Nubeqa - Drug Monograph

Introduction

Nubeqa (darolutamide) is an oral androgen receptor inhibitor developed by Bayer Healthcare Pharmaceuticals. It was approved by the FDA in July 2019 for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). Nubeqa represents a significant advancement in prostate cancer treatment, offering improved survival outcomes with a favorable safety profile compared to earlier generation anti-androgens.

Mechanism of Action

Darolutamide competitively inhibits androgen binding to androgen receptors, thereby blocking androgen receptor nuclear translocation and androgen receptor-mediated transcription. Unlike some other anti-androgens, darolutamide has a distinct chemical structure that may limit its ability to cross the blood-brain barrier, potentially reducing the risk of central nervous system-related adverse effects. The drug demonstrates potent antagonistic activity even against mutant androgen receptors commonly found in castration-resistant prostate cancer.

Indications

Nubeqa is indicated in combination with androgen deprivation therapy for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC). This indication is based on the ARAMIS clinical trial which demonstrated a significant improvement in metastasis-free survival and overall survival.

Dosage and Administration

• Standard dosage: 600 mg (two 300 mg tablets) taken 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 (eGFR ≥30 mL/min/1.73 m²). Use caution in severe impairment (eGFR <30 mL/min/1.73 m²) - Hepatic impairment: No dosage adjustment necessary for mild impairment (Child-Pugh A). Use caution in moderate impairment (Child-Pugh B). Not recommended in severe impairment (Child-Pugh C) - Geriatric patients: No dosage adjustment required - Pediatric patients: Safety and effectiveness not established

Pharmacokinetics

• Absorption: Time to peak plasma concentration (Tmax) is approximately 4 hours under fed conditions
• Distribution: Plasma protein binding is approximately 92%, primarily to albumin
• Metabolism: Primarily metabolized via CYP3A4 and UGT1A9 enzymes, with minor contributions from CYP2C8 and CYP2C9
• Elimination: Elimination half-life is approximately 20 hours. Approximately 63% excreted in urine (mostly as metabolites) and 32% in feces
• Bioavailability: Increased by approximately 2 to 2.5-fold when administered with food

Contraindications

• Hypersensitivity to darolutamide or any component of the formulation
• Pregnancy (may cause fetal harm based on mechanism of action and animal studies)

Warnings and Precautions

• Embryo-fetal toxicity: May cause fetal harm. Patients should use effective contraception during treatment and for 1 week after final dose
• Fatigue and asthenia: May occur; patients should be cautioned about operating machinery or driving
• Cardiovascular events: Ischemic heart disease and heart failure have been reported. Monitor for signs and symptoms of cardiovascular disorders
• Seizures: Although rare, seizures have occurred (0.2% in clinical trials). Use with caution in patients with history of seizures or predisposing factors

Drug Interactions

• Strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin): May decrease darolutamide concentrations. Avoid concomitant use
• BCRP substrates (e.g., rosuvastatin, methotrexate): Darolutamide may increase concentrations of these drugs. Monitor for adverse effects and consider dose reduction
• P-gp substrates (e.g., digoxin): Darolutamide may increase concentrations. Monitor digoxin levels and adjust dose as needed
• OATP1B1/B3 substrates (e.g., statins): May have increased exposure. Consider alternative drugs or monitor for adverse effects

Adverse Effects

• Fatigue (16%)
• Pain in extremity (12%)
• Rash (12%)
• Constipation (9%)
• Arthralgia (8%)
• Diarrhea (8%)
• Hypertension (8%)
• Nausea (6%)

• Ischemic heart disease (3.2%)
• Heart failure (2.1%)
• Seizure (0.2%)

Monitoring Parameters

• Prostate-specific antigen (PSA) levels regularly
• Complete blood count periodically
• Liver function tests at baseline and periodically
• Blood pressure monitoring
• Signs and symptoms of cardiovascular disease
• Bone health assessment (consider bone density scanning)
• Assessment for fatigue and cognitive function
• Monitoring for seizures in predisposed patients

Patient Education

• Take Nubeqa exactly as prescribed, with food, at approximately the same times each day
• Do not stop treatment without consulting your healthcare provider
• Inform all healthcare providers about your Nubeqa treatment
• Report any new or worsening symptoms, especially:

- Chest pain, shortness of breath, or irregular heartbeat - Severe fatigue or weakness - Dizziness, confusion, or seizure activity - Rash or other skin changes

• Use effective contraception during treatment and for 1 week after final dose if sexually active with a partner who can become pregnant
• Maintain regular follow-up appointments for monitoring
• Store medication at room temperature in original container

References

1. FDA prescribing information: Nubeqa (darolutamide) tablets. July 2019. 2. Fizazi K, et al. Darolutamide in Nonmetastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2019;380(13):1235-1246. 3. Shore ND, et al. Darolutamide in nonmetastatic castration-resistant prostate cancer: extended follow-up and subgroup analysis of the phase III ARAMIS trial. Eur Urol. 2021;80(3):330-338. 4. Smith MR, et al. Darolutamide and health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the phase III ARAMIS trial. Eur Urol. 2021;79(3):397-406. 5. Moilanen AM, et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep. 2015;5:12007.