Enzalutamide

Enzalutamide, a 2nd generation androgen receptor antagonist , inhibits the androgen receptor signaling pathway and is used for the therapy of metastatic castration-resistant prostate cancer.

Enzalutamide, like all members of the family of androgen receptor inhibitors, is an inhibitor of the androgen-receptor signalling cascade, which is interrupted at three levels:

• inhibition of the activation of the androgen receptor
• Inhibition of nuclear translocation of activated androgen receptors
• Inhibition of the association of activated androgen receptors with chromatin.

The effects lead to reduced growth of carcinoma cells, apoptosis induction and tumor regression.

Enzalutamide was approved in a placebo-controlled Phase III study (AFFIRM study). The primary endpoint was overall survival (OS) at 18.4 months (median) in the verum arm versus 13.6 months in the placebo arm. The response rate in the quality of life analysis was 43.2% in the verum arm and 18.3% in the placebo arm. Following these study results, enzalutamide was approved as another relevant treatment option for patients with mCRPC in progression during or after docetaxel chemotherapy.

Metastatic castration-resistant prostate carcinoma that progresses during or after treatment with the cytostatic drug docetaxel or for the treatment of metastatic castration-resistant prostate carcinoma with asymptomatic or mildly asymptomatic progression after failure of androgen deprivation therapy if chemotherapy is not yet clinically indicated.

In the pivotal study (n=1199 patients), enzalutamide was administered in a dose of 1 x 160 mg daily per os.

Headache, hot flashes, hallucinations, anxiety, attention deficit disorder, memory loss (amnesia), memory disorder, high blood pressure, dry skin, itching, bone fractures, lack of white blood cells, muscle pain (myalgia), muscle cramps, muscular weakness, nausea, vomiting, asthenia.

Enzalutamide is a potent enzyme inducer and can lead to a loss of effectiveness of many common drugs. Before starting treatment with enzalutamide, an overview of all drugs used simultaneously should be available. The simultaneous use of enzalutamide with drugs that are substrates of certain metabolizing enzymes or transporters should be avoided unless their therapeutic effect is indispensable for the patient (in which case a dose adjustment in the rain is advisable). Treatment with vitamin K antagonists should also be avoided if possible (see specialist information).

CYP2C8 inhibitors and inducers: CYP2C8 plays an important role in the elimination of enzalutamide. Strong inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin) of CYP2C8 should therefore not be taken together with enzalutamide, or only with great caution.

CYP3A4 inhibitors and inductors: CYP3A4 plays a minor role in the metabolism of enzalutamide, therefore no dose adjustment of enzalutamide is necessary.

Enzalutamide inducible enzymes include: CYP3A4 (in liver and intestine), CYP2C9, CYP2C19, CYP1A2 and uridine-5′-diphospho-glucuronosyltransferase; the efflux transporter protein P-gp and possibly others the Multidrug Resistance-Associated Protein 2 (MRP2), Breast Cancer Resistance Protein (BCRP) and Organic Anion Transporting Polypeptide 1B1 (OATP1B1).

The following groups of drugs, among others, are affected:

- Analgesics (e.g. fentanyl, tramadol)

- antibiotics (e.g. clarithromycin, doxycycline)

- cancer drugs (e.g. cabazitaxel)

- Anticoagulants (e.g. acenocoumarol, warfarin)

- Antiepileptic drugs (e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid)

- Antipsychotics (e.g. Haloperidol)

- Beta-blockers (e.g. bisoprolol, propranolol)

- calcium antagonists (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil)

- cardiac glycosides (e.g. digoxin)

- Corticosteroids (e.g. dexamethasone, prednisolone)

- Antiviral HIV drugs (e.g. indinavir, ritonavir)

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

- Statins which are metabolised via CYP3A4 (e.g. Atorva-, Simvastatin)

- Thyroid hormones (e.g. levothyroxine)

Enzalutamide has been described in in vivo studies as a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. The use of enzalutamide (1 x 160 mg/day) together with a single dose of sensitive CYP substrates in patients with prostate carcinoma led to the following clinically relevant changes:

• 86% decrease in AUC of midazolam (CYP3A4 substrate)
• 56 % decrease in AUC of S-warfarin (CYP2C9 substrate)
• 70% decrease in AUC of omeprazole (CYP2C19 substrate).

In contrast, the intake of food has no clinically relevant influence on the metabolism of enzalutamide. In clinical studies, enzalutamide was therefore given without consideration of food intake.

Hypersensitivity to the active substance enzalutamide or any of the other ingredients.

Pregnant women or women who may become pregnant.

Xtandi®

Enzalutamide was approved in June 2013

Risk of seizures: Caution is advised when using enzalutamide in patients with known epilepsy or the following risk factors for seizures: brain injury, stroke, primary brain tumor, brain metastases, or alcoholism. The risk of seizures may also increase if the seizure threshold is lowered by taking other medicines.

1. Beer TM et al (2017) Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol 71:151-154.
2. Gibbons JA et al (2015) Clinical Pharmacokinetic Studies of Enzalutamide. Clin Pharmacokinetics 54:1043-1055.
3. Hussain M et al (2018) Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med 378:2465-2474.
4. Scott LJ (2018) Enzalutamide: A Review in Castration-Resistant Prostate Cancer.Drugs 78:1913-1924.