Apalutamide

Apalutamide is an orally administered targeted anticancer medicine belonging to the androgen receptor inhibitor class. It selectively binds to the androgen receptor and interferes with androgen-dependent signaling by preventing receptor activation, nuclear translocation and transcription of androgen-responsive genes. Because prostate cancer cells can depend on androgen receptor signaling for growth and survival, blocking this pathway can delay disease progression in appropriate patients. Apalutamide is used with androgen deprivation therapy in adults with non-metastatic castration-resistant prostate cancer who are at high risk of developing metastatic disease and in adults with metastatic hormone-sensitive prostate cancer. Medical castration with a gonadotropin-releasing hormone analogue is generally continued during treatment in patients who have not undergone bilateral orchiectomy. Apalutamide is available as oral tablets and the current U.S. recommended dose is 240 mg once daily, with or without food. Treatment is generally continued until disease progression or unacceptable toxicity, although treatment interruption or dose reduction may be required for significant adverse reactions. Important monitoring considerations include skin reactions, falls and fractures, thyroid function, cardiovascular health, seizures, and other neurologic or treatment-related effects.

Apalutamide was developed as a non-steroidal androgen receptor inhibitor designed to block androgen signaling in prostate cancer. The U.S. Food and Drug Administration initially approved Erleada in February 2018 for men with non-metastatic castration-resistant prostate cancer at high risk of developing metastatic disease, based primarily on the SPARTAN clinical trial. In September 2019, FDA expanded the indication to include metastatic castration-sensitive prostate cancer in combination with androgen deprivation therapy based on the TITAN trial. The European Commission granted marketing authorisation for Erleada on 14 January 2019, with the current European indication covering non-metastatic castration-resistant prostate cancer at high risk of developing metastatic disease and metastatic hormone-sensitive prostate cancer in combination with androgen deprivation therapy. Indian CDSCO records document approval of apalutamide 60 mg tablets in November 2022, initially including metastatic castration-resistant and non-metastatic castration-resistant prostate cancer, with subsequent regulatory activity concerning manufacture and marketing. Key clinical development programmes include SPARTAN and TITAN, which evaluated apalutamide in different stages of advanced prostate cancer.

Apalutamide is used with androgen deprivation therapy for selected adult men with prostate cancer. In non-metastatic castration-resistant prostate cancer, it is indicated for patients whose disease remains resistant to testosterone-lowering treatment and who have a high risk of developing metastatic disease. In metastatic hormone-sensitive or castration-sensitive prostate cancer, apalutamide is used in combination with androgen deprivation therapy for patients with metastatic disease that remains responsive to hormonal treatment. The exact approved indication can differ between regulatory jurisdictions and product labels, and Indian regulatory records have included an indication for metastatic castration-resistant prostate cancer. Apalutamide is generally used alongside continued androgen deprivation rather than replacing medical or surgical castration. Treatment selection should consider disease stage, testosterone status, previous treatment, metastatic burden, comorbidities, potential drug interactions and the approved indication applicable to the specific product.

Apalutamide is administered orally at a recommended adult dose of 240 mg once daily. Current U.S. prescribing information permits administration with or without food, while tablets should be swallowed whole. Patients who have not undergone bilateral orchiectomy should continue treatment with a gonadotropin-releasing hormone analogue as part of androgen deprivation therapy. Treatment is generally continued until disease progression or unacceptable toxicity. If a significant or intolerable adverse reaction occurs, treatment may be temporarily withheld until symptoms improve and can then be resumed at the same dose or at a reduced dose when appropriate. Current European product information provides reduced dosing options of 180 mg or 120 mg daily when clinically warranted, while the U.S. prescribing information recommends 120 mg once daily for patients with severe hepatic impairment. Missed doses should generally be taken as soon as possible on the same day, with the regular schedule resumed the following day rather than taking extra tablets.

Common side effects of apalutamide include fatigue, skin rash, hypertension, hot flushes, joint pain, diarrhea, decreased appetite, weight loss, falls and fractures. Hypothyroidism can occur and may require monitoring of thyroid-stimulating hormone and appropriate treatment. Other adverse effects may include muscle discomfort, dizziness and laboratory abnormalities. Because androgen deprivation itself can contribute to bone loss, falls and fractures, patients receiving combined hormonal therapy require appropriate assessment of bone health and fracture risk. The frequency and severity of adverse reactions can vary according to the treatment setting, duration of therapy and individual patient characteristics. Many adverse effects can be managed with supportive treatment, monitoring, temporary treatment interruption or dose reduction under medical supervision.

Important serious risks associated with apalutamide include ischemic cardiovascular disease, cerebrovascular events, seizures, severe skin reactions, falls and fractures. Patients with clinically significant cardiovascular disease or cardiovascular risk factors require appropriate assessment and monitoring during treatment. Apalutamide may increase the risk of falls and fractures, particularly in patients with other factors contributing to reduced bone strength or balance problems. Seizures have been reported and require particular caution in patients with a history of seizure disorders or other predisposing factors. Severe or potentially life-threatening skin reactions can rarely occur and may require permanent treatment discontinuation. Hypothyroidism and other endocrine abnormalities should also be identified and managed appropriately. Patients should be monitored for signs of cardiovascular or neurologic complications and treatment should be interrupted or discontinued when clinically significant toxicity develops according to the severity and applicable prescribing information.

Before starting treatment, healthcare professionals should assess cardiovascular history, blood pressure, thyroid function, bone health, fracture risk, fall risk and relevant neurologic history. Thyroid-stimulating hormone should be monitored during treatment because hypothyroidism is a recognized adverse effect. Patients at increased risk of fractures may require appropriate bone-health assessment and preventive management. Apalutamide can induce several drug-metabolizing enzymes and transport proteins, including CYP3A4, CYP2C9, CYP2C19 and P-glycoprotein, and may therefore reduce exposure to medicines that are substrates of these pathways. Medication reconciliation is important, particularly for medicines with a narrow therapeutic range or those for which reduced exposure could lead to loss of efficacy. Strong enzyme-inducing effects can also affect exposure to certain hormonal and other concomitant treatments. Patients should inform healthcare professionals about prescription medicines, over-the-counter products and supplements before starting or changing therapy. Apalutamide can cause fetal harm, and appropriate contraception is required for patients who may become pregnant and for partners who may become pregnant according to the applicable prescribing information.

Prescribers should confirm the prostate cancer disease state, testosterone status, metastatic status and applicable regulatory indication before initiating apalutamide. Baseline assessment should include cardiovascular history, blood pressure, thyroid function, fall and fracture risk, bone health and medication review. Patients should be counselled about the possibility of rash, fatigue, dizziness, falls and fractures and should report severe skin reactions, seizures, chest pain, neurologic symptoms or significant changes in blood pressure promptly. Thyroid function should be monitored periodically during treatment. Pharmacists should verify the 240 mg once-daily regimen, administration requirements, continued androgen deprivation therapy when applicable, formulation and potential enzyme-mediated drug interactions. Medicines with narrow therapeutic windows may require particular attention because apalutamide can substantially reduce exposure to certain concomitant drugs. Coordination between oncology, urology, pharmacy and primary-care teams can help maintain cardiovascular, endocrine and bone-health monitoring throughout therapy.