Pharmacology Update
Enzalutamide Capsules (Xtandi®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.
A new androgen receptor antagonist has been approved for the treatment of late-stage prostate cancer. Enzalutamide was approved 3 months ahead of schedule due to a priority review by the FDA. The drug is comarketed by Astellas Pharma and Medivation as Xtandi.
Indications
Enzalutamide is indicated for the treatment of metastatic castration-resistant prostate cancer in patients who have previously received docetaxel.1
Dosage
The recommended dose is 160 mg (4 × 40 mg) once daily without regard to meals.1 The capsules should be swallowed whole. The dose should not be coadministered with a strong CYP2C8 inhibitor (e.g., gemfibrozil). If this is unavoidable, the dose should be reduced to 80 mg daily.
Enzalutamide is available as 40 mg capsules.
Potential Advantages
Enzalutamide prolonged survival in men with metastatic castration-resistant prostate cancer after treatment with chemotherapy (e.g., docetaxel).1,2
Potential Disadvantages
Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYPC19.1 Concomitant administration of enzalutamide and substrates of these isoenzymes will reduce their systemic exposure and possibly their effectiveness. The most common adverse events associated with enzalutamide are fatigue, diarrhea, hot flashes, musculoskeletal pain, and headache. Seizures were the most common adverse events resulting in treatment discontinuation (0.9% for enzalutamide vs 0% for placebo).3 The frequency of fall-related injuries and grade 1 or 2 hallucinations was also higher vs placebo (4.6% vs 1.3%) and (1.6% vs 0.3%).
Comments
Enzalutamide and its major active metabolite, N-desmethyl enzalutamide, are competitive androgen inhibitors. These have been shown to induce prostate cancer cell death and decrease tumor volume in cancer xenograft models.1 The efficacy and safety of enzalutamide has been evaluated in a Phase 3, randomized, placebo-controlled trial in patients with metastatic castration-resistant prostate cancer who received prior treatment with docetaxel.1,2 Patients (n = 1199) were randomized at a 2:1 ratio to enzalutamide 160 mg daily (n = 800) or placebo (n = 399) and androgen deprivation therapy was continued in all patients. Treatment continued until disease progression, initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal of treatment. Disease progression was defined as radiographic progression, a skeletal-related event, or clinical progression. Approximately one-half of each group received glucocorticoids. The primary outcome was overall survival. Secondary endpoints included measure of response (50% reduction in PSA and soft-tissue response based on assessment of lesions and tumor burden using the RECIST criteria); quality-of-life scores (10-point improvement in FACT-P); and measure of progression for PSA, radiographic, and first skeletal-related event. Analyses were based on intent-to-treat analysis. Percent survival was 61.5% for enzalutamide and 46.9% for placebo (hazard ratio [95% confidence interval]; 0.63 [0.53, 0.75] P < 0.0001). The median survival time was 18.4 months and 13.6 months, respectively. PSA response rate was 54% vs 2% and soft-tissue response rates were 29% vs 4% for enzalutamide and placebo, respectively. Median times to PSA progression (8.3 vs 3.0 months), radiographic progression-free survival (8.3 vs 2.9 months), and time to first skeletal-related event (16.7 vs 13.3 months) were statistically in favor of enzalutamide.2 Quality-of-life response rate was 43% vs 18% (P < 0.001).
Clinical Implications
Enzalutamide prolonged survival for approximately 5 months. The number needed to treat to achieve this benefit is approximately 7. A clinical trial is currently recruiting patients to compare enzalutamide to bicalutamide in patients with recurrent prostate cancer who have serologic and/or radiographic disease progression despite primary androgen deprivation therapy.4
References
1. Xtandi Prescribing Information. Northbrook, IL: Astellas Pharma; August 2012.
2. Scher HI, et al. N Engl J Med 2012;367:1187-1197.
3. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203415Orig1s000SumR. Accessed November 9, 2012.
4. Safety and efficacy study of enzalutamide versus bicalutamide in men with prostate cancer (STRIVE). http://clinicaltrials.gov/show/NCT01664923. Accessed November 9, 2012.
A new androgen receptor antagonist has been approved for the treatment of late-stage prostate cancer. Enzalutamide was approved 3 months ahead of schedule due to a priority review by the FDA. The drug is comarketed by Astellas Pharma and Medivation as Xtandi.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content. TESTING
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