Enzalutamide – formerly known as MDV3100 – prolonged overall survival by a median of 4.8 months and reduced the risk of death by 37%, according to newly published data from the phase III, placebo-controlled AFFIRM study of men with metastatic, castration-resistant prostate cancer.

An experimental oral agent inhibiting signaling by the androgen receptor, enzalutamide is under priority review by the Food and Drug Administration with an action date of Nov. 22, 2012, trial sponsors Medivation and Astellas Pharma have announced.

The randomized, double-blind AFFIRM trial underpins their New Drug Application in men with castration-resistant prostate cancer previously treated with docetaxel (Taxotere)-based chemotherapy. Based on the findings, an independent data and safety monitoring committee halted the trial, and those receiving placebo were offered treatment with enzalutamide.

At the time of a planned interim analysis, median overall survival was 18.4 months among 800 men randomized to receive a daily 160-mg oral dose of enzalutamide. It was 13.6 months in 399 men who received a placebo, Dr. Howard I. Scher of Memorial Sloan-Kettering Cancer Center, New York, and his colleagues reported "online first" Aug. 15 in the New England Journal of Medicine.

The drug was also superior to placebo with respect to all secondary end points, including prostate-specific antigen (PSA) response rate (54% vs. 2%), soft-tissue response rate (29% vs. 4%), FACT-P quality of life response (43% vs. 18%), time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25), radiographic progression-free survival (8.3 vs. 2.9 months; HR, 0.40), and time to first skeletal-related event (16.7 vs. 13.3 months; HR, 0.69). The results were consistent across all subgroups, and were maintained after adjustment for stratification factors and baseline prognostic factors.

They confirm that the androgen receptor and androgen-receptor signaling have a central role in the progression of prostate cancer "throughout the spectrum of disease," the investigators said (N. Engl. J. Med. 2012 [doi: 10.1056/NEJMoa1207506]).

Participants in AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) were men with progressive prostate cancer that had been treated with one or two chemotherapy regimens, at least one of which included docetaxel. The subjects, who were enrolled at 156 sites in 15 countries between September 2009 and November 2010, had a histologically or cytologically confirmed diagnosis of prostate cancer and testosterone levels of less than 50 ng/dL.

Despite longer observation with enzalutamide, adverse event rates were generally similar between the treatment and control groups; of note, those in the enzalutamide group experienced a lower incidence of adverse events of grade 3 or above (45.3% vs. 53.1%).

"The median time to any initial adverse event of grade 3 or higher was 8.4 months longer in the enzalutamide group than in the placebo groups (12.6 vs. 4.2 months) owing to improved long-term control of disease-related symptoms without an increase in drug reactions of grade 3 or higher," the investigators said.

More patients in the treatment group, however, experienced fatigue, diarrhea, hot flashes, musculoskeletal pain, and headache. In addition, seizures occurred in five (0.6%) patients in the treatment group, whereas no seizures were reported in those receiving placebo. Predisposing factors were present in several patients experiencing seizures, including brain metastases in two patients, inadvertent IV administration of lidocaine in one patient, and brain atrophy in one patient.

The findings of this study substantiate preclinical work showing that androgen-receptor signaling contributes to disease progression despite castrate levels of testosterone and despite prior treatment with conventional antiandrogen therapy, the investigators said. This – coupled with other recent findings – establishes that these tumors are not refractory to hormones as previously thought, even after chemotherapy has been administered, they added.

"This novel agent is anticipated to join the therapeutic armamentarium of anticancer drugs with diverse mechanisms of action that confer a survival benefit in men with castration-resistant prostate cancer. These results validate androgen-receptor signaling as a key therapeutic target throughout the clinical spectrum of prostate cancer, including in men who have received previous chemotherapy," they concluded, noting that clinical trials of the drug in earlier-stage prostate cancer are ongoing.

Earlier studies of enzalutamide have been announced in patients with metastatic chemotherapy-naive prostate cancer.

This study was supported by Medivation, the maker of enzalutamide, and Astellas Pharma Global Development. Dr. Scher reported relationships with Aragon Pharmaceuticals, Centocor Ortho Biotech, and other companies. He holds stock or stock options in Johnson & Johnson. Other study authors also made disclosures; details are available with the full text of the article at NEJM.org.

Dr. Scher presented results from the AFFIRM trial at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium in February 2012.

Click here to see a 2009 video of Dr. Scher discussing the rationale behind MDV3100 efficacy in advanced prostate cancer.

Enzalutamide Prolongs Prostate Cancer Survival After Chemotherapy Fails