NUBEQA 300mg tablets medication leaflet

NUBEQA 300 mg film-coated tablets

Each film-coated tablet contains 300 mg of darolutamide.

Each film-coated tablet contains 186 mg of lactose monohydrate (see section 4.4).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

White to off-white, oval tablets with a length of 16 mm and a width of 8 mm, marked with “300” onone side, and “BAYER” on the other side.

NUBEQA is indicated for the treatment of adult men with

- non-metastatic castration resistant prostate cancer (nmCRPC) who are at high risk of developingmetastatic disease (see section 5.1).

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

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

The recommended dose is 600 mg darolutamide (two tablets of 300 mg) taken twice daily, equivalentto 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) analogue should becontinued during treatment of patients not surgically castrated.

metastatic hormone-sensitive prostate cancer (mHSPC)mHSPC patients should start darolutamide in combination with docetaxel (see section 5.1). The first of6 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 withdarolutamide should be continued until disease progression or unacceptable toxicity even if a cycle ofdocetaxel is delayed, interrupted, or discontinued.

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

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 symptomsimprove. 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 beenestablished.

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

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).

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), therecommended starting dose is 300 mg twice daily (see sections 4.4 and 5.2.).

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

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).

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 (seesections 4.2 and 5.2).

The available data in patients with moderate hepatic impairment are limited, and darolutamide has notbeen studied in patients with severe hepatic impairment.

As exposure might be increased those patients should be closely monitored for adverse reactions (seesections 4.2 and 5.2).

Patients with clinically significant cardiovascular disease in the past 6 months including stroke,myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, andsymptomatic congestive heart failure were excluded from the clinical studies. Therefore, the safety ofdarolutamide in these patients has not been established.

If NUBEQA is prescribed, patients with clinically significant cardiovascular disease should be treatedfor these conditions according to established guidelines.

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

Use of strong CYP3A4 and P-gp inducers during treatment with darolutamide may decrease theplasma concentration of darolutamide and is not recommended, unless there is no therapeuticalternative. 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 asco-administration with darolutamide may increase the plasma concentrations of these substrates.

Co-administration with rosuvastatin should be avoided unless there is no therapeutic alternative (seesection 4.5).

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

NUBEQA contains lactose. Patients with rare hereditary problems of galactose intolerance, totallactase 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 singledose 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 inhibitoradministration. 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 increasesdarolutamide exposure which may increase the risk of darolutamide adverse reactions. It isrecommended to monitor patients more frequently for darolutamide adverse reactions and modifydarolutamide 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 5together with food) resulted in a 1.7-fold increase in mean exposure (AUC0-72) and a 1.4-fold increaseof 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 withdarolutamide 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 relevantchanges 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 singledose of rosuvastatin (5 mg) together with food resulted in approximately 5-fold increase in meanexposure (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 productinformation of these substrates should be followed when co-administered with darolutamide.

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 ornifedipine). Co-administration of darolutamide together with the sensitive P-gp substrate dabigatranetexilate did not reveal any increase in exposure (AUC and Cmax) of dabigatran.

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 singledose of the sensitive CYP3A4 substrate midazolam (1 mg) together with food, decreased the meanexposure (AUC) and Cmax of midazolam by 29% and 32%, respectively.

Darolutamide did not inhibit the metabolism of selected CYP substrates in vitro at clinically relevantconcentrations.

Docetaxel

Administration of darolutamide in combination with docetaxel resulted in no clinically relevantchanges 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 withmedicinal products known to prolong the QT interval or medicinal products able to induce Torsade depointes 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) antiarrhythmicmedicinal 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 inwomen 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 engagedin 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.

Based on its mechanism of action, darolutamide may cause foetal harm. No non-clinical reproductivetoxicity 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 engagedin sexual activity with a pregnant woman, a condom should be used during and for 1 week aftercompletion of treatment with NUBEQA. Exposure of the foetus to an androgen receptor inhibitorthrough seminal transfer to the pregnant woman has to be avoided, as this could affect development ofthe foetus.

It is unknown whether darolutamide or its metabolites are excreted in human milk. No studies inanimals 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.

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 (seesection 5.3).

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

The most frequently observed adverse reactions in patients with

- nmCRPC receiving darolutamide are fatigue/asthenic conditions (15.8%)

- mHSPC receiving darolutamide in combination with docetaxel are rash (16.6%) andhypertension (13.8%).

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

The adverse reactions observed in patients with nmCRPC treated with darolutamide are listed in

Table 1. The adverse reactions observed in patients with mHSPC treated with darolutamide incombination with docetaxel are listed in Table 2.

Adverse reactions are classified according to System Organ Class. They are grouped according to theirfrequencies. 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); veryrare (< 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 the ARAMIS studya

System organ class Very common Common(MedDRA)

Cardiac disorders Ischaemic heart diseaseb

Heart failurec

Skin and subcutaneous tissue disorders Rashd

Musculoskeletal and connective tissue Pain in extremitydisorders Musculoskeletal pain

Fractures

General disorders and administration Fatigue/asthenic conditionsesite conditions

Investigationsf Neutrophil count decreased

Blood bilirubin increased

AST increaseda The median duration of exposure was 14.8 months (range: 0.0 to 44.3 months) in patients treated withdarolutamide and 11.0 months (range: 0.1 to 40.5 months) in patients treated with placebo.

b Includes arteriosclerosis coronary artery, coronary artery disease, coronary artery occlusion, coronaryartery 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.

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 4.03. The incidence is based onvalues reported as laboratory abnormalities.

Table 2: Adverse reactions reported in mHSPC patients treated with darolutamide incombination with docetaxel in the ARASENS studya, b

System organ class Very common Common(MedDRA)

Vascular disorders Hypertensionc

Skin and subcutaneous tissue disorders Rashd, e

Musculoskeletal and connective tissue Fracturesdisorders

Reproductive system and breast Gynaecomastiadisorders

Investigationsf Neutrophil count decreased

Blood bilirubin increased

ALT increased

AST increaseda The median duration of exposure was 41.0 months (range: 0.1 to 56.5 months) in patients treated withdarolutamide+docetaxel and 16.7 months (range: 0.3 to 55.8 months) in patients treated withplacebo+docetaxel.

b Adverse reactions incidences may not be attributable to darolutamide alone but may contain contributionsfrom 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, rashpapular, 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 onvalues reported as laboratory abnormalities.

Cases of idiosyncratic drug-induced liver injury with grade 3 and 4 increases in alanineaminotransferase (ALT) and/or aspartate aminotransferase (AST) to ≥ 5 and ≥ 20 x upper limit ofnormal (ULN) have been reported with darolutamide treatment including increased transaminasesalong with a simultaneous increase in total bilirubin to ≥ 2 x ULN. Time to onset ranged from 1 monthto 12 months after initiation of darolutamide. In many cases the ALT and AST elevations werereversible upon darolutamide discontinuation. For specific recommendations, see section 4.4.

non-metastatic castration resistant prostate cancer (nmCRPC)

Fatigue/asthenic conditions were reported in 15.8% of patients treated with darolutamide and in 11.4%of patients treated with placebo. Events with worst grade of 3 were reported in 0.6% of patients treatedwith darolutamide and in 1.1% of patients treated with placebo. Fatigue (not including asthenia,lethargy or malaise) occurred in the majority of patients (12.1% of patients treated with darolutamideand 8.7% of patients treated with placebo).

Fractures

Fractures occurred in 4.2% of patients treated with darolutamide and in 3.6% of patients treated withplacebo.

Ischaemic heart disease and heart failure

Ischaemic heart disease occurred in 3.2% of patients treated with darolutamide and in 2.5% of patientstreated with placebo. Grade 5 events occurred in 0.3% of patients treated with darolutamide and 0.2%of patients treated with placebo. Heart failure occurred in 1.9% of patients treated with darolutamideand in 0.9% of patients treated with placebo.

Neutrophil count decreased

Neutrophil count decreased was reported as a laboratory abnormality in 19.6% of patients treated withdarolutamide and in 9.4% of patients treated with placebo. The median time to nadir was 256 days.

The laboratory tests abnormalities manifested predominantly as grade 1 or 2 intensity. Neutrophilcount decreased of grade 3 and 4 was reported in 3.5% and 0.5% of patients, respectively. Only onepatient permanently discontinued darolutamide due to neutropenia. Neutropenia was either transient orreversible (88% 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 16.4% of patients treated withdarolutamide and in 6.9% of patients treated with placebo. The episodes were predominantly ofgrade 1 or 2 intensity, not associated with any clinically relevant signs or symptoms, and reversibleafter darolutamide was discontinued. Bilirubin increased of grade 3 was reported in 0.1% of patientstreated with darolutamide and in 0% of patients treated with placebo. In the darolutamide arm, themean time to first onset of increased bilirubin was 153 days, and the mean duration of the first episodewas 182 days. No patients were discontinued from treatment due to increase in bilirubin.

AST increased

AST increased was reported as a laboratory abnormality in 22.5% of patients treated withdarolutamide and in 13.6% of patients treated with placebo. The episodes were predominantly ofgrade 1 or 2 intensity, not associated with any clinically relevant signs or symptoms, and reversibleafter darolutamide was discontinued. AST increased of grade 3 was reported in 0.5% of patientstreated with darolutamide and in 0.2% of patients treated with placebo. In the darolutamide arm, themean time to first onset of increased AST was 258 days, and the mean duration of the first episodewas 118 days. No patients were discontinued from treatment due to increase in AST.

metastatic hormone-sensitive prostate cancer (mHSPC)

In the ARASENS study hypertension was reported in 13.8% of patients treated withdarolutamide+docetaxel and 9.4% of patients treated with placebo+docetaxel.

Grade 3 hypertension was reported in 6.4% of patients treated with darolutamide+docetaxel comparedto 3.5% of patients treated with placebo+docetaxel. One patient had grade 4 hypertension in eachtreatment arm.

One case was reported as grade 5 hypertension with grade 5 arteriosclerosis in thedarolutamide+docetaxel arm. This patient had a long-standing history of hypertension and smokingand the case occurred more than 3 years after starting darolutamide treatment. Events of hypertensionwere reported more commonly in patients with no medical history of hypertension in both treatmentarms.

Fractures

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

Neutrophil count decreased

Neutrophil count decreased was reported as a laboratory abnormality in 50.6% of patients treated withdarolutamide+docetaxel and in 45.5% of patients treated with placebo+docetaxel. Grade 3 and 4neutrophil count decreased was reported in 34.4% of patients treated with darolutamide+docetaxel andin 31.4% of patients treated with placebo+docetaxel. In both treatment arms, the incidences ofneutrophil count decreased and neutropenia were highest during the first months of treatment, afterwhich 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 withdarolutamide+docetaxel and in 10.0% of patients treated with placebo+docetaxel. The events werepredominantly of grade 1 or 2 intensity. Grade 3 and 4 bilirubin increased was reported in 0.5% ofpatients 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% ofpatients 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% ofpatients 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 wasreported in 3.7% of patients treated with darolutamide+docetaxel and in 3.0% of patients treated withplacebo+docetaxel. Grade 3 and 4 AST increased was reported in 3.6% of patients treated withdarolutamide+docetaxel and in 2.3% of patients treated with placebo+docetaxel.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The highest dose of darolutamide studied clinically was 900 mg twice daily, equivalent to a total dailydose 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 becontinued with the next dose as scheduled.

There is no specific antidote for darolutamide and symptoms of overdose are not established.

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

Darolutamide is an androgen receptor (AR) inhibitor with a flexible polar-substituted pyrazolestructure that binds with high affinity directly to the receptor ligand binding domain.

Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR mediatedtranscription. A major metabolite, keto-darolutamide, exhibited similar in vitro activity todarolutamide. Darolutamide treatment decreases prostate tumour cell proliferation leading to potentantitumour activity.

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

Efficacy and safety were established in two randomised placebo-controlled multicentre phase IIIstudies in patients with nmCRPC (ARAMIS) and mHSPC (ARASENS). All patients received aluteinising hormone-releasing hormone (LHRH) analogue concurrently or had a bilateral orchiectomy.

non-metastatic castration resistant prostate cancer (nmCRPC)

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 assessedby conventional imaging CT, bone scan, MRI) castration resistant prostate cancer with aprostate-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 thenadir taken at least 1 week apart during androgen deprivation therapy, PSA ≥ 2 ng/mL at screeningand 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, apalutamideand darolutamide, or CYP17 enzyme inhibitors such as abiraterone acetate as well as patientsreceiving systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/daywithin 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).

Patients with presence of pelvic lymph nodes < 2 cm in short axis below the aortic bifurcation wereallowed to enter the study. Absence or presence of metastasis was assessed by independent centralradiological review. Included in these analyses were 89 patients that were retrospectively identifiedwith metastasis at baseline. Randomization was stratified by PSADT (≤ 6 months or > 6 months) anduse of osteoclast-targeted therapy at study entry (yes or no).

The following patient demographics and disease characteristics were balanced between treatmentarms. The median age was 74 years (range 48-95) and 9% of patients were 85 years of age or older.

The racial distribution was 79% White, 13% Asian, and 3% Black. A majority of patients had a

Gleason score of 7 or higher at diagnosis (73%). The median PSADT was 4.5 months. Nine percent(9%) of patients had prior orchiectomy, 25% of patients had prior prostatectomy and 50% of patientshad at least one prior radiotherapy. Seventy-six percent (76%) of patients received more than one prioranti-hormonal treatment. Patients had an Eastern Cooperative Oncology Group Performance Status(ECOG PS) score of 0 (69%) or 1 (31%) at study entry.

Treatment with darolutamide continued until radiographic disease progression as assessed byconventional imaging (CT, bone scan, MRI) by blinded central review, unacceptable toxicity orwithdrawal.

The primary efficacy endpoint was metastasis free survival (MFS). Secondary endpoints were overallsurvival (OS), time to pain progression, time to initiation of first cytotoxic chemotherapy for prostatecancer, and time to first symptomatic skeletal events (defined as occurrence of any of the following:external beam radiotherapy to relieve skeletal symptoms, new symptomatic pathologic bone fracture,spinal cord compression, or tumour-related orthopaedic surgical intervention).

Treatment with darolutamide resulted in an improvement in MFS compared to placebo (see Table 3and Figure 1).

MFS results were consistent across patient subgroups regardless of PSADT, prior use ofbone-targeting agents or loco-regional disease. Additional subgroups with consistent MFS resultsincluded PSA at baseline, Gleason score at diagnosis, age, geographical region, ECOG PS at baseline,race, and number of prior hormonal therapies.

After the primary analysis of MFS, once the study was unblinded, patients receiving placebo wereoffered treatment with open-label darolutamide (cross-over option). Among the 554 patientsrandomised to placebo, 170 (31%) crossed over to receive darolutamide treatment. The OS analysiswas not adjusted for confounding effects of cross-over.

At the time of the final analysis, treatment with darolutamide resulted in a statistically significantimprovement in overall survival compared to placebo (median was not reached in either arm, see

Table 3 and Figure 2).

Treatment with darolutamide also resulted in statistically significant delays in time to painprogression, time to initiation of first cytotoxic chemotherapy and time to first symptomatic skeletalevent compared to placebo (see Table 3).

At the time of final analysis, the median duration of treatment in patients treated with darolutamidewas 33.3 months (range: 0.0 to 74.0 months) during combined double-blind and open-label period.

All analyses were performed in the full analysis set.

Table 3: Efficacy results from the ARAMIS study

Number (%) of patients with bevents Median (months) (95% CI) Hazard Ratio

Efficacy (95% Confidenceparameter Darolutamide Placeboa Darolutamide Placeboa Interval [CI])(N=955) (N=554) (N=955) (N=554) p-value(two-sided)

Metastasis 221 (23.1%) 216 (39.0%) 40.4 18.4 0.413free survivalc (34.3, NR) (15.5, 22.3) (0.341, 0.500)<0.000001

Overall 148 (15.5%) 106 (19.1%) NR NR 0.685survival (56.1, NR) (46.9, NR) (0.533, 0.881)0.003048

Time to pain 251 (26.3%) 178 (32.1%) 40.3 25.4 0.647progressionc, d (33.2, 41.2) (19.1, 29.6) (0.533, 0.785)0.000008

Time to 127 (13.3%) 98 (17.7%) NR NR 0.579initiation of (NR, NR) (NR, NR) (0.444, 0.755)first cytotoxic 0.000044chemotherapy

Time to first 29 (3.0%) 28 (5.1%) NR NR 0.484symptomatic (NR, NR) (NR, NR) (0.287, 0.815)skeletal event 0.005294a including 170 patients who crossed over to open-label darolutamideb Hazard ratio < 1 favours darolutamidec for MFS and time to pain progression, the analysis performed at the time of primary completion isconsidered as the final analysisd Patient reported outcome as evaluated by Brief Pain Inventory-Short Form questionnaire

NR: Not reached.

Treatment with darolutamide resulted in a longer progression free survival (PFS, median 36.8 vs14.8 months, HR=0.380, nominal p<0.000001) and time to PSA progression (median 29.5 vs7.2 months, HR=0.164, nominal p<0.000001). Consistency of effect was observed across all measuresof survival (MFS, OS and PFS).

Figure 1: Kaplan-Meier curves of metastasis free survival (ARAMIS)

Darolutamide (N = 955)

Placebo (N = 554)

Patients at risk Months from Randomisation

Darolutamide

Placebo

Figure 2: Kaplan-Meier curves of overall survival (ARAMIS)

Darolutamide (N = 955)

Placebo (N = 554)

Months from Randomisation

Patients at risk

Darolutamide

Placebo

Patients receiving darolutamide in the ARAMIS study (double-blind period) demonstrated asignificantly higher confirmed PSA response rate (defined as a ≥ 50% reduction from baseline),compared with patients receiving placebo, 84.0% vs 7.9% (difference = 76.1%, p<0.000001 (nominalp-value, for information only)).

Metastasis Free Survival Probability (%)

Overall Survival Probability (%)metastatic hormone-sensitive prostate cancer (mHSPC)

The efficacy and safety of darolutamide in combination with docetaxel was assessed in a multicentre,double-blind, placebo-controlled phase III study (ARASENS) in patients with mHSPC. In total,1306 patients were randomised 1:1 to receive 600 mg darolutamide orally twice daily (n=651) ormatching placebo (n=655), concomitantly with 75 mg/m2 of docetaxel for 6 cycles. Treatment withdarolutamide or placebo continued until symptomatic progressive disease, change of antineoplastictherapy, unacceptable toxicity, death, or withdrawal.

Presence of metastasis was assessed by independent central radiological review. Patients with regionallymph node involvement only (M0) were excluded from the study. Randomisation was stratified byextent of disease (non-regional lymph nodes metastases only (M1a), bone metastases with or withoutlymph node metastases (M1b) or visceral metastases with or without lymph node metastases or with orwithout bone metastases (M1c)) and by alkaline phosphatase level (< or ≥ upper limit of normal) atstudy entry. Patients with brain metastases were allowed to enter the study but there were no patientswith brain metastasis enrolled.

The following patient demographics and disease characteristics were balanced between treatmentarms. The median age was 67 years (range 41-89) and 0.5% of patients were 85 years of age or older.

The racial distribution was 52% White, 36% Asian, and 4% Black. A majority of patients had a

Gleason score of 8 or higher at diagnosis (78%). 71% of patients had an ECOG PS score of 0 and 29%of patients had an ECOG PS score of 1. There were 86.1% of patients with de novo and 12.9% ofpatients with recurrent disease. At study entry 3% of patients had M1a, 79.5% had M1b and 17.5%had M1c; alkaline phosphatase was < ULN in 44.5% of patients and ≥ ULN in 55.5% of patients;median PSA level at baseline was 30.3 µg/L and 24.2 µg/L for darolutamide vs the placebo group,respectively. Patients with a medical history of seizure were allowed to enter the study, and 4 patients(0.6%) were enrolled in the darolutamide+docetaxel arm.

77.0% of patients had high-volume disease and 23.0% had low-volume disease. High-volume diseasewas defined as presence of visceral metastases or 4 or more bone lesions, with at least 1 metastasisbeyond the vertebral column and pelvic bones. Around 25% of patients received concomitanttreatment with bisphosphonates or denosumab.

The primary efficacy endpoint was overall survival (OS). Secondary endpoints were time tocastration-resistant prostate cancer, time to pain progression, symptomatic skeletal event free survival(SSE-FS), time to first symptomatic skeletal event (SSE), time to initiation of subsequentantineoplastic therapy, time to worsening of disease-related physical symptoms, and time to initiationof opioid use for ≥ 7 consecutive days. Pain progression was assessed using the patient-reportedoutcome (PROs) Brief Pain Inventory-Short Form (BPI-SF), defined as at least a 2-point worseningfrom nadir, and initiation of short- or long-acting opioid use for pain for ≥7 consecutive days.

The median duration of treatment was 41.0 months (range: 0.1 to 56.5 months) in patients treated withdarolutamide+docetaxel and 16.7 months (range: 0.3 to 55.8 months) in patients treated withplacebo+docetaxel. 87.6% and 85.5% of patients received full 6 cycles of docetaxel and 1.5% and2.0% of patients did not receive docetaxel in darolutamide+docetaxel and placebo+docetaxel arm,respectively.

Table 4: Efficacy results from the ARASENS study

Number (%) of patients Median (months) Hazard Ratiob

Efficacy with events (95% CI) (95% Confidenceparameter Darolutamide Placebo Darolutamide Placebo Interval [CI])+ docetaxel + docetaxel + docetaxel + docetaxel p-value(N=651) (N=654)a (N=651) (N=654)a (one-sided)c

Overall survivald 229 (35.2%) 304 (46.5%) NR 48.9 0.675(NR, NR) (44.4, NR) (0.568, 0.801)<0.0001a one patient in placebo arm was excluded from all analysesb Hazard ratio < 1 favours darolutamidec based on stratified log-rank testd OS results were consistent across patient subgroups, including extent of disease and alkaline phosphataselevels

NR: not reached

The following secondary efficacy endpoints showed a statistically significant advantage in favour ofthe patients in the darolutamide+docetaxel arm compared to patients in the placebo+docetaxel arm:time to castration-resistant prostate cancer (median NR vs 19.1 months; HR=0.357, p<0.0001); time tofirst symptomatic skeletal event (median NR vs NR months; HR=0.712, p=0.0081); time to initiationof subsequent antineoplastic chemotherapy (median NR vs 25.3 months; HR=0.388, p<0.0001); timeto pain progression (median NR vs 27.5 months; HR=0.792, p=0.0058); symptomatic skeletal eventfree survival time (median 51.2 vs 39.7 months; HR=0.609, p<0.0001).

Figure 3: Kaplan-Meier curves of overall survival (ARASENS)a1 - Darolutamide+docetaxel (N = 651)2 - Placebo+docetaxel (N = 654)

Months from Randomization

Patients at riska OS rate at 36 months was 72.3% (95% CI, 68.8 to 75.8) in the darolutamide+docetaxel arm vs 63.8%(95% CI, 60.1 to 67.6) in the placebo+docetaxel arm.

OS rate at 48 months was 62.7% (95% CI, 58.7 to 66.7) in the darolutamide+docetaxel arm vs 50.4%(95% CI, 46.3 to 54.6) in the placebo+docetaxel arm.

Overall Survival Probability (%)

The European Medicines Agency has waived the obligation to submit the results of studies withdarolutamide in all subsets of the paediatric population in prostate malignant neoplasms (seesection 4.2 for information on paediatric use).

General introduction

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

Following oral administration of 600 mg (2 tablets of 300 mg) twice daily, peak plasma concentrationsof darolutamide at steady state were 4.79 mg/L (coefficient of variation: 30.9%) in nmCRPC patientsin 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 ofthe two diastereomers, (S,R)-darolutamide to (S,S)-darolutamide, changed from a 1:1 ratio in the tabletto an approximately 1:9 ratio in plasma based on AUC0-12 data at steady-state. Following oraladministration together with food, steady-state is reached after 2-5 days of repeated twice-dailydosing.

The absolute bioavailability compared to an intravenous injection is approximately 30% following oraladministration 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. Asimilar increase of exposure was observed for the major metabolite keto-darolutamide.

The apparent volume of distribution of darolutamide after intravenous administration is 119 Lindicating that darolutamide is widely distributed throughout the body to both intracellular andextracellular fluid spaces.

Darolutamide is moderately (92%) bound to human plasma proteins without any difference betweenthe two diastereomers. The major metabolite of darolutamide, keto-darolutamide, is highly (99.8%)bound to plasma proteins.

Passage of darolutamide across the blood-brain barrier has not been studied clinically. However, brainexposures to darolutamide in terms of AUC0-24 are very low with 4.5% of plasma exposure after singledose in rats and 1.9-3.9% after repeated dose in mice. This indicates low passage of darolutamideacross the intact blood-brain barrier in rats and mice and a low likelihood that darolutamide crosses theintact blood-brain barrier in humans to a clinically relevant extent.

The diastereomers (S,R)-darolutamide and (S,S)-darolutamide are able to interconvert via themetabolite keto-darolutamide with a preference for (S,S)-darolutamide.

Following single oral administration of 300 mg14 C-darolutamide given as an oral solution,keto-darolutamide is the only major metabolite with about 2-fold higher total exposure in plasmacompared to darolutamide. Darolutamide and keto-darolutamide accounted together for 87.4% ofthe 14 C-radioactivity in plasma indicating that all other metabolites are of minor importance.

Darolutamide is metabolised primarily by oxidative metabolism mediated mainly by CYP3A4, as wellas by direct glucuronidation mediated preferentially by UGT1A9 and UGT1A1. In addition, mainlythe AKR1C isoforms were shown to catalyse the reduction of keto-darolutamide to the substancediastereomers.

The effective half-life of darolutamide and keto-darolutamide in plasma of patients is approximately18 to 20 hours. Of the two diastereomers comprising darolutamide, (S,R)-darolutamide has a shortereffective half-life of 9 hours compared to (S,S)-darolutamide with an effective half-life of 22 hours.

The clearance of darolutamide following intravenous administration was 116 mL/min (CV: 39.7%). Atotal of 63.4% of substance-related material is excreted in the urine (approximately 7% unchanged),32.4% is excreted in the faeces. More than 95% of the dose was recovered within 7 days afteradministration.

Linearity/Non-linearity

In the dose range of 100 to 700 mg (after single dose and at steady state), the exposure to the twodiastereomers and the major metabolite keto-darolutamide increases linearly in a nearly dose-relatedmanner. Based on a saturated absorption, no further increase in exposure to darolutamide wasobserved at 900 mg twice daily.

No clinically relevant differences in the pharmacokinetics of darolutamide were observed(65-95 years).

In a clinical pharmacokinetic study, AUC and Cmax for darolutamide were 2.5 and 1.6-fold higher inpatients with severe renal impairment (estimated Glomerular Filtration Rate [eGFR] 15 to29 mL/min/1.73 m2) compared to healthy volunteers.

A population pharmacokinetic analysis indicates a 1.1-, 1.3- and an approximately 1.5-fold higherexposure (AUC) of darolutamide in patients with mild, moderate and severe renal impairment (eGFR15 to 89 mL/min/1.73 m2) compared to patients with normal renal function.

The pharmacokinetics of darolutamide has not been studied in patients with end-stage renal diseasereceiving dialysis (eGFR < 15 mL/min/1.73 m2).

In a clinical pharmacokinetic study, Cmax and AUC for darolutamide were 1.5 and 1.9-fold higher inpatients with moderate hepatic impairment (Child-Pugh B) compared to healthy volunteers. There areno data for patients with severe hepatic impairment (Child-Pugh C).

Ethnic differences

No clinically relevant differences in the pharmacokinetics of darolutamide were observed based onethnicity (White, Japanese, non-Japanese Asian, Black or African American). A populationpharmacokinetic analysis indicated a geometric mean increase in exposure (AUC) of up to 1.56-fold(90% CI: 1.43 to 1.70) in Japanese patients compared to patients from all other regions in both the

ARAMIS and ARASENS studies.

In repeated dose toxicity studies in rats and dogs, the main findings were changes in the malereproductive organs (decreases in organ weight with atrophy of the prostate and epididymides). Theseeffects occurred at systemic exposures in the range of or below the anticipated human exposure (basedon AUC comparison). Additional changes to reproductive tissues included minimal increase invacuolation of the pituitary gland, atrophy and secretory reduction in seminal vesicles and mammaryglands in rats as well as testicular hypospermia, seminiferous tubule dilatation and degeneration indogs. Changes in the male reproductive organs in both species were consistent with thepharmacological activity of darolutamide and reversed or partially resolved after 4- to 8-weekrecovery periods.

Embryotoxicity/teratogenicity

Studies on developmental toxicity have not been performed.

Reproduction toxicity

Studies on reproductive toxicity have not been performed. However, male fertility is likely to beimpaired based on the findings in repeat-dose toxicity studies in rats and dogs, which are consistentwith the pharmacological activity of darolutamide.

Darolutamide did not induce mutations in the microbial mutagenesis (Ames) assay. At highconcentrations, darolutamide did induce structural chromosome aberrations in vitro in cultured humanlymphocytes. However, in the in vivo combined bone marrow micronucleus test and the Comet assayin the liver and duodenum of the rat, no genotoxicity was observed at exposures in excess of themaximum human exposure.

Oral administration of darolutamide to male rasH2 transgenic mice for 6 months did not showcarcinogenic potential at doses up to 1000 mg/kg/day, which is 0.9-1.3 times for darolutamide and2.1-2.3 times for keto-darolutamide the clinical exposure (AUC) at the recommended clinical dailydose of 1200 mg/day. Based on this study carcinogenic risk of darolutamide cannot be completelyexcluded.

Safety pharmacology

In vitro, darolutamide weakly inhibited the hERG potassium current and the L-type calcium channel.

In vivo, in anaesthetised dogs, darolutamide slightly decreased the QT interval duration, but this effectwas not found in conscious dogs.

Calcium hydrogen phosphate (E 341)

Croscarmellose sodium

Lactose monohydrate

Magnesium stearate (E 470b)

Povidone (E 1201)

Hypromellose

Lactose monohydrate

Macrogol (E 1521)

Titanium dioxide (E 171)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

PVC/Aluminium foil blisters containing 16 film-coated tablets.

Each pack contains 112 film-coated tablets.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Bayer AG51368 Leverkusen

Germany

EU/1/20/1432/001 112 film-coated tablets

Date of first authorisation: 27 March 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.