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.
of darolutamide added to castration may include fatigue, asthenia, pain in the and , and rash.
Darolutamide was patented in 2011
Medical uses
Darolutamide is approved for use concurrently with a gonadotropin-releasing hormone (GnRH) agonist or antagonist or bilateral orchiectomy in the treatment of non-
metastatic castration-resistant prostate cancer (nmCRPC) in men.
It is used at a dosage of 600 mg orally twice per day (1,200 mg/day total) 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 (600 mg/day total) 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-analysis 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.
Available forms
Darolutamide is provided in the form of 300 mg oral film-coated tablets.
Contraindications
Darolutamide has no
in men.
However, the medication may have
effects in male
due to its
effects and hence should not be used by women who are
pregnancy.
Side effects
The most common
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).
In the clinical studies, 88% of patients treated with darolutamide were age 65 years or older.
No have been observed with darolutamide in clinical trials.
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
enzyme inducer such as
rifampicin may decrease blood levels of darolutamide, while combined P-glycoprotein and strong CYP3A4
enzyme inhibitor such as
itraconazole may increase blood levels of darolutamide.
Darolutamide is an inhibitor of the breast cancer resistance protein (BCRP) 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 (NSAA).
It acts as a selective competitive silent antagonist of the androgen receptor (AR), the biological target of
like
testosterone and dihydrotestosterone (DHT).
Its affinity (K
i) 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 (K
i = 8 nM; IC
50 = 38 nM).
In addition to its actions as an AR antagonist, darolutamide has been found to act as a silent antagonist of the progesterone receptor (PR), 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 (PSA) levels of more than 90% in men with prostate cancer.
Darolutamide shows some advantages in comparison to enzalutamide and apalutamide, two other second-generation NSAAs.
Darolutamide inhibits the organic anion transporting polypeptide (OATP) transporters OATP1B1 and OATP1B3 in vitro.
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.
Following a single 600-mg dose of darolutamide, peak levels of darolutamide occur after approximately 4 hours.
Steady-state levels of darolutamide occur after 2 to 5 days of continuous administration with food, during which time an approximate 2-fold accumulation in darolutamide levels occurs.
At steady state with 600 mg/day darolutamide, mean levels of darolutamide are 4.79 μg/mL and area-under-the-curve levels of darolutamide over time 0 to 12 hours (AUC
0–12) are 52.82 h•μg/mL.
Total exposure to ketodarolutamide is approximately 1.7-fold that of darolutamide.
Distribution
The volume of distribution of darolutamide with intravenous administration is 119 L.
The plasma protein binding of darolutamide is 92%, with 8% circulating freely, and of ketodarolutamide is 99.8%, with 0.2% circulating unbound.
As such, free levels of darolutamide in the circulation are about 40-fold higher than those of ketodarolutamide.
Both darolutamide and ketodarolutamide are bound mainly to albumin.
Darolutamide and ketodarolutamide has been claimed to negligibly cross the blood–brain barrier both in mice and humans.
However, a subsequent study of darolutamide monotherapy in men with prostate cancer found that it increased testosterone levels, a centrally mediated antiandrogenic action.
Darolutamide is a known substrate of
P-glycoprotein and the breast cancer resistance protein (BCRP).
P-Glycoprotein is known to play a major role in excluding drugs from the
brain due to efflux back across the blood–brain barrier.
Metabolism
Darolutamide is primarily
metabolism into ketodarolutamide via
dehydrogenation by CYP3A4 in the
liver.
The medication is also conjugated via
glucuronidation by UGT1A9 and UGT1A1.
The elimination half-life of darolutamide and ketodarolutamide has been reported to be approximately 20 hours.
A clinical study found that the elimination half-lives of darolutamide and ketodarolutamide at steady-state were 15.8 hours and 10.0 hours, respectively, with these half-lives being independent of dosage across a dose range of darolutamide of 200 to 1,800 mg/day.
The elimination half-life of darolutamide is far shorter than that of
enzalutamide (e.g., 1.6 hours vs. 18.3 hours in mice).
The clearance of darolutamide following intravenous administration is 116 mL/min.
Excretion
After a single oral dose of darolutamide, more than 95% of the dose is
excretion in
urine and
feces within one week following administration.
A total of 63.4% darolutamide-related material is recovered in urine (about 7% as unchanged darolutamide) and a total of 32.4% darolutamide-related material (about 30% as unchanged darolutamide) is recovered in
feces.
Variability
No clinically significant differences in the
pharmacokinetics of darolutamide have been observed in men with nmCRPC on the basis of age (48 to 95 years), race (white, Asian, black), mild-to-moderate
renal impairment, or mild hepatic impairment.
In non-nmCRPC individuals with severe renal impairment not on
Kidney dialysis, exposure to darolutamide was increased by about 2.5-fold relative to healthy people.
In non-nmCRPC individuals with moderate hepatic impairment, darolutamide exposure was increased by about 1.9-fold compared to healthy controls.
The pharmacokinetics of darolutamide have not been assessed in end-stage
kidney disease or severe hepatic impairment.
Chemistry
Darolutamide is a
nonsteroidal compound and is structurally distinct from other marketed NSAAs, including enzalutamide and apalutamide.
History
Darolutamide was developed by Orion Corporation and
Bayer HealthCare.
Orion Corporation applied for a
patent on darolutamide in October 2010, and this patent was published in May 2011.
Darolutamide entered phase I
in April 2011,
with the results of the first clinical study of darolutamide initially published in 2012.
The U.S. Food and Drug Administration (FDA) approved darolutamide in July 2019, under the agency's
Priority Review designation.
Approval was based on ARAMIS,
The primary endpoint was metastasis free survival (MFS), defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first. The median MFS was 40.4 months (95% CI: 34.3, not reached) for patients treated with darolutamide compared with 18.4 months (95% CI: 15.5, 22.3) for those receiving placebo (hazard ratio 0.41; 95% CI: 0.34, 0.50; p<0.0001).
Darolutamide was associated with greater benefits than placebo for all secondary end points, including overall survival (hazard ratio 0.69; 95% CI: 0.53-0.88; P=0.003), time to pain progression (median 40.3 months vs. 25.4 months; hazard ratio 0.65; 95% CI: 0.53-0.79; P<0.001), time to cytotoxic chemotherapy (hazard ratio 0.43; 95% CI: 0.31-0.60), and time to a symptomatic skeletal event (hazard ratio 0.43; 95% CI: 0.22-0.84).
Society and culture
Generic names
Darolutamide is the
generic drug of the medication and its and .
It is also known by its developmental code names ODM-201 and BAY-1841788.
Brand names
Darolutamide is marketed under the brand name Nubeqa.
Availability
Darolutamide is available in the United States, Canada and the European Union.
Research
Darolutamide monotherapy is being studied in comparison to androgen deprivation therapy with
GnRH agonist or
GnRH antagonist monotherapy in men with treatment-naive prostate cancer.
As of 2018, it is entering a phase II
clinical trial for this indication.
In 2020, completion of this study had been expected in 2021 or 2022.
Darolutamide is being studied for the treatment of breast cancer in women.
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