Enzalutamide

Prostate cancer is androgen sensitive and responds to inhibition of androgen receptor signalling. Even when serum androgen levels are low or undetectable, androgen receptor signalling continues to drive progression. Enzalutamide is a potent androgen receptor signalling inhibitor that blocks several steps of this pathway and, in preclinical studies, has no androgen receptor agonist activity.

Mechanism of Action

• Receptor blockade: enzalutamide competitively inhibits the binding of androgens to the androgen receptor.
• Nuclear translocation: it prevents the activated receptor from moving into the cell nucleus.
• DNA binding: it prevents the activated receptor from associating with DNA, even when the receptor is overexpressed and in prostate cancer cells resistant to anti-androgens.
• Effect on tumour cells: it decreases the growth of prostate cancer cells and can induce cell death and tumour regression.
• PSA response: in the AFFIRM study (after docetaxel), 54% of patients on enzalutamide had a PSA fall of at least 50%, against 1.5% on placebo; in the PREVAIL study (before chemotherapy) the figures were 78.0% and 3.5%.

Pharmacokinetics

• Absorption: oral absorption is at least 84.2%, and peak levels occur 1 to 2 hours after a dose. Enzalutamide is poorly water-soluble, so the capsules contain an emulsifier to improve absorption. Food has no clinically significant effect. Steady state is reached in about one month, with about 8.3-fold accumulation and little daily fluctuation (peak-to-trough ratio 1.25).
• Distribution: volume of distribution about 110 L, greater than total body water. Enzalutamide is 97–98% bound to plasma proteins (mainly albumin) and its active metabolite 95%. In rodents both cross the blood-brain barrier.
• Metabolism: extensive, mainly by CYP2C8 and less by CYP3A4/5, which form the active metabolite N-desmethyl enzalutamide. This circulates at about the same concentration as enzalutamide and is equally active. An inactive carboxylic acid metabolite is formed by carboxylesterase 1.
• Elimination: mean terminal half-life 5.8 days and apparent clearance about 0.52–0.56 L/h. After a radiolabelled dose, 71.0% was recovered in urine (mostly the inactive metabolite) and 13.6% in faeces (0.39% as unchanged enzalutamide).
• Special populations: age has no clinically relevant effect, and exposure was similar in Japanese and Chinese patients. In severe hepatic impairment total exposure was little changed but the half-life doubled (10.4 against 4.7 days). Patients with creatinine clearance below 30 mL/min have not been evaluated.

Enzalutamide is indicated in adult men:

• High-risk biochemical recurrent (BCR) non-metastatic hormone-sensitive prostate cancer (nmHSPC): as monotherapy or in combination with androgen deprivation therapy, in men unsuitable for salvage radiotherapy.
• Metastatic hormone-sensitive prostate cancer (mHSPC): in combination with androgen deprivation therapy.
• High-risk non-metastatic castration-resistant prostate cancer (CRPC).
• Metastatic CRPC, before chemotherapy: asymptomatic or mildly symptomatic after failure of androgen deprivation therapy, when chemotherapy is not yet clinically indicated.
• Metastatic CRPC after docetaxel: disease that has progressed on or after docetaxel therapy.

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

The most common reactions are asthenia and fatigue, hot flush, hypertension, fractures, falls and headache; ischaemic heart disease and seizure are other important reactions. Seizure occurred in 0.6% of enzalutamide-treated patients, 0.1% of those on placebo and 0.3% of those on bicalutamide. Rare cases of posterior reversible encephalopathy syndrome and Stevens-Johnson syndrome have been reported.

Very common (≥1/10): headache, hot flush, hypertension, fractures, fall, asthenia, fatigue.

Common (≥1/100 to <1/10): anxiety, memory impairment, amnesia, disturbance in attention, dysgeusia, restless legs syndrome, cognitive disorder, ischaemic heart disease, dry skin, pruritus, gynaecomastia, and (with enzalutamide alone) nipple pain and breast tenderness.

Uncommon (≥1/1,000 to <1/100): leucopenia, neutropenia, visual hallucination, seizure, increased hepatic enzymes.

Not known (spontaneous post-marketing reports): thrombocytopenia, face, tongue, lip and pharyngeal oedema, decreased appetite, posterior reversible encephalopathy syndrome, QT prolongation, dysphagia (including choking), nausea, vomiting, diarrhoea, erythema multiforme, Stevens-Johnson syndrome, rash, myalgia, muscle spasms, muscular weakness, back pain.

In controlled studies 31 of 5,112 patients (0.6%) had a seizure; the risk appears to depend on dose, and patients with prior seizures or risk factors were excluded. Ischaemic heart disease occurred in 3.5% of patients on enzalutamide plus androgen deprivation therapy against 2.1% on placebo, and was fatal in 0.4% against 0.1%. In the EMBARK study, gynaecomastia occurred in 8.8% of men on enzalutamide plus leuprorelin and 46% of those on enzalutamide alone.

Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19, and it may induce CYP2B6, UGT enzymes and some transporters. It is also affected by CYP2C8 inhibitors.

• Strong CYP2C8 inhibitors (for example gemfibrozil): gemfibrozil raised enzalutamide AUC by 326%. Avoid them or use with caution; if unavoidable, reduce enzalutamide to 80 mg once daily, and return to the previous dose once the inhibitor is stopped.
• CYP3A4 inhibitors and inducers: itraconazole raised enzalutamide AUC by 41% and rifampicin lowered AUC (enzalutamide plus active metabolite) by 37%. No dose adjustment is needed. St John’s wort induces CYP3A4 and may lower enzalutamide levels, so it is best avoided.
• Medicines whose effect may be lost (by induction): enzalutamide lowered the AUC of midazolam by 86%, S-warfarin by 56% and omeprazole by 70%. Affected groups include analgesics, antibiotics, anticancer agents, antiepileptics, antipsychotics, antithrombotics, beta-blockers, calcium channel blockers, cardiac glycosides, corticosteroids, HIV antivirals, hypnotics, immunosuppressants, proton pump inhibitors, statins metabolised by CYP3A4, and thyroid agents. Review all medicines when starting, avoid sensitive substrates when their effect is important and the dose cannot be adjusted, and expect the effect to build over about a month and to persist for a month or more after stopping.
• Warfarin and coumarin-like anticoagulants: avoid. If an anticoagulant metabolised by CYP2C9 (warfarin, acenocoumarol) is used, monitor INR more often.
• Paracetamol: the risk of liver injury is suspected to be higher with enzyme inducers.
• P-glycoprotein substrates (colchicine, dabigatran etexilate, digoxin): digoxin AUC rose by 33%; use with caution and adjust the dose if needed. Digoxin results from the chemiluminescent microparticle immunoassay may be falsely high and should be confirmed by another method.
• QT-prolonging medicines (class IA and III antiarrhythmics, methadone, moxifloxacin, antipsychotics): evaluate the combination carefully.
• No relevant effect on caffeine, pioglitazone, rosuvastatin or intravenous docetaxel exposure, although more docetaxel-induced neutropenia cannot be excluded.

Treatment is started and supervised by specialist physicians experienced in the medical treatment of prostate cancer. The soft capsules are swallowed whole with enough water, never chewed, dissolved or opened. The tablets are also swallowed whole with water, never cut, crushed or chewed. Both can be taken with or without food. Tablets are intended for men who have difficulty swallowing large capsules or a history of dysphagia.

Recommended Dose

• 160 mg once daily: four 40 mg soft capsules, four 40 mg film-coated tablets, or two 80 mg film-coated tablets.
• LHRH analogue: medical castration continues in men with CRPC or mHSPC who have not had surgical castration.
• High-risk BCR nmHSPC: enzalutamide may be given with or without an LHRH analogue. If PSA is undetectable (below 0.2 ng/mL) after 36 weeks, treatment can be suspended, and restarted when PSA reaches 2.0 ng/mL or more after prior radical prostatectomy, or 5.0 ng/mL or more after prior primary radiotherapy. If PSA is still detectable after 36 weeks, treatment continues.

Dose Adjustments

• Toxicity: for a grade 3 or higher reaction, or one that is not tolerated, withhold the dose for one week or until symptoms improve to grade 2 or less, then resume at the same dose or, if warranted, at 120 mg or 80 mg.
• Strong CYP2C8 inhibitors: avoid if possible; otherwise reduce to 80 mg once daily.

Special Populations

• Elderly: no dose adjustment.
• Hepatic impairment: no adjustment in mild, moderate or severe impairment (Child-Pugh A, B or C), although the half-life is longer in severe impairment.
• Renal impairment: no adjustment in mild or moderate impairment; caution in severe impairment or end-stage renal disease.
• Children and adolescents: there is no relevant use in the paediatric population.

Missed Dose

Take the dose as close as possible to the usual time. If a whole day is missed, resume the next day at the usual daily dose.

Seizure and Posterior Reversible Encephalopathy Syndrome

Enzalutamide is associated with seizure, and the decision to continue after a seizure is taken case by case. It may lower the seizure threshold by inhibiting the GABA-gated chloride channel. Rare cases of posterior reversible encephalopathy syndrome (seizure, headache, confusion, blindness and other visual or neurological disturbances, with or without hypertension) have been reported; MRI confirms the diagnosis, and treatment should be stopped. There is no antidote in overdose, and the seizure risk may be higher.

Heart and QT Interval

Phase 3 studies excluded men with a myocardial infarction in the last 6 months, unstable angina in the last 3 months, NYHA class III or IV heart failure (unless LVEF is 45% or more), bradycardia or uncontrolled hypertension, which should be considered when prescribing. Androgen deprivation therapy may prolong the QT interval, so the benefit-risk balance, including torsade de pointes, should be assessed in men with a history of, or risk factors for, QT prolongation or taking QT-prolonging medicines.

Skin and Hypersensitivity Reactions

Severe cutaneous reactions, including Stevens-Johnson syndrome, can be life-threatening or fatal. Patients are told the signs at the start and monitored closely, and enzalutamide is withdrawn immediately if they appear. Hypersensitivity reactions such as rash or swelling of the face, tongue, lips or pharynx have been seen.

Second Primary Malignancies

Second primary cancers have been reported; the most frequent, more than with placebo, were bladder cancer (0.3%), colon adenocarcinoma (0.2%), transitional cell carcinoma (0.2%) and malignant melanoma (0.2%). Patients should promptly report signs of gastrointestinal bleeding, visible blood in the urine, dysuria or urinary urgency.

Other Precautions

• Interactions: because of enzyme induction, review all medicines before starting (see Drug Interactions).
• Chemotherapy: safety and efficacy with cytotoxic chemotherapy have not been established.
• BCR nmHSPC: in the EMBARK study, enzalutamide alone and with androgen deprivation therapy were not equivalent. The combination is the preferred option unless adding androgen deprivation therapy would cause unacceptable toxicity or risk.
• Swallowing: choking and difficulty swallowing were reported mostly with the capsules, so tablets are recommended in men with swallowing problems.
• Impairment: caution in severe renal impairment, which has not been studied. In severe hepatic impairment, steady state, the peak effect and the onset and decline of enzyme induction may take longer.

Pregnancy, Breastfeeding and Fertility

• Women: enzalutamide is not for use in women. It is contraindicated in women who are or may become pregnant, as it may harm the unborn child or cause loss of pregnancy. It is not known whether enzalutamide is present in human milk; it and its metabolites pass into rat milk.
• Contraception for men: it is not known whether enzalutamide is present in semen. A condom is required during treatment and for 3 months afterwards if the patient has sex with a pregnant woman; with a woman of childbearing potential, a condom and another form of birth control are needed for the same period.
• Fertility: animal studies showed effects on the reproductive system of male rats and dogs.
• Handling: capsules should be handled only by the patient or caregivers. Women who are or may become pregnant should not handle damaged or opened capsules without protection, such as gloves.

Excipients with Known Effect

Each soft capsule contains 57.8 mg of sorbitol (E420).

Effect on Driving

Enzalutamide may have a moderate influence on the ability to drive and use machines, because psychiatric and neurological events including seizure have been reported. Patients should be told of this risk.

The capsules and tablets need no special storage conditions. The capsules are supplied in blister wallets of 28, in cartons of four wallets (112 capsules).

Soft capsules: 3 years. Film-coated tablets: 4 years. Do not use after the expiry date.

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