Wikipedia

Enzalutamide

Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer.[2][9] It is indicated for use in conjunction with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC),[2] nonmetastatic castration-resistant prostate cancer,[2] and metastatic castration-sensitive prostate cancer (mCSPC).[10] It is taken by mouth.[2]

Enzalutamide
Clinical data
Trade namesXtandi
Other namesMDV-3100; ASP-9785
AHFS/Drugs.comMonograph
MedlinePlusa612033
License data
Pregnancy
category
  • AU: X (High risk)[1]
Routes of
administration		By mouth[2][3]
Drug classNonsteroidal antiandrogen
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityRats: 89.7%[7]
Humans: unknown (but at least 84.6% based on recovery from excretion)[8][3]
Protein bindingEnzalutamide: 97–98% (primarily to albumin)[2]
NDME: 95%[2]
MetabolismLiver (primarily CYP2C8 and CYP3A4)[2]
Metabolites• NDMETooltip N-Desmethylenzalutamide (active)[2][3]
• Carboxylic acid derivative metabolite (inactive)[3]
Elimination half-lifeEnzalutamide: 5.8 days (range 2.8–10.2 days)[2]
NDME: 7.8–8.6 days[2]
ExcretionUrine: 71.0%[3]
Bile: 13.6%[3]
Feces: 0.39%[3]
Identifiers
  • 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.231.722 Edit this at Wikidata
Chemical and physical data
FormulaC21H16F4N4O2S
Molar mass464.44 g·mol−1
3D model (JSmol)
  • CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1F
  • InChI=1S/C21H16F4N4O2S/c1-20(2)18(31)28(12-5-4-11(10-26)15(8-12)21(23,24)25)19(32)29(20)13-6-7-14(16(22)9-13)17(30)27-3/h4-9H,1-3H3,(H,27,30)
  • Key:WXCXUHSOUPDCQV-UHFFFAOYSA-N

Side effects of enzalutamide when added to castration include asthenia, back pain, diarrhea, arthralgia, and hot flashes.[2] Rarely, it can cause seizures.[2] It has a high potential for drug interactions.[2] Enzalutamide is an antiandrogen, and acts as an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone.[2] In doing so, it prevents the effects of these hormones in the prostate gland and elsewhere in the body.[2]

Enzalutamide was first described in 2006, and was introduced for the treatment of prostate cancer in 2012.[11][12][13] It was the first second-generation NSAA to be introduced.[14] It is on the World Health Organization's List of Essential Medicines.[15]

Medical uses

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Enzalutamide is indicated for the treatment of people with castration-resistant prostate cancer; metastatic castration-sensitive prostate cancer; and non‑metastatic castration‑sensitive prostate cancer with biochemical recurrence at high risk for metastasis.[2]

Prostate cancer

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There is good evidence that enzalutamide is an effective treatment for increasing overall survival among people with high-risk non-metastatic castration-resistant prostate cancer, particularly those with a PSA doubling time ≤ 6 months.[16]

Other uses

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Enzalutamide can be used as an antiandrogen in feminizing hormone therapy for transgender women.[17][18]

Available forms

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Enzalutamide is provided as a capsule or tablet.[2]

Contraindications

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Enzalutamide is contraindicated in women during pregnancy.[2] It may cause fetal harm.[2]

Side effects

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Notable side effects of enzalutamide seen in clinical trials have included gynecomastia, breast pain/tenderness, fatigue, diarrhea, hot flashes, headache, sexual dysfunction, and, less commonly, seizures.[19][20][21][22] Other "common" side effects reported in clinical trials have included neutropenia, visual hallucinations, anxiety, cognitive disorder, memory impairment, hypertension, dry skin, and pruritus (itching).[23] Enzalutamide monotherapy is regarded as having a moderate negative effect on sexual function and activity, significantly less than that of GnRH analogues but similar to that of other NSAAs such as bicalutamide.[24]

Central adverse effects

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Seizures have occurred in approximately 1% of patients treated with enzalutamide in clinical trials.[19][21] This is thought to be due to enzalutamide crossing the blood–brain barrier[25][26] and exerting off-target binding to and inhibition of the GABAA receptor in the central nervous system (it has been found to inhibit the GABAA receptor in vitro (IC50Tooltip half-maximal inhibitory concentration = 3.6 μM)[26][27][28] and induces convulsions in animals at high doses).[19][21] In addition to seizures, other potentially GABAA receptor-related side effects observed with enzalutamide treatment in clinical trials have included anxiety, insomnia, vertigo, paresthesia, and headache.[29] Due to its ability to lower the seizure threshold, patients with known seizure disorders or brain injury should be closely monitored during enzalutamide treatment.[30] NSAA-induced seizures are responsive to benzodiazepine treatment, and it has been suggested that GABAA receptor inhibition by enzalutamide could be treated with these drugs.[27] In dose-ranging studies, severe fatigue was observed with enzalutamide at doses of 240 mg/day and above.[31][32]

Rare adverse reactions

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There is a single case report of posterior reversible encephalopathy syndrome (PRES) with enzalutamide treatment.[33] The mechanism of action of the side effect is unknown, but it was proposed to a consequence of inhibition of the GABAA receptor by enzalutamide.[33]

Overdose

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Enzalutamide may cause seizures in overdose.[2]

Interactions

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Enzalutamide is a moderate to strong inducer of multiple cytochrome P450 enzymes including CYP3A4, CYP2C9, and CYP2C19 and hence has a high potential for clinically relevant drug interactions.[2] Circulating concentrations of enzalutamide may be altered by inhibitors and inducers of CYP2C8 and CYP3A4, and should be avoided if possible.[34]

In a clinical study of enzalutamide for ERTooltip estrogen receptor-positive breast cancer in women, enzalutamide was found to decrease serum concentrations of the aromatase inhibitors anastrozole and exemestane by 90% and 50%, respectively, which could reduce their effectiveness.[35]

Pharmacology

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Pharmacodynamics

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Enzalutamide acts as a selective silent antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). Unlike the first-generation NSAA bicalutamide, enzalutamide does not promote translocation of AR to the cell nucleus and in addition prevents binding of AR to deoxyribonucleic acid (DNA) and AR to coactivator proteins.[36] As such, it has been described as an AR signaling inhibitor in addition to antagonist.[19] The drug is described as a "second-generation" NSAA because it has greatly increased efficacy as an antiandrogen relative to so-called "first-generation" NSAAs like flutamide and bicalutamide. The drug has only 2-fold lower affinity for the AR than DHT, the endogenous ligand of the AR in the prostate gland.[37]

When LNCaP cells (a prostate cancer cell line) engineered to express elevated levels of AR (as found in patients with advanced prostate cancer) were treated with enzalutamide, the expression of androgen-dependent genes PSA and TMPRSS2 was down regulated in contrast to bicalutamide where the expression was upregulated.[36] In VCaP cells which over-express the AR, enzalutamide induced apoptosis whereas bicalutamide did not.[36] Furthermore, enzalutamide behaves as an antagonist of the W741C mutant AR in contrast to bicalutamide which behaves as a pure agonist when bound to the W741C mutant.[36]

Dose-ranging studies of enzalutamide in men with prostate cancer have been performed.[32]

Changes in hormone levels

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Enzalutamide monotherapy at a dosage of 160 mg/day has been found to increase circulating levels of testosterone by 114.3%, dihydrotestosterone (DHT) by 51.7%, estradiol by 71.7%, sex hormone-binding globulin (SHBG) by 100.6%, dehydroepiandrosterone (DHEA) by 9.6%, androstenedione by 51.1%, luteinizing hormone (LH) by 184.7%, follicle-stimulating hormone (FSH) by 47.0%, and prolactin by 16.8%.[24][38] These changes in hormone levels are similar to those with high-dose bicalutamide monotherapy.[24][38] The median maximum decrease in levels of prostate-specific antigen (PSA) levels was 99.6%.[24]

Comparison with other antiandrogens

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Enzalutamide has approximately 8-fold higher binding affinity for the androgen receptor (AR) compared to bicalutamide.[36][39] One study found an IC50Tooltip half-maximal inhibitory concentration of 21 nM for enzalutamide and 160 nM for bicalutamide at the AR in the LNCaP cell line (7.6-fold difference),[40] while another found respective IC50 values of 36 nM and 159 nM (4.4-fold difference).[41] In accordance, clinical findings suggest that enzalutamide is a significantly more potent and effective antiandrogen in comparison to first-generation NSAAs such as bicalutamide, flutamide, and nilutamide.[24][38] Also, unlike with the first-generation NSAAs, there has been no evidence of hepatotoxicity or elevated liver enzymes in association with enzalutamide treatment in clinical trials.[42][43]

Resistance mechanisms in prostate cancer

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Enzalutamide is only effective for a certain period of time, after that the growth of the cancer is not inhibited by this antiandrogen. The mechanisms of resistance to Enzalutamide are being intensively studied.[44] Currently, several mechanisms have been found:

Cytochrome P450 modulation

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Enzalutamide is reported to be a strong inducer of the enzyme CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19, and can affect the circulating concentrations of drugs that are metabolized by these enzymes.[54][34]

Pharmacokinetics

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The bioavailability of enzalutamide in humans is unknown, but is at least 84.6% based on the amount recovered from urine and bile in excretion studies.[8][3] Similarly, the bioavailability of enzalutamide in rats is 89.7%.[7] Steady-state concentrations of enzalutamide are achieved within 28 days of treatment initiation.[40] The plasma protein binding of enzalutamide is 97 to 98%, while that of N-desmethylenzalutamide (NDME), its major metabolite, is 95%.[2] Enzalutamide is primarily bound to albumin.[2] The medication is metabolized in the liver, mainly by the cytochrome P450 enzymes CYP2C8 and CYP3A4.[2] CYP2C8 is primarily responsible for the formation of NDME.[34] Enzalutamide has a long elimination half-life of 5.8 days on average, with a range of 2.8 to 10.2 days.[2] The elimination half-life of NDME is even longer, at about 7.8 to 8.6 days.[2] Enzalutamide is eliminated 71.0% in urine, 13.6% in bile, and 0.39% in feces.[3]

Chemistry

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See also: Nonsteroidal antiandrogen and List of antiandrogens § Nonsteroidal antiandrogens

Enzalutamide is a synthetic diaryl thiohydantoin derivative and is structurally related to the earlier first-generation NSAAs such as flutamide, nilutamide, and bicalutamide as well as to newer second-generation NSAAs like apalutamide and proxalutamide.[55]

History

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Enzalutamide was discovered by Charles Sawyers and Michael Jung at the University of California, Los Angeles.[56][57][58] They and their colleagues synthesized and evaluated nearly 200 thiohydantoin derivatives of RU-59063, an analogue of nilutamide, for AR antagonism in human prostate cancer cells, and identified enzalutamide and RD-162 as lead compounds.[36][58] These compounds were patented in 2006 and described in 2007.[11] Enzalutamide was developed and marketed by Medivation for the treatment of prostate cancer.[59] It was approved by the US Food and Drug Administration (FDA) for the treatment of mCRPC in the United States in August 2012, and for the treatment of nonmetastatic castration-resistant prostate cancer in July 2018.[19][60] Enzalutamide was the first new AR antagonist to be approved for the treatment of prostate cancer in over 15 years, following the introduction of the first-generation NSAA bicalutamide in 1995.[61] It was the first second-generation NSAA to be introduced.[14]

In July 2018, the FDA approved enzalutamide for the treatment of people with castration-resistant prostate cancer.[62] The approval broadens the indication to include people with both non-metastatic castration-resistant prostate cancer and metastatic castration-resistant prostate cancer.[62] Enzalutamide was previously approved for the treatment of people with metastatic castration-resistant prostate cancer.[62]

In December 2019, the FDA approved enzalutamide for the treatment of people with metastatic castration-sensitive prostate cancer (mCSPC).[10] Enzalutamide was previously approved for the treatment of people with castration-resistant prostate cancer.[10]

In June 2023, the FDA approved talazoparib, in combination with enzalutamide, for the treatment of people with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).[63]

In November 2023, the FDA approved enzalutamide for the treatment of people with non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis (high-risk BCR).[64] Efficacy was evaluated in EMBARK (NCT02319837), a randomized, controlled clinical trial of 1068 patients with nmCSPC with high-risk BCR.[64] All patients had prior definitive therapy with radical prostatectomy and/or radiotherapy with curative intent, had PSA doubling time ≤ 9 months, and were not candidates for salvage radiotherapy at enrollment.[64] Patients were randomized 1:1:1 to receive blinded enzalutamide 160 mg once daily plus leuprolide, open-label single- agent enzalutamide 160 mg once daily, or blinded placebo once daily plus leuprolide.[64] The application was granted priority review and fast track designations.[64]

Society and culture

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In June 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Enzalutamide Viatris, intended for the treatment of prostate cancer.[65][66] The applicant for this medicinal product is Viatris Limited.[65] Enzalutamide Viatris is a generic of Xtandi.[65]

Research

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Breast cancer

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Research suggests that enzalutamide may be effective in the treatment of certain types of breast cancer in women.[67][68] It has been tested for the treatment of triple-negative, AR-positive breast cancer in a phase II clinical trial.[69][70]

Hirsutism

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Enzalutamide has been suggested as a potential treatment for hirsutism and hyperandrogenism in women with polycystic ovary syndrome.[71][72]

References

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  1. ^ "Enzalutamide (Xtandi) Use During Pregnancy". Drugs.com. 4 September 2018. Archived from the original on 22 December 2019. Retrieved 21 December 2019.
  2. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab "Xtandi- enzalutamide capsule; Xtandi- enzalutamide tablet". DailyMed. 20 November 2023. Retrieved 9 March 2024.
  3. ^ a b c d e f g h i Gibbons JA, Ouatas T, Krauwinkel W, Ohtsu Y, van der Walt JS, Beddo V, et al. (2015). "Clinical Pharmacokinetic Studies of Enzalutamide". Clin Pharmacokinet. 54 (10): 1043–55. doi:10.1007/s40262-015-0271-5. PMC 4580721. PMID 25917876.
  4. ^ "Prescription medicines: registration of new chemical entities in Australia, 2014". Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 10 April 2023.
  5. ^ "Product monograph brand safety updates". Health Canada. February 2024. Retrieved 24 March 2024.
  6. ^ "Xtandi EPAR". European Medicines Agency (EMA). 21 June 2013. Retrieved 4 June 2024.
  7. ^ a b Kim TH, Jeong JW, Song JH, Lee KR, Ahn S, Ahn SH, et al. (November 2015). "Pharmacokinetics of enzalutamide, an anti-prostate cancer drug, in rats". Archives of Pharmacal Research. 38 (11): 2076–82. doi:10.1007/s12272-015-0592-9. PMID 25956695. S2CID 26903608.
  8. ^ a b Benoist GE, Hendriks RJ, Mulders PF, Gerritsen WR, Somford DM, Schalken JA, et al. (2016). "Pharmacokinetic Aspects of the Two Novel Oral Drugs Used for Metastatic Castration-Resistant Prostate Cancer: Abiraterone Acetate and Enzalutamide". Clin Pharmacokinet. 55 (11): 1369–1380. doi:10.1007/s40262-016-0403-6. PMC 5069300. PMID 27106175.
  9. ^ "Medivation's MDV3100 Shown to Be Effective in a Preclinical Model of Hormone-Refractory Prostate Cancer" (Press release). Medivation, Inc. 26 February 2007. Archived from the original on 16 September 2007. Retrieved 10 May 2009.
  10. ^ a b c "FDA approves enzalutamide for metastatic castration-sensitive prostate cancer". U.S. Food and Drug Administration (FDA). 17 December 2019. Archived from the original on 22 December 2019. Retrieved 21 December 2019.   This article incorporates text from this source, which is in the public domain.
  11. ^ a b Sawyers, C., Jung, M., Chen, C., Ouk, S., Welsbie, D., Tran, C., ... & Yoo, D. (2006). U.S. Patent Application No. 11/433,829. https://patents.google.com/patent/US20070004753 [1]
  12. ^ "FDA approves new treatment for a type of late stage prostate cancer" (Press release). U.S. Food and Drug Administration (FDA). 31 August 2012. Archived from the original on 2 October 2013. Retrieved 16 December 2019.
  13. ^ Anna Azvolinsky (4 September 2012). "FDA Approves Enzalutamide (Xtandi) for Late-Stage Prostate Cancer". CancerNetwork. Archived from the original on 13 September 2012. Retrieved 6 September 2012.
  14. ^ a b Saad F, Heinrich D (2013). "New Therapeutic Options for Castration-resistant Prostate Cancer". The Journal of Oncopathology. 1 (4): 23–32. doi:10.13032/tjop.2052-5931.100072 (inactive 11 November 2024).{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
  15. ^ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
  16. ^ Wenzel M, Nocera L, Collà Ruvolo C, Würnschimmel C, Tian Z, Shariat SF, et al. (May 2021). "Overall survival and adverse events after treatment with darolutamide vs. apalutamide vs. enzalutamide for high-risk non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis". Prostate Cancer Prostatic Dis (Systematic review). 25 (2): 139–148. doi:10.1038/s41391-021-00395-4. PMC 9184262. PMID 34054128.
  17. ^ Fishman SL, Paliou M, Poretsky L, Hembree WC (2019). "Endocrine Care of Transgender Adults". Transgender Medicine. Contemporary Endocrinology. pp. 143–163. doi:10.1007/978-3-030-05683-4_8. ISBN 978-3-030-05682-7. ISSN 2523-3785. S2CID 86772102. Non-steroidal selective androgen receptor antagonists, developed as a treatment for androgen-sensitive prostate cancer, are occasionally used in transgender females who do not achieve their desired results or do not tolerate alternative drugs [52]. There are isolated reports of successful outcomes with flutamide (Eulexin), though reportedly not as effective as cyproterone acetate in reducing testosterone levels [12]. Both flutamide and bicalutamide (Casodex), in conjunction with oral contraceptive pills, have shown significant improvements in hirsutism in natal females with polycystic ovarian syndrome (PCOS) [53, 54, 55, 56, 57]. The use of these agents as antiandrogens in transgender patients has been limited by concerns of hepatotoxicity. However, at low doses, these agents have shown to be both well tolerated and effective when used for the treatment of hirsutism [57]. [...] Table 8.2: Antiandrogens: [...] Androgen receptor blocker: [...] Type: Enzalutamide. Route: Oral. Dose: 160 mg/day.
  18. ^ Chan Swe N, Ahmed S, Eid M, Poretsky L, Gianos E, Cusano NE (March 2022). "The effects of gender-affirming hormone therapy on cardiovascular and skeletal health: A literature review". Metabol Open. 13: 100173. doi:10.1016/j.metop.2022.100173. PMC 8907681. PMID 35282421.
  19. ^ a b c d e Antonarakis ES (June 2013). "Enzalutamide: The emperor of all anti-androgens". Translational Andrology and Urology. 2 (2): 119–120. doi:10.3978/j.issn.2223-4683.2012.09.04. PMC 3785324. PMID 24076589.
  20. ^ Payton S (May 2014). "Prostate cancer: enzalutamide impresses in European studies". Nature Reviews. Urology. 11 (5): 243. doi:10.1038/nrurol.2014.98. PMID 24776976. S2CID 29251381.
  21. ^ a b c Golshayan AR, Antonarakis ES (2013). "Enzalutamide: an evidence-based review of its use in the treatment of prostate cancer". Core Evidence. 8: 27–35. doi:10.2147/CE.S34747. PMC 3622394. PMID 23589709.
  22. ^ Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, et al. (November 2015). "Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer: 1- and 2-Year Open-label Follow-up Results". European Urology. 68 (5): 787–94. doi:10.1016/j.eururo.2015.01.027. PMID 25687533.
  23. ^ Jeffrey K Aronson (4 March 2014). Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions. Newnes. pp. 740–. ISBN 978-0-444-62636-3.
  24. ^ a b c d e Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, et al. (May 2014). "Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study". The Lancet. Oncology. 15 (6): 592–600. doi:10.1016/S1470-2045(14)70129-9. PMID 24739897.
  25. ^ Vogelzang NJ (September 2012). "Enzalutamide--a major advance in the treatment of metastatic prostate cancer". The New England Journal of Medicine. 367 (13): 1256–7. doi:10.1056/NEJMe1209041. PMID 23013078.
  26. ^ a b Poole A, Alva A, Batten J, Agarwal N (17 December 2014). "Metastatic Castrate-Resistant Prostate Cancer: Role of Androgen Signaling Inhibitors". In Dicker AP, Kelly WK, Trabulsi EJ, Zaorsky NG (eds.). Prostate Cancer: A Multidisciplinary Approach to Diagnosis and Management. Demos Medical Publishing. p. 342. ISBN 978-1-936287-59-8. Archived from the original on 10 January 2023. Retrieved 5 January 2016.
  27. ^ a b Foster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J, et al. (2011). "Drug safety is a barrier to the discovery and development of new androgen receptor antagonists". The Prostate. 71 (5): 480–8. doi:10.1002/pros.21263. PMID 20878947. S2CID 24620044.
  28. ^ 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.
  29. ^ Jerome Z. Litt (25 January 2013). Litt's Drug Eruptions and Reactions Manual, 19th Edition. CRC Press. pp. 148–. ISBN 978-1-84214-599-9. Archived from the original on 10 January 2023. Retrieved 5 January 2016.
  30. ^ Tan PS, Haaland B, Montero AJ, Kyriakopoulos CE, Lopes G (2014). "Hormonal Therapeutics Enzalutamide and Abiraterone Acetate in the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC) Post-docetaxel-an Indirect Comparison". Clinical Medicine Insights: Oncology. 8: 29–36. doi:10.4137/CMO.S13671. PMC 3964205. PMID 24678245.
  31. ^ Labrie F (January 2015). "Combined blockade of testicular and locally made androgens in prostate cancer: a highly significant medical progress based upon intracrinology". J. Steroid Biochem. Mol. Biol. 145: 144–56. doi:10.1016/j.jsbmb.2014.05.012. PMID 24925260. S2CID 23102323.
  32. ^ a b Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, et al. (April 2010). "Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study". Lancet. 375 (9724): 1437–46. doi:10.1016/S0140-6736(10)60172-9. PMC 2948179. PMID 20398925.
  33. ^ a b Crona DJ, Whang YE (June 2015). "Posterior reversible encephalopathy syndrome induced by enzalutamide in a patient with castration-resistant prostate cancer". Investigational New Drugs. 33 (3): 751–4. doi:10.1007/s10637-014-0193-3. PMC 4451215. PMID 25467090.
  34. ^ a b c McCutcheon SB (2013). "Enzalutamide: a new agent for the prostate cancer treatment armamentarium". J Adv Pract Oncol. 4 (3): 182–5. doi:10.6004/jadpro.2013.4.3.7. PMC 4093421. PMID 25031999.
  35. ^ Narayanan R, Coss CC, Dalton JT (2018). "Development of selective androgen receptor modulators (SARMs)". Mol. Cell. Endocrinol. 465: 134–142. doi:10.1016/j.mce.2017.06.013. PMC 5896569. PMID 28624515.
  36. ^ a b c d e f Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. (May 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.
  37. ^ Li JJ, Johnson DS (14 December 2015). "Chapter 6: Enzalutamide". Innovative Drug Synthesis. John Wiley & Sons. p. 103. ISBN 978-1-118-82005-6.
  38. ^ a b c Ricci F, Buzzatti G, Rubagotti A, Boccardo F (November 2014). "Safety of antiandrogen therapy for treating prostate cancer". Expert Opinion on Drug Safety. 13 (11): 1483–99. doi:10.1517/14740338.2014.966686. PMID 25270521. S2CID 207488100.
  39. ^ Rodriguez-Vida A, Galazi M, Rudman S, Chowdhury S, Sternberg CN (2015). "Enzalutamide for the treatment of metastatic castration-resistant prostate cancer". Drug Design, Development and Therapy. 9: 3325–39. doi:10.2147/DDDT.S69433. PMC 4492664. PMID 26170619.
  40. ^ a b Annual Reports in Medicinal Chemistry. Elsevier Science. 13 September 2013. pp. 498–. ISBN 978-0-12-417151-0.
  41. ^ K.C Balaji (25 April 2016). Managing Metastatic Prostate Cancer In Your Urological Oncology Practice. Springer. pp. 24–25. ISBN 978-3-319-31341-2. Archived from the original on 10 January 2023. Retrieved 1 October 2016.
  42. ^ Keating GM (March 2015). "Enzalutamide: a review of its use in chemotherapy-naïve metastatic castration-resistant prostate cancer". Drugs & Aging. 32 (3): 243–9. doi:10.1007/s40266-015-0248-y. PMID 25711765. S2CID 29563345.
  43. ^ Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. (July 2014). "Enzalutamide in metastatic prostate cancer before chemotherapy". The New England Journal of Medicine. 371 (5): 424–33. doi:10.1056/NEJMoa1405095. PMC 4418931. PMID 24881730.
  44. ^ Claessens F, Helsen C, Prekovic S, Van den Broeck T, Spans L, Van Poppel H, et al. (December 2014). "Emerging mechanisms of enzalutamide resistance in prostate cancer". Nature Reviews Urology. 11 (12): 712–6. doi:10.1038/nrurol.2014.243. PMID 25224448. S2CID 13313385.
  45. ^ Balbas MD, Evans MJ, Hosfield DJ, Wongvipat J, Arora VK, Watson PA, et al. (April 2016). "Overcoming mutation-based resistance to antiandrogens with rational drug design". eLife. 2: e00499. doi:10.7554/eLife.00499. PMC 3622181. PMID 23580326.
  46. ^ Prekovic S, van Royen ME, Voet AR, Geverts B, Houtman R, Melchers D, et al. (May 2016). "The effect of F877L and T878A mutations on androgen receptor response to Enzalutamide". Molecular Cancer Therapeutics. 15 (7): 1702–12. doi:10.1158/1535-7163.MCT-15-0892. PMID 27196756.
  47. ^ Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. (September 2014). "AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer". New England Journal of Medicine. 371 (11): 1028–38. doi:10.1056/NEJMoa1315815. PMC 4201502. PMID 25184630.
  48. ^ Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, et al. (December 2013). "Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade". Cell. 155 (6): 1309–22. doi:10.1016/j.cell.2013.11.012. PMC 3932525. PMID 24315100.
  49. ^ Cui Y, Nadiminty N, Liu C, Lou W, Schwartz CT, Gao AC (June 2014). "Upregulation of glucose metabolism by NF-κB2/p52 mediates enzalutamide resistance in castration-resistant prostate cancer cells". Endocrine-Related Cancer. 21 (3): 435–42. doi:10.1530/ERC-14-0107. PMC 4021715. PMID 24659479.
  50. ^ Nguyen HG, Yang JC, Kung HJ, Shi XB, Tilki D, Lara PN, et al. (September 2014). "Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model". Oncogene. 33 (36): 4521–30. doi:10.1038/onc.2014.25. PMC 4155805. PMID 24662833.
  51. ^ Miyamoto DT, Zheng Y, Wittner BS, Lee RJ, Zhu H, Broderick KT, et al. (September 2015). "RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance". Science. 349 (6254): 1351–6. Bibcode:2015Sci...349.1351M. doi:10.1126/science.aab0917. PMC 4872391. PMID 26383955.
  52. ^ Liu C, Lou W, Zhu Y, Yang JC, Nadiminty N, Gaikwad NW, et al. (April 2015). "Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer". Cancer Research. 75 (7): 1413–22. doi:10.1158/0008-5472.CAN-14-3080. PMC 4383695. PMID 25649766.
  53. ^ Liu C, Zhu Y, Lou W, Cui Y, Evans CP, Gao AC (February 2014). "Inhibition of constitutively active Stat3 reverses enzalutamide resistance in LNCaP derivative prostate cancer cells". The Prostate. 74 (2): 201–9. doi:10.1002/pros.22741. PMC 4437226. PMID 24307657.
  54. ^ Hamilton RJ, ed. (4 December 2013). Tarascon Pocket Pharmacopoeia 2014 Deluxe Lab-Coat Edition. Jones & Bartlett Publishers. pp. 336–. ISBN 978-1-284-05399-9. Archived from the original on 10 January 2023. Retrieved 5 January 2016.
  55. ^ Georg F. Weber (22 July 2015). Molecular Therapies of Cancer. Springer. pp. 318–. ISBN 978-3-319-13278-5.
  56. ^ Borman S (2008). "New prostate cancer agent class". Chemical & Engineering News. 86 (38): 84–87. doi:10.1021/cen-v086n038.p084.
  57. ^ Jung ME, Ouk S, Yoo D, Sawyers CL, Chen C, Tran C, et al. (April 2010). "Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC)". Journal of Medicinal Chemistry. 53 (7): 2779–96. doi:10.1021/jm901488g. PMC 3180999. PMID 20218717.
  58. ^ a b 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.
  59. ^ "Enzalutamide - Astellas Pharma/Medivation - AdisInsight". Archived from the original on 17 July 2018. Retrieved 19 November 2017.
  60. ^ "FDA expands Xtandi approval for prostate cancer". www.healio.com. Archived from the original on 17 July 2018. Retrieved 17 July 2018.
  61. ^ Gohil K (August 2015). "Exciting Therapies Ahead in Prostate Cancer". P & T. 40 (8): 530–1. PMC 4517537. PMID 26236143.
  62. ^ a b c "FDA approves enzalutamide for castration-resistant prostate cancer". U.S. Food and Drug Administration. 13 July 2018. Retrieved 9 March 2024.   This article incorporates text from this source, which is in the public domain.
  63. ^ "FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer". U.S. Food and Drug Administration. 20 June 2023. Retrieved 9 March 2024.   This article incorporates text from this source, which is in the public domain.
  64. ^ a b c d e "FDA approves enzalutamide for non-metastatic castration-sensitive prostate cancer with biochemical recurrence". U.S. Food and Drug Administration (FDA). 16 November 2023. Retrieved 9 March 2024.   This article incorporates text from this source, which is in the public domain.
  65. ^ a b c "Enzalutamide Viatris EPAR". European Medicines Agency. 27 June 2024. Retrieved 29 June 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  66. ^ "Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 24-27 June 2024". European Medicines Agency. 28 June 2024. Archived from the original on 12 July 2024. Retrieved 12 July 2024.
  67. ^ "Preclinical Evaluation of Enzalutamide in Breast Cancer Models". Archived from the original on 23 February 2013.
  68. ^ "Medivation and Astellas Announce New Preclinical Study Results Showing MDV3100 Blocks Breast Cancer Cell Growth" (Press release). MarketWatch. 4 August 2011. Retrieved 25 September 2011.
  69. ^ Traina TA, O'Shaughnessy J, Nanda R, Schwartzberg L, Abramson V, Cortes J, et al. (2015). "Abstract P5-19-09: Preliminary results from a phase 2 single-arm study of enzalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC)". Cancer Research. 75 (9 Supplement): P5-19-09. doi:10.1158/1538-7445.SABCS14-P5-19-09.
  70. ^ Le Du F, Eckhardt BL, Lim B, Litton JK, Moulder S, Meric-Bernstam F, et al. (May 2015). "Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype?". Oncotarget. 6 (15): 12890–12908. doi:10.18632/oncotarget.3849. PMC 4536987. PMID 25973541.
  71. ^ Moretti C, Guccione L, Di Giacinto P, Simonelli I, Exacoustos C, Toscano V, et al. (2017). "Combined Oral Contraception and Bicalutamide in Polycystic Ovary Syndrome and Severe Hirsutism - a Double-blind RTC". J. Clin. Endocrinol. Metab. 103 (3): 824–838. doi:10.1210/jc.2017-01186. PMID 29211888.
  72. ^ Luque-Ramírez M, Escobar-Morreale HF (2015). "Targets to treat androgen excess in polycystic ovary syndrome". Expert Opin Ther Targets. 19 (11): 1545–60. doi:10.1517/14728222.2015.1075511. PMID 26549181. S2CID 207486790.
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