Enzalutamide - A Breakthrough Treatment for Prostate Cancer

Overview

Enzalutamide is a hormone therapy used for males diagnosed with prostate cancer that has spread to several body parts. It is a nonsteroidal antiandrogen medicine that can be used with castration to manage metastatic castration-resistant prostate cancer (mCRPC), metastatic castration-sensitive prostate cancer, and non-metastatic castration-resistant prostate cancer. The drug is usually taken orally and is in no way linked to clinically apparent cases of jaundice along with liver injury. Enzalutamide is recommended for males whose prostate cancer does not respond to other forms of treatments. The most significant consideration associated with the drug is that patients should have either undergone an orchiectomy or consumed a drug that works together with Enzalutamide to lower their testosterone levels. This drug can prevent the rapid spread of prostate cancer.

Enzalutamide Approval and Development History:

• Enzalutamide is a combined discovery of Charles Sawyers and Micheal Jung at the University of California.

• The researchers evaluated about 200 thiohydantoin derivatives of RU-59063, an analog of Nilutamide. This discovery aimed to discover compounds for the antagonism in human prostate cells.

• As a result, Enzalutamide and RD-162 were discovered as lead compounds in managing prostate cancer.

• Medivation currently markets Enzalutamide to treat prostate cancer.

• Finally, Enzalutamide was approved by the US (United States) FDA (Food and Drug Administration) to manage CRPC in August 2012 for patients taking Docatexal.

• Enzalutamide was granted FDA approval in 2014 for patients undergoing chemotherapy for metastatic CRPC.

• In addition, Enzalutamide was approved by the FDA on 16th December 2019 for patients diagnosed with metastatic castration-sensitive prostate cancer.

Clinical Efficacy of Enzalutamide:

• Enzalutamide belongs to the class of second-generation androgen receptor inhibitors. This implies that Enzalutamide competitively inhibits the binding of androgen to androgen receptors. In addition, it prohibits androgen receptor nuclear translocation and DNA (deoxyribonucleic acid) interaction.

• A randomized, double-blinded, and placebo-controlled trial was done on patients with metastatic castration-resistant prostate cancer. Enzalutamide, 160 mg was given orally to these patients.

• The trial aims to determine overall survival. The results demonstrate that patients who took Enzalutamide had an overall survival of 18.4 months, whereas the ones who took a placebo had a survival of 13.6 months.

Clinical Safety of Enzalutamide:

• The common adverse reactions associated with Enzalutamide during the clinical trials were asthenia, diarrhea, fatigue, insomnia, and lower respiratory tract infections.

• Out of all the patients who took Enzalutamide, 47 % reported grade 3 adverse reactions, whereas out of the patients who took a placebo, 53 % had adverse reactions.

• Discontinuation of the drug due to grade 3 or 4 reactions was done in only eight percent of patients.

• Seizures were reported in seven of the 800 patients who took Enzalutamide. However, seizures are only seen in patients taking higher doses.

How Does Enzalutamide Work to Treat Prostate Cancer?

Enzalutamide works against several types of prostate cancer. The peculiar features of different types of prostate cancers are that cancer cells proliferate when exposed to androgens (a group of hormones comprising testosterone). The active ingredient is Enzalutamide which works by blocking or inhibiting the binding of androgens to their receptors. Hence, the drug aims to retard the growth of prostate cancer which inhibits the growth of tumors and the death of cancer cells. The drug is typically effective against cancer resistant to other treatment forms. The onset of action of Enzalutamide depends on the severity of cancer. Hence, it is difficult to determine the drug's exact onset time.

For Patients:

What Is Prostate Cancer?

In a general sense, cancer refers to the unabated and rapid proliferation of body cells. Cancer can affect any body organ; hence when cancer originates from the prostate gland, it is known as prostate cancer. The prostate gland is exclusively found in males, and the gland's main function is to produce fluid or semen. Though prostate cancer is the most prevalent cancer in males, it usually remains confined to the gland and rarely causes any harm. People diagnosed with prostate cancer remain asymptomatic in the initial stages, but the symptoms become noticeable when cancer turns aggressive or spreads rapidly.

Signs and Symptoms of Prostate Cancer:

• Difficulties in passing urine.

• Inability to start the urine stream.

• Presence of blood in the urine.

• Blood in the semen.

• Unexpected weight loss.

• Erectile dysfunction.

• Pain in the bones.

What Is Enzalutamide?

Enzalutamide is a prescription drug used to treat males with castration-sensitive or resistant prostate cancer, which:

• Fails to respond to hormonal therapy or surgical methods that lower testosterone levels.

• Has spread to other body parts or responds to hormonal therapy or surgical methods to lower testosterone levels.

Nothing has been known about the safety and efficacy of Enzalutamide in pregnant females and children.

What Should the Patient Inform the Doctor Before Taking Enzalutamide?

Before starting the drug, the patient must inform the doctor about all his medical conditions. In addition, the patient needs to inform if they:

• Have a history of seizures, strokes, brain tumors, and head injuries.

• Have been diagnosed with heart disease previously.

• Is suffering from or has been diagnosed with hypertension or high blood pressure.

• Has high cholesterol or fat levels in the blood (dyslipidemia).

• Is having a partner who might become pregnant -

  • Males whose female partners can become pregnant must use effective birth control methods during and three months after the treatment.

  • Males planning to take Enzalutamide must use condoms while having intercourse.

• If they are taking any over-the-counter or prescription drugs or herbal supplements. This is because Enzalutamide might affect the way other drugs function. As a result, the patient must start or stop taking the medications and keep a list to avoid complications or drug interactions.

How Should the Patient Take Enzalutamide?

• The drug must be taken exactly as recommended by the doctor.

• Enzalutamide is taken once daily at the same time each day.

• The doctor might alter the dose as required.

• Avoid altering the prescribed drug dose without consulting the doctor.

• Enzalutamide can be taken with or without food.

• The patient must swallow the entire capsule without crushing or breaking it.

• Patients taking gonadotropin-releasing hormones must continue with the treatment. However, the ones who have undergone surgical castration must consult their doctor before the therapy.

• In the case of a missed dose, the patient must take the dose as soon as possible. However, one must not take more or less of the drug dose.

What Are Some of the Possible Side Effects of Enzalutamide?

The possible side effects of Enzalutamide are listed below:

• Seizures - Patients taking Enzalutamide are at a higher risk of developing seizures. Hence, one must avoid activities that can lead to sudden loss of consciousness or other health hazards.

• Allergic Reactions - Allergic reactions have been commonly observed in people consuming Enzalutamide. Hence, the patient must consult the doctor in case of side effects like nose, lips, tongue, or face swelling.

• Posterior Reversible Encephalopathy Syndrome (PRES) - Patients taking Enzalutamide are at a higher risk of developing a condition that affects the brain known as PRES. Hence the patient must immediately consult the doctor in case of headache, dizziness, confusion, and reduced alertness.

• Heart Diseases - People receiving Enzalutamide therapy are at a higher risk of developing blockage of the arteries of the heart or ischemic heart disease. The patient must report to the doctor immediately in case of discomfort, chest pain, or shortness of breath.

• Fractures - Enzalutamide can increase the risk of falls and fractures. Hence, the patient can consult the doctor if falls or fractures are not associated with unconsciousness.

Some of the other common side effects of Enzalutamide are listed below:

• Weakness.

• Tiredness.

• Back pain.

• Fatigue.

• Reduced appetite.

• Flashes.

• Constipation.

• Joint pain.

• High blood pressure.

• Diarrhea.

How Should the Patient Store Enzalutamide?

The patient must store Enzalutamide between 68 to 77 degrees Fahrenheit in a dry and tightly closed container.

For Doctors:

Indications and Usage:

Enzalutamide is indicated for managing patients with the following:

• Castration-resistant prostate cancer.

• Metastatic castration-sensitive prostate cancer.

Dosage and Administration:

1. Information Related to Drug Dosage: The recommended dose of Enzalutamide is 160 mg, taken orally twice daily. In addition, one must take the capsule on the whole without crushing or chewing.

2. Dosage Modifications: Patients who experience grade 3 or higher toxicity or adverse reactions can withhold the dose for a week or until the symptoms subside. In the meantime, if the symptoms reduce to grade 2, the patient can resume the normal or reduced drug dose.

3. Drug Administration Instructions: Patients taking Enzalutamide must concomitantly receive a gonadotropin-releasing hormone analog or should have undergone bilateral orchiectomy.

4. Dosage Form and Strength: Enzalutamide, 40 mg capsules are white or off-white oblong and soft gelatin capsules.

5. Description: Enzalutamide competitively binds to androgen receptors. The chemical name of the drug is 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5 dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. The molecular weight of Enzalutamide is 464.44, whereas the molecular formula of the drug is C21H16F4N4O2S. Enzalutamide is a white crystalline and non-hygroscopic solid insoluble in water.

Clinical Pharmacology:

1. Mechanism of Action: Enzalutamide inhibits androgen receptors; it works differently in the androgen receptor signaling pathway. It has been observed that the drug competitively inhibits androgen binding to its receptors. In addition, the drug inhibits the nuclear translocation of androgen receptors and their DNA interaction. During the in vitro studies, it was observed that a major metabolite named N-desmethyl Enzalutamide is similar to the drug itself. In addition, the drug reduced proliferation and induced the death of prostate cancer cells.

2. Composition:

• Active Ingredient - Enzalutamide.

• Inactive Ingredients - Gelatin, purified water, sorbitol sorbitan solution, butylated hydroxyanisole, glycerin, titanium dioxide, caprylocaproyl polyoxylglycerides, butylated Hydroxytoluene, and black iron oxide

3. Pharmacodynamics: A clinical trial was done on 796 patients with metastatic CRPC to study the effects of Enzalutamide on QTc intervals. The trial participants were given Enzalutamide 160 mg per day. However, no clinically significant effects were observed in the QT intervals from baseline. The researchers did not exclude the small elevations in the mean QTc intervals due to Enzalutamide.

4. Pharmacokinetics: A clinical trial was conducted on healthy males and those with metastatic CRPC to evaluate the pharmacokinetics of Enzalutamide and its metabolite.

5. Absorption: After the drug was orally administered in clinical trials, the median time to reach the maximum plasma concentration (Cmax) was observed to be one hour. At a steady state, the Cmax values of Enzalutamide are 16.6 micrograms per mL and 12.7 micrograms per mL. The steady state is achieved within 28 days. At a steady state, the drug shows dose-proportional pharmacokinetics over 30 to 360 mg.

6. Drug Distribution and Protein Binding: Enzalutamide's apparent volume of distribution is 110 liters after a single oral dose. It is 97 to 98 % bound to plasma proteins. Enzalutamide's metabolite, N-desmethyl Enzalutamide, is 95 % bound to plasma proteins.

7. Metabolism: Enzalutamide 160 mg was administered once daily for 77 days in patients. The plasma samples were analyzed, and it was observed that Enzalutamide and its active metabolite were responsible for 88 % of the radioactivity in the plasma. In vitro studies reveal that CYP2C8 and CYP3A4 are known for the drug's metabolism.

8. Elimination: Enzalutamide is particularly eliminated by hepatic metabolism. After the single oral dose administration of Enzalutamide, 85 % of the radioactivity was observed in 77 days. 71 % of the drug is expelled in urine, whereas 14 % is recovered in feces. Enzalutamide’s apparent clearance is 0.56 L per hour. The drug’s mean terminal half-life after a single oral dose is 5.8 days.

Warnings and Precautions:

• Seizure - Seizures have been reported in 0.5 % of patients taking Enzalutamide during randomized clinical trials. However, the patients with predisposing factors for seizures were excluded from the study. Seizure episodes were reported 13 to 1776 days after the initiation of Enzalutamide therapy. Hence, the patients with seizures were permanently discontinued from the therapy. During the single-arm trials, 2.2 % of Enzalutamide treated patients experienced seizures. However, it has not been known if Enzalutamide can be taken along with anti-epileptic drugs to reduce seizures. The trial participants had one or more of the following predisposing factors:

  • History of the brain or head injuries.

  • Medical history of transient ischemic attack or cerebrovascular accidents.

  • Alzheimer’s disease.

  • Meningioma.

  • Leptomeningeal disease due to prostate cancer.

  • Loss of consciousness.

  • History of arteriovenous malformations and brain infections.

• Posterior Reversible Encephalopathy Syndrome (PRES) - Incidences of PRES have been reported in patients receiving Enzalutamide therapy. It is a neurological condition wherein the patient has abrupt symptoms, including lethargy, headache, blindness, confusion, and other visual symptoms. Hence, the patient must be counseled to undergo appropriate imaging tests like brain imaging or magnetic resonance imaging (MRI) before starting the therapy.

• Hypersensitivity - Several randomized clinical trials have revealed that Enzalutamide can cause hypersensitivity reactions like edema (swelling) of the tongue, face, or lips. In addition, pharyngeal edema has been observed in post-marketing cases. Patients with hypersensitivity symptoms must be advised to discontinue the drug temporarily.

• Ischemic Heart Disease - Four randomized placebo-controlled clinical trials reported that incidences of ischemic heart disease occurred more in Enzalutamide-treated patients than the ones who received a placebo. Grade 3 to 4 ischemic reactions were observed in 1.4 % of patients. In addition, ischemic heart disease leads to the death of 0.4 % of the patients. Hence, the patient must be carefully evaluated for the signs and symptoms of ischemic heart disease and should be asked to discontinue the drug in case of severe reactions.

• Falls or Fractures - Falls and fractures were reported in patients receiving Enzalutamide. Monitor the patients according to the established treatment guidelines and bone-targeted therapies. During the randomized controlled trials, 11 % of them reported falls and fractures. In contrast, grade 3 or 4 fractures occurred in 3 % of the patients. The median time of onset of fractures was observed to be 336 days.

• Embryo-Fetal Toxicity - Nothing has been known about the safety and efficacy of Enzalutamide in females. However, incidences of fetal harm, miscarriage, or loss of pregnancy have been observed in animal studies. Hence, males and females with reproductive potential must use effective contraceptive methods.

What Are the Adverse Reactions of Enzalutamide?

The adverse reactions of Enzalutamide are listed below:

• General Disorders:

  • Peripheral edema.

  • Asthenic conditions.

• Musculoskeletal Disorders:

  • Back pain.

  • Arthralgia.

  • Muscle weakness.

  • Pain in the muscles.

  • Muscular stiffness.

• Gastrointestinal Disorders:

  • Nausea.

  • Constipation.

  • Diarrhea.

• Vascular Disorders:

  • Hot flushes.

  • Hypertension.

• Neurological Disorders:

  • Dizziness.

  • Headache.

  • Spinal cord compression.

  • Cauda equina syndrome.

  • Paresthesia.

  • Hypoesthesia.

  • Mental disorders.

• Infections or Infestations:

  • Upper respiratory infections.

  • Lung infections.

  • Lower respiratory tract infections.

• Psychiatric Diseases:

  • Anxiety.

  • Insomnia.

• Kidney Disorders:

  • Hematuria.

  • Pollakiuria.

• Injuries or Poisoning:

  • Falls.

  • Non-pathologic fractures.

• Dermatologic Disorder:

  • Dry skin.

  • Pruritus.

• Respiratory Problems:

  • Asthma.

• Laboratory Abnormalities:

  • Reduced neutrophil count.

  • White blood cell count is reduced.

• Chemistry:

  • Hyperglycemia.

  • Hypermagnesemia.

  • Hyponatremia.

  • Hypercalcemia.

Drug Interactions:

1. Drugs Inhibiting CYP28: Concomitant administration of strong CYP28 inhibitors like Gemfibrozil and Enzalutamide has been associated with an increase in the area under the plasma concentration and time curve. Hence, the patient must not be given CYP28 inhibitors along with Enzalutamide, or the dosage must be reduced.

2. Drugs Inducing CYP3A4: Concomitant administration of Enzalutamide must be avoided with Rifampin, a strong CYP3A4 inducer, and a moderate CYP28 inducer. Hence, the following drugs must be avoided with Enzalutamide:

• Carbamazepine.

• Phenobarbital.

• Phenytoin.

• Rifabutin.

• Rifampin.

• Rifapentine.

• St. John’s wort.

3. Enzalutamide and Drug-Metabolizing Enzymes: Enzalutamide can reduce plasma exposure to certain drugs. Hence, it must not be administered along with drugs having a low therapeutic index, including the following:

• Midazolam.

• Warfarin.

• Omeprazole.

• Alfentanil.

• Cyclosporine.

• Dihydroergotamine.

• Ergotamine.

• Pimozide.

• Fentanyl.

• Quinidine.

• Sirolimus.

• Tacrolimus.

• Clopidogrel.

• S-mephenytoin.

Chemical Taxonomy of Enzalutamide:

The chemical taxonomy of Enzalutamide is enlisted below:

• Kingdom - Organic compounds.

• Superclass - Organic heterocyclic compounds.

• Class - Oxazolidines.

• Subclass - Imidazolines.

Use in Specific Populations:

1. Pregnancy: Not much information is available regarding the safety and efficacy of Enzalutamide in females. However, the drug has been tested on animals regarding the same. The studies reveal the risk of fetal toxicity and pregnancy loss. In addition, Enzalutamide can interfere with organogenesis as per animal studies.

2. Lactation: Nothing has been known about the safety and efficacy of Enzalutamide in lactating females. However, animal studies report that Enzalutamide and its effective metabolites can be found in breast milk if the drug is taken at a dose four times the recommended dose.

3. Males and Females of Reproductive Potential: Based on animal study reports, males and females of reproductive potential must use condoms and other effective birth control methods. In addition, Enzalutamide can impair fertility in males.

4. Geriatric Use: Out of the 4081 patients who were given Enzalutamide in randomized clinical trials, 78 % were above 65, and the remaining patients were below 70. However, no clinically significant differences were noted in the overall safety and efficacy of the drug in young and elderly patients.

5. Patients With Kidney Problems: Clinical trials have not yet been conducted to know about the effects of Enzalutamide on patients with kidney diseases. However, population pharmacokinetic data reveals that no significant differences are noticeable in the renal clearance of the drug.

6. Patients With Liver Problems: Several trials have been conducted to compare the systemic exposure of Enzalutamide in patients with mild, moderate, or severe hepatic impairment to healthy individuals. However, the area under the plasma concentration versus the time curve remained the same. Hence, no dose adjustments are required in patients with baseline or moderate to severe hepatic impairments.

Clinical Trials:

The following four clinical trials were done to evaluate the safety and efficacy of the drug under different situations:

Trial 1- Enzalutamide Versus Placebo in Metastatic CRPC After Chemotherapy:

This trial was done on 1199 patients suffering from metastatic CRPC and who had received Docetaxel previously. The duration of the treatment was 8.3 months with Enzalutamide and three months with a placebo. Grade 3 and other higher adverse reactions were reported in 47 % of patients who took Enzalutamide.

Trial 2 - Enzalutamide Versus Placebo in Chemotherapy-Naive Metastatic CRPC:

This trial was done on 1717 patients who did not take Docetaxel previously. The median duration was 17.5 months for patients taking Enzalutamide, whereas it was 4.6 months for the ones taking a placebo.

Grade three or four adverse reactions were reported in 44 % of the Enzalutamide-treated patients and 37 % of the placebo-treated patients.

Trial 3 - Enzalutamide Versus Bicalutamide in Chemotherapy-Naive Metastatic CRPC:

This trial was done on 375 patients who had not received Docetaxel previously 372 of them had received Bicalutamide. The median duration was 11.6 months for the ones taking Enzalutamide, whereas it was 5.8 months for those taking Bicalutamide. The adverse reactions were reported in 7.6 % of Enzalutamide-treated patients and 6.3 % of Bicalutamide-treated patients.

Trial 4 - Enzalutamide Versus Placebo in Non-metastatic CRPC Patients:

This trial was done on 1401 patients who were randomized to 2:1 because they received either Enzalutamide 160 mg or a placebo. The duration of treatment was 18.4 months with Enzalutamide and 11.1 months with placebo. Grade 3 or higher adverse reactions were observed in 31 % of Enzalutamide-treated patients and 23 % of placebo-treated patients.