Enzalutamide, a nonsteroidal antiandrogen, is an antineoplastic agent.1, 2, 3, 4, 8
Castration-resistant Prostate Cancer
Enzalutamide is used for the treatment of castration-resistant prostate cancer.1, 2, 5, 14, 16, 17, 18, 24
This indication is based principally on the results of 3 randomized, double-blind, placebo-controlled, phase 3 studies (AFFIRM, PREVAIL, and PROSPER) and results of a multicenter, double-blind, randomized, phase 2 study (TERRAIN).1, 2, 16, 17, 18, 24
In the AFFIRM study, 1199 patients with metastatic, castration-resistant, prostate cancer that had progressed following treatment with 1 or 2 cytotoxic regimens, at least one of which had to contain docetaxel, were randomized in a 2:1 ratio to receive either enzalutamide (160 mg once daily) or placebo; androgen deprivation therapy was continued in all patients.1, 2 Treatment was continued until disease progression or unacceptable toxicity occurred, new treatment was initiated, or the patient withdrew from the study.1, 2 Continuation or initiation of glucocorticoid therapy was permitted but not required; 48 or 46% of patients receiving enzalutamide or placebo, respectively, received glucocorticoids.1, 2 The primary measure of efficacy was overall survival.2 The median age of patients enrolled in the study was 69 years; 93% were Caucasian, 91% had bone metastases, 59% had disease progression based on radiographic evidence, 41% had prostate specific antigen (PSA)-only progression, 24% had received 2 prior cytotoxic regimens, and 23% had visceral (lung and/or liver) involvement.1 The majority (92%) of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and 28% of patients had a mean Brief Pain Inventory score of 4 or greater.1
In the AFFIRM study, a planned interim analysis after a specified number of deaths occurred indicated that patients receiving enzalutamide had a longer median overall survival (18.4 versus 13.6 months) than those receiving placebo.1, 2 The median follow-up at the time of the interim analysis was 14.4 months, and the median duration of treatment was 8.3 months for patients receiving enzalutamide and 3 months for those receiving placebo.2 Because of the survival benefit observed at the interim analysis, study investigators permitted patients previously randomized to receive placebo to cross over to open-label enzalutamide therapy.2 At the interim analysis, patients receiving enzalutamide also had higher PSA response rates (54 versus 2%), higher soft tissue response rates (29 versus 4%), higher quality-of-life response rates (43 versus 18%), longer median time to PSA progression (8.3 versus 3 months), longer median progression-free survival based on radiographic evidence (8.3 versus 2.9 months), and longer median time to the first skeletal-related event (16.7 versus 13.3 months) compared with those receiving placebo.2
In the PREVAIL study, 1717 patients with chemotherapy-naïve, metastatic, castration-resistant, prostate cancer were randomized in a 1:1 ratio to receive either enzalutamide (160 mg once daily) or placebo; androgen deprivation therapy was continued in all patients.1, 16 Treatment was continued until disease progression or unacceptable toxicity occurred, new treatment was initiated, or the patient withdrew from the study.1, 16 Continuation or initiation of glucocorticoid therapy was permitted but not required; 27 or 30% of patients receiving enzalutamide or placebo, respectively, received glucocorticoids.1, 16 The primary measures of efficacy were overall survival and progression-free survival based on radiographic evidence (as evaluated by a central review committee according to Prostate Cancer Clinical Trials Working Group [PCCTWG] criteria for bone lesions and/or Response Evaluation Criteria in Solid Tumors [RECIST] for soft tissue lesions).1, 16 The median age of patients enrolled in the study was 71 years; 77% of patients were Caucasian, 54% had radiographic evidence of disease progression, 43% had PSA-only progression, and 12% had visceral (lung and/or liver) involvement.1 Baseline pain assessment indicated the presence of mild or no pain in 32 or 67%, respectively, of patients enrolled in the study.1 All patients enrolled in the study had an ECOG performance status of 0 or 1.1
At a median follow-up of approximately 22 months in the PREVAIL study, patients receiving enzalutamide had longer median overall survival (32.4 versus 30.2 months) and progression-free survival based on radiographic evidence (20 versus 5.4 months) than those receiving placebo.1, 20 Overall survival for enzalutamide-treated patients at the time of updated analysis (at a median follow-up of 31 months) remained similar to the interim results.1, 20 At the time of the updated analysis, 52% of enzalutamide-treated patients and 81% of placebo recipients had received subsequent antineoplastic therapy associated with overall survival benefit; 29% of patients randomized to receive placebo crossed over to receive enzalutamide therapy.1, 20 Results of a subgroup analysis (based on age, geographic region, ECOG performance status, Gleason score, PSA-only progression, disease progression based on radiographic evidence, visceral involvement, baseline PSA concentration, baseline LDH concentration, baseline hemoglobin concentration) suggested that the drug's effect on overall survival was consistent across all subgroups.20 Patients receiving enzalutamide also had a longer median time to initiation of antineoplastic chemotherapy and first skeletal-related event (i.e., radiation therapy or surgery for prostate cancer-related bone metastases, pathologic bone fracture, spinal cord compression, subsequent antineoplastic therapy for the treatment of prostate cancer-related bone pain) compared with those receiving placebo.1
In the TERRAIN study, 375 patients with chemotherapy-naïve, metastatic, castration-resistant, prostate cancer were randomized in a 1:1 ratio to receive either enzalutamide (160 mg once daily) or bicalutamide (50 mg once daily); androgen deprivation therapy was continued in all patients.1, 17 Treatment was continued until disease progression or unacceptable toxicity occurred, new treatment was initiated, or the patient withdrew from the study.1, 17 The primary measure of efficacy was progression-free survival based on radiographic evidence (as evaluated by an independent central review committee according to PCCTWG criteria and/or RECIST for soft tissue lesions).1, 17 The median age of patients enrolled in the study was 71 years; 93% were Caucasian, 98% had radiographic evidence of disease progression, and 46% had received prior therapy with bicalutamide.1 Baseline pain assessment indicated the presence of mild or no pain in 36 or 58%, respectively, of patients enrolled in the study.1 All patients enrolled in the study were enzalutamide-naïve and had an ECOG performance status of 0 or 1.1 Patients were excluded from the study if disease progression occurred during prior treatment with an antiandrogen (e.g., bicalutamide).1 Patients receiving enzalutamide had longer median progression-free survival based on radiographic evidence than those receiving bicalutamide (19.5 versus 13.4 months).1
In the PROSPER study, 1401 patients with nonmetastatic, castration-resistant, prostate cancer were randomized (stratified by PSA doubling time and use of bone resorption inhibitors) in a 2:1 ratio to receive either enzalutamide (160 mg once daily) or placebo; androgen deprivation therapy was continued in all patients.1, 18 Treatment was continued until disease progression or unacceptable toxicity occurred, new treatment was initiated, or the patient withdrew from the study.1, 18 The primary measure of efficacy was metastasis-free survival.1, 18 Patients were enrolled in the study if they had a PSA doubling time of 10 months or less and serum PSA concentration of 2 ng/mL or greater.1 The median age of patients enrolled in the study was 74 years; 77% had a Gleason score of 7 or higher, 71% were Caucasian, and 54% had undergone prior surgery or radiation therapy of the prostate.1 The majority (63%) of patients had received therapy with an antiandrogen; 56 or 11% had received bicalutamide or flutamide, respectively.1 All patients enrolled in the study had an ECOG performance status of 0 or 1.1
At a median follow-up of 18.5 or 15.1 months in patients receiving enzalutamide or placebo, respectively, in the PROSPER study, patients receiving enzalutamide had longer median metastasis-free survival than those receiving placebo (36.6 versus 14.7 months).1, 18 Results of a subgroup analysis (based on PSA doubling time and previous therapy with a bone resorption inhibitor) suggested that the drug's effect on metastasis-free survival was consistent across all subgroups.1 At 27 months after the metastasis-free survival analysis, patients receiving enzalutamide had longer median overall survival than those receiving placebo (67 versus 56.3 months).1, 24 The effect of enzalutamide on overall survival was generally consistent across all subgroups, except those who received a bone resorption inhibitor at baseline; however, the sample size of patients who received a bone resorption inhibitor at baseline was small.24 Patients receiving enzalutamide also had longer median time to initiation of antineoplastic chemotherapy (39.6 versus 17.7 months) and longer median time to PSA progression (37.2 versus 3.9 months) compared with those receiving placebo.1, 18
According to a joint guideline from American Urological Association (AUA), American Society for Radiation Oncology (ASTRO), and the Society of Urologic Oncology (SUO), the decision to add an androgen receptor antagonist to androgen deprivation therapy in patients with non-metastatic , castration-resistant, prostate cancer is dependent on metastatic risk.27 The risk of metastasis is determined by the time to doubling of PSA levels.27 If the PSA doubling time is 10 months or less, metastatic risk is high and the guideline recommends use of either apalutamide, darolutamide, or enzalutamide in addition to androgen deprivation therapy.27 Continuation of androgen deprivation therapy with observation is recommended for patients who have a PSA doubling time greater than 10 months as risk of metastasis is considered to be lower.27 In patients with newly diagnosed metastatic , castration-resistant, prostate cancer, who have not received prior androgen receptor pathway inhibitors, clinicians should offer continued androgen deprivation therapy with abiraterone acetate plus prednisone, docetaxel, or enzalutamide.27
Metastatic Castration-sensitive Prostate Cancer
Enzalutamide is used for the treatment of metastatic, castration-sensitive, prostate cancer.1, 23
This indication is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study (ARCHES).1, 23
In the ARCHES study, 1150 patients with metastatic, castration-sensitive, prostate cancer were randomized in a 1:1 ratio to receive either enzalutamide (160 mg once daily) or placebo; concurrent therapy with a gonadotropin-releasing hormone (GnRH) analog was permitted unless the patient had previously undergone bilateral orchiectomy.1, 23 Patients were stratified by prior docetaxel therapy and volume of disease; concurrent therapy with docetaxel was not permitted during the trial.1, 23 Enzalutamide therapy was continued until disease progression or unacceptable toxicity occurred, new treatment was initiated, or the patient withdrew from the study.1, 23 The primary measure of efficacy was progression-free survival based on radiographic evidence (as evaluated by a blinded central review committee according to PCCTWG criteria for bone lesions and/or RECIST for soft tissue lesions).1, 23 The median age of patients enrolled in the study was 70 years; 81% were Caucasian, 66% had a Gleason score of 8 or greater, and 63% had a high volume of disease.1, 23 A majority of patients (82%) had not received prior docetaxel therapy.1, 23 Concomitant bone resorption inhibitors were used in 12% of patients for prostate cancer or other indications.1, 23 All patients enrolled in the study had an ECOG performance status of 0 or 1.1, 23
At a median follow-up of 14.4 months, patients receiving enzalutamide had a lower rate of disease progression (based on radiographic evidence) or death than those receiving placebo (15.5 versus 34.4%).1, 23 Median progression-free survival based on radiographic evidence and overall survival had not been reached at the time of analysis.1, 23 Results of a subgroup analysis (based on age, geographic region, ECOG performance status, Gleason score, disease localization, PSA value, disease volume, prior docetaxel therapy, and prior androgen deprivation therapy or orchiectomy) suggested the effect of the drug on progression-free survival was consistent across all subgroups.23 Patients receiving enzalutamide also had longer median time to PSA progression and median time to initiation of antineoplastic chemotherapy compared with those receiving placebo.23
According to a joint guideline from AUA, ASTRO, and SUO, clinicians should offer androgen deprivation therapy in combination with androgen pathway directed therapy (abiraterone plus prednisone, apalutamide, or enzalutamide) or docetaxel for the treatment of metastatic, castration-sensitive, prostate cancer.27 Oral androgen pathway directed therapy should not be offered without concomitant androgen deprivation therapy.27 A guideline from the American Society of Clinical Oncology (ASCO) similarly states that standard of care therapy for metastatic, castration-sensitive, prostate cancer is androgen deprivation therapy combined with docetaxel, abiraterone, enzalutamide, apalutamide, or darolutamide.28 With the exception of the triplet therapies of docetaxel plus abiraterone plus androgen deprivation therapy and docetaxel plus darolutamide plus androgen deprivation therapy, the use of any of these agents in any other particular combination or in any particular series cannot yet be recommended.28 Enzalutamide plus androgen deprivation therapy should be offered to men with metastatic, castration-sensitive, prostate cancer, including those with de novo metastatic disease and those who have received prior therapy (e.g., radical prostatectomy or radiotherapy for localized disease).28
Non-metastatic Castration-Sensitive Prostate Cancer
Enzalutamide is used for the treatment of non-metastatic, castration-sensitive, prostate cancer with biochemical recurrence at high risk for metastasis.1, 26 This indication is based principally on the results of a randomized, phase 3 study (EMBARK).1, 26
In the EMBARK study, 1068 patients with non-metastatic, castration-sensitive, prostate cancer were randomly assigned in a 1:1:1 ratio to either enzalutamide (160 mg once daily) plus leuprolide, enzalutamide (160 mg once daily) as open-label monotherapy, or placebo once daily plus leuprolide.1, 26 Patients were stratified by screening PSA (≤10 ng/mL versus >10 ng/mL), PSA doubling time (≤3 months versus >3 months to ≤ 9 months), and prior hormonal therapy.1, 26 For patients with an undetectable PSA level (<0.2 ng/mL) at week 36, treatment was suspended at week 37 and restarted when the PSA level increased to ≥2.0 ng/mL (with prior prostatectomy) or ≥5.0 ng/mL (without prior prostatectomy).1, 26 Patients continued to receive assigned treatments until confirmed imaging-based disease progression, unacceptable toxicity, study withdrawal, or initiation of a new treatment.1 The primary endpoint was metastasis-free survival (defined as the time from randomization to the date of earliest evidence of imaging-based disease progression or death from any cause) in patients administered enzalutamide plus leuprolide compared to those receiving placebo plus leuprolide.1, 26 The median age of patients enrolled in the study was 69 years (range: 49-93 years); 83% of patients were white, 7% Asian, 4% Black, and 5.5% were Hispanic or Latino.1, 26 The median PSA doubling time was 4.9 months.1 Seventy-four percent (74%) of patients had prior definitive therapy with radical prostatectomy, 34% had prior primary radiotherapy (including brachytherapy), and 49% had prior therapy with both surgery and radiotherapy (including adjuvant and salvage radiotherapy).1 A Gleason score of ≥8 was recorded in 32% of patients.1 All patients enrolled in the study had an ECOG performance status of 0 or 1.1
At a median follow-up of 60.7 months, results revealed that patients receiving enzalutamide plus leuprolide had a significant improvement in metastasis-free survival compared to placebo plus leuprolide (12.7% versus 25.7%).26 A significant improvement in metastasis-free survival was also seen in patients assigned to enzalutamide monotherapy as compared to placebo plus leuprolide (17.7% versus 25.7%).1 Patients receiving the combination of enzalutamide plus leuprolide also had improvement in time to PSA progression, time to use of new antineoplastic therapy, and overall survival.26
Enzalutamide is administered orally without regard to meals.1
Enzalutamide is commercially available in capsule and tablet formulations.1 Each capsule or tablet should be taken with a sufficient amount of water to ensure that all medication is successfully swallowed.1 Capsules and tablets should be swallowed whole; capsules should not be chewed, dissolved, or opened and tablets should not be cut, crushed, or chewed.1
Enzalutamide is commercially available in capsule and tablet formulations; these formulations are equivalent on a mg-per-mg basis.1
Castration-resistant Prostate Cancer
For the treatment of castration-resistant prostate cancer, the recommended adult dosage of enzalutamide is 160 mg once daily until disease progression or unacceptable toxicity.1
Metastatic Castration-sensitive Prostate Cancer
For the treatment of metastatic castration-sensitive prostate cancer, the recommended adult dosage of enzalutamide is 160 mg once daily until disease progression or unacceptable toxicity.1
Non-metastatic Castration-sensitive Prostate Cancer
For the treatment of non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis, the recommended adult dosage of enzalutamide is 160 mg once daily until disease progression or unacceptable toxicity.1
Treatment can be suspended if prostate specific antigen (PSA) is undetectable (<0.2 ng/mL) after 36 weeks of therapy.1 Treatment can be reinitiated when PSA has increased to ≥2 ng/mL for patients who have undergone a radical prostatectomy or ≥5 ng/mL for patients who had prior primary radiation therapy.1
If an intolerable adverse effect or grade 3 or greater toxicity occurs, enzalutamide therapy should be interrupted for one week or until symptoms improve to grade 2 or less.1 Enzalutamide therapy may then be resumed with or without a dosage reduction.1 If a dosage reduction is necessary, the dosage of enzalutamide should be reduced to 120 or 80 mg once daily.1
Concomitant Use with Strong CYP2C8 Inhibitors
Concomitant use of enzalutamide with strong CYP2C8 inhibitors should be avoided.1 If concomitant use cannot be avoided, the enzalutamide dosage should be reduced to 80 mg once daily.1 Upon discontinuation of the strong CYP2C8 inhibitor, the enzalutamide dosage should be increased to the dosage used prior to initiation of the strong CYP2C8 inhibitor.1
Concomitant use with Strong CYP3A4 Inducers
Concomitant use of enzalutamide with strong CYP3A4 inducers should be avoided.1 If concomitant use cannot be avoided, the enzalutamide dosage should be increased from 160 mg to 240 mg once daily.1 Upon discontinuation of the strong CYP3A4 inducer, the enzalutamide dosage should be decreased to the dosage used prior to initiation of the strong CYP3A4 inducer.1
Dosage adjustment is not necessary in patients with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C).1
Dosage adjustment is not necessary in patients with mild or moderate renal impairment (creatinine clearance 30-89 mL/minute).1 Enzalutamide has not been evaluated in patients with severe renal impairment (creatinine clearance <30 mL/minute) or end-stage renal disease.1
No specific dosage adjustments are recommended in geriatric patients; however, greater sensitivity of some older individuals to therapy cannot be ruled out.1
Seizures have occurred in patients receiving enzalutamide.1 In clinical trials, seizure was reported in 0.6% of patients receiving enzalutamide; seizures resolved following permanent discontinuance of the drug.1, 2 Time to onset of seizures ranged from 13-2250 days following initiation of enzalutamide therapy.1
Patients with predisposing factors for seizures generally were excluded from clinical trials.1 However, in a trial designed to assess the risk of seizures in such patients, seizure was reported in 8 of 366 enzalutamide-treated patients (2.2%) with predisposing factors for seizures (i.e., concomitant use of drugs that lower seizure threshold; history of cerebrovascular accident, transient ischemic attack, head trauma, seizure, cerebral arteriovenous malformation, or CNS infection; Alzheimer's disease; meningioma; prostate cancer with leptomeningeal involvement; unexplained loss of consciousness within the past 12 months; presence of space-occupying brain lesion).1 Enzalutamide therapy was resumed in all patients experiencing seizure; seizure recurred in 3 patients following resumption of the drug.1 Approximately 17% of patients had more than one risk factor for developing seizure.1 It is not known whether anticonvulsants will prevent seizures in patients receiving enzalutamide.1
Enzalutamide should be permanently discontinued in patients who develop a seizure during treatment.1
Posterior Reversible Encephalopathy Syndrome
Posterior reversible encephalopathy syndrome (PRES) has occurred in patients receiving enzalutamide.1 PRES is a neurologic disorder that may manifest with seizure, headache, lethargy, confusion, blindness, or other visual and neurologic disturbances.1 Hypertension may occur, but it is not necessary for the diagnosis of PRES.1 Brain imaging, preferably magnetic resonance imaging (MRI), is used to confirm the diagnosis.1 Enzalutamide therapy should be discontinued in patients who develop PRES.1
Hypersensitivity reactions, including angioedema, have occurred in patients receiving enzalutamide.1 In clinical trials, edema of the face, tongue, or lip was reported in 0.5, 0.1, or 0.1%, respectively, of patients receiving enzalutamide.1 Pharyngeal edema also has been reported during postmarketing experience.1 Patients who experience symptoms of hypersensitivity should temporarily discontinue enzalutamide and seek immediate medical care.1
Enzalutamide should be permanently discontinued in patients who develop a serious hypersensitivity reaction during treatment.1
Ischemic heart disease, sometimes fatal, has occurred in patients receiving enzalutamide.1 In clinical studies in patients with prostate cancer, ischemic heart disease was reported in 3.5% of patients receiving enzalutamide compared with 2% of those receiving placebo; grade 3 or 4 ischemic events occurred in 1.8% of patients receiving the drug compared with 1.1% of those receiving placebo.1 Fatal ischemic events occurred in 0.4% of patients receiving enzalutamide and 0.1% of those receiving placebo.1
Patients receiving enzalutamide therapy should be monitored for signs or symptoms of ischemic heart disease, and management of preexisting cardiovascular risk factors (e.g., hypertension, diabetes mellitus, dyslipidemia) should be optimized.1 Enzalutamide therapy should be discontinued in patients who develop grade 3 or 4 ischemic heart disease.1
In a pooled safety analysis of clinical studies, the incidence of hypertension with enzalutamide or placebo was 14 or 7%, respectively.1 Less than 1% of both enzalutamide- and placebo-treated patients withdrew from the study because of hypertension.1
Falls and fractures have occurred in patients receiving enzalutamide.1 In a pooled safety analysis of clinical studies in patients with prostate cancer, falls were reported in 12% of patients receiving enzalutamide compared with 6% of those receiving placebo and were not associated with loss of consciousness or seizure.1 Fractures were reported in 13% of patients receiving enzalutamide compared with 6% of those receiving placebo; grade 3 or 4 fractures occurred in 3.4% of patients receiving the drug compared with 1.9% of those receiving placebo.1 The median time to occurrence of fracture was 420 days (range: 1-2348 days) in patients receiving enzalutamide.1 Routine bone density assessments were not performed during these studies.1 In addition, bone-targeting agents for the prevention of bone loss in the setting of osteoporosis were not administered.1
Patients receiving enzalutamide should be evaluated for fracture and fall risk.1 Patients at risk for fractures should be monitored and managed according to established treatment guidelines; therapy with bone-targeting agents should be considered.1
Enzalutamide may cause fetal harm in humans based on its mechanism of action and animal findings; the drug has been shown to be teratogenic, embryotoxic, and fetotoxic in animals.1 Safety and efficacy of enzalutamide have not been established in females.1 Reproduction studies in mice revealed post-implantation loss and resorption, decreased anogenital distance, cleft palate, and absent palatine bone at dosages below the maximum recommended human dosage.1 However, there was no evidence of developmental toxicity in rabbits at exposure levels approximately 0.4 times the human exposure.1 If used during pregnancy or if the patient becomes pregnant while receiving enzalutamide, the patient should be apprised of the potential hazard to the fetus and the potential risk for loss of the pregnancy.1
Because it is not known whether enzalutamide or its metabolites distribute into semen, males receiving the drug should use a condom during sexual encounters with pregnant females and should use an effective contraceptive method during sexual encounters with females of reproductive potential.1 These contraceptive measures are required during enzalutamide therapy and for 3 months after the last dose of the drug.1
Severe dysphagia or choking, including potentially life-threatening events requiring medical intervention and fatalities, may occur due to the formulation size of enzalutamide.1 Patients should be advised to take each capsule or tablet whole with a sufficient amount of water to ensure that all medication is successfully swallowed.1 For patients who have difficulty swallowing, clinicians should consider use of a smaller tablet size of enzalutamide.1 Enzalutamide should be discontinued in patients who cannot swallow capsules or tablets.1
Interference with Immunoassay Measurement of Digoxin
Enzalutamide can interfere with certain digoxin immunoassays (e.g., Chemiluminescent Microparticle Immunoassays); this interference may result in falsely elevated digoxin plasma concentration results.1 In patients concurrently administered enzalutamide and digoxin, clinicians should notify the laboratory conducting the digoxin plasma concentration assay to use an appropriate method.1
Based on its mechanism of action and animal findings, enzalutamide can cause fetal harm and potential loss of pregnancy if administered to pregnant females.1
Enzalutamide and/or its metabolites are distributed into milk in rats; peak concentrations in milk (achieved 4 hours following oral administration of the drug) are 4 times higher than plasma concentrations.1 It is not known whether the drug distributes into human milk or if the drug has any effect on milk production or on the nursing infant.1
Females and Males of Reproductive Potential
Males with female partners of reproductive potential should use effective contraception during enzalutamide treatment and for 3 months after the last dose of the drug.1 Males should also use a condom during sexual intercourse with pregnant females.1
Results of animal studies suggest that enzalutamide may impair male fertility.1 In repeat-dose toxicity studies in animals, hypospermatogenesis and atrophy of seminal vesicles, prostate, and epididymis were observed.1
Safety and efficacy of enzalutamide have not been established in pediatric patients.1
In clinical trials evaluating enzalutamide in men with prostate cancer, 78% of patients were 65 years of age or older and 33% were 75 years of age or older.1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults.1, 21 However, the possibility of increased sensitivity to the drug in some geriatric patients cannot be ruled out.1
Following a single 160-mg dose of enzalutamide, systemic exposure to the major active forms of the drug (i.e., enzalutamide plus N -desmethylenzalutamide) in individuals with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) was similar to that in individuals with normal hepatic function.1, 19
The effect of renal impairment on the pharmacokinetic disposition of enzalutamide has not been specifically studied to date.1 In a population pharmacokinetic analysis, clearance of enzalutamide in patients with mild to moderate renal impairment (creatinine clearance 30-89 mL/minute) was similar to that in individuals with normal renal function.1 Enzalutamide has not been evaluated systematically in patients with severe renal impairment (creatinine clearance <30 mL/minute) or end-stage renal disease.1
Adverse effects reported in 10% or more of patients receiving enzalutamide for the treatment of prostate cancer and at an incidence that is at least 2% higher than that reported with placebo include musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, diarrhea, hypertension, hemorrhage, fall, fracture, and headache.1
In vivo studies indicate that enzalutamide is a strong inducer of cytochrome P-450 (CYP) isoenzyme 3A4 and a moderate inducer of CYP isoenzymes 2C9 and 2C19; enzalutamide does not induce CYP1A2 at clinically relevant concentrations.1 Enzalutamide also induces CYP2B6 in vitro.1 In vitro studies show that enzalutamide and its 2 major metabolites (an active N -desmethyl metabolite and an inactive carboxylic acid metabolite) are inhibitors of CYP isoenzymes 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5; enzalutamide also causes time-dependent inhibition of CYP1A2 in vitro.1 In vitro, N -desmethylenzalutamide is not a substrate of CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, or 3A4/5.1 In vitro studies indicate that neither enzalutamide nor its 2 major metabolites are substrates of P-glycoprotein (P-gp); however, both enzalutamide and N -desmethylenzalutamide are inhibitors of P-gp.1 Enzalutamide is metabolized by CYP isoenzymes 2C8 and 3A4; formation of the active N -desmethyl metabolite is mediated principally by CYP2C8.1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of enzalutamide with strong inhibitors of CYP2C8 may result in increased systemic exposure to enzalutamide and its active N -desmethyl metabolite.1 When the strong CYP2C8 inhibitor gemfibrozil (600 mg twice daily) was administered concomitantly with enzalutamide (single 160-mg dose) in healthy individuals, systemic exposure to the major active forms of the antiandrogen (i.e., enzalutamide plus N -desmethylenzalutamide) was increased by approximately 2.2-fold; however, peak plasma concentrations of these active forms of the drug were not substantially affected.1 Concomitant use of enzalutamide with strong CYP2C8 inhibitors should be avoided if possible.1 If concomitant use cannot be avoided, the dosage of enzalutamide should be reduced to 80 mg once daily.1 If concomitant use of the strong CYP2C8 inhibitor is discontinued, the enzalutamide dosage should be returned to the dosage used prior to initiation of the strong CYP2C8 inhibitor.1
When the strong CYP3A4 inhibitor itraconazole (200 mg once daily) was administered concomitantly with enzalutamide (single 160-mg dose) in healthy individuals, systemic exposure to the major active forms of the antiandrogen (i.e., enzalutamide plus N -desmethylenzalutamide) was increased by approximately 1.3-fold; peak plasma concentrations of these active forms of the drug were not affected.1 Initial dosage adjustment is not necessary.1
Concomitant use of enzalutamide with strong inducers of CYP3A4 (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may result in decreased systemic exposure to enzalutamide.1 When the combined strong CYP3A4 and moderate CYP2C8 inducer rifampin (600 mg once daily) was administered concomitantly with enzalutamide (single 160-mg dose) in healthy individuals, systemic exposure to the major active forms of the antiandrogen (i.e., enzalutamide plus N -desmethylenzalutamide) was decreased by 37%; however, peak plasma concentrations of these active forms of the drug were not affected.1
Concomitant use of enzalutamide with strong CYP3A4 inducers should be avoided if possible.1 If concomitant use cannot be avoided, the dosage of enzalutamide should be increased from 160 mg to 240 mg once daily.1 If concomitant use of the strong CYP3A4 inducer is discontinued, the enzalutamide dosage should be returned to the dosage used prior to initiation of the strong CYP3A4 inducer.1
St. John's wort ( Hypericum perforatum ) is an inducer of CYP3A4 and can decrease systemic exposure to enzalutamide.1 Concomitant use of enzalutamide with St. John's wort should be avoided.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Concomitant use of enzalutamide with drugs that are metabolized by CYP isoenzymes 3A4, 2C9, or 2C19 may result in decreased systemic exposure to the substrate drug.1 When the CYP3A4 substrate midazolam (single 2-mg dose), CYP2C9 substrate warfarin sodium (single 10-mg dose), and CYP2C19 substrate omeprazole (single 20-mg dose) were administered concomitantly with enzalutamide (160 mg daily), systemic exposure and peak plasma concentrations of midazolam were decreased by 86 and 77%, respectively; systemic exposure to S -warfarin was decreased by 56%; and systemic exposure and peak plasma concentrations of omeprazole were decreased by 70%.1, 13 Concomitant use of enzalutamide with CYP3A4, 2C9, or 2C19 substrates that have a narrow therapeutic index (e.g., alfentanil, clopidogrel, cyclosporine, dihydroergotamine, ergotamine, fentanyl, phenytoin, pimozide, quinidine, sirolimus, tacrolimus, warfarin) should be avoided.1 If concomitant use with warfarin cannot be avoided, additional monitoring of the international normalized ratio (INR) is recommended.1
When the CYP2C8 substrate pioglitazone (single 30-mg dose) was administered concomitantly with enzalutamide (160 mg daily), clinically important changes in systemic exposure to pioglitazone were not observed; therefore, dosage adjustment is not necessary.1
When the CYP1A2 substrate caffeine (single 100-mg dose) and CYP2D6 substrate dextromethorphan (single 30-mg dose) were administered concomitantly with enzalutamide (160 mg daily), clinically important changes in systemic exposure to caffeine and dextromethorphan were not observed; therefore, dosage adjustment is not necessary.1
Because enzalutamide and N -desmethylenzalutamide are highly protein bound (97-98 and 95%, respectively),1 the drug could be displaced from binding sites by, or could displace from binding sites, other protein-bound drugs.1 In vitro data indicate that displacement between enzalutamide and other highly protein-bound drugs (i.e., salicylates, ibuprofen) is unlikely at clinically relevant concentrations.1
Enzalutamide can interfere with certain digoxin immunoassays (e.g., Chemiluminescent Microparticle Immunoassays); this interference may result in falsely elevated digoxin plasma concentration results.1 In patients concurrently administered enzalutamide and digoxin, clinicians should notify the laboratory conducting the digoxin plasma concentration assay to use an appropriate method.1
Enzalutamide, a nonsteroidal antiandrogen, is an antineoplastic agent.1, 2, 3, 4, 8 Like conventional nonsteroidal antiandrogens (e.g., bicalutamide, flutamide, nilutamide), enzalutamide competitively inhibits androgen binding to androgen receptors;1, 6 blockade of androgen receptors may result in growth arrest or apoptosis of prostate cancer cells through inhibition of nuclear translocation of the activated androgen receptor and through inhibition of androgen-dependent binding of the androgen receptor complex to DNA.4, 6, 7, 9 In vitro, enzalutamide has been shown to reduce tumor growth and induce apoptosis of tumor cells; the drug also has been shown to induce tumor regression in mouse models of castration-resistant prostate cancer.1, 3, 5 The binding affinity of enzalutamide at the androgen receptor is 5-8 times greater than that of bicalutamide.3, 8 The main circulating metabolite of enzalutamide, an N -desmethyl derivative, has been shown to have activity similar to that of the parent drug in vitro.1
In castration-resistant prostate cancer, alterations in androgen receptor signaling (e.g., androgen receptor gene mutation or amplification and androgen receptor overexpression) have been shown to result in persistence of androgen receptor signaling and to contribute to disease progression despite castrate levels of androgens.2, 3, 4, 5 Androgen receptor overexpression has been associated with resistance to conventional antiandrogens.2, 5, 8 In cells that overexpress the androgen receptor, conventional antiandrogens (e.g., bicalutamide, flutamide, nilutamide) have been shown to have partial agonistic effects on the androgen receptor, which results in continued activation of the androgen receptor signaling axis despite castrate levels of androgens; this paradoxical effect has been attributed to alterations in the androgen signaling cascade (e.g., androgen receptor gene amplification or mutation).8, 10, 11, 12 Unlike these conventional antiandrogens, enzalutamide appears to lack agonistic effects in cells that overexpress the androgen receptor, which may result in retained antagonism of the androgen receptor despite overexpression of the receptor.2, 3, 5, 8
Pharmacokinetics of enzalutamide are dose proportional over a dosage range of 30-360 mg daily.1 Following oral administration, the median time to peak plasma concentrations is 1 hour.1, 19 Steady-state concentrations of enzalutamide are achieved after 28 days of once-daily dosing and the accumulation ratio is approximately 8.3-fold.1, 19 Administration of enzalutamide with a high-fat meal did not affect the extent of absorption.1, 19 Following a single 160-mg dose of enzalutamide in healthy males, the extent of absorption was comparable between the tablet and capsule formulations; however, mean peak plasma concentration following administration of the tablet formulation was 10-28% lower than that of capsules.1 Peak plasma concentration and AUC of enzalutamide and N -desmethyl enzalutamide at steady state were comparable between the tablet and capsule formulations.1 Enzalutamide is metabolized by cytochrome P-450 (CYP) isoenzymes 2C8 and 3A4.1 Major metabolites of the drug include an active N -desmethyl derivative and an inactive carboxylic acid derivative; formation of N -desmethylenzalutamide is mediated principally by CYP2C8.1 Enzalutamide and N -desmethylenzalutamide are 97-98 and 95% bound, respectively, to plasma proteins.1 The terminal half-lives of enzalutamide and N -desmethylenzalutamide following a single oral dose of the drug are 5.8 and approximately 7.8-8.6 days, respectively.1 Following oral administration of a radiolabeled dose of enzalutamide, about 71% of the dose is recovered in urine (including only trace amounts of unchanged drug and N -desmethylenzalutamide) and 14% of the dose is recovered in feces (0.4% as unchanged drug and 1% as N -desmethylenzalutamide).1, 19
In a dose-finding study, the maximum tolerated dosage of enzalutamide was 240 mg daily; decreases in serum prostate specific antigen (PSA) concentrations were dose dependent at dosages of 30-150 mg daily, but reached a plateau at dosages between 150-240 mg daily.3, 5
The pharmacokinetics of enzalutamide do not appear to be affected by age, body weight, or race (Asian versus non-Asian).1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Enzalutamide can only be obtained through designated specialty pharmacies.22 Contact manufacturer for specific ordering and availability information.22
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions May 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Astellas Pharma US, Inc. Xtandi® (enzalutamide) capsules and tablets prescribing information. Northbrook, IL; 2025 Dec.
2. Scher HI, Fizazi K, Saad F et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med . 2012; 367:1187-97. [PubMed 22894553]
3. Golshayan AR, Antonarakis ES. Enzalutamide: an evidence-based review of its use in the treatment of prostate cancer. Core Evid . 2013; 8:27-35. [PubMed 23589709]
4. Sternberg CN. Novel hormonal therapy for castration-resistant prostate cancer. Ann Oncol . 2012; 23 Suppl 10:x259-63. [PubMed 22987973]
5. Scher HI, Beer TM, Higano CS et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet . 2010; 375:1437-46. [PubMed 20398925]
6. Vogelzang NJ. Enzalutamide--a major advance in the treatment of metastatic prostate cancer. N Engl J Med . 2012; 367:1256-7. [PubMed 23013078]
7. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203415Orig1s000: Summary review. From FDA website. [Web]
8. Tran C, Ouk S, Clegg NJ et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science . 2009; 324:787-90. [PubMed 19359544]
9. Abdulla A, Kapoor A. Emerging novel therapies in the treatment of castrate-resistant prostate cancer. Can Urol Assoc J . 2011; 5:120-33. [PubMed 21470540]
10. Small EJ, Halabi S, Dawson NA et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol . 2004; 22:1025-33. [PubMed 15020604]
11. Taplin ME, Bubley GJ, Shuster TD et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med . 1995; 332:1393-8. [PubMed 7723794]
12. Nieh PT. Withdrawal phenomenon with the antiandrogen casodex. J Urol . 1995; 153:1070-2; discussion 1072-3. [PubMed 7531785]
13. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203415Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]
14. Lowrance WT, Breau RH, Chou R et al. Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II. J Urol . 2021; 205:22-29. [PubMed 32960678]
16. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med . 2014; 371:1755-6. [PubMed 25354111]
17. Shore ND, Chowdhury S, Villers A et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol . 2016; 17:153-163. [PubMed 26774508]
18. Hussain M, Fizazi K, Saad F et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med . 2018; 378:2465-2474. [PubMed 29949494]
19. Gibbons JA, Ouatas T, Krauwinkel W et al. Clinical Pharmacokinetic Studies of Enzalutamide. Clin Pharmacokinet . 2015; 54:1043-55. [PubMed 25917876]
20. Beer TM, Armstrong AJ, Rathkopf D et al. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol . 2017; 71:151-154. [PubMed 27477525]
21. Graff JN, Baciarello G, Armstrong AJ et al. Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL. Ann Oncol . 2016; 27:286-94. [PubMed 26578735]
22. Astellas. Xtandi®: How to get Xtandi®. From Xtandi® for US Health Care Professionals website. Accessed 2024 May 23. [Web]
23. Armstrong AJ, Szmulewitz RZ, Petrylak DP et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol . 2019; 37:2974-2986. [PubMed 31329516]
24. Sternberg CN, Fizazi K, Saad F et al. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med . 2020; 382:2197-2206. [PubMed 32469184]
26. Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med . 2023;389:1453-65.
27. Lowrance W, Dreicer R, Jarrard DF, et al. Updates to advanced prostate cancer: AUA/SUO guideline (2023). J Urol . 2023;209(6):1082-90.
28. Virgo KS, Rumble RB, Talcott J. Initial management of noncastrate advanced, recurrent, or metastatic prostate cancer: ASCO guideline update. J Clin Oncol . 2023;41(20):1-9