Darolutamide has been found to block the activity of all tested/well-known mutant ARs in prostate cancer, including the recently identified clinically-relevant F876L mutation that produces resistance to enzalutamide and apalutamide. The medication shows higher affinity and inhibitory potency at the AR relative to enzalutamide and apalutamide in vitro (Ki = 11 nM relative to 86 nM for enzalutamide and 93 nM for apalutamide; IC50 = 26 nM relative to 219 nM for enzalutamide and 200 nM for apalutamide).Darolutamide inhibits the organic anion transporting polypeptide (OATP) transporters OATP1B1 and OATP1B3 in vitro. It shows no inhibition or induction of cytochrome P450 enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4) at clinically relevant concentrations. Similarly, darolutamide shows no inhibition of a variety of other transporters (P-glycoprotein, MRP2, BSEP, OATs, OCTs, MATEs, OATP2B1, NTCP) at therapeutic concentrations. Pharmacokinetics
Absorption
The absolute bioavailability of darolutamide with oral administration of a single 300-mg dose without food is approximately 30%. The bioavailability of darolutamide is increased by about 2- to 2.5-fold when administered with food, with a similar increase in exposure occurring for ketodarolutamide. Exposure to darolutamide and ketodarolutamide increases in a nearly linear or dose-proportional manner across a dose range of 100 to 700 mg (or about 0.17- to 1.17-fold the recommended 600-mg dosage). No further increase in exposure to darolutamide was observed at a dosage of darolutamide of 900 mg twice per day (or 1.5 times the recommended 600-mg dosage), indicating a saturation of absorption at doses above 700 mg.
No dosage adjustment is needed for mild to moderate renal impairment or mild hepatic impairment, whereas appropriate dosage adjustment for end-stage kidney disease and severe hepatic impairment is unknown.Two 2020 meta-analyses reported that enzalutamide and apalutamide seemed to be more effective than darolutamide in improving metastasis-free survival (MFS), however 2021 matched adjusted indirect comparison showed no significant differences between drugs in terms of MFS. According to 2021 meta-analysis darolutamide was ranked first in terms of improving overall survival (OS). Also, darolutamide showed significantly lower rate of grade 3-5 adverse events (AE) compared to both enzalutamide and apalutamide. Available forms
Darolutamide is provided in the form of 300 mg oral film-coated tablets. Contraindications
Darolutamide has no contraindications in men. However, the medication may have teratogenic effects in male fetuses due to its antiandrogenic effects and hence should not be used by women who are pregnant. Side effects
The most common side effects of darolutamide in clinical trials (≥2% incidence) in castrated men included fatigue and asthenia (16% vs. 11% for placebo), pain in extremities (6% vs. 3% for placebo), and rash (3% vs. 1% for placebo). Darolutamide was also associated with higher incidences of ischemic heart disease (4.0% vs. 3.4% for placebo) and heart failure (2.1% vs. 0.9% for placebo). In terms of laboratory test abnormalities, darolutamide was associated with decreased neutrophil count (20% vs. 9% for placebo), increased aspartate aminotransferase (AST) (23% vs. 14% for placebo; Grade 3–4: 0.5% vs. 0.2% for placebo), and increased bilirubin (16% vs. 7% for placebo).