Apalutamide

Approved Indications:

• Non-metastatic Castration-Resistant Prostate Cancer (nmCRPC):
  Indicated for adult men with prostate cancer that continues to progress despite medical or surgical castration and has no detectable metastases.
• Metastatic Castration-Sensitive Prostate Cancer (mCSPC):
  Indicated for use in combination with androgen deprivation therapy (ADT) in patients with newly diagnosed, hormone-sensitive metastatic prostate cancer.

Important Off-label or Investigational Uses:

• Biochemically Recurrent Prostate Cancer:
  Occasionally considered in select high-risk patients following definitive local therapy, though not standard of care.
• High-Risk Localized Prostate Cancer (Investigational):
  Under ongoing clinical evaluation in earlier-stage hormone-sensitive disease.

Adults:

• Standard Dose:
  240 mg orally once daily (administered as four 60 mg tablets) with or without food.
• With Androgen Deprivation Therapy (ADT):
  Continue concurrent use of a GnRH analog or bilateral orchiectomy.

Pediatrics:

• Not indicated. Safety and efficacy in pediatric patients have not been established.

Geriatrics:

• No dose adjustment required. Tolerability and exposure are generally similar to younger adults.

Renal Impairment:

• Mild to Moderate (eGFR ≥30 mL/min): No adjustment needed.
• Severe Renal Impairment/ESRD (eGFR <30 mL/min): Use with caution due to limited data.

Hepatic Impairment:

• Mild (Child-Pugh A): No adjustment necessary.
• Moderate to Severe (Child-Pugh B or C): Use not recommended due to lack of safety data.

Administration Guidelines:

• Swallow tablets whole.
• Can be taken with or without meals.
• If a dose is missed, it should be taken as soon as possible on the same day. Do not take extra doses.

Apalutamide is a selective, non-steroidal androgen receptor (AR) inhibitor. It binds directly to the ligand-binding domain of the AR and prevents its activation by testosterone or dihydrotestosterone (DHT). This inhibition blocks nuclear translocation of the AR, its DNA binding, and transcriptional activation of androgen-responsive genes. These actions collectively suppress androgen signaling, which is essential for the growth and survival of prostate cancer cells. Unlike some first-generation antiandrogens, apalutamide exhibits minimal agonist activity and provides a more complete androgen blockade in castration-resistant and castration-sensitive settings.

• Absorption:
  Oral absorption is high. Peak plasma concentration (Tmax) occurs approximately 2 hours after administration. Food does not significantly alter bioavailability.
• Distribution:
  Highly protein-bound (~96%).
  Volume of distribution (Vd): ~276 L, suggesting extensive tissue penetration.
• Metabolism:
  Metabolized primarily in the liver by CYP2C8 and CYP3A4 to form the active metabolite N-desmethyl apalutamide.
• Elimination:
• Half-life: ~3 days
• Excretion:
• 65% via urine (mainly metabolites)
• 24% via feces
• Steady State:
  Achieved in approximately 4 weeks of daily administration.

• Pregnancy:
  Contraindicated in pregnant women. Although not FDA-categorized under the old system, apalutamide is embryotoxic and teratogenic in animal studies. It is not for use in women. Men with female partners of reproductive potential must use effective contraception during treatment and for at least 3 months after the last dose.
• Lactation:
  Not applicable. It is unknown whether apalutamide is excreted in human milk. Use in breastfeeding women is contraindicated due to potential risks to a nursing infant.

• Primary Class: Androgen Receptor Inhibitor
• Subclass: Second-generation non-steroidal antiandrogen

• Known hypersensitivity to apalutamide or any component of the formulation
• Use in women, especially pregnant or breastfeeding
• Patients at high risk for seizures due to structural brain lesions, recent stroke, or concurrent use of drugs that lower seizure threshold

• Seizures:
  Apalutamide may lower the seizure threshold. Discontinue if a seizure occurs. Avoid in patients with predisposing conditions.
• Falls and Fractures:
  Increased risk of falls and fractures reported. Consider bone health assessments and preventive therapy.
• Hypothyroidism:
  Regular monitoring of thyroid function is recommended.
• Hepatotoxicity:
  Monitor liver enzymes periodically, especially in those with pre-existing hepatic impairment.
• Hypertension:
  Blood pressure should be regularly monitored and managed.
• Cardiovascular Risk:
  May increase the risk of ischemic heart disease and other events. Use with caution in those with known cardiovascular disease.

Common Adverse Effects (≥10%):

• General: Fatigue, decreased appetite, weight loss
• Musculoskeletal: Fractures, arthralgia, back pain, falls
• Endocrine/Metabolic: Hypothyroidism
• Dermatologic: Rash
• Cardiovascular: Hypertension
• Neurological: Dizziness

Serious or Rare Adverse Effects:

• Seizures (<0.2%)
• Hepatotoxicity (elevated liver enzymes)
• Myocardial infarction and ischemic heart disease
• Interstitial lung disease (very rare)
• QT prolongation (in patients with predisposing factors)

Severity & Onset:

• Most side effects are mild to moderate and appear within the first 3–6 weeks.
• Serious effects (e.g., seizure) are rare but warrant immediate discontinuation.

• CYP Enzyme Induction:
  Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and a moderate inducer of CYP2C9. It may reduce plasma concentrations of drugs metabolized by these enzymes (e.g., warfarin, midazolam, omeprazole, clopidogrel).
• Seizure Risk Potentiators:
  Use with caution or avoid combining with medications that lower seizure threshold (e.g., bupropion, SSRIs, fluoroquinolones, clozapine).
• QT-Prolonging Drugs:
  Caution with drugs that prolong the QT interval (e.g., amiodarone, sotalol).
• P-gp/BCRP Substrates:
  Apalutamide may reduce levels of P-gp and BCRP substrates such as digoxin or rosuvastatin.
• Food & Alcohol:
  Food has no clinically significant interaction. Alcohol may increase sedation or fall risk; caution advised.

• NCCN Guidelines (2023–2024):
  Apalutamide remains a Category 1 recommendation for both nmCRPC and mCSPC settings in combination with ADT.
• FDA Safety Update (2022):
  Strengthened labeling for seizure risk and emphasized liver function monitoring.
• EMA Advisory (2023):
  Recommends evaluation and prophylactic treatment for bone loss when starting apalutamide.

• Temperature:
  Store at below 25°C (77°F). Allowable temperature excursions between 15°C and 30°C.
• Protection:
  Keep in original container. Protect from light and moisture.
• Handling Instructions:
  No special handling needed. Keep away from children.
• Reconstitution/Refrigeration:
  Not applicable. Tablets should not be split or crushed.