Darolutamide, sold under the brand name Nubeqa, is an

antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the ...

medication which is used in the treatment of non-metastatic castration-resistant prostate cancer in men. It is specifically approved to treat non-

metastatic Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

castration-resistant prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that surr ...

(nmCRPC) in conjunction with

surgical Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pat ...

or medical castration. The medication is taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

twice per day with food.

Side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s of darolutamide added to castration may include fatigue,

asthenia Weakness is a symptom of a number of different conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, i ...

, pain in the

arm In human anatomy, the arm refers to the upper limb in common usage, although academically the term specifically means the upper arm between the glenohumeral joint (shoulder joint) and the elbow joint. The distal part of the upper limb between th ...

s and

leg A leg is a weight-bearing and locomotive anatomical structure, usually having a columnar shape. During locomotion, legs function as "extensible struts". The combination of movements at all joints can be modeled as a single, linear element ca ...

s, and

rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...

. Darolutamide is a

nonsteroidal antiandrogen A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like ...

(NSAA), and acts as a selective antagonist of the androgen receptor (AR). It has been referred to as a second- or third-generation NSAA. Darolutamide was patented in 2011 and was approved for medical use in USA in July 2019, in the European Union in March 2020 and in Australia in July 2020.

Medical uses

Darolutamide is approved for use concurrently with a

gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and release ...

(GnRH) agonist or antagonist or bilateral orchiectomy in the treatment of non-

(nmCRPC) in men. It is used at a dosage of 600 mg orally twice per day (1,200 mg/day total) with food. In individuals with severe

renal impairment Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

or moderate hepatic impairment, darolutamide is used at a dosage of 300 mg orally twice per day (600 mg/day total) with food. 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. Two 2020

meta-analyses A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...

reported that

enzalutamide Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castrat ...

and

apalutamide Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is specifically indicated for use in conjunction with castration in the treatme ...

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. According to 2021 meta-analysis darolutamide was ranked first in terms of improving overall survival (OS). Also, darolutamide showed significantly lower rate of grade 3-5 adverse events (AE) compared to both enzalutamide and apalutamide.

Available forms

Darolutamide is provided in the form of 300 mg

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or or ...

film-coated tablets.

Contraindications

Darolutamide has no

contraindication In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...

s in men. However, the medication may have teratogenic effects in male

fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal dev ...

es due to its

ic effects and hence should not be used by women who are pregnant.

Side effects

The most common

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s of darolutamide in clinical trials (≥2% incidence) in castrated men included fatigue and

(16% vs. 11% for

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. In general, placebos can af ...

), pain in extremities (6% vs. 3% for placebo), and

(3% vs. 1% for placebo). Darolutamide was also associated with higher incidences of ischemic heart disease (4.0% vs. 3.4% for placebo) and heart failure (2.1% vs. 0.9% for placebo). In terms of laboratory test abnormalities, darolutamide was associated with decreased neutrophil count (20% vs. 9% for placebo), increased

aspartate aminotransferase Aspartate transaminase (AST) or aspartate aminotransferase, also known as AspAT/ASAT/AAT or (serum) glutamic oxaloacetic transaminase (GOT, SGOT), is a pyridoxal phosphate (PLP)-dependent transaminase enzyme () that was first described by Arthur ...

(AST) (23% vs. 14% for placebo; Grade 3–4: 0.5% vs. 0.2% for placebo), and increased bilirubin (16% vs. 7% for placebo). In the clinical studies, 88% of patients treated with darolutamide were age 65 years or older. No

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

s have been observed with darolutamide in clinical trials. Darolutamide is an expected teratogen and has a theoretical risk of

birth defect A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities ca ...

s in male infants if taken by women during

pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

. It may impair male fertility. When used as a monotherapy (i.e., without surgical or medical castration) in men, NSAAs are known to produce feminizing

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and sec ...

changes including

breast tenderness Breast pain is the symptom of discomfort in either one or both breasts. Pain in both breasts is often described as ''breast tenderness'', is usually associated with the menstrual period and is not serious. Pain that involves only one part of a br ...

and

gynecomastia Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse ( ...

Overdose

Darolutamide has been studied at a dosage of up to 1,800 mg/day in clinical trials. There were no dose-limiting toxicities seen at this dosage. 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. There is no specific

antidote An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon) antidoton'', "(medicine) given as a remedy". Antidotes for anticoagulants are s ...

for overdose of darolutamide. In the event of darolutamide overdose, if there is no toxicity, treatment can be continued as normal. 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.

Interactions

Combined P-glycoprotein and strong or moderate CYP3A4

inducer In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely: *By disabling repressors. The gene is expressed because an inducer binds to the repressor. The binding of the inducer to the r ...

s such as rifampicin may decrease blood levels of darolutamide, while combined P-glycoprotein and strong CYP3A4 inhibitors such as

itraconazole Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mo ...

may increase blood levels of darolutamide. Darolutamide is an inhibitor of the breast cancer resistance protein (BCRP) transporter and can increase blood levels of substrates for BCRP protein, such as

rosuvastatin Rosuvastatin, sold under the brand name Crestor among others, is a statin medication, used to prevent cardiovascular disease in those at high risk and treat abnormal lipids. It is recommended to be used together with dietary changes, exercise, ...

, by approximately 5-fold.

Pharmacology

Pharmacodynamics

Darolutamide is a second- or third-generation

(NSAA). It acts as a selective

competitive Competition is a rivalry where two or more parties strive for a common goal which cannot be shared: where one's gain is the other's loss (an example of which is a zero-sum game). Competition can arise between entities such as organisms, indivi ...

silent antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of recep ...

of the androgen receptor (AR), the

biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...

androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...

s like

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...

and

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includ ...

(DHT). Its affinity (K_i) for the AR is 11 nM and its functional inhibition () of the AR is 26 nM. The major metabolite of darolutamide, ketodarolutamide, has similar antiandrogenic activity relative to darolutamide (K_i = 8 nM; IC₅₀ = 38 nM). 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. A dosage of darolutamide of 1,200 mg/day has been found to result in a mean decrease in

prostate specific antigen Prostate-specific antigen (PSA), also known as gamma-seminoprotein or kallikrein-3 (KLK3), P-30 antigen, is a glycoprotein enzyme encoded in humans by the ''KLK3'' gene. PSA is a member of the kallikrein-related peptidase family and is secreted b ...

(PSA) levels of more than 90% in men with prostate cancer. 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. Darolutamide shows some advantages in comparison to

and

, two other second-generation NSAAs. It appears to negligibly cross the blood–brain barrier, and hence has reduced risk of

s and other central

s from off-target GABA_A receptor inhibition. In accordance with its diminished central penetration, darolutamide does not appear to increase

levels. 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. The medication shows higher affinity and inhibitory potency at the AR relative to enzalutamide and apalutamide ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...

'' (K_i = 11 nM relative to 86 nM for enzalutamide and 93 nM for apalutamide; = 26 nM relative to 219 nM for enzalutamide and 200 nM for apalutamide). Darolutamide inhibits the organic anion transporting polypeptide (OATP) transporters

OATP1B1 Solute carrier organic anion transporter family member 1B1 is a protein that in humans is encoded by the ''SLCO1B1'' gene. Pharmacogenomic research indicates that genetic variations in this gene are associated with response to simvastatin. Clinica ...

and

OATP1B3 Solute carrier organic anion transporter family member 1B3 (SLCO1B3) also known as organic anion-transporting polypeptide 1B3 (OATP1B3) is a protein that in humans is encoded by the ''SLCO1B3'' gene. OATP1B3 is a 12-transmembrane domain influx tra ...

''in vitro''. It shows no

inhibition Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

induction Induction, Inducible or Inductive may refer to: Biology and medicine * Labor induction (birth/pregnancy) * Induction chemotherapy, in medicine * Induced stem cells, stem cells derived from somatic, reproductive, pluripotent or other cell t ...

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

s (

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4) at clinically relevant concentrations. Similarly, darolutamide shows no inhibition of a variety of other transporters ( P-glycoprotein,

MRP2 MRP2 may refer to: * Multidrug resistance-associated protein 2 * Manufacturing resource planning Manufacturing resource planning (MRP II) is defined as a method for the effective planning of all resources of a manufacturing company. Ideally, it ...

, BSEP,

OAT The oat (''Avena sativa''), sometimes called the common oat, is a species of cereal grain grown for its seed, which is known by the same name (usually in the plural, unlike other cereals and pseudocereals). While oats are suitable for human con ...

s, OCTs,

MATE Mate may refer to: Science * Mate, one of a pair of animals involved in: ** Mate choice, intersexual selection ** Mating * Multi-antimicrobial extrusion protein, or MATE, an efflux transporter family of proteins Person or title * Friendship ...

OATP2B1 Solute carrier organic anion transporter family member 2B1 also known as organic anion-transporting polypeptide 2B1 (OATP2B1) is a protein that in humans is encoded by the gene In biology, the word gene (from , ; "... Wilhelm Johannsen coine ...

, NTCP) at therapeutic concentrations.

Pharmacokinetics

Absorption

The

absolute bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100 ...

of darolutamide with

oral administration Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are ...

of a single 300-mg dose without food is approximately 30%. 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. 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). 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. Following a single 600-mg dose of darolutamide, peak levels of darolutamide occur after approximately 4 hours. 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. At steady state with 600 mg/day darolutamide, mean levels of darolutamide are 4.79 μg/mL and

area-under-the-curve levels In the field of pharmacokinetics, the area under the curve (AUC) is the definite integral of the concentration of a drug in blood plasma as a function of time (this can be done using liquid chromatography–mass spectrometry). In practice, the dru ...

of darolutamide over time 0 to 12 hours (AUC_0–12) are 52.82 h•μg/mL. Total exposure to ketodarolutamide is approximately 1.7-fold that of darolutamide.

Distribution

The

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

of darolutamide with

intravenous administration Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutri ...

is 119 L. The

plasma protein binding Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse t ...

of darolutamide is 92%, with 8% circulating freely, and of ketodarolutamide is 99.8%, with 0.2% circulating unbound. As such, free levels of darolutamide in the circulation are about 40-fold higher than those of ketodarolutamide. Both darolutamide and ketodarolutamide are bound mainly to

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...

. Darolutamide and ketodarolutamide appear to negligibly cross the blood–brain barrier both in mice and humans. Darolutamide is a known substrate of P-glycoprotein and the breast cancer resistance protein (BCRP). P-Glycoprotein is known to play a major role in excluding drugs from the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

due to efflux back across the blood–brain barrier.

Metabolism

Darolutamide is primarily

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

into ketodarolutamide via

dehydrogenation In chemistry, dehydrogenation is a chemical reaction that involves the removal of hydrogen, usually from an organic molecule. It is the reverse of hydrogenation. Dehydrogenation is important, both as a useful reaction and a serious problem. At ...

by CYP3A4 in the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

. The medication is also conjugated via

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gl ...

UGT1A9 UDP-glucuronosyltransferase 1-9 is an enzyme that in humans is encoded by the ''UGT1A9'' gene. Function This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such a ...

and

UGT1A1 UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the ''UGT1A1'' gene. UGT-1A is a uridine diphosphate glucuronosyltransferase (UDP-glucuronosyltransferase, UDPGT), an enzyme of the glucuronidation pat ...

. The

elimination half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

of darolutamide and ketodarolutamide has been reported to be approximately 20 hours. 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. The elimination half-life of darolutamide is far shorter than that of

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

Excretion

After a single oral dose of darolutamide, more than 95% of the dose is

excreted Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellular ...

and feces within one week following administration. 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.

Variability

No clinically significant differences in the pharmacokinetics of darolutamide have been observed in men with nmCRPC on the basis of age (48 to 95 years), race (white, Asian, black), mild-to-moderate

, or mild hepatic impairment. 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. In non-nmCRPC individuals with moderate hepatic impairment, darolutamide exposure was increased by about 1.9-fold compared to healthy controls. The pharmacokinetics of darolutamide have not been assessed in end-stage kidney disease or severe hepatic impairment.

Chemistry

Darolutamide is a

nonsteroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents. List of nonsteroidal steroid receptor mo ...

compound Compound may refer to: Architecture and built environments * Compound (enclosure), a cluster of buildings having a shared purpose, usually inside a fence or wall ** Compound (fortification), a version of the above fortified with defensive struc ...

and is structurally distinct from other marketed NSAAs, including enzalutamide and apalutamide.

History

Darolutamide was developed by

Orion Corporation Orion Corporation ( fi, Orion Oyj), founded in 1917 and headquartered at Espoo, Finland, is a globally operating Finnish company which develops, manufactures and markets human and veterinary pharmaceuticals and active pharmaceutical ingredients ...

and

Bayer HealthCare Bayer AG (, commonly pronounced ; ) is a German multinational pharmaceutical and biotechnology company and one of the largest pharmaceutical companies in the world. Headquartered in Leverkusen, Bayer's areas of business include pharmaceutica ...

. Orion Corporation applied for a

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A ...

on darolutamide in October 2010, and this patent was published in May 2011. Darolutamide entered phase I

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

s in April 2011, with the results of the first clinical study of darolutamide initially published in 2012. The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) approved darolutamide in July 2019, under the agency's

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

designation. Approval was based on ARAMIS, 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. 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).

Society and culture

Generic names

Darolutamide is the generic name of the medication and its and . It is also known by its developmental code names ODM-201 and BAY-1841788.

Brand names

Darolutamide is marketed under the brand name Nubeqa.

Availability

Darolutamide is available in the United States and the European Union.

Research

Darolutamide monotherapy is being studied in comparison to

androgen deprivation therapy Androgen deprivation therapy (ADT), also called androgen suppression therapy, is an antihormone therapy whose main use is in treating prostate cancer. Prostate cancer cells usually require androgen hormones, such as testosterone, to grow. ADT red ...

with

GnRH agonist A gonadotropin-releasing hormone agonist (GnRH agonist) is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treat ...

or antagonist monotherapy in men with treatment-naive prostate cancer. As of 2018, it is entering a phase II

for this indication. This study is expected for completion in 2021 or 2022. Darolutamide is being studied for the treatment of

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...

in women. As of November 2019, it is in phase II

s for this indication.

References

External links

* {{Portal bar , Medicine Antiprogestogens Carboxamides Chloroarenes Hormonal antineoplastic drugs Nitriles Nonsteroidal antiandrogens Peripherally selective drugs Pyrazoles