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Apalutamide: Antiandrogen for Castration-resistant Prostate Cancer

Indications for Apalutamide

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Apalutamide combined with androgen deprivation therapy for Castration-sensible metastatic prostate cancer (M1 CSPC):

The TITAN trial (n=1052) demonstrated that androgen deprivation combined with apalutamide improved overall survival (HR 0.67) and slowed disease progression (HR 0.48) (Chiet al., 2019). Apalutamide has been approved for the treatment of hormone-sensitive prostate cancer in all risk groups since 1/2020.

Castration-resistant non-metastatic prostate cancer (M0 CRPC):

Apalutamide is a treatment option for patients with rising PSA levels under androgen deprivation therapy without metastasis in imaging studies (scintigraphy, CT-scan). The approval is limited to patients at high risk: PSA doubling time under 10 months. In the pivotal study (SPARTAN), treatment with apalutamide combined with classic antiandrogen therapy improved metastasis-free survival (41 months vs. 16 months with placebo and hormone therapy). Overall survival was improved with apalutamide, but this was statistically only a trend (Smith et al., NEJM 2018).

Castration-resistant metastatic prostate cancer (M1 CRPC):

Apalutamid is not approved for treatment of M1 CRPC.

Mechanism of Action of Apalutamide

Apalutamide inhibits the signal transduction of the androgen receptor:

• Competitive inhibition of the androgen binding to the androgen receptor
• Prevents translocation of activated receptors to the cell nucleus
• Inhibits the binding of the activated androgen receptor to the DNA

Pharmacokinetics of Apalutamide

100% bioavailability independent from meals, 96% plasma protein binding, hepatic metabolism of apalutamide mainly via CYP2C8 and CYP3A4, half-life 3 days, renal (65%) and fecal excretion of the inactive metabolites.

Side Effects of Apalutamide

The most common side effects are fatigue (30%) and rash (24% all severity grades and 5% grade 3 or 4). In more than 80% of patients the exanthem improved by dose reduction, systemic corticosteroids or pausing of the medication (see dosage). Further side effects are weight loss (16%), arthralgia (16%), increased risk of falling with fractures (12%), hypothyroidism (8%), epilepsy (<1%).

Interactions with Apalutamide

Apalutamide is a potent enzyme inducer, so caution is recommended with many drug groups such as antiepileptics or oral anticoagulation.

Contraindications for Apalutamide

• Allergy and intolerance
• Women and children
• Severe hepatic impairment

Dosage of Apalutamide

240 mg apalutamide (four 60 mg capsules) p.o. once a day. The addition of prednisolone is unnecessary. For rash ≥grade 3, the medication should be paused to allow recovery. If necessary add local or systemic glucocorticoids. If the rash recurs at re-dosing of 240 mg, a dose reduction to 120–180 mg should be attempted. Discontinue treatment in patients with progressive disease or persistent intolerance to enzalutamide.

References

  Deutsche Version: Apalutamid