Darolutamide

Source: Wikipedia, the free encyclopedia.

Darolutamide
Clinical data
Trade namesNubeqa
Other namesDarramamide, ODM-201, BAY-1841788
AHFS/Drugs.comMonograph
MedlinePlusa619045
License data
Pregnancy
category
  • AU: X (High risk)
Routes of
administration		By mouth
Drug classNonsteroidal antiandrogen
ATC code
Legal status
Legal status
UGT1A1)[4]
MetabolitesKetodarolutamide[4][7]
Elimination half-life16–20 hours[4][7]
ExcretionUrine: 63.4%[4]
Feces: 32.4%[4]
Identifiers
  • N-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide
JSmol)
  • C[C@@H](Cn1ccc(n1)c2ccc(c(c2)Cl)C#N)NC(=O)c3cc([nH]n3)C(C)O
  • InChI=1S/C19H19ClN6O2/c1-11(22-19(28)18-8-17(12(2)27)23-24-18)10-26-6-5-16(25-26)13-3-4-14(9-21)15(20)7-13/h3-8,11-12,27H,10H2,1-2H3,(H,22,28)(H,23,24)/t11-,12?/m0/s1
  • Key:BLIJXOOIHRSQRB-PXYINDEMSA-N
  (verify)

Darolutamide, sold under the brand name Nubeqa, is an

medical castration.[4] The medication is taken by mouth twice per day with food.[4]

asthenia, pain in the arms and legs, and rash.[4] Darolutamide is a nonsteroidal antiandrogen (NSAA), and acts as a selective antagonist of the androgen 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,

Medical uses

Darolutamide is approved for use concurrently with a

hepatic 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 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.[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]

Available forms

Darolutamide is provided in the form of 300 mg oral film-coated tablets.[4]

Contraindications

Darolutamide has no

teratogenic effects in male fetuses due to its antiandrogenic effects and hence should not be used by women who are pregnant.[4]

Side effects

The most common

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).[4] In the clinical studies, 88% of patients treated with darolutamide were age 65 years or older.[4]

No

breast tenderness and gynecomastia.[21]

Overdose

Darolutamide has been studied at a dosage of up to 1,800 mg/day in clinical trials.

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.[4] There is no specific antidote 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]

Interactions

Combined

substrates for BCRP protein, such as rosuvastatin, by approximately 5-fold.[4]

Pharmacology

Pharmacodynamics

Darolutamide is a second- or third-generation

IC50Tooltip half-maximal inhibitory concentration) of the AR is 26 nM.[10] The major metabolite 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 the progesterone 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 in

prostate 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 increase testosterone 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% with enzalutamide monotherapy[23] and high-dose bicalutamide monotherapy increases testosterone levels by about 59 to 97% in men with prostate cancer.[24][25][26][27] A phase 2 clinical 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 and

IC50Tooltip half-maximal inhibitory concentration = 26 nM relative to 219 nM for enzalutamide and 200 nM for apalutamide).[10]

Darolutamide inhibits the

OATP2B1, NTCP) at therapeutic concentrations.[4][32]

Pharmacokinetics

Absorption

The

area-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]

Distribution

The

breast cancer resistance protein (BCRP).[33][34][35] P-Glycoprotein is known to play a major role in excluding drugs from the brain due to efflux back across the blood–brain barrier.[36][37]

Metabolism

Darolutamide is primarily

elimination 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 of enzalutamide (e.g., 1.6 hours vs. 18.3 hours in mice).[10] The clearance of darolutamide following intravenous administration is 116 mL/min.[4]

Excretion

After a single oral dose of darolutamide, more than 95% of the dose is excreted in urine and feces 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 in feces.[4]

Variability

No clinically significant differences in the

hepatic impairment.[4] In non-nmCRPC individuals with severe renal impairment not on dialysis, 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-stage kidney disease or severe hepatic impairment.[4]

Chemistry

Darolutamide is a nonsteroidal compound and is structurally distinct from other marketed NSAAs, including enzalutamide and apalutamide.[10]

History

Darolutamide was developed by

priority 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]

Society and culture

Generic names

Darolutamide is the

INNTooltip International Nonproprietary Name and USANTooltip United States Adopted Name.[42] It is also known by its developmental code names ODM-201 and BAY-1841788.[38]

Brand names

Darolutamide is marketed under the brand name Nubeqa.[4][8][5]

Availability

Darolutamide is available in the United States and the European Union.[4][8][5][43]

Research

Darolutamide monotherapy is being studied in comparison to

antagonist monotherapy in men with treatment-naive prostate cancer.[22][44] As of 2018, it is entering a phase II clinical 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 of breast cancer in women.[38] As of November 2019, it is in phase II clinical trials for this indication.[38]

References

  1. ^ "Nubeqa Australian prescription medicine decision summary". Therapeutic Goods Administration (TGA). 4 March 2020. Retrieved 16 August 2020.
  2. ^ "Product Monograph" (PDF). hres.ca. Retrieved 25 October 2023.
  3. ^ "Summary Basis of Decision (SBD) for Nubeqa". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  4. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl "Nubeqa- darolutamide tablet, film coated". DailyMed. 31 July 2019. Retrieved 22 November 2019.
  5. ^ a b c d e "Nubeqa EPAR". European Medicines Agency (EMA). 29 January 2020. Retrieved 16 August 2020.
  6. ^ "Nubeqa Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  7. ^
    PMID 24974051
    .
  8. ^ a b c d e f Public Domain This article incorporates text from this source, which is in the public 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. Retrieved 22 November 2019.
  9. ^
    PMID 26313416
    .
  10. ^
    PMID 26137992
    .
  11. ^
    S2CID 20624649
    .
  12. ^
    S2CID 19162538
    .
  13. ^ a b "Androgen receptor modulating compounds".
  14. ^ a b Public Domain This article incorporates text from this source, which is in the public domain: "Drug Trials Snapshots: Nubeqa". U.S. Food and Drug Administration (FDA). 9 August 2019. Archived from the original on 23 November 2019. Retrieved 22 November 2019.
  15. ^ "AusPAR: Darolutamide". Therapeutic Goods Administration (TGA). 3 August 2020. Retrieved 22 September 2020.
  16. S2CID 215748376
    .
  17. PMID 32924096
    .
  18. PMID 33818140
    .
  19. ^
    PMID 34054128
    .
  20. PMID 24658665
    .
  21. S2CID 8639102
    .
  22. ^
    PMID 30197098
    .
  23. ^
    PMID 38272747
    . 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.
  24. ISBN 978-1-4557-5972-9
    .
  25. PMID 9471040
    .
  26. ISBN 978-0-08-055347-4. Archived
    from the original on 11 June 2016.
  27. S2CID 25200595
    .
  28. ISSN 0732-183X
    .
  29. ISSN 0732-183X
    .
  30. ^ Clinical trial number NCT05526248 for "A Study Called ARAMON to Learn to What Extent Does Study Treatment With Darolutamide Affects Testosterone Levels in Men With Prostate Cancer That Had Not Been Treated With Hormonal Therapy Compared to Treatment With Enzalutamide (ARAMON)" at ClinicalTrials.gov
  31. PMID 24857068
    .
  32. S2CID 87513637
    .
  33. S2CID 232159762
    .
  34. PMID 31571146
    .
  35. PMID 31571095
    .
  36. PMID 10837715
    .
  37. PMID 10706193
    .
  38. ^ a b c d "Darolutamide - Bayer HealthCare/Orion". Adis Insight. Springer Nature Switzerland AG.
  39. ISBN 978-1-936287-46-8
    .
  40. PMID 23355790
    .
  41. ^ a b Clinical trial number NCT02200614 for "Efficacy and Safety Study of Darolutamide (ODM-201) in Men With High-risk Nonmetastatic Castration-resistant Prostate Cancer (ARAMIS)" at ClinicalTrials.gov
  42. ^ "Darolutamide". ChemIDplus. U.S. National Library of Medicine.
  43. ^ Chustecka Z (31 January 2020). "Darolutamide (Nubeqa) Gets OK in Europe for Prostate Cancer". MedScape.
  44. ^
    ISSN 0732-183X
    .
  45. ^ "ODM-201 vs Androgen Deprivation Therapy in Hormone naïve Prostate Cancer". ClinicalTrials.gov. 23 November 2016. Retrieved 16 August 2020.

External links

  • "Darolutamide". Drug Information Portal. U.S. National Library of Medicine.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Darolutamide&oldid=1216844428"