Darolutamide

Usage

Darolutamide is prescribed for the treatment of:

• Non-metastatic castration-resistant prostate cancer (nmCRPC): In men at high risk of developing metastatic disease.
• Metastatic hormone-sensitive prostate cancer (mHSPC): In combination with docetaxel.

Pharmacological Classification: Nonsteroidal antiandrogen, androgen receptor inhibitor.

Mechanism of Action: Darolutamide competitively binds to androgen receptors, inhibiting androgen binding, nuclear translocation, and ultimately, androgen receptor-mediated transcription. This blocks the effects of androgens (like testosterone) on prostate cancer cells, inhibiting their growth and proliferation.

Alternate Names

Generic Name: Darolutamide

Brand Name: Nubeqa®

How It Works

Pharmacodynamics: Darolutamide exerts its anti-cancer effects by directly targeting androgen receptors within prostate cancer cells. By blocking the action of androgens, darolutamide inhibits the growth and proliferation of these cells.

Pharmacokinetics:

• Absorption: Darolutamide reaches maximum concentration (Cmax) approximately 4 hours after oral administration. Food increases bioavailability 2 to 2.5-fold. Absorption is saturable at higher doses.
• Distribution: Darolutamide crosses the blood-brain barrier.
• Metabolism: Primarily hepatic metabolism via CYP3A4 to its active metabolite, ketodarolutamide.
• Elimination: Primarily via feces, with a small portion excreted in urine. Elimination half-life of darolutamide is approximately 40 hours.

Mode of Action: Darolutamide competitively inhibits androgen binding to androgen receptors. This prevents the receptor from translocating to the nucleus and initiating androgen-dependent gene transcription, thus disrupting prostate cancer cell growth.

Receptor Binding: Darolutamide directly binds to the ligand-binding domain of the androgen receptor.

Enzyme Inhibition: Darolutamide inhibits BCRP (Breast Cancer Resistance Protein) and may weakly inhibit CYP2C9.

Dosage

Standard Dosage

Adults:

• nmCRPC: 600 mg (two 300 mg tablets) orally twice daily with food.
• mHSPC: 600 mg (two 300 mg tablets) orally twice daily with food in combination with docetaxel (75 mg/m² IV every 3 weeks for up to 6 cycles).

Children: Use is not recommended. Safety and efficacy have not been established in pediatric patients.

Special Cases:

• Elderly Patients: No dose adjustment is generally necessary.
• Patients with Renal Impairment:
  • Mild to moderate: No dose adjustment necessary.
  • Severe (eGFR 15–29 mL/min/1.73 m²): 300 mg twice daily.
• Patients with Hepatic Dysfunction:
  • Mild: No dose adjustment necessary.
  • Moderate (Child-Pugh Class B): 300 mg twice daily.
  • Severe (Child-Pugh Class C): No data available, use with caution.
• Patients with Comorbid Conditions: Use with caution in patients with cardiovascular disease, seizures, brain injury, or brain tumors. Optimize cardiovascular risk management and monitor closely.

Clinical Use Cases

Darolutamide is not indicated for the clinical situations mentioned (intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations). It is specifically indicated for nmCRPC and mHSPC, as outlined above.

Dosage Adjustments

For Grade ≥3 toxicity or intolerable adverse reaction: Withhold or reduce dose to 300 mg twice daily until symptoms improve. Therapy may then be resumed at 600 mg twice daily.

Side Effects

Common Side Effects:

• Fatigue
• Rash
• Decreased appetite
• Falls
• Fracture
• Hypertension

Rare but Serious Side Effects:

• Ischemic heart disease
• Heart failure
• Seizures
• Drug-induced liver injury

Long-Term Effects: May increase risk of osteoporosis with long-term use.

Adverse Drug Reactions (ADR): Falls and fractures are significant ADRs, especially in elderly patients, requiring assessment and appropriate interventions.

Contraindications

• Hypersensitivity to darolutamide or any of its components.
• Women who are or may become pregnant.

Drug Interactions

• CYP3A4 Inducers (e.g., rifampicin): Reduce darolutamide exposure; avoid concomitant use.
• Combined P-gp and strong CYP3A4 Inhibitors (e.g., itraconazole): Increase darolutamide exposure; monitor closely for adverse reactions.
• BCRP Substrates (e.g., rosuvastatin): Darolutamide may increase BCRP substrate exposure, increasing their risk of toxicities. Avoid coadministration or select alternative medications.

Pregnancy and Breastfeeding

Pregnancy Safety Category: Contraindicated in women who are or may become pregnant. Darolutamide may cause fetal harm. Males with female partners of reproductive potential should use effective contraception during treatment and for 1 week after the last dose.

Breastfeeding: Contraindicated. It is unknown if darolutamide is present in human milk.

Drug Profile Summary

• Mechanism of Action: Androgen receptor inhibitor.
• Side Effects: Fatigue, rash, decreased appetite, falls, fractures, and others (see above).
• Contraindications: Hypersensitivity, pregnancy.
• Drug Interactions: CYP3A4 inducers/inhibitors, P-gp inhibitors, BCRP substrates.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: 600 mg BID orally with food (adjustments may be needed - see above).
• Monitoring Parameters: Liver function tests (LFTs), complete blood count (CBC), cardiovascular status.

Popular Combinations

• mHSPC: Darolutamide + docetaxel + androgen deprivation therapy (ADT).

Precautions

• Evaluate cardiovascular risk and manage hypertension before starting treatment.
• Monitor for signs and symptoms of falls and fractures, especially in the elderly.
• Assess and manage any other comorbidities, including seizures or hepatic/renal dysfunction.
• Patients with female partners of reproductive potential should use effective contraception.
• Do not take with grapefruit products.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Darolutamide?

A: For nmCRPC and mHSPC, the standard adult dose is 600 mg orally twice daily with food. Dosage adjustments are necessary for moderate hepatic impairment and severe renal impairment (300 mg twice daily). It is not recommended for use in children.

Q2: How does Darolutamide differ from other androgen receptor inhibitors?

A: While all AR inhibitors target the androgen receptor, they have different chemical structures and potentially different side effect profiles. Darolutamide has been associated with a lower risk of certain side effects like seizures and cognitive impairment compared to some other AR inhibitors.

Q3: Can Darolutamide be used in patients with liver or kidney problems?

A: Yes, but dosage adjustments are needed for moderate hepatic impairment and severe renal impairment. For severe hepatic impairment and end-stage renal disease, data are limited and caution is advised.

Q4: What are the most common side effects of Darolutamide?

A: The most common side effects are fatigue, rash, decreased appetite, falls, fractures, and hypertension.

Q5: Are there any drug interactions I should be aware of with Darolutamide?

A: Yes. Avoid concomitant use with strong CYP3A4 inducers and combined P-gp and strong CYP3A4 inhibitors. Co-administration with BCRP substrates may require dosage adjustments or alternate medications.

Q6: Can Darolutamide be used in women?

A: No. Darolutamide is contraindicated in women, particularly those who are pregnant or may become pregnant.

Q7: What should I do if a patient misses a dose of Darolutamide?

A: The patient should take the missed dose as soon as remembered, unless the next scheduled dose is within 6 hours. Do not double the dose.

Q8: How should Darolutamide be stored?

A: Store at room temperature (20-25°C), protected from light and moisture. Keep the bottle tightly closed after opening.

Q9: Does Darolutamide interact with food?

A: Yes, darolutamide should be taken with food. Food increases its bioavailability.

Q10: How does darolutamide affect the heart?

A: Darolutamide may increase the risk of ischemic heart disease. Monitor patients for chest pain, discomfort, irregular heartbeat, and other related symptoms.