In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On July 13, 2018, enzalutamide (Xtandi) was approved for the treatment of all patients with castration-resistant prostate cancer.1,2 Enzalutamide was previously approved for the treatment of patients with metastatic castration-resistant prostate cancer.
Supporting Efficacy Data
Approval was based on the finding of improved metastasis-free survival for enzalutamide vs placebo in the phase III double-blind PROSPER trial, in which 1,401 patients were randomized 2:1 to receive oral enzalutamide at 160 mg once daily (n = 933) or placebo (n = 468).2,3 All patients were continued on androgen-deprivation therapy with gonadotropin-releasing hormone treatment or had undergone bilateral orchiectomy. Randomization was stratified by prostate-specific antigen (PSA) doubling time and use of bone-targeting agents. Patients had to have PSA doubling time ≤ 10 months. The median age of patients was between 74 and 75 years.
Metastasis-free survival was defined as the time from randomization to locoregional or distant radiographic disease progression on blinded independent central review or death up to 112 days after treatment discontinuation without radiographic disease progression. Median metastasis-free survival was 36.6 months in the enzalutamide group vs 14.7 months in the placebo group (hazard ratio [HR= 0.29, P < .0001). Results were consistent in analysis considering distant radiographic disease progression events or deaths alone regardless of the cutoff date and in analysis in the subgroups stratified by PSA doubling time (< 6 months or ≥ 6 months) and by prior use of a bone-targeting agent. The median time to first use of a new antineoplastic treatment was 39.6 months vs 17.7 months (HR = 0.21, P < .0001). Overall survival data were not mature at the time of the analysis.
How It Works
Enzalutamide is an androgen receptor inhibitor that acts at a number of steps in the androgen receptor signaling pathway. It has been shown to competitively inhibit androgen binding to androgen receptors and to consequently inhibit androgen receptor nuclear translocation and interaction with DNA. A major metabolite of enzalutamide, N-desmethyl enzalutamide, exhibited similar in vitro activity to the parent compound. Enzalutamide decreased proliferation and induced death of prostate cancer cells in vitro and reduced tumor volume in a prostate cancer mouse xenograft model.
How It Is Used
The recommended dose of enzalutamide in the current indication is 160 mg once daily. Patients should also receive a gonadotropin-releasing hormone analog concurrently with treatment or should have had bilateral orchiectomy.
Dose modification for adverse events include withholding dosing for 1 week or until symptoms improve to grade ≤ 2 in patients with grade ≥ 3 toxicity or intolerable side effects; dosing can then be resumed at the same or reduced dose (120 mg or 80 mg), if warranted.
Enzalutamide has warnings/precautions for seizure, posterior reversible encephalopathy syndrome, hypersensitivity, ischemic heart disease, falls and fractures, and embryofetal toxicity.
Concomitant use of strong CYP2C8 inhibitors (eg, gemfibrozil [Lopid], clopidogrel [Plavix], lopinavir) should be avoided. If such use cannot be avoided, the enzalutamide dose should be reduced to 80 mg once daily; the dose used prior to initiation of the strong inhibitor can be resumed upon its discontinuation.
Concomitant use of strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin, St John’s wort) should be avoided. If such use cannot be avoided, the enzalutamide dose should be increased from 160 mg to 240 mg once daily and can be resumed at the dose used prior to the start of the strong inducer upon its discontinuation.
In the PROSPER trial, the most common adverse events of any grade (≥ 10%) that occurred in at least 2% more frequently in the enzalutamide vs placebo groups were asthenia/fatigue (40% vs 20%), hot flush (13% vs 8%), hypertension (12% vs 5%), dizziness (12% vs 5%), nausea (11% vs 9%), and falls (11% vs 4%). Fractures were reported in 9.8% vs 4.9%. Grade ≥ 3 adverse events occurred in 31% vs 23% of patients, with the most common in the enzalutamide group including hypertension (4.6% vs 2.2%) and asthenia/fatigue (4.0% vs 0.9%). The most common grade 3 or 4 laboratory abnormality (≥ 2%) in the enzalutamide group was hyperglycemia (2.9% vs 1.3%). Adverse events led to discontinuation of treatment in 9.4% of the enzalutamide group vs 6.0% of the placebo group, with the most common reason in the enzalutamide group being fatigue (1.6%).
Adverse events led to death in 32 patients (3.4%) in the enzalutamide group, with the most common causes being coronary artery disorders (n = 7), sudden death (n = 2), cardiac arrhythmia (n = 2), general physical health deterioration (n = 2), stroke (n = 2), and secondary malignancy (n = 5; one each of acute myeloid leukemia, brain neoplasm, mesothelioma, small cell lung cancer, and malignant neoplasm of unknown primary site). Adverse events led to death in 3 patients (0.6%) in the placebo group, with causes consisting of cardiac arrest, left ventricular failure, and pancreatic carcinoma.
Enzalutamide has warnings/precautions for seizure, posterior reversible encephalopathy syndrome, hypersensitivity, ischemic heart disease, falls and fractures (which have occurred in 10% and 8% of patients, respectively), and embryofetal toxicity. Seizure has occurred in 0.4% of patients and in 2.2% of patients with predisposing factors. Enzalutamide should be permanently discontinued in patients who develop a seizure during treatment. Patients should have management of cardiovascular risk factors optimized; treatment should be discontinued for grade 3 or 4 events ischemic heart disease events. Treatment should be discontinued for hypersensitivity reactions and posterior reversible encephalopathy syndrome. ■
1. U.S. Food and Drug Administration: FDA approves enzalutamide for castration-resistant prostate cancer. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm613543.htm. Accessed August 6, 2018.
2. Xtandi (enzalutamide) capsules prescribing information, Astellas Pharma US, Inc, July 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/203415s014lbl.pdf. Accessed August 6, 2018.
3. Hussain M, Fizazi K, Saad F, et al: Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med 378:2465-2474, 2018.
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).