Introduction
Darolutamide is a novel nonsteroidal androgen receptor inhibitor approved for the treatment of prostate cancer. It represents a significant advancement in the management of non-metastatic castration-resistant prostate cancer (nmCRPC), offering a distinct pharmacological profile with potentially improved safety and efficacy compared to earlier generation antiandrogens.
Mechanism of Action
Darolutamide competitively inhibits androgen binding to androgen receptors, thereby blocking androgen receptor nuclear translocation and impairing androgen receptor-mediated transcription. Unlike some other antiandrogens, darolutamide demonstrates a unique chemical structure that may limit central nervous system penetration, potentially reducing certain CNS-related adverse effects. The drug exhibits high affinity for androgen receptors while showing low affinity for gamma-aminobutyric acid type A (GABA-A) receptors, which may contribute to its favorable safety profile.
Indications
Darolutamide is FDA-approved for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease. The European Medicines Agency has similarly approved darolutamide for this indication. Clinical trials have demonstrated significant improvement in metastasis-free survival in this patient population.
Dosage and Administration
Standard dosing: 600 mg (two 300 mg tablets) orally twice daily with food Administration: Should be taken with food to improve bioavailability Special populations:- Renal impairment: No dosage adjustment necessary for mild to moderate impairment. Use with caution in severe renal impairment (CrCl <30 mL/min)
- Hepatic impairment: No dosage adjustment necessary for mild impairment (Child-Pugh A). Use with caution in moderate to severe hepatic impairment (Child-Pugh B or C)
- Elderly patients: No dosage adjustment required based on age alone
Pharmacokinetics
Absorption: Bioavailability is approximately 30-40% when taken with food. Tmax occurs approximately 4 hours after administration. Distribution: Volume of distribution is approximately 119 L. Protein binding is >92%, primarily to albumin. Metabolism: Primarily metabolized via UGT1A9, UGT1A1, and CYP3A4 enzymes. The active metabolite, keto-darolutamide, is formed via oxidation. Elimination: Elimination half-life is approximately 20 hours. Excretion is primarily fecal (63.4%) with renal excretion accounting for 32.4% of the dose.Contraindications
- Hypersensitivity to darolutamide or any component of the formulation
- Pregnancy (may cause fetal harm based on mechanism of action)
- Women who are or may become pregnant
Warnings and Precautions
Central Nervous System Effects: Although designed for limited CNS penetration, fatigue and mental impairment disorders have been observed. Monitor patients for cognitive function. Cardiovascular Events: Ischemic heart disease and heart failure have been reported. Assess cardiovascular risk before initiation. Fracture Risk: Androgen deprivation therapy may decrease bone mineral density. Consider bone density monitoring and supplementation. Embryo-Fetal Toxicity: May cause fetal harm. Males with female partners of reproductive potential should use effective contraception during treatment and for 1 week after final dose.Drug Interactions
Strong CYP3A4 Inducers: Avoid concomitant use with drugs such as rifampin, carbamazepine, phenytoin, and St. John's wort, as they may decrease darolutamide concentrations BCRP and P-gp Substrates: Darolutamide may increase concentrations of substrates such as rosuvastatin, dabigatran, and digoxin. Monitor closely and consider dose reduction OATP1B1 and OATP1B3 Substrates: May increase exposure to statins and other substrates. Consider alternative agents or monitor for adverse effectsAdverse Effects
Common adverse reactions (≥10%):- Fatigue (16%)
- Pain in extremity (12%)
- Rash (11%)
- Constipation (7%)
- Hypertension (7%)
- Cardiovascular events (myocardial infarction, heart failure)
- Fractures
- Cognitive impairment
- Neutropenia
- Increased AST/ALT
Monitoring Parameters
- Prostate-specific antigen (PSA) levels regularly
- Complete blood count with differential at baseline and periodically
- Liver function tests at baseline and periodically
- Bone health assessment (consider DEXA scan)
- Cardiovascular assessment including blood pressure monitoring
- Cognitive function assessment
- Signs and symptoms of disease progression
Patient Education
- Take medication exactly as prescribed with food
- Do not stop treatment without consulting your healthcare provider
- Report any new or worsening symptoms, especially chest pain, shortness of breath, or neurological changes
- Use effective contraception if your partner could become pregnant
- Maintain regular follow-up appointments for monitoring
- Be aware of potential drug interactions and inform all healthcare providers about darolutamide use
- Report any signs of infection, as neutropenia may occur
- Maintain bone health through adequate calcium and vitamin D intake and weight-bearing exercise
References
1. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2019;380(13):1235-1246. 2. FDA Approval Letter: NDA 212099. U.S. Food and Drug Administration. 2019. 3. Zurth C, Sandmann S, Trummel D, et al. Blood-Brain Barrier Permeation of Darolutamide Compared with Enzalutamide and Apalutamide. J Clin Pharmacol. 2020;60(10):1309-1317. 4. Darolutamide [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2022. 5. 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. 6. 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.