AR-V7-and-Resistance-to-Enzalutamide-and-Abiratero

Thenewenglandjournalofmedicinenengljmednejm.org1originalarticleAR-V7andResistancetoEnzalutamideandAbirateroneinProstateCancerEmmanuelS.Antonarakis,M.D.,ChangxueLu,Ph.D.,HaoWang,Ph.D.,BrandonLuber,Sc.M.,MaryNakazawa,M.H.S.,JeffreyC.Roeser,B.S.,YanChen,Ph.D.,TabrezA.Mohammad,Ph.D.,YidongChen,Ph.D.,HelenL.Fedor,B.S.,TamaraL.Lotan,M.D.,QizhiZheng,M.D.,AngeloM.DeMarzo,M.D.,Ph.D.,JohnT.Isaacs,Ph.D.,WilliamB.Isaacs,Ph.D.,RosaNadal,M.D.,ChanningJ.Paller,M.D.,SamuelR.Denmeade,M.D.,MichaelA.Carducci,M.D.,MarioA.Eisenberger,M.D.,andJunLuo,Ph.D.FromtheDepartmentsofOncology(E.S.A.,H.W.,B.L.,J.T.I.,R.N.,C.J.P.,S.R.D.,M.A.C.,M.A.E.),Pathology(H.L.F.,T.L.L.,Q.Z.,A.M.D.M.),andUrology(C.L.,M.N.,J.C.R.,YanChen,W.B.I.,J.L.),JohnsHop-kinsUniversitySchoolofMedicine,Balti-more;andGreeheyChildren’sCancerResearchInstitute(T.A.M.,YidongChen)andtheDepartmentofEpidemiologyandBiostatistics(YidongChen),UniversityofTexasHealthScienceCenteratSanAnto-nio,SanAntonio.AddressreprintrequeststoDr.AntonarakisattheProstateCancerResearchProgram,SidneyKimmelCom-prehensiveCancerCenteratJohnsHop-kins,1650OrleansSt.,CRB1–1M45,Bal-timore,MD21287,[e-mail];ortoDr.LuoattheJamesBuchananBradyUrologicalInstituteandtheDe-partmentofUrology,JohnsHopkinsUni-versitySchoolofMedicine,600N.WolfeSt.,Baltimore,MD21287,[e-mail]nSeptember3,2014,atNEJM.org.DOI:10.1056/NEJMoa1315815Copyright©2014MassachusettsMedicalSociety.AbstractBackgroundTheandrogen-receptorisoformencodedbysplicevariant7lackstheligand-bindingdomain,whichisthetargetofenzalutamideandabiraterone,butremainsconsti-tutivelyactiveasatranscriptionfactor.Wehypothesizedthatdetectionofandro-gen-receptorsplicevariant7messengerRNA(AR-V7)incirculatingtumorcellsfrommenwithadvancedprostatecancerwouldbeassociatedwithresistancetoenzalutamideandabiraterone.MethodsWeusedaquantitativereverse-transcriptase–polymerase-chain-reactionassaytoeval-uateAR-V7incirculatingtumorcellsfromprospectivelyenrolledpatientswithmetastaticcastration-resistantprostatecancerwhowereinitiatingtreatmentwitheitherenzalutamideorabiraterone.WeexaminedassociationsbetweenAR-V7status(positivevs.negative)andprostate-specificantigen(PSA)responserates(theprimaryendpoint),freedomfromPSAprogression(PSAprogression–freesurvival),clinicalorradiographicprogression–freesurvival,andoverallsurvival.ResultsAtotalof31enzalutamide-treatedpatientsand31abiraterone-treatedpatientswereenrolled,ofwhom39%and19%,respectively,haddetectableAR-V7incirculatingtumorcells.Amongmenreceivingenzalutamide,AR-V7–positivepatientshadlow-erPSAresponseratesthanAR-V7–negativepatients(0%vs.53%,P=0.004)andshorterPSAprogression–freesurvival(median,1.4monthsvs.6.0months;P0.001),clinicalorradiographicprogression–freesurvival(median,2.1monthsvs.6.1months;P0.001),andoverallsurvival(median,5.5monthsvs.notreached;P=0.002).Sim-ilarly,amongmenreceivingabiraterone,AR-V7–positivepatientshadlowerPSAresponseratesthanAR-V7–negativepatients(0%vs.68%,P=0.004)andshorterPSAprogression–freesurvival(median,1.3monthsvs.notreached;P0.001),clinicalorradiographicprogression–freesurvival(median,2.3monthsvs.notreached;P0.001),andoverallsurvival(median,10.6monthsvs.notreached,P=0.006).TheassociationbetweenAR-V7detectionandtherapeuticresistancewasmaintainedafteradjustmentforexpressionoffull-lengthandrogenreceptormessengerRNA.ConclusionsDetectionofAR-V7incirculatingtumorcellsfrompatientswithcastration-resis-tantprostatecancermaybeassociatedwithresistancetoenzalutamideandabiraterone.Thesefindingsrequirelarge-scaleprospectivevalidation.(FundedbytheProstateCancerFoundationandothers.)TheNewEnglandJournalofMedicineDownloadedfromnejm.orgonSeptember4,2014.Forpersonaluseonly.Nootheruseswithoutpermission.Copyright©2014MassachusettsMedicalSociety.Allrightsreserved.Thenewenglandjournalofmedicinenengljmednejm.org2Itisnowacceptedthatcastration-resistantprostatecancerisnotandrogen-independentandcontinuestorelyonandro-gensignaling.1Owingtothisnewunderstanding,severaldrugshaverecentlyemergedforthetreat-mentofcastration-resistantprostatecancer;theseagentseithersuppressthesynthesisofextrago-nadalandrogensortargettheandrogenreceptordirectly.2Enzalutamideisaninhibitorofandro-gen-receptorsignalingthatexertsitsactivitybybindingavidlytotheligand-bindingdomainoftheandrogenreceptor,competingwithanddis-placingthenaturalligandsofthisreceptor(testos-teroneanddihydrotestosterone)whilealsoinhib-itingtranslocationoftheandrogenreceptorintothenucleusandimpairingtranscriptionalactiva-tionofandrogen-responsivetargetgenes.3,4Abir-ateroneisaninhibitorofcytochromeP45017A1(CYP17A1)thatimpairsandrogen-receptorsig-nalingbydepletingadrenalandintratumoralandrogens.5,6Afterstudiesshowedimprovedsurvivalwiththesedrugs,7-9bothagentswereap-provedbytheFoodandDrugAdministrationforthetreatmentofmetastaticcastration-resistantprostatecancer.Althoughenzalutamideandabirateronerep-resentbreakthroughsinthetreatmentofmeta-staticcastration-resistantprostatecancer,approxi-mately20to40%ofpatientshavenoresponsetotheseagentswithres