Enzalutamide

Indications

Enzalutamide is used for: Prostate Cancer, Castration-resistant prostate cancer (CRPC), Metastatic castration-sensitive prostate cancer (mCSPC), Non-metastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR)

Adult Dose

Oral The recommended dosage is 160 mg as a single dose once daily. If greater than or equal to grade 3 toxicity or intolerable side effects occur, withhold treatment for 1 week or until symptoms improve to less than or equal to grade 2 toxicity, then resume to normal dosing or reduce to 80-120 mg once daily if needed. CRPC or mCSPC: Patients should also receive a gonadotropic-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy nmCSPC with high-risk BCR May be treated with enzalutamide with or without a GnRH analog Treatment can be suspended if PSA is undetectable (<0.2 ng/mL) after 36 weeks of therapy Reinitiate treatment when PSA increases to >2 ng/mL for patients who had prior radical prostatectomy or ?5 ng/mL for patients who had prior primary radiation therapy Hepatic impairment Mild-to-severe (Child Pugh A to C): No dosage adjustment necessary

Child Dose

Renal Dose

Renal impairment Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment is necessary Severe (CrCl <30 mL/min) and end-stage renal disease: Not assessed

Administration

May administered with or without food

Contra Indications

Precautions

The seizure occurred in 0.5% of patients receiving Enzalutamide. In patients with predisposing factors, seizures were reported in 2.2% of patients. Permanently discontinue Enzalutamide in patients who develop a seizure during treatment. Posterior reversible encephalopathy syndrome (PRES): Discontinue Enzalutamide. Hypersensitivity: Discontinue Enzalutamide. Ischemic Heart Disease: Optimize management of cardiovascular risk factors. Discontinue Enzalutamide for Grade 3-4 events. Falls and Fractures occurred in 11% and 10% of patients receiving Enzalutamide, respectively. Evaluate patients for fracture and fall risk, and treat patients with bone-targeted agents according to established guidelines. Embryo-Fetal Toxicity: Enzalutamide can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception.

Pregnancy-Lactation

Pregnancy Safety and efficacy not established in females Drug should not be handled by females who are or may become pregnant Animal data Based on animal reproductive studies and mechanism of action, enzalutamide may cause fetal harm and loss of pregnancy There are no human data on use in pregnant females In animal reproduction studies, oral administration of enzalutamide in pregnant mice during organogenesis caused adverse developmental effects at doses lower than the maximum recommended human dose Contraception Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the final dose Infertility Based on animal studies, may impair fertility in males of reproductive potential Lactation Not indicated for use in females; unknown whether distributed in breast milk

Interactions

Strong CYP2C8 inhibitors The coadministration of this drug with gemfibrozil (a strong CYP2C8 inhibitor) increases plasma concentrations of enzalutamide plus N-desmethyl enzalutamide, which may increase the incidence and severity of adverse reactions of the drug Avoid coadministration of with strong CYP2C8 inhibitors; if the coadministration with a strong CYP2C8 inhibitor cannot be avoided, reduce the dosage of this drug Strong CYP3A4 Inducers The coadministration of this drug with rifampin (a strong CYP3A4 inducer and a moderate CYP2C8 inducer) decreases plasma concentrations of enzalutamide plus N-desmethyl enzalutamide, which may decrease the efficacy of the drug Avoid coadministration of this drug with strong CYP3A4 inducers; if the coadministration with a strong CYP3A4 inducer cannot be avoided, increase the dosage of this drug

Adverse Effects

Side effects of Enzalutamide : >10% All grades Asthenic conditions (47-51%) Back pain (26-29%) Constipation (23%) Diarrhea (22%) Arthralgia (21%) Hot flush (18-20%) Decreased appetite (19%) Upper respiratory tract infection (16%) Peripheral edema (12-15%) Musculoskeletal pain (15%) Hypertension (6.4-14%) Falls (4.6-13%) Headache (11-12%) Decreased weight (12%) Dyspnea (11%) Dizziness (9.5-11%) 1-10% H3 All grades Muscular weakness (9.8%) Insomnia (8.2-8.8%) Hematuria (6.9-8.8%) Nonpathologic fractures (4-8.8%) Lower respiratory tract and lung infection (7.9-8.5%) Dysgeusia (7.6%) Spinal cord compression and cauda equina syndrome (7.4%) Anxiety (6.5%) Pollakiuria (4.8%) Pruritus (3.8%) Dry skin (3.5%) Epistaxis (3.3%) Grade 3-4 Asthenic conditions (3.4-9%) Hypertension (7.2%) Spinal cord compression and cauda equina syndrome (6.6%) Paresthesia (6.6%) Back pain (2.5-5.3%) Mental impairment disorders (4.3-5.7%) Hypoesthesia (4%) Gynecomastia (3.4%) Arthralgia (1.6-2.5%) Lower respiratory tract and lung infection (1.5-2.4%) Hypertension (2.1%) Restless leg syndrome (2.1%) Nonpathologic fractures (1.4-2.1%) Hematuria (1.3-1.8%) Falls (0.3-1.6%) Muscular weakness (1.5%) Musculoskeletal pain (1.3%) Diarrhea (0.3-1.1%) Peripheral edema (0.2-1%)

Mechanism of Action

Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors; and consequently, inhibits nuclear translocation of androgen receptors and their interaction with DNA. A major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro, and decreased tumor volume in a mouse prostate cancer xenograft model.