Darolutamide

Darolutamide is an androgen receptor (AR) inhibitor. Androgens act through the AR to support the growth and survival of prostate cancer cells, so blocking the receptor reduces tumour cell proliferation and lowers prostate-specific antigen (PSA). In the pivotal studies every patient also received a luteinising hormone-releasing hormone (LHRH) agonist or antagonist, or had undergone bilateral orchiectomy.

Mechanism of Action

• Receptor binding: darolutamide has a flexible, polar-substituted pyrazole structure and binds with high affinity directly to the ligand-binding domain of the AR.
• Inhibition: it competitively inhibits androgen binding, nuclear translocation of the receptor and AR-mediated transcription. This decreases the proliferation of prostate tumour cells and gives potent antitumour activity.
• Active metabolite: the main circulating metabolite, keto-darolutamide, showed similar activity to darolutamide in vitro. Darolutamide consists of two diastereomers, (S,R) and (S,S), which interconvert through keto-darolutamide; all three substances have similar pharmacological activity.
• Cardiac electrophysiology: no prolongation of the mean QTcF interval (more than 10 ms) was seen after 600 mg twice daily compared with placebo.

Pharmacokinetics

• Absorption: peak plasma concentrations at steady state after 600 mg twice daily were 4.79 mg/L in patients with nmCRPC and 3.84 mg/L in patients with mHSPC, reached after a median of 3 to 4 hours. Absolute bioavailability is about 30% on an empty stomach and rises 2.0- to 2.5-fold with food, which is why the tablets are taken with a meal. Steady state is reached after 2 to 5 days of twice-daily dosing with food. Exposure increases roughly in proportion to dose between 100 and 700 mg; absorption saturates, with no further rise at 900 mg twice daily.
• Distribution: the volume of distribution after an intravenous dose is 119 L. Darolutamide is 92% bound to plasma proteins and keto-darolutamide 99.8%. Brain exposure in rats and mice was very low, which suggests little passage across the intact blood–brain barrier.
• Metabolism: mainly oxidation by CYP3A4, together with direct glucuronidation by UGT1A9 and UGT1A1. Keto-darolutamide is the only major metabolite, with about twice the plasma exposure of darolutamide.
• Elimination: the effective half-life of darolutamide and keto-darolutamide is about 18 to 20 hours, and clearance after an intravenous dose is 116 mL/min. After a radiolabelled dose, 63.4% of the material appeared in urine (about 7% unchanged) and 32.4% in faeces, with more than 95% recovered within 7 days.
• Special populations: no clinically relevant difference was found in the elderly (65–95 years). In severe renal impairment (eGFR 15–29 mL/min/1.73 m²) AUC was 2.5-fold and Cmax 1.6-fold higher than in healthy volunteers; in moderate hepatic impairment (Child-Pugh B) AUC was 1.9-fold and Cmax 1.5-fold higher. There are no data in severe hepatic impairment or in patients on dialysis. No clinically relevant differences were seen by ethnicity, although a population analysis estimated up to 1.56-fold higher exposure in Japanese patients.

Darolutamide is indicated for the treatment of adult men with:

• Non-metastatic castration-resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease.
• Metastatic hormone-sensitive prostate cancer (mHSPC) with androgen deprivation therapy: darolutamide in combination with androgen deprivation therapy.
• Metastatic hormone-sensitive prostate cancer (mHSPC) with docetaxel: darolutamide in combination with docetaxel and androgen deprivation therapy.

• Hypersensitivity to darolutamide or to any of the excipients.
• Women who are or may become pregnant.

The most frequent adverse reaction in men with nmCRPC or mHSPC taking darolutamide is fatigue or asthenic conditions (13.7%). When darolutamide is combined with docetaxel for mHSPC, the most frequent are rash (16.6%) and hypertension (13.8%). The groups below follow the two SmPC tables: one for darolutamide with androgen deprivation therapy (ARAMIS and ARANOTE studies) and one for the docetaxel combination (ARASENS study), where some frequencies may partly reflect the other medicines used.

Very common (≥1/10): fatigue and asthenic conditions (fatigue, asthenia, lethargy, malaise); decreased neutrophil count, increased blood bilirubin, increased ALT and increased AST (reported as laboratory abnormalities). With docetaxel, also hypertension and rash.

Common (≥1/100 to <1/10): ischaemic heart disease, heart failure, rash, pain in extremity and fractures (darolutamide with androgen deprivation therapy); fractures and gynaecomastia (with docetaxel).

In the studies with androgen deprivation therapy, ischaemic heart disease occurred in 3.4% of patients on darolutamide (2.2% on placebo), with fatal events in 0.4% in each group, and heart failure in 1.6% (0.9% on placebo). Fractures occurred in 4.1% (3.2% on placebo), and in 7.5% (5.1%) in the docetaxel study. Cases of idiosyncratic drug-induced liver injury with grade 3 and 4 transaminase rises have been reported, starting 1 to 12 months after treatment began; the rises were often reversible after darolutamide was stopped. With docetaxel, hypertension was reported mostly in patients with no history of it, and rash was most frequent in the first 6 months.

Darolutamide is a substrate of CYP3A4, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), and it inhibits BCRP, OATP1B1 and OATP1B3.

• Strong and moderate CYP3A4 and P-gp inducers (carbamazepine, phenobarbital, St John’s wort, phenytoin, rifampicin): not recommended unless there is no therapeutic alternative. Rifampicin reduced darolutamide exposure (AUC) by 72% and peak concentration by 52%. An alternative with no or weak induction potential should be considered.
• Combined P-gp and strong CYP3A4 inhibitors: itraconazole raised darolutamide exposure (AUC) 1.7-fold and peak concentration 1.4-fold. Patients should be monitored more often for adverse reactions and the dose modified as needed. Inhibitors of CYP3A4, P-gp or BCRP on their own, and UGT1A9 inhibitors, can be given without restriction.
• BCRP, OATP1B1 and OATP1B3 substrates: rosuvastatin exposure rose about 5-fold, so rosuvastatin should be avoided unless there is no alternative. Other substrates (for example methotrexate, sulfasalazine, fluvastatin, atorvastatin, pitavastatin) may also reach higher levels; patients should be monitored for their adverse reactions and the recommendations in their own product information followed. Other BCRP substrates should be avoided where possible.
• P-gp substrates: no clinically relevant interaction is expected (for example digoxin, verapamil, nifedipine); exposure to dabigatran etexilate did not increase.
• CYP3A4 substrates: darolutamide is a mild CYP3A4 inducer. It lowered the exposure of a sensitive CYP3A4 probe substrate by 29% (AUC) and 32% (peak), and can be given with warfarin, L-thyroxine or omeprazole.
• Docetaxel: no clinically relevant change in the pharmacokinetics of either medicine.
• Medicines that prolong the QT interval: because androgen deprivation therapy may prolong the QT interval, combinations with class IA (quinidine, disopyramide) or class III (amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmics, methadone, moxifloxacin or antipsychotics (such as haloperidol) should be carefully evaluated.
• Food and herbal products: the tablets are taken with food, which increases absorption. St John’s wort should be avoided.

Treatment should be started and supervised by a specialist physician experienced in the treatment of prostate cancer. The tablets are swallowed whole, with food.

Recommended Dose

• 600 mg (two 300 mg tablets) twice daily, a total daily dose of 1,200 mg.
• Treatment continues until disease progression or unacceptable toxicity.
• Medical castration with an LHRH agonist or antagonist (GnRH analogue) continues in patients who have not been surgically castrated.
• With docetaxel (mHSPC): darolutamide is started together with docetaxel, and the first of 6 cycles of docetaxel is given within 6 weeks of starting darolutamide. Darolutamide continues until disease progression or unacceptable toxicity even if a docetaxel cycle is delayed, interrupted or stopped. Docetaxel is dosed according to its own product information.

Dose Adjustments

• For a grade 3 or higher toxicity, or an intolerable adverse reaction related to darolutamide, the dose is withheld or reduced to 300 mg twice daily until symptoms improve; 600 mg twice daily may then be resumed.
• Reducing the dose below 300 mg twice daily is not recommended, because efficacy has not been established.
• Treatment is stopped permanently if liver test abnormalities suggest idiosyncratic drug-induced liver injury.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no adjustment in mild or moderate impairment. In severe impairment (eGFR 15–29 mL/min/1.73 m²) not on haemodialysis, the recommended starting dose is 300 mg twice daily.
• Hepatic impairment: no adjustment in mild impairment. In moderate and severe impairment (Child-Pugh B and C) the recommended starting dose is 300 mg twice daily.
• Children and adolescents: darolutamide has no relevant use in the paediatric population.

Missed Dose

Take the missed dose as soon as it is remembered, before the next scheduled dose. Do not take two doses together to make up for a missed dose.

Renal and Hepatic Impairment

Data in severe renal impairment and in moderate hepatic impairment are limited, and darolutamide has not been studied in severe hepatic impairment. Exposure may be higher in these patients, so they should be monitored closely for adverse reactions and begin at the reduced dose (see Administration and Dosage).

Recent Cardiovascular Disease

Patients with clinically significant cardiovascular disease in the previous 6 months (stroke, myocardial infarction, severe or unstable angina, coronary or peripheral artery bypass graft, symptomatic congestive heart failure) were excluded from the clinical studies, so the safety of darolutamide in these patients has not been established. Patients with clinically significant cardiovascular disease should be treated for it according to established guidelines.

Liver Injury

Treatment is stopped permanently if liver function test abnormalities suggest idiosyncratic drug-induced liver injury.

QT Prolongation

Androgen deprivation therapy may prolong the QT interval. In patients with risk factors for QT prolongation, or who take medicines that may prolong it, the doctor should weigh benefit against risk, including the potential for torsade de pointes, before starting darolutamide.

Interacting Medicines

Strong CYP3A4 and P-gp inducers lower darolutamide levels and are not recommended unless there is no therapeutic alternative. Patients taking BCRP, OATP1B1 or OATP1B3 substrates should be monitored for adverse reactions, and rosuvastatin should be avoided unless there is no alternative.

Pregnancy, Breastfeeding and Fertility

• Women: darolutamide is not indicated in women of childbearing potential and must not be used by women who are, or may be, pregnant or breastfeeding.
• Contraception for men: it is not known whether darolutamide or its metabolites are present in semen. A man who is sexually active with a woman of childbearing potential must use a highly effective contraceptive method (failure rate below 1% per year) during treatment and for 1 week after the last dose. With a pregnant partner, a condom should be used during treatment and for 1 week afterwards, so that the foetus is not exposed to an androgen receptor inhibitor through seminal transfer.
• Pregnancy: because of its mechanism of action darolutamide may cause foetal harm. No non-clinical reproductive toxicity studies have been conducted.
• Breastfeeding: it is unknown whether darolutamide or its metabolites pass into human milk, and a risk to the breastfed child cannot be excluded.
• Fertility: there are no human data. In animal studies darolutamide may impair fertility in males of reproductive potential.

Lactose

Each tablet contains 186 mg of lactose monohydrate. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Effect on Driving

Darolutamide has no or negligible influence on the ability to drive and use machines.

Nubeqa tablets do not require any special storage conditions. They are supplied in PVC/aluminium foil blisters of 16 tablets, with 112 tablets in each pack. Keep out of the sight and reach of children.

3 years. Do not use after the expiry date stated on the pack.

Prescription only (Rx), subject to restricted medical prescription: treatment is started and supervised by a specialist physician experienced in the treatment of prostate cancer. Darolutamide is a tablet taken at home, so it is supplied to the patient or to the treating clinic on prescription.