Chemistry:Enzalutamide

From HandWiki
Short description: Antiandrogen medication used in treatment of prostate cancer
Enzalutamide
Antiandrogen MDV3100.png
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 (capsules)[2][3]
Drug classNonsteroidal antiandrogen
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityRats: 89.7%[5]
Humans: unknown (but at least 84.6% based on recovery from excretion)[6][3]
Protein bindingEnzalutamide: 97–98% (primarily to albumin)[2]
NDME: 95%[2]
MetabolismLiver (primarily CYP2C8 and CYP3A4)[2]
Metabolites• NDME (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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H16F4N4O2S
Molar mass464.44 g·mol−1
3D model (JSmol)

Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer.[2][7] 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).[8] It is taken by mouth.[2]

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.[9][10][11] It was the first second-generation NSAA to be introduced.[12] It is on the World Health Organization's List of Essential Medicines.[13]


Medical uses

Prostate cancer

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.[14]

Other uses

Enzalutamide can be used as an antiandrogen in feminizing hormone therapy for transgender women.[15][16]

Available forms

Enzalutamide is provided in the form of a 40 mg Capsule.[2] It is taken orally at a dosage of 160 mg once per day (four capsules).[2]

Contraindications

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

Side effects

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.[17][18][19][20] Other "common" side effects reported in clinical trials have included neutropenia, visual hallucinations, anxiety, cognitive disorder, memory impairment, hypertension, dry skin, and pruritus (itching).[21] 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.[22]

Central adverse effects

Seizures have occurred in approximately 1% of patients treated with enzalutamide in clinical trials.[17][19] This is thought to be due to enzalutamide crossing the blood–brain barrier[23][24] 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 (IC50 = 3.6 μM)[24][25][26] and induces convulsions in animals at high doses).[17][19] 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.[27] Due to its ability to lower the seizure threshold, patients with known seizure disorders or brain injury should be closely monitored during enzalutamide treatment.[28] 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.[25] In dose-ranging studies, severe fatigue was observed with enzalutamide at doses of 240 mg/day and above.[29][30]

Rare adverse reactions

There is a single case report of posterior reversible encephalopathy syndrome (PRES) with enzalutamide treatment.[31] 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.[31]

Overdose

Enzalutamide may cause seizures in overdose.[2]

Interactions

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.[32]

In a clinical study of enzalutamide for ER-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.[33]

Pharmacology

Pharmacodynamics

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.[34] As such, it has been described as an AR signaling inhibitor in addition to antagonist.[17] 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.[35]

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.[34] In VCaP cells which over-express the AR, enzalutamide induced apoptosis whereas bicalutamide did not.[34] 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.[34]

Dose-ranging studies of enzalutamide in men with prostate cancer have been performed.[30]

Changes in hormone levels

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%.[22][36] These changes in hormone levels are similar to those with high-dose bicalutamide monotherapy.[22][36] The median maximum decrease in levels of prostate-specific antigen (PSA) levels was 99.6%.[22]

Comparison with other antiandrogens

Enzalutamide has approximately 8-fold higher binding affinity for the androgen receptor (AR) compared to bicalutamide.[34][37] One study found an IC50 of 21 nM for enzalutamide and 160 nM for bicalutamide at the AR in the LNCaP cell line (7.6-fold difference),[38] while another found respective IC50 values of 36 nM and 159 nM (4.4-fold difference).[39] 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.[22][36] 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.[40][41]

Resistance mechanisms in prostate cancer

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.[42] Currently, several mechanisms have been found:

Cytochrome P450 modulation

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.[52][32]

Pharmacokinetics

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.[6][3] Similarly, the bioavailability of enzalutamide in rats is 89.7%.[5] Steady-state concentrations of enzalutamide are achieved within 28 days of treatment initiation.[38] 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.[32] 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

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.[53]

History

Enzalutamide was discovered by Charles Sawyers, now at the Memorial Sloan–Kettering Cancer Center,[54] and Michael Jung at the University of California, Los Angeles.[55][56][57] 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.[34][57] These compounds were patented in 2006 and described in 2007.[9] Enzalutamide was developed and marketed by Medivation for the treatment of prostate cancer.[58] It was approved by the U.S. 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.[17][59] 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.[60] It was the first second-generation NSAA to be introduced.[12]

Research

Breast cancer

Research suggests that enzalutamide may be effective in the treatment of certain types of breast cancer in women.[61][62] It has been tested for the treatment of triple-negative, AR-positive breast cancer in a phase II clinical trial.[63][64]

Hirsutism

Enzalutamide has been suggested as a potential treatment for hirsutism and hyperandrogenism in women with polycystic ovary syndrome.[65][66]

References

  1. ↑ "Enzalutamide (Xtandi) Use During Pregnancy". 4 September 2018. https://www.drugs.com/pregnancy/enzalutamide.html. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 "Xtandi- enzalutamide capsule". 9 July 2018. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b129fdc9-1d8e-425c-a5a9-8a2ed36dfbdf. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 "Clinical Pharmacokinetic Studies of Enzalutamide". Clin Pharmacokinet 54 (10): 1043–55. 2015. doi:10.1007/s40262-015-0271-5. PMID 25917876. 
  4. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2014". 21 June 2022. https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014. 
  5. ↑ 5.0 5.1 "Pharmacokinetics of enzalutamide, an anti-prostate cancer drug, in rats". Archives of Pharmacal Research 38 (11): 2076–82. November 2015. doi:10.1007/s12272-015-0592-9. PMID 25956695. 
  6. ↑ 6.0 6.1 "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. 2016. doi:10.1007/s40262-016-0403-6. PMID 27106175. 
  7. ↑ "Medivation's MDV3100 Shown to Be Effective in a Preclinical Model of Hormone-Refractory Prostate Cancer" (Press release). Medivation, Inc. 2007-02-26. Archived from the original on 2007-09-16. Retrieved 2009-05-10.
  8. ↑ "FDA approves enzalutamide for metastatic castration-sensitive prostate cancer". 17 December 2019. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-metastatic-castration-sensitive-prostate-cancer.  This article incorporates text from this source, which is in the public domain.
  9. ↑ 9.0 9.1 Sawyers, C., Jung, M., Chen, C., Ouk, S., Welsbie, D., Tran, C., ... & Yoo, D. (2006). U.S. Patent Application No. 11/433,829. https://www.google.com/patents/US20070004753
  10. ↑ "FDA approves new treatment for a type of late stage prostate cancer" (Press release). U.S. Food and Drug Administration (FDA). 2012-08-31. Archived from the original on 2 October 2013. Retrieved 16 December 2019.
  11. ↑ Anna Azvolinsky (September 4, 2012). "FDA Approves Enzalutamide (Xtandi) for Late-Stage Prostate Cancer". CancerNetwork. http://www.cancernetwork.com/prostate-cancer/content/article/10165/2099887. 
  12. ↑ 12.0 12.1 "New Therapeutic Options for Castration-resistant Prostate Cancer". The Journal of Oncopathology 1 (4): 23–32. 2013. doi:10.13032/tjop.2052-5931.100072. "[...] enzalutamide was the first second-generation AR antagonist to be approved by the FDA in 2012 and by the EMA and Health Canada in 2013 [...]". 
  13. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  14. ↑ "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 25 (2): 139–148. May 2021. doi:10.1038/s41391-021-00395-4. PMID 34054128. 
  15. ↑ "Endocrine Care of Transgender Adults". Transgender Medicine. Contemporary Endocrinology. 2019. pp. 143–163. doi:10.1007/978-3-030-05683-4_8. ISBN 978-3-030-05682-7. "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." 
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  25. ↑ 25.0 25.1 "Drug safety is a barrier to the discovery and development of new androgen receptor antagonists". The Prostate 71 (5): 480–8. 2011. doi:10.1002/pros.21263. PMID 20878947. 
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  27. ↑ 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. https://books.google.com/books?id=IaTSBQAAQBAJ&pg=PA148. 
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  29. ↑ "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. January 2015. doi:10.1016/j.jsbmb.2014.05.012. PMID 24925260. 
  30. ↑ 30.0 30.1 "Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study". Lancet 375 (9724): 1437–46. April 2010. doi:10.1016/S0140-6736(10)60172-9. PMID 20398925. 
  31. ↑ 31.0 31.1 "Posterior reversible encephalopathy syndrome induced by enzalutamide in a patient with castration-resistant prostate cancer". Investigational New Drugs 33 (3): 751–4. June 2015. doi:10.1007/s10637-014-0193-3. PMID 25467090. 
  32. ↑ 32.0 32.1 32.2 "Enzalutamide: a new agent for the prostate cancer treatment armamentarium". J Adv Pract Oncol 4 (3): 182–5. 2013. doi:10.6004/jadpro.2013.4.3.7. PMID 25031999. 
  33. ↑ "Development of selective androgen receptor modulators (SARMs)". Mol. Cell. Endocrinol. 465: 134–142. 2018. doi:10.1016/j.mce.2017.06.013. PMID 28624515. 
  34. ↑ 34.0 34.1 34.2 34.3 34.4 34.5 "Development of a second-generation antiandrogen for treatment of advanced prostate cancer". Science 324 (5928): 787–90. May 2009. doi:10.1126/science.1168175. PMID 19359544. Bibcode: 2009Sci...324..787T. 
  35. ↑ "Chapter 6: Enzalutamide". Innovative Drug Synthesis. John Wiley & Sons. 14 December 2015. pp. 103. ISBN 978-1-118-82005-6. https://books.google.com/books?id=MT8xBwAAQBAJ&pg=PA103. 
  36. ↑ 36.0 36.1 36.2 "Safety of antiandrogen therapy for treating prostate cancer". Expert Opinion on Drug Safety 13 (11): 1483–99. November 2014. doi:10.1517/14740338.2014.966686. PMID 25270521. 
  37. ↑ "Enzalutamide for the treatment of metastatic castration-resistant prostate cancer". Drug Design, Development and Therapy 9: 3325–39. 2015. doi:10.2147/DDDT.S69433. PMID 26170619. 
  38. ↑ 38.0 38.1 Annual Reports in Medicinal Chemistry. Elsevier Science. 13 September 2013. pp. 498–. ISBN 978-0-12-417151-0. https://books.google.com/books?id=IUATAAAAQBAJ&pg=PA498. 
  39. ↑ 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. https://books.google.com/books?id=1U4WDAAAQBAJ&pg=PA25. 
  40. ↑ "Enzalutamide: a review of its use in chemotherapy-naïve metastatic castration-resistant prostate cancer". Drugs & Aging 32 (3): 243–9. March 2015. doi:10.1007/s40266-015-0248-y. PMID 25711765. 
  41. ↑ "Enzalutamide in metastatic prostate cancer before chemotherapy". The New England Journal of Medicine 371 (5): 424–33. July 2014. doi:10.1056/NEJMoa1405095. PMID 24881730. 
  42. ↑ "Emerging mechanisms of enzalutamide resistance in prostate cancer". Nature Reviews Urology 11 (12): 712–6. December 2014. doi:10.1038/nrurol.2014.243. PMID 25224448. 
  43. ↑ "Overcoming mutation-based resistance to antiandrogens with rational drug design". eLife 2: e00499. April 2016. doi:10.7554/eLife.00499. PMID 23580326. 
  44. ↑ "The effect of F877L and T878A mutations on androgen receptor response to Enzalutamide". Molecular Cancer Therapeutics 15 (7): 1702–12. May 2016. doi:10.1158/1535-7163.MCT-15-0892. PMID 27196756. 
  45. ↑ "AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer". New England Journal of Medicine 371 (11): 1028–38. September 2014. doi:10.1056/NEJMoa1315815. PMID 25184630. 
  46. ↑ "Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade". Cell 155 (6): 1309–22. December 2013. doi:10.1016/j.cell.2013.11.012. PMID 24315100. 
  47. ↑ "Upregulation of glucose metabolism by NF-κB2/p52 mediates enzalutamide resistance in castration-resistant prostate cancer cells". Endocrine-Related Cancer 21 (3): 435–42. June 2014. doi:10.1530/ERC-14-0107. PMID 24659479. 
  48. ↑ "Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model". Oncogene 33 (36): 4521–30. September 2014. doi:10.1038/onc.2014.25. PMID 24662833. 
  49. ↑ "RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance". Science 349 (6254): 1351–6. September 2015. doi:10.1126/science.aab0917. PMID 26383955. Bibcode: 2015Sci...349.1351M. 
  50. ↑ "Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer". Cancer Research 75 (7): 1413–22. April 2015. doi:10.1158/0008-5472.CAN-14-3080. PMID 25649766. 
  51. ↑ "Inhibition of constitutively active Stat3 reverses enzalutamide resistance in LNCaP derivative prostate cancer cells". The Prostate 74 (2): 201–9. February 2014. doi:10.1002/pros.22741. PMID 24307657. 
  52. ↑ Tarascon Pocket Pharmacopoeia 2014 Deluxe Lab-Coat Edition. Jones & Bartlett Publishers. 4 December 2013. pp. 336–. ISBN 978-1-284-05399-9. https://books.google.com/books?id=BwqEAgAAQBAJ&pg=PA336. 
  53. ↑ Georg F. Weber (22 July 2015). Molecular Therapies of Cancer. Springer. pp. 318–. ISBN 978-3-319-13278-5. https://books.google.com/books?id=dhs_CgAAQBAJ&pg=PA318. 
  54. ↑ "The Charles Sawyers Lab". Memorial Sloan–Kettering Cancer Center. https://www.mskcc.org/research-areas/labs/charles-sawyers. 
  55. ↑ "New prostate cancer agent class". Chemical & Engineering News 86 (38): 84–87. 2008. doi:10.1021/cen-v086n038.p084. 
  56. ↑ "Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC)". Journal of Medicinal Chemistry 53 (7): 2779–96. April 2010. doi:10.1021/jm901488g. PMID 20218717. 
  57. ↑ 57.0 57.1 "Developments in nonsteroidal antiandrogens targeting the androgen receptor". ChemMedChem 5 (10): 1651–61. 2010. doi:10.1002/cmdc.201000259. PMID 20853390. 
  58. ↑ "Enzalutamide - Astellas Pharma/Medivation - AdisInsight". http://adisinsight.springer.com/drugs/800026688. 
  59. ↑ "FDA expands Xtandi approval for prostate cancer". https://www.healio.com/hematology-oncology/prostate-cancer/news/online/%7Bc932ba92-2ba2-4572-af33-51b20462cedc%7D/fda-expands-xtandi-approval-for-prostate-cancer. 
  60. ↑ "Exciting Therapies Ahead in Prostate Cancer". P & T 40 (8): 530–1. August 2015. PMID 26236143. 
  61. ↑ "Preclinical Evaluation of Enzalutamide in Breast Cancer Models". http://cancerres.aacrjournals.org/cgi/content/meeting_abstract/72/24_MeetingAbstracts/P2-14-02. 
  62. ↑ "Medivation and Astellas Announce New Preclinical Study Results Showing MDV3100 Blocks Breast Cancer Cell Growth" (Press release). MarketWatch. 2011-08-04. Retrieved 2011-09-25.
  63. ↑ "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. 2015. doi:10.1158/1538-7445.SABCS14-P5-19-09. 
  64. ↑ "Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype?". Oncotarget 6 (15): 12890–12908. May 2015. doi:10.18632/oncotarget.3849. PMID 25973541. 
  65. ↑ "Combined Oral Contraception and Bicalutamide in Polycystic Ovary Syndrome and Severe Hirsutism - a Double-blind RTC". J. Clin. Endocrinol. Metab. 103 (3): 824–838. 2017. doi:10.1210/jc.2017-01186. PMID 29211888. 
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External links

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AR agonists
Progonadotropins
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See also
Androgen receptor modulators
Estrogens and antiestrogens
Progestogens and antiprogestogens
List of androgens/anabolic steroids

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See also
Receptor/signaling modulators
GABAA receptor positive modulators
GABA metabolism/transport modulators

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