Pre-Chemo Trial of Enzalutamide Halted After Meeting Endpoints

Tomasz M. Beer, MD

The phase III PREVAIL trial of enzalutamide (Xtandi) in chemotherapy-naïve patients with advanced prostate cancer has been stopped early after meeting its co-primary endpoints of overall survival (OS) and radiographic progression-free survival (rPFS).

The recommendation to stop the trial and allow participants in the placebo arm be offered enzalutamide was based on positive findings in a preplanned interim analysis conducted by an Independent Data Monitoring Committee, said the developers of the androgen receptor antagonist, Medivation Inc. and Astellas Pharma, in a written statement.

The PREVAIL trial included men with metastatic castration-resistant prostate cancer (mCRPC) following progression on androgen deprivation therapy before treatment with chemotherapy. Based on its results, the two companies plan to seek an expanded indication for the drug, which was approved by the FDA in 2011 based on a phase III clinical trial that was also stopped early for patients previously treated with docetaxel for their mCRPC.

In the statement, the study’s co-principal investigator, Tomasz M. Beer, MD, said PREVAIL demonstrated that enzalutamide provides a clear benefit to men in this population.

"To my knowledge, the benefits in overall survival and radiographic progression-free survival reported in today's PREVAIL trial results are unprecedented in this patient population," said Beer, professor of Medicine and deputy director of the Knight Cancer Institute at Oregon Health & Science University.

In the trial, 1715 men with mCRPC were administered either placebo or daily oral enzalutamide at a dose of 160 mg. The trial was fully enrolled as of May 2012, and the interim analysis was scheduled to occur after 516 patient deaths.

As compared to those receiving placebo, patients in the enzalutamide arm of the study experienced a statistically significant 30% reduction in risk of death (hazard ratio [HR] = 0.70; 95% confidence interval [CI], 0.59-0.83; P = .0001), the companies stated. At the data cutoff date for the interim analysis, 72% patients in the enzalutamide arm were alive, as compared with 65% in the placebo arm. Based on a calculated point estimate, median OS was projected at 32.4 months for patients in the enzalutamide arm versus 30.2 months for those taking placebo.

As for rPFS, patients taking enzalutamide experienced an 81% reduction in their risk of radiographic progression compared with those taking placebo (HR = 0.19; 95% CI, 015-0.23; P < .0001), the companies reported. Median rPFS was 3.9 months (95% CI, 3.7-5.4) in the placebo arm, and had not been reached in the enzalutamide arm (95% CI, 13.8 months-upper limit not yet reached).

Two patients in the study experienced seizure, according to the companies, which promised to present further analysis of the drug’s safety profile, along with other data from the trial, at a medical conference. As part of its current label, enzalutamide comes with a warning that 0.9% of the patients who received the drug in the AFFIRM trial—which led to its FDA approval—experienced seizure, while no patients on the placebo arm had that side effect.

Other common adverse drug reactions observed in ≥5% of patients who took enzalutamide in the AFFIRM trial included fatigue, back or joint pain, diarrhea, hot flush, peripheral edema, headache, respiratory infection, dizziness, insomnia, spinal cord compression and cauda equina syndrome, hypertension, and neutropenia. Falls or injuries related to falls occurred in 4.6% of patients taking enzalutamide and 1.3% of those taking placebo.

Enzalutamide is also being investigated in other settings: in combination with abiraterone acetate for the treatment of prostate cancer, and for safety and efficacy as a monotherapy in triple-negative breast cancer.