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Darolutamide: Mechanism, Side Effects, Contraindications, and Dosage

Indications for Darolutamide

Castration-sensitive metastatic prostate cancer (M1 CSPC) with high tumor burden:

In randomized trials, the triplet combination of standard hormonal therapy intensified with darolutamide and docetaxel chemotherapy showed advantages in terms of survival and disease progression. Triplet therapy in the ARASENS trial led to better survival (HR 0.68) and prolonged progression-free survival compared to hormone therapy and docetaxel (Smith et al., 2022a). Triple therapy with darolutamide has been approved in the USA since 2022 and in Europe since 2023.

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

Darolutamide 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 (ARAMIS), treatment with darolutamide combined with classic antiandrogen therapy improved metastasis-free survival (40 months vs. 18 months with placebo and hormone therapy). Overall survival was improved as a trend (Fizazi et al., 2019).

Darolutamid is not approved for treatment of castration-resistant metastatic prostate cancer (M1 CRPC).

Mechanism of Action of Darolutamide

Darolutamide 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 Darolutamide

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

Side Effects of Darolutamide

The most common side effects are fatigue (16%). Increased cardiovascular risk (e.g., heart failure 2% vs. 1%). Mild neutropenia or increased liver enzymes. Compared to apalutamide or enzalutamide, there are fewer central nervous system side effects such as falls, epilepsy or fatigue (Halabi et al., 2021).

Interactions with Darolutamide

CYP3A4 inducers such as rifampicin reduce efficacy, caution with CYP3A4 inhibitors such as antifungals.

Contraindications for Darolutamide

• Allergy and intolerance
• Women and children

Dosage of Darolutamide

600 mg darolutamide (two 300 mg capsules) p.o. 2-0-2 with the meals, the daily dosage is 1200 mg. The addition of prednisolone is unnecessary. Reduce the dosage to 300 mg 1-0-1 in case of renal or hepatic side effects. Discontinue treatment in patients with progressive disease or persistent intolerance to darolutamide.

References

K. Fizazi et al., “Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer.,” NEJM, vol. 380, no. 13, pp. 1235–1246, 2019.

S. Halabi et al., “Indirect Comparison of Darolutamide versus Apalutamide and Enzalutamide for Nonmetastatic Castration-Resistant Prostate Cancer.,” J Urol, vol. 206, no. 2, pp. 298–307, 2021, doi: 10.1097/JU.0000000000001767.

M. R. Smith et al., “Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer.,” NEJM, vol. 386, no. 12, pp. 1132–1142, 2022, doi: 10.1056/NEJMoa2119115.

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