Oral Therapies in Metastatic Prostate Cancer

Prostate cancer is one of the most commonly diagnosed cancers in Australia, where it is estimated that 1 in 6 males will be diagnosed with prostate cancer by the age of 85. Prostate cancer starts from abnormal cells growing uncontrollably in the prostate gland, which can result in a malignant tumour. Prostate cancer cell growth is stimulated by androgens, which are mainly testosterone and dihydrotestosterone. Hence, reducing androgen levels is the main goal in treating prostate cancer. Prostate cancer is managed with a variety of treatments, including surgery, chemotherapy, radiation and androgen-deprivation therapies. However, over time, many patients acquire castration resistance, where the cancer no longer completely responds to testosterone-lowering treatment. The adrenal glands and prostate cancer tissue continue to produce androgens, which contribute to prostate cancer growth. This results in castrate-resistant prostate cancer, which is difficult to treat and associated with poor prognosis.

It is found that castration-resistant prostate cancer is often associated with increased PSA (prostate-specific antigen) levels, which suggests that prostate cancer continues to be driven by androgen-receptor signalling despite androgen-deprivation therapy. Androgen receptor mutations, adrenal gland testosterone production and intratumoral androgen production, are some of the reasons prostate cancer progresses. Hence, it suggests that further suppression of androgen-receptor signalling may give options to treat castrate-resistant prostate cancer.

Over the last ten years, there have been many advances in endocrine therapies which have improved survival in patients with castrate-resistant prostate cancer. Various novel oral anti-androgen therapies have been included under the Pharmaceutical Benefits Scheme to treat castrate-resistant prostate cancer. This includes darolutamide, apalutamide, abiraterone and enzalutamide. Darolutamide, apalutamide and enzalutamide belong to the same class of second-generation antiandrogens. Abiraterone works differently by blocking cytochrome P450 17 alpha-hydroxylase (CYP17) to reduce androgen production.

Darolutamide, enzalutamide and apalutamide are second-generation antiandrogens, where first-generation antiandrogens include bicalutamide. Compared to bicalutamide, it is found that the second-generation anti-androgens tend to have a much higher affinity for the androgen receptor, where apalutamide has a 7 to 10-fold increased affinity and enzalutamide a 5 to 8-fold increased affinity compared to bicalutamide. All anti-androgens can cause infertility in males.

Darolutamide (Nubeqa®)

The usual dose of daroluatmide is 600mg twice a day. Due to the low bioavailability of darolutamide, it needs to be taken with food. Darolutamide needs to be dose reduced to 300mg twice daily in patients with reduced kidney function (15 to 30 mL/min/1.73m²) and those with moderate hepatic impairment. Darolutamide is a mild CYP3A4 substrate. Caution should still be warranted when a patient is on an existing drug which is either a strong inhibitor or inducer of CYP3A4 as this can affect the levels of darolutamide. However, compared to apalutamide and enzalutamide, it is least affected by CYP metabolism, which results in less drug interactions. The most common adverse effect of darolutamide is fatigue. If the fatigue is severe, treatment is delayed until resolved or the dose reduced to 300mg twice daily.

Enzalutamide (Xtandi®)

Enzalutamide comes as 40mg capsules. The usual dose is 160mg once daily and can be taken with or without food. Depending on symptoms, the dose can be reduced. It does not need dose adjustment in patients with hepatic impairment or creatinine clearance greater than 30 mL/min/1.73.m². It has not been studied in patients with creatinine clearance lower than 30. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. This means that the co-administration of enzalutamide with drugs with a narrow therapeutic index that are substrates of CYP3A4, CYP2C9 or CYP2C19 is not recommended. These include commonly seen drugs such as warfarin (CYP2C9) and colchicine (CYP3A4). The common adverse effects of enzalutamide include fatigue, muscle pain, fractures and hypertension. Fatigue is the most common side effect however it can be accumulative and severe. A dose reduction to 120mg daily is recommended on first occurrence, however if it is ongoing, it is suggested to switch to a different therapy.

Apalutamide (Erlyand®)

Apalutamide is readily absorbed and can be taken with or without food. It comes as 60mg tablets and the usual dose is 240mg daily. No dose adjustments are recommended in hepatic and renal impairment, however it has not been studied in patients with severe hepatic impairment or patients with eGFR less than 30 mL/min/1.73m². Apalutamide is a substrate of CYP3A4/5 and CYP2C8. It is a weak inducer of CYP2C9 but a strong inducer of CYP2C19 and CYP3A4/5. Common side effects include fatigue, hypertension, rash, falls and fractures. From trials studying apalutamide, it is found that ischaemic cardiovascular events have been associated with apalutamide which have resulted in death. It is important to monitor for signs and symptoms of ischaemic heart disease and reduce the dose of apalutamide or cease.

Abiraterone (Zytiga®)

Abiraterone comes as 250mg or 500mg tablets. The dose is 1g once daily. It is taken on an empty stomach, at least two hours after food and wait at least one hour before eating again. Taking abiraterone with food can increase the risk of side effects. Unlike the other second-generation antiandrogens, abiraterone is taken together with prednisone/prednisolone 10mg daily. This is due to the mechanism of action of abiraterone, where it not only suppresses testosterone but also cortisol production. This results in lower cortisol levels and a compensatory increase in adrenocorticotropic hormone (ACTH). Prednisone acts as a glucocorticoid replacement therapy to reduce mineralocorticoid-related adverse effects such as fluid retention, hypertension and hypokalaemia. Due to these common side effects, patients on abiraterone need to monitor for blood pressure, potassium concentration, fluid retention as well as liver function. Abiraterone is mainly eliminated via the liver so it is contraindicated in severe hepatic impairment.