Apalutamide

Apalutamide is a selective androgen receptor (AR) inhibitor taken by mouth. Prostate cancer cells depend on androgen receptor signalling, which persists in castration-resistant disease through AR gene amplification or mutation, increased receptor expression or increased androgen synthesis within the tumour. Apalutamide acts on the receptor itself.

Mechanism of Action

• Receptor blockade: apalutamide binds directly to the ligand-binding domain of the AR, prevents the receptor moving into the nucleus, inhibits its binding to DNA and impedes receptor-mediated transcription. It has no agonist activity. Tumour cell proliferation falls and apoptosis (programmed cell death) rises.
• Active metabolite: N-desmethyl apalutamide has about one-third of the in vitro activity of the parent drug and probably contributes to the clinical effect.
• PSA response: with ADT, prostate-specific antigen (PSA) became undetectable (below 0.2 ng/mL) at any time in 68% of men with mHSPC (TITAN study; 32% with ADT alone) and in 38% of men with nmCRPC (SPARTAN study; none with ADT alone). A PSA fall of at least 50% occurred in 90% of men in both studies.
• Cardiac electrophysiology: in a dedicated QT study in 45 patients with castration-resistant prostate cancer, the maximum mean QTcF change from baseline at steady state was 12.4 ms (upper limit of the 90% confidence interval 16.0 ms).

Pharmacokinetics

• Absorption: oral bioavailability is about 100%, with a median time to peak concentration of 2 hours. A high-fat meal caused no clinically relevant change in peak concentration or in the area under the concentration–time curve (AUC) and delayed the peak by about 2 hours, so the tablets can be taken with or without food. Acid-lowering medicines are not expected to affect absorption, because apalutamide is not ionised at physiological pH.
• Steady state: with 240 mg once daily, steady state is reached after 4 weeks, with about 5-fold accumulation and little fluctuation over the day. The active metabolite reaches a similar peak concentration and an AUC about 1.3 times that of the parent drug.
• Distribution: the apparent volume of distribution at steady state is about 276 L. Plasma protein binding is 96% for apalutamide and 95% for N-desmethyl apalutamide.
• Metabolism: mainly by CYP2C8 and CYP3A4, which form N-desmethyl apalutamide. Their contributions are about 58% and 13% after a single dose and 40% and 37% at steady state. Apparent clearance rises with repeated dosing, from 1.3 L/h after a single dose to 2.0 L/h at steady state, likely because apalutamide induces its own metabolism.
• Elimination: up to 70 days after a single radiolabelled dose, 65% was recovered in urine and 24% in faeces, with little as unchanged apalutamide (1.2% in urine, 1.5% in faeces). The mean effective half-life at steady state in nmCRPC is about 3 days.

Apalutamide is indicated in adult men:

• Non-metastatic castration-resistant prostate cancer (nmCRPC): for treatment in men at high risk of developing metastatic disease.
• Metastatic hormone-sensitive prostate cancer (mHSPC): in combination with androgen deprivation therapy (ADT).

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

The most common reactions are fatigue (26%), skin rash (26% of any grade and 6% grade 3 or 4), hypertension (22%), hot flush (18%), arthralgia (17%), diarrhoea (16%), fall (13%) and weight decreased (13%). Other important reactions include fractures (11%), decreased appetite (11%) and hypothyroidism (8%).

Very common (≥1/10): decreased appetite, hot flush, hypertension, diarrhoea, skin rash, fracture, arthralgia, fatigue, weight decreased, fall.

Common (≥1/100 to <1/10): neutropenia, hypothyroidism, hypercholesterolaemia, hypertriglyceridaemia, dysgeusia, ischaemic cerebrovascular disorders (including transient ischaemic attack and stroke), ischaemic heart disease (including angina and myocardial infarction), pruritus, alopecia, muscle spasm.

Uncommon (≥1/1,000 to <1/100): seizure, restless legs syndrome, lichenoid eruption.

Not known: agranulocytosis, QT prolongation, interstitial lung disease, drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).

Important serious reactions are seizure, falls and fractures, ischaemic heart disease and ischaemic cerebrovascular disorders (some fatal), and the severe skin reactions and interstitial lung disease listed above.

Apalutamide induces enzymes and transporters and may increase the elimination of many commonly used medicines. Its own elimination depends on CYP2C8 and CYP3A4 to a similar extent at steady state, so inhibitors or inducers of either enzyme are not expected to change overall exposure in a clinically meaningful way.

• Medicines affected by enzyme induction: their effect may be lost, so all concomitant medicines should be reviewed when apalutamide is started. Sensitive substrates of many metabolising enzymes or transporters should generally be avoided if their effect is of great importance and doses cannot easily be adjusted by monitoring efficacy or plasma levels.
• Warfarin and coumarin-like anticoagulants: avoid. If apalutamide is given with an anticoagulant metabolised by CYP2C9 (warfarin or acenocoumarol), monitor the INR more closely.
• Strong CYP2C8 inhibitors (gemfibrozil, clopidogrel): gemfibrozil raised the apalutamide AUC by 68% (45% for the active moieties combined). No initial dose adjustment, but consider a dose reduction based on tolerability.
• Strong CYP3A4 inhibitors: itraconazole lowered the apalutamide peak concentration by 22% with a similar AUC.
• Medicines that lower the seizure threshold: they may increase the risk of seizure.
• QT interval: QT prolongation has been reported with a frequency that is not known; see sections 4.4 and 4.5 of the SmPC for the precautions.
• Food: apalutamide can be taken with or without food.

Treatment should be started and supervised by specialist physicians experienced in the medical treatment of prostate cancer. The tablets are swallowed whole, at about the same time each day, with or without food; they must not be crushed or split.

Recommended Dose

• 240 mg once daily, as four 60 mg tablets or as one 240 mg tablet.
• Medical castration with a gonadotropin-releasing hormone (GnRH) analogue should be continued during treatment in patients who have not been surgically castrated.

Dose Adjustments

• If a grade 3 or higher toxicity or an intolerable reaction occurs, hold the dose rather than stopping permanently until symptoms improve to grade 1 or the original grade. Then resume at the same dose or, if warranted, at a reduced dose of 180 mg or 120 mg.
• Severe hepatic impairment: 120 mg (two 60 mg tablets) once daily.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no dose adjustment for mild to moderate impairment. Use with caution in severe impairment, which has not been studied; if treatment is started, monitor for adverse reactions and reduce the dose as described above.
• Hepatic impairment: no dose adjustment for mild or moderate impairment (Child-Pugh A or B); 120 mg once daily in severe impairment (Child-Pugh C).
• Children and adolescents: there is no relevant use in the paediatric population.

Missed Dose

Take it as soon as possible on the same day and return to the normal schedule the next day. Do not take extra tablets to make up for it.

Patients Who Cannot Swallow Tablets Whole

• Dispersing in a drink or soft food: place the whole dose in a cup without crushing or splitting the tablets, add about 20 mL of non-fizzy water (about 10 mL for the single 240 mg tablet), wait 2 minutes until the tablets break up and stir. Add 30 mL of non-fizzy orange juice, green tea, apple sauce, drinkable yoghurt or more water, stir and swallow immediately. Rinse the cup with enough water to take the whole dose and drink it at once. Do not keep the mixture.
• Nasogastric tube (8 French or larger): put the whole dose in the barrel of a syringe of at least 50 mL (at least 20 mL for the 240 mg tablet), draw up 20 mL of non-fizzy water (10 mL for the 240 mg tablet), wait 10 minutes, shake vigorously and give at once through the tube. Refill the syringe with non-fizzy water and repeat until no residue is left.

Seizure

Apalutamide is not recommended in patients with a history of seizures or predisposing factors, including underlying brain injury, recent stroke (within one year), primary brain tumours or brain metastases. Treatment is stopped permanently if a seizure develops, and the risk may be higher with medicines that lower the seizure threshold. In the SPARTAN and TITAN studies, which excluded patients with such a history, seizure occurred in 0.6% of patients on apalutamide and 0.2% on placebo. There is no experience of giving apalutamide again after a seizure.

Falls and Fractures

Fracture and fall risk should be assessed before treatment starts, and patients monitored and managed according to established guidelines. The use of bone-targeted agents should be considered.

Ischaemic Heart Disease and Ischaemic Cerebrovascular Disorders

These events, some fatal, have occurred, mostly in patients with risk factors. Patients should be monitored for signs and symptoms, and risk factors such as hypertension, diabetes and dyslipidaemia optimised according to standard of care.

Recent Cardiovascular Disease

Patients with clinically significant cardiovascular disease in the previous 6 months (such as severe or unstable angina, myocardial infarction, symptomatic heart failure, thromboembolic events or ventricular arrhythmias) were excluded from the studies, so safety in them is not established. If apalutamide is prescribed, they should be monitored for risk factors such as hypercholesterolaemia, hypertriglyceridaemia and other cardio-metabolic disorders.

Pregnancy, Contraception, Breastfeeding and Fertility

• Pregnancy: contraindicated in women who are or may become pregnant. Based on an animal reproductive study and its mechanism of action, apalutamide may cause foetal harm and loss of pregnancy; there are no data in pregnant women.
• Contraception: it is not known whether apalutamide or its metabolites are present in semen. Patients having sex with female partners of reproductive potential should use a condom together with another highly effective contraceptive method during treatment and for 3 months after the last dose.
• Breastfeeding: a risk to the suckling child cannot be excluded, and apalutamide should not be used during breastfeeding.
• Fertility: animal studies suggest that apalutamide may decrease fertility in men of reproductive potential.

Effect on Driving

Apalutamide has no or negligible influence on the ability to drive and use machines. Seizures have been reported, and patients should be told of this risk in relation to driving or operating machines.

Erleada tablets must be kept in the original package to protect them from moisture; no special temperature storage conditions are required. They are supplied in a bottle of 120 tablets with 6 g of silica gel desiccant, or in blister wallet packs (28-day cartons of 112 tablets, 30-day cartons of 120 tablets) for the 60 mg tablets. The 240 mg tablets are supplied in a bottle of 30 tablets with 2 g of silica gel desiccant, or in blister wallet packs (28-day cartons of 28 tablets, 30-day cartons of 30 tablets, 84-day cartons of 84 tablets); not all pack sizes may be marketed. Keep out of the sight and reach of children.

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

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