ERLEADA

Apalutamide is a potent androgen receptor (AR) antagonist that selectively binds to the ligand-binding domain of AR and blocks AR nuclear translocation or binding to androgen response elements 1.

It has been used in trials studying the treatment of Prostate Cancer, Hepatic Impairment, Prostatic Neoplasms, Castration-Resistant Prostate Cancer, and Prostatic Neoplasms, Castration-Resistant, among others.

Exerting an antitumor action, apalutamide blocking the effect of androgens that promote tumor growth.

It targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets in prostate tumors 1.

In mice bearing human

CRPC xenograft models, apalutamide treatment produced tumor regressions in a dose-dependent manner that was more effective than that of Bicalutamide or Enzalutamide.

Unlike bicalutamide, apalutamide antagonized AR-mediated signaling in AR overexpressing human CRPC cell lines 1.

Androgen-deprivation therapy, or hormone therapy, can be used as part of maintenance therapy for patients with non-metastatic prostate cancer.

Although most patients achieve therapeutic responses at the initial hormone therapy, many patients progress to non-metastatic castration-resistant (resistance to hormone therapy) prostate cancer which is the second-most common cause of cancer-related deaths in American males 2.

Castration-resistant prostate cancer is often incurable, which poses significant clinical challenges for patients.

Approximately 10-20 % of prostate cancer cases are castration-resistant, and up to 16% of these patients show no evidence of cancer metastasis at the time of castration-resistant diagnosis 5.

Higher prostate-specific antigen (PSA) and shorter PSA doubling time (PSA DT) are associated with a higher risk for metastases and death 1.

In a phase-2 multicenter open-label study, 89% of patients with non-metastatic, castration-resistant prostate cancer had ≥50% PSA decline at week of apalutamide treatment 1.

In a randomized trial, the median metastasis-free survival for patients taking apalutamide was 40.5 months compared to 16.2 months for patients taking a placebo 5.

Apalutamide displayed good tolerability and safety profile in clinical studies.

Apalutamide was approved in February by the FDA as Erleada for the treatment of patients with non-metastatic prostate cancer that is resistant to treatment with hormone therapy (castration-resistant).

It is available as oral tablets.

Apalutamide is the first

FDA-approved treatment for non-metastatic, castration-resistant prostate cancer 5.

Apalutamide is indicated for the treatment of patients with metastatic castration-sensitive prostate cancer and non-metastatic castration-resistant prostate cancer.

In androgen receptors (AR)-overexpressing LNCaP cells, apaludatamide was reported to have a 7-10-fold greater affinity to the AR than bicalutamide.

Additionally, apalutamide still possesses total antagonistic activity in AR-overexpressing cell lines with bicalutamide-resistance mutations such as T878A and W741C.

In castrate mice with

LNCaP/AR(cs) tumors, apalutamide produced tumor regression (defined by >50% regression in tumor volume) in 8 mice compared to only for bicalutamide.

The apalutamide-treated tumors also have a 60% decrease in proliferative index and a 10-fold increase in apoptotic rate compared with vehicle.

In an open-label, uncontrolled, multicenter, single-arm dedicated QT study in 45 patients with CRPC, an exposure-QT analysis suggested a concentration-dependent increase in QTcF for apalutamide and its active metabolite.

Apalutamide demonstrated antitumor activity in the mouse xenograft models of prostate cancer, where it decreased tumor cell proliferation and reduced tumor volume.

Mean absolute oral bioavailability was approximately 100%.

The median time to achieve peak plasma concentration (t max ) was 2 hours (range: 1-5 hours).

The major active metabolite N-desmethyl apalutamide

C max was 5.9 mcg/mL and AUC was 124 mcg-h/mL at steady-state after the recommended dosage.

Administration of apalutamide to healthy subjects under fasting conditions and with a high-fat meal (approximately 500-600 fat calories, 250 carbohydrate calories, and 150 protein calories) resulted in no clinically relevant changes in C max and AUC.

The median time to reach t max was delayed approximately 2 hours with food.

Following administration of the recommended dosage, apalutamide steady-state was achieved after 4 weeks and the mean accumulation ratio was approximately 5-fold.

C max was 6.0 mcg/mL and AUC was 100 mcg-h/mL at steady-state.

Daily fluctuations in apalutamide plasma concentrations were low, with the mean peak-to-trough ratio of 1.63.

Oral administration of four 60 mg apalutamide tablets dispersed in applesauce resulted in no clinically relevant changes in Cmax and AUC compared to the administration of four intact 60 mg tablets under fasting conditions.

The mean apparent volume of distribution at steady state of apalutamide was approximately 276 L.

is the main route of elimination of apalutamide.

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.

The auto-induction of

CYP3A4-mediated metabolism by apalutamide may explain the increase in CYP3A4 enzymatic activity at steady-state.

Hover over products below to view reaction partners Apalutamide N-desmethyl apalutamide M4 apalutamide.

Apalutamide and its main active metabolite are subject to both renal and focal elimination.

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).

The mean effective half-life for apalutamide in patients with NM-CRPC was approximately 3 days at steady-state.

CL/F of apalutamide was 1.3 L/h after single dosing and increased to 2.0 L/h at steady-state after once-daily dosing likely due to CYP3A4 auto-induction.

The auto-induction effect likely reached its maximum at the recommended dosage because exposure to apalutamide across the dose range of 30-480 mg is dose-proportional.

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There is no known specific antidote for apalutamide overdose.

In the event of an overdose, stop apalutamide, undertake general supportive measures until clinical toxicity has been diminished or resolved.

The safety and efficacy of apalutamide have not been established in females.

Based on findings from animals and its mechanism of action, apalutamide can cause fetal harm and loss of pregnancy when administered to a pregnant female. available data on apalutamide use in pregnant women to inform a drug-associated risk.

In an animal reproduction study, oral administration of apalutamide to pregnant rats during and after organogenesis resulted in fetal abnormalities and embryo-fetal lethality at maternal exposures ≥ 2 times the human clinical exposure (AUC) at the recommended dose.

In a 2-year carcinogenicity study in male rats, apalutamide was administered by oral gavage at doses of 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.

mg orally once daily.

Swallow tablets whole.

ERLEADA can be taken with or without food.

The recommended

ERLEADA dosage in patients with severe hepatic impairment is 120 mg orally once daily.

Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. 2.1 Recommended Dosage The recommended dosage of ERLEADA is 240 mg orally once daily.

Swallow the tablet(s) whole.

Do not crush or split tablet(s).

Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had a bilateral orchiectomy. 2.2 Dosage Modifications for Adverse Reactions If Grade 3 or 4 adverse reactions, or other intolerable adverse reactions occur, withhold ERLEADA.

Consider permanent discontinuation of ERLEADA for

Grade 3 or 4 cerebrovascular and ischemic cardiovascular events.

Permanently discontinue ERLEADA for severe

ILD/pneumonitis or if no other potential causes of ILD/pneumonitis are identified, or confirmed SCARs, or for other Grade 4 skin reactions.

For other adverse reactions, including those that may be related to increased exposure to ERLEADA due to drug interactions, resume ERLEADA at the same dose or at a reduced dose (180 mg or 120 mg) when symptoms improve to less than or equal to Grade 1 or original grade, if warranted.

If the

ERLEADA dose was reduced for an adverse reaction while receiving a drug that increases exposure to ERLEADA, consider resuming the previously tolerated dose after the drug has been discontinued for at least 3 half-lives. 2.3 Recommended Dosage in Patients with Severe Hepatic Impairment The recommended dosage of ERLEADA for patients with severe hepatic impairment (Child-Pugh Class C) is 120 mg orally once daily. 2.4 Alternate Methods of Administration Disperse Tablet(s) in Water and Administer with Orange Juice, Applesauce, or Additional Water For patients who cannot swallow tablets whole, the recommended dose of ERLEADA tablet(s) can be dispersed in non-carbonated water and then administered with either orange juice, applesauce, or additional water as follows: Place the entire prescribed dose of ERLEADA tablet(s) in a cup.

Do not crush or split the tablet(s).

For one 240 mg tablet: Add about 2 teaspoons (10 mL) of non-carbonated water to make sure that the tablet is completely immersed in water.

For 60 mg tablets (prescribed dose of 240 mg, 180 mg, or 120 mg): Add about 4 teaspoons (20 mL) of non-carbonated water to make sure that the tablets are completely immersed in water.

Wait 2 minutes until the tablet(s) are broken up and spread out, then stir the mixture.

Add 2 tablespoons (30 mL) of either orange juice, applesauce, or additional water and stir the mixture.

Swallow the mixture immediately.

Rinse the cup with enough water to make sure the whole dose is taken and drink it immediately.

Do not store

ERLEADA that is mixed with non-carbonated water, orange juice, or applesauce for later use.

Tablet(s) Through a Feeding Tube ERLEADA tablet(s) can be administered through a feeding tube 8 French or greater as follows: For one 240 mg tablet: Place the tablet in the barrel of the syringe (use at least a 20 mL syringe) and draw up 10 mL of non-carbonated water into the syringe.

For 60 mg tablets (prescribed dose of 240 mg, 180 mg, or 120 mg): Place the entire prescribed dose of ERLEADA tablets in the barrel of the syringe (use at least a 50 mL syringe) and draw up 20 mL of non-carbonated water into the syringe.

Wait 10 minutes and then shake vigorously to disperse contents completely.

Administer immediately through the feeding tube.

Refill the syringe with non-carbonated water and administer.

Repeat until no tablet residue is left in the syringe or feeding tube.

® (apalutamide) tablets are available in the strengths and packages listed below: ERLEADA ® 240 mg Tablets Film coated, bluish grey to grey, oval-shaped tablets debossed with "E240" on one side.

Number 59676‐604‐30.

• 30 tablets available in bottles with a silica gel desiccant and has a child-resistant closure ERLEADA ® 60 mg Tablets Film coated, slightly yellowish to greyish green, oblong-shaped tablets debossed with "AR 60" on one side.

Number 59676‐600‐12.

• 120 tablets available in bottles with a silica gel desiccant and has a child-resistant closure Storage and Handling Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) .

Store in original package to protect from light and moisture.

Do not discard desiccant.

Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) .

Store in original package to protect from light and moisture.

Do not discard desiccant.

Risk Summary The safety and efficacy of ERLEADA have not been established in females.

Based on findings from animals and its mechanism of action, ERLEADA can cause fetal harm and loss of pregnancy when administered to a pregnant female.

There are no available data on

ERLEADA use in pregnant women to inform a drug-associated risk.

In an animal reproduction study, oral administration of apalutamide to pregnant rats during and after organogenesis resulted in fetal abnormalities and embryo-fetal lethality at maternal exposures ≥ 2 times the human clinical exposure (AUC) at the recommended dose.

In a pilot embryo-fetal developmental toxicity study in rats, apalutamide caused developmental toxicity when administered at oral doses of 25, 50 or 100 mg/kg/day throughout and after the period of organogenesis (gestational days 6–20).

Findings included embryo-fetal lethality (resorptions) at doses ≥50 mg/kg/day, decreased fetal anogenital distance, misshapen pituitary gland, and skeletal variations (unossified phalanges, supernumerary short thoracolumbar rib(s), and small, incomplete ossification, and/or misshapen hyoid bone) at ≥25 mg/kg/day. A dose of 100 mg/kg/day caused maternal toxicity.

The doses tested in rats resulted in systemic exposures (AUC) approximately and 6 times, respectively, the AUC in patients.

Safety and effectiveness of

ERLEADA in pediatric patients have not been established.

Of the 1327 patients who received ERLEADA in clinical studies, 19% of patients were less than 65 years, 41% of patients were 65 years to 74 years, and 40% were 75 years and over.

No overall differences in effectiveness were observed between older and younger patients.

Of patients treated with

ERLEADA (n=1073), Grade 3–4 adverse reactions occurred in 39% of patients younger than 65 years, 41% of patients 65–74 years, and 49% of patients 75 years or older.

Falls in patients receiving

ERLEADA with androgen deprivation therapy was elevated in the elderly, occurring in 8% of patients younger than 65 years, 10% of patients 65–74 years, and 19% of patients 75 years or older.