Darolutamide (Monograph)

Brand name: Nubeqa
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Sep 25, 2023. Written by ASHP.

Introduction

Antineoplastic agent; a nonsteroidal antiandrogen.

Uses for Darolutamide

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 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.

Related/similar drugs

Erleada, estradiol, Premarin, Xtandi, Zytiga, Casodex, Lynparza

Cautions for Darolutamide

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.

Drug Interactions

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

Darolutamide Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability of a 300-mg dose administered orally under fasted conditions is approximately 30%.

Following oral administration of a single 600-mg dose, peak plasma concentration is attained in approximately 4 hours.

Steady-state concentrations are achieved after 2–5 days of repeated dosing with food, with approximately twofold accumulation.

Exposure is nearly dose proportional over a dose range of 100–700 mg.

Food

Bioavailability increases 2 to 2.5-fold when administered with food.

Special Populations

Mild hepatic impairment (Child-Pugh class A): No clinically important effect on pharmacokinetics in patients with nonmetastatic castration-resistant prostate cancer.

Moderate hepatic impairment (Child-Pugh class B): Darolutamide exposure increased 1.9-fold compared with individuals with normal hepatic function.

Severe hepatic impairment (Child-Pugh class C): Effect on pharmacokinetics not established.

Mild to moderate renal impairment (eGFR 30–80 mL/minute per 1.73 m²): No clinically important effect on pharmacokinetics in prostate cancer patients.

Severe renal impairment (eGFR 15–29 mL/minute per 1.73 m²) not receiving dialysis: Darolutamide exposure in individuals without cancer increased 2.5-fold compared with those with normal renal function.

End-stage renal disease (eGFR <15 mL/minute per 1.73 m²): Effect on pharmacokinetics not established.

Age (range: 48–95 years): No clinically important effects on pharmacokinetics of darolutamide in prostate cancer patients.

Race: No clinically important effects on pharmacokinetics of darolutamide in prostate cancer patients.

Distribution

Extent

Not known whether darolutamide or its metabolites are distributed into milk.

Crosses blood-brain barrier to negligible or lesser extent compared with enzalutamide and apalutamide.

Plasma Protein Binding

Darolutamide: 92% (mainly albumin).

Keto-darolutamide: 99.8% (mainly albumin).

Elimination

Metabolism

Metabolized principally by CYP3A4 to form keto-darolutamide, as well as by UGT1A9 and 1A1. Keto-darolutamide has similar activity as the parent drug in vitro, but is expected to be of minor pharmacologic importance in vivo because of its small unbound fraction.

Elimination Route

Excreted in urine (63.4%; 7% as unchanged drug) and feces (32.4%; 30% as unchanged drug).

Half-life

Darolutamide: Approximately 20 hours.

Keto-darolutamide: Approximately 20 hours.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C). Keep bottle tightly closed.

Actions

• Competitively inhibits androgen binding to androgen receptors; mechanisms of action are similar to those of enzalutamide and apalutamide.

• Inhibits nuclear translocation of the androgen receptor, interaction of the androgen receptor with DNA, and androgen receptor-mediated gene transcription.

• Inhibits tumor growth in vitro and decreases tumor volume in xenograft models of castration-resistant prostate cancer in mice.

• Structurally unrelated to enzalutamide and apalutamide; darolutamide appears to cross blood-brain barrier to negligible or lesser extent and to have less affinity for GABA type A (GABA_A) receptors, with the potential for an improved CNS adverse effect profile (e.g., decreased seizure risk).

• Unlike conventional antiandrogens but similar to other second generation antiandrogens (e.g., enzalutamide, apalutamide), darolutamide does not exhibit agonistic activity in cells that overexpress the androgen receptor.

• In addition to inhibiting wild-type androgen receptors, darolutamide also inhibits mutant androgen receptors known to trigger bicalutamide, enzalutamide, and apalutamide antagonist-to-agonist switch.

Advice to Patients

• Inform patients that darolutamide has been associated with an increased risk of ischemic heart disease. Advise patients to seek immediate medical attention if any symptoms suggestive of an ischemic heart disease event occur.

• Inform patients that darolutamide has been associated with an increased risk of seizures and discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their healthcare provider right away if they experience loss of consciousness or a seizure.

• Advise patients currently receiving gonadotropin-releasing hormone (GnRH) analog therapy to continue this therapy during darolutamide therapy.

• Advise patients to take darolutamide as instructed with food and to swallow tablets whole. If a dose is missed, the missed dose should be taken as soon as it is remembered prior to the next scheduled dose. The dose should not be doubled to make up for a missed dose.

• Risk of fetal harm and loss of pregnancy. Advise patients with female partners of reproductive potential to use effective methods of contraception during darolutamide therapy and for 1 week after the last dose of the drug.

• Advise patients that darolutamide may impair male fertility.

• Advise patients to inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Darolutamide can only be obtained through designated specialty pharmacies. Contact the manufacturer or consult the Nubeqa specialty pharmacy network ([Web]) for specific information.

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