Enzalutamide

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Enzalutamide
Names
Pronunciation/ɛksˈtændi/ eks-TAN-dee
Trade namesXtandi
Other namesMDV-3100; ASP-9785
  • 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide
Clinical data
Drug classNonsteroidal antiandrogen (NSAA)[1]
Main usesProstate cancer[2]
Side effectsTiredness, back pain, diarrhea, joint pain, high blood pressure, hot flashes[2]
Pregnancy
category
  • AU: X (High risk)[3]
  • US: N (Not classified yet)[3]
Routes of
use		By mouth (capsules)[2][4]
Typical dose160 mg OD[2]
External links
AHFS/Drugs.comMonograph
MedlinePlusa612033
Legal
License data
Legal status
Pharmacokinetics
BioavailabilityRats: 89.7%[5]
Humans: unknown (but at least 84.6% based on recovery from excretion)[6][4]
Protein bindingEnzalutamide: 97–98% (primarily to albumin)[2]
NDME: 95%[2]
MetabolismLiver (primarily CYP2C8 and CYP3A4)[2]
Metabolites• NDME (active)[2][4]
• Carboxylic acid derivative metabolite (inactive)[4]
Elimination half-lifeEnzalutamide: 5.8 days (range 2.8–10.2 days)[2]
NDME: 7.8–8.6 days[2]
ExcretionUrine: 71.0%[4]
Bile: 13.6%[4]
Feces: 0.39%[4]
Chemical and physical data
FormulaC21H16F4N4O2S
Molar mass464.44 g·mol−1
3D model (JSmol)
  • CC1(C(=O)N(C(=S)N1C2=CC(=C(C=C2)C(=O)NC)F)C3=CC(=C(C=C3)C#N)C(F)(F)F)C
  • 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

Enzalutamide, sold under the brand name Xtandi, is a medication used to treat prostate cancer.[2] Specifically it is us to treat castration-resistant prostate cancer (mCRPC), and metastatic castration-sensitive prostate cancer (mCSPC).[2] It is taken by mouth.[2]

Common side effects include tiredness, back pain, diarrhea, joint pain, high blood pressure, and hot flashes.[2] Other side effects may include seizures, posterior reversible encephalopathy syndrome, allergic reactions, and falls.[2] Use during pregnancy, including by the male, may harm the baby.[2] There are a number of medication interactions.[2] It is a nonsteroidal antiandrogen (NSAA) which works by blocking androgens like testosterone, from binding to the androgen receptor.[1]

Enzalutamide was patented in 2006 and approved for medical use in the United States in 2012.[7][1] It is on the World Health Organization's List of Essential Medicines as an alternative abiraterone.[8] In the United Kingdom 4 weeks of treatment costs the NHS about £2,700 as of 2021.[9] This amount in the United States costs about 12,000 USD.[10]

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.[11]

Other uses

Enzalutamide can be used as an antiandrogen in feminizing hormone therapy for transgender women.[12]

Dosage

Enzalutamide is provided in the form of a 40 mg Capsule.[2] It is taken by mouth 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.[13][14][15][16] Other "common" side effects reported in clinical trials have included neutropenia, visual hallucinations, anxiety, cognitive disorder, memory impairment, hypertension, dry skin, and pruritus (itching).[17] 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.[18]

Central nervous system

Seizures have occurred in approximately 1% of people treated with enzalutamide in clinical trials.[13][15] This is thought to be due to enzalutamide crossing the blood–brain barrier[19][20] 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)[20][21][22] and induces convulsions in animals at high doses).[13][15] 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.[23] Due to its ability to lower the seizure threshold, patients with known seizure disorders or brain injury should be closely monitored during enzalutamide treatment.[24] 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.[21] In dose-ranging studies, severe fatigue was observed with enzalutamide at doses of 240 mg/day and above.[25][26]

Rare reactions

There is a single case report of posterior reversible encephalopathy syndrome (PRES) with enzalutamide treatment.[27] 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.[27]

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.[28]

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.[29]

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.[30] As such, it has been described as an AR signaling inhibitor in addition to antagonist.[13] 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.[31]

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.[30] In VCaP cells which over-express the AR, enzalutamide induced apoptosis whereas bicalutamide did not.[30] 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.[30]

Dose-ranging studies of enzalutamide in men with prostate cancer have been performed.[26]

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%.[18][32] These changes in hormone levels are similar to those with high-dose bicalutamide monotherapy.[18][32] The median maximum decrease in levels of prostate-specific antigen (PSA) levels was 99.6%.[18]

Comparison with other antiandrogens

Enzalutamide has approximately 8-fold higher binding affinity for the androgen receptor (AR) compared to bicalutamide.[30][33] 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),[34] while another found respective IC50 values of 36 nM and 159 nM (4.4-fold difference).[35] 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.[18][32] 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.[36][37]

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.[38] 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.[48][28]

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][4] Similarly, the bioavailability of enzalutamide in rats is 89.7%.[5] Steady-state concentrations of enzalutamide are achieved within 28 days of treatment initiation.[34] 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.[28] 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.[4]

Chemistry

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.[49] The 3D structure of enzalutamide can be viewed using QRChem.net. Archived 2021-04-16 at the Wayback Machine

History

Enzalutamide was discovered by Charles Sawyers who is now[when?] at Memorial Sloan–Kettering Cancer Center and Michael Jung at the University of California, Los Angeles.[50][51][52] 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.[30][52] These compounds were patented in 2006 and described in 2007.[53] Enzalutamide was developed and marketed by Medivation for the treatment of prostate cancer.[54] 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.[13][55] 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.[56] It was the first second-generation NSAA to be introduced.[57]

Research

Breast cancer

Research suggests that enzalutamide may be effective in the treatment of certain types of breast cancer in women.[58][59] It has been tested for the treatment of triple-negative, AR-positive breast cancer in a phase II clinical trial.[60][61]

Hirsutism

Enzalutamide has been suggested for the treatment of hirsutism and hyperandrogenism in women with polycystic ovary syndrome.[62]

References

  1. ↑ 1.0 1.1 1.2 "Enzalutamide Monograph for Professionals". Drugs.com. Archived from the original on 22 December 2019. Retrieved 15 December 2021.
  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 2.27 "Xtandi- enzalutamide capsule". DailyMed. 9 July 2018. Archived from the original on 20 December 2015. Retrieved 21 December 2019.
  3. ↑ 3.0 3.1 "Enzalutamide (Xtandi) Use During Pregnancy". Drugs.com. 4 September 2018. Archived from the original on 22 December 2019. Retrieved 21 December 2019.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Gibbons JA, Ouatas T, Krauwinkel W, Ohtsu Y, van der Walt JS, Beddo V, de Vries M, Mordenti J (2015). "Clinical Pharmacokinetic Studies of Enzalutamide". Clin Pharmacokinet. 54 (10): 1043–55. doi:10.1007/s40262-015-0271-5. PMC 4580721. PMID 25917876.
  5. ↑ 5.0 5.1 Kim TH, Jeong JW, Song JH, Lee KR, Ahn S, Ahn SH, Kim S, Koo TS (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.
  6. ↑ 6.0 6.1 Benoist GE, Hendriks RJ, Mulders PF, Gerritsen WR, Somford DM, Schalken JA, van Oort IM, Burger DM, van Erp NP (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.
  7. ↑ Sawyers, Charles; Jung, Michael; Chen, Charlie; Ouk, Samedy; Welsbie, Derek; Tran, Chris; Wongvipat, John; Yoo, Dongwon (4 January 2007). "Diarylhydantoin compounds". Archived from the original on 5 October 2016. Retrieved 15 December 2021.
  8. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  9. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 991. ISBN 978-0857114105.
  10. ↑ "Xtandi Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 17 December 2021. Retrieved 15 December 2021.
  11. ↑ Wenzel M, Nocera L, Collà Ruvolo C, Würnschimmel C, Tian Z, 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). doi:10.1038/s41391-021-00395-4. PMID 34054128.
  12. ↑ Fishman, Sarah L.; Paliou, Maria; Poretsky, Leonid; Hembree, Wylie C. (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. 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.
  13. ↑ 13.0 13.1 13.2 13.3 13.4 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.
  14. ↑ 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.
  15. ↑ 15.0 15.1 15.2 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.
  16. ↑ Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, Iversen P, Braeckman J, Heracek J, Baskin-Bey E, Ouatas T, Perabo F, Phung D, Baron B, Hirmand M, Smith MR (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.
  17. ↑ 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. Archived from the original on 27 July 2020. Retrieved 4 October 2021.
  18. ↑ 18.0 18.1 18.2 18.3 18.4 Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, Iversen P, Braeckman J, Heracek J, Baskin-Bey E, Ouatas T, Perabo F, Phung D, Hirmand M, Smith MR (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.
  19. ↑ 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.
  20. ↑ 20.0 20.1 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 14 May 2016. Retrieved 4 October 2021.
  21. ↑ 21.0 21.1 Foster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J, Arezzo JC, Powlin SS, Dinchuk JE, Balog A, Salvati ME, Attar RM, Gottardis MM (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.
  22. ↑ 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.
  23. ↑ 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 25 April 2020. Retrieved 4 October 2021.
  24. ↑ 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.
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  26. ↑ 26.0 26.1 Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila DC, Humm J, Larson S, Fleisher M, Sawyers CL (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.
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  29. ↑ 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.
  30. ↑ 30.0 30.1 30.2 30.3 30.4 30.5 Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL (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.
  31. ↑ Li JJ, Johnson DS (14 December 2015). "Chapter 6: Enzalutamide". Innovative Drug Synthesis. John Wiley & Sons. p. 103. ISBN 978-1-118-82005-6.
  32. ↑ 32.0 32.1 32.2 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.
  33. ↑ 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.
  34. ↑ 34.0 34.1 Annual Reports in Medicinal Chemistry. Elsevier Science. 13 September 2013. pp. 498–. ISBN 978-0-12-417151-0. Archived from the original on 8 September 2017. Retrieved 4 October 2021.
  35. ↑ 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 27 July 2020. Retrieved 4 October 2021.
  36. ↑ 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.
  37. ↑ Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B (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.
  38. ↑ Claessens F, Helsen C, Prekovic S, Van den Broeck T, Spans L, Van Poppel H, Joniau S (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.
  39. ↑ Balbas MD, Evans MJ, Hosfield DJ, Wongvipat J, Arora VK, Watson PA, Chen Y, Greene GL, Shen Y, Sawyers CL (April 2016). "Overcoming mutation-based resistance to antiandrogens with rational drug design". eLife. 2: e00499. doi:10.7554/eLife.00499. PMC 3622181. PMID 23580326.
  40. ↑ Prekovic S, van Royen ME, Voet AR, Geverts B, Houtman R, Melchers D, Zhang KY, Van den Broeck T, Smeets E, Spans L, Houtsmuller AB, Joniau S, Claessens F, Helsen C (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.
  41. ↑ Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL (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.
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