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| Trade names | Nubeqa |
| Other names | Darramamide, ODM-201, BAY-1841788 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a619045 |
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| Routes of administration | By mouth |
| Drug class | Nonsteroidal antiandrogen |
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| Pharmacokinetic data | |
| Bioavailability | ≤30%[4] |
| Protein binding | Darolutamide: 92%[4] Ketodarolutamide: 99.8%[4] |
| Metabolism | Dehydrogenation (CYP3A4),glucuronidation (UGT1A9,UGT1A1)[4] |
| Metabolites | Ketodarolutamide[4][7] |
| Eliminationhalf-life | 16–20 hours[4][7] |
| Excretion | Urine: 63.4%[4] Feces: 32.4%[4] |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.264.885 |
| Chemical and physical data | |
| Formula | C19H19ClN6O2 |
| Molar mass | 398.85 g·mol−1 |
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Darolutamide, sold under the brand nameNubeqa, is anantiandrogen medication which is used in the treatment of non-metastatic castration-resistantprostate cancer in men.[8][4][5][9][10] It is specifically approved to treat non-metastaticcastration-resistant prostate cancer (nmCRPC) in conjunction withsurgical ormedical castration.[4] The medication is takenby mouth twice per day with food.[4]
Side effects of darolutamide added to castration may includefatigue,asthenia,pain in thearms andlegs, andrash.[4] Darolutamide is anonsteroidal antiandrogen (NSAA), and acts as aselectiveantagonist of theandrogen receptor (AR).[4][9][10] It has been referred to as a second- or third-generation NSAA.[11][12]
Darolutamide was patented in 2011[13] and was approved for medical use in USA in July 2019,[8][14] in the European Union in March 2020[5] in Australia in July 2020.[15] and in Canada in 2020,
Darolutamide is approved for use concurrently with agonadotropin-releasing hormone (GnRH)agonist orantagonist orbilateral orchiectomy in the treatment of non-metastaticcastration-resistant prostate cancer (nmCRPC) in men.[9][10] It is used at a dosage of 600 mgorally twice per day (1,200 mg/day total) with food.[4] In individuals with severerenal impairment or moderatehepatic impairment, darolutamide is used at a dosage of 300 mg orally twice per day (600 mg/day total) with food.[4] 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.[4]
Two 2020meta-analyses reported thatenzalutamide andapalutamide 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.[16][17][18] According to 2021 meta-analysis darolutamide was ranked first in terms of improving overall survival (OS).[19] Also, darolutamide showed significantly lower rate of grade 3-5 adverse events (AE) compared to both enzalutamide and apalutamide.[19]
Darolutamide is provided in the form of 300 mgoral film-coatedtablets.[4]
Darolutamide has nocontraindications in men.[4] However, the medication may haveteratogenic effects in malefetuses due to itsantiandrogenic effects and hence should not be used by women who arepregnant.[4]
The most commonside effects of darolutamide in clinical trials (≥2% incidence) in castrated men includedfatigue andasthenia (16% vs. 11% forplacebo),pain inextremities (6% vs. 3% for placebo), andrash (3% vs. 1% for placebo).[4] Darolutamide was also associated with higher incidences ofischemic heart disease (4.0% vs. 3.4% for placebo) andheart failure (2.1% vs. 0.9% for placebo).[4] In terms of laboratory test abnormalities, darolutamide was associated withdecreased neutrophil count (20% vs. 9% for placebo), increasedaspartate aminotransferase (AST) (23% vs. 14% for placebo; Grade 3–4: 0.5% vs. 0.2% for placebo), and increasedbilirubin (16% vs. 7% for placebo).[4] In the clinical studies, 88% of patients treated with darolutamide were age 65 years or older.[4]
Noseizures have been observed with darolutamide in clinical trials.[7][20] Darolutamide is an expectedteratogen and has a theoretical risk ofbirth defects in male infants if taken by women duringpregnancy.[4] It mayimpair male fertility.[4] When used as a monotherapy (i.e., without surgical or medical castration) in men, NSAAs are known to producefeminizingbreast changes includingbreast tenderness andgynecomastia.[21]
Darolutamide has been studied at a dosage of up to 1,800 mg/day in clinical trials.[4] There were no dose-limiting toxicities seen at this dosage.[4] Due to its saturableabsorption and lack of acute toxicity, overdose of darolutamide is not expected to result in systemic toxicity in people with intact hepatic and renal function.[4] There is no specificantidote for overdose of darolutamide.[4] In the event of darolutamide overdose, if there is no toxicity, treatment can be continued as normal.[4] 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.[4]
CombinedP-glycoprotein and strong or moderateCYP3A4inducers such asrifampicin may decrease blood levels of darolutamide, while combined P-glycoprotein and strong CYP3A4inhibitors such asitraconazole may increase blood levels of darolutamide.[4] Darolutamide is an inhibitor of thebreast cancer resistance protein (BCRP) transporter and can increase blood levels ofsubstrates for BCRP protein, such asrosuvastatin, by approximately 5-fold.[4]
Darolutamide is a second- or third-generationnonsteroidal antiandrogen (NSAA).[11][12] It acts as aselectivecompetitivesilent antagonist of theandrogen receptor (AR), thebiological target ofandrogens liketestosterone anddihydrotestosterone (DHT).[4] Its affinity (Ki) for the AR is 11 nM and its functional inhibition (IC50Tooltip half-maximal inhibitory concentration) of the AR is 26 nM.[10] The majormetabolite of darolutamide,ketodarolutamide, has similar antiandrogenic activity relative to darolutamide (Ki = 8 nM; IC50 = 38 nM).[4][10] In addition to its actions as an AR antagonist, darolutamide has been found to act as a silent antagonist of theprogesterone receptor (PR), with approximately 1% of the potency of its AR antagonism.[4]
A dosage of darolutamide of 1,200 mg/day has been found to result in a mean decrease inprostate specific antigen (PSA) levels of more than 90% in men with prostate cancer.[4][additional citation(s) needed] 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.[22][10][7] In accordance with its antiandrogenic activity, darolutamide monotherapy (600 mg b.i.d.) has been found to increasetestosterone levels in men with prostate cancer by 43.3% on average (range 5.7 to 144.0%), from median 413 ng/dL (range 209–1183 ng/dL) at baseline to median 595 ng/dL (range 260–1500 ng/dL), after 24 weeks of treatment.[23] For comparison, testosterone levels increased by 114.3% withenzalutamide monotherapy[23] and high-dose bicalutamide monotherapy increases testosterone levels by about 59 to 97% in men with prostate cancer.[24][25][26][27] Aphase 2clinical trial directly comparing testosterone increases with darolutamide monotherapy versus enzalutamide monotherapy is underway as of January 2024.[28][29][30]
Darolutamide shows some advantages in comparison to enzalutamide andapalutamide, two other second-generation NSAAs.[10] It has been claimed to negligibly cross theblood–brain barrier, and hence is thought to have a reduced risk ofseizures and othercentralside effects from off-targetGABAA receptor inhibition.[10] However, darolutamide monotherapy has subsequently been found to increase testosterone levels, a centrally mediated antiandrogenic action.[23] 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.[10] The medication shows higher affinity and inhibitory potency at the AR relative to enzalutamide and apalutamidein vitro (Ki = 11 nM relative to 86 nM for enzalutamide and 93 nM for apalutamide;IC50Tooltip half-maximal inhibitory concentration = 26 nM relative to 219 nM for enzalutamide and 200 nM for apalutamide).[10]
Darolutamide inhibits theorganic anion transporting polypeptide (OATP) transportersOATP1B1 andOATP1B3in vitro.[4] It shows noinhibition orinduction ofcytochrome P450enzymes (CYP1A2,2A6,2B6,2C8,2C9,2C19,2D6,2E1,3A4) at clinically relevant concentrations.[31] Similarly, darolutamide shows no inhibition of a variety of other transporters (P-glycoprotein,MRP2,BSEP,OATs,OCTs,MATEs,OATP2B1,NTCP) at therapeutic concentrations.[4][32]
Theabsolute bioavailability of darolutamide withoral administration of a single 300-mg dose without food is approximately 30%.[4] 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.[4] 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).[4] 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.[4] Following a single 600-mg dose of darolutamide, peak levels of darolutamide occur after approximately 4 hours.[4]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.[4] At steady state with 600 mg/day darolutamide, mean levels of darolutamide are 4.79 μg/mL andarea-under-the-curve levels of darolutamide over time 0 to 12 hours (AUC0–12) are 52.82 h•μg/mL.[4] Total exposure to ketodarolutamide is approximately 1.7-fold that of darolutamide.[4]
Thevolume of distribution of darolutamide withintravenous administration is 119 L.[4] Theplasma protein binding of darolutamide is 92%, with 8% circulating freely, and of ketodarolutamide is 99.8%, with 0.2% circulating unbound.[4] As such, free levels of darolutamide in the circulation are about 40-fold higher than those of ketodarolutamide.[4] Both darolutamide and ketodarolutamide are bound mainly toalbumin.[4] Darolutamide and ketodarolutamide has been claimed to negligibly cross theblood–brain barrier both in mice and humans.[10] However, a subsequent study of darolutamide monotherapy in men with prostate cancer found that it increased testosterone levels, a centrally mediated antiandrogenic action.[23] Darolutamide is a knownsubstrate ofP-glycoprotein and thebreast cancer resistance protein (BCRP).[33][34][35] P-Glycoprotein is known to play a major role in excluding drugs from thebrain due to efflux back across theblood–brain barrier.[36][37]
Darolutamide is primarilymetabolized into ketodarolutamide viadehydrogenation byCYP3A4 in theliver.[4] The medication is alsoconjugated viaglucuronidation byUGT1A9 andUGT1A1.[4] Theelimination half-life of darolutamide and ketodarolutamide has been reported to be approximately 20 hours.[4] 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.[7] The elimination half-life of darolutamide is far shorter than that ofenzalutamide (e.g., 1.6 hours vs. 18.3 hours in mice).[10] Theclearance of darolutamide following intravenous administration is 116 mL/min.[4]
After a single oral dose of darolutamide, more than 95% of the dose isexcreted inurine andfeces within one week following administration.[4] 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 infeces.[4]
No clinically significant differences in thepharmacokinetics of darolutamide have been observed in men with nmCRPC on the basis of age (48 to 95 years), race (white, Asian, black), mild-to-moderaterenal impairment, or mildhepatic impairment.[4] In non-nmCRPC individuals with severe renal impairment not ondialysis, exposure to darolutamide was increased by about 2.5-fold relative to healthy people.[4] In non-nmCRPC individuals with moderate hepatic impairment, darolutamide exposure was increased by about 1.9-fold compared to healthy controls.[4] The pharmacokinetics of darolutamide have not been assessed in end-stagekidney disease or severe hepatic impairment.[4]
Darolutamide is anonsteroidalcompound and is structurally distinct from other marketed NSAAs, including enzalutamide and apalutamide.[10]
Darolutamide was developed byOrion Corporation andBayer HealthCare.[38] Orion Corporation applied for apatent on darolutamide in October 2010, and this patent was published in May 2011.[13] Darolutamide enteredphase Iclinical trials in April 2011,[39] with the results of the first clinical study of darolutamide initially published in 2012.[40] The U.S.Food and Drug Administration (FDA) approved darolutamide in July 2019, under the agency'spriority review designation.[8]
Approval was based on ARAMIS,[41] a multicenter, double-blind, placebo-controlled clinical trial in 1,509 patients with non-metastatic castration resistant prostate cancer. Patients were randomized (2:1) to receive either 600 mg darolutamide orally twice daily (n=955) or matching placebo (n=554). All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm.[8][14]
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).[41]
Darolutamide is thegeneric name of the medication and itsINNTooltip International Nonproprietary Name andUSANTooltip United States Adopted Name.[42] It is also known by its developmental code names ODM-201 and BAY-1841788.[38]
Darolutamide is marketed under the brand name Nubeqa.[4][8][5]
Darolutamide is available in the United States, Canada and the European Union.[4][8][5][43]
Darolutamide monotherapy is being studied in comparison toandrogen deprivation therapy withGnRH agonist orantagonist monotherapy in men with treatment-naive prostate cancer.[22][44] As of 2018, it is entering aphase IIclinical trial for this indication.[22][44] In 2020, completion of this study had been expected in 2021 or 2022.[45]
Darolutamide is being studied for the treatment ofbreast cancer in women.[38] As of November 2019, it is inphase IIclinical trials for this indication.[38]
This article incorporates text from this source, which is in thepublic domain:"FDA approves darolutamide for non-metastatic castration-resistant prostate cancer".U.S.Food and Drug Administration (FDA) (Press release). 31 July 2019.Archived from the original on 23 November 2019. Retrieved22 November 2019. This article incorporates text from this source, which is in thepublic domain:"Drug Trials Snapshots: Nubeqa".U.S.Food and Drug Administration (FDA). 9 August 2019. Archived fromthe original on 23 November 2019. Retrieved22 November 2019.In the darolutamide arm, the median (range) value of testosterone was 413 (209.0–1183.0) ng/dl at baseline and increased by 43.3% (5.7–144.0%) to a median (range) of 595.0 (260.0–1500.0) ng/dl at week 24. In the GnRH arm, the median (range) value of testosterone was 333.0 (210.9–844.0) ng/dl at baseline and decreased by –96.0% (–99.6% to –80.8%) to a median (range) of 12.9 (1.2–52.8) ng/dl at week 24. Figure 3 shows the absolute change in testosterone values from baseline over time for the two arms. [...] The median testosterone level increased by 43.4% at 24 wk. In comparison, testosterone increased by 114.3% at week 25 with enzalutamide monotherapy in the phase II trial of enzalutamide. This difference and its potential consequences will need to be studied further.
