental Therapeutics Committee of US Oncology. The median survival and dramatic rates of PSA reduction seen with MDV3100 are "unprecedented. This is going to definitely change the way we take care of patients every day in the office."
"This is a landmark study," Dr. Adam S. Kibel agreed in an interview at the meeting. "I think this is a drug that will be widely used, assuming it gets FDA approved."
Dr. Adam Kibel
Initially, MDV3100 is likely to be used in the postdocetaxel space, said, Dr. Kibel, chief of urology at Brigham and Women’s Hospital and the Dana Farber Cancer Institute and a professor at Harvard Medical School, all in Boston. "I imagine that it would probably be the first-line drug because it appears to have a little less side effect profile than abiraterone and certainly lower than cabazitaxel."
"The one tripper in there is, will insurance pay for it and how much is it going to cost?" said Dr. Kibel.
MDV3100 is also being tested in patients who have not yet received docetaxel. "I will be shocked if [those data] are not positive," he commented. And should it perform well there, "it will move prior to docetaxel, because it appears to be very well tolerated from the data presented."
The AFFIRM trial enrolled 1,199 men with castration-resistant prostate cancer who had experienced progression after receiving docetaxel – a population for whom there was no standard of care at the time the trial began, Dr. Scher noted. They were assigned in 2:1 ratio to once-daily treatment with MDV3100 (manufactured by Medivation) or placebo.
The first-in-class drug has a three-pronged mechanism of action, as well as some advantages over other antiandrogen agents, according to Dr. Scher, chief of the genitourinary oncology service and D. Wayne Calloway Chair in Urologic Oncology at the Memorial Sloan-Kettering Cancer Center in New York.
It "binds more tightly [to the androgen receptor] than the currently available agents, but is also unique in that it inhibits nuclear translocation [of the receptor] as well as the association of the receptor with DNA, inducing cell death," he explained.
The patients studied had a median age of 69 years. Most (90%) had bone metastases, and the large majority (70%) also had soft tissue metastases.
Main results showed that men given MDV3100 lived 18.4 months, whereas their counterparts given the placebo lived 13.6 months (hazard ratio, 0.63; P less than .0001). Stratified analyses showed similar benefit across most patient subgroups.
Men treated with the drug also had longer median radiographic progression free survival (8.3 vs. 2.9 months; HR, 0.40) and were more likely to have a soft tissue response on imaging (29% vs. 4%) and at least a halving of their PSA level (54% vs. 2%) (all P less than .0001).
There was no increase with MDV3100 in the rate of grade 3 or higher adverse events (45% vs. 53%) or the overall rate of treatment discontinuation due to adverse events (8% vs. 10%).