The investigational oral androgen receptor signaling inhibitor MDV3100 significantly extended survival by about 5 months versus placebo in men with metastatic castration-resistant prostate cancer (CRPC) who received prior treatment with docetaxel (Taxotere).
San Francisco-The investigational oral androgen receptor signaling inhibitor MDV3100 significantly extended survival by about 5 months versus placebo in men with metastatic castration-resistant prostate cancer (CRPC) who received prior treatment with docetaxel (Taxotere), according to a recent multicenter study.
An interim analysis of the phase III AFFIRM trial demonstrated this survival advantage as well as advantages in tumor shrinkage and suppression of PSA levels. The side effect profile was comparable to that of placebo for the most part.
"MDV3100 joins a list of drugs that show a survival advantage in advanced prostate cancer. The drug has a favorable toxicity profile, and that, combined with its survival advantage, will likely position MDV3100 as the front-line agent in the post-docetaxel setting," said lead author Howard I. Scher, MD, chief of the genitourinary oncology service at Memorial Sloan-Kettering Cancer Center, New York.
MDV3100 represents the first in a new class of androgen receptor (AR) signaling inhibitors.
"This oral investigational agent was rationally designed to inhibit AR signaling, which is a key driver of prostate growth. The drug inhibits binding of testosterone to AR and also inhibits gene transcription," Dr. Scher explained.
AFFIRM randomized 1,199 patients with progressive CRPC who failed docetaxel chemotherapy in a 2:1 ratio to either oral MDV3100, 160 mg/day, or matched placebo.
Survival prolonged by nearly 5 months
MDV3100 significantly prolonged survival by an average of 4.8 months, achieving a 37% reduction in the risk of death. Median overall survival was 18.4 months in the MDV3100 arm versus 13.6 months in the placebo arm (p<.0001). The survival benefit was evident in all subgroups. Due to the impressive survival advantage in the MDV3100 arm, an Independent Data Monitoring Committee recommended that the trial be halted and all patients on the placebo arm be offered MDV3100.
A significantly higher proportion of patients treated with MDV3100 showed tumor shrinkage by RECIST (Response Evaluation Criteria in Solid Tumors) criteria: 28.9% in the MDV3100-treated group versus 3.8% in the placebo group (p<.0001). MDV3100 had a significantly greater effect on achieving a 50% or greater decline in PSA level (p<.0001). Time to progression, assessed by imaging and PSA, was about 5 months longer in patients treated with the experimental agent.
"These favorable changes [in imaging and PSA] are consistent with the survival benefit observed," Dr. Scher told symposium attendees.
The adverse event profile of MDV3100 is similar to placebo; in fact, more patients had serious adverse events in the placebo arm (38.6%) than in the MDV3100 arm (33.5%). More grade 3 or higher adverse events were also reported in the placebo arm than in the MDV3100 arm (53.1% vs. 45.3%).
Adverse events of interest included a slightly higher incidence of fatigue in the MDV3100 group, but no difference between the two treatment arms in cardiac disease, myocardial infarction, or liver function test results. Seizures were slightly increased in the MDV3100 group.
"There were five cases of seizure, and these were well studied. Two of the patients had brain metastases. In our opinion, seizures [as a side effect of this drug] are a non-issue," Dr. Scher said.
Nicholas Vogelzang, MD, medical oncologist at the Comprehensive Cancer Centers of Nevada, Henderson, and chair and medical director of the developmental therapeutics committee of U.S. Oncology Research, said of the results: "Wow!"
Dr. Scher is a consultant/adviser for Medivation, Inc.