Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level, Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non-castrate prostate cancer: impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. [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] and in Australia in July 2020. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. [4], Darolutamide has no contraindications in men. Using resources including PubMed, meeting abstracts, guidelines of care, and www.clinicaltrials.gov, the authors reviewed available medical literature through February 2020 for relevant Phase 3 trials, comprehensive reviews, and treatment guidelines. 2016;69:83440. Darolutamide is an androgen receptor antagonist used for castration-resistant, non-metastatic prostate cancer and metastatic hormone-sensitive prostate cancer. Metastatic Hormone Sensitive Prostate Cancer, Non-Metastatic Castration-Resistant Prostate Cancer, L02B HORMONE ANTAGONISTS AND RELATED AGENTS, L ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS, Antineoplastic and Immunomodulating Agents, Metastatic Hormone-Sensitive Prostate Cancer (mHSPC), Predicted MS/MS Spectrum - 10V, Positive (Annotated), Predicted MS/MS Spectrum - 20V, Positive (Annotated), Predicted MS/MS Spectrum - 40V, Positive (Annotated), Predicted MS/MS Spectrum - 10V, Negative (Annotated), Predicted MS/MS Spectrum - 20V, Negative (Annotated), Predicted MS/MS Spectrum - 40V, Negative (Annotated), ATP-binding cassette sub-family G member 2, Solute carrier organic anion transporter family member 1B1, Solute carrier organic anion transporter family member 1B3. Until 2018, patients in this group had no FDA-approved treatment options. This information should not be interpreted without the help of a healthcare provider. [34], Darolutamide is the generic name of the medication and its INN and USAN. Darolutamide induced the expression of PSMA in androgen-sensitive VCaP and LNCaP cells in vitro, and the efficacy of darolutamide in combination with PSMA-TTC was synergistic in these cells. [4] In non-nmCRPC individuals with moderate hepatic impairment, darolutamide exposure was increased by about 1.9-fold compared to healthy controls. 33 Darolutamide's proposed mechanism of action is shown in Figure 1. The authors acknowledge the contributions of medical writer John Jesitus in helping to prepare this manuscript. Unable to load your collection due to an error, Unable to load your delegates due to an error. Shore N, Zurth C, Fricke R, Gieschen H, Graudenz K, Koskinen M, Ploeger B, Moss J, Prien O, Borghesi G, Petrenciuc O, Tammela TL, Kuss I, Verholen F, Smith MR, Fizazi K. Target Oncol. When androgens bind to the AR, these chaperones are released, allowing the AR to homodimerize and translocate to the nucleus. 2019 Mar 28;380(13):1235-1246. doi: 10.1056/NEJMoa1815671. Keto-darolutamide (active metabolite) has similar in vitro activity to darolutamide. Among third-generation ARIs, darolutamide is unique in that it incorporates two pharmacologically active diastereomers and has demonstrated resistance to all known androgen receptor (AR) mutations. This site needs JavaScript to work properly. National Library of Medicine Based on its mechanism of action, darolutamide may cause foetal harm. 2018 Oct;16(5):332-340. doi: 10.1016/j.clgc.2018.07.017. Learn about side effects, cost, uses, dosage, and more. [4][8][5][36], Darolutamide monotherapy is being studied in comparison to androgen deprivation therapy with GnRH agonist or antagonist monotherapy in men with treatment-naive prostate cancer. Therapies targeted to androgen receptor signaling axis in prostate cancer: progress, challenges, and hope, Stimulatory effect of synthetic progestins currently used for the treatment of prostate cancer on growth of the androgen-sensitive Shionogi tumor in mice. Except for fatigue, AEs that occurred or worsened during treatment and had a frequency of 5% impacted less than 10% of patients in either group. [4] When used as a monotherapy (i.e., without surgical or medical castration) in men, NSAAs are known to produce feminizing breast changes including breast tenderness and gynecomastia. Target Oncol. In patients with healthy kidney and liver function, a high dose of darolutamide will likely not lead to systemic toxicity.6 If a high dose (higher than recommended on labeling) is ingested in a patient with renal or hepatic impairment, and toxic symptoms occur, pause treatment with darolutamide and offer supportive treatment until symptoms resolve.6, Pan T, Xia C, Jiang H, Zhang Z, Zhu X, Yang Y. Go to: 2 [4] The medication is also conjugated via glucuronidation by UGT1A9 and UGT1A1. Labrie F, Luthy I, Veilleux R, Simard J, Blanger A, Dupont A. This is called non-metastatic castrate-resistant prostate cancer. Darolutamide: A Review in Non-Metastatic Castration-Resistant Prostate Cancer. The site is secure. [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. The serum concentration of Afatinib can be increased when it is combined with Darolutamide. [10] The clearance of darolutamide following intravenous administration is 116mL/min. 2019 Dec;44(6):747-759. doi: 10.1007/s13318-019-00577-5. Darolutamide (NUBEQA ) is a hormonal therapy drug used to treat prostate cancer. 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. Safety and antitumour activity of ODM-201 (BAY-1841788) in castration-resistant, CYP17 Inhibitor-naive prostate cancer: results from extended follow-up of the ARADES trial. Accessibility A study of two ODM-201 formulations with a safety and tolerability extension phase in patients with metastatic chemotherapy-naive castration-resistant prostate cancer (CRPC). Erectile dysfunction (ED) is often a symptom . Proposed mechanisms of commonly used antiandrogens. Part II: treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer, The role of gonadotropin-releasing hormone in cancer cell proliferation and metastasis. Called ODM-201 during development, darolutamide is a synthetic compound discovered by screening campaign that used an AR transactivation assay in AR-HEK293 cells. Massard C, Tammela TLJ, Vjaters E, et al. Current clinical recommendation in M0CRPC is that darolutamide be combined with ADT or bilateral orchiectomy.58 This strategy dovetails with the trend toward combination therapies designed to attack PCa via multiple mechanisms to overcome resistance15 and supports earlier use of potent AR signaling inhibitors in patients with M0CRPC.1,59 Additional settings in which darolutamide is being explored include localized and castration-sensitive PCa (Table 6), in combined and head-to-head regimens. In addition to androgen binding inhibition, darolutamide also inhibits androgen receptor translocation and androgen receptor-mediated transcription. Ongoing research will further characterize its place among treatments for nonmetastatic CRPC, and perhaps other PCa types. [4] Both darolutamide and ketodarolutamide are bound mainly to albumin. Lancet Oncol. [4] 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. Unauthorized use of these marks is strictly prohibited. McCarthy M, Francis R, Tang C, Watts J, Campbell A. The highest dose clinically documented was a twice daily dose of 900 mg, totalling 1800 mg. Dose-limiting toxicities have not been observed with this drug. Eur Urol. . Patients were randomized (2:1) to receive either 600mg darolutamide orally twice daily (n=955) or matching placebo (n=554). This herb induces CYP3A and P glycoprotein and may reduce the serum concentration of darolutamide. The .gov means its official. 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. A major metabolite, ketodarolutamide, exhibited similar in vitro activity to darolutamide. Clin Genitourin Cancer. The Phase 2 portion included 12 patients from Phase 1 and an additional 110 who were randomized to darolutamide 200, 400, or 1400 mg/day. Darolutamide offers a unique molecular structure, incorporating a 1:1 mixture of two pharmacologically active diastereomers[S,R]-darolutamide and [S,S]-darolutamidewhich interconvert through the active major metabolite keto-darolutamide.33,34 In preclinical development, darolutamide and keto-darolutamide inhibited testosterone-induced AR translocation to the nucleus.33 Compared to enzalutamide and apalutamide, darolutamide and keto-darolutamide also demonstrated tighter AR bonding, stronger suppression of androgen-induced cell growth in vertebral metastatic cells (VCaP), and imperviousness to all known AR mutations shown to enable resistance to first- and second-generation ADTs.33 Additionally, oral darolutamide (50 mg/kg) once or twice daily provided antitumor activity in VCaP tumor-bearing mice. Target Oncol. Thorpe SC, Azmatullah S, Fellows GJ, Gingell JC, OBoyle PJ. [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. Incidence of other AEs of interest, including hypertension, cognitive disorders, dizziness, and rash, varied only slightly between study arms, and the differences decreased or disappeared after adjustment for treatment duration or observation period. Nubeqa (darolutamide) is a prescription tablet used to treat a type of prostate cancer. Description Clinical Pharmacology Nonclinical Toxicology Clinical Studies How Supplied/Storage and Handling Patient Counseling Information Indications and Usage for Nubeqa Nubeqa is indicated for the treatment of adult patients with: non-metastatic castration resistant prostate cancer (nmCRPC) Potential obstacles for darolutamide include the possibility that, as the third drug approved for M0CRPC, it may have difficulty gaining market share.41 On a more specific note, the ARASENS trial in combination with ADT and docetaxel has not yet reported results. 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. N Engl J Med. Disclaimer. The serum concentration of Abemaciclib can be increased when it is combined with Darolutamide. Monitor more frequently for darolutamide toxicity; modify darolutamide dosage as needed . Excipient with known effect Each film-coated tablet contains 186 mg of lactose monohydrate (see section 4.4). Table 4 shows respective rates of fatigue, falls, fractures, rashes, and other AEs commonly associated with third-generation antiandrogens vs placebo in these drugs Phase 3 trials. [4], The most common side effects 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). 2019 Oct;76(4):536-537. doi: 10.1016/j.eururo.2019.04.028. 12.1 Mechanism of Action . Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Eur J Drug Metab Pharmacokinet. Prespecified Secondary and Exploratory Efficacy Endpoints (ITT Population) Darolutamide (n = 955) Placebo (n = 554), Note: From Fizazi K, Shore N, Tammela TL, et al. Conversely, darolutamide brain concentrations were near the lower limit of quantification, approximately 26 and 46 times lower than levels of apalutamide and enzalutamide, respectively.36. Massard C, Penttinen HM, Vjaters E, et al. In ARAFOR, the most common AEs were fatigue and nausea, each affecting 13% of patients. 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. As with any fairly recently approved drug, postmarketing data are expected to highlight delayed and rare AEs. 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). 8600 Rockville Pike 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). including its pharmacokinetics, mechanism of action, efficacy and . being able to get an erection sometimes, but not every time you want to have sex. 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. [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. 10, 11 It has a unique chemical structure, exists as two pharmacologically active diastereomers, (S,R)- and (S,S)-darolutamide, 12 and forms keto-darolutamide . [4], The volume of distribution of darolutamide with intravenous administration is 119L.[4] The plasma protein binding of darolutamide is 92%, with 8% circulating freely, and of ketodarolutamide is 99.8%, with 0.2% circulating unbound. [10] The medication shows higher affinity and inhibitory potency at the AR relative to enzalutamide and apalutamide in vitro (Ki = 11nM relative to 86nM for enzalutamide and 93nM for apalutamide; IC50 = 26nM relative to 219nM for enzalutamide and 200nM for apalutamide). Various authors attribute the low incidence of CNS-related AEs to darolutamides minimal penetration of the bloodbrain barrier (BBB). Darolutamide in nonmetastatic, castration-resistant prostate cancer. [13] Darolutamide entered phase I clinical trials in April 2011,[7][32] with the results of the first clinical study of darolutamide initially published in 2012. It is not known whether darolutamide or its metabolites are present in semen. While enzalutamide, apalutamide, and darolutamide block the AR, AA inhibits CYP17AI, which is involved in testosterone biosynthesis.15,50,51 AA remains the only androgen biosynthesis inhibitor approved by the FDA for PCa. Accessibility They are mainly bound to albumin.6, Darolutamide is mainly metabolized by the CYP3A4 hepatic microsomal enzyme1 in addition to UGT1A9 and UGT1A1. Build, train, & validate predictive machine-learning models with structured datasets. [4] In the event of darolutamide overdose, if there is no toxicity, treatment can be continued as normal. [4] In individuals with severe renal impairment or moderate hepatic impairment, darolutamide is used at a dosage of 300mg orally twice per day (600mg/day total) with food. [4], No seizures have been observed with darolutamide in clinical trials. [10] The major metabolite of darolutamide, ketodarolutamide, has similar antiandrogenic activity relative to darolutamide (Ki = 8nM; IC50 = 38nM). [4] Darolutamide is a nonsteroidal antiandrogen (NSAA), and acts as a selective antagonist of the androgen receptor (AR). The recommended dose of Nubeqa is 600 mg . Third-generation ARIs have risen to represent the standard of care in nonmetastatic CRPC.3,4,7 Darolumatide provides a valuable addition to the therapeutic armamentarium for several reasons. No non-clinical reproductive toxicity studies have been conducted (see section 5.3). Other side effects ranging from hot flashes to hypothyroidism also occurred at rates similar to those of the placebo arm in Phase 3. Expert Rev Anticancer Ther. This work is published and licensed by Dove Medical Press Limited. Until recently, no US Food and Drug Administration (FDA)-approved options for nonmetastatic castration-resistant prostate cancer (M0CRPC/nmCRPC) existed. [33] The U.S. Food and Drug Administration (FDA) approved darolutamide in July 2019, under the agency's priority review designation. 2015;15(9):1007-17. doi: 10.1586/14737140.2015.1081566. [4], Darolutamide is a nonsteroidal compound and is structurally distinct from other marketed NSAAs, including enzalutamide and apalutamide. The https:// ensures that you are connecting to the This year, the American Cancer Society has predicted 191,930 new PCa cases and 33,330 PCa deaths.2 Treatment options for high-risk PCa aim to prolong life and preserve QOL. government site. A prospective, randomised study to compare goserelin acetate (Zoladex) versus cyproterone acetate (Cyprostat) versus a combination of the two in the treatment of metastatic prostatic carcinoma. [, Matsubara N, Mukai H, Hosono A, Onomura M, Sasaki M, Yajima Y, Hashizume K, Yasuda M, Uemura M, Zurth C: Phase 1 study of darolutamide (ODM-201): a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer. The serum concentration of Alpelisib can be increased when it is combined with Darolutamide. If you believe you are experiencing an interaction, contact a healthcare provider immediately. ARAMIS is an international Phase III trial demonstrating the beneficial role of darolutamide, a novel anti-androgen that has been found to prolong metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer. In the Phase 1/2 ARADES trial in progressive mCRPC, darolutamide had a median time to maximum plasma concentration (Cmax) of 3.0 to 5.01 hours and a mean half-life of 15.8 hours (at steady-state) independent of dose.37 Because area under the curve (AUC) and Cmax values were approximately two times higher, and Cmax was delayed by two to three hours after a high-fat meal versus fasting,38 subsequent trials required that darolutamide be taken with food. [29][30], Darolutamide is primarily metabolized into ketodarolutamide via dehydrogenation by CYP3A4 in the liver. Darolutamide is a novel nonsteroidal androgen receptor antagonist that has unique structurally distinct properties with low blood-brain barrier penetration that was shown to improve metastasis-free survival by 22 months compared to placebo (40.4 months vs18.4 months), reducing the risk of metastasis or death by 59%. Darolutamide AUC and peak plasma concentration increased by 1.7- and 1.4-fold, respectively. Saranyutanon S, Srivastava SK, Pai S, Singh S, Singh AP. Take with food. [10] In accordance with its diminished central penetration, darolutamide does not appear to increase testosterone levels. Evaluation of Clinically Relevant Drug-Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial. 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. -, Massard C, Penttinen HM, Vjaters E, Bono P, Lietuvietis V, et al. Crawford ED, Schellhammer PF, McLeod DG, et al. 2019;380(13):12351246. (2017).Chemical Synthesis of the ODM-201's Diastereomers through an Efficient Intramolecular 1,3-Dipolar Cycloaddition.Chem Pharm Bull (Tokyo).Jun 1;65(6):582-585, Drug created at October 21, 2016 01:30 / Updated at June 08, 2023 10:19, Structured drug data for data science & ML, Clinical intelligence tool for your software, Search for drug interactions with our API, Get drug allergy and cross sensitivities info. 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 hazard ratio (HR) for metastasis or death in ARAMIS darolutamide group was 0.41 (95%) confidence interval/CI: 0.340.50; P<0.001. 3. [31] Orion Corporation applied for a patent on darolutamide in October 2010, and this patent was published in May 2011. 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