Introduction
Erleada (apalutamide) is a novel oral antiandrogen medication developed for the treatment of prostate cancer. It is a next-generation androgen receptor inhibitor specifically designed to target the androgen signaling pathway, which plays a crucial role in prostate cancer progression. Approved by the FDA in 2018, Erleada represents a significant advancement in the management of both non-metastatic and metastatic castration-resistant prostate cancer.
Mechanism of Action
Erleada works through direct inhibition of the androgen receptor. Apalutamide binds to the ligand-binding domain of the androgen receptor, preventing androgen-induced receptor translocation into the nucleus. This inhibition blocks androgen receptor-mediated gene transcription, thereby interfering with prostate cancer cell proliferation and survival. Unlike first-generation antiandrogens, apalutamide does not demonstrate agonist activity in clinical settings and effectively suppresses tumor growth even in the presence of androgen receptor overexpression or specific mutations.
Indications
- Non-metastatic castration-resistant prostate cancer (nmCRPC)
- Metastatic castration-sensitive prostate cancer (mCSPC)
- Used in combination with androgen deprivation therapy
Dosage and Administration
Standard dosing: 240 mg (four 60 mg tablets) orally once daily Administration: Can be taken with or without food. Tablets should be swallowed whole with water. Special populations:- Renal impairment: No dosage adjustment necessary for mild to moderate impairment. Use with caution in severe renal impairment.
- Hepatic impairment: No dosage adjustment necessary for mild impairment. Reduce dose to 180 mg daily in moderate impairment (Child-Pugh Class B). Not recommended in severe hepatic impairment (Child-Pugh Class C).
- Geriatric patients: No dosage adjustment required.
- Race/Ethnicity: No specific dosage recommendations based on race.
Pharmacokinetics
Absorption: Median Tmax is approximately 2 hours. High-fat meal reduces Cmax by 22% and AUC by 10%. Distribution: Apparent volume of distribution is 276 L. Protein binding is 96%, primarily to albumin. Metabolism: Primarily metabolized via CYP2C8 and CYP3A4. N-desmethyl apalutamide is the major active metabolite. Elimination: Half-life is approximately 113 hours. Excretion is primarily fecal (65%) with renal elimination accounting for 35% of the dose.Contraindications
- Hypersensitivity to apalutamide or any component of the formulation
- Pregnancy (based on mechanism of action and animal studies)
- Women who are or may become pregnant
Warnings and Precautions
Seizure: Erleada may increase the risk of seizures. Permanently discontinue in patients who experience a seizure. Falls and fractures: Increased risk of falls and fractures has been observed. Evaluate patients for fracture risk. Cardiovascular adverse events: Ischemic heart disease and heart failure have been reported. Monitor for cardiovascular signs and symptoms. Rash: Various skin reactions including erythema, pruritis, and maculopapular rash may occur. Hypothyroidism: May cause thyroid-stimulating hormone (TSH) elevation. Monitor thyroid function during treatment.Drug Interactions
Strong CYP3A4 inducers: Avoid concomitant use with drugs such as rifampin, carbamazepine, and St. John's wort CYP3A4 substrates: May decrease concentrations of sensitive CYP3A4 substrates (e.g., midazolam, simvastatin) CYP2C8 substrates: May decrease concentrations of CYP2C8 substrates (e.g., repaglinide, paclitaxel) P-gp substrates: May decrease concentrations of P-gp substrates (e.g., digoxin) Warfarin: Monitor INR more frequently when co-administeredAdverse Effects
Most common adverse reactions (≥10%):- Fatigue (39%)
- Hypertension (25%)
- Rash (24%)
- Diarrhea (20%)
- Nausea (18%)
- Arthralgia (16%)
- Weight decreased (16%)
- Hot flush (14%)
- Falls (16%)
- Fractures (12%)
- Seizure (0.4%)
- Ischemic heart disease (3.6%)
- Heart failure (2.1%)
- Severe skin reactions
Monitoring Parameters
- PSA levels at baseline and every 3-6 months
- Complete blood count periodically
- Liver function tests at baseline and periodically
- Thyroid function tests (TSH) at baseline and during treatment
- Blood pressure monitoring regularly
- Bone density assessment in patients at risk for fracture
- Neurological assessment for seizure risk factors
- Cardiovascular assessment regularly
- Signs and symptoms of rash and skin reactions
Patient Education
- Take medication exactly as prescribed at the same time each day
- Do not stop treatment without consulting your healthcare provider
- Report any falls, dizziness, or balance problems immediately
- Inform all healthcare providers about Erleada use before starting new medications
- Use effective contraception if partner is pregnant or may become pregnant
- Report any skin changes, rashes, or itching
- Be aware of potential increased risk of seizures and avoid activities where sudden loss of consciousness could cause serious harm
- Maintain regular follow-up appointments for monitoring
- Report any chest pain, shortness of breath, or palpitations
References
1. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. 2. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. 3. Erleada (apalutamide) prescribing information. Janssen Pharmaceutical Companies; 2022. 4. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465-2474. 5. Rathkopf DE, Smith MR, Ryan CJ, et al. Safety and efficacy of apalutamide in patients with metastatic castration-sensitive prostate cancer: final analysis of the TITAN study. J Clin Oncol. 2021;39(20):2294-2303. 6. National Comprehensive Cancer Network. Prostate Cancer Guidelines Version 2.2023. 7. US Food and Drug Administration. Erleada approval documents. 2018.