Xtandi® (enzalutamide) - Oral Drug to Treat Castration-Resistant Prostate Cancer

The FDA approved Xtandi^® (enzalutamide) in August 2012 to treat patients with metastatic castration-resistant prostate cancer who previously failed treatment with docetaxel. The oral drug, marketed by Astellas Pharma, Inc. and Medivation, Inc., is an androgen receptor inhibitor. Enzalutamide was formally known as MDV3100.

The recommended dosage is four, 40-mg capsules taken once daily with or without food. Patients are advised to swallow the capsules whole and not to chew, dissolve, or open them.

Under the FDA’s priority review designation program, enzalutamide was approved nearly 3 months before its Prescription Drug User Fee Act date of November 22, 2012.

As part of the approval, the FDA required Astellas and Medivation to conduct an open-label study to assess the safety of 160 mg daily of enzalutamide in patients who are at high risk for seizure. In a news release, the companies said the safety data would be available in 2019. In a phase 3 trial, 7 of the 800 patients who received enzalutamide had a seizure, but none of the 399 patients who received placebo had a seizure. Patients who had a seizure stopped taking the medication and none had a recurrent seizure.

The following adverse reactions occurred in at least 5% of patients taking enzalutamide, according to the product’s Prescribing Information: asthenia, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

The FDA approved enzalutamide based on the results of the AFFIRM (A Study Evaluating the Efficacy and Safety of Investigational Drug MDV3100) trial. The study was an international, phase 3, randomized, double-blind, placebo-controlled trial of enzalutamide in patients with metastatic castration-resistant prostate cancer. Astellas and Medivation funded the study.

This First Report Managed Care Product Spotlight provides a summary of the pivotal trial that evaluated the safety and efficacy of enzalutamide. 

PHASE 3 TRIAL

Below is a summary of a phase 3, double-blind, placebo-controlled trial that evaluated the safety and effectiveness of enzalutamide in men with castration-resistant prostate cancer after they received chemotherapy.

Reference

Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. New England Journal of Medicine [2012;367(13):1187-1197].

Study Objective

The trial was designed to assess the efficacy of enzalutamide in prolonging survival in patients with progressive, metastatic castration-resistant prostate cancer after receiving 1 or 2 chemotherapy regimens, including docetaxel.

Method

The authors randomized patients in a 2:1 ratio to receive 160 mg of enzalutamide or placebo once daily. They were allowed to take prednisone and other glucocorticoids, and could take the drug with or without food.

Patients were stratified according to their Eastern Cooperative Oncology Group (ECOG) performance status score at baseline and their score on question 3 of the Brief Pain Inventory-Short Form (BPI-SF) that evaluated their pain during the 7 days before randomization.

Scores on the ECOG test range from 0 (full activity) to 5 (no activity), and this study only included patients with a score of 0, 1 (restriction in strenuous activity but can continue working), or 2 (inability to work). The BPI-SF scores for question 3 ranged from 0 to 10, with higher numbers indicating more severe pain.

Patients took the study drug until they had disease progression confirmed through radiography and required antineoplastic therapy.

Astellas and Medivation performed the data analysis. The cutoff date was September 25, 2011.

Population

The authors screened 1720 patients and then randomized 1199 patients to the groups between September 2009 and November 2010. Patients were eligible if they had histologically or cytologically confirmed prostate cancer, castrate levels of testosterone (<50 ng per deciliter), progressive disease, and previous treatment with docetaxel.

The groups were well balanced. The median age was approximately 69 years, and the median time since diagnosis was approximately 6 years. In addition, approximately 92.0% of patients had an ECOG performance status score of 0 or 1, and 71% had a score <4 on question 3 of the BPI-SF.

Primary end point

• Overall survival

Secondary end points

·      Confirmed PSA decline

·      Soft-tissue objective response

·      Quality-of-life response

·      Time to PSA progression

·      Radiographic progression-free survival

Results

The authors concluded that patients taking enzalutamide had a significant improvement in overall survival compared with the placebo group. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 months to not yet reached) in the enzalutamide group and 13.6 months (95% CI, 11.3 months to 15.8 months) in the placebo group (hazard ratio, 0.63; 95% CI, 0.53 to 0.75; P<.001). The benefit in overall survival was in all subgroups, including age, baseline pain intensity, geographic region, and type of disease progression at study entry.

After an independent data and safety monitoring committee evaluated the results during a planned interim analysis, the committee recommended the study be halted and unblended. The authors followed the recommendation and allowed patients in the placebo group to take enzalutamide. At the time of this analysis, 39% of patients in the enzalutamide group and 53% of patients in the placebo group had died.

Patients who took enzalutamide also had significant improvements in the secondary end points compared with the placebo group: PSA-level response rate (54% vs 2%, P<.001), soft-tissue response rate (29% vs 4%, P<.001), quality-of-life response (43% vs 18%, P<.001), time to PSA progression (8.3 months vs 3.0 months; P<.001), progression-free survival (8.3 months vs 2.9 months; P<.001), and time to first skeletal-related event (16.7 months vs 13.3 months; P<.001).

SAFETY NOTES

In the pivotal AFFIRM study, 45.3% of patients in the enzalutamide group and 53.1% of patients in the placebo group had a grade ≥3 adverse event. The median time to a grade 3 adverse event was 12.6 months in the enzalutamide group and 4.2 months in the placebo group. The following adverse events were more common in patients taking enzalutamide: fatigue, diarrhea, hot flashes, musculoskeletal pain, and headache.

The product’s Prescribing Information noted that patients might have seizures when taking enzalutamide. Patients should inform their providers immediately after having a seizure or loss of consciousness as well as if they have a history of seizures, brain injury, stroke, or brain tumors.

Common side effects associated with enzalutamide include back pain, diarrhea, muscle or bone pain, headache, muscle weakness, insomnia, pneumonia, anxiety, and hypertension.

Xtandi Facts

•    Xtandi was approved by the FDA on August 31, 2012, to treat patients with metastatic   castration-resistant prostate cancer who previously received docetaxel.

•    Xtandi is marketed by Astellas Pharma, Inc. and Medivation, Inc.