darolutamide: prescribing information – dosing, contraindications, interactions, side effects

NUBEQA 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 (see section 5.1).
- metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (see section 5.1).
- metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel and androgen deprivation therapy (see section 5.1).

Treatment should be initiated and supervised by a specialist physician experienced in treatment of prostate cancer.

Posology

The recommended dose is 600 mg darolutamide (two tablets of 300 mg) taken twice daily, equivalent to a total daily dose of 1200 mg (see section 5.2).

Darolutamide should be continued until disease progression or unacceptable toxicity.

Medical castration with a luteinising hormone-releasing hormone (LHRH) agonist or antagonist (GnRH analogue) should be continued during treatment of patients not surgically castrated.

metastatic hormone-sensitive prostate cancer (mHSPC) – treatment with darolutamide in combination with docetaxel mHSPC patients should start darolutamide in combination with docetaxel (see section 5.1). The first of 6 cycles of docetaxel should be administered within 6 weeks after the start of darolutamide treatment.
The recommendation in the product information of docetaxel should be followed. Treatment with darolutamide should be continued until disease progression or unacceptable toxicity even if a cycle of docetaxel is delayed, interrupted, or discontinued.

Missed dose
If a dose is missed, the dose should be taken as soon as the patient remembers prior to the next scheduled dose. The patient should not take two doses together to make up for a missed dose.

Dose modification
If a patient experiences a ≥ Grade 3 toxicity or an intolerable adverse reaction related to darolutamide (see sections 4.4 and 4.8), dosing should be withheld or reduced to 300 mg twice daily until symptoms improve. Treatment may then be resumed at a dose of 600 mg twice daily.

Dose reduction below 300 mg twice daily is not recommended, because efficacy has not been established.

Special populations

Elderly
No dose adjustment is necessary in elderly patients (see section 5.2).

Renal impairment
No dose adjustment is necessary for patients with mild or moderate renal impairment.
For patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) not receiving haemodialysis, the recommended starting dose is 300 mg twice daily (see sections 4.4 and 5.2).

Hepatic impairment
No dose adjustment is necessary for patients with mild hepatic impairment.
The available data on darolutamide pharmacokinetics in moderate hepatic impairment is limited.
Darolutamide has not been studied in patients with severe hepatic impairment.
For patients with moderate and severe hepatic impairment (Child-Pugh Classes B and C), the recommended starting dose is 300 mg twice daily (see sections 4.4 and 5.2.).

Paediatric population
There is no relevant use of darolutamide in the paediatric population.

Method of administration

NUBEQA is for oral use.

The tablets should be taken whole with food (see section 5.2).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Women who are or may become pregnant (see section 4.6).

Summary of the safety profile

The most frequently observed adverse reactions in patients with
- nmCRPC or mHSPC receiving darolutamide are fatigue/asthenic conditions (13.7%)
- mHSPC receiving darolutamide in combination with docetaxel are rash (16.6%) and hypertension (13.8%).

For additional safety information when darolutamide is administered in combination, refer to the product information of the individual medicinal products.

Tabulated list of adverse reactions

The adverse reactions observed in patients with nmCRPC or mHSPC treated with darolutamide are listed in Table 1. The adverse reactions observed in patients with mHSPC treated with darolutamide in combination with docetaxel are listed in Table 2.
Adverse reactions are classified according to System Organ Class. They are grouped according to their frequencies. Frequency groups are defined by the following convention: very common (≥ 1/10);
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).
Within each frequency group, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions reported in nmCRPC and mHSPC patients treated with darolutamide in ARAMIS and ARANOTE studiesa System organ class (MedDRA) Very common Common Cardiac disorders

Ischaemic heart diseaseb
Heart failurec
Skin and subcutaneous tissue disorders

Rashd
Musculoskeletal and connective tissue disorders

Pain in extremity
Fractures
General disorders and administration site conditions
Fatigue/asthenic conditionse
Investigationsf
Neutrophil count decreased
Blood bilirubin increased
ALT increased
AST increased

a
The median duration of exposure in the ARAMIS and ARANOTE studies was 18.2 months (range:
0.0 to 44.3 months) in patients treated with darolutamide and 11.6 months (range: 0.0 to 40.5 months) in patients treated with placebo.
b
Includes arteriosclerosis coronary artery, coronary artery disease, coronary artery occlusion, coronary artery stenosis, acute coronary syndrome, acute myocardial infarction, angina pectoris, angina unstable, myocardial infarction, myocardial ischaemia.
c
Includes cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiogenic shock, heart failure with preserved ejection fraction.
d
Includes rash, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, dermatitis.
e
Includes fatigue and asthenia, lethargy and malaise.

f
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The incidence is based on values reported as laboratory abnormalities.

Table 2: Adverse reactions reported in mHSPC patients treated with darolutamide in combination with docetaxel in the ARASENS studya, b System organ class (MedDRA) Very common Common Vascular disorders Hypertensionc

Skin and subcutaneous tissue disorders
Rashd, e

Musculoskeletal and connective tissue disorders

Fractures
Reproductive system and breast disorders

Gynaecomastia
Investigationsf
Neutrophil count decreased
Blood bilirubin increased
ALT increased
AST increased

a
The median duration of exposure was 41.0 months (range: 0.1 to 56.5 months) in patients treated with darolutamide+docetaxel and 16.7 months (range: 0.3 to 55.8 months) in patients treated with placebo+docetaxel.
b
Adverse reactions incidences may not be attributable to darolutamide alone but may contain contributions from other medicinal products used in combination.
c
Includes hypertension, blood pressure increased, hypertensive emergency.
d
Includes rash, drug eruption, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, erythema, dermatitis.
e
The incidence was highest during the first 6 months of treatment.
f
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The incidence is based on values reported as laboratory abnormalities.

Description of selected adverse reactions

Liver function tests
Cases of idiosyncratic druginduced liver injury with grade 3 and 4 increases in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) to ≥ 5 and ≥ 20 x upper limit of normal (ULN) have been reported with darolutamide treatment including increased transaminases along with a simultaneous increase in total bilirubin to ≥ 2 x ULN. Time to onset ranged from 1 month to 12 months after initiation of darolutamide. In many cases the ALT and AST elevations were reversible upon darolutamide discontinuation. For specific recommendations, see section 4.4.

non-metastatic castration resistant prostate cancer (nmCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC) - treatment with darolutamide Fatigue Fatigue/asthenic conditions were reported in 13.7% of patients treated with darolutamide and in 11.7% of patients treated with placebo. Events with worst grade of 3 were reported in 0.4% of patients treated with darolutamide and in 0.9% of patients treated with placebo. Fatigue (not including asthenia, lethargy or malaise) occurred in the majority of patients (10.0% of patients treated with darolutamide and 8.5% of patients treated with placebo).

Fractures
Fractures occurred in 4.1% of patients treated with darolutamide and in 3.2% of patients treated with placebo.

Ischaemic heart disease and heart failure
Ischaemic heart disease occurred in 3.4% of patients treated with darolutamide and in 2.2% of patients treated with placebo. Grade 5 events occurred in 0.4% of patients treated with darolutamide and 0.4% of patients treated with placebo. Heart failure occurred in 1.6% of patients treated with darolutamide and in 0.9% of patients treated with placebo.

Neutrophil count decreased
Neutrophil count decreased was reported as a laboratory abnormality in 17.3% of patients treated with darolutamide and in 7.4% of patients treated with placebo. The median time to nadir was 225 days.
The laboratory tests abnormalities manifested predominantly as grade 1 or 2 intensity. Neutrophil count decreased of grade 3 and 4 was reported in 2.6% and 0.3% of patients, respectively. Only one patient permanently discontinued darolutamide due to neutropenia. Neutropenia was either transient or reversible (83% of patients) and were not associated with any clinically relevant signs or symptoms.

Blood bilirubin increased
Bilirubin increased was reported as a laboratory abnormality in 16.1% of patients treated with darolutamide and in 6.1% of patients treated with placebo. The episodes were predominantly of grade 1 or 2 intensity, not associated with any clinically relevant signs or symptoms, and reversible after darolutamide was discontinued. Bilirubin increased of grade 3 and 4 was reported in 0.2% of patients treated with darolutamide and in 0% of patients treated with placebo. In the darolutamide arm, the mean time to first onset of increased bilirubin was 187 days, and the mean duration of the first episode was 172 days. One patient was discontinued from treatment due to increase in bilirubin.

ALT and AST increased
ALT increased was reported as a laboratory abnormality in 13.3% of patients treated with darolutamide and in 9.7% of patients treated with placebo. AST increased was reported as a laboratory abnormality in 22.0% of patients treated with darolutamide and in 13.4% of patients treated with placebo. The episodes were predominantly of grade 1 or 2 intensity, not associated with any clinically relevant signs or symptoms, and reversible after darolutamide was discontinued. ALT increased of grade 3 and 4 was reported in 0.9% of patients treated with darolutamide and in 0.3% of patients treated with placebo. AST increased of grade 3 and 4 was reported in 1.2% of patients treated with darolutamide and in 0.3% of patients treated with placebo. In the darolutamide arm, the mean time to first onset of increased ALT was 253 days and for increased AST 257 days. The mean duration of the first episode was 122 days for ALT increase and 121 days for AST increase. Two and 3 patients were discontinued from treatment due to increase in ALT and AST, respectively.

metastatic hormone-sensitive prostate cancer (mHSPC) - treatment with darolutamide in combination with docetaxel Hypertension In the ARASENS study hypertension was reported in 13.8% of patients treated with darolutamide+docetaxel and 9.4% of patients treated with placebo+docetaxel.
Grade 3 hypertension was reported in 6.4% of patients treated with darolutamide+docetaxel compared to 3.5% of patients treated with placebo+docetaxel. One patient had grade 4 hypertension in each treatment arm.
One case was reported as grade 5 hypertension with grade 5 arteriosclerosis in the darolutamide+docetaxel arm. This patient had a long-standing history of hypertension and smoking and the case occurred more than 3 years after starting darolutamide treatment. Events of hypertension were reported more commonly in patients with no medical history of hypertension in both treatment arms.

Fractures
Fractures occurred in 7.5% of patients treated with darolutamide+docetaxel and in 5.1% of patients treated with placebo+docetaxel.

Neutrophil count decreased
Neutrophil count decreased was reported as a laboratory abnormality in 50.6% of patients treated with darolutamide+docetaxel and in 45.5% of patients treated with placebo+docetaxel. Grade 3 and 4 neutrophil count decreased was reported in 34.4% of patients treated with darolutamide+docetaxel and in 31.4% of patients treated with placebo+docetaxel. In both treatment arms, the incidences of neutrophil count decreased and neutropenia were highest during the first months of treatment, after which the incidence and severity of the events decreased.

Blood bilirubin increased
Bilirubin increased was reported as a laboratory abnormality in 19.6% of patients treated with darolutamide+docetaxel and in 10.0% of patients treated with placebo+docetaxel. The events were predominantly of grade 1 or 2 intensity. Grade 3 and 4 bilirubin increased was reported in 0.5% of patients treated with darolutamide+docetaxel and in 0.3% of patients treated with placebo+docetaxel.

ALT and AST increased
Alanine aminotransferase (ALT) increased was reported as a laboratory abnormality in 42.3% of patients treated with darolutamide+docetaxel and in 38.0% of patients treated with placebo+docetaxel.
Aspartate aminotransferase (AST) increased was reported as a laboratory abnormality in 43.9% of patients treated with darolutamide+docetaxel and in 39.3% of patients treated with placebo+docetaxel.
ALT and AST elevations were predominantly of grade 1 intensity. Grade 3 and 4 ALT increased was reported in 3.7% of patients treated with darolutamide+docetaxel and in 3.0% of patients treated with placebo+docetaxel. Grade 3 and 4 AST increased was reported in 3.6% of patients treated with darolutamide+docetaxel and in 2.3% of patients treated with placebo+docetaxel.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Renal impairment

The available data in patients with severe renal impairment are limited.
As exposure might be increased those patients should be closely monitored for adverse reactions (see sections 4.2 and 5.2).

Hepatic impairment

The available data in patients with moderate hepatic impairment are limited, and darolutamide has not been studied in patients with severe hepatic impairment.
As exposure might be increased those patients should be closely monitored for adverse reactions (see sections 4.2 and 5.2).

Recent cardiovascular disease

Patients with clinically significant cardiovascular disease in the past 6 months including stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, and symptomatic congestive heart failure were excluded from the clinical studies. Therefore, the safety of darolutamide in these patients has not been established.
If NUBEQA is prescribed, patients with clinically significant cardiovascular disease should be treated for these conditions according to established guidelines.

Hepatotoxicity

In case of liver function test abnormalities suggestive of idiosyncratic drug-induced liver injury, permanently discontinue treatment with darolutamide (see section 4.8).

Concomitant use with other medicinal products

Use of strong CYP3A4 and P-gp inducers during treatment with darolutamide may decrease the plasma concentration of darolutamide and is not recommended, unless there is no therapeutic alternative. Selection of an alternate concomitant medicinal product with less potential to induce CYP3A4 or P-gp should be considered (see section 4.5).

Patients should be monitored for adverse reactions of BCRP, OATP1B1 and OATP1B3 substrates as co-administration with darolutamide may increase the plasma concentrations of these substrates.
Co-administration with rosuvastatin should be avoided unless there is no therapeutic alternative (see section 4.5).

Androgen deprivation therapy may prolong the QT interval

In patients with a history of risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5), physicians should assess the benefit-risk ratio including the potential for Torsade de pointes prior to initiating NUBEQA.

Information about excipients

NUBEQA contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Effects of other medicinal products on darolutamide

CYP3A4 and P-gp inducers
Darolutamide is a substrate of CYP3A4 and P-glycoprotein (P-gp).
Use of strong and moderate CYP3A4 inducers and P-gp inducers (e.g. carbamazepine, phenobarbital, St. John's Wort, phenytoin, and rifampicin) during treatment with darolutamide is not recommended, unless there is no therapeutic alternative. Selection of an alternate concomitant medicinal product, with no or weak potential to induce CYP3A4 or P-gp should be considered.
Repeated administration of rifampicin (600 mg), a strong CYP3A4 and a P-gp inducer, with a single dose of darolutamide (600 mg) together with food, resulted in a decrease of 72% in mean exposure (AUC0-72) and a decrease of 52% in Cmax of darolutamide.

CYP3A4, P-gp and BCRP inhibitors
Darolutamide is a substrate of CYP3A4, P-gp and breast cancer resistance protein (BCRP).
No clinically relevant drug-drug interaction is expected in case of CYP3A4, P-gp or BCRP inhibitor administration. Darolutamide may be given concomitantly with CYP3A4, P-gp or BCRP inhibitors.
Concomitant use of darolutamide with a combined P-gp and strong CYP3A4 inhibitor increases darolutamide exposure which may increase the risk of darolutamide adverse reactions. It is recommended to monitor patients more frequently for darolutamide adverse reactions and modify darolutamide dose as needed.
Administration of itraconazole (200 mg twice daily on day 1 and once daily on the following 7 days), a strong CYP3A4, P-gp and BCRP inhibitor, with a single dose of darolutamide (600 mg on day 5 together with food) resulted in a 1.7-fold increase in mean exposure (AUC0-72) and a 1.4-fold increase of Cmax of darolutamide.

UGT1A9 inhibitors
Darolutamide is a substrate of UGT1A9.
No clinically relevant drug-drug interaction is expected in case of UGT1A9 inhibitor administration.
Darolutamide may be given concomitantly with UGT1A9 inhibitors.
A population pharmacokinetic analysis showed that co-administration of UGT1A9 inhibitors with darolutamide resulted in a 1.2-fold increase in exposure (AUC0-72) of darolutamide.

Docetaxel
Administration of darolutamide in combination with docetaxel resulted in no clinically relevant changes in the pharmacokinetics of darolutamide in mHSPC patients (see section 5.1).

Effects of darolutamide on other medicinal products

BCRP, OATP1B1 and OATP1B3 substrates
Darolutamide is an inhibitor of breast cancer resistance protein (BCRP) and Organic Anion Transporting Polypeptides (OATP) 1B1 and 1B3.
Co-administration of rosuvastatin should be avoided unless there is no therapeutic alternative.
Selection of an alternative concomitant medicinal product with less potential to inhibit BCRP, OATP1B1 and OATP1B3 should be considered.
Administration of darolutamide (600 mg twice daily for 5 days) prior to co-administration of a single dose of rosuvastatin (5 mg) together with food resulted in approximately 5-fold increase in mean exposure (AUC) and Cmax of rosuvastatin.
Co-administration of darolutamide with other BCRP substrates should be avoided where possible.
Co-administration of darolutamide may increase the plasma concentrations of other concomitant BCRP, OATP1B1 and OATP1B3 substrates (e.g. methotrexate, sulfasalazine, fluvastatin, atorvastatin, pitavastatin). Therefore, it is recommended to monitor patients for adverse reactions of BCRP, OATP1B1 and OATP1B3 substrates. In addition, the related recommendation in the product information of these substrates should be followed when co-administered with darolutamide.

P-gp substrates
No clinically relevant drug-drug interaction is expected in case of P-gp substrate administration.
Darolutamide may be given concomitantly with P-gp substrates (e.g. digoxin, verapamil or nifedipine). Co-administration of darolutamide together with the sensitive P-gp substrate dabigatran etexilate did not reveal any increase in exposure (AUC and Cmax) of dabigatran.

CYP3A4 substrates
Darolutamide is a mild inducer of CYP3A4.
No clinically relevant drug-drug interaction is expected in case of CYP substrate administration.
Darolutamide may be given concomitantly with CYP substrates (e.g. warfarin, L-thyroxine, omeprazole).
Administration of darolutamide (600 mg twice daily for 9 days) prior to co-administration of a single dose of the sensitive CYP3A4 substrate midazolam (1 mg) together with food, decreased the mean exposure (AUC) and Cmax of midazolam by 29% and 32%, respectively.
Darolutamide did not inhibit the metabolism of selected CYP substrates in vitro at clinically relevant concentrations.

Docetaxel
Administration of darolutamide in combination with docetaxel resulted in no clinically relevant changes in the pharmacokinetics of docetaxel in mHSPC patients (see section 5.1).

Medicinal products that prolong the QT interval

Since androgen deprivation treatment may prolong the QT interval, the co-administration with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes should be carefully evaluated. These include medicinal products such as class IA (e.g., quinidine, disopyramide) or class III (e.g., amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, and antipsychotics (e.g. haloperidol).

This medicinal product is not indicated in women of childbearing potential. It is not to be used in women who are, or may be, pregnant or breast-feeding (see sections 4.1 and 4.3).

Women of childbearing potential / contraception in males and females

It is not known whether darolutamide or its metabolites are present in semen. If the patient is engaged in sexual activity with a woman of childbearing potential, a highly effective contraceptive method (< 1% failure rate per year) should be used during and for 1 week after completion of treatment with NUBEQA to prevent pregnancy.

Pregnancy

Based on its mechanism of action, darolutamide may cause foetal harm. No non-clinical reproductive toxicity studies have been conducted (see section 5.3).
It is not known whether darolutamide or its metabolites are present in semen. If the patient is engaged in sexual activity with a pregnant woman, a condom should be used during and for 1 week after completion of treatment with NUBEQA. Exposure of the foetus to an androgen receptor inhibitor through seminal transfer to the pregnant woman has to be avoided, as this could affect development of the foetus.

Breast-feeding

It is unknown whether darolutamide or its metabolites are excreted in human milk. No studies in animals have been conducted to evaluate the excretion of darolutamide or its metabolites into milk (see section 5.3). A risk to the breast-fed child cannot be excluded.

Fertility

There are no human data on the effect of darolutamide on fertility.
Based on animal studies, NUBEQA may impair fertility in males of reproductive potential (see section 5.3).

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

The highest dose of darolutamide studied clinically was 900 mg twice daily, equivalent to a total daily dose of 1800 mg. No dose limiting toxicities were observed with this dose.
Considering the saturable absorption (see section 5.2) and the absence of evidence for acute toxicity, an intake of a higher than recommended dose of darolutamide is not expected to lead to toxicity.
In the event of intake of a higher than recommended dose, treatment with darolutamide can be continued with the next dose as scheduled.
There is no specific antidote for darolutamide and symptoms of overdose are not established.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Endocrine therapy, anti-androgens; ATC code: L02BB06

Mechanism of action

Darolutamide is an androgen receptor (AR) inhibitor with a flexible polar-substituted pyrazole structure that binds with high affinity directly to the receptor ligand binding domain.
Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR mediated transcription. A major metabolite, keto-darolutamide, exhibited similar in vitro activity to darolutamide. Darolutamide treatment decreases prostate tumour cell proliferation leading to potent antitumour activity.

Pharmacodynamic effects

No prolongation of the mean QTcF interval (i.e., greater than 10 ms) was observed after oral administration of 600 mg darolutamide twice daily compared to placebo.

Clinical efficacy and safety

Efficacy and safety were established in 3 randomised placebo-controlled multicentre phase III studies in patients with nmCRPC (ARAMIS) and mHSPC (ARANOTE and ARASENS). All patients received a luteinising hormone-releasing hormone (LHRH) agonist or antagonist concurrently or had a bilateral orchiectomy.

non-metastatic castration resistant prostate cancer (nmCRPC) - treatment with darolutamide The efficacy and safety of darolutamide was assessed in a randomised, double-blind, placebo-controlled multicentre phase III study (ARAMIS) in patients with non-metastatic (as assessed by conventional imaging CT, bone scan, MRI) castration resistant prostate cancer with a prostate-specific antigen doubling time (PSADT) of ≤ 10 months.
Patients were included in the trial if they had 3 rising prostate-specific antigen (PSA) levels after the nadir taken at least 1 week apart during androgen deprivation therapy, PSA ≥ 2 ng/mL at screening and castrate level of serum testosterone < 1.7 nmol/L.
Patients with a medical history of seizure were allowed to enter the study. There were 12 patients (0.21%) enrolled on the darolutamide arm with a history of seizure.
Patients with uncontrolled hypertension or recent (in the past 6 months) stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure New York Heart Association (NYHA) Class III or IV were excluded from the study.
Patients with prior treatment with second generation AR inhibitors such as enzalutamide, apalutamide and darolutamide, or CYP17 enzyme inhibitors such as abiraterone acetate as well as patients receiving systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/day within 28 days before randomisation were excluded from the study.
In total, 1509 patients were randomized 2:1 to receive either 600 mg darolutamide orally twice daily (n=955) or matching placebo (n=554).

General introduction

Darolutamide consists of two diastereomers [(S,R)-darolutamide and (S,S)-darolutamide] which interconvert via the main circulating metabolite called keto-darolutamide. In vitro, all three substances show similar pharmacological activity. Darolutamide is poorly soluble in aqueous solvents over a large pH range and generally more soluble in organic solvents.

Months from Randomization
Patients at risk
Overall Survival Probability (%)
1 - Darolutamide+docetaxel (N = 651)

2 - Placebo+docetaxel (N = 654)

Absorption

Following oral administration of 600 mg (2 tablets of 300 mg) twice daily, peak plasma concentrations of darolutamide at steady state were 4.79 mg/L (coefficient of variation: 30.9%) in nmCRPC patients in the ARAMIS study and 3.84 mg/L (coefficient of variation: 35.6%) in mHSPC patients in the ARASENS study. Median time to achieve peak plasma concentrations was 3 to 4 hours. The ratio of the two diastereomers, (S,R)-darolutamide to (S,S)-darolutamide, changed from a 1:1 ratio in the tablet to an approximately 1:9 ratio in plasma based on AUC0-12 data at steady-state. Following oral administration together with food, steady-state is reached after 2-5 days of repeated twice-daily dosing.
The absolute bioavailability compared to an intravenous injection is approximately 30% following oral administration of a NUBEQA tablet containing 300 mg darolutamide under fasted conditions.
Bioavailability of darolutamide was enhanced by 2.0- to 2.5-fold when administered with food. A similar increase of exposure was observed for the major metabolite keto-darolutamide.

Distribution

The apparent volume of distribution of darolutamide after intravenous administration is 119 L indicating that darolutamide is widely distributed throughout the body to both intracellular and extracellular fluid spaces.