Parent: 15.8 hours|
Metabolite: 10.0 hours
|Chemical and physical data|
|Molar mass||398.84616 g/mol|
|3D model (Jmol)||Interactive image|
|(what is this?)|
Darolutamide (INN) (developmental code names ODM-201, BAY-1841788) is a non-steroidal antiandrogen (NSAA) – specifically, a selective high affinity silent antagonist of the androgen receptor (AR) – that is under development by Orion and Bayer HealthCare for the treatment of advanced, castration-resistant prostate cancer (CRPC).
Relative to enzalutamide (MDV3100 or Xtandi) and apalutamide (ARN-509), two other recent NSAAs, darolutamide shows some advantages. Darolutamide appears to negligibly cross the blood-brain-barrier. This is beneficial due to the reduced risk of seizures and other central side effects from off-target GABAA receptor inhibition that tends to occur in NSAAs that are structurally similar to enzalutamide. Moreover, in accordance with its lack of central penetration, darolutamide does not seem to increase testosterone levels in mice or humans, unlike other NSAAs. Another advantage is that 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. Finally, darolutamide shows higher affinity and inhibitory efficacy at the AR (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) and greater potency/efficaciousness in non-clinical models of prostate cancer.
ORM-15341 is the main active metabolite of darolutamide. It, similarly, is a full antagonist of the AR, with an affinity (Ki) of 8 nM and an IC50 of 38 nM.
The mean terminal half-lives of darolutamide and its active metabolite ORM-15341 at steady-state are 15.8 hours and 10.0 hours, respectively. The half-lives are independent of dosage with 200–1800 mg/day dosages of darolutamide. The half-life of darolutamide is far shorter than that of enzalutamide (1.6 hours and 18.3 hours in mice, respectively), necessitating higher dosages and more frequent administration in the case of darolutamide.
Darolutamide has been studied in phase I and phase II clinical trials and has thus far been found to be effective and well-tolerated, with the most commonly reported side effects including fatigue, nausea, and diarrhea. No seizures have been observed. As of June 2016, darolutamide is in phase III trials for CRPC.
- Fizazi, Karim; Massard, Christophe; Bono, Petri; Jones, Robert; Kataja, Vesa; James, Nicholas; Garcia, Jorge A; Protheroe, Andrew; Tammela, Teuvo L; Elliott, Tony; Mattila, Leena; Aspegren, John; Vuorela, Annamari; Langmuir, Peter; Mustonen, Mika (2014). "Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial". The Lancet Oncology. 15 (9): 975–985. doi:10.1016/S1470-2045(14)70240-2. ISSN 1470-2045.
- "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.". Sci Rep. 5: 12007. 2015. doi:10.1038/srep12007. PMC 4490394. PMID 26137992.
- Fizazi K, Albiges L, Loriot Y, Massard C (2015). "ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer". Expert Rev Anticancer Ther. 15 (9): 1007–17. doi:10.1586/14737140.2015.1081566. PMID 26313416.
- Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ (2015). "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies". Sci Rep. 5: 12007. doi:10.1038/srep12007. PMC 4490394. PMID 26137992.
- Moilanen, Anu-Maarit; Riikonen, Reetta; Oksala, Riikka; Ravanti, Laura; Aho, Eija; Wohlfahrt, Gerd; Nykänen, Pirjo S.; Törmäkangas, Olli P.; Palvimo, Jorma J.; Kallio, Pekka J. (2015). "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies". Scientific Reports. 5: 12007. doi:10.1038/srep12007. ISSN 2045-2322.
- "ODM-201 is safe and active in metastatic castration-resistant prostate cancer". Cancer Discov. 4 (9): OF10. 2014. doi:10.1158/2159-8290.CD-RW2014-150. PMID 25185192.
- Pinto Á (2014). "Beyond abiraterone: new hormonal therapies for metastatic castration-resistant prostate cancer". Cancer Biol. Ther. 15 (2): 149–55. doi:10.4161/cbt.26724. PMC 3928129. PMID 24100689.
- Fizazi K, Massard C, Bono P, Jones R, Kataja V, James N, Garcia JA, Protheroe A, Tammela TL, Elliott T, Mattila L, Aspegren J, Vuorela A, Langmuir P, Mustonen M (2014). "Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial". Lancet Oncol. 15 (9): 975–85. doi:10.1016/S1470-2045(14)70240-2. PMID 24974051.
- Agarwal N, Di Lorenzo G, Sonpavde G, Bellmunt J (2014). "New agents for prostate cancer". Ann. Oncol. 25 (9): 1700–9. doi:10.1093/annonc/mdu038. PMID 24658665.