FDA Approves Pre-Chemo Enzalutamide for mCRPC

The FDA has expanded the approval for enzalutamide to include the treatment of men with chemotherapy-naive metastatic castration-resistant prostate cancer.

Tomasz M. Beer, MD

The FDA has expanded the approval for enzalutamide (Xtandi) to include the treatment of men with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), based on survival data from the phase III PREVAIL trial.

In the study, treatment with enzalutamide improved overall survival (OS) by 29% and radiographic progression-free survival (rPFS) by 81% compared with placebo. The expanded indication for the androgen receptor inhibitor was granted under the FDA's priority review program. Enzalutamide was initially approved for chemotherapy-pretreated men with mCRPC in August 2012.

"Enzalutamide has been shown to extend overall survival and significantly delay the progression of prostate cancer," co-principal investigator Tomasz M. Beer, MD, the deputy director of the Knight Cancer Institute and professor of medicine at Oregon Health & Science University, said in a press release. "In the PREVAIL trial, the median time to initiating chemotherapy was delayed by 17 months with enzalutamide treatment as compared to placebo, so the result is a meaningful period of time during which men have their disease controlled without the need for chemotherapy."


In the phase III study, 1717 men with a median age of 71 years received treatment with enzalutamide (n = 872) or placebo (n = 845). Enzalutamide was administered at 160 mg daily. Concurrent glucocorticoids were administered to 27% of patients treated with enzalutamide and 30% of patients in the placebo arm. The co-primary endpoints of the study were OS and rPFS. Castration-resistance was determined by PSA-only progression in 43% of patients and 54% demonstrated radiographic evidence of disease progression prior to entering the study. An interim analysis was conducted following 540 deaths, which demonstrated a statistically significant advantage for enzalutamide for both OS and rPFS. At this point, the study was halted and men in the placebo arm were allowed to crossover to receive enzalutamide.

The most common subsequent therapies for patients in the enzalutamide and placebo arm were docetaxel (33% and 57%) and abiraterone acetate (21% and 46%). Forty percent of patients in the enzalutamide arm received subsequent therapies compared with 70% with placebo.

According to data published in The New England Journal of Medicine, the median OS was 32.4 months with enzalutamide versus 30.2 months with placebo (HR = 0.71; P <.0001). The median rPFS was not yet reached in the enzalutamide arm compared with 3.9 months with placebo (HR = 0.19; P <.0001). The overall response rate was 58.8% versus 5%, for enzalutamide and placebo, respectively (P <.0001).

The median time to the initiation of chemotherapy was prolonged by 17.2 months for enzalutamide compared with placebo (28 vs 10.8 months; HR = 0.35; P < .0001). The median time to first skeletal-related event was 31.1 months for enzalutamide and 31.3 months with placebo (HR = 0.72; P <.0001). A PSA decline of greater than 90% was detected in 46.8% of patients treated with enzalutamide compared with 1.2% for placebo (P <.0001).

The most common adverse events for enzalutamide versus placebo were fatigue (35.6% vs 25.8%), back pain (27.0% vs 22.2%), constipation (22.2% vs 17.2%), and arthralgia (20.3% vs 16.0%). Seizure was reported in 1 patient in each treatment arm (0.1%). Patients with a prior history of seizure were excluded from the study.

Grade 3/4 adverse events were reported in 43% of the patients in the enzalutamide arm compared with 37% with placebo. The median time to the first grade 3/4 event was 22.3 months with enzalutamide versus 13.3 months with placebo.

“By and large Xtandi was well tolerated. In the PREVAIL trial, the side effects that we observed more commonly with Xtandi than with placebo were fatigue, back pain, joint pains, constipation, hot flushes, hypertension, upper respiratory tract infection, and falls," Beer said in an interview. "We saw one seizure event in the Xtandi group and one in the placebo group.”

Medivation, Inc., and Astellas Pharma, Inc., co-develop enzalutamide. The expansion of the label triggered a $90 million payment by Astellas to Medivation under an agreement between the two companies.

"The FDA's priority review and approval of this new indication for Xtandi now enables the use of an important therapy by patients with metastatic castration-resistant prostate cancer at all stages of their disease," said Sef Kurstjens, MD, PhD, chief medical officer of Astellas Pharma Inc. and president of Astellas Pharma Global Development, Inc. "We are pleased that these patients now have Xtandi available as a treatment option."