XTANDI 40mg capsule me medication leaflet

Xtandi - 40 mg soft capsules

Xtandi - 40 mg soft capsules

Each soft capsule contains 40 mg of enzalutamide.

Each soft capsule contains 57.8 mg of sorbitol.

For the full list of excipients, see section 6.1.

Soft capsule.

White to off-white oblong soft capsules (approximately 20 mm x 9 mm) imprinted with “ENZ” inblack ink on one side.

Xtandi is indicated:

* as monotherapy or in combination with androgen deprivation therapy for the treatment of adultmen with high-risk biochemical recurrent (BCR) non-metastatic hormone-sensitive prostatecancer (nmHSPC) who are unsuitable for salvage-radiotherapy (see section 5.1).

* in combination with androgen deprivation therapy for the treatment of adult men withmetastatic hormone-sensitive prostate cancer (mHSPC) (see section 5.1).

* for the treatment of adult men with high-risk non-metastatic castration-resistant prostatecancer (CRPC) (see section 5.1).

* for the treatment of adult men with metastatic CRPC who are asymptomatic or mildlysymptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yetclinically indicated (see section 5.1).

* for the treatment of adult men with metastatic CRPC whose disease has progressed on or afterdocetaxel therapy.

Treatment with enzalutamide should be initiated and supervised by specialist physicians experiencedin the medical treatment of prostate cancer.

The recommended dose is 160 mg enzalutamide (four 40 mg soft capsules) as a single oral daily dose.

Medical castration with a luteinising hormone-releasing hormone (LHRH) analogue should becontinued during treatment of patients with CRPC or mHSPC who are not surgically castrated.

Patients with high-risk BCR nmHSPC may be treated with Xtandi with or without a LHRH analogue.

For patients who receive Xtandi with or without a LHRH analogue, treatment can be suspended if PSAis undetectable (< 0.2 ng/mL) after 36 weeks of therapy. Treatment should be reinitiated when PSAhas increased to ≥ 2.0 ng/mL for patients who had prior radical prostatectomy or ≥ 5.0 ng/mL forpatients who had prior primary radiation therapy. If PSA is detectable (≥ 0.2 ng/mL) after 36 weeks oftherapy, treatment should continue (see section 5.1).

If a patient misses taking Xtandi at the usual time, the prescribed dose should be taken as close aspossible to the usual time. If a patient misses a dose for a whole day, treatment should be resumed thefollowing day with the usual daily dose.

If a patient experiences a ≥ Grade 3 toxicity or an intolerable adverse reaction, dosing should bewithheld for one week or until symptoms improve to ≤ Grade 2, then resumed at the same or a reduceddose (120 mg or 80 mg) if warranted.

Concomitant use with strong CYP2C8 inhibitors

The concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If patients must beco-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mgonce daily. If co-administration of the strong CYP2C8 inhibitor is discontinued, the enzalutamide doseshould be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor (see section 4.5).

No dose adjustment is necessary for elderly patients (see sections 5.1 and 5.2).

No dose adjustment is necessary for patients with mild, moderate or severe hepatic impairment (Child-

Pugh Class A, B or C, respectively). An increased half-life of enzalutamide has however beenobserved in patients with severe hepatic impairment (see sections 4.4 and 5.2).

No dose adjustment is necessary for patients with mild or moderate renal impairment (see section 5.2).

Caution is advised in patients with severe renal impairment or end-stage renal disease (see section 4.4).

There is no relevant use of enzalutamide in the paediatric population in the indication of treatment ofadult men with CRPC, mHSPC, or high-risk BCR nmHSPC.

Swallowing difficulties/history of dysphagia population

Enzalutamide is also available as tablets (40 mg and 80 mg) for patients who have difficultiesswallowing large capsules or for patients with a history of dysphagia.

Xtandi is for oral use. The soft capsules should not be chewed, dissolved or opened but should beswallowed whole with a sufficient amount of water, and can be taken with or without food.

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Women who are or may become pregnant (see sections 4.6 and 6.6).

Use of enzalutamide has been associated with seizure (see section 4.8). The decision to continuetreatment in patients who develop seizures should be taken case by case.

There have been rare reports of posterior reversible encephalopathy syndrome (PRES) in patientsreceiving Xtandi (see section 4.8). PRES is a rare, reversible, neurological disorder which can presentwith rapidly evolving symptoms including seizure, headache, confusion, blindness, and other visualand neurological disturbances, with or without associated hypertension. A diagnosis of PRES requiresconfirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinuation of

Xtandi in patients who develop PRES is recommended.

Cases of second primary malignancies have been reported in patients treated with enzalutamide inclinical studies. In phase 3 clinical studies, the most frequently reported events in enzalutamide treatedpatients, and greater than placebo, were bladder cancer (0.3%), adenocarcinoma of the colon (0.2%),transitional cell carcinoma (0.2%) and malignant melanoma (0.2%).

Patients should be advised to promptly seek the attention of their physician if they notice signs ofgastrointestinal bleeding, macroscopic haematuria, or other symptoms such as dysuria or urinaryurgency develop during treatment with enzalutamide.

Enzalutamide is a potent enzyme inducer and may lead to loss of efficacy of many commonly usedmedicinal products (see examples in section 4.5). A review of concomitant medicinal products shouldtherefore be conducted when initiating enzalutamide treatment. Concomitant use of enzalutamide withmedicinal products that are sensitive substrates of many metabolising enzymes or transporters (seesection 4.5) should generally be avoided if their therapeutic effect is of large importance to the patient,and if dose adjustments cannot easily be performed based on monitoring of efficacy or plasmaconcentrations.

Co-administration with warfarin and coumarin-like anticoagulants should be avoided. If Xtandi isco-administered with an anticoagulant metabolised by CYP2C9 (such as warfarin or acenocoumarol),additional International Normalised Ratio (INR) monitoring should be conducted (see section 4.5).

Caution is required in patients with severe renal impairment as enzalutamide has not been studied inthis patient population.

An increased half-life of enzalutamide has been observed in patients with severe hepatic impairment,possibly related to increased tissue distribution. The clinical relevance of this observation remainsunknown. A prolonged time to reach steady state concentrations is however anticipated, and the timeto maximum pharmacological effect as well as time for onset and decline of enzyme induction (seesection 4.5) may be increased.

The phase 3 studies excluded patients with recent myocardial infarction (in the past 6 months) orunstable angina (in the past 3 months), New York Heart Association Class (NYHA) III or IV heartfailure except if Left Ventricular Ejection Fraction (LVEF) ≥ 45%, bradycardia or uncontrolledhypertension. This should be taken into account if Xtandi is prescribed in these patients.

In patients with a history of or 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 Xtandi.

The safety and efficacy of concomitant use of Xtandi with cytotoxic chemotherapy has not beenestablished. Co-administration of enzalutamide has no clinically relevant effect on thepharmacokinetics of intravenous docetaxel (see section 4.5); however, an increase in the occurrence ofdocetaxel-induced neutropenia cannot be excluded.

Severe skin reactions

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, which can be lifethreatening or fatal, has been reported with enzalutamide treatment.

At the time of prescription, patients should be advised of the signs and symptoms and monitoredclosely for skin reactions.

If signs and symptoms suggestive of this reaction appear, enzalutamide should be withdrawnimmediately and an alternative treatment considered (as appropriate).

Hypersensitivity reactions manifested by symptoms including, but not limited to, rash, or face, tongue,lip, or pharyngeal oedema, have been observed with enzalutamide (see section 4.8).

Xtandi as monotherapy in patients with high-risk BCR nmHSPC

Results of the EMBARK study suggest that Xtandi as monotherapy and in combination with androgendeprivation therapy are not equivalent treatment options in patients with high-risk BCR nmHSPC (seesections 4.8 and 5.1). Xtandi in combination with androgen deprivation therapy is considered thepreferred treatment option except for cases in which the addition of androgen deprivation therapy mayresult in unacceptable toxicity or risk.

Dysphagia related to product formulation

There have been reports of patients experiencing difficulty swallowing Xtandi, including reports ofchoking. The swallowing difficulties and choking events were mostly reported with the capsuleformulation, which could be related to a larger product size. Patients should be advised to swallow thecapsules whole with a sufficient amount of water.

In patients who have difficulties swallowing large capsules or patients with a history of dysphagia, it isrecommended to use enzalutamide tablet formulations instead.

Xtandi contains 57.8 mg sorbitol (E420) per soft capsule.

CYP2C8 plays an important role in the elimination of enzalutamide and in the formation of its activemetabolite. Following oral administration of the strong CYP2C8 inhibitor gemfibrozil (600 mg twicedaily) to healthy male subjects, the AUC of enzalutamide increased by 326% while Cmax ofenzalutamide decreased by 18%. For the sum of unbound enzalutamide plus the unbound activemetabolite, the AUC increased by 77% while Cmax decreased by 19%. Strong inhibitors (e.g.gemfibrozil) of CYP2C8 are to be avoided or used with caution during enzalutamide treatment. Ifpatients must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should bereduced to 80 mg once daily (see section 4.2).

CYP3A4 plays a minor role in the metabolism of enzalutamide. Following oral administration of thestrong CYP3A4 inhibitor itraconazole (200 mg once daily) to healthy male subjects, the AUC ofenzalutamide increased by 41% while Cmax was unchanged. For the sum of unbound enzalutamide plusthe unbound active metabolite, the AUC increased by 27% while Cmax was again unchanged. No doseadjustment is necessary when Xtandi is co-administered with inhibitors of CYP3A4.

Following oral administration of the moderate CYP2C8 and strong CYP3A4 inducer rifampin (600 mgonce daily) to healthy male subjects, the AUC of enzalutamide plus the active metabolite decreased by37% while Cmax remained unchanged. No dose adjustment is necessary when Xtandi is co-administered with inducers of CYP2C8 or CYP3A4.

Enzalutamide is a potent enzyme inducer and increases the synthesis of many enzymes andtransporters; therefore, interaction with many common medicinal products that are substrates ofenzymes or transporters is expected. The reduction in plasma concentrations can be substantial, andlead to lost or reduced clinical effect. There is also a risk of increased formation of active metabolites.

Enzymes that may be induced include CYP3A in the liver and gut, CYP2B6, CYP2C9, CYP2C19, anduridine 5'-diphospho-glucuronosyltransferase (UGTs - glucuronide conjugating enzymes). Sometransporters may also be induced, e.g. multidrug resistance-associated protein 2 (MRP2) and theorganic anion transporting polypeptide 1B1 (OATP1B1).

In vivo studies have shown that enzalutamide is a strong inducer of CYP3A4 and a moderate inducerof CYP2C9 and CYP2C19. Co-administration of enzalutamide (160 mg once daily) with single oraldoses of sensitive CYP substrates in prostate cancer patients resulted in an 86% decrease in the AUCof midazolam (CYP3A4 substrate), a 56% decrease in the AUC of S-warfarin (CYP2C9 substrate),and a 70% decrease in the AUC of omeprazole (CYP2C19 substrate). UGT1A1 may have beeninduced as well. In a clinical study in patients with metastatic CRPC, Xtandi (160 mg once daily) hadno clinically relevant effect on the pharmacokinetics of intravenously administered docetaxel(75 mg/m2 by infusion every 3 weeks). The AUC of docetaxel decreased by 12% [geometric meanratio (GMR) = 0.882 (90% CI: 0.767, 1.02)] while Cmax decreased by 4% [GMR = 0.963 (90% CI:0.834, 1.11)].

Interactions with certain medicinal products that are eliminated through metabolism or active transportare expected. If their therapeutic effect is of large importance to the patient, and dose adjustments arenot easily performed based on monitoring of efficacy or plasma concentrations, these medicinalproducts are to be avoided or used with caution. The risk for liver injury after paracetamoladministration is suspected to be higher in patients concomitantly treated with enzyme inducers.

Groups of medicinal products that can be affected include, but are not limited to:

* Analgesics (e.g. fentanyl, tramadol)

* Antibiotics (e.g. clarithromycin, doxycycline)

* Anticancer agents (e.g. cabazitaxel)

* Antiepileptics (e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid)

* Antipsychotics (e.g. haloperidol)

* Antithrombotics (e.g. acenocoumarol, warfarin, clopidogrel)

* Betablockers (e.g. bisoprolol, propranolol)

* Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil)

* Cardiac glycosides (e.g. digoxin)

* Corticosteroids (e.g. dexamethasone, prednisolone)

* HIV antivirals (e.g. indinavir, ritonavir)

* Hypnotics (e.g. diazepam, midazolam, zolpidem)

* Immunosuppressant (e.g. tacrolimus)

* Proton pump inhibitor (e.g. omeprazole)

* Statins metabolised by CYP3A4 (e.g. atorvastatin, simvastatin)

* Thyroid agents (e.g. levothyroxine)

The full induction potential of enzalutamide may not occur until approximately 1 month after the startof treatment, when steady-state plasma concentrations of enzalutamide are reached, although someinduction effects may be apparent earlier. Patients taking medicinal products that are substrates of

CYP2B6, CYP3A4, CYP2C9, CYP2C19 or UGT1A1 should be evaluated for possible loss ofpharmacological effects (or increase in effects in cases where active metabolites are formed) duringthe first month of enzalutamide treatment and dose adjustment should be considered as appropriate. Inconsideration of the long half-life of enzalutamide (5.8 days, see section 5.2), effects on enzymes maypersist for one month or longer after stopping enzalutamide. A gradual dose reduction of theconcomitant medicinal product may be necessary when stopping enzalutamide treatment.

Enzalutamide (160 mg once daily) did not cause a clinically relevant change in the AUC or Cmax ofcaffeine (CYP1A2 substrate) or pioglitazone (CYP2C8 substrate). The AUC of pioglitazone increasedby 20% while Cmax decreased by 18%. The AUC and Cmax of caffeine decreased by 11% and 4%,respectively. No dose adjustment is indicated when a CYP1A2 or CYP2C8 substrate isco-administered with Xtandi.

In vitro data indicate that enzalutamide may be an inhibitor of the efflux transporter P-gp. A mildinhibitory effect of enzalutamide, at steady-state, on P-gp was observed in a study in patients withprostate cancer that received a single oral dose of the probe P-gp substrate digoxin before andconcomitantly with enzalutamide (concomitant administration followed at least 55 days of once dailydosing of 160 mg enzalutamide). The AUC and Cmax of digoxin increased by 33% and 17%,respectively. Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g.colchicine, dabigatran etexilate, digoxin) should be used with caution when administeredconcomitantly with Xtandi and may require dose adjustment to maintain optimal plasmaconcentrations.

At steady-state, enzalutamide did not cause a clinically meaningful change in exposure to the probebreast cancer resistance protein (BCRP) substrate rosuvastatin in patients with prostate cancer thatreceived a single oral dose of rosuvastatin before and concomitantly with enzalutamide (concomitantadministration followed at least 55 days of once daily dosing of 160 mg enzalutamide). The AUC ofrosuvastatin decreased by 14% while Cmax increased by 6%. No dose adjustment is necessary when a

BCRP substrate is co-administered with Xtandi.

Based on in vitro data, inhibition of MRP2 (in the intestine), as well as organic anion transporter 3(OAT3) and organic cation transporter 1 (OCT1) (systemically) cannot be excluded. Theoretically,induction of these transporters is also possible, and the net effect is presently unknown.

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Xtandi withmedicinal products known to prolong the QT interval or medicinal products able to induce Torsade depointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide,ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should becarefully evaluated (see section 4.4).

Food has no clinically significant effect on the extent of exposure to enzalutamide. In clinical trials,

Xtandi was administered without regard to food.

There are no human data on the use of Xtandi in pregnancy and this medicinal product is not for use inwomen of childbearing potential. This medicine may cause harm to the unborn child or potential lossof pregnancy if taken by women who are pregnant (see sections pct. 4.3, 5.3, and 6.6).

It is not known whether enzalutamide or its metabolites are present in semen. A condom is requiredduring and for 3 months after treatment with enzalutamide if the patient is engaged in sexual activitywith a pregnant woman. If the patient engages in sexual intercourse with a woman of childbearingpotential, a condom and another form of birth control must be used during and for 3 months aftertreatment. Studies in animals have shown reproductive toxicity (see section 5.3).

Enzalutamide is not for use in women. Enzalutamide is contraindicated in women who are or maybecome pregnant (see sections pct. 4.3, 5.3, and 6.6).

Enzalutamide is not for use in women. It is not known if enzalutamide is present in human milk.

Enzalutamide and/or its metabolites are secreted in rat milk (see section 5.3).

Animal studies showed that enzalutamide affected the reproductive system in male rats and dogs (seesection 5.3).

Xtandi may have moderate influence on the ability to drive and use machines as psychiatric andneurologic events including seizure have been reported (see section 4.8). Patients should be advised ofthe potential risk of experiencing a psychiatric or neurological event while driving or operatingmachines. No studies to evaluate the effects of enzalutamide on the ability to drive and use machineshave been conducted.

The most common adverse reactions are asthenia/fatigue, hot flush, hypertension, fractures, and fall.

Other important adverse reactions include ischemic heart disease and seizure.

Seizure occurred in 0.6% of enzalutamide-treated patients, 0.1% of placebo-treated patients and 0.3%in bicalutamide-treated patients.

Rare cases of posterior reversible encephalopathy syndrome have been reported in enzalutamide-treated patients (see section 4.4).

Stevens-Johnson syndrome has been reported with enzalutamide treatment (see section 4.4).

Adverse reactions observed during clinical studies are listed below by frequency category. Frequencycategories are defined as follows: 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 beestimated from the available data). Within each frequency grouping, adverse reactions are presented inorder of decreasing seriousness.

Table 1: Adverse reactions identified in controlled clinical trials and post-marketing

MedDRA System organ class Adverse reaction and frequency

Blood and lymphatic system Uncommon: leucopenia, neutropeniadisorders Not known*: thrombocytopenia

Immune system disorders Not known*: face oedema, tongue oedema, lip oedema,pharyngeal oedema

Metabolism and nutrition Not known*: decreased appetitedisorders

Psychiatric disorders Common: anxiety

Uncommon: visual hallucination

Nervous system disorders Common: headache, memory impairment, amnesia,disturbance in attention, dysgeusia, restless legs syndrome,cognitive disorder

MedDRA System organ class Adverse reaction and frequency

Uncommon: seizure¥

Not known*: posterior reversible encephalopathy syndrome

Cardiac disorders Common: ischemic heart disease†

Not known*: QT-prolongation (see sections 4.4 and 4.5)

Vascular disorders Very common: hot flush, hypertension

Gastrointestinal disorders Not known*: dysphagia∞, nausea, vomiting, diarrhoea

Hepatobiliary disorders Uncommon: hepatic enzymes increased

Skin and subcutaneous tissue Common: dry skin, pruritusdisorders Not known*: erythema multiforme, Stevens-Johnson syndrome,rash

Musculoskeletal and connective Very common: fractures‡tissue disorders Not known*: myalgia, muscle spasms, muscular weakness, backpain

Reproductive system and breast Common: gynaecomastia, nipple pain#, breast tenderness#disorder

General disorders and Very common: asthenia, fatigueadministration site conditions

Injury, poisoning and Very common: fallprocedural complications

* Spontaneous reports from post-marketing experience.

¥ As evaluated by narrow SMQs of ‘Convulsions’ including convulsion, grand mal convulsion, complex partial seizures,partial seizures, and status epilepticus. This includes rare cases of seizure with complications leading to death.

† As evaluated by narrow SMQs of ‘Myocardial Infarction’ and ‘Other Ischemic Heart Disease’ including the followingpreferred terms observed in at least two patients in randomized placebo-controlled phase 3 studies: angina pectoris,coronary artery disease, myocardial infarctions, acute myocardial infarction, acute coronary syndrome, angina unstable,myocardial ischaemia, and arteriosclerosis coronary artery.

‡ Includes all preferred terms with the word ‘fracture’ in bones.

# Adverse reactions for enzalutamide as monotherapy.

∞ There have been reports of dysphagia, including reports of choking. Both events have mostly been reported with thecapsule formulation, which could be related to a larger product size (see section 4.4).

In controlled clinical studies, 31 patients (0.6%) experienced a seizure out of 5110 patients treated witha daily dose of 160 mg enzalutamide, whereas four patients (0.1%) receiving placebo and one patient(0.3%) receiving bicalutamide, experienced a seizure. Dose appears to be an important predictor of therisk of seizure, as reflected by preclinical data, and data from a dose-escalation study. In the controlledclinical studies, patients with prior seizure or risk factors for seizure were excluded.

In the 9785-CL-0403 (UPWARD) single-arm trial to assess incidence of seizure in patients withpredisposing factors for seizure (whereof 1.6% had a history of seizures), 8 of 366 (2.2%) patientstreated with enzalutamide experienced a seizure. The median duration of treatment was 9.3 months.

The mechanism by which enzalutamide may lower the seizure threshold is not known but could berelated to data from in vitro studies showing that enzalutamide and its active metabolite bind to andcan inhibit the activity of the GABA-gated chloride channel.

In randomised placebo-controlled clinical studies, ischemic heart disease occurred in 3.5% of patientstreated with enzalutamide plus ADT compared to 2% of patients treated with placebo plus ADT.

Fourteen (0.4%) patients treated with enzalutamide plus ADT and 3 (0.1%) patients treated withplacebo plus ADT had an ischemic heart disease event that led to death.

In the EMBARK study, ischemic heart disease occurred in 5.4% of patients treated with enzalutamideplus leuprolide and 9% of patients treated with enzalutamide as monotherapy. No patients treated withenzalutamide plus leuprolide and one (0.3%) patient treated with enzalutamide as monotherapy had anischemic heart disease event that led to death.

Gynaecomastia

In the EMBARK study, gynaecomastia (all grades) was observed in 29 of 353 patients (8.2%) whowere treated with enzalutamide plus leuprolide and 159 of 354 patients (44.9%) who were treated withenzalutamide as monotherapy. Grade 3 or higher gynaecomastia was not observed in any patients whowere treated with enzalutamide plus leuprolide, and was observed in 3 patients (0.8%) who weretreated with enzalutamide as monotherapy.

Nipple pain

In the EMBARK study, nipple pain (all grades) was observed in 11 of 353 patients (3.1%) who weretreated with enzalutamide plus leuprolide and 54 of 354 patients (15.3%) who were treated withenzalutamide as monotherapy. Grade 3 or higher nipple pain was not observed in any patients whowere treated with enzalutamide plus leuprolide or with enzalutamide as monotherapy.

Breast tenderness

In the EMBARK study, breast tenderness (all grades) was observed in 5 of 353 patients (1.4%) whowere treated with enzalutamide plus leuprolide and 51 of 354 patients (14.4%) who were treated withenzalutamide as monotherapy. Grade 3 or higher breast tenderness was not observed in any patientswho were treated with enzalutamide plus leuprolide or with enzalutamide as monotherapy.

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.

There is no antidote for enzalutamide. In the event of an overdose, treatment with enzalutamide shouldbe stopped and general supportive measures initiated taking into consideration the half-life of 5.8 days.

Patients may be at increased risk of seizures following an overdose.

Pharmacotherapeutic group: hormone antagonists and related agents, anti-androgens, ATC code:

L02BB04.

Prostate cancer is known to be androgen sensitive and responds to inhibition of androgen receptorsignalling. Despite low or even undetectable levels of serum androgen, androgen receptor signallingcontinues to promote disease progression. Stimulation of tumour cell growth via the androgen receptorrequires nuclear localization and DNA binding. Enzalutamide is a potent androgen receptor signallinginhibitor that blocks several steps in the androgen receptor signalling pathway. Enzalutamidecompetitively inhibits androgen binding to androgen receptors, and consequently; inhibits nucleartranslocation of activated receptors and inhibits the association of the activated androgen receptor with

DNA even in the setting of androgen receptor overexpression and in prostate cancer cells resistant toanti-androgens. Enzalutamide treatment decreases the growth of prostate cancer cells and can inducecancer cell death and tumour regression. In preclinical studies enzalutamide lacks androgen receptoragonist activity.

In a phase 3 clinical trial (AFFIRM) of patients who failed prior chemotherapy with docetaxel, 54% ofpatients treated with enzalutamide, versus 1.5% of patients who received placebo, had at least a 50%decline from baseline in PSA levels.

In another phase 3 clinical trial (PREVAIL) in chemo-naïve patients, patients receiving enzalutamidedemonstrated a significantly higher total PSA response rate (defined as a ≥ 50% reduction frombaseline), compared with patients receiving placebo, 78.0% versus 3.5% (difference = 74.5%,p < 0.0001).

In a phase 2 clinical trial (TERRAIN) in chemo-naïve patients, patients receiving enzalutamidedemonstrated a significantly higher total PSA response rate (defined as a ≥ 50% reduction frombaseline), compared with patients receiving bicalutamide, 82.1% versus 20.9% (difference = 61.2%,p < 0.0001).

In a single arm trial (9785-CL-0410) of patients previously treated with at least 24 weeks ofabiraterone (plus prednisone), 22.4% had a ≥ 50% decrease from baseline in PSA levels. According toprior chemotherapy history, the results proportion of patients with a ≥ 50% decrease in PSA levelswere 22.1% and 23.2%, for the no prior chemotherapy and prior chemotherapy patient groups,respectively.

In the MDV3100-09 clinical trial (STRIVE) of non-metastatic and metastatic CRPC, patients receivingenzalutamide demonstrated a significantly higher total confirmed PSA response rate (defined as a≥ 50% reduction from baseline) compared with patients receiving bicalutamide, 81.3% versus 31.3%(difference = 50.0%, p < 0.0001).

In the MDV3100-14 clinical trial (PROSPER) of non-metastatic CRPC, patients receivingenzalutamide demonstrated a significantly higher confirmed PSA response rate (defined as a ≥ 50%reduction from baseline), compared with patients receiving placebo, 76.3% versus 2.4%(difference = 73.9%, p < 0.0001).

Efficacy of enzalutamide was established in three randomised placebo-controlled multicentre phase 3clinical studies [MDV3100-14 (PROSPER), CRPC2 (AFFIRM), MDV3100-03 (PREVAIL)] ofpatients with progressive prostate cancer who had disease progression on androgen deprivation therapy[LHRH analogue or after bilateral orchiectomy]. The PREVAIL study enrolled metastatic CRPCchemotherapy-naïve patients; whereas the AFFIRM study enrolled metastatic CRPC patients who hadreceived prior docetaxel; and the PROSPER study enrolled patients with non-metastatic CRPC.

Efficacy in patients with mHSPC was established in one randomised, placebo-controlled multicentrephase 3 clinical study [9785-CL-0335 (ARCHES)]. Another randomised, placebo-controlledmulticentre phase 3 clinical study [MDV3100-13 (EMBARK)] established efficacy in patients withhigh-risk BCR nmHSPC. All patients were treated with a LHRH analogue or had bilateralorchiectomy, unless otherwise indicated.

In the active treatment arms, Xtandi was administered orally at a dose of 160 mg daily. In the fiveclinical studies (EMBARK, ARCHES, PROSPER, AFFIRM and PREVAIL), patients receivedplacebo in the control arm and patients were not required to take prednisone.

Changes in PSA serum concentration independently do not always predict clinical benefit. Therefore,in the five studies it was recommended that patients be maintained on their study treatments untilsuspension or discontinuation criteria were met as specified below for each study.

MDV3100-13 (EMBARK) Study (patients with high-risk BCR non-metastatic HSPC)

The EMBARK study enrolled 1068 patients with high-risk BCR nmHSPC who were randomised 1:1:1to receive treatment with enzalutamide orally at a dose of 160 mg once daily concurrently with ADT(N = 355), enzalutamide orally at a dose of 160 mg once daily as open-label monotherapy (N = 355),or placebo orally once daily concurrently with ADT (N = 358) (ADT defined as leuprolide). Allpatients had prior definitive therapy with radical prostatectomy or radiotherapy (includingbrachytherapy) or both, with curative intent. Patients were required to have confirmation ofnon-metastatic disease by blinded independent central review (BICR), and high-risk biochemicalrecurrence (defined by a PSA doubling time ≤ 9 months). Patients were also required to have PSAvalues ≥ 1 ng/mL if they had prior radical prostatectomy (with or without radiotherapy) as the primarytreatment for prostate cancer, or PSA values at least 2 ng/mL above the nadir if they had priorradiotherapy only. Patients who had a prior prostatectomy and were suitable candidates for salvageradiotherapy as determined by the investigator were excluded from the study.

Patients were stratified by screening PSA (≤ 10 ng/mL vs. > 10 ng/mL), PSA doubling time(≤ 3 months versus > 3 months to ≤ 9 months), and prior hormonal therapy (prior hormonal therapy vs.no prior hormonal therapy). For patients whose PSA values were undetectable (< 0.2 ng/mL) at week36, treatment was suspended at week 37 and then reinitiated when PSA values increased to≥ 2.0 ng/mL for patients with prior prostatectomy or ≥ 5.0 ng/mL for patients without priorprostatectomy. For patients whose PSA values were detectable at week 36 (≥ 0.2 ng/mL), treatmentcontinued without suspension until permanent treatment discontinuation criteria were met. Treatmentwas permanently discontinued when development of radiographic progression was confirmed bycentral review after the initial local read.

The demographic and baseline characteristics were well balanced between the three treatment groups.

The overall median age at randomisation was 69 years (range: 49.0 - 93.0). Most patients in the totalpopulation were Caucasian (83.2%), 7.3% were Asian, and 4.4% were Black. The median PSAdoubling time was 4.9 months. Seventy-four percent of patients had prior definitive therapy withradical prostatectomy, 75% of patients had prior therapy with radiotherapy (including brachytherapy),and 49% of patients had prior therapy with both. Thirty-two percent of patients had a Gleason score of≥ 8. The Eastern Cooperative Oncology Group Performance Status (ECOG PS) score was 0 for 92% ofpatients and 1 for 8% of patients at study entry.

Metastasis-free survival (MFS) in patients randomised to receive enzalutamide plus ADT compared topatients randomised to receive placebo plus ADT was the primary endpoint. Metastasis-free survivalwas defined as the time from randomisation to radiographic progression or death on study, whicheveroccurred first.

Multiplicity tested secondary endpoints that were assessed were time to PSA progression, time to firstuse of antineoplastic therapy, and overall survival. Another multiplicity tested secondary endpoint was

MFS in patients randomised to receive enzalutamide as monotherapy compared to patients randomisedto receive placebo plus ADT.

Enzalutamide plus ADT and as monotherapy demonstrated a statistically significant improvement in

MFS as compared to placebo plus ADT. Key efficacy results are presented in Table 2.

Table 2: Summary of efficacy in patients treated with either enzalutamide plus ADT, placeboplus ADT, or enzalutamide as monotherapy, in the EMBARK study (intent-to-treat analysis)

Enzalutamide plus Placebo plus Enzalutamide as

ADT ADT Monotherapy(N = 355) (N = 358) (N = 355)

Metastasis-free Survival1

Number of events (%)2 45 (12.7) 92 (25.7) 63 (17.7)

Median, months (95% CI)3 NR (NR, NR) NR (85.1, NR) NR (NR, NR)

Hazard ratio relative to

Placebo plus ADT (95% 0.42 (0.30, 0.61) -- 0.63 (0.46, 0.87)

CI)4

P-value for comparison to

Placebo plus ADT5 p < 0.0001 -- p = 0.0049

Enzalutamide plus Placebo plus Enzalutamide as

ADT ADT Monotherapy(N = 355) (N = 358) (N = 355)

Time to PSA Progression6

Number of events (%)2 8 (2.3) 93 (26.0) 37 (10.4)

Median, months (95% CI)3 NR (NR, NR) NR (NR, NR) NR (NR, NR)

Hazard ratio relative to

Placebo plus ADT (95% 0.07 (0.03, 0.14) -- 0.33 (0.23, 0.49)

CI)4

P-value for comparison to

Placebo plus ADT5 p < 0.0001 -- p < 0.0001

Time to Start of New Antineoplastic Therapy

Number of events (%)7 58 (16.3) 140 (39.1) 84 (23.7)

Median, months (95% CI)3 NR (NR, NR) 76.2 (71.3, NR) NR (NR, NR)

Hazard ratio relative to

Placebo plus ADT (95% 0.36 (0.26, 0.49) -- 0.54 (0.41, 0.71)

CI)4

P-value for comparison to

Placebo plus ADT5 p < 0.0001 -- p < 0.0001

Overall Survival8

Number of events (%) 33 (9.3) 55 (15.4) 42 (11.8)

Median, months (95% CI)3 NR (NR, NR) NR (NR, NR) NR (NR, NR)

Hazard ratio relative to

Placebo plus ADT (95% 0.59 (0.38, 0.91) -- 0.78 (0.52, 1.17)

CI)4

P-value for comparison to 9 9

Placebo plus ADT5 p = 0.0153 -- p = 0.2304

NR = Not reached.1. Median follow-up time of 61 months.2. Based on the earliest contributing event (radiographic progression or death).3. Based on Kaplan-Meier estimates.4. Hazard Ratio is based on a Cox regression model stratified by screening PSA, PSA doubling time, and priorhormonal therapy.5. Two-sided P-value is based on a stratified log-rank test by screening PSA, PSA doubling time, and prior hormonaltherapy.6. Based on the PSA Progression compliant with Prostate Cancer Clinical Trials Working Group 2 criteria.7. Based on the first postbaseline use of antineoplastic therapy for prostate cancer.8. Based upon a pre-specified interim analysis with data cutoff date of 31 Jan 2023 and a median follow-up time of65 months.9. The result did not meet the pre-specified two-sided significance level of p ≤ 0.0001.

20 Treatment No. of Subjects15 Enzalutamide+ADT 35510 Placebo+ADT 3585 Stratified Log-Rank Test: p= <0.00010 Stratified Hazard Ratio (95% CI): 0.424 (0.296, 0.607)0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Month

Enzalutamide+ADT:

Patients at Risk 355 331 324 318 304 292 281 265 251 234 180 116 60 24 6 0 0

Placebo+ADT:

Patients at Risk 358 335 321 303 280 259 238 221 203 183 138 88 32 15 6 1 0

Fig u r e 1: K ap la n- M e ier c ur ve s o f M FS in the En z alut ami de p lu s AD T vs. Pla ce b o plu s ADTtrea tment a r m s o f the EM BA R K study (i ntent-to-tr ea t analy s is)20 Treatment No. of Subjects15 Enzalutamide Monotherapy 35510 Placebo+ADT 3585 Stratified Log-Rank Test: p= 0.00490 Stratified Hazard Ratio (95% CI): 0.631 (0.456, 0.871)0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Month

Enzalutamide Monotherapy:

Patients at Risk 355 342 328 309 287 273 260 247 228 209 171 108 52 26 5 0 0

Placebo+ADT:

Patients at Risk 358 335 321 303 280 259 238 221 203 183 138 88 32 15 6 1 0

Fig ur e 2: Ka p lan- M eier c urve s of MFS in th e En zal ut am ide a s Mo n ot herapy vs. Placebo plus

ADT treatm en t a rms of the EMBARK study (intent-to-treat analysis)

Following the administration of ADT as enzalutamide plus ADT or placebo plus ADT, testosteronelevels rapidly decreased to castrate levels and remained low until treatment interruption at 37 weeks.

Following the interruption, testosterone levels gradually rose to near-baseline levels. Upon re-initiationof treatment, they fell again to castrate levels. In the enzalutamide as monotherapy arm, testosteronelevels increased after treatment initiation and returned towards baseline levels upon treatmentinterruption. They increased once again after treatment with enzalutamide was re-initiated.

The ARCHES study enrolled 1150 patients with mHSPC randomised 1:1 to receive treatment withenzalutamide plus ADT or placebo plus ADT (ADT defined as LHRH analogue or bilateralorchiectomy). Patients received enzalutamide at 160 mg once daily (N = 574) or placebo (N = 576).

Metastasis-Free Survival (%) Metastasis-Free Survival (%)

Patients with metastatic prostate cancer documented by positive bone scan (for bone disease) ormetastatic lesions on CT or MRI scan (for soft tissue) were eligible. Patients whose disease spread waslimited to regional pelvic lymph nodes were not eligible. Patients were allowed to receive up to 6cycles of docetaxel therapy with final treatment administration completed within 2 months of day 1and no evidence of disease progression during or after the completion of docetaxel therapy. Excludedwere patients with known or suspected brain metastasis or active leptomeningeal disease or with ahistory of seizure or any contribution that may dispose to seizure.

The demographic and baseline characteristics were well balanced between the two treatment groups.

The median age at randomisation was 70 years in both treatment groups. Most patients in the totalpopulation were Caucasian (80.5%); 13.5% were Asian and 1.4% were Black. The Eastern

Cooperative Oncology Group Performance Status (ECOG PS) score was 0 for 78% of patients and 1for 22% of patients at study entry. Patients were stratified by low versus high volume of disease andprior docetaxel therapy for prostate cancer. Thirty-seven percent of patients had a low volume ofdisease and 63% of patients had a high volume of disease. Eighty-two percent of patients had notreceived prior docetaxel therapy, 2% received 1-5 cycles and 16% received 6 prior cycles. Treatmentwith concurrent docetaxel was not allowed.

Radiographic progression-free survival (rPFS), based on independent central review, was the primaryendpoint defined as the time from randomisation to the first objective evidence of radiographic diseaseprogression or death (due to any cause from time of randomisation up until 24 weeks from study drugdiscontinuation), whichever occurred first.

Enzalutamide demonstrated a statistically significant 61% reduction in the risk of an rPFS eventcompared to placebo [HR = 0.39 (95% CI: 0.30, 0.50); p < 0.0001]. Consistent rPFS results wereobserved in patients with high or low volume of disease and patients with and without prior docetaxeltherapy. The median time to an rPFS event was not reached in the enzalutamide arm and was19.0 months (95% CI: 16.6, 22.2) in the placebo arm.

Table 3: Summary of efficacy in patients treated with either enzalutamide or placebo in the

ARCHES study (intent-to-treat analysis)

Enzalutamide plus ADT Placebo plus ADT(N = 574) (N = 576)

Radiographic Progression-free Survival

Number of events (%) 91 (15.9) 201 (34.9)

Median, months (95% CI)1 NR 19.0 (16.6, 22.2)

Hazard ratio (95% CI)2 0.39 (0.30, 0.50)

P-value2 p < 0.0001

NR = Not reached.1. Calculated using Brookmeyer and Crowley method.2. Stratified by volume of disease (low vs high) and prior docetaxel use (yes or no).

Figure 3: Kaplan-Meier curve of rPFS in ARCHES study (intent-to-treat analysis)

Key secondary efficacy endpoints assessed in the study included time to PSA progression, time to startof new antineoplastic therapy, PSA undetectable rate (decline to < 0.2 µg/L), and objective responserate (RECIST 1.1 based on independent review). Statistically significant improvements in patientstreated with enzalutamide compared to placebo were demonstrated for all these secondary endpoints.

Another key secondary efficacy endpoint assessed in the study was overall survival. At thepre-specified final analysis for overall survival, conducted when 356 deaths were observed, astatistically significant 34% reduction in the risk of death was demonstrated in the group randomisedto receive enzalutamide compared with the group randomised to receive placebo [HR = 0.66,(95% CI: 0.53; 0.81), p < 0.0001]. The median time for overall survival was not reached in eithertreatment group. The estimated median follow-up time for all patients was 44.6 months (see Figure 4).

Figure 4: Kaplan-Meier Curves of overall survival in the ARCHES study (intent-to-treatanalysis)

The PROSPER study enrolled 1401 patients with asymptomatic, high-risk non-metastatic CRPC whocontinued on androgen deprivation therapy (ADT; defined as LHRH analogue or prior bilateralorchiectomy). Patients were required to have a PSA doubling time ≤ 10 months, PSA ≥ 2 ng/mL, andconfirmation of non-metastatic disease by blinded independent central review (BICR).

Patients with a history of mild to moderate heart failure (NYHA Class I or II), and patients takingmedicinal products associated with lowering the seizure threshold were allowed. Patients wereexcluded with a previous history of seizure, a condition that might predispose them to seizure, orcertain prior treatments for prostate cancer (i.e., chemotherapy, ketoconazole, abiraterone acetate,aminoglutethimide and/or enzalutamide).

Patients were randomised 2:1 to receive either enzalutamide at a dose of 160 mg once daily (N = 933)or placebo (N = 468). Patients were stratified by Prostate Specific Antigen (PSA) Doubling Time(PSADT) (< 6 months or ≥ 6 months) and the use of bone-targeting agents (yes or no).

The demographic and baseline characteristics were well-balanced between the two treatment arms.

The median age at randomisation was 74 years in the enzalutamide arm and 73 years in the placeboarm. Most patients (approximately 71%) in the study were Caucasian; 16% were Asian and 2% were

Black. Eighty-one percent (81%) of patients had an ECOG performance status score of 0 and 19%patients had an ECOG performance status of 1.

Metastasis-free survival (MFS) was the primary endpoint defined as the time from randomisation toradiographic progression or death within 112 days of treatment discontinuation without evidence ofradiographic progression, whichever occurred first. Key secondary endpoints assessed in the studywere time to PSA progression, time to first use of new antineoplastic therapy (TTA), overall survival(OS). Additional secondary endpoints included time to first use of cytotoxic chemotherapy andchemotherapy-free survival. See results below (Table 4).

Enzalutamide demonstrated a statistically significant 71% reduction in the relative risk of radiographicprogression or death compared to placebo [HR = 0.29 (95% CI: 0.24, 0.35), p < 0.0001]. Median MFSwas 36.6 months (95% CI: 33.1, NR) on the enzalutamide arm versus 14.7 months (95% CI: 14.2,15.0) on the placebo arm. Consistent MFS results were also observed in all pre-specified patient sub-groups including PSADT (< 6 months or ≥ 6 months), demographic region (North America, Europe,rest of world), age (< 75 or ≥ 75), use of a prior bone-targeting agent (yes or no) (see Figure 5).

Table 4: Summary of efficacy results in the PROSPER study (intent-to-treat analysis)

Enzalutamide Placebo(N = 933) (N = 468)

Primary Endpoint

Metastasis-free survival

Number of Events (%) 219 (23.5) 228 (48.7)

Median, months (95% CI)1 36.6 (33.1, NR) 14.7 (14.2, 15.0)

Hazard Ratio (95% CI)2 0.29 (0.24, 0.35)

P-value3 p < 0.0001

Key Secondary Efficacy Endpoints

Overall Survival4

Number of Events (%) 288 (30.9) 178 (38.0)

Median, months (95% CI)1 67.0 (64.0, NR) 56.3 (54.4, 63.0)

Hazard Ratio (95% CI)2 0.734 (0.608, 0.885)

P-value3 p = 0.0011

Time to PSA progression

Number of Events (%) 208 (22.3) 324 (69.2)

Median, months (95% CI)1 37.2 (33.1, NR) 3.9 (3.8, 4.0)

Hazard Ratio (95% CI)2 0.07 (0.05, 0.08)

P-value3 p < 0.0001

Time to first use of new antineoplastic therapy

Number of Events (%) 142 (15.2) 226 (48.3)

Enzalutamide Placebo(N = 933) (N = 468)

Median, months (95% CI)1 39.6 (37.7, NR) 17.7 (16.2, 19.7)

Hazard Ratio (95% CI)2 0.21 (0.17, 0.26)

P-value3 p < 0.0001

NR = Not reached.1. Based on Kaplan-Meier estimates.2. HR is based on a Cox regression model (with treatment as the only covariate) stratified by PSA doubling time andprior or concurrent use of a bone targeting agent. The HR is relative to placebo with < 1 favouring enzalutamide.3. P-value is based on a stratified log-rank test by PSA doubling time (< 6 months, ≥ 6 months) and prior orconcurrent use of a bone targeting agent (yes, no).4. Based upon a prespecified interim analysis with data cutoff date of 15 Oct 2019.

Figure 5: Kaplan-Meier Curves of metastasis-free survival in the PROSPER study (intent-to-treat analysis)

At the final analysis for overall survival, conducted when 466 deaths were observed, a statisticallysignificant improvement in overall survival was demonstrated in patients randomised to receiveenzalutamide compared with patients randomised to receive placebo with a 26.6% reduction in risk ofdeath [hazard ratio (HR) = 0.734, (95% CI: 0.608; 0.885), p = 0.0011] (see Figure 6). The medianfollow-up time was 48.6 and 47.2 months for the enzalutamide and placebo groups, respectively.

Thirty-three percent of enzalutamide-treated and 65% of placebo-treated patients received at least onesubsequent antineoplastic therapy that may prolong overall survival.

Figure 6: Kaplan-Meier Curves of overall survival in the PROSPER study (intent-to-treatanalysis)

Enzalutamide demonstrated a statistically significant 93% reduction in the relative risk of PSAprogression compared to placebo [HR = 0.07 (95% CI: 0.05, 0.08), p < 0.0001]. Median time to PSAprogression was 37.2 months (95% CI: 33.1, NR) on the enzalutamide arm versus 3.9 months(95% CI: 3.8, 4.0) on the placebo arm.

Enzalutamide demonstrated a statistically significant delay in the time to first use of newantineoplastic therapy compared to placebo [HR = 0.21 (95% CI: 0.17, 0.26), p < 0.0001]. Mediantime to first use of new antineoplastic therapy was 39.6 months (95% CI: 37.7, NR) on theenzalutamide arm versus 17.7 months (95% CI: 16.2, 19.7) on the placebo arm (see Figure 7).

Figure 7: Kaplan-Meier curves of time to first use of new antineoplastic therapy in the

PROSPER study (intent-to-treat analysis)

The STRIVE study enrolled 396 non-metastatic or metastatic CRPC patients who had serologic orradiographic disease progression despite primary androgen deprivation therapy who were randomisedto receive either enzalutamide at a dose of 160 mg once daily (N = 198) or bicalutamide at a dose of50 mg once daily (N = 198). PFS was the primary endpoint defined as the time from randomisation tothe earliest objective evidence of radiographic progression, PSA progression, or death on study.

Median PFS was 19.4 months (95% CI: 16.5, not reached) in the enzalutamide group versus5.7 months (95% CI: 5.6, 8.1) in the bicalutamide group [HR = 0.24 (95% CI: 0.18, 0.32), p < 0.0001].

Consistent benefit of enzalutamide over bicalutamide on PFS was observed in all pre-specified patientsubgroups. For the non-metastatic subgroup (N = 139) a total of 19 out of 70 (27.1%) patients treatedwith enzalutamide and 49 out of 69 (71.0%) patients treated with bicalutamide had PFS events(68 total events). The hazard ratio was 0.24 (95% CI: 0.14, 0.42) and the median time to a PFS eventwas not reached in the enzalutamide group versus 8.6 months in the bicalutamide group (see Figure 8).

Figure 8: Kaplan-Meier Curves of progression-free survival in the STRIVE study (intent-to-treatanalysis)9785-CL-0222 (TERRAIN) study (chemotherapy-naïve patients with metastatic CRPC)

The TERRAIN study enrolled 375 chemo- and antiandrogen-therapy naïve patients with metastatic

CRPC who were randomised to receive either enzalutamide at a dose of 160 mg once daily (N = 184)or bicalutamide at a dose of 50 mg once daily (N = 191). Median PFS was 15.7 months for patients onenzalutamide versus 5.8 months for patients on bicalutamide [HR = 0.44 (95% CI: 0.34, 0.57),p < 0.0001]. Progression-free survival was defined as objective evidence of radiographic diseaseprogression by independent central review, skeletal-related events, initiation of new antineoplastictherapy or death by any cause, whichever occurred first. Consistent PFS benefit was observed acrossall pre-specified patient subgroups.

A total of 1717 asymptomatic or mildly symptomatic chemotherapy-naïve patients were randomised1:1 to receive either enzalutamide orally at a dose of 160 mg once daily (N = 872) or placebo orallyonce daily (N = 845). Patients with visceral disease, patients with a history of mild to moderate heartfailure (NYHA Class I or II), and patients taking medicinal products associated with lowering theseizure threshold were allowed. Patients with a previous history of seizure or a condition that mightpredispose to seizure and patients with moderate or severe pain from prostate cancer were excluded.

Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression) and the initiation of either a cytotoxic chemotherapy or aninvestigational agent, or until unacceptable toxicity.

Patient demographics and baseline disease characteristics were balanced between the treatment arms.

The median age was 71 years (range 42 - 93) and the racial distribution was 77% Caucasian,10% Asian, 2% Black and 11% other or unknown races. Sixty-eight percent (68%) of patients had an

ECOG performance status score of 0 and 32% patients had an ECOG performance status of 1.

Baseline pain assessment was 0 - 1 (asymptomatic) in 67% of patients and 2 - 3 (mildly symptomatic)in 32% of patients as defined by the Brief Pain Inventory Short Form (worst pain over past 24 hourson a scale of 0 to 10). Approximately 45% of patients had measurable soft tissue disease at studyentry, and 12% of patients had visceral (lung and/or liver) metastases.

Co-primary efficacy endpoints were overall survival and radiographic progression-free survival(rPFS). In addition to the co-primary endpoints, benefit was also assessed using time to initiation ofcytotoxic chemotherapy, best overall soft tissue response, time to first skeletal-related event, PSAresponse (≥ 50% decrease from baseline), time to PSA progression, and time to FACT-P total scoredegradation.

Radiographic progression was assessed with the use of sequential imaging studies as defined by

Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria (for bone lesions) and/or Response

Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria (for soft tissue lesions). Analysis of rPFSutilised centrally-reviewed radiographic assessment of progression.

At the pre-specified interim analysis for overall survival when 540 deaths were observed, treatmentwith enzalutamide demonstrated a statistically significant improvement in overall survival compared totreatment with placebo with a 29.4% reduction in risk of death [HR = 0.706 (95% CI: 0.60; 0.84),p < 0.0001]. An updated survival analysis was conducted when 784 deaths were observed. Resultsfrom this analysis were consistent with those from the interim analysis (Table 5). At the updatedanalysis 52% of enzalutamide-treated and 81% of placebo-treated patients had received subsequenttherapies for metastatic CRPC that may prolong overall survival.

A final analysis of 5-year PREVAIL data showed a statistically significant increase in overall survivalwas maintained in patients treated with enzalutamide compared to placebo [HR = 0.835,(95% CI: 0.75, 0.93); p-value = 0.0008] despite 28% of patients on placebo crossing over toenzalutamide. The 5-year OS rate was 26% for the enzalutamide arm compared to 21% for the placeboarm.

Table 5: Overall survival of patients treated with either enzalutamide or placebo in the

PREVAIL study (intent-to-treat analysis)

Enzalutamide Placebo(N = 872) (N = 845)

Pre-specified interim analysis

Number of deaths (%) 241 (27.6%) 299 (35.4%)

Median survival, months (95% CI) 32.4 (30.1, NR) 30.2 (28.0, NR)

P-value1 p < 0.0001

Hazard ratio (95% CI)2 0.71 (0.60, 0.84)

Updated survival analysis

Number of deaths (%) 368 (42.2%) 416 (49.2%)

Median survival, months (95% CI) 35.3 (32.2, NR) 31.3 (28.8, 34.2)

P-value1 p = 0.0002

Hazard ratio (95% CI)2 0.77 (0.67, 0.88)5-year survival analysis

Number of deaths (%) 689 (79) 693 (82)

Median survival, months (95% CI) 35.5 (33.5, 38.0) 31.4 (28.9, 33.8)

P-value1 p = 0.0008

Hazard ratio (95% CI)2 0.835 (0.75, 0.93)

NR = Not reached.1. P-value is derived from an unstratified log-rank test.2. Hazard Ratio is derived from an unstratified proportional hazards model. Hazard ratio < 1 favours enzalutamide.

Figure 9: Kaplan-Meier curves of overall survival based on 5-year survival analysis in the

PREVAIL study (intent-to-treat analysis)

Figure 10: 5-year overall survival analysis by subgroup: Hazard ratio and 95% confidenceinterval in the PREVAIL study (intent-to-treat analysis)

At the pre-specified rPFS analysis, a statistically significant improvement was demonstrated betweenthe treatment groups with an 81.4% reduction in risk of radiographic progression or death [HR = 0.19(95% CI: 0.15, 0.23), p < 0.0001]. One hundred and eighteen (14%) enzalutamide-treated patients and321 (40%) of placebo-treated patients had an event. The median rPFS was not reached (95% CI: 13.8,not reached) in the enzalutamide-treated group and was 3.9 months (95% CI: 3.7, 5.4) in the placebo-treated group (Figure 11). Consistent rPFS benefit was observed across all pre-specified patientsubgroups (e.g. age, baseline ECOG performance, baseline PSA and LDH, Gleason score at diagnosis,and visceral disease at screening). A pre-specified follow-up rPFS analysis based on the investigatorassessment of radiographic progression demonstrated a statistically significant improvement betweenthe treatment groups with a 69.3% reduction in risk of radiographic progression or death [HR = 0.31(95% CI: 0.27, 0.35), p < 0.0001]. The median rPFS was 19.7 months in the enzalutamide group and5.4 months in the placebo group.

At the time of the primary analysis there were 1,633 patients randomised.

Figure 11: Kaplan-Meier curves of radiographic progression-free survival in the PREVAILstudy (intent-to-treat analysis)

In addition to the co-primary efficacy endpoints, statistically significant improvements were alsodemonstrated in the following prospectively defined endpoints.

The median time to initiation of cytotoxic chemotherapy was 28.0 months for patients receivingenzalutamide and 10.8 months for patients receiving placebo [HR = 0.35 (95% CI: 0.30, 0.40),p < 0.0001].

The proportion of enzalutamide-treated patients with measurable disease at baseline who had anobjective soft tissue response was 58.8% (95% CI: 53.8, 63.7) compared with 5.0% (95% CI: 3.0, 7.7)of patients receiving placebo. The absolute difference in objective soft tissue response betweenenzalutamide and placebo arms was [53.9% (95% CI: 48.5, 59.1), p < 0.0001]. Complete responseswere reported in 19.7% of enzalutamide-treated patients compared with 1.0% of placebo-treatedpatients, and partial responses were reported in 39.1% of enzalutamide-treated patients versus 3.9% ofplacebo-treated patients.

Enzalutamide significantly decreased the risk of the first skeletal-related event by 28% [HR = 0.718(95% CI: 0.61, 0.84), p < 0.0001]. A skeletal-related event was defined as radiation therapy or surgeryto bone for prostate cancer, pathologic bone fracture, spinal cord compression, or change ofantineoplastic therapy to treat bone pain. The analysis included 587 skeletal-related events, of which389 events (66.3%) were radiation to bone, 79 events (13.5%) were spinal cord compression, 70 events(11.9%) were pathologic bone fracture, 45 events (7.6%) were change in antineoplastic therapy to treatbone pain, and 22 events (3.7%) were surgery to bone.

Patients receiving enzalutamide demonstrated a significantly higher total PSA response rate (definedas a ≥ 50% reduction from baseline), compared with patients receiving placebo, 78.0% versus 3.5%(difference = 74.5%, p < 0.0001).

The median time to PSA progression per PCWG2 criteria was 11.2 months for patients treated withenzalutamide and 2.8 months for patients who received placebo [HR = 0.17 (95% CI: 0.15, 0.20),p < 0.0001].

Treatment with enzalutamide decreased the risk of FACT-P degradation by 37.5% compared withplacebo (p < 0.0001). The median time to degradation in FACT-P was 11.3 months in theenzalutamide group and 5.6 months in the placebo group.

The efficacy and safety of enzalutamide in patients with metastatic CRPC who had received docetaxeland were using a LHRH analogue or had undergone orchiectomy were assessed in a randomised,placebo-controlled, multicentre phase 3 clinical trial. A total of 1199 patients were randomised 2:1 toreceive either enzalutamide orally at a dose of 160 mg once daily (N = 800) or placebo once daily(N = 399). Patients were allowed but not required to take prednisone (maximum daily dose allowedwas 10 mg prednisone or equivalent). Patients randomised to either arm were to continue treatmentuntil disease progression (defined as confirmed radiographic progression or the occurrence of askeletal-related event) and initiation of new systemic antineoplastic treatment, unacceptable toxicity,or withdrawal.

The following patient demographics and baseline disease characteristics were balanced between thetreatment arms. The median age was 69 years (range 41 - 92) and the racial distribution was 93%

Caucasian, 4% Black, 1% Asian, and 2% Other. The ECOG performance score was 0 - 1 in 91.5% ofpatients and 2 in 8.5% of patients; 28% had a mean Brief Pain Inventory score of ≥ 4 (mean ofpatient’s reported worst pain over the previous 24 hours calculated for seven days prior torandomisation). Most (91%) patients had metastases in bone and 23% had visceral lung and/or liverinvolvement. At study entry, 41% of randomised patients had PSA progression only, whereas 59% ofpatients had radiographic progression. Fifty-one percent (51%) of patients were on bisphosphonates atbaseline.

The AFFIRM study excluded patients with medical conditions that may predispose them to seizures(see section 4.8) and medicinal products known to decrease the seizure threshold, as well as clinicallysignificant cardiovascular disease such as uncontrolled hypertension, recent history of myocardialinfarction or unstable angina, New York Heart Association class III or IV heart failure (unless ejectionfraction was ≥ 45%), clinically significant ventricular arrhythmias or AV block (without permanentpacemaker).

The protocol pre-specified interim analysis after 520 deaths showed a statistically significantsuperiority in overall survival in patients treated with enzalutamide compared to placebo (Table 6 and

Figures 12 and 13).

Table 6: Overall survival of patients treated with either enzalutamide or placebo in the AFFIRMstudy (intent-to-treat analysis)

Enzalutamide (N = 800) Placebo (N = 399)

Deaths (%) 308 (38.5%) 212 (53.1%)

Median survival (months) (95% CI) 18.4 (17.3, NR) 13.6 (11.3, 15.8)

P-value1 p < 0.0001

Hazard ratio (95% CI)2 0.63 (0.53, 0.75)

NR = Not Reached.1. P-value is derived from a log rank test stratified by ECOG performance status score (0-1 vs. 2) and mean pain score(< 4 vs. ≥ 4).2. Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favours enzalutamide.

Figure 12: Kaplan-Meier curves of overall survival in the AFFIRM study (intent-to-treatanalysis)

ECOG: Eastern Cooperative Oncology Group; BPI-SF: Brief Pain Inventory-Short Form; PSA: Prostate Specific Antigen

Figure 13: Overall survival by subgroup in the AFFIRM study - Hazard ratio and 95%confidence interval

In addition to the observed improvement in overall survival, key secondary endpoints (PSAprogression, radiographic progression-free survival, and time to first skeletal-related event) favouredenzalutamide and were statistically significant after adjusting for multiple testing.

Radiographic progression-free survival as assessed by the investigator using RECIST v 1.1 for softtissue and appearance of 2 or more bone lesions in bone scan was 8.3 months for patients treated withenzalutamide and 2.9 months for patients who received placebo [HR = 0.40 (95% CI: 0.35, 0.47),p < 0.0001]. The analysis involved 216 deaths without documented progression and 645 documentedprogression events, of which 303 (47%) were due to soft tissue progression, 268 (42%) were due tobone lesion progression and 74 (11%) were due to both soft tissue and bone lesions.

Confirmed PSA decline of 50% or 90% were 54.0% and 24.8%, respectively, for patients treated withenzalutamide and 1.5% and 0.9%, respectively, for patients who received placebo (p < 0.0001). Themedian time to PSA progression was 8.3 months for patients treated with enzalutamide and 3.0 monthsfor patients who received placebo [HR = 0.25 (95% CI: 0.20, 0.30), p < 0.0001].

The median time to first skeletal-related event was 16.7 months for patients treated with enzalutamideand 13.3 months for patients who received placebo [HR = 0.69 (95% CI: 0.57, 0.84), p < 0.0001]. Askeletal-related event was defined as radiation therapy or surgery to bone, pathologic bone fracture,spinal cord compression or change of antineoplastic therapy to treat bone pain. The analysis involved448 skeletal-related events, of which 277 events (62%) were radiation to bone, 95 events (21%) werespinal cord compression, 47 events (10%) were pathologic bone fracture, 36 events (8%) were changein antineoplastic therapy to treat bone pain, and 7 events (2%) were surgery to bone.

The study was a single-arm study in 214 patients with progressing metastatic CRPC who receivedenzalutamide (160 mg once daily) after at least 24 weeks of treatment with abiraterone acetate plusprednisone. Median rPFS (radiologic progression free survival, the study´s primary endpoint) was8.1 months (95% CI: 6.1, 8.3). Median OS was not reached. PSA Response (defined as ≥ 50%decrease from baseline) was 22.4% (95% CI: 17.0, 28.6). For the 69 patients who previously receivedchemotherapy, median rPFS was 7.9 months (95% CI: 5.5, 10.8). PSA Response was 23.2% (95% CI:13.9, 34.9). For the 145 patients who had no previous chemotherapy, median rPFS was 8.1 months(95% CI: 5.7, 8.3). PSA Response was 22.1% (95% CI: 15.6, 29.7).

Although there was a limited response in some patients from treatment with enzalutamide afterabiraterone, the reason for this finding is currently unknown. The study design could neither identifythe patients who are likely to benefit, nor the order in which enzalutamide and abiraterone should beoptimally sequenced.

Of the 5110 patients in the controlled clinical trials who received enzalutamide, 3988 patients (78%)were 65 years and over and 1703 patients (33%) were 75 years and over. No overall differences insafety or effectiveness were observed between these elderly patients and younger patients.

The European Medicines Agency has waived the obligation to submit the results of studies withenzalutamide in all subsets of the paediatric population in prostate carcinoma (see section 4.2 forinformation on paediatric use).

Enzalutamide is poorly water soluble. The solubility of enzalutamide is increased by caprylocaproylmacrogolglycerides as emulsifier/surfactant. In preclinical studies, the absorption of enzalutamide wasincreased when dissolved in caprylocaproyl macrogolglycerides.

The pharmacokinetics of enzalutamide have been evaluated in prostate cancer patients and in healthymale subjects. The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is5.8 days (range 2.8 to 10.2 days), and steady state is achieved in approximately one month. With dailyoral administration, enzalutamide accumulates approximately 8.3-fold relative to a single dose. Dailyfluctuations in plasma concentrations are low (peak-to-trough ratio of 1.25). Clearance ofenzalutamide is primarily via hepatic metabolism, producing an active metabolite that is equally asactive as enzalutamide and circulates at approximately the same plasma concentration as enzalutamide.

Maximum plasma concentrations (Cmax) of enzalutamide in patients are observed 1 to 2 hours afteradministration. Based on a mass balance study in humans, oral absorption of enzalutamide is estimatedto be at least 84.2%. Enzalutamide is not a substrate of the efflux transporters P-gp or BCRP. Atsteady state, the mean Cmax values for enzalutamide and its active metabolite are 16.6 μg/mL (23%coefficient of variation [CV]) and 12.7 μg/mL (30% CV), respectively.

Food has no clinically significant effect on the extent of absorption. In clinical trials, Xtandi wasadministered without regard to food.

The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose is110 L (29% CV). The volume of distribution of enzalutamide is greater than the volume of total bodywater, indicative of extensive extravascular distribution. Studies in rodents indicate that enzalutamideand its active metabolite can cross the blood brain barrier.

Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. The active metabolite is95% bound to plasma proteins. There was no protein binding displacement between enzalutamide andother highly bound medicinal products (warfarin, ibuprofen and salicylic acid) in vitro.

Enzalutamide is extensively metabolised. There are two major metabolites in human plasma:

N-desmethyl enzalutamide (active) and a carboxylic acid derivative (inactive). Enzalutamide ismetabolised by CYP2C8 and to a lesser extent by CYP3A4/5 (see section 4.5), both of which play arole in the formation of the active metabolite. In vitro, N-desmethyl enzalutamide is metabolised to thecarboxylic acid metabolite by carboxylesterase 1, which also plays a minor role in the metabolism ofenzalutamide to the carboxylic acid metabolite. N-desmethyl enzalutamide was not metabolised by

CYPs in vitro.

Under conditions of clinical use, enzalutamide is a strong inducer of CYP3A4, a moderate inducer of

CYP2C9 and CYP2C19, and has no clinically relevant effect on CYP2C8 (see section 4.5).

The mean apparent clearance (CL/F) of enzalutamide in patients ranges from 0.520 and 0.564 L/h.

Following oral administration of 14C-enzalutamide, 84.6% of the radioactivity is recovered by 77 dayspost dose: 71.0% is recovered in urine (primarily as the inactive metabolite, with trace amounts ofenzalutamide and the active metabolite), and 13.6% is recovered in faeces (0.39% of dose asunchanged enzalutamide).

In vitro data indicate that enzalutamide is not a substrate for OATP1B1, OATP1B3, or OCT1; and

N-desmethyl enzalutamide is not a substrate for P-gp or BCRP.

In vitro data indicate that enzalutamide and its major metabolites do not inhibit the followingtransporters at clinically relevant concentrations: OATP1B1, OATP1B3, OCT2, or OAT1.

No major deviations from dose proportionality are observed over the dose range 40 to 160 mg. Thesteady-state Cmin values of enzalutamide and the active metabolite in individual patients remainedconstant during more than one year of chronic therapy, demonstrating time-linear pharmacokineticsonce steady-state is achieved.

No formal renal impairment study for enzalutamide has been completed. Patients with serumcreatinine > 177 μmol/L (2 mg/dL) were excluded from clinical studies. Based on a populationpharmacokinetic analysis, no dose adjustment is necessary for patients with calculated creatinineclearance (CrCL) values ≥ 30 mL/min (estimated by the Cockcroft and Gault formula). Enzalutamidehas not been evaluated in patients with severe renal impairment (CrCL < 30 mL/min) or end-stagerenal disease, and caution is advised when treating these patients. It is unlikely that enzalutamide willbe significantly removed by intermittent haemodialysis or continuous ambulatory peritoneal dialysis.

Hepatic impairment did not have a pronounced effect on the total exposure to enzalutamide or itsactive metabolite. The half-life of enzalutamide was however doubled in patients with severe hepaticimpairment compared with healthy controls (10.4 days compared to 4.7 days), possibly related to anincreased tissue distribution.

The pharmacokinetics of enzalutamide were examined in subjects with baseline mild (N = 6),moderate (N = 8) or severe (N = 8) hepatic impairment (Child-Pugh Class A, B or C, respectively) andin 22 matched control subjects with normal hepatic function. Following a single oral 160 mg dose ofenzalutamide, the AUC and Cmax for enzalutamide in subjects with mild impairment increased by 5%and 24%, respectively, the AUC and Cmax of enzalutamide in subjects with moderate impairmentincreased by 29% and decreased by 11%, respectively, and the AUC and Cmax of enzalutamide insubjects with severe impairment increased by 5% and decreased by 41%, respectively, compared tohealthy control subjects. For the sum of unbound enzalutamide plus the unbound active metabolite, the

AUC and Cmax in subjects with mild impairment increased by 14% and 19%, respectively, the AUCand Cmax in subjects with moderate impairment increased by 14% and decreased by 17%, respectively,and the AUC and Cmax in subjects with severe hepatic impairment increased by 34% and decreased by27%, respectively, compared to healthy control subjects.

Most patients in the controlled clinical studies (> 75%) were Caucasian. Based on pharmacokineticdata from studies in Japanese and Chinese patients with prostate cancer, there were no clinicallyrelevant differences in exposure among the populations. There are insufficient data to evaluatepotential differences in the pharmacokinetics of enzalutamide in other races.

No clinically relevant effect of age on enzalutamide pharmacokinetics was seen in the elderlypopulation pharmacokinetic analysis.

Enzalutamide treatment of pregnant mice resulted in an increased incidence of embryo-fetal deaths andexternal and skeletal changes. Fertility studies were not conducted with enzalutamide, but in studies inrats (4 and 26 weeks) and dogs (4, 13, and 39 weeks), atrophy, aspermia/hypospermia, andhypertrophy/hyperplasia in the reproductive system were noted, consistent with the pharmacologicalactivity of enzalutamide. In studies in mice (4 weeks), rats (4 and 26 weeks) and dogs (4, 13, and39 weeks), changes in the reproductive organs associated with enzalutamide were decreases in organweight with atrophy of the prostate and epididymis. Leydig cell hypertrophy and/or hyperplasia wereobserved in mice (4 weeks) and dogs (39 weeks). Additional changes to reproductive tissues includedhypertrophy/hyperplasia of the pituitary gland and atrophy in seminal vesicles in rats and testicularhypospermia and seminiferous tubule degeneration in dogs. Gender differences were noted in ratmammary glands (male atrophy and female lobular hyperplasia). Changes in the reproductive organsin both species were consistent with the pharmacological activity of enzalutamide and reversed orpartially resolved after an 8-week recovery period. There were no other important changes in clinicalpathology or histopathology in any other organ system, including the liver, in either species.

Studies in pregnant rats have shown that enzalutamide and/or its metabolites are transferred to fetuses.

After oral administration of radiolabeled 14C-enzalutamide to rats on day 14 of pregnancy at a dose of30 mg/kg (~ 1.9 times the maximum dose indicated in humans), the maximum radioactivity in thefetus was reached 4 hours after administration and was lower than that in the maternal plasma withtissue/plasma ratio of 0.27. The radioactivity in the fetus decreased to 0.08 times the maximumconcentration at 72 hours after administration.

Studies in lactating rats have shown that enzalutamide and/or its metabolites are secreted in rat milk.

After oral administration of radiolabeled 14C-enzalutamide to lactating rats at a dose of 30 mg/kg(~ 1.9 times the maximum dose indicated in humans), the maximum radioactivity in the milk wasreached 4 hours after administration and was up to 3.54-fold higher than that in the maternal plasma.

Study results also have shown that enzalutamide and/or its metabolites are transferred to infant rattissues via milk and subsequently eliminated.

Enzalutamide was negative for genotoxicity in a standard battery of in vitro and in vivo tests. In a6-month study in transgenic rasH2 mice, enzalutamide did not show carcinogenic potential (absence ofneoplastic findings) at doses up to 20 mg/kg per day (AUC24h ~317 µg·h/mL), which resulted inplasma exposure levels similar to the clinical exposure (AUC24h ~322 µg·h/mL) in mCRPC patientsreceiving 160 mg, daily.

Daily dosing of rats for two years with enzalutamide produced an increased incidence of neoplasticfindings. These included benign thymoma, fibroadenoma in the mammary glands, benign Leydig celltumours in the testes and urothelium papilloma and carcinoma of urinary bladder in males; benigngranulosa cell tumour in the ovaries in females and adenoma in the pars distalis of the pituitary in bothsexes. The human relevance of thymoma, pituitary adenoma and mammary fibroadenoma as well asurothelium papilloma and carcinoma of urinary bladder cannot be ruled out.

Enzalutamide was not phototoxic in vitro.

Caprylocaproyl macrogol-8 glycerides

Butylhydroxyanisole (E320)

Butylhydroxytoluene (E321)

Gelatin

Sorbitol sorbitan solution

Glycerol

Titanium dioxide (E171)

Purified water

Iron oxide black (E172)

Polyvinyl acetate phthalate

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Cardboard wallet incorporating a PVC/PCTFE/aluminium blister of 28 soft capsules. Each cartoncontains 4 wallets (112 soft capsules).

Xtandi should not be handled by persons other than the patient or his caregivers. Based on itsmechanism of action and embryo-fetal toxicity observed in mice, Xtandi may harm a developing fetus.

Women who are or may become pregnant should not handle damaged or opened Xtandi capsuleswithout protection, e.g. gloves. See section 5.3 Pre-clinical safety data.

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

Astellas Pharma Europe B.V.

Sylviusweg 622333 BE Leiden

The Netherlands

EU/1/13/846/001

Date of first authorisation: 21 June 2013

Date of latest renewal: 8 February 2018

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

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