Enzalutamide

Enzalutamide is an oral androgen receptor inhibitor used in the treatment of prostate cancer. It belongs to the androgen receptor signaling inhibitor class and works by interfering with several steps of androgen receptor activity. Enzalutamide binds to the androgen receptor and reduces receptor signaling, including receptor movement into the cell nucleus and interaction with DNA. Because prostate cancer cells can depend on androgen signaling for growth and survival, blocking this pathway can slow disease progression. Enzalutamide is administered orally as capsules or tablets and is generally taken once daily. Depending on the clinical setting, it may be used alone or together with androgen deprivation therapy. In patients with castration-resistant prostate cancer or metastatic hormone-sensitive prostate cancer who have not undergone surgical removal of the testes, medical castration with a gonadotropin-releasing hormone analogue is generally continued. Enzalutamide has become an important treatment option across several stages of prostate cancer, including metastatic disease and selected high-risk biochemical recurrence. Its clinical development included major phase III studies such as AFFIRM, PREVAIL, PROSPER, and EMBARK, which evaluated its role in different prostate cancer settings.

Enzalutamide was developed as a direct inhibitor of androgen receptor signaling, with early clinical development demonstrating antitumor activity in castration-resistant prostate cancer. The U.S. Food and Drug Administration granted its initial approval in 2012 for metastatic castration-resistant prostate cancer. The European Commission granted marketing authorization in the European Union on 21 June 2013, with subsequent indication expansions. In India, the Central Drugs Standard Control Organisation approved enzalutamide 160 mg tablets in 2022 for specified metastatic castration-resistant prostate cancer indications, with additional strengths and dosage forms subsequently considered through regulatory processes. Major clinical development programs included AFFIRM in previously docetaxel-treated metastatic castration-resistant disease, PREVAIL in metastatic castration-resistant disease before chemotherapy, PROSPER in non-metastatic castration-resistant disease, and EMBARK in high-risk biochemical recurrent hormone-sensitive prostate cancer.

Enzalutamide is approved for several prostate cancer settings. In the United States, it is indicated for castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, and non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis. European indications include high-risk biochemical recurrent non-metastatic hormone-sensitive prostate cancer in adults unsuitable for salvage radiotherapy, metastatic hormone-sensitive prostate cancer in combination with androgen deprivation therapy, high-risk non-metastatic castration-resistant prostate cancer, and selected metastatic castration-resistant prostate cancer settings before or after docetaxel. For high-risk biochemical recurrence without metastases, enzalutamide may be used alone or with androgen deprivation therapy under the applicable indication, while metastatic hormone-sensitive disease is treated in combination with androgen deprivation therapy.

The recommended adult dose is 160 mg of enzalutamide taken orally once daily, with or without food. Available oral formulations include capsules and tablets, with tablets available in 40 mg and 80 mg strengths in current prescribing information. The dose may need modification or temporary interruption when clinically significant adverse reactions occur or when certain interacting medicines are required. Patients receiving treatment for castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer who have not undergone bilateral orchiectomy should generally continue a gonadotropin-releasing hormone analogue. In non-metastatic castration-sensitive prostate cancer with high-risk biochemical recurrence, treatment may be given with or without androgen deprivation therapy according to the applicable indication. Treatment duration is individualized according to disease response, tolerability, and clinical assessment.

Commonly reported adverse effects with enzalutamide include fatigue, hot flushes, headache, hypertension, dizziness, falls, decreased appetite, weight loss, diarrhea, musculoskeletal symptoms, and, in some patients, cognitive or concentration-related effects. Fatigue is particularly common across several prostate cancer treatment settings. The frequency and severity of side effects can vary according to disease stage, other treatments, age, and individual health status. Patients should report persistent or troublesome symptoms so that the treating healthcare professional can determine whether supportive treatment, dose modification, or treatment interruption is appropriate.

Important serious risks include seizures, posterior reversible encephalopathy syndrome, hypersensitivity reactions, ischemic heart disease, falls and fractures, and embryo-fetal toxicity. Seizures have been reported in patients receiving enzalutamide, including patients with and without recognized predisposing factors, and treatment should be permanently discontinued if a seizure occurs. Posterior reversible encephalopathy syndrome is a rare neurological condition that requires prompt recognition and discontinuation of treatment. Cardiovascular risk should be considered particularly in patients with relevant underlying disease. Patients should also be monitored for falls and fractures, especially when other factors affecting bone health are present. Enzalutamide should not be used during pregnancy because androgen receptor inhibition may cause fetal harm.

Before treatment, clinicians should review the patient's prostate cancer status, previous therapies, cardiovascular history, seizure risk, neurological history, concomitant medicines, and general risk of falls and fractures. Enzalutamide is extensively metabolized through hepatic pathways and can affect the exposure of several other medicines. Strong CYP2C8 inhibitors should generally be avoided or managed with an appropriate dose adjustment, while strong CYP3A4 inducers should also be avoided when possible because they can alter enzalutamide exposure. Enzalutamide may reduce concentrations of certain medicines metabolized through CYP3A4, CYP2C9, or CYP2C19, which can be clinically important when a small reduction in the concentration of the interacting medicine could cause treatment failure. Medication review is therefore important before and during therapy.

Treatment should be initiated and supervised by clinicians experienced in prostate cancer management. Confirm the disease state and treatment objective before selecting enzalutamide alone or in combination with androgen deprivation therapy. Review cardiovascular history, seizure risk, fall and fracture risk, and all prescription, non-prescription, and herbal medicines before starting treatment. Patients should be counselled to take the medicine consistently once daily and to swallow the formulation as directed. Monitor disease response, blood pressure, neurological symptoms, fatigue, falls, cardiovascular symptoms, and clinically relevant laboratory parameters according to the overall treatment plan. Pharmacists should perform an interaction review because enzalutamide can substantially alter exposure to several concomitant medicines. Patients should promptly report seizures, new neurological symptoms, chest pain, severe allergic symptoms, or other significant changes during treatment.