Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that su ...

. It is indicated for use in conjunction with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC), nonmetastatic castration-resistant prostate cancer, and metastatic castration-sensitive prostate cancer (mCSPC). It is taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

. Side effects of enzalutamide when added to castration include asthenia, back pain,

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin ...

, arthralgia, and hot flashes. Rarely, it can cause seizures. It has a high potential for drug interactions. Enzalutamide is an antiandrogen, and acts as an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone. In doing so, it prevents the effects of these hormones in the prostate gland and elsewhere in the body. Enzalutamide was first described in 2006, and was introduced for the treatment of prostate cancer in 2012. It was the first

second-generation NSAA A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens lik ...

to be introduced. It is on the World Health Organization's List of Essential Medicines.

Medical uses

Prostate cancer

There is good evidence that enzalutamide is an effective treatment for increasing overall survival among people with high-risk non-metastatic castration-resistant prostate cancer, particularly those with a PSA doubling time ≤ 6 months.

Other uses

Enzalutamide can be used as an antiandrogen in feminizing hormone therapy for transgender women.

Available forms

Enzalutamide is provided in the form of a 40 mg Capsule. It is taken orally at a dosage of 160 mg once per day (four capsules).

Contraindications

Enzalutamide is contraindicated in women during pregnancy. It may cause fetal harm.

Side effects

Notable side effects of enzalutamide seen in

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s have included gynecomastia, breast pain/tenderness, fatigue,

, hot flashes, headache, sexual dysfunction, and, less commonly, seizures. Other "common" side effects reported in clinical trials have included neutropenia, visual hallucinations,

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil Turmoil may refer to: * ''Turmoil'' (1984 video game), a 1984 video game released by Bug-Byte * ''Turmoil'' (2016 video game), a 2016 indie oil tycoon video ...

, cognitive disorder, memory impairment, hypertension, dry skin, and pruritus (itching). Enzalutamide monotherapy is regarded as having a moderate negative effect on sexual function and activity, significantly less than that of GnRH analogues but similar to that of other NSAAs such as bicalutamide.

Central adverse effects

Seizures have occurred in approximately 1% of patients treated with enzalutamide in clinical trials. This is thought to be due to enzalutamide crossing the blood–brain barrier and exerting off-target binding to and inhibition of the GABA_A receptor in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

(it has been found to inhibit the GABA_A receptor ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and ...

'' ( = 3.6 μM) and induces

convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a ...

s in animals at high doses). In addition to seizures, other potentially GABA_A receptor-related side effects observed with enzalutamide treatment in clinical trials have included

, insomnia,

vertigo Vertigo is a condition where a person has the sensation of movement or of surrounding objects moving when they are not. Often it feels like a spinning or swaying movement. This may be associated with nausea, vomiting, sweating, or difficulties ...

, paresthesia, and headache. Due to its ability to lower the seizure threshold, patients with known seizure disorders or brain injury should be closely monitored during enzalutamide treatment. NSAA-induced seizures are responsive to benzodiazepine treatment, and it has been suggested that GABA_A receptor inhibition by enzalutamide could be treated with these drugs. In dose-ranging studies, severe fatigue was observed with enzalutamide at doses of 240 mg/day and above.

Rare adverse reactions

There is a single

case report In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurr ...

of posterior reversible encephalopathy syndrome (PRES) with enzalutamide treatment. The mechanism of action of the side effect is unknown, but it was proposed to a consequence of inhibition of the GABA_A receptor by enzalutamide.

Overdose

Enzalutamide may cause seizures in overdose.

Interactions

Enzalutamide is a moderate to strong inducer of multiple

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

s including CYP3A4, CYP2C9, and CYP2C19 and hence has a high potential for clinically relevant drug interactions. Circulating concentrations of enzalutamide may be altered by

inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

s and inducers of CYP2C8 and CYP3A4, and should be avoided if possible. In a clinical study of enzalutamide for -positive

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

in women, enzalutamide was found to decrease serum concentrations of the aromatase inhibitors anastrozole and exemestane by 90% and 50%, respectively, which could reduce their effectiveness.

Pharmacology

Pharmacodynamics

Enzalutamide acts as a selective silent antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). Unlike the first-generation NSAA bicalutamide, enzalutamide does not promote

translocation Translocation may refer to: * Chromosomal translocation, a chromosome abnormality caused by rearrangement of parts ** Robertsonian translocation, a chromosomal rearrangement in pairs 13, 14, 15, 21, and 22 ** Nonreciprocal translocation, transfer ...

of AR to the cell nucleus and in addition prevents binding of AR to deoxyribonucleic acid (DNA) and AR to coactivator

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

s. As such, it has been described as an AR signaling inhibitor in addition to antagonist. The drug is described as a "second-generation" NSAA because it has greatly increased efficacy as an antiandrogen relative to so-called "first-generation" NSAAs like flutamide and bicalutamide. The drug has only 2-fold lower affinity for the AR than DHT, the endogenous ligand of the AR in the prostate gland. When LNCaP cells (a prostate cancer cell line) engineered to express elevated levels of AR (as found in patients with advanced prostate cancer) were treated with enzalutamide, the expression of androgen-dependent genes PSA and TMPRSS2 was down regulated in contrast to bicalutamide where the expression was upregulated. In VCaP cells which over-express the AR, enzalutamide induced apoptosis whereas bicalutamide did not. Furthermore, enzalutamide behaves as an antagonist of the W741C mutant AR in contrast to bicalutamide which behaves as a pure agonist when bound to the W741C mutant. Dose-ranging studies of enzalutamide in men with prostate cancer have been performed.

Changes in hormone levels

Enzalutamide monotherapy at a dosage of 160 mg/day has been found to increase circulating levels of testosterone by 114.3%, dihydrotestosterone (DHT) by 51.7%, estradiol by 71.7%, sex hormone-binding globulin (SHBG) by 100.6%, dehydroepiandrosterone (DHEA) by 9.6%,

androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehy ...

by 51.1%, luteinizing hormone (LH) by 184.7%, follicle-stimulating hormone (FSH) by 47.0%, and prolactin by 16.8%. These changes in hormone levels are similar to those with high-dose bicalutamide monotherapy. The median maximum decrease in levels of prostate-specific antigen (PSA) levels was 99.6%.

Comparison with other antiandrogens

Enzalutamide has approximately 8-fold higher binding affinity for the androgen receptor (AR) compared to bicalutamide. One study found an of 21 nM for enzalutamide and 160 nM for bicalutamide at the AR in the LNCaP cell line (7.6-fold difference), while another found respective IC₅₀ values of 36 nM and 159 nM (4.4-fold difference). In accordance, clinical findings suggest that enzalutamide is a significantly more potent and effective antiandrogen in comparison to first-generation NSAAs such as bicalutamide, flutamide, and nilutamide. Also, unlike with the first-generation NSAAs, there has been no evidence of

hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fr ...

or elevated liver enzymes in association with enzalutamide treatment in clinical trials.

Resistance mechanisms in prostate cancer

Enzalutamide is only effective for a certain period of time, after that the growth of the cancer is not inhibited by this antiandrogen. The mechanisms of resistance to Enzalutamide are being intensively studied. Currently, several mechanisms have been found: * AR mutations * AR splice variants * Glucocorticoid receptor bypass * Increase in

flux Flux describes any effect that appears to pass or travel (whether it actually moves or not) through a surface or substance. Flux is a concept in applied mathematics and vector calculus which has many applications to physics. For transport ...

of glycolysis * Autophagy mediated resistance * Wnt signaling activation * Increase in intra-tumoral androgen biosynthesis mediated by

AKR1C3 Aldo-keto reductase family 1 member C3 (AKR1C3), also known as 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5, HSD17B5) is a key steroidogenic enzyme that in humans is encoded by the ''AKR1C3'' gene. Function This gene encodes a member of t ...

enzyme * Interleukin 6 signaling mediated resistance

Cytochrome P450 modulation

Enzalutamide is reported to be a strong inducer of the

CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19, and can affect the circulating concentrations of drugs that are metabolized by these enzymes.

Pharmacokinetics

The bioavailability of enzalutamide in humans is unknown, but is at least 84.6% based on the amount recovered from

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellular ...

and

bile Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver b ...

excretion Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks afte ...

studies. Similarly, the bioavailability of enzalutamide in rats is 89.7%. Steady-state concentrations of enzalutamide are achieved within 28 days of treatment initiation. The plasma protein binding of enzalutamide is 97 to 98%, while that of ''N''-desmethylenzalutamide (NDME), its major metabolite, is 95%. Enzalutamide is primarily bound to albumin. The medication is metabolized in the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

, mainly by the

s CYP2C8 and CYP3A4. CYP2C8 is primarily responsible for the formation of NDME. Enzalutamide has a long elimination half-life of 5.8 days on average, with a range of 2.8 to 10.2 days. The elimination half-life of NDME is even longer, at about 7.8 to 8.6 days. Enzalutamide is eliminated 71.0% in

, 13.6% in

, and 0.39% in

feces Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a rela ...

Chemistry

Enzalutamide is a

synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to: Science * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic o ...

di aryl thiohydantoin

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...

and is structurally related to the earlier first-generation NSAAs such as flutamide, nilutamide, and bicalutamide as well as to newer second-generation NSAAs like apalutamide and proxalutamide.

History

Enzalutamide was discovered by Charles Sawyers, now at the Memorial Sloan–Kettering Cancer Center, and Michael Jung at the

University of California, Los Angeles The University of California, Los Angeles (UCLA) is a public university, public Land-grant university, land-grant research university in Los Angeles, California. UCLA's academic roots were established in 1881 as a Normal school, teachers colle ...

. They and their colleagues synthesized and evaluated nearly 200 thiohydantoin

s of RU-59063, an analogue of nilutamide, for AR antagonism in human prostate cancer cells, and identified enzalutamide and RD-162 as lead compounds. These compounds were

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an sufficiency of disclosure, enabling disclo ...

ed in 2006 and described in 2007.Sawyers, C., Jung, M., Chen, C., Ouk, S., Welsbie, D., Tran, C., ... & Yoo, D. (2006). U.S. Patent Application No. 11/433,829. https://www.google.com/patents/US20070004753 Enzalutamide was developed and marketed by

Medivation Medivation was an American biopharmaceutical company focused on development of novel therapies to treat serious diseases for which there are limited treatment options. Medivation was headquartered in San Francisco, California, beginning operations ...

for the treatment of prostate cancer. It was approved by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) for the treatment of mCRPC in the United States in August 2012, and for the treatment of nonmetastatic castration-resistant prostate cancer in July 2018. Enzalutamide was the first new AR antagonist to be approved for the treatment of prostate cancer in over 15 years, following the introduction of the first-generation NSAA bicalutamide in 1995. It was the first second-generation NSAA to be introduced.

Research

Breast cancer

Research suggests that enzalutamide may be effective in the treatment of certain types of

in women. It has been tested for the treatment of triple-negative, AR-positive breast cancer in a

phase II Phase II, Phase 2 or Phase Two may refer to: Media * Marvel Cinematic Universe: Phase Two, six American superhero films from 2013–2015 * ''Star Trek: Phase II'', an unrealized television series based on the characters of Gene Roddenberry's ''S ...

Hirsutism

Enzalutamide has been suggested as a potential treatment for hirsutism and hyperandrogenism in women with polycystic ovary syndrome.

References

External links

* {{Portal bar , Medicine Astellas Pharma Pfizer brands Benzamides CYP3A4 inducers Fluoroarenes GABAA receptor negative allosteric modulators Hormonal antineoplastic drugs Imidazolidines Lactams Nitriles Nonsteroidal antiandrogens Progonadotropins Prostate cancer Thioureas Trifluoromethyl compounds