Enzalutamide

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Enzalutamide
Enzalutamide-01.svg
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
Licence data US FDA:link
  • US: X (Contraindicated)
Oral
Identifiers
915087-33-1
L02BB04
PubChem CID 15951529
ChemSpider 13093347
UNII 93T0T9GKNU
ChEBI CHEBI:68534 YesY
Chemical data
Formula C21H16F4N4O2S
464.44 g/mol

Enzalutamide (marketed as Xtandi and formerly known as MDV3100) is an androgen receptor antagonist drug developed by the pharmaceutical company Medivation for the treatment of metastatic castration-resistant prostate cancer.[1] Medivation has reported up to an 89% decrease in prostate specific antigen serum levels after a month of taking the medicine.[2] Early preclinical studies also suggest that enzalutamide inhibits breast cancer cell growth.[3][4] In August 2012, the U.S. Food and Drug Administration approved enzalutamide for the treatment of castration-resistant prostate cancer.[5][6]

Discovery[edit]

Enzalutamide was discovered by Charles Sawyers who is now at Memorial Sloan–Kettering Cancer Center and Michael Jung at UCLA.[7][8]

Preclinical pharmacology[edit]

Enzalutamide has approximately fivefold higher binding affinity for the androgen receptor (AR) compared to the antiandrogen bicalutamide.[9] As opposed to bicalutamide, enzalutamide does not promote translocation of AR to the nucleus and in addition prevents binding of AR to DNA and AR to coactivator proteins.[9]

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.[9] In VCaP cells which over express androgen receptors, enzalutamide induced apoptosis whereas bicalutamide did not.[9] Furthermore enzalutamide behaves as an antagonist of the W741C mutant androgen receptor in contrast to bicalutamide which behaves as a pure agonist when bound to the W741C mutant.[9]

Clinical studies[edit]

Enzalutamide is clinically active in metastatic castration-resistant prostate cancer.[10] PSA level decreased more than 50 percent in 40/65 chemo-naive patients and 38/75 chemotherapy-treated patients.[10] Median time to radiographic progression was 56 weeks for chemo-naive patients and 25 weeks for the post-chemotherapy population.[11]

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.[12] In November 2011, this trial was halted after an interim analysis revealed that patients given the drug lived for approximately 5 months longer than those taking placebo.[13] FDA approval was granted in August 2012.[5][14]

Another phase III trial known as PREVAIL is investigating the effectiveness of enzalutamide with patients who have not yet received chemotherapy.[15] On October 22, 2011, 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).[16] In addition, a phase II trial began in March 2011 comparing enzalutamide with a commonly used anti-androgen, bicalutamide, in prostate cancer patients who have progressed while on LHRH analogue therapy (e,g., leuprorelin) or surgical castration.[17][18]

See also[edit]

References[edit]

  1. ^ "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. 
  2. ^ "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. 
  3. ^ "Preclinical Evaluation of Enzalutamide in Breast Cancer Models". 
  4. ^ "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. 
  5. ^ a b "FDA approves new treatment for a type of late stage prostate cancer". press release. United States Food and Drug Administration. 2012-08-31. 
  6. ^ Anna Azvolinsky (September 4, 2012). "FDA Approves Enzalutamide (Xtandi) for Late-Stage Prostate Cancer". CancerNetwork. 
  7. ^ Borman S (2008). "New prostate cancer agent class". Chemical & Engineering News 86 (38): 84–87. doi:10.1021/cen-v086n038.p084. 
  8. ^ 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. 
  9. ^ a b c d e 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. 
  10. ^ a b 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. 
  11. ^ 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. 
  12. ^ "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) 
  13. ^ 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. 
  14. ^ Loftus P (2011-11-04). "Prostate Cancer Drug Shows Promise in Study". Health & Wellness. The Wall Street Journal. Retrieved 2011-11-04. 
  15. ^ "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) 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ "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