Introduction

Antineoplastic agent; a nonsteroidal antiandrogen.

Uses for Darolutamide (Systemic)

Nonmetastatic Castration-resisitant Prostate Cancer

Treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) in adult patients who are either receiving concomitant treatment with a gonadotropin-releasing hormone (GnRH) analog or who have had a bilateral orchiectomy.

The use of an androgen receptor antagonist (i.e., darolutamide, apalutamide, enzalutamide) is recommended for patients with nmCRPC who are at high risk of metastases.

Metastatic Hormone-sensitive Prostate Cancer

Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel in adult patients who are receiving concomitant treatment with a GnRH analog or who have had a bilateral orchiectomy.

In selected patients with de novo mHSPC, clinicians should offer androgen deprivation therapy (ADT) in combination with docetaxel and either abiraterone acetate plus prednisone or darolutamide.

Darolutamide (Systemic) Dosage and Administration

General

Patient Monitoring

• Monitor for signs and symptoms of ischemic heart disease.

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), darolutamide is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Other General Considerations

• Ensure patient is receiving concomitant treatment with a GnRH analog or has had a bilateral orchiectomy.

Administration

Oral Administration

Administer orally twice daily with food. Swallow tablets whole.

Dosage

Adults

Nonmetastic Castration-resistant Prostate Cancer

Oral

600 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Metastatic Hormone-sensitive Prostate Cancer

Oral

600 mg twice daily.

In combination with docetaxel, administer the first of 6 cycles of docetaxel within 6 weeks after the start of darolutamide treatment. Refer to docetaxel prescribing information for additional dosing information, including dosage modifications.

Continue treatment until disease progression or unacceptable toxicity occurs, even if a cycle of docetaxel is delayed, interrupted, or discontinued.

Dosage Modifications for Toxicity

Oral

Interupt therapy or reduce dosage to 300 mg twice daily if intolerable or grade 3 or greater adverse effect occurs. Resume dosage of 600 mg twice daily when the adverse reaction returns to baseline. Dosage reduction <300 mg twice daily not recommended.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): No initial dosage adjustment required.

Moderate hepatic impairment (Child-Pugh class B): 300 mg twice daily.

Severe hepatic impairment (Child-Pugh class C): Not studied.

Renal Impairment

Mild or moderate renal impairment (eGFR 30–89 mL/minute per 1.73 m²): No initial dosage adjustment required.

Severe renal impairment (eGFR 15–29 mL/minute per 1.73 m²) not receiving hemodialysis: 300 mg twice daily.

End-stage renal disease (eGFR <15 mL/minute per 1.73 m²): Not studied.

Geriatric Use

No special dosage recommendations; most patients in principal efficacy study were geriatric.

Contraindications

• None.

Warnings/Precautions

Ischemic Heart Disease

Ischemic heart disease reported, including fatalities.

Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue for Grade 3 or 4 ischemic heart disease.

Seizures

Seizures reported.

Unknown whether anti-epileptic medications will prevent seizures. Advise patients of risk of seizures and risk of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation in patients who develop a seizure during treatment.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm and potential loss of pregnancy. Safety and efficacy not established in females.

Males with female partners of reproductive potential should use effective methods of contraception during therapy and for 1 week after the last dose of the drug.

Specific Populations

Pregnancy

May cause fetal harm and potential loss of pregnancy.

Lactation

Not known whether darolutamide or its metabolites are distributed into milk, affect milk production, or affect nursing infants.

Female and Males of Reproductive Potential

Males with female partners of reproductive potential should use effective methods of contraception during darolutamide therapy and for 1 week after the last dose of the drug.

Based on animal studies, darolutamide may impair fertility in males of reproductive potential.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No overall differences in safety or efficacy relative to younger adults.

Hepatic Impairment

Exposure to darolutamide increased in individuals with moderate hepatic impairment. Pharmacokinetics not established in patients with severe hepatic impairment.

Renal Impairment

Exposure to darolutamide increased in individuals with severe renal impairment not receiving dialysis. Pharmacokinetics not established in patients with end-stage renal disease.

Common Adverse Effects

Adverse effects occurring in ≥2% of patients with nmCRPC include fatigue, pain in extremity, and rash. Laboratory test abnormalities reported in ≥2% of these patients include increased AST, decreased neutrophil count, and increased bilirubin.

Adverse effects occuring in ≥10% of patients with mHSPC include constipation, decreased appetite, rash, hemorrhage, increased weight, and hypertension. Laboratory test abnormalities in these patients (≥30%) include anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST and ALT, and hypocalcemia.

General

Patient Monitoring

• Monitor for signs and symptoms of ischemic heart disease.

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), darolutamide is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Other General Considerations

• Ensure patient is receiving concomitant treatment with a GnRH analog or has had a bilateral orchiectomy.

Administration

Oral Administration

Administer orally twice daily with food. Swallow tablets whole.

Dosage

Adults

Nonmetastic Castration-resistant Prostate Cancer

Oral

600 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Metastatic Hormone-sensitive Prostate Cancer

Oral

600 mg twice daily.

In combination with docetaxel, administer the first of 6 cycles of docetaxel within 6 weeks after the start of darolutamide treatment. Refer to docetaxel prescribing information for additional dosing information, including dosage modifications.

Continue treatment until disease progression or unacceptable toxicity occurs, even if a cycle of docetaxel is delayed, interrupted, or discontinued.

Dosage Modifications for Toxicity

Oral

Interupt therapy or reduce dosage to 300 mg twice daily if intolerable or grade 3 or greater adverse effect occurs. Resume dosage of 600 mg twice daily when the adverse reaction returns to baseline. Dosage reduction <300 mg twice daily not recommended.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): No initial dosage adjustment required.

Moderate hepatic impairment (Child-Pugh class B): 300 mg twice daily.

Severe hepatic impairment (Child-Pugh class C): Not studied.

Renal Impairment

Mild or moderate renal impairment (eGFR 30–89 mL/minute per 1.73 m²): No initial dosage adjustment required.

Severe renal impairment (eGFR 15–29 mL/minute per 1.73 m²) not receiving hemodialysis: 300 mg twice daily.

End-stage renal disease (eGFR <15 mL/minute per 1.73 m²): Not studied.

Geriatric Use

No special dosage recommendations; most patients in principal efficacy study were geriatric.

Metabolized principally by CYP3A4; also metabolized by UGT1A9 and UGT1A1.

Induces CYP3A4 and inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro; also inhibits organic anion transport protein (OATP) 1B1 and OATP1B3 in vitro.

Did not inhibit the major CYP enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 or transporters, including multidrug resistance protein 2 (MRP2), bile salt export pump (BSEP), organic anion transporters (OATs), organic cation transporters (OCTs), multidrug and toxin extrusion transporters (MATEs), OATP2B1, and sodium taurocholate co-transporting polypeptide (NTCP), at clinically relevant concentrations.

Drugs Affecting Hepatic Microsomal Enzymes and P-glycoprotein

Combined P-gp and potent CYP3A4 inhibitors: Increased darolutamide exposure and possible increased risk of darolutamide adverse effects. Monitor patients more frequently for darolutamide toxicity, and modify darolutamide dosage as needed.

Combined P-gp and moderate or potent CYP3A4 inducers: Decreased darolutamide exposure and possible decreased darolutamide activity. Avoid concomitant use.

Moderate CYP3A4 inducers: Decrease of 36–58% in darolutamide exposure expected.

Drugs Affected by Breast Cancer Resistance Protein and Organic Anion Transport Protein

BCRP substrates: Increased exposure of BCRP substrate and possible increased risk of BCRP substrate-related toxicity. Avoid concomitant use when possible. If concomitant use cannot be avoided, monitor patients more frequently for adverse effects; consult manufacturer's prescribing information for BCRP substrate and consider dosage reduction of BCRP substrate.

OATP1B1/OATP1B3 substrates: Increased exposure of OATP1B1 or OATP1B3 substrate and possible increased risk of substrate-related toxicity. Monitor for adverse reactions of these drugs and reduce dosage if needed while taking darolutamide.

Specific Drugs