Enzalutamide

Enzalutamide (INN, USAN)
Clinical data
Pronunciation ex-TAN-dee
Trade names Xtandi
AHFS/Drugs.com xtandi
License data
Pregnancy
category
  • US: X (Contraindicated) [1]
Routes of
administration		 Oral (capsules)
ATC code L02BB04 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 89.7% (rat)[2]
Protein binding 97–98%
Metabolism Hepatic (primarily CYP2C8 and CYP3A4)
Biological half-life 8–9 days[1]
Excretion Renal (71%), biliary (14%)
Identifiers
Synonyms MDV3100
CAS Number 915087-33-1
PubChem (CID) 15951529
IUPHAR/BPS 6812
ChemSpider 13093347
UNII 93T0T9GKNU
KEGG D10218
ChEBI CHEBI:68534 YesY
Chemical and physical data
Formula C21H16F4N4O2S
Molar mass 464.44 g·mol−1
3D model (Jmol) Interactive image

Enzalutamide (brand name Xtandi) is a synthetic non-steroidal antiandrogen (NSAA) which was developed by the pharmaceutical company Medivation for the treatment of metastatic castration-resistant prostate cancer.[3] Medivation has reported up to an 89% decrease in serum prostate specific antigen (PSA) levels after a month of taking the drug.[4] Research suggests that enzalutamide may also be effective in the treatment of certain types of breast cancer.[5][6] In August 2012, the United States (U.S.) Food and Drug Administration (FDA) approved enzalutamide for the treatment of castration-resistant prostate cancer.[7][8]

Medical uses

Prostate cancer

Enzalutamide is clinically active in metastatic castration-resistant prostate cancer.[9] PSA level decreased more than 50% in 40 of 65 chemo-naive patients and 38 of 75 chemotherapy-treated patients.[9] Median time to radiographic progression was 56 weeks for chemo-naive patients and 25 weeks for the post-chemotherapy population.[10]

Medivation conducted an international phase III trial that began in September 2009 known as AFFIRM. The aim of this trial was determine the safety and effectiveness of enzalutamide in patients who have previously failed chemotherapy treatment with docetaxel.[11] In November 2011, this trial was stopped early after an interim analysis revealed that patients given the drug lived for approximately 5 months longer than those taking placebo.[12] FDA approval was granted in August 2012.[7][13]

Another phase III trial known as PREVAIL is investigating the effectiveness of enzalutamide with patients who have not yet received chemotherapy.[14] On October 22, 2013, Medivation and Astellas announced that the PREVAIL trial met both co-primary endpoints of overall survival, with a 30% reduction in the risk of death compared with placebo (hazard ratio = 0.7; 95% confidence interval, range of 0.59–0.83), and radiographic progression-free survival, with an 81% reduction in risk of radiographic progression or death compared with placebo (hazard ratio = 0.19); 95% conficence interval, 0.15-0.23).[15] In addition, a phase II trial began in March 2011 comparing enzalutamide with bicalutamide in prostate cancer patients who have progressed while on gonadotropin-releasing hormone (GnRH) analogue therapy (e,g., leuprorelin) or surgical castration.[16][17]

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

Enzalutamide 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.[23]

Central side effects

Seizures have occurred in approximately 1% of patients treated with enzalutamide in clinical trials.[18][20] This is thought to be due to enzalutamide crossing the blood-brain-barrier[24][25] 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)[25][26][27] and induces seizures in animals at high doses).[18][20] 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.[1] 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.[26]

Rare reactions

There is a single case report of posterior reversible encephalopathy syndrome (PRES) with enzalutamide treatment.[29] 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.[29]

Comparison with other antiandrogens

Enzalutamide has approximately 5- to 8-fold higher binding affinity for the androgen receptor (AR) compared to bicalutamide.[30][31] 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),[32] while another found respective IC50 values of 36 nM and 159 nM (4.4-fold difference).[33] In accordance, enzalutamide, at a dosage of 160 mg/day, has been found to produce similar increases in testosterone, estradiol, and luteinizing hormone (LH) levels relative to high-dosage bicalutamide (300 mg/day), and an almost two-fold higher increase in testosterone levels relative to 150 mg/day bicalutamide (114% versus 66%).[23][34] These findings suggest that enzalutamide is a significantly more potent and effective antiandrogen in comparison.[23][34] Also, unlike with the first-generation NSAAs (flutamide, nilutamide, and bicalutamide), there has been no evidence of hepatotoxicity or elevated liver enzymes in association with enzalutamide treatment in clinical trials.[35][36]

Pharmacology

Antiandrogen

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.[18]

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]

Enzalutamide has only 2- to 3-fold lower affinity for the AR relative to the endogenous ligand dihydrotestosterone (DHT).[37]

Cytochrome P450 modulator

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.[38][39]

Pharmacokinetics

Enzalutamide has a very long half-life of 8–9 days.[1] Steady-state concentrations of enzalutamide are achieved within 28 days of treatment initiation.[32] The drug is metabolized hepatically by CYP2C8 and CYP3A4, with CYP2C8 primarily responsible for the formation of an active metabolite, N-desmethylenzalutamide.[39] Circulating concentrations of enzalutamide may be altered by inhibitors and inducers of CYP2C8 and CYP3A4, and should be avoided if possible.[39]

Chemistry

Enzalutamide is a diarylthiohydantoin derivative, and is structurally related to earlier NSAAs such as flutamide, nilutamide, and bicalutamide.[40]

History

Enzalutamide was discovered by Charles Sawyers who is now at Memorial Sloan–Kettering Cancer Center and Michael Jung at UCLA.[41][42]

Research

Enzalutamide has been tested for the treatment of triple-negative, AR-positive breast cancer in a phase II clinical trial.[43][44]

Resistance mechanisms

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

See also

References

  1. 1 2 3 4 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.
  2. ↑ 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.
  3. ↑ "Medivation's MDV3100 Shown to Be Effective in a Preclinical Model of Hormone-Refractory Prostate Cancer". Press release. Medivation, Inc. 2007-02-26. Retrieved 2009-05-10.
  4. ↑ "Medivation's MDV3100 Demonstrates Substantial PSA Reductions In First Patient Groups Treated In Phase 1-2 Hormone Refractory Prostate Cancer Trial". Medical News Today. 2007-11-06. Retrieved 2009-05-10.
  5. ↑ "Preclinical Evaluation of Enzalutamide in Breast Cancer Models".
  6. ↑ "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.
  7. 1 2 "FDA approves new treatment for a type of late stage prostate cancer". press release. United States Food and Drug Administration. 2012-08-31.
  8. ↑ Anna Azvolinsky (September 4, 2012). "FDA Approves Enzalutamide (Xtandi) for Late-Stage Prostate Cancer". CancerNetwork.
  9. 1 2 Scher HI, Beer TM, Higano CS, Taplin M, Efstathiou E, Anand A, Hung D, Hirmand M, Fleisher M (2009). "Antitumor activity of MDV3100 in a phase I/II study of castration-resistant prostate cancer (CRPC)". J Clin Oncol. 27 (15s): abstr 5011.
  10. ↑ Medivation, Inc. (2011-02-15). "Medivation and Astellas Announce Positive New, Long-Term Follow-Up Data From Phase 1-2 Trial of MDV3100 in Advanced Prostate Cancer Patients". Acquire Media. Retrieved 2011-03-24.
  11. ↑ "NCT00974311". ClinicalTrials.gov, United States National Institutes of Health. Retrieved 2009-10-29. Safety and Efficacy Study of MDV3100 in Patients With Castration-Resistant Prostate Cancer Who Have Been Previously Treated With Docetaxel-based Chemotherapy (AFFIRM)
  12. ↑ Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Fléchon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS (September 2012). "Increased survival with enzalutamide in prostate cancer after chemotherapy". The New England Journal of Medicine. 367 (13): 1187–97. doi:10.1056/NEJMoa1207506. PMID 22894553.
  13. ↑ Loftus P (2011-11-04). "Prostate Cancer Drug Shows Promise in Study". Health & Wellness. The Wall Street Journal. Retrieved 2011-11-04.
  14. ↑ "NCT01212991". ClinicalTrials.gov, United States National Institutes of Health. Retrieved 2011-11-06. A Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer (PREVAIL)
  15. ↑ Medivation, Inc. (2013-10-22). "Medivation and Astellas Announce the Phase 3 PREVAIL Trial of Enzalutamide Meets Both Co-Primary Endpoints of Overall Survival and Radiographic Progression-Free Survival in Chemotherapy-Naive Patients With Advanced Prostate Cancer". Acquire Media. Retrieved 2013-11-10.
  16. ↑ Medivation, Inc. (2011-03-30). "Medivation and Astellas Announce Initiation of Phase 2 Clinical Trial Comparing MDV3100 With Bicalutamide in Advanced Prostate Cancer". Press Release. Acquire Media. Retrieved 2011-04-02.
  17. ↑ "NCT01288911". ClinicalTrials.gov, United States National Institutes of Health. Retrieved 2011-11-06. A Study of MDV3100 Versus Bicalutamide in Castrate Men With Metastatic Prostate Cancer
  18. 1 2 3 4 Antonarakis ES (June 2013). "Enzalutamide: The emperor of all anti-androgens". Translational Andrology and Urology. 2 (2): 119–120. PMC 3785324Freely accessible. PMID 24076589.
  19. ↑ 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.
  20. 1 2 3 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 3622394Freely accessible. PMID 23589709.
  21. ↑ 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.
  22. ↑ 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.
  23. 1 2 3 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.
  24. ↑ 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.
  25. 1 2 Wm Kevin Kelly; Edouard J. Trabulsi, MD; Nicholas G. Zaorsky, MD (17 December 2014). Prostate Cancer: A Multidisciplinary Approach to Diagnosis and Management. Demos Medical Publishing. pp. 342–. ISBN 978-1-936287-59-8.
  26. 1 2 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.
  27. ↑ 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 3788593Freely accessible. PMID 23337756.
  28. ↑ 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 3964205Freely accessible. PMID 24678245.
  29. 1 2 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. PMID 25467090.
  30. 1 2 3 4 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. doi:10.1126/science.1168175. PMC 2981508Freely accessible. PMID 19359544.
  31. ↑ 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. PMID 26170619.
  32. 1 2 Annual Reports in Medicinal Chemistry. Elsevier Science. 13 September 2013. pp. 498–. ISBN 978-0-12-417151-0.
  33. ↑ 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.
  34. 1 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.
  35. ↑ 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.
  36. ↑ 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 4418931Freely accessible. PMID 24881730.
  37. ↑ Jie Jack Li; Douglas S. Johnson (14 December 2015). Innovative Drug Synthesis. John Wiley & Sons. pp. 103–. ISBN 978-1-118-82005-6.
  38. ↑ Richard J., Editor in Chief Hamilton FAAEM FACMT (4 December 2013). Tarascon Pocket Pharmacopoeia 2014 Deluxe Lab-Coat Edition. Jones & Bartlett Publishers. pp. 336–. ISBN 978-1-284-05399-9.
  39. 1 2 3 McCutcheon SB (2013). "Enzalutamide: a new agent for the prostate cancer treatment armamentarium". J Adv Pract Oncol. 4 (3): 182–5. PMC 4093421Freely accessible. PMID 25031999.
  40. ↑ Georg F. Weber (22 July 2015). Molecular Therapies of Cancer. Springer. pp. 318–. ISBN 978-3-319-13278-5.
  41. ↑ Borman S (2008). "New prostate cancer agent class". Chemical & Engineering News. 86 (38): 84–87. doi:10.1021/cen-v086n038.p084.
  42. ↑ Jung ME, Ouk S, Yoo D, Sawyers CL, Chen C, Tran C, Wongvipat J (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 3180999Freely accessible. PMID 20218717.
  43. ↑ Traina TA, O'Shaughnessy J, Nanda R, Schwartzberg L, Abrasion 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–P5–19–09. doi:10.1158/1538-7445.SABCS14-P5-19-09.
  44. ↑ Le Du F, Eckhardt BL, Lim B, Litton JK, Moulder S, Meric-Bernstam F, Gonzalez-Angulo AM, Ueno NT (May 2015). "Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype?". Oncotarget. 6 (15): 12890–908. doi:10.18632/oncotarget.3849. PMC 4536987Freely accessible. PMID 25973541.
  45. ↑ 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. PMID 25224448.
  46. ↑ 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. PMID 23580326.
  47. ↑ 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. PMID 27196756.
  48. ↑ 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. PMID 25184630.
  49. ↑ Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, Shah N, Cai L, Efstathiou E, Logothetis C, Zheng D (December 2013). ". Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade". Cell. PMID 24315100.
  50. ↑ 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. PMID 24659479.
  51. ↑ Nguyen HG, Yang JC, Kung HJ, Shi XB, Tilki D, Lara PN, White RD, Gao AC, Evans CP (September 2014). "Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model". Oncogene. PMID 24662833.
  52. ↑ Miyamoto DT, Zheng Y, Wittner BS, Lee RJ, Zhu H, Broderick KT, Desai R, Fox DB, Brannigan BW, Trautwein J, Arora KS (September 2015). "RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance". Science. PMID 26383955.
  53. ↑ Liu C, Lou W, Zhu Y, Yang JC, Nadiminty N, Gaikwad NW, Evans CP, Gao AC (April 2015). "Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer". Cancer research. PMID 25649766.
  54. ↑ 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. PMID 24307657.
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