ERLEADA Apalutamide 240 mg Tablet, Film Coated, 30-count — NDC 59676-604-30 (Billing 59676-0604-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Apalutamide is an Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. A major metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third the activity of apalutamide in an in vitro transcriptional reporter assay.

Apalutamide administration caused decreased tumor cell proliferation and increased apoptosis leading to decreased tumor volume in mouse xenograft models of prostate cancer.

12.2Pharmacodynamics ERLEADA 240 mg daily in addition to ADT in patients with mCSPC (TITAN) reduced PSA to undetectable levels (<0.2 ng/mL) in 68% of patients compared to 32% of patients taking ADT alone. ERLEADA 240 mg daily in addition to ADT in patients with nmCRPC (SPARTAN) reduced PSA to undetectable levels (<0.2 ng/mL) in 38% of patients compared to no patients (0%) taking ADT alone. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of apalutamide have not been fully characterized.

Cardiac Electrophysiology At the approved recommended dosage, the maximum mean QTcF change from baseline was 12.4 ms (2-sided 90% upper CI: 16.0 ms). An exposure-QT analysis suggested a concentration-dependent increase in QTcF for apalutamide and its active metabolite.

12.3Pharmacokinetics Apalutamide and N-desmethyl apalutamide pharmacokinetic parameters were observed at steady-state following the approved recommended dosage for ERLEADA and are presented as the mean [standard deviation (SD)] unless otherwise specified. Apalutamide maximum concentration (C max ) is 6 mcg/mL (1.7) and total systemic exposure (AUC) is 100 mcg∙h/mL (32). Apalutamide C max and AUC increases in a dose proportional manner following repeated once-daily dosing of 30 to 480 mg (0.125 to 2 times the recommended dosage).

Apalutamide steady-state is achieved after 4 weeks and the mean accumulation ratio is approximately 5-fold. The major active metabolite N-desmethyl apalutamide C max is 5.9 mcg/mL (1) and AUC is 124 mcg∙h/mL (23). Mean AUC metabolite/parent drug ratio for N-desmethyl apalutamide following repeat-dose administration is 1.3.

Based on systemic exposure, relative potency, and pharmacokinetic properties, N-desmethyl apalutamide likely contributes to the clinical activity of apalutamide. Absorption Apalutamide absolute oral bioavailability is approximately 100%. Apalutamide median (min, max) time to maximum plasma concentration (t max ) is 2 hours (1, 5 hours).

No clinically significant changes in C max and AUC were observed following oral administration of four 60 mg tablets dispersed in applesauce compared to administration of four intact 60 mg tablets under fasting condition. Effect of Food No clinically significant differences in apalutamide C max and AUC were observed following administration of a high-fat meal (approximately 500 to 600 fat calories, 250 carbohydrate calories, and 150 protein calories). Median time to reach t max was delayed approximately 2 hours with food.

Distribution Apalutamide apparent volume of distribution is approximately 276 L. Apalutamide is 96% and N-desmethyl apalutamide is 95% bound to plasma proteins with no concentration dependency. Elimination Apalutamide half-life is approximately 3 days.

The CL/F of apalutamide is

1.3 L/h after single dosing and increases to

2.0L/h at steady-state after once-daily dosing likely due to CYP3A4 auto-induction. Metabolism Apalutamide is primarily metabolized by CYP2C8 and CYP3A4 to form active metabolite, N-desmethyl apalutamide. The contribution of CYP2C8 and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and 13% following single dose but changes to 40% and 37%, respectively at steady-state.

Apalutamide represented 45% and N-desmethyl apalutamide represented 44% of the total AUC following a single oral… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Apalutamide is an Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. A major metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third the activity of apalutamide in an in vitro transcriptional reporter assay.

Apalutamide administration caused decreased tumor cell proliferation and increased apoptosis leading to decreased tumor volume in mouse xenograft models of prostate cancer.

12.3Pharmacokinetics Apalutamide and N-desmethyl apalutamide pharmacokinetic parameters were observed at steady-state following the approved recommended dosage for ERLEADA and are presented as the mean [standard deviation (SD)] unless otherwise specified. Apalutamide maximum concentration (C max ) is 6 mcg/mL (1.7) and total systemic exposure (AUC) is 100 mcg∙h/mL (32). Apalutamide C max and AUC increases in a dose proportional manner following repeated once-daily dosing of 30 to 480 mg (0.125 to 2 times the recommended dosage).

Apalutamide steady-state is achieved after 4 weeks and the mean accumulation ratio is approximately 5-fold. The major active metabolite N-desmethyl apalutamide C max is 5.9 mcg/mL (1) and AUC is 124 mcg∙h/mL (23). Mean AUC metabolite/parent drug ratio for N-desmethyl apalutamide following repeat-dose administration is 1.3.

Based on systemic exposure, relative potency, and pharmacokinetic properties, N-desmethyl apalutamide likely contributes to the clinical activity of apalutamide. Absorption Apalutamide absolute oral bioavailability is approximately 100%. Apalutamide median (min, max) time to maximum plasma concentration (t max ) is 2 hours (1, 5 hours).

No clinically significant changes in C max and AUC were observed following oral administration of four 60 mg tablets dispersed in applesauce compared to administration of four intact 60 mg tablets under fasting condition. Effect of Food No clinically significant differences in apalutamide C max and AUC were observed following administration of a high-fat meal (approximately 500 to 600 fat calories, 250 carbohydrate calories, and 150 protein calories). Median time to reach t max was delayed approximately 2 hours with food.

Distribution Apalutamide apparent volume of distribution is approximately 276 L. Apalutamide is 96% and N-desmethyl apalutamide is 95% bound to plasma proteins with no concentration dependency. Elimination Apalutamide half-life is approximately 3 days.

The CL/F of apalutamide is

1.3 L/h after single dosing and increases to

2.0L/h at steady-state after once-daily dosing likely due to CYP3A4 auto-induction. Metabolism Apalutamide is primarily metabolized by CYP2C8 and CYP3A4 to form active metabolite, N-desmethyl apalutamide. The contribution of CYP2C8 and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and 13% following single dose but changes to 40% and 37%, respectively at steady-state.

Apalutamide represented 45% and N-desmethyl apalutamide represented 44% of the total AUC following a single oral administration of radiolabeled apalutamide 240 mg. Excretion Up to 70 days following a single oral administration of radiolabeled apalutamide, 65% of the dose was recovered in urine (1.2% of dose as unchanged apalutamide and 2.7% as N-desmethyl apalutamide) and 24% was recovered in feces (1.5% of dose as unchanged apalutamide and 2% as N-desmethyl apalutamide). Specific Populations No clinically significant differences in the pharmacokinetics of apalutamide or N-desmethyl apalutamide were observed based on age (18-94 years), race (Black, non-Japanese Asian, Japanese), or eGFR 30-89 mL/min/1.73 m 2 (estimated by MDRD equation).

The effect of eGFR ≤29 mL/min/1.73 m 2 on apalutamide pharmacokinetics is unknown. Patients with Hepatic Impairment In subjects with severe hepatic impairment (Child-Pugh C), AUC for the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide) increased 2.1-fold compared to subjects with normal hepatic function. In subjects with mild to moderate hepatic impairment (Child-Pugh A to B), no clinically significant differences in the pharmacokinetics of apalutamide or N-desmethyl apalutamide were observed compared to subjects with normal hepatic function.

Drug Interactions Clinical Studies and Model-Informed Approaches Strong CYP2C8 inhibitors : Apalutamide C max decreased by 21% while AUC increased by 68% following co-administration of ERLEADA as a 240 mg sin… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics ERLEADA 240 mg daily in addition to ADT in patients with mCSPC (TITAN) reduced PSA to undetectable levels (<0.2 ng/mL) in 68% of patients compared to 32% of patients taking ADT alone. ERLEADA 240 mg daily in addition to ADT in patients with nmCRPC (SPARTAN) reduced PSA to undetectable levels (<0.2 ng/mL) in 38% of patients compared to no patients (0%) taking ADT alone. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of apalutamide have not been fully characterized.

Cardiac Electrophysiology At the approved recommended dosage, the maximum mean QTcF change from baseline was 12.4 ms (2-sided 90% upper CI: 16.0 ms). An exposure-QT analysis suggested a concentration-dependent increase in QTcF for apalutamide and its active metabolite.

14 CLINICAL STUDIES The efficacy and safety of ERLEADA was established in two randomized placebo-controlled clinical trials. TITAN (NCT02489318): Metastatic Castration-sensitive Prostate Cancer (mCSPC) TITAN was a randomized, double-blind, placebo-controlled, multinational, clinical trial in which 1052 patients with mCSPC were randomized (1:1) to receive either ERLEADA orally at a dose of 240 mg once daily (N=525) or placebo once daily (N=527). All patients in the TITAN trial received concomitant GnRH analog or had prior bilateral orchiectomy.

Patients were stratified by Gleason score at diagnosis, prior docetaxel use, and region of the world. Patients with both high- and low-volume mCSPC were eligible for the study. High volume of disease was defined as metastases involving the viscera with 1 bone lesion or the presence of 4 or more bone lesions, at least 1 of which must be in a bony structure beyond the vertebral column and pelvic bones.

The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 68 years (range 43–94) and 23% of patients were 75 years of age or older. The racial distribution was 68% Caucasian, 22% Asian, and 2% Black.

Sixty-three percent (63%) of patients had high-volume disease and 37% had low-volume disease. Sixteen percent (16%) of patients had prior surgery, radiotherapy of the prostate or both. A majority of patients had a Gleason score of 8 or higher (67%).

Sixty-eight percent (68%) of patients received prior treatment with an anti-androgen (bicalutamide, flutamide, or nilutamide). All patients except one in the placebo group, had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry. The major efficacy outcome measures of the study were overall survival (OS) and radiographic progression-free survival (rPFS).

Radiographic progression-free survival was based on investigator assessment and was defined as time from randomization to radiographic disease progression or death. Radiographic disease progression was defined by identification of 2 or more new bone lesions on a bone scan with confirmation (Prostate Cancer Working Group 2 criteria) and/or progression in soft tissue disease. A statistically significant improvement in OS and rPFS was demonstrated in patients randomized to receive ERLEADA compared with patients randomized to receive placebo.

The results for OS are based upon a prespecified interim efficacy analysis. An updated OS analysis was conducted at the time of final study analysis when 405 deaths were observed. The median follow-up time was 44 months.

Thirty-nine percent of patients in the placebo arm crossed over to receive ERLEADA. Efficacy results of TITAN are summarized in Table 5 and Figures 1 and 2. Table 5: Efficacy Results from the TITAN Study Endpoint ERLEADA (N=525) Placebo (N=527) Primary Overall Survival Interim analysis is based on 50% of the number of events planned for the final analysis.

Allocated alpha = 0.01. Deaths (%) 83 (16%) 117 (22%) Median, months (95% CI) NE=Not Estimable. NE (NE, NE) NE (NE, NE) Hazard Ratio (95% CI) Hazard ratio is from stratified proportional hazards model.

Hazard ratio <1 favors ERLEADA. 0.67 (0.51, 0.89) p-value p-value is from the log-rank test stratified by Gleason score at diagnosis (≤7 vs. >7), Region (NA/EU vs. Other Countries) and Prior docetaxel use (Yes vs.

No). 0.0053 Updated Overall Survival Deaths (%) 170 (32%) 235 (45%) Median, months (95% CI) NE (NE, NE) 52 (42, NE) Hazard Ratio (95% CI) 0.65 (0.53, 0.79) Radiographic Progression-free Survival Disease progression or death (%) 134 (26%) 231 (44%) Median, months (95% CI) NE (NE, NE) 22.1 (18, 33) Hazard Ratio (95% CI) 0.48 (0.39, 0.60) p-value <0.0001 Consistent improvement in rPFS was observed across the following patient subgroups: disease volume (high vs low), prior docetaxel use (yes or no), and Gleason score at diagnosis (≤7 vs. >7).

Consistent improvement in OS was… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in male rats, apalutamide was administered by oral gavage at doses of 5, 15 and 50 mg/kg/day. Apalutamide increased the incidence of Leydig interstitial cell adenoma in the testes at doses ≥ 5 mg/kg/day (0.2 times the human exposure based on AUC). The findings in the testes are considered to be related to the pharmacological activity of apalutamide.

Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Oral administration of apalutamide to male rasH2 transgenic mice for 6 months did not result in increased incidence of neoplasms at doses up to 30 mg/kg/day. Apalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either in vitro chromosome aberration assay or the in vivo rat bone marrow micronucleus assay or the in vivo rat Comet assay.

In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), atrophy of the prostate gland and seminal vesicles, aspermia/hypospermia, tubular degeneration and/or hyperplasia or hypertrophy of the interstitial cells in the reproductive system were observed at ≥ 25 mg/kg/day in rats (1.4 times the human exposure based on AUC) and ≥ 2.5 mg/kg/day in dogs (0.9 times the human exposure based on AUC). In a fertility study in male rats, a decrease in sperm concentration and motility, increased abnormal sperm morphology, lower copulation and fertility rates (upon pairing with untreated females) along with reduced weights of the secondary sex glands and epididymis were observed following 4 weeks of dosing at ≥ 25 mg/kg/day (0.8 times the human exposure based on AUC).

A reduced number of live fetuses due to increased pre- and/or post-implantation loss was observed following 4 weeks of 150 mg/kg/day administration (5.7 times the human exposure based on AUC). Effects on male rats were reversible after 8 weeks from the last apalutamide administration.