Apalutamide, a nonsteroidal antiandrogen, is an antineoplastic agent.1, 2, 3, 4
Metastatic Castration-Sensitive Prostate Cancer
Apalutamide is used for the treatment of metastatic castration-sensitive prostate cancer in patients who are either receiving concomitant treatment with a gonadotropin-releasing hormone (GnRH) analog or who have had a bilateral orchiectomy.1 Guidelines recommend androgen deprivation therapy combined with abiraterone, apalutamide, darolutamide, enzalutamide, or docetaxel for the treatment of metastatic castration-sensitive prostate cancer.3017, 3018, 3019
The indication for apalutamide in metastatic castration-sensitive prostate cancer is based principally on the results of a randomized, double-blind, placebo-controlled phase 3 study (TITAN) in 1052 patients.1, 15 Patients were randomized in a 1:1 ratio to receive either apalutamide (240 mg once daily) or placebo; androgen deprivation therapy was continued in all patients.1, 15 Patients were stratified by Gleason score at diagnosis, prior docetaxel use, and region of the world. 1, 15 The primary measures of efficacy were radiographic progression-free survival and overall survival.1, 15 The median age of patients enrolled in the study was 68 years; 23% of patients were 75 years of age or older.1 The majority of patients (63%) had high-volume disease; 67% had a Gleason score of 8 or higher, 68% had received prior treatment with an antiandrogen (bicalutamide, flutamide, or nilutamide), 16% had prior surgery, radiotherapy, or both for prostate cancer, and all patients except 1 had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at baseline.1
At a median follow-up of 44 months, the median radiographic progression-free survival was not reached in the apalutamide group and was 22.1 months in the placebo group.1 Median overall survival was not reached in the apalutamide group and was 52 months in the placebo group.1, 16 Improvements in radiographic progression-free survival and overall survival were consistent across subgroups based on disease volume and Gleason score at diagnosis.1 Patients receiving apalutamide also had a longer time to initiation of cytotoxic chemotherapy.1 Time to pain worsening was prolonged with apalutamide, and health-related quality of life did not worsen with the addition of apalutamide to androgen deprivation therapy.17, 18
According to a joint guideline from the American Urological Association (AUA), American Society for Radiation Oncology (ASTRO), and the Society of Urologic Oncology (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.3017, 3019 A guideline from the American Society of Clinical Oncology (ASCO) similarly states that standard of care therapy for noncastrate metastatic prostate cancer is androgen deprivation therapy combined with docetaxel, abiraterone, darolutamide, enzalutamide, or apalutamide.3018 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.3018 Apalutamide plus androgen deprivation therapy should be offered to men with metastatic noncastration-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).3018
Nonmetastatic Castration-Resistant Prostate Cancer
Apalutamide is used for the treatment of nonmetastatic castration-resistant prostate cancer in patients who are either receiving concomitant treatment with a GnRH analog or who have had a bilateral orchiectomy.1, 2 The use of an androgen receptor antagonist (i.e., darolutamide, apalutamide, enzalutamide) is recommended for patients with nonmetastatic castration-resistant prostate cancer who are at high risk of metastases.3016
The indication for apalutamide in nonmetastatic castration-resistant prostate cancer is based principally on the results of a randomized, double-blind, placebo-controlled phase 3 study (SPARTAN) in 1207 patients who were at high risk for metastasis (i.e., prostate specific antigen [PSA] doubling time of 10 months or less despite continuous androgen deprivation therapy).1, 2 Patients were randomized in a 2:1 ratio to receive either apalutamide (240 mg once daily) or placebo; androgen deprivation therapy was continued in all patients.1, 2 Patients were stratified by PSA doubling time, use of bone resorption inhibitors, and presence of locoregional nodal disease.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 The primary measure of efficacy was metastasis-free survival; secondary end points included time to metastasis, progression-free (including locoregional or distant metastatic progression) survival, time to symptomatic progression, overall survival, and time to initiation of cytotoxic chemotherapy.1, 2 The median age of patients enrolled in the study was 74 years; 26% of patients were 80 years of age or older.1 Most patients (77%) had undergone prior surgery or radiation therapy of the prostate; 78% had a Gleason score of 7 or higher, 73% had received prior treatment with a nonsteroidal antiandrogen (69% had received bicalutamide and 10% had received flutamide), and all had an ECOG performance status of 0 or 1.1, 2
At a median follow-up of 20.3 months, metastasis-free survival was substantially longer in apalutamide-treated patients compared with those who received placebo (40.5 and 16.2 months, respectively).1, 2 Results of a subgroup analysis (based on PSA doubling time, baseline PSA concentration, number of prior hormonal therapies, use of bone resorption inhibitors, locoregional nodal disease, age, race, ECOG performance status, and geographic region) suggested that the drug's effect on metastasis-free survival was consistent across all subgroups.1, 2 Patients receiving apalutamide also had longer time to metastasis, progression-free survival, time to symptomatic progression, and time to initiation of cytotoxicity chemotherapy compared with those receiving placebo.1, 2 In the final overall survival analysis (conducted 32 months after the primary endpoint analysis), median overall survival was significantly prolonged in patients receiving apalutamide compared with those receiving placebo (73.9 months versus 59.9 months).1, 14
According to a joint guideline from AUA, ASTRO, and SUO, the decision to add an androgen receptor antagonist to androgen deprivation therapy in patients with nonmetastatic castration-resistant prostate cancer is dependent on metastatic risk.3016 The risk of metastasis is determined by the time to doubling of PSA levels.3016 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.3016 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.3016
Apalutamide is administered orally once daily without regard to food.1 The tablets should be swallowed whole; do not crush or split tablets.1 Store tablets in the original package at 20-25°C (excursions permitted between 15-30°C); protect from light and moisture, and do not discard the desiccant.1 If a dose is missed, the dose should be taken as soon as possible on the same day, with a return to the normal dosing schedule on the following day.1 Patients should not take extra tablets to make up for the missed dose.1
For patients who have difficulty swallowing, apalutamide may be dispersed in non-carbonated water and then administered with either orange juice, applesauce, or additional water.1 Place the entire prescribed dose of apalutamide tablet(s) in a cup; do not crush or split the tablet(s).1 For the 240 mg tablet, add approximately 2 teaspoons (10 mL) of non-carbonated water to fully immerse the tablet in water.1 For the 60 mg tablets (prescribed dose of 240 mg, 180 mg, or 120 mg), add approximately 4 teaspoons (20 mL) of non-carbonated water to fully immerse the tablets in water.1 Wait 2 minutes until the tablet(s) are broken up and spread out, then stir the mixture.1 Add 2 tablespoons (30 mL) of either orange juice, applesauce, or additional water and stir the mixture.1 Swallow the mixture immediately.1 Rinse the cup with enough water to ensure the whole dose is administered and drink immediately.1 Do not store apalutamide mixed with non-carbonated water, orange juice, or applesauce for later use.1
Apalutamide tablets can be administered through a feeding tube (8 French or greater).1 For the 240 mg tablet, place the tablet in the barrel of at least a 20 mL syringe and draw up 10 mL of non-carbonated water into the syringe.1 For the 60 mg tablets (prescribed dose of 240 mg, 180 mg, or 120 mg), place the entire prescribed dose of tablets in the barrel of at least a 50 mL syringe and draw up 20 mL of non-carbonated water into the syringe.1 Wait 10 minutes and then shake the syringe vigorously to disperse contents completely.1 Administer immediately through the feeding tube.1 Refill the syringe with non-carbonated water and administer.1 Repeat this process until no tablet residue is left in the syringe or feeding tube.1
Metastatic Castration-Sensitive Prostate Cancer
For the treatment of metastatic castration-sensitive prostate cancer, the recommended dosage of apalutamide in adults is 240 mg once daily (given as four 60 mg tablets or one 240 mg tablet).1
Nonmetastatic Castration-Resistant Prostate Cancer
For the treatment of nonmetastatic castration-resistant prostate cancer, the recommended dosage of apalutamide in adults is 240 mg once daily (given as four 60 mg tablets or one 240 mg tablet).1
Dosage Modification for Toxicity
If an intolerable adverse effect or grade 3 or greater toxicity occurs, apalutamide therapy should be interrupted until symptoms improve to grade 1 or less or return to baseline.1 Apalutamide therapy may then be resumed with or without a dosage reduction.1 If a dosage reduction is warranted, the dosage of apalutamide may be reduced to 180 or 120 mg once daily.1
Consider permanent discontinuation of apalutamide for grade 3 or 4 cerebrovascular and ischemic cardiovascular events.1 Permanently discontinue apalutamide for severe interstitial lung disease (ILD)/pneumonitis or if no other etiologies of ILD/pneumonitis are identified, or for confirmed severe cutaneous adverse reactions or for other grade 4 skin reactions.1
Initial dosage adjustment is not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).8
Apalutamide has not been studied in patients with severe hepatic impairment (Child-Pugh class C).1
Initial dosage adjustment is not necessary in patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] of 30-89 mL/minute per 1.73 m2).8
Apalutamide has not been studied in patients with severe renal impairment (eGFR ≤29 mL/minute per 1.73 m2).1
The manufacturer makes no special dosage recommendations for geriatric patients; most patients (81%) in the principal efficacy studies were ≥65 years of age.1
None.1
Cerebrovascular and Ischemic Cardiovascular Events
Cerebrovascular and ischemic cardiovascular events, including events leading to death, occurred in patients receiving apalutamide.1 In a study of patients with nonmetastatic castration-resistant prostate cancer (SPARTAN), 3.7% of apalutamide-treated patients experienced ischemic cardiovascular events compared to 2% of patients receiving placebo.1 In a study of patients with metastatic castration-sensitive prostate cancer (TITAN), 4.4% of apalutamide-treated patients experienced ischemic cardiovascular events compared to 1.5% of patients receiving placebo.1 Across both studies, 4 patients (0.3%) receiving apalutamide died from an ischemic cardiovascular event, compared to 2 patients (0.2%) receiving placebo.1
In the SPARTAN study, cerebrovascular events occurred in 2.5% of apalutamide-treated patients and 1% of patients receiving placebo; in the TITAN study, cerebrovascular events occurred in 1.9% of apalutamide-treated patients and 2.1% of patients receiving placebo.1 Across both studies, death due to a cerebrovascular event occurred in 3 apalutamide-treated patients (0.2%) and 2 patients receiving placebo (0.2%).1
Patients with a history of unstable angina, myocardial infarction, congestive heart failure, stroke, or transient ischemic attack within 6 months of randomization were excluded from the SPARTAN and TITAN studies.1
Monitor for signs and symptoms of ischemic heart disease and cerebrovascular disorders during apalutamide therapy.1 Optimize management of cardiovascular risk factors (e.g., hypertension, diabetes, dyslipidemia), and consider discontinuation of apalutamide for grade 3 and 4 events.1
Fractures have occurred in patients receiving apalutamide.1 In a study of patients with nonmetastatic castration-resistant prostate cancer (SPARTAN), fractures were reported in 12% of apalutamide-treated patients compared with 7% of those receiving placebo; grade 3 or 4 fractures occurred in 2.7% of patients receiving the drug compared with 0.8% of those receiving placebo.1 The median time to onset of fracture was 314 days (range: 20-953 days) in patients receiving apalutamide.1 In a study of patients with metastatic castration-sensitive prostate cancer (TITAN), fractures were reported in 9% of apalutamide-treated patients and 6% of patients receiving placebo; grade 3 or 4 fractures occurred in 1.5% of patients in both study arms.1 The median time to onset of fracture was 56 days (range: 2-111 days) in patients receiving apalutamide.1 Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed during either study.1
Evaluate patients for fracture risk.1 Monitor and manage patients at risk for fractures according to established treatment guidelines; consider therapy with bone-targeted agents.1
Falls have occurred in patients receiving apalutamide, with increased frequency observed in geriatric patients.1 In a study of patients with nonmetastatic castration-resistant prostate cancer (SPARTAN), falls occurred in 16% of apalutamide-treated patients and 9% of patients receiving placebo.1 In clinical studies, falls occurred in 8% of patients <65 years of age, 10% of patients 65-74 years of age, and 19% of patients ≥75 years of age receiving the drug.1 Falls were not associated with loss of consciousness or seizure.1
Evaluate patients for fall risk.1
Seizures have occurred in patients receiving apalutamide.1 In 2 randomized studies in patients with prostate cancer, seizures were reported in 0.4% of patients receiving apalutamide compared with 0.1% of those receiving placebo.1 Patients with a history of seizures, predisposing factors for seizures, or concomitant use of drugs that can lower the seizure threshold or induce seizures were excluded from these studies.1 Time to onset of seizures ranged from 159-650 days following initiation of the drug.1
It is not known whether anticonvulsants will prevent seizures in patients receiving apalutamide.1 The safety of resuming apalutamide therapy in patients who experienced a seizure while receiving the drug has not been established.1 Permanently discontinue apalutamide in patients who develop a seizure during treatment.1
Severe Cutaneous Adverse Reactions
Fatal and life-threatening severe cutaneous adverse reactions (e.g., Stevens-Johnson syndrome/toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported in patients receiving apalutamide.1 Inform patients of the signs and symptoms of these reactions (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy) and monitor for development.1
If a severe cutaneous adverse reaction is suspected, interrupt apalutamide therapy until the cause of the reaction is determined.1 Consulting a dermatologist is recommended.1 If a severe cutaneous adverse reaction (or other grade 4 skin reaction) is confirmed, permanently discontinue apalutamide.1
Interstitial Lung Disease (ILD)/Pneumonitis
Fatal and life-threatening ILD or pneumonitis can occur in patients receiving apalutamide.1 In clinical trials, 0.8% of 1327 patients administered apalutamide experienced ILD/pneumonitis, including 0.2% with grade 3 events.1
Patients should be monitored for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever).1 If ILD/pneumonitis is suspected, immediately withhold apalutamide therapy.1 Apalutamide therapy should be permanently discontinued in patients with severe ILD/pneumonitis or if no other potential causes of ILD/pneumonitis are identified.1
Fetal/Neonatal Morbidity and Mortality
Safety and efficacy of apalutamide have not been established in females.1 Based on its mechanism of action and findings from animal studies, apalutamide may cause fetal harm and loss of pregnancy.1 Fetal abnormalities and embryofetal lethality were observed in pregnant rats when oral apalutamide was administered during and after organogenesis at maternal exposures ≥2 times the human clinical exposure at the recommended dose.1
Advise males with female partners of reproductive potential to use effective methods of contraception during apalutamide therapy and for 3 months after the last dose of the drug; in addition, males should not donate sperm while receiving the drug and for 3 months after the drug is discontinued.1, 8 Male patients receiving the drug should use a condom during sexual encounters with pregnant females.1
Safety and efficacy of apalutamide have not been established in females.1 Based on its mechanism of action and findings from animal studies, apalutamide may cause fetal harm and loss of pregnancy.1 Fetal abnormalities and embryofetal lethality were observed in pregnant rats when oral apalutamide was administered during and after organogenesis at maternal exposures ≥2 times the human clinical exposure at the recommended dose.1
Safety and efficacy of apalutamide have not been established in females.1 It is not known whether apalutamide or its metabolites are distributed into human milk.1 The effects of apalutamide on nursing infants or on milk production also are not known.1
Females and Males of Reproductive Potential
Advise males with female partners of reproductive potential to use effective methods of contraception during apalutamide therapy and for 3 months after the last dose of the drug; in addition, males should not donate sperm while receiving the drug and for 3 months after the drug is discontinued.1, 8 Male patients receiving the drug should use a condom during sexual encounters with pregnant females.1
Based on animal studies, apalutamide may impair male fertility.1 In male rats, apalutamide was associated with decreased sperm concentration and motility, increased abnormal sperm morphology, reduced epididymis and secondary sex gland weights, lower copulation and fertility rates upon pairing with untreated females, and a reduced number of live fetuses secondary to increased pre- and/or post-implantation loss; effects on male rats were reversible following discontinuance of the drug.1
Safety and efficacy of apalutamide have not been established in pediatric patients.1
In the principal efficacy studies evaluating apalutamide, 81% of patients were ≥65 years of age and 40% were ≥75 years of age.1 No overall differences in efficacy were observed between geriatric patients and younger adults.1 Grade 3 or 4 adverse reactions occurred in 39% of patients <65 years of age, 41% of patients 65-74 years of age, and 49% of patients ≥75 years of age.1 Falls occurred more frequently in geriatric patients, with falls reported in 8% of patients <65 years of age, 10% of patients 65-74 years of age, and 19% of patients ≥75 years of age.1
No clinically important differences in systemic exposure of apalutamide or N -desmethylapalutamide were observed in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) compared with individuals with normal hepatic function.1, 8 The unbound fraction of apalutamide or N -desmethylapalutamide was not affected by hepatic impairment.8
Pharmacokinetics of apalutamide have not been established in patients with severe hepatic impairment (Child-Pugh class C).1
Renal impairment is not expected to affect the elimination of apalutamide or N -desmethylapalutamide.8 No clinically important differences in systemic exposure of apalutamide or N -desmethylapalutamide were observed in patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] of 30-89 mL/minute per 1.73 m2) compared with individuals with normal renal function.1, 8
Pharmacokinetics of apalutamide have not been established in patients with severe renal impairment (eGFR ≤29 mL/minute per 1.73 m2).1
Adverse effects reported in ≥10% of patients receiving apalutamide include fatigue, arthralgia, rash, decreased appetite, falls, decreased weight, hypertension, hot flush, diarrhea, and fracture.1
Apalutamide is metabolized principally by cytochrome P-450 (CYP) isoenzymes 2C8 and 3A4 to form its major active metabolite, N -desmethylapalutamide.1
Apalutamide is a potent inducer of CYP3A4 and 2C19 and a weak inducer of CYP2C9 in humans.1 In addition, in vitro studies indicate that apalutamide and N -desmethylapalutamide are moderate to potent inducers of CYP3A4 and 2B6, moderate inhibitors of CYP2B6 and 2C8, and weak inhibitors of CYP2C9, 2C19, and 3A4.1 Apalutamide and N -desmethylapalutamide neither inhibit nor induce CYP1A2 or 2D6 at clinically relevant concentrations.1
Apalutamide and N -desmethylapalutamide are substrates of P-glycoprotein (P-gp) in vitro; however, apalutamide absorption is not limited by P-gp.1 Apalutamide and N -desmethylapalutamide are not substrates of breast cancer resistance protein (BCRP), organic anion transport protein (OATP) 1B1, or OATP1B3.1
Apalutamide is a weak inducer of P-gp, BCRP, and OATP1B1 in humans.1 In vitro, apalutamide and N -desmethylapalutamide inhibit organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3), and multidrug and toxin extrusion (MATE) transporters.1 Apalutamide may induce uridine diphosphate-glucuronosyltransferase (UGT).1, 8 Apalutamide and N -desmethylapalutamide do not inhibit organic anion transporter 1 (OAT1).1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of apalutamide with potent inhibitors of CYP2C8 or 3A4 may result in increased steady-state exposure of the total active forms of apalutamide (i.e., unbound apalutamide plus potency-adjusted unbound N -desmethylapalutamide).1 No initial dosage adjustment is necessary; however, reduction of apalutamide dosage may be necessary based on tolerability.1
Mild or moderate inhibitors of CYP2C8 or 3A4 are not expected to affect the exposure of apalutamide.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Concomitant use of apalutamide with drugs that are principally metabolized by CYP3A4, 2C9, or 2C19 may result in decreased exposure of the CYP substrate.1 The manufacturer of apalutamide recommends that concomitant use be avoided when possible (e.g., by switching to an alternative drug that is not metabolized by these isoenzymes); if concomitant use cannot be avoided, patients should be monitored for decreased therapeutic effect of the CYP substrate.1
Concomitant administration of apalutamide with a CYP2C8 substrate did not result in clinically important changes in exposure of the CYP2C8 substrate.1, 8
Drugs Affecting or Affected by P-glycoprotein Transport
Inhibition or induction of P-gp is not expected to affect the bioavailability of apalutamide.1
Concomitant use of apalutamide and P-gp substrates may result in decreased exposure of the P-gp substrate.1 If concomitant use is necessary, caution should be exercised and patients should be monitored for decreased therapeutic effect of the P-gp substrate.1
Drugs Affected by Breast Cancer Resistance Protein and/or Organic Anion Transport Polypeptide 1B1
Concomitant use of apalutamide with drugs that are substrates of BCRP or OATP1B1 may result in decreased exposure of the BCRP or OATP1B1 substrate.1 If concomitant use is necessary, caution should be exercised and patients should be monitored for decreased therapeutic effect of the BCRP or OATP1B1 substrate.1
Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase
Concomitant use of apalutamide with drugs that are substrates of UGT may result in decreased exposure of the UGT substrate.1, 8 If concomitant use is necessary, caution should be exercised and patients should be monitored for decreased therapeutic effect of the UGT substrate.1
Drugs Affected by Other Transporters
In vitro, apalutamide and N -desmethylapalutamide inhibit OCT2, OAT3, and MATE transporters, but do not inhibit OAT1.1 Apalutamide is not expected to cause clinically important changes in exposure of OAT3 substrates (e.g., penicillin G).1, 8
Drugs Affecting Gastric Acidity
Because apalutamide remains un-ionized at physiologic pH, concomitant administration of apalutamide and drugs that increase gastric pH (e.g., proton-pump inhibitors, histamine H2-receptor antagonists, antacids) are not expected to have a clinically important effect on the solubility and bioavailability of apalutamide.1
Concomitant administration of the potent CYP3A4 inhibitor itraconazole and apalutamide (single 240-mg dose) decreased peak plasma concentrations of apalutamide and N -desmethylapalutamide by 22 and 15%, respectively; areas under the concentration-time curve (AUCs) were not affected.1, 8
No initial dosage adjustment is necessary; however, reduction of apalutamide dosage may be necessary based on tolerability in patients receiving concomitant itraconazole therapy.1
Based on pharmacokinetic modeling, concomitant use of ketoconazole (a potent CYP3A4 inhibitor) and apalutamide is expected to increase AUC of single-dose apalutamide by 24% with no change in apalutamide peak plasma concentration, and to increase steady-state AUC and peak plasma concentration of apalutamide by 51 and 38%, respectively.1, 8 At steady state, AUC and peak plasma concentration of the total active forms of apalutamide (i.e., unbound apalutamide plus potency-adjusted unbound N -desmethylapalutamide) are expected to increase by 28 and 23%, respectively.1, 8
No initial dosage adjustment is necessary; however, reduction of apalutamide dosage may be necessary based on tolerability in patients receiving concomitant ketoconazole therapy.1
Concomitant administration of the P-gp substrate fexofenadine (single dose) and apalutamide (240 mg daily at steady state) decreased fexofenadine AUC by 30%.1, 8 If concomitant use of fexofenadine and apalutamide is necessary, caution should be exercised and patients should be monitored for decreased therapeutic effect of fexofenadine.1
Concomitant administration of the potent CYP2C8 inhibitor gemfibrozil and apalutamide decreased peak plasma concentration of apalutamide by 21% and increased AUC of apalutamide by 68%.1, 8 Based on pharmacokinetic modeling, gemfibrozil is expected to increase steady-state AUC and peak plasma concentrations of apalutamide by 44 and 32%, respectively, and to increase steady-state AUC and peak plasma concentrations of the total active forms of apalutamide (i.e., unbound apalutamide plus potency-adjusted unbound N -desmethylapalutamide) by 23 and 19%, respectively.1, 8
No initial dosage adjustment is necessary; however, reduction of apalutamide dosage may be necessary based on tolerability in patients receiving concomitant gemfibrozil therapy.1
Pharmacokinetic data indicate that apalutamide has no apparent effect on steady-state exposure to leuprolide when co-administered.1
Concomitant administration of the CYP3A4 substrate midazolam (single oral dose) and apalutamide (240 mg daily) decreased midazolam AUC by 92%.1, 8 Concomitant use of apalutamide and midazolam should be avoided when possible (e.g., by switching to an alternative drug that is not metabolized by CYP3A4); if concomitant use cannot be avoided, patients should be monitored for decreased therapeutic effect of midazolam.1, 8
Concomitant administration of the CYP2C19 substrate omeprazole (single dose) and apalutamide (240 mg daily) decreased omeprazole AUC by 85%.1, 8 Concomitant use of apalutamide and omeprazole should be avoided when possible (e.g., by switching to an alternative drug that is not metabolized by CYP2C19); if concomitant use cannot be avoided, patients should be monitored for decreased therapeutic effect of omeprazole.1, 8
Concomitant administration of the CYP2C8 substrate pioglitazone (single dose) and apalutamide (240 mg daily) decreased pioglitazone AUC by 18%.8
Based on pharmacokinetic modeling, concomitant use of the potent CYP3A4 and moderate CYP2C8 inducer rifampin (600 mg daily) and apalutamide is expected to decrease steady-state AUC and peak plasma concentrations of apalutamide by 34 and 25%, respectively, and to decrease steady-state AUC and peak plasma concentrations of the total active forms of apalutamide (i.e., unbound apalutamide plus potency-adjusted unbound N -desmethylapalutamide) by 19 and 15%, respectively.1, 8 However, no pharmacokinetic interactions were observed between apalutamide and CYP3A4 inducers in a population pharmacokinetic analysis based on limited data.8
Concomitant administration of the BCRP and OATP1B1 substrate rosuvastatin (single dose) and apalutamide (240 mg daily) decreased rosuvastatin AUC by 41% with no change in rosuvastatin peak plasma concentration.1, 8 If concomitant use of rosuvastatin and apalutamide is necessary, caution should be exercised and patients should be monitored for decreased therapeutic effect of rosuvastatin.1
Concomitant administration of the CYP2C9 substrate warfarin (single dose) and apalutamide (240 mg daily) decreased AUC of S -warfarin by 46%.1, 8 If apalutamide is used concomitantly with warfarin, international normalized ratio (INR) should be monitored at initiation of concomitant therapy and upon discontinuance of apalutamide.8
Apalutamide, a nonsteroidal antiandrogen, is an antineoplastic agent.1, 2, 3, 4 The drug competitively inhibits androgen binding to androgen receptors;3, 6 its mechanisms of action are similar to those of enzalutamide.4, 6 Apalutamide binds directly to the ligand-binding domain of the androgen receptor and inhibits nuclear translocation of the activated androgen receptor, androgen-dependent binding of the androgen receptor complex to DNA, and androgen receptor-mediated gene transcription in cells that overexpress the androgen receptor.1, 2, 3, 4 Apalutamide reduced tumor growth and induced apoptosis of tumor cells, leading to decreased tumor volume, in xenograft models of castration-resistant prostate cancer in mice.1, 3
In castration-resistant prostate cancer, alterations in androgen receptor signaling (e.g., androgen receptor gene mutation or amplification, 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.3, 4, 5, 6, 7 Resistance to conventional antiandrogens (e.g., bicalutamide, flutamide, nilutamide) in castration-resistant prostate cancer has been associated with paradoxical agonistic effects of these drugs and continued androgen receptor signaling.3, 13 Unlike these conventional antiandrogens but similar to enzalutamide, apalutamide does not exhibit agonistic activity in cells that overexpress the androgen receptor.3, 4, 5, 13
The binding affinity of apalutamide at the androgen receptor is 7-10 times greater than that of bicalutamide.4 Although apalutamide and enzalutamide exhibit similar antiandrogenic activity in vitro, apalutamide demonstrated greater activity than enzalutamide in xenograft models of castration-resistant prostate cancer.3 At equivalent dosages, steady-state concentrations of apalutamide and enzalutamide in xenograft tumors in mice were similar, but steady-state plasma and CNS concentrations of apalutamide were twofold to fourfold lower and fourfold lower, respectively, compared with concentrations of enzalutamide.3, 4 Whether these higher murine tumor-to-plasma and tumor-to-CNS ratios for apalutamide translate into a lower risk of adverse effects, including seizures and other CNS toxicity, remains to be established.3, 4
Apalutamide exhibits dose-proportional pharmacokinetics over a dosage range of 30-480 mg once daily.1 Following oral administration, the median time to peak plasma concentrations is 2 hours; the mean absolute bioavailability of apalutamide is approximately 100%.1 Steady-state concentrations of apalutamide are achieved after 4 weeks of once-daily dosing and the mean accumulation ratio is approximately fivefold.1 Oral administration of apalutamide tablets dispersed in applesauce did not result in any clinically relevant changes in time to peak plasma concentration or area under the concentration-time curve (AUC) when compared with administration of intact tablets under fasting conditions.1 Administration of apalutamide with a high-fat meal delays time to peak plasma concentration by approximately 2 hours but has no clinically important effects on AUC.1 Apalutamide is metabolized principally by cytochrome P-450 (CYP) isoenzymes 2C8 and 3A4 to form its major active metabolite, N -desmethylapalutamide, which exhibits antiandrogenic activity at one-third the potency of the parent drug in vitro.1 The contributions of CYP2C8 and 3A4 to the metabolism of apalutamide are approximately 58 and 13%, respectively, following a single dose and 40 and 37%, respectively, at steady state.1 Apalutamide and N -desmethylapalutamide account for 45 and 44%, respectively, of the total drug exposure following a single 240-mg dose of apalutamide.1
Apalutamide and N -desmethylapalutamide are 96 and 95% bound, respectively, to plasma proteins; the extent of binding is independent of plasma concentration.1 Clearance of apalutamide is increased at steady state, suggesting that the drug may induce its own metabolism by CYP3A4.1 The mean steady-state half-life of apalutamide is approximately 3 days.1 Following oral administration of a single radiolabeled dose of apalutamide, 65% of the dose was recovered in urine (1.2% as unchanged drug and 2.7% as N -desmethylapalutamide) and 24% of the dose was recovered in feces (1.5% as unchanged drug and 2% as N -desmethylapalutamide).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.
Apalutamide can only be obtained through designated specialty pharmacies and specialty distributors.12 Contact Janssen CarePath at 877-227-3728 or consult the Janssen CarePath website for specific availability information ([Web]).12
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 60 mg | Janssen | |
240 mg | Erleada® |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions May 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Janssen Products, LP. Erleada® (apalutamide) tablets prescribing information. Horsham, PA; 2024 Aug. [Web]
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4. Chong JT, Oh WK, Liaw BC. Profile of apalutamide in the treatment of metastatic castration-resistant prostate cancer: evidence to date. Onco Targets Ther . 2018; 11:2141-2147. [PubMed 29695920]
5. Gupta E, Guthrie T, Tan W. Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC). BMC Urol . 2014; 14:55. [PubMed 25062956]
6. Crona DJ, Whang YE. Androgen Receptor-Dependent and -Independent Mechanisms Involved in Prostate Cancer Therapy Resistance. Cancers (Basel) . 2017; 9 [PubMed 28604629]
7. Karantanos T, Corn PG, Thompson TC. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene . 2013; 32:5501-11. [PubMed 23752182]
8. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 210951Orig1s000: Multi-discipline review. From FDA website. [Web]
12. Janssen Biotech, Inc. Janssen Biotech, Inc. Reimbursement and access guide: information to support the reimbursement and access process for Erleada® (apalutamide). From the Janssen CarePath website. [Web]
13. Rathkopf D, Scher HI. Androgen receptor antagonists in castration-resistant prostate cancer. Cancer J . 2013; 19:43-9.
14. Smith MR, Saad F, Chowdhury S, et al. Apalutamide and Overall Survival in Prostate Cancer. Eur Urol . 2021;79(1):150-158.
15. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med . 2019;381(1):13-24.
16. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol . 2021;39(20):2294-2303.
17. Agarwal N, McQuarrie K, Bjartell A, et al. Apalutamide plus Androgen Deprivation Therapy for Metastatic Castration-Sensitive Prostate Cancer: Analysis of Pain and Fatigue in the Phase 3 TITAN Study. J Urol . 2021;206(4):914-923.
18. Agarwal N, McQuarrie K, Bjartell A, et al. Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study. Lancet Oncol . 2019;20(11):1518-1530.
3016. Lowrance WT, Breau RH, Chou R, et al. Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II. J Urol . 2021;205(1):22-29.
3017. Lowrance WT, Breau RH, Chou R, et al. Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART I. J Urol . 2021;205(1):14-21.
3018. 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):3652-3656.
3019. Lowrance W, Dreicer R, Jarrard DF, et al. Updates to advanced prostate cancer AUA/SUO guideline (2023). J Urol. 2023;209:1082-1090.