In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On September 10, 2014, the androgen receptor inhibitor enzalutamide (Xtandi) was approved for use in men with metastatic castration-resistant prostate cancer who have not received chemotherapy. Enzalutamide was approved in 2012 for use in men with castration-resistant prostate cancer who had previously received docetaxel.
The new indication is based on results of the double-blind phase III PREVAIL trial, in which 1,717 patients with minimally symptomatic or asymptomatic metastatic castration-resistant prostate cancer who had not received cytotoxic chemotherapy were randomly assigned to receive oral enzalutamide 160 mg/day (n = 872) or placebo (n = 845) until disease progression and the initiation of cytotoxic chemotherapy or an investigational agent, unacceptable toxicity, or withdrawal. Continued androgen-deprivation therapy was required.
Patients with visceral metastases or history of mild to moderate heart failure and patients taking medications associated with lowering seizure threshold were permitted to enroll. Those with history of seizure or a condition that might predispose to seizure and those with moderate or severe pain from prostate cancer were excluded. The co-primary endpoints were overall survival and radiographic progression-free survival.
Patients had a median age of 71 years (range, 42–93 years), 77% were white and 10% were Asian, Eastern Cooperative Oncology Group performance status was 0 in 68% and 1 in 32%, baseline pain assessment was asymptomatic in 67% and mildly symptomatic in 32%, 54% had radiographic evidence of progression and 43% had prostate-specific antigen–only progression, and 12% had visceral (lung or liver) involvement. During the study, 27% of enzalutamide patients and 30% of placebo patients received glucocorticoids.
Subsequent therapy was received by 40% of enzalutamide patients and 70% of placebo patients. Enzalutamide was associated with significantly prolonged median overall survival (32.4 vs 30.2 months, hazard ratio [HR] = 0.71, P < .0001) and radiographic progression-free survival (not reached, 95% confidence interval = 13.8 months–not reached, vs 3.7 months, 95% CI = 3.6–4.6 months, HR = 0.17; P < .0001). Enzalutamide also significantly prolonged median time to initiation of cytotoxic chemotherapy (28.0 vs 10.8 months, HR = 0.35, P < .0001) and time to first skeletal-related event (31.1 vs 31.3 months, HR = 0.72, P < .0001).
How It Works
Enzalutamide 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 inhibit androgen receptor nuclear translocation and interaction with DNA. Enzalutamide decreased proliferation and induced death of prostate cancer cells in vitro and reduced tumor volume in a prostate cancer xenograft model.
How It Is Given
The recommended dose of enzalutamide is 160 mg once daily. Treatment should be withheld for 1 week or until symptoms improve to grade ≤ 2 in patients with a grade ≥ 3 or intolerable adverse event and then resumed at the same dose or at reduced doses of 120 or 80 mg once daily if warranted. Enzalutamide should be permanently discontinued in patients with seizure.
Concomitant use of a strong CYP2C8 inhibitor should be avoided. If one must be used, the enzalutamide dose should be reduced to 80 mg once daily and can be returned to the prior dose level when use of the strong inhibitor is discontinued. Concomitant use of strong or moderate CYP3A4 or CYP2C8 inducers (which may decrease enzalutamide exposure) and CYP3A4, CYP2C9, and CYP2C19 substrates (exposure levels of which may be reduced with enzalutamide coadministration) with a narrow therapeutic index should be avoided.
No initial dose adjustment is necessary in patients with mild to moderate renal or hepatic impairment. Enzalutamide has not been assessed in patients with severe renal impairment or end-stage renal disease or severe hepatic impairment.
In PREVAIL, median durations of treatment were 17.5 months with enzalutamide and 4.6 months with placebo. The most common adverse events of any grade in the enzalutamide group were asthenic conditions (47% vs 33% in the placebo group), back pain (29% vs 22%), constipation (23% vs 17%), and arthralgia (21% vs 16%). Grade 3 or 4 adverse events occurred in 44% vs 37% of patients, with the most common being hypertension (7.2% vs 2.3%), asthenic conditions (3.4% vs 2.8%), back pain (2.5% vs 3.0%), and nonpathologic fracture (2.1% vs 1.1%). Discontinuations due to adverse events occurred in 6% vs 6% of patients, with the most common cause being fatigue/asthenia (1% vs 1%).
In combined data from PREVAIL and a randomized trial in patients previously treated with docetaxel (AFFIRM), any grade neutropenia occurred in 15% of enzalutamide patients vs 6% of placebo patents (grade 3 or 4 in 1% vs 0.5%) and thrombocytopenia occurred in 6% vs 5% (grade 3 or 4 in 0.3% vs 0.5%). Death due to infection/sepsis occurred in 1% vs 0.3% in AFFIRM and in 0.1% vs 0.1% in PREVAIL. Seizure occurred in 0.9% of patients receiving enzalutamide in AFFIRMED and in 0.1% of enzalutamide patients in PREVAIL. In the combined trials, falls, including fall-related injuries, occurred in 9% vs 4% and were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in enzalutamide patients, including nonpathologic fractures, joint injuries, and hematomas. Hypertension occurred in 11% vs 4% of patients, and led to discontinuation in < 1% vs < 1%.
Enzalutamide carries warnings/precautions for seizure. There is no clinical trial experience with the drug in patients with a history of seizure.
Report Adverse Events
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 (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088). ■
1. XTANDI® (enzalutamide) capsules prescribing information, Astella Pharma US, Inc, September 2014. Available at www.astellas.us/docs/us/12A005-ENZ-WPI.pdf.
2. Beer TM, Armstrong AJ, Rathkopf DE, et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 371:424-433, 2014.