Apalutamide

Last updated

Apalutamide
Apalutamide.svg
Apalutamide molecule ball.png
Clinical data
Trade names Erleada, others
Other namesARN-509; JNJ-56021927; JNJ-927; A52
AHFS/Drugs.com Monograph
MedlinePlus a618018
License data
Pregnancy
category
Routes of
administration 		By mouth [2]
Drug class Nonsteroidal antiandrogen
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 100% [2]
Protein binding Apalutamide: 96% [2]
NDMA: 95% [2]
Metabolism Liver (CYP2C8, CYP3A4) [2]
Metabolites • NDMA Tooltip N-Desmethylapalutamide [2]
Elimination half-life Apalutamide: 3–4 days (at steady-state) [7] [2]
Excretion Urine: 65% [2]
Feces: 24% [2]
Identifiers
  • 4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.235.115 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H15F4N5O2S
Molar mass 477.44 g·mol−1
3D model (JSmol)
  • CNC(=O)C1=C(C=C(C=C1)N2C(=S)N(C(=O)C23CCC3)C4=CN=C(C(=C4)C(F)(F)F)C#N)F
  • InChI=1S/C21H15F4N5O2S/c1-27-17(31)13-4-3-11(8-15(13)22)30-19(33)29(18(32)20(30)5-2-6-20)12-7-14(21(23,24)25)16(9-26)28-10-12/h3-4,7-8,10H,2,5-6H2,1H3,(H,27,31)
  • Key:HJBWBFZLDZWPHF-UHFFFAOYSA-N

Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication used for the treatment of prostate cancer. [2] [8] [9] It is an androgen receptor inhibitor. [2] It is taken by mouth. [2] [10]

Contents

Side effects of apalutamide when added to castration include fatigue, nausea, abdominal pain, diarrhea, high blood pressure, rash, falls, bone fractures, and an underactive thyroid. [2] [11] [12] [10] [13] Rarely, it can cause seizures. [2] [10] The medication has a high potential for drug interactions. [2] [10] Apalutamide is an antiandrogen, and acts as an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone. [2] [10] [14] In doing so, it prevents the effects of these hormones in the prostate gland and elsewhere in the body. [2] [10] [14]

Apalutamide was first described in 2007, and was approved for the treatment of prostate cancer in February 2018. [8] [9] [10] [15] It is the first medication to be approved specifically for the treatment of non-metastatic castration-resistant prostate cancer. [2] [10] [9]

Medical uses

Apalutamide is indicated for the treatment of people with metastatic castration-sensitive prostate cancer and the treatment of people with non-metastatic castration-resistant prostate cancer. [2] [6]

Apalutamide is used in conjunction with castration, either via bilateral orchiectomy or gonadotropin-releasing hormone analogue (GnRH analogue) therapy, as a method of androgen deprivation therapy in the treatment of non-metastatic castration-resistant prostate cancer. [2] [16] [17] [18] It is also a promising potential treatment for metastatic castration-resistant prostate cancer (mCRPC), which the NSAA enzalutamide and the androgen synthesis inhibitor abiraterone acetate are used to treat. [13]

Contraindications

Contraindications of apalutamide include pregnancy and a history of or susceptibility to seizures. [2]

Side effects

Apalutamide has been found to be well tolerated in clinical trials, [19] [16] with the most common side effects reported when added to surgical or medical castration including fatigue, nausea, abdominal pain, and diarrhea. [11] [12] [20] Other side effects have included rash, falls and bone fractures, and hypothyroidism, as well as seizures (in 0.2%), among others. [2] [10] [9] Apalutamide is an expected teratogen and has a theoretical risk of birth defects in male infants if taken by women during pregnancy. [2] It may impair male fertility. [2] When used as a monotherapy (i.e., without surgical or medical castration) in men, NSAAs are known to produce additional, estrogenic side effects like breast tenderness, gynecomastia, and feminization in general by increasing estradiol levels. [21] Similarly to the related second-generation NSAA enzalutamide but unlike first-generation NSAAs like flutamide and bicalutamide, elevated liver enzymes and hepatotoxicity have not been reported with apalutamide. [2] Case reports of rare interstitial lung disease with apalutamide exist similarly to with first-generation NSAAs however. [22] [23] [24]

Overdose

There is no known antidote for overdose of apalutamide. [2] General supportive measures should be undertaken until clinical toxicity, if any, diminishes or resolves. [2]

Interactions

Apalutamide has a high potential for drug interactions. [2] In terms of effects of apalutamide on other drugs, the exposure of substrates of CYP3A4, CYP2C19, CYP2C9, UDP-glucuronosyltransferase, P-glycoprotein, ABCG2, or OATP1B1 may be reduced to varying extents. [2] In terms of effects of other drugs on apalutamide, strong CYP2C8 or CYP3A4 inhibitors may increase levels of apalutamide or its major active metabolite N-desmethylapalutamide, while mild to moderate CYP2C8 or CYP3A4 inhibitors are not expected to affect their exposure. [2]

Pharmacology

Pharmacodynamics

Antiandrogenic activity

Apalutamide acts as a selective competitive silent antagonist of the androgen receptor (AR), via the ligand-binding domain, and hence is an antiandrogen. [10] [14] [11] [16] It is similar both structurally and pharmacologically to the second-generation NSAA enzalutamide, [19] [25] but shows some advantages, including higher antiandrogenic activity as well as several-fold reduced central nervous system distribution. [14] [11] [16] The latter difference may reduce its comparative risk of seizures and other central side effects. [14] [11] [16] Apalutamide has 5- to 10-fold greater affinity for the AR than bicalutamide, a first-generation NSAA. [18] [17]

The acquired F876L mutation of the AR identified in advanced prostate cancer cells has been found to confer resistance to both enzalutamide and apalutamide. [26] [27] A newer NSAA, darolutamide, is not affected by this mutation, nor has it been found to be affected by any other tested/well-known AR mutations. [28] Apalutamide may be effective in a subset of prostate cancer patients with acquired resistance to abiraterone acetate. [19]

Other activities

Apalutamide shows potent induction potential of cytochrome P450 enzymes similarly to enzalutamide. [2] [29] [30] It is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9, as well as an inducer of UDP-glucuronosyltransferase. [2] In addition, apalutamide is an inducer of P-glycoprotein, ABCG2, and OATP1B1. [2]

Apalutamide binds weakly to and inhibits the GABAA receptor in vitro similarly to enzalutamide (IC50 Tooltip half-maximal inhibitory concentration = 3.0 and 2.7 μM, respectively), [14] but due to its relatively lower central concentrations, may have a lower risk of seizures in comparison. [14] [11] [20]

Apalutamide has been found to significantly and concentration-dependently increase QT interval. [2]

Pharmacokinetics

The mean absolute oral bioavailability of apalutamide is 100%. [2] Mean peak levels of apalutamide occur 2 hours following administration, with a range of 1 to 5 hours. [2] Food delays the median time to peak levels of apalutamide by approximately 2 hours, with no significant changes in the peak levels themselves or in area-under-curve levels. [2] Steady-state levels of apalutamide are achieved following 4 weeks of administration, with an approximate 5-fold accumulation. [2] Peak concentrations for 160 mg/day apalutamide at steady-state are 6.0 μg/mL (12.5 μmol/L), [2] relative to peak levels of 16.6 μg/mL (35.7 μmol/L) for 160 mg/day enzalutamide and mean (R)-bicalutamide levels of 21.6 μg/mL (50.2 μmol/L) for 150 mg/day bicalutamide. [31] [32] The mean volume of distribution of apalutamide at steady-state is approximately 276 L. [2] The plasma protein binding of apalutamide is 96%, while that of its major metabolite N-desmethylapalutamide is 95%, both irrespective of concentration. [2]

Apalutamide is metabolized in the liver by CYP2C8 and CYP3A4. [2] A major active metabolite, N-desmethylapalutamide, is formed by these enzymes, with similar contribution of each of these enzymes to its formation at steady-state. [2] Following a single oral dose of 200 mg apalutamide, apalutamide represented 45% and N-desmethylapalutamide 44% of total area-under-curve levels. [2] The mean elimination half-life of apalutamide at steady-state is 3 to 4 days. [2] [7] Fluctuations in apalutamide exposure are low and levels are stable throughout the day, with mean peak-to-trough ratios of 1.63 for apalutamide and 1.27–1.3 for N-desmethylapalutamide. [2] After a single dose of apalutamide, its clearance rate (CL/F) was 1.3 L/h, while its clearance rate increased to 2.0 L/h at steady-state. [10] This change is considered to be likely due to CYP3A4 auto-induction. [10] Approximately 65% of apalutamide is excreted in urine (1.2% as unchanged apalutamide and 2.7% as N-desmethylapalutamide) while 24% is excreted in feces (1.5% as unchanged apalutamide and 2% as N-desmethylapalutamide). [2]

Chemistry

Apalutamide is a structural analogue of enzalutamide and RD-162. [18] [33] It is a pyridyl variant of RD-162. Enzalutamide and RD-162 were derived from the nonsteroidal androgen RU-59063, which itself was derived from the first-generation NSAA nilutamide and by extension from flutamide. [34]

Chemical structures of apalutamide and its predecessors

History

Apalutamide was originated by the University of California system and was developed primarily by Janssen Research & Development, a division of Johnson & Johnson. [35] It was first described in the literature in a United States patent application that was published in November 2007 and in another that was submitted in July 2010. [15] [36] A March 2012 publication described the discovery and development of apalutamide. [14] A phase I clinical trial of apalutamide was completed by March 2012, and the results of this study were published in 2013. [14] [37] Information on phase III clinical studies, including ATLAS, SPARTAN, and TITAN, was published between 2014 and 2016. [38] [39] [40] Positive results for phase III trials were first described in 2017, and Janssen submitted a New Drug Application for apalutamide to the United States Food and Drug Administration on 11 October 2017. [41] Apalutamide was approved by the Food and Drug Administration in the United States, under the brand name Erleada, for the treatment of non-metastatic castration-resistant prostate cancer in February 2018. [8] [9] It was subsequently approved in Canada, the European Union, and Australia. [42] [6]

Society and culture

Generic names

Apalutamide is the generic name of the medication and is its international nonproprietary name. [43] [42] It is also known by its developmental code names ARN-509 and JNJ-56021927. [35] [10]

Brand names

Apalutamide is marketed under the brand names Erleada and Erlyand. [2] [8] [9] [42]

Availability

Apalutamide is available in the United States, Canada, the European Union, and Australia. [2] [8] [9] [42] [6]

Related Research Articles

<span class="mw-page-title-main">Bicalutamide</span> Prostate cancer treatment

Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer (mPC). To a lesser extent, it is used at high doses for locally advanced prostate cancer (LAPC) as a monotherapy without castration. Bicalutamide was also previously used as monotherapy to treat localized prostate cancer (LPC), but authorization for this use was withdrawn following unfavorable trial findings. Besides prostate cancer, bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women, as a puberty blocker and component of feminizing hormone therapy for transgender girls and women, to treat gonadotropin-independent early puberty in boys, and to prevent overly long-lasting erections in men. It is taken by mouth.

<span class="mw-page-title-main">Nilutamide</span> Chemical compound

Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer. It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women. It is taken by mouth.

<span class="mw-page-title-main">Enzalutamide</span> Antiandrogen medication used in treatment of prostate cancer

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 castration-resistant prostate cancer (mCRPC), nonmetastatic castration-resistant prostate cancer, and metastatic castration-sensitive prostate cancer (mCSPC). It is taken by mouth.

The first antiandrogen was discovered in the 1960s. Antiandrogens antagonise the androgen receptor (AR) and thereby block the biological effects of testosterone and dihydrotestosterone (DHT). Antiandrogens are important for men with hormonally responsive diseases like prostate cancer, benign prostatic hyperplasia (BHP), acne, seborrhea, hirsutism and androgen alopecia. Antiandrogens are mainly used for the treatment of prostate diseases. Research from 2010 suggests that ARs could be linked to the disease progression of triple-negative breast cancer and salivary duct carcinoma and that antiandrogens can potentially be used to treat it.

<span class="mw-page-title-main">Galeterone</span> Chemical compound

Galeterone is a steroidal antiandrogen which was under development by Tokai Pharmaceuticals for the treatment of prostate cancer. It possesses a unique triple mechanism of action, acting as an androgen receptor antagonist, androgen receptor down regulator, and CYP17A1 inhibitor, the latter of which prevents the biosynthesis of androgens. As a CYP17A1 inhibitor, galeterone shows selectivity for 17,20-lyase over 17α-hydroxylase.

EPI-001 is the first inhibitor of the androgen receptor amino-terminal domain. The single stereoisomer of EPI-001, EPI-002, is a first-in-class drug that the USAN council assigned a new stem class "-aniten" and the generic name "ralaniten". This distinguishes the anitens novel molecular mechanism from anti androgens that bind the C-terminus ligand-binding domain and have the stem class "lutamide". EPI-001 and its stereoisomers and analogues were discovered by Marianne Sadar and Raymond Andersen, who co-founded the pharmaceutical company ESSA Pharma Inc for the clinical development of anitens for the treatment of castration-resistant prostate cancer (CRPC).

<span class="mw-page-title-main">Nonsteroidal antiandrogen</span> Antiandrogen with a nonsteroidal chemical structure

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 testosterone and dihydrotestosterone (DHT). NSAAs are used in the treatment of androgen-dependent conditions in men and women. They are the converse of steroidal antiandrogens (SAAs), which are antiandrogens that are steroids and are structurally related to testosterone.

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. It is specifically approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration. The medication is taken by mouth twice per day with food.

<span class="mw-page-title-main">Ralaniten acetate</span> Chemical compound

Ralaniten acetate is a first-in-class antiandrogen that targets the N-terminal domain (NTD) of the androgen receptor (AR) developed by ESSA Pharmaceuticals and was under investigation for the treatment of prostate cancer. This mechanism of action is believed to allow the drug to block signaling from the AR and its splice variants. EPI-506 is a derivative of bisphenol A and a prodrug of ralaniten (EPI-002), one of the four stereoisomers of EPI-001, and was developed as a successor of EPI-001. The drug reached phase I/II prior to the discontinuation of its development. It showed signs of efficacy in the form of prostatic specific antigen (PSA) decreases (4–29%) predominantly at higher doses (≥1,280 mg) in some patients but also caused side effects and was discontinued by its developer in favor of next-generation AR NTD inhibitors with improved potency and tolerability.

Ketodarolutamide is a nonsteroidal antiandrogen (NSAA) and the major active metabolite of darolutamide, an NSAA which is used in the treatment of prostate cancer in men. Similarly to its parent compound, ketodarolutamide acts as a highly selective, high-affinity, competitive silent antagonist of the androgen receptor (AR). Both agents show much higher affinity and more potent inhibition of the AR relative to the other NSAAs enzalutamide and apalutamide, although they also possess much shorter and comparatively less favorable elimination half-lives. They have also been found not to activate certain mutant AR variants that enzalutamide and apalutamide do activate. Both darolutamide and ketodarolutamide show limited central nervous system distribution, indicating peripheral selectivity, and little or no inhibition or induction of cytochrome P450 enzymes such as CYP3A4, unlike enzalutamide and apalutamide.

<i>N</i>-Desmethylenzalutamide Chemical compound

N-Desmethylenzalutamide is a nonsteroidal antiandrogen (NSAA) and the major metabolite of enzalutamide, an NSAA which is used as a hormonal antineoplastic agent in the treatment of metastatic prostate cancer. It has similar activity to that of enzalutamide and, with enzalutamide therapy, circulates at similar concentrations to those of enzalutamide at steady state. N-Desmethylenzalutamide is formed from enzalutamide in the liver by the cytochrome P450 enzymes CYP2C8 and CYP3A4. It has a longer terminal half-life than enzalutamide.

5<i>N</i>-Bicalutamide Chemical compound

5N-Bicalutamide, or 5-azabicalutamide, is a highly potent nonsteroidal antiandrogen (NSAA) which was discovered in 2016. It is a structural modification of bicalutamide differing it from it only by the replacement of a carbon atom with a nitrogen atom in one of its phenyl rings. Similarly to bicalutamide, the drug acts as a selective antagonist of the androgen receptor (AR). However, unlike bicalutamide, it is a reversible covalent antagonist and stays bound to the receptor for a far longer amount of time. As a result of this difference, 5N-bicalutamide has markedly improved potency relative to bicalutamide, with approximately 150-fold higher affinity for the AR (Ki = 0.15 nM versus 22.3 nM) and about 20-fold greater functional inhibition (IC50Tooltip Half-maximal inhibitory concentration = 15 nM versus 310 nM) of the AR. Future studies of 5N-bicalutamide in normal and mutated prostate cancer cells are planned or underway and it is anticipated that N-bicalutamide may be able to overcome resistance. to current antiandrogens that are used in the treatment of prostate cancer.

The medical uses of bicalutamide, a nonsteroidal antiandrogen (NSAA), include the treatment of androgen-dependent conditions and hormone therapy to block the effects of androgens. Indications for bicalutamide include the treatment of prostate cancer in men, skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women, high testosterone levels in women, hormone therapy in transgender women, as a puberty blocker to prevent puberty in transgender girls and to treat early puberty in boys, and the treatment of long-lasting erections in men. It may also have some value in the treatment of paraphilias and hypersexuality in men.

Comparison of the nonsteroidal antiandrogen (NSAA) bicalutamide with other antiandrogens reveals differences between the medications in terms of efficacy, tolerability, safety, and other parameters. Relative to the other first-generation NSAAs, flutamide and nilutamide, bicalutamide shows improved potency, efficacy, tolerability, and safety, and has largely replaced these medications in clinical practice. Compared to the second-generation NSAAs, enzalutamide and apalutamide, bicalutamide has inferior potency and efficacy but similar tolerability and safety and a lower propensity for drug interactions.

<span class="mw-page-title-main">Pharmacology of bicalutamide</span>

The pharmacology of bicalutamide is the study of the pharmacodynamic and pharmacokinetic properties of the nonsteroidal antiandrogen (NSAA) bicalutamide. In terms of pharmacodynamics, bicalutamide acts as a selective antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has no capacity to activate the AR. It does not decrease androgen levels and has no other important hormonal activity. The medication has progonadotropic effects due to its AR antagonist activity and can increase androgen, estrogen, and neurosteroid production and levels. This results in a variety of differences of bicalutamide monotherapy compared to surgical and medical castration, such as indirect estrogenic effects and associated benefits like preservation of sexual function and drawbacks like gynecomastia. Bicalutamide can paradoxically stimulate late-stage prostate cancer due to accumulated mutations in the cancer. When used as a monotherapy, bicalutamide can induce breast development in males due to its estrogenic effects. Unlike other kinds of antiandrogens, it may have less adverse effect on the testes and fertility.

<span class="mw-page-title-main">RD-162</span> Chemical compound

RD-162 is a second-generation nonsteroidal antiandrogen (NSAA) which was developed for the treatment of prostate cancer but was never marketed. It acts as a potent and selective silent antagonist of the androgen receptor (AR). The drug is a diarylthiohydantoin derivative. It is closely related to enzalutamide and apalutamide. Both RD-162 and enzalutamide show 5- to 8-fold higher affinity for the AR than the first-generation NSAA bicalutamide, and only 2- to 3-fold lower affinity than dihydrotestosterone (DHT), the major endogenous ligand of the receptor in the prostate gland.

<span class="mw-page-title-main">RU-59063</span> Chemical compound

RU-59063 is a nonsteroidal androgen or selective androgen receptor modulator (SARM) which was first described in 1994 and was never marketed. It was originally thought to be a potent antiandrogen, but subsequent research found that it actually possesses dose-dependent androgenic activity, albeit with lower efficacy than dihydrotestosterone (DHT). The drug is an N-substituted arylthiohydantoin and was derived from the first-generation nonsteroidal antiandrogen (NSAA) nilutamide. The second-generation NSAAs enzalutamide, RD-162, and apalutamide were derived from RU-59063.

<i>N</i>-Desmethylapalutamide Chemical compound

N-Desmethylapalutamide is a nonsteroidal antiandrogen (NSAA) and the major active metabolite of apalutamide, an NSAA which is used as a hormonal antineoplastic agent in the treatment of metastatic prostate cancer. It has similar activity to that of apalutamide and, with apalutamide therapy, circulates at similar concentrations to those of apalutamide at steady state. N-Desmethylapalutamide is formed from apalutamide in the liver by the cytochrome P450 enzymes CYP2C8 and CYP3A4.

Masofaniten, also known by its developmental code name EPI-7386, is an N-terminal domain antiandrogen, or antagonist of the N-terminal domain (NTD) of the androgen receptor (AR), which is under development for the treatment of prostate cancer. The compound was developed as a successor of previous drugs in the EPI series such as EPI-001, ralaniten (EPI-002), and ralaniten acetate (EPI-506). Masofaniten shows 20-fold higher antiandrogenic potency than ralaniten in vitro (IC50Tooltip Half-maximal inhibitory concentration = 535 nM vs. 9,580 nM, respectively), as well as greater stability in human hepatocytes. It was planned to enter phase I clinical trials in 2020. Preliminary results of a phase I/II clinical trial were published in 2023.

<span class="mw-page-title-main">Rezvilutamide</span> Chemical compound

Rezvilutamide, sold under the brand name Ariane, is a nonsteroidal antiandrogen which is approved for the treatment of prostate cancer in China and is or was under development for the treatment of breast cancer. It is a selective androgen receptor antagonist with reduced brain distribution compared to the structurally related nonsteroidal antiandrogen enzalutamide. The drug was developed by Jiangsu Hengrui Medicine. Other structural analogues of rezvilutamide that are also used as antiandrogens besides enzalutamide include apalutamide and proxalutamide.

References

  1. ↑ "Apalutamide (Erleada) Use During Pregnancy". Drugs.com. 20 July 2020. Archived from the original on 29 November 2020. Retrieved 28 September 2020.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 "Erleada- apalutamide tablet, film coated". DailyMed. 27 October 2020. Archived from the original on 9 November 2020. Retrieved 8 November 2020.
  3. ↑ "Product monograph including patient medication information" (PDF). Janssen Inc. 6 July 2021. Archived (PDF) from the original on 3 November 2022. Retrieved 3 November 2022.
  4. ↑ "Regulatory Decision Summary for Erleada". Health Canada . 2 August 2023. Archived from the original on 2 April 2024. Retrieved 2 April 2024.
  5. ↑ "Drug and medical device highlights 2018: Helping you maintain and improve your health". Health Canada . 14 October 2020. Archived from the original on 17 April 2024. Retrieved 17 April 2024.
  6. 1 2 3 4 "Erleada EPAR". European Medicines Agency (EMA). 13 November 2018. Archived from the original on 28 December 2020. Retrieved 9 November 2020.
  7. 1 2 Rathkopf DE, Morris MJ, Fox JJ, Danila DC, Slovin SF, Hager JH, et al. (October 2013). "Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer". Journal of Clinical Oncology. 31 (28): 3525–30. doi:10.1200/JCO.2013.50.1684. PMC   3782148 . PMID   24002508.
  8. 1 2 3 4 5 "FDA approves new treatment for a certain type of prostate cancer using novel clinical trial endpoint". Food and Drug Administration (Press release). 24 March 2020. Archived from the original on 23 April 2019. Retrieved 15 February 2018.
  9. 1 2 3 4 5 6 7 Mulcahy N (14 February 2018). "FDA Approves Apalutamide for Nonmetastatic Prostate Cancer". Medscape. Archived from the original on 24 November 2020. Retrieved 16 August 2024.
  10. 1 2 3 4 5 6 7 8 9 10 11 12 13 Al-Salama ZT (April 2018). "Apalutamide: First Global Approval". Drugs. 78 (6): 699–705. doi:10.1007/s40265-018-0900-z. PMID   29626324. S2CID   4653827.
  11. 1 2 3 4 5 6 Schweizer MT, Antonarakis ES (August 2012). "Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: a new era of hormonal therapies is born". Therapeutic Advances in Urology. 4 (4): 167–78. doi:10.1177/1756287212452196. PMC   3398601 . PMID   22852027.
  12. 1 2 Leibowitz-Amit R, Joshua AM (December 2012). "Targeting the androgen receptor in the management of castration-resistant prostate cancer: rationale, progress, and future directions". Current Oncology. 19 (Suppl 3): S22-31. doi:10.3747/co.19.1281. PMC   3553559 . PMID   23355790.
  13. 1 2 Dellis AE, Papatsoris AG (June 2018). "Apalutamide: The established and emerging roles in the treatment of advanced prostate cancer". Expert Opin Investig Drugs. 27 (6): 553–559. doi:10.1080/13543784.2018.1484107. PMID   29856649. S2CID   46925616.
  14. 1 2 3 4 5 6 7 8 9 Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, et al. (March 2012). "ARN-509: a novel antiandrogen for prostate cancer treatment". Cancer Research. 72 (6): 1494–503. doi:10.1158/0008-5472.CAN-11-3948. PMC   3306502 . PMID   22266222.
  15. 1 2 WO 2007126765,Jung ME, Sawyers CL, Ouk S, Tran C, Wongvipat J,"Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases",published 8 November 2007, assigned to The Regents Of The University Of California. Archived 4 November 2021 at the Wayback Machine
  16. 1 2 3 4 5 Rathkopf D, Scher HI (2013). "Androgen receptor antagonists in castration-resistant prostate cancer". Cancer Journal. 19 (1): 43–9. doi:10.1097/PPO.0b013e318282635a. PMC   3788593 . PMID   23337756.
  17. 1 2 Kim W, Ryan CJ (February 2015). "Quo vadis: advanced prostate cancer-clinical care and clinical research in the era of multiple androgen receptor-directed therapies". Cancer. 121 (3): 361–71. doi: 10.1002/cncr.28929 . PMID   25236176. S2CID   6309403.
  18. 1 2 3 Kawahara T, Miyamoto H (June 2014). "Androgen Receptor Antagonists in the Treatment of Prostate Cancer". Clinical Immunology, Endocrine & Metabolic Drugs. 1 (1): 11–19. doi:10.2174/22127070114019990002. ISSN   2212-7070.
  19. 1 2 3 Patel JC, Maughan BL, Agarwal AM, Batten JA, Zhang TY, Agarwal N (2013). "Emerging molecularly targeted therapies in castration refractory prostate cancer". Prostate Cancer. 2013: 981684. doi: 10.1155/2013/981684 . PMC   3684034 . PMID   23819055.
  20. 1 2 Pinto Á (February 2014). "Beyond abiraterone: new hormonal therapies for metastatic castration-resistant prostate cancer". Cancer Biology & Therapy. 15 (2): 149–55. doi:10.4161/cbt.26724. PMC   3928129 . PMID   24100689.
  21. ↑ Anderson J (March 2003). "The role of antiandrogen monotherapy in the treatment of prostate cancer". BJU Int. 91 (5): 455–61. doi: 10.1046/j.1464-410x.2003.04026.x . PMID   12603397. S2CID   8639102.
  22. ↑ Kirishima F, Shigematsu Y, Kobayashi K (May 2022). "Interstitial lung disease induced by apalutamide therapy for castration-resistant prostate cancer: A report of a rare case". IJU Case Rep. 5 (3): 153–155. doi:10.1002/iju5.12420. PMC   9057741 . PMID   35509772.
  23. ↑ Kobe H, Tachikawa R, Masuno Y, Matsunashi A, Murata S, Hagimoto H, et al. (September 2021). "Apalutamide-induced severe interstitial lung disease: A report of two cases from Japan". Respir Investig. 59 (5): 700–705. doi:10.1016/j.resinv.2021.05.006. PMID   34144936. S2CID   235481675.
  24. ↑ Wu B, Shen P, Yin X, Yu L, Wu F, Chen C, et al. (March 2022). "Analysis of adverse event of interstitial lung disease in men with prostate cancer receiving hormone therapy using the Food and Drug Administration Adverse Event Reporting System". Br J Clin Pharmacol. 89 (2): 440–448. doi:10.1111/bcp.15336. PMID   35349180. S2CID   247777754.
  25. ↑ Tao YX (11 June 2014). Pharmacology and Therapeutics of Constitutively Active Receptors. Elsevier Science. pp. 351–. ISBN   978-0-12-417206-7. ARN-509 is related structurally to enzalutamide with greater in vivo activity in CRPC xenograft models (Clegg et al., 2012).
  26. ↑ Joseph JD, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D, et al. (September 2013). "A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509". Cancer Discovery. 3 (9): 1020–9. doi: 10.1158/2159-8290.CD-13-0226 . PMID   23779130.
  27. ↑ Nelson WG, Yegnasubramanian S (September 2013). "Resistance emerges to second-generation antiandrogens in prostate cancer". Cancer Discovery. 3 (9): 971–4. doi:10.1158/2159-8290.CD-13-0405. PMC   3800038 . PMID   24019330.
  28. ↑ Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, et al. (July 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. Bibcode:2015NatSR...512007M. doi:10.1038/srep12007. PMC   4490394 . PMID   26137992.
  29. ↑ Fizazi K, Albiges L, Loriot Y, Massard C (2015). "ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer". Expert Review of Anticancer Therapy. 15 (9): 1007–17. doi:10.1586/14737140.2015.1081566. PMC   4673554 . PMID   26313416.
  30. ↑ Ivachtchenko AV, Mitkin OD, Kudan EV, Rjahovsky AA, Vorobiev AA, Trifelenkov AS, et al. (2014). "Preclinical Development of ONC1-13B, Novel Antiandrogen for Prostate Cancer Treatment". Journal of Cancer. 5 (2): 133–42. doi:10.7150/jca.7773. PMC   3909768 . PMID   24494031.
  31. ↑ "Reference at www.accessdata.fda.gov" (PDF). Archived (PDF) from the original on 27 August 2021. Retrieved 24 February 2018.
  32. ↑ Cockshott ID (2004). "Bicalutamide: clinical pharmacokinetics and metabolism". Clin Pharmacokinet. 43 (13): 855–78. doi:10.2165/00003088-200443130-00003. PMID   15509184. S2CID   29912565.
  33. ↑ Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. (2009). "Development of a second-generation antiandrogen for treatment of advanced prostate cancer". Science. 324 (5928): 787–90. Bibcode:2009Sci...324..787T. doi:10.1126/science.1168175. PMC   2981508 . PMID   19359544.
  34. ↑ Liu B, Su L, Geng J, Liu J, Zhao G (2010). "Developments in nonsteroidal antiandrogens targeting the androgen receptor". ChemMedChem. 5 (10): 1651–61. doi:10.1002/cmdc.201000259. PMID   20853390. S2CID   23228778.
  35. 1 2 "Apalutamide - Janssen Research and Development". AdisInsight. Springer Nature Switzerland AG. Archived from the original on 3 January 2019. Retrieved 6 September 2015.
  36. ↑ US 20100190991,Ouerfelli O, Dilhas A, Yang G, Zhao H,"Synthesis of thiohydantoins",issued 11 June 2013, assigned to Sloan Kettering Institute for Cancer Research. Archived 5 November 2021 at the Wayback Machine
  37. ↑ Rathkopf DE, Morris MJ, Fox JJ, Danila DC, Slovin SF, Hager JH, et al. (October 2013). "Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer". Journal of Clinical Oncology. 31 (28): 3525–3530. doi:10.1200/JCO.2013.50.1684. PMC   3782148 . PMID   24002508.
  38. ↑ Smith MR, Liu G, Shreeve SM, Matheny S, Sosa A, Kheoh TS, et al. A randomized double-blind, comparative study of ARN-509 plus androgen deprivation therapy (ADT) versus ADT alone in nonmetastatic castration-resistant prostate cancer (M0-CRPC): The SPARTAN trial. 2014 ASCO Annual Meeting. doi:10.1200/jco.2014.32.15_suppl.tps5100.
  39. ↑ Bossi A, Dearnaley D, McKenzie M, Baskin-Bey E, Tyler R, Tombal B, et al. (2016). "ATLAS: A phase 3 trial evaluating the efficacy of apalutamide (ARN-509) in patients with high-risk localized or locally advanced prostate cancer receiving primary radiation therapy". Annals of Oncology. 27 (suppl_6): vi263. doi: 10.1093/annonc/mdw372.52 . ISSN   0923-7534.
  40. ↑ Chi K, Chowdhury S, Radziszewski P, Lebret T, Ozguroglu M, Sternberg C, et al. (2016). "TITAN: A randomized, double-blind, placebo-controlled, phase 3 trial of apalutamide (ARN-509) plus androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC)". Annals of Oncology. 27 (suppl_6): vi265. doi: 10.1093/annonc/mdw372.54 . ISSN   0923-7534.{{cite journal}}: CS1 maint: overridden setting (link)
  41. ↑ "Janssen Submits New Drug Application to U.S. FDA for Apalutamide (ARN-509) to Treat Men with Non-Metastatic Castration-Resistant Prostate Cancer" (Press release). Janssen. Archived from the original on 15 February 2018. Retrieved 15 February 2018– via PR Newswire.
  42. 1 2 3 4 "Apalutamide Monograph for Professionals". Drugs.com. 10 April 2024. Archived from the original on 10 December 2022. Retrieved 16 August 2024.
  43. ↑ World Health Organization (2016). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75". WHO Drug Information. 30 (1). hdl: 10665/331046 .

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