Based on its mechanism of action, NUBEQA can cause fetal harm and loss of pregnancy when administered to a pregnant female [see Clinical Pharmacology (12.1)]. [33] The U.S. Food and Drug Administration (FDA) approved darolutamide in July 2019, under the agency's priority review designation. Go to: 2 Generic Name Darolutamide DrugBank Accession Number DB12941 Background Darolutamide is a nonsteroidal androgen receptor antagonist for the treatment of castrate-resistant, non-metastatic prostate cancer (nmCRPC). 8600 Rockville Pike The AUC 0-12h is approximately 52.82 hg/mL.6, The absolute bioavailability of darolutamide is approximately 30% after fasting and taking a single 300 mg dose. 2019;9:801. Darolutamide also showed improvement in secondary and exploratory endpoints including progression-free survival, prolonged time to PSA progression, PSA response and time to initiating additional antineoplastic therapy, time to pain progression, and time to cytotoxic chemotherapy, but overall survival is not yet reached in either the darolutamide or the placebo arm. [, Fizazi K, Albiges L, Loriot Y, Massard C: ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer. [4] At steady state with 600mg/day darolutamide, mean levels of darolutamide are 4.79g/mL and area-under-the-curve levels of darolutamide over time 0 to 12hours (AUC012) are 52.82hg/mL. Eur Urol. [31] As of November 2019, it is in phase II clinical trials for this indication.[31]. Darolutamide AUC and peak plasma concentration increased by 1.7- and 1.4-fold, respectively. 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. [19] Also, darolutamide showed significantly lower rate of grade 3-5 adverse events (AE) compared to both enzalutamide and apalutamide. Androgen receptor-targeted treatments of prostate cancer: 35 years of progress with antiandrogens, Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group, Clinical development of darolutamide: a novel androgen receptor antagonist for the treatment of prostate cancer. 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. N Engl J Med. Labrie F, Luthy I, Veilleux R, Simard J, Blanger A, Dupont A. Would you like email updates of new search results? Various authors attribute the low incidence of CNS-related AEs to darolutamides minimal penetration of the bloodbrain barrier (BBB). Moilanen AM, Riikonen R, Oksala R, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. 2018;378:246574. There, it acts as a transcription factor for androgen-responsive genes such as PSA and others.15. Additionally, the Phase 1 ARAFOR trial of darolutamide 1200 mg/day in chemotherapy-nave and CYP17-inhibitor-nave mCRPC showed an 83% PSA response at week 12.39. Search terms such as darolutamide, androgen deprivation therapy/ADT, antiandrogens, and nonmetastatic castrate resistant prostate cancer/M0CRPC/nmCRPC yielded more than 100 publications, from which the most relevant were selected for inclusion in this review. Alectinib may decrease the excretion rate of Darolutamide which could result in a higher serum level. As ADT in itself raises cardiovascular risk, the cardiovascular safety of third-generation antiandrogens as a category warrants continued scrutiny. ED is often a symptom of another health problem or health-related factor. and transmitted securely. This condition occurs in the majority of patients with advanced prostate cancer who have been treated with androgen receptor antagonists.4 Though prior treatment for prostate cancer has been successful for these patients, the cancer eventually progresses to become resistant to existing therapies. It is used when treatment has stopped responding to other types of hormonal therapy but has not yet spread to other parts of the body. [11][12] It acts as a selective competitive silent antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). With a limited number of darolutamide studies presently available, efficacy and safety data are based largely on clinical trials. It inhibits cancer cell growth and markedly lowers prostate specific antigen (PSA) levels through potent androgen receptor antagonism.3,4,6, The actions of androgens on androgen receptors (AR) potentiate the growth and survival of prostate cancer cells.5 Darolutamide competitively inhibits androgens from binding to their receptors, inhibiting AR nuclear translocation, as well as AR-mediated transcription. Eur Urol. docetaxel shows a distinct mechanism of action that might prevent the lineage plasticity induced by AR inhibition and might represent a potential opportunity once new biomarkers are able to identify patients . D - Adverse Effects [4] It shows no inhibition or induction of cytochrome P450 enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4) at clinically relevant concentrations. Mortality results from a randomized prostate-cancer screening trial, Use of cyproterone acetate in prostate cancer, Prostate Cancer Trialists Collaborative Group. In the dose-escalation portion of ARADES, all six darolutamide doses tested (between 200 and 1800 mg/day) showed antitumor activity at week 12, and 81% of patients achieved 50% serum PSA reductions. Ongoing research will determine darolutamides potential role in additional disease states such as localized and castration-sensitive PCa. Darolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. [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. Additionally, patients taking darolutamide appear to experience comparatively few central nervous system-related adverse events (AEs) such as fatigue and falls, and no increases in seizures have been reported in the drugs clinical or preclinical development. official website and that any information you provide is encrypted For a better understanding of the regulatory mechanisms underlying the transcriptional blockade of androgen action by darolutamide, we analyzed the AR cistrome in VCaP and LAPC4 cells treated for 22 h with the 2 m darolutamide concentration by performing ChIP-seq with an AR-specific antibody. Adapted with permission. [31] Orion Corporation applied for a patent on darolutamide in October 2010, and this patent was published in May 2011. The latter designation applies when ADT leads to castration resistance, but conventional imaging detects no metastases except to lymph nodes below the aortic bifurcation.12,13 Some cases originally diagnosed as nonmetastatic using conventional imaging may be reclassified as metastatic when examined with more sensitive staging techniques such as 68 Gallium prostate-specific membrane antigen (PSMA)-11 positron emission tomography (PET)-computed tomography (CT).14. [10] The major metabolite of darolutamide, ketodarolutamide, has similar antiandrogenic activity relative to darolutamide (Ki = 8nM; IC50 = 38nM). [4] There were no dose-limiting toxicities seen at this dosage. Introduction: Androgen deprivation therapy (ADT) is a mainstay initial treatment for advanced hormone-sensitive prostate cancer (HSPC), but disease progression to castration-resistant prostate canc. All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a previous bilateral orchiectomy. The .gov means its official. Cases in the management of nonmetastatic castration-resistant prostate cancer: darolutamide as the first androgen receptor inhibitor in a fit, older man. A multicenter prospective clinical trial of, Second-generation antiandrogens: from discovery to standard of care in castration resistant prostate cancer, The current landscape of treatments in nonmetastatic castration-resistant prostate cancer. [31], Darolutamide is marketed under the brand name Nubeqa. Approval of the new androgen receptor axis-targeted (ARAT) agents (abiraterone acetate, enzalutamide, apalutamide, and darolutamide) has altered the course of advanced PCa. -, Fizazi K, Massard C, Bono P, Jones R, Kataja V, et al. [4], Side effects of darolutamide added to castration may include fatigue, asthenia, pain in the arms and legs, and rash. Alghazo O, Thangasamy I, Sathianathen N, Murphy DG. Various guidelines recommend androgen deprivation therapy (ADT) as a cornerstone of the standard of careboth as an adjuvant to radical therapy for localized disease, and for recurrence/prostate-specific antigen (PSA) relapse after primary treatment.35 Chemical ADT seeks to decrease testosterone production by the testes to levels produced by bilateral orchiectomy.6 In both metastatic and nonmetastatic CRPC, guidelines strongly recommend continuing ADT to maintain testosterone below 20 ng/dL.4,5,7, Although most prostate cancers initially respond to ADT, nearly all eventually progress to CRPC.4,8,9 A CRPC diagnosis requires two to three rising serum PSA concentrations from nadir and/or evidence of radiographic progression despite castrate levels of serum testosterone.10 The American Urological Association (AUA) guidelines7 define PSA-only recurrence as the Prostate Cancer Clinical Trials Working Group 2 did: PSA 2 ng/mL higher than nadir that must also be at least 25% over the nadir, confirmed by a second PSA test at least three weeks later, in the presence of castrate testosterone levels and no radiographic evidence of metastases.11, CRPC presents as either metastatic (mCRPC) or nonmetastatic (M0CRPC/nmCRPC). With highly similar efficacy profiles, these drugs safety, cost, and ease of accessibility for patients may become increasingly important determinants of adoption as physicians attempt to match patients with the optimal therapies for their clinical situations, preferences, and lifestyles. Ongoing Trials in Additional PCa Settings, Along with disease progression, treatment-associated AEs can decrease health-related QOL.42 ARAMIS authors Fizazi et al observe that because patients with nmCRPC may already be suffering adverse effects from their ongoing ADT, they can ill afford additional toxic effects associated with their choice of M0CRPC therapy.1, With virtually identical Phase 3 efficacy levels for apalutamide, enzalutamide, and darolutamide, these drugs safety and QOL profiles will be important to guiding their use, particularly as most men with M0CRPC are asymptomatic when they begin treatment.12,16, Compared to earlier-generation AAs, the main new side effect associated with enzalutamide and apalutamide is increased risk of seizure, due to penetration of these compounds through the BBB and subsequent inhibition of the y-aminobutyric acid receptor (GABAA).1,15 Nevertheless, rates of seizures in Phase 3 trials of enzalutamide and apalutamide were low and did not reach statistical significance. -. Priority was given to clinical and preclinical trials of darolutamide reporting efficacy and safety outcomes, as well as to reviews that discussed third generation ARIs as a category. Metabolism Darolutamide is metabolized primarily via oxidation by CYP3A4, and also through glucoronidation by UGT1A9 and UGT1A1. While flutamide, nilutamide and bicalutamide offered improvements over steroidal antiandrogens, all three earlier-generation nonsteroidal antiandrogens have been associated with the risk of both liver and gastrointestinal toxicities.10 Moreover, their relatively low affinity for the AR leaves an estimated 510% of DHT free to stimulate the AR and continued PCa growth.26 Additionally, resistance to these agents develops rather quickly.27 In the context of excess AR, which aggressive PCa commonly produces, first- and second-generation nonsteroidal AR antagonists undergo a mechanistic switch to agonists, promoting tumor progression in preclinical models.28 Flutamide, nilutamide, and bicalutamide furthermore are almost completely susceptible to AR mutations,29 and with bicalutamide in particular, discontinuation leads to androgen withdrawal syndrome, in which tumors regress due to AR mutations and bicalutamide agonist activity.29. OFarrell S, Garmo H, Holmberg L, Adolfsson J, Stattin P, Van Hemelrijck M. Risk and timing of cardiovascular disease after androgen-deprivation therapy in men with prostate cancer. Potential role in additional disease states such as localized and castration-sensitive PCa Massard C, Bono,! Screening trial, Use of cyproterone acetate in prostate cancer: darolutamide as the androgen... V, et al N, Murphy DG: darolutamide as the first androgen receptor in..., prostate cancer Luthy I, Veilleux R, et al Oksala R, J! Androgen-Responsive genes such as PSA and others.15 is a potent androgen-receptor inhibitor that been... Massard C, Bono P, Jones R, et al ) analog concurrently or had a previous orchiectomy! Simard J, Blanger a, Dupont a and safety data are based largely on clinical trials for indication. Based largely on clinical trials for this indication. 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