Enzalutamide

Enzalutamide
Systematic (IUPAC) name
4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide
Clinical data
Trade names Xtandi
AHFS/Drugs.com entry
License data
Pregnancy
category
  • US: X (Contraindicated) [1]
Routes of
administration		 Oral (capsules)
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%) and biliary (14%)
Identifiers
CAS Number 915087-33-1
ATC code L02BB04 (WHO)
PubChem CID 15951529
IUPHAR/BPS 6812
ChemSpider 13093347
UNII 93T0T9GKNU
KEGG D10218
ChEBI CHEBI:68534 YesY
Chemical data
Formula C21H16F4N4O2S
Molar mass 464.44 g·mol−1

Enzalutamide (INN, USAN) (brand name Xtandi ex-TAN-dee and former developmental code name MDV3100) is a synthetic, non-steroidal pure antiandrogen 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]

Discovery

Enzalutamide was discovered by Charles Sawyers who is now at Memorial Sloan–Kettering Cancer Center and Michael Jung at UCLA.[9][10]

Preclinical pharmacology

Enzalutamide has approximately 5- to 8-fold higher binding affinity for the androgen receptor (AR) compared to bicalutamide.[11][12] As opposed to 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.[11] As such, it has been described as an AR signaling inhibitor in addition to antagonist.[13]

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.[11] In VCaP cells which over-express the AR, enzalutamide induced apoptosis whereas bicalutamide did not.[11] 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.[11]

Clinical studies

Enzalutamide is clinically-active in metastatic castration-resistant prostate cancer.[14] PSA level decreased more than 50% in 40/65 chemo-naive patients and 38/75 chemotherapy-treated patients.[14] Median time to radiographic progression was 56 weeks for chemo-naive patients and 25 weeks for the post-chemotherapy population.[15]

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.[16] 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.[17] FDA approval was granted in August 2012.[7][18]

Another phase III trial known as PREVAIL is investigating the effectiveness of enzalutamide with patients who have not yet received chemotherapy.[19] 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).[20] 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.[21][22]

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 (300–600 mg/day), and substantially greater increases in testosterone levels relative to 150 mg/day bicalutamide (114% versus 66%), suggesting that, in accordance with its higher binding affinity to the AR and AR-related mechanistic improvements, enzalutamide is a significantly more potent and effective antiandrogen in comparison.[23][24]

Adverse 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][25][26][27]

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 non-steroidal antiandrogens such as bicalutamide.[23]

In regards to seizures, they have occurred in approximately 1% of patients treated with enzalutamide in clinical trials.[13][26] This is thought to be due to enzalutamide crossing the blood-brain-barrier[28][29] 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[29][30] and induces seizures in animals at high doses).[13][26] 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.[31]

There is a single case report of posterior reversible encephalopathy syndrome (PRES) with enzalutamide treatment.[32]

Pharmacokinetics

Enzalutamide has a very long half-life of 8–9 days.[1]

Enzalutamide is reported to be a strong inducer of the enzyme CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19.[33]

Research

In September 2015, it was announced that enzalutamide had shown effectiveness in the treatment of triple-negative, AR-positive breast cancer in a phase II clinical trial.[34][35]

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. 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. ↑ Borman S (2008). "New prostate cancer agent class". Chemical & Engineering News 86 (38): 84–87. doi:10.1021/cen-v086n038.p084.
  10. ↑ 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)". J. Med. Chem. 53 (7): 2779–96. doi:10.1021/jm901488g. PMC: 3180999. PMID 20218717.
  11. 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: 2981508. PMID 19359544.
  12. ↑ Rodriguez-Vida, Alejo; Chowdhury, Simon; Sternberg, Cora; Rudman, Sarah; Galazi, Myria (2015). "Enzalutamide for the treatment of metastatic castration-resistant prostate cancer". Drug Design, Development and Therapy 9: 3325–39. doi:10.2147/DDDT.S69433. ISSN 1177-8881. PMID 26170619.
  13. 1 2 3 4 Antonarakis ES (2013). "Enzalutamide: The emperor of all anti-androgens". Transl Androl Urol 2 (2): 119–120. PMC: 3785324. PMID 24076589.
  14. 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.
  15. ↑ 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.
  16. ↑ "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)
  17. ↑ 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". N. Engl. J. Med. 367 (13): 1187–97. doi:10.1056/NEJMoa1207506. PMID 22894553.
  18. ↑ Loftus P (2011-11-04). "Prostate Cancer Drug Shows Promise in Study". Health & Wellness. The Wall Street Journal. Retrieved 2011-11-04.
  19. ↑ "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)
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ "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
  23. 1 2 Tombal, Bertrand; Borre, Michael; Rathenborg, Per; Werbrouck, Patrick; Van Poppel, Hendrik; Heidenreich, Axel; Iversen, Peter; Braeckman, Johan; Heracek, Jiri; Baskin-Bey, Edwina; Ouatas, Taoufik; Perabo, Frank; Phung, De; Hirmand, Mohammad; Smith, Matthew R (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. ISSN 1470-2045. PMID 24739897.
  24. ↑ Ricci, Francesco; Buzzatti, Giulia; Rubagotti, Alessandra; Boccardo, Francesco (2014). "Safety of antiandrogen therapy for treating prostate cancer". Expert Opinion on Drug Safety 13 (11): 1483–1499. doi:10.1517/14740338.2014.966686. ISSN 1474-0338. PMID 25270521.
  25. ↑ Payton, Sarah (2014). "Prostate cancer: Enzalutamide impresses in European studies". Nature Reviews Urology 11 (5): 243–243. doi:10.1038/nrurol.2014.98. ISSN 1759-4812.
  26. 1 2 3 Golshayan AR, Antonarakis ES (2013). "Enzalutamide: an evidence-based review of its use in the treatment of prostate cancer". Core Evid 8: 27–35. doi:10.2147/CE.S34747. PMC: 3622394. PMID 23589709.
  27. ↑ Tombal, Bertrand; Borre, Michael; Rathenborg, Per; Werbrouck, Patrick; Van Poppel, Hendrik; Heidenreich, Axel; Iversen, Peter; Braeckman, Johan; Heracek, Jiri; Baskin-Bey, Edwina; Ouatas, Taoufik; Perabo, Frank; Phung, De; Baron, Benoit; Hirmand, Mohammad; Smith, Matthew R. (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. doi:10.1016/j.eururo.2015.01.027. ISSN 0302-2838. PMID 25687533.
  28. ↑ Vogelzang NJ (2012). "Enzalutamide--a major advance in the treatment of metastatic prostate cancer". N. Engl. J. Med. 367 (13): 1256–7. doi:10.1056/NEJMe1209041. PMID 23013078.
  29. 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.
  30. ↑ Rathkopf, Dana; Scher, Howard I. (2013). "Androgen Receptor Antagonists in Castration-Resistant Prostate Cancer". The Cancer Journal 19 (1): 43–49. doi:10.1097/PPO.0b013e318282635a. ISSN 1528-9117. PMC: 3788593. PMID 23337756.
  31. ↑ 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". Clin Med Insights Oncol 8: 29–36. doi:10.4137/CMO.S13671. PMC: 3964205. PMID 24678245.
  32. ↑ Crona DJ, Whang YE (2015). "Posterior reversible encephalopathy syndrome induced by enzalutamide in a patient with castration-resistant prostate cancer". Invest New Drugs 33 (3): 751–4. doi:10.1007/s10637-014-0193-3. PMID 25467090.
  33. ↑ 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.
  34. ↑ Traina, Tiffany A; O'Shaughnessy, Joyce; Nanda, Rita; Schwartzberg, Lee; Abramson, Vandana; Cortes, Javier; Peterson, Amy; Tudor, Iulia Cristina; Blaney, Martha; Steinberg, Joyce L; Kelly, Catherine; Trudeau, Maureen; Awada, Ahmad; Winer, Eric; Hudis, Clifford; Schmid, Peter; Yardley, Denise A (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. ISSN 0008-5472.
  35. ↑ Du, Fanny Le; Eckhardt, Bedrich L.; Lim, Bora; Litton, Jennifer K.; Moulder, Stacy; Meric-Bernstam, Funda; Gonzalez-Angulo, Ana M.; Ueno, Naoto T. (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. ISSN 1949-2553.
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