Darolutamide
Darolutamide, sold under the brand name Nubeqa, is an antiandrogen medication which is used in the treatment of non-metastatic castration-resistant prostate cancer in men. It is specifically approved to treat non-metastatic castration-resistant prostate cancer in conjunction with surgical or medical castration. The medication is taken by mouth twice per day with food.
Side effects of darolutamide added to castration may include fatigue, asthenia, pain in the arms and legs, and rash. Darolutamide is a nonsteroidal antiandrogen, and acts as a selective antagonist of the androgen receptor. It has been referred to as a second- or third-generation NSAA.
Darolutamide was patented in 2011 and was approved for medical use in USA in July 2019, in the European Union in March 2020 in Australia in July 2020. and in Canada in 2020,
Medical uses
Darolutamide is approved for use concurrently with a gonadotropin-releasing hormone agonist or antagonist or bilateral orchiectomy in the treatment of non-metastatic castration-resistant prostate cancer in men. It is used at a dosage of 600 mg orally twice per day with food. In individuals with severe renal impairment or moderate hepatic impairment, darolutamide is used at a dosage of 300 mg orally twice per day with food. 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, 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. Also, darolutamide showed significantly lower rate of grade 3-5 adverse events 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 in castrated men included fatigue and asthenia, pain in extremities, and rash. Darolutamide was also associated with higher incidences of ischemic heart disease and heart failure. In terms of laboratory test abnormalities, darolutamide was associated with decreased neutrophil count, increased aspartate aminotransferase , and increased bilirubin. In the clinical studies, 88% of patients treated with darolutamide were age 65 years or older.No seizures have been observed with darolutamide in clinical trials. Darolutamide is an expected teratogen and has a theoretical risk of birth defects in male infants if taken by women during pregnancy. It may impair male fertility. When used as a monotherapy in men, NSAAs are known to produce feminizing breast changes including breast tenderness and gynecomastia.
Overdose
Darolutamide has been studied at a dosage of up to 1,800 mg/day in clinical trials. There were no dose-limiting toxicities seen at this dosage. Due to its saturable absorption and lack of acute toxicity, overdose of darolutamide is not expected to result in systemic toxicity in people with intact hepatic and renal function. There is no specific antidote for overdose of darolutamide. In the event of darolutamide overdose, if there is no toxicity, treatment can be continued as normal. If there is suspicion of toxicity, general supportive measures should be undertaken until clinical toxicity has decreased or resolved and then treatment may be continued.Interactions
Combined P-glycoprotein and strong or moderate CYP3A4 inducers such as rifampicin may decrease blood levels of darolutamide, while combined P-glycoprotein and strong CYP3A4 inhibitors such as itraconazole may increase blood levels of darolutamide. Darolutamide is an inhibitor of the breast cancer resistance protein transporter and can increase blood levels of substrates for BCRP protein, such as rosuvastatin, by approximately 5-fold.Pharmacology
Pharmacodynamics
Darolutamide is a second- or third-generation nonsteroidal antiandrogen. It acts as a selective competitive silent antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone. Its affinity for the AR is 11 nM and its functional inhibition of the AR is 26 nM. The major metabolite of darolutamide, ketodarolutamide, has similar antiandrogenic activity relative to darolutamide. In addition to its actions as an AR antagonist, darolutamide has been found to act as a silent antagonist of the progesterone receptor, with approximately 1% of the potency of its AR antagonism.A dosage of darolutamide of 1,200 mg/day has been found to result in a mean decrease in prostate specific antigen levels of more than 90% in men with prostate cancer. The addition of darolutamide to castration has been found to decrease PSA levels by more than 50% in about 50% of men at 200 mg/day, 69% of men at 400 mg/day, 83% of men at 1,200 mg/day, and 86% of men at 1,400 mg/day. In accordance with its antiandrogenic activity, darolutamide monotherapy has been found to increase testosterone levels in men with prostate cancer by 43.3% on average, from median 413ng/dL at baseline to median 595ng/dL, after 24weeks of treatment. For comparison, testosterone levels increased by 114.3% with enzalutamide monotherapy and high-dose bicalutamide monotherapy increases testosterone levels by about 59 to 97% in men with prostate cancer. A phase 2 clinical trial directly comparing testosterone increases with darolutamide monotherapy versus enzalutamide monotherapy is underway as of January 2024.
Darolutamide shows some advantages in comparison to enzalutamide and apalutamide, two other second-generation NSAAs. It has been claimed to negligibly cross the blood–brain barrier, and hence is thought to have a reduced risk of seizures and other central side effects from off-target GABAA receptor inhibition. However, darolutamide monotherapy has subsequently been found to increase testosterone levels, a centrally mediated antiandrogenic action. 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.
Darolutamide inhibits the organic anion transporting polypeptide transporters OATP1B1 and OATP1B3 in vitro. It shows no inhibition or induction of cytochrome P450 enzymes at clinically relevant concentrations. Similarly, darolutamide shows no inhibition of a variety of other transporters at therapeutic concentrations.