Enzalutamide - A Breakthrough Treatment for Prostate Cancer

How Does Enzalutamide Work for Prostate Cancer?

Enzalutamide works against several types of prostate cancer. The peculiar feature of different types of prostate cancers is that cancer cells proliferate when exposed to androgens (a group of hormones comprising testosterone). Enzalutamide is an active ingredient that 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 the cancer. Hence, it is difficult to determine the drug's exact onset time.

For Patients:

What Is Enzalutamide?

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

• It does not respond to treatments that lower testosterone levels.

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

What Should the Patient Inform the Doctor Before Taking Enzalutamide?

Before starting the drug, the patient must inform the doctor about all their 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 for three months after the treatment.

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

• Suppose 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 strictly 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. If falls or fractures are not associated with unconsciousness, the patient should consult the doctor.

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, tightly closed container.

For Doctors:

Indications and Usage:

Enzalutamide is given for the following:

• Castration-resistant prostate cancer.

• Metastatic castration-sensitive prostate cancer.

Dosage and Administration:

• Information Related to Drug Dosage: The recommended dose of Enzalutamide is 160 mg, taken orally twice daily. The capsule must be taken whole without crushing or chewing.

• 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.

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

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

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:

• Mechanism of Action: The mechanism of action for Enzalutamide involves several steps that disrupt the androgen receptor signaling pathway.

  • Competitive Inhibition: The drug competitively inhibits the binding of androgen to its receptors.

  • Nuclear Translocations: It prevents androgen receptors from moving into the cell nucleus.

  • DNA Interaction: It blocks the interaction of the androgen receptor with DNA.

Additionally, the drug has a major metabolite, N-desmethyl Enzalutamide, which demonstrates activity similar to the drug itself. Through these combined actions, Enzalutamide reduces the proliferation of prostate cancer cells and induces cell death.

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

• Pharmacodynamics: Enzalutamide is designed to fight prostate cancer by blocking the signals that tell cancer cells to grow. It prevents androgens from attaching to their receptors on the cancer cells and stops these receptors from moving into the cells’ control center (the nucleus).

Even if the receptors do get inside, the drugs stop them from sticking to the cell’s DNA and keep the receptors from calling for helper proteins that aid in cell growth. By cutting off these signals, the drug causes prostate cancer cells to stop growing and eventually die. Also, the drug slightly changes the heart’s electrical timing (the QTc interval), so doctors sometimes monitor this during treatment.

• Pharmacokinetics: To evaluate the pharmacokinetics of Enzalutamide and its metabolite, a clinical trial was done on healthy males and those with metastatic CRPC.

  • Absorption: The drug is absorbed quickly after swallowing. About 84 percent of the medicine enters the system. It reaches its highest level in the blood about one to two hours after taking it. While food does not significantly change how much of the drug is absorbed, taking it on an empty stomach might cause the blood level to peak 30 percent higher. At a steady state, the drug shows dose-proportional pharmacokinetics over 30 to 360 mg.

  • Drug Distribution and Protein Binding: The drug spreads out widely into the body’s tissues rather than staying just in the blood. It is very sticky to proteins in the blood, with about 97 to 98% of it bound to them. The drug is also capable of entering the brain.

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

  • Elimination: Enzalutamide is mainly eliminated by hepatic metabolism. After the single oral dose administration of Enzalutamide, 85 percent of the radioactivity was seen in 77 days. 71 percent of the drug is eliminated in urine, whereas 14 percent 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 in randomized trials and 2.2% in single-arm studies, though high-risk individuals were excluded. Events occurred between 13 and 1776 days after starting therapy, leading to permanent discontinuation. The safety of combining Enzalutamide with antiepileptic drugs remains unclear. Predisposing factors include prior brain injury, stroke, Alzheimer’s disease, meningioma, leptomeningeal disease, loss of consciousness, and brain infections.

• Posterior Reversible Encephalopathy Syndrome (PRES) - It has symptoms such as headache, confusion, vision changes, and lethargy. Brain imaging, including MRI, may be required for evaluation.

• Hypersensitivity - Hypersensitivity reactions, including swelling of the face, lips, tongue, and pharynx, have been observed and may require temporary discontinuation.

• Ischemic Heart Disease - Ischemic heart disease occurred more frequently in treated patients, with severe (grade 3 to 4) events in 1.4% and death in 0.4%. Patients should be monitored and therapy discontinued if severe symptoms occur.

• Falls or Fractures - It was reported in 11% of patients, with severe fractures in 3%, typically occurring around 336 days. Monitoring and bone-protective strategies are recommended.

• Embryo-Fetal Toxicity - It may cause embryo-fetal toxicity based on animal studies. Effective contraception is advised for patients with reproductive potential.

What Are the Adverse Reactions of Enzalutamide?

The adverse reactions of Enzalutamide are listed below:

General Disorders:

• Peripheral edema (swelling in the extremities, such as the legs, feet, ankles, arms, or hands, caused by fluid buildup in the tissues)

• Asthenic conditions.

Musculoskeletal Disorders:

• Back pain.

• Arthralgia (joint pain or stiffness)

• 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 (a rare and severe condition that occurs when the nerves at the bottom of the spinal cord are compressed).

• Paresthesia.

• Hypoesthesia (a condition where you experience a loss or decreased sensation in a part of the body).

Mental Disorders:

• Infections or Infestations:

• Upper respiratory infections.

• Lung infections.

• Lower respiratory tract infections.

Psychiatric Diseases:

• Anxiety.

• Insomnia.

Kidney Disorders:

• Hematuria (the presence of red blood cells in urine)

• Pollakiuria (a condition that causes frequent urination, especially during the day)

Respiratory Problems:

• Asthma.

• Laboratory Abnormalities:

• Reduced neutrophil count.

• White blood cell count is reduced.

Chemistry:

• Hyperglycemia (a condition in which there is too much glucose in the blood).

• Hypermagnesemia (a condition with too much magnesium in the blood).

• Hyponatremia (a condition where the sodium level in the blood is lower than normal).

• Hypercalcemia (a condition where there is too much calcium in the blood).

Drug Interactions:

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

Use in Specific Populations:

• 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.

• Lactation: Little is 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.

• 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.

• Geriatric Use: Out of the 4081 patients given Enzalutamide in randomized clinical trials, 78 percent 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.

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

• 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 who had previously received Docetaxel for metastatic CRPC. 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 percent of Enzalutamide patients.

• Trial 2 - Enzalutamide Versus Placebo in Chemotherapy-Naive Metastatic CRPC: This trial was done on 1717 patients who had not previously taken Docetaxel. The median duration was 17.5 months for patients taking Enzalutamide, whereas it was 4.6 months for those taking a placebo. Grade three or four adverse reactions were reported in 44 percent of the Enzalutamide-treated patients and 37 percent 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 those taking Enzalutamide, whereas it was 5.8 months for those taking bicalutamide. Adverse reactions were reported in 7.6 percent of Enzalutamide-treated patients and 6.3 percent of Bicalutamide-treated patients.

• Trial 4 - Enzalutamide Versus Placebo in Non-Metastatic CRPC Patients: This trial was done on 1401 patients randomized in a 2:1 ratio 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 percent of Enzalutamide-treated patients and 23 percent of placebo-treated patients.