title: Enzalutamide: targeting the androgen signalling pathway in metastatic castration-resistant prostate cancer.
abstract: Significant progress has been made in the understanding of the underlying cancer biology of castration-resistant prostate cancer (CRPC) with the androgen receptor (AR) signalling pathway remaining implicated throughout the prostate cancer disease continuum. Reactivation of the AR signalling pathway is considered to be a key driver of CRPC progression and, as such, the AR is a logical target for therapy in CRPC. The objective of this review was to understand the importance of AR signalling in the treatment of patients with metastatic CRPC (mCRPC) and to discuss the clinical benefits associated with inhibition of the AR signalling pathway. A search was conducted to identify articles relating to the role of AR signalling in CRPC and therapies that inhibit the AR signalling pathway. Current understanding of prostate cancer has identified the AR signalling pathway as a logical target for the treatment of CRPC. Available therapies that inhibit the AR signalling pathway include AR blockers, androgen biosynthesis inhibitors, and AR signalling inhibitors. Enzalutamide, the first approved AR signalling inhibitor, has a novel mode of action targeting AR signalling at three key stages. The direct mode of action of enzalutamide has been shown to translate into clinical responses in patients with mCRPC. In conclusion, the targeting of the AR signalling pathway in patients with mCRPC results in numerous clinical benefits. As the number of treatment options increase, more trials evaluating the sequencing and combination of treatments are required. This review highlights the continued importance of targeting a key driver in the progression of CRPC, AR signalling, and the clinical benefits associated with inhibition of the AR signalling pathway in the treatment of patients with CRPC.
authors.affiliation: Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Jack
authors.initials: J
authors.lastname: Schalken
authors.affiliation: Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: John M
authors.initials: JM
authors.lastname: Fitzpatrick
mesh_terms: D059002:Androgen Receptor Antagonists / Q000627:therapeutic use*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy / Q000639:trends; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D011944:Receptors, Androgen / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide
keywords: androgen receptor signalling; castration-resistant; enzalutamide; mechanism of action; metastatic; prostate cancer
references.citation: Urology. 2000 Mar;55(3):323-7
references.pmid: 10699601
references.citation: Lancet Oncol. 2014 Aug;15(9):975-85
references.pmid: 24974051
references.citation: Cancer Res. 2012 May 1;72(9):2176-82
references.pmid: 22411952
references.citation: Eur Urol. 2015 Jan;67(1):53-60
references.pmid: 24882673
references.citation: Nat Med. 2004 Jan;10(1):33-9
references.pmid: 14702632
references.citation: Urol Clin North Am. 1997 May;24(2):421-31
references.pmid: 9126240
references.citation: Curr Cancer Drug Targets. 2009 Mar;9(2):237-49
references.pmid: 19275762
references.citation: Urol Oncol. 2011 Nov-Dec;29(6 Suppl):S1-8
references.pmid: 22074657
references.citation: N Engl J Med. 2004 Oct 7;351(15):1502-12
references.pmid: 15470213
references.citation: Ann Oncol. 2013 Jul;24(7):1802-7
references.pmid: 23585511
references.citation: Elife. 2013;2:e00499
references.pmid: 23580326
references.citation: J Clin Invest. 2010 Aug;120(8):2715-30
references.pmid: 20644256
references.citation: Lancet Oncol. 2014 Sep;15(10):1147-56
references.pmid: 25104109
references.citation: Adv Ther. 2014 Feb;31(2):234-41
references.pmid: 24442834
references.citation: Eur Urol. 2015 Aug;68(2):317-24
references.pmid: 25108579
references.citation: Eur Urol. 2014 Jan;65(1):30-6
references.pmid: 23849416
references.citation: N Engl J Med. 2012 Sep 27;367(13):1187-97
references.pmid: 22894553
references.citation: J Clin Oncol. 2002 Jul 1;20(13):3001-15
references.pmid: 12089231
references.citation: Endocr Rev. 1995 Jun;16(3):271-321
references.pmid: 7671849
references.citation: PLoS One. 2011;6(11):e27970
references.pmid: 22114732
references.citation: Science. 2009 May 8;324(5928):787-90
references.pmid: 19359544
references.citation: Expert Rev Endocrinol Metab. 2010 Sep;5(5):753-764
references.pmid: 21318111
references.citation: Nat Genet. 1995 Apr;9(4):401-6
references.pmid: 7795646
references.citation: Cancer Res. 2011 Sep 15;71(18):6019-29
references.pmid: 21799031
references.citation: Clin Cancer Res. 2009 May 15;15(10):3251-5
references.pmid: 19447877
references.citation: N Engl J Med. 2004 Oct 7;351(15):1513-20
references.pmid: 15470214
references.citation: Lancet. 2010 Oct 2;376(9747):1147-54
references.pmid: 20888992
references.citation: Eur Urol. 2015 Jun;67(6):981-5
references.pmid: 25484141
references.citation: Endocr Rev. 2004 Apr;25(2):276-308
references.pmid: 15082523
references.citation: J Med Chem. 2010 Apr 8;53(7):2779-96
references.pmid: 20218717
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7379-84
references.pmid: 9636157
references.citation: Eur Urol. 2015 Jul;68(1):147-53
references.pmid: 25457020
references.citation: N Engl J Med. 2014 Sep 11;371(11):1028-38
references.pmid: 25184630
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16759-65
references.pmid: 20823238
references.citation: J Clin Oncol. 2011 Sep 20;29(27):3651-8
references.pmid: 21859989
references.citation: Ann Oncol. 2013 Jul;24(7):1807-12
references.pmid: 23576708
references.citation: Ann Oncol. 2014 Feb;25(2):429-34
references.pmid: 24478320
references.citation: Eur Urol. 2015 Feb;67(2):223-30
references.pmid: 25171902
references.citation: Lancet Oncol. 2009 Oct;10(10):981-91
references.pmid: 19796750
references.citation: Cancer Res. 2009 Apr 1;69(7):2912-8
references.pmid: 19339269
references.citation: Scand J Urol. 2014 Jun;48(3):268-75
references.pmid: 24255983
references.citation: Eur Urol. 2014 Sep;66(3):459-65
references.pmid: 24411987
references.citation: Cancer Res. 1997 Jan 15;57(2):314-9
references.pmid: 9000575
references.citation: Urol Oncol. 2009 May-Jun;27(3):251-7
references.pmid: 19414113
references.citation: J Clin Oncol. 2013 Oct 1;31(28):3525-30
references.pmid: 24002508
references.citation: N Engl J Med. 2014 Jul 31;371(5):424-33
references.pmid: 24881730
references.citation: Int J Clin Pract. 2011 Nov;65(11):1180-92
references.pmid: 21995694
references.citation: N Engl J Med. 2011 May 26;364(21):1995-2005
references.pmid: 21612468
references.citation: Cancer Res. 2009 Jan 1;69(1):16-22
references.pmid: 19117982
references.citation: PLoS One. 2013;8(5):e63466
references.pmid: 23658830
references.citation: Eur J Cancer. 2014 Mar;50(5):1040-1
references.pmid: 24462374
references.citation: N Engl J Med. 2013 Jan 10;368(2):138-48
references.pmid: 23228172
references.citation: Ther Adv Urol. 2012 Aug;4(4):167-78
references.pmid: 22852027
references.citation: Eur Urol. 2014 Jun;65(6):1198-204
references.pmid: 23910941
references.citation: BJU Int. 2015 Jan;115(1):41-9
references.pmid: 25123978
references.citation: J Clin Oncol. 2004 Mar 15;22(6):1025-33
references.pmid: 15020604
references.citation: Cancer. 2014 Apr 1;120(7):968-75
references.pmid: 24382803
references.citation: Lancet. 2010 Apr 24;375(9724):1437-46
references.pmid: 20398925
references.citation: Eur J Cancer. 2014 Jan;50(1):78-84
references.pmid: 24074764
references.citation: Prostate Cancer Prostatic Dis. 2015 Jun;18(2):122-7
references.pmid: 25600186
references.citation: Eur Urol. 2013 Aug;64(2):177-88
references.pmid: 22939387
references.citation: Expert Rev Endocrinol Metab. 2011 May;6(3):483-493
references.pmid: 22389648
references.citation: Lancet. 2000 Apr 29;355(9214):1491-8
references.pmid: 10801170
references.citation: Cancer Res. 2012 Mar 15;72(6):1494-503
references.pmid: 22266222
references.citation: Ann Oncol. 2013 May;24(5):1141-62
references.pmid: 23303340