The 4Kscore Test Accurately Identifies Risk for Aggressive ...4kscore.com/wp-content/uploads/2017/09/4Kscore-Dossier_0917.pdf · 6 BioReference Laboratories, Inc. (an OPKO Health

The 4Kscore® Test Accurately Identifies Risk for Aggressive Prostate Cancer

and Reduces Unnecessary Prostate Biopsies (April 2017)

Prepared by:

BioReference Laboratories, Inc. An OPKO Health, Inc. Company

481 Edward H. Ross Drive Elmwood Park, New Jersey 07407

http://bioreference.com

2

BioReferenceLaboratories,Inc.(anOPKOHealthCompany)481EdwardH.RossDrive,ElmwoodPark,NJ07407

TableofContents

ExecutiveSummary.................................................................................................................3

IntendedUseandTargetPopulation.................................................................................5

ClinicalScenario........................................................................................................................5CurrentStandardofCare.................................................................................................................5PublicHealthImportance................................................................................................................6ThresholdPSAValueof1.5ng/mLforFurtherEvaluation.................................................7

EvidenceSupportingtheIntendedUseofthe4KscoreTest......................................8AnalyticalValidityofthe4KscoreTest.......................................................................................8ClinicalValidityintheDecisiontoPerformProstateBiopsy.............................................9ClinicalUtilityintheDecisiontoPerformaProstateBiopsy..........................................12ClinicalUtilitybyDecisionCurveAnalysis(DCA)................................................................13ReviewsinMedicalLiterature....................................................................................................14

IndependentRecommendationsandGuidelines.......................................................15NCCNGuidelinesforProstateCancerEarlyDetection.......................................................15EuropeanAssociationofUrology(EAU)ProstateCancerGuidelines...........................16

RegulationandCPTCode....................................................................................................16FederalLaboratoryRegulation..................................................................................................16StatePermits.....................................................................................................................................16LaboratoryAccreditation.............................................................................................................174KscoreTestCategoryICPTCode.............................................................................................17

Discussion................................................................................................................................17Developmentofthe4KscoreTest..............................................................................................17TheAbilityofthe4KscoreTesttoPredicttheRiskofDistantMetastasis..................18

Conclusions..............................................................................................................................19

References................................................................................................................................21

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ExecutiveSummary

Widespreadscreeningforprostatecancerwiththeprostate‐specificantigen(PSA)testbeganintheUnitedStatesinthelate1980s,andsubsequentlya45%declineinprostatecancermortalityhasbeenobserved.OwingtothelowspecificityofPSA,unnecessaryprostatebiopsiesandovertreatmentofindolentcancerhaveledtosignificantmorbidityandharm.Prostatebiopsyisapainfulprocedureassociatedwithupto4%ofmenexperiencingsignificantcomplicationssuchasbleeding,infectionandbacterialsepsis.Prostatebiopsycanalsoleadtoovertreatmentofindolent(Gleasonscore6)prostatecancerwithsurgeryorradiationtherapy.

AsaresultofthisandthefailureofaU.S.randomizedclinicalstudyofPSAscreeningtodemonstratebenefit,theUnitedStatesPreventativeServicesTaskForce(USPSTF)in2012advisedagainstroutinePSAscreeningforprostatecancer.Consequently,fewernumbersofmenarebeingscreenedanddiagnosed,butproportionallymoremenarebeingdiagnosedwithmoreadvanceddisease,reversingpasttrends.

InordertoavoidthedilemmacausedbythelowspecificityofthePSAtest,ofeitheroverdiagnosingprostatecancerormissingaggressiveprostatecancerduetoreducedscreening,amoreaccurateandnoninvasivetestisneeded.ThistestwouldbeperformedasaseconddecisionpointafterfindinganabnormalPSAresultand/ordigitalrectalexamination(DRE),butbeforeadecisiontoproceedwithaprostatebiopsy.

The4Kscoretestisdesignedtominimizethepotentialharmsstemmingfromunnecessaryprostatebiopsies,whilestillallowingfortheaccuratedetectionofaggressive,high‐grade(Gleasonscore7andhigher)prostatecancerintimetointervenewitheffectivetreatment.The4Kscoretestisanalgorithm‐basedtestcombiningthebloodlevelsoffourkallikreinproteinsandapatient’sclinicalinformationtoprovideaman’sriskforaggressiveprostatecanceronprostatebiopsy.Itisintendedtobeusedinmenaged45‐75yearswithaPSAbetween1.5and10ng/mLand/oranabnormaldigitalrectalexaminationpriortoprostatebiopsy.

Theclinicalvalidityofthe4Kscoretestwasdemonstratedinaprospective,doubleblinded,1012patientclinicaltrialconductedin2013‐14,at26centersacrosstheUnitedStates.All1012mensubmittedtheirbloodsamplespriortoaprostatebiopsyandtheinvestigatorsandpathologistswereblindedtothe4Kscoreresults.Theareaunderthereceiveroperatorcurve(AUC)fordiscriminatingthepresenceofGleasonscore7andhigherprostatecancerwas0.821forthe4Kscoretestvs.0.694fortotalPSAand0.713for%freePSA.Thedataalsoindicatedthatuseofthe4Kscoretestcouldresultinasignificantreductionofthenumberofunnecessarybiopsies(30‐58%),whilestillidentifyingaveryhighpercentageofthosemenwhomaybeathigherriskforaggressiveprostatecancer.

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Furthersub‐analysisofthiscohortshowedthatinmen45‐75yearsofagewithaPSAbetween1.5‐10ng/mL,the4KscoredemonstratedanAUCof0.774vs0.676for%freePSAand0.607fortPSA.Inthisgroup,therewasapotentialbiopsyreductionof35%usinga4Kscorecutoffof7.5%.

ArecentprospectivestudywithintheVeteran’sAffairs(VA)HealthSystemhasfurthervalidatedthe4KscorewithinacohortincludingalargesubsetofAfricanAmericanmen.AfricanAmericanmenhaveahigherincidenceandhigherriskofaggressiveprostatecancer,makingitimperativetohaveanaccuratetesttoevaluatetheriskforthispopulation.Of366menat8siteswith4Kscoreandcompletedata,205(56%)wereAfricanAmerican.TheAUCof4Kscore(0.81)outperformedthebasemodel(0.74)anddemonstratedhigherutilityondecisionanalysis.TherewasnosignificantdifferenceintheAUCofthe4KscoretestbetweenAfricanAmericanandnon‐AfricanAmericanmen(0.80and0.84respectively,p=0.32).

Theclinicalutilityofthe4Kscoretestwasconfirmedinaretrospective611patientstudyperformedatU.S.basedcommunityandacademicurologycenters.Theresultsdemonstrateda64.6%overallreductioninprostatebiopsies.Menwithalowrisk4Kscore(<7.5%)hada94%reductioninprostatebiopsies,whilemenwithahighrisk4Kscore(20%orhigher)hadonlya19%reduction.

The4KscoretesthasbeenincludedintheNCCN2015and2016guidelinesforProstateCancerEarlyDetectionwithlevel2Aevidenceasameanstoimprovetheselectionofmenathigherriskforclinicallysignificant,aggressiveprostatecancerwhoshouldundergoprostatebiopsyduetoanabnormalPSAtestand/orDREfinding.Itisalsoincludedinthe2016EuropeanAssociationofUrologyProstateCancerGuidelines.TheAmericanMedicalAssociation(AMA)hasapprovedthe4KscoretestforaCategoryICPTcode,effectiveJanuary2017.

ThescientificbasisofresearchontheuseofthefourkallikreinproteinstoenhancethesensitivityandspecificityofdetectingaggressiveprostatecancerwasledbyateamofinvestigatorsfromMemorialSloanKetteringCancerCenter.Thecommerciallyavailable4Kscoretestincorporatedtheirscientificknowledge,andwasfurtherrefined,developedandvalidatedbyOPKOinitsownclinicallaboratoryandwhollyownedsubsidiary,BioReferenceLaboratories.

The4Kscoretestisanon‐invasivebloodbasedtestthatprovidesaseconddecisionpointpriortoaprostatebiopsyformenaged45‐75years,withaPSAbetween1.5and10ng/mLand/oranabnormalDRE.Itprovidesanaccurateriskofaggressiveprostatecancer,allowingforearlydetectionofhighriskmen,whilereducingthenumberofunnecessaryprostatebiopsies.ItcorrelateswithlongtermriskofdistantmetastasisinmenwithanelevatedPSA,andisincludedinNCCNguidelinesforProstateCancerEarlyDetection.Useofthe4Kscorewillreducethecostsandcomplicationsofunnecessaryprostatebiopsies,whileidentifyingmenatahigherriskofaggressivecancer,whowouldbenefitfrommoreextensiveevaluation.

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IntendedUseandTargetPopulation

The4Kscoretestprovidesaman’spercentagerisk(reportedonascaleoflessthan1%togreaterthan95%)ofhavingaGleasonscore7orhigherprostatecancerdiagnosedifheweretohaveaprostatebiopsyperformed.The4Kscoretestisintendedtobeusedasaseconddecisionpointinmenaged45‐75yearswithaPSAbetween1.5and10ng/mLand/oranabnormalDRE,priortoperformingaprostatebiopsyinbiopsynaïvemenandmenwithaprevioushistoryofbenign(negative)biopsies.

The4Kscoretestisnotascreeningtest.Theinformationprovidedbythe4Kscoretestallowstheclinicianandpatienttomakeamoreinformeddecisiononwhetherornotaprostatebiopsyiswarranted.Theevidencetosupportthisintendeduseisprovidedinthisdossier.

The4Kscoretestincorporatesbothlaboratorybloodtestdataandthepatient’sclinicaldata.Thelaboratorybloodtestsareperformedoneitherserumorplasmatomeasuretheconcentrationsoffourprostatespecifickallikreinproteinsthatareprostatespecific.Twoofthebloodtestsareroutinelyperformedintheclinicallaboratory:totalPSA(tPSA)andfreePSA(fPSA),whiletheothertwotests,intactPSA(iPSA)andhumankallikrein‐relatedpeptidase2(hK2),areproprietarytoOPKOandessentialfortheintegrityandpredictiveaccuracyofthe4Kscoretestforhigh‐grade(Gleasonscore7andhigher)prostatecancer.Amongtheclinicaldataincorporatedinthe4Kscoretestarethepatient’sage,DREfindingsifavailable,andconsiderationofanypreviousbenign(negative)prostatebiopsyfinding.

OPKOHealth,Inc.developedthe4Kscoretestandoffersthe4KscoretestservicethroughBioReferenceLaboratories,Inc.,itswhollyownedsubsidiary.The4KscoretesthasbeendevelopedandvalidatedatBioReferenceinstrictcompliancewithCLIAregulations,andisperformedinasinglefacilityinaccordancewiththeLaboratoryDevelopedTest(LDT)regulations.

ClinicalScenario

CurrentStandardofCare

CurrentclinicalpracticeforprostatecancerearlydetectionisbasedonPSAtestingand/orDRE,typicallyperformedbyaprimarycarephysician(PCP).ThediscoveryofanabnormalPSAtestand/orDREistheprimaryindicationforreferraltoaurologistforfurtherevaluationthatcouldleadtoaprostatebiopsytodiagnoseprostatecancer.Thiscurrentparadigmleadstoanestimated1millionprostatebiopsiesbeingperformedeachyearintheUnitedStates.However,75%oftheseprostatebiopsiesperformedareunnecessary,astheyshoweithernocancerorlowgrade(Gleasonscore6)prostatecancer,1anindolentformofprostatecancerthatisage‐associatedandhighlyunlikelytocauseharm.2,3Becauseofconcernthatamoreserious,high‐gradecancercouldbemissedbythebiopsy,manymenwithadiagnosisofGleasonscore6prostatecancerchoosetohavetreatment(radical

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prostatectomyorradiation).However,66%ofGleasonscore6cancersdetectedbybiopsyareconfirmedasGleasonscore6intheradicalprostatectomysurgicalspecimen,renderingtheaggressivetreatmentforthesemenunnecessary.4Consequently,inthecurrentparadigmwithanoverrelianceonthePSAtest,manymenareneedlesslyexposedtotheharmsofbiopsy(bleeding,infection,andhospitalization)5andsufferlongtermimpairedurologicalfunctionfromunnecessaryradicalprostatectomyorradiationtherapy.6

Theultimategoalofprostatecancerscreeningistodiagnoseandtreathigh‐grade,aggressiveprostatecancerwhenitisorganconfinedandwhensuccessfultreatmentispossible,whileminimizingtheharmsofunnecessarybiopsiesandovertreatmentofindolentcancers.Itisapparentthattoachievethisgoal,physiciansrequireatestthatismoresensitiveandspecificforidentificationofthesubsetofmenwithhigherriskforaggressiveprostatecancer.Anewtestthatcouldbetterselectthosemenwhoshouldhaveaprostatebiopsywouldbeextremelyvaluable.The4Kscoretestwasdevelopedtofulfillthisclinicalneed.

PublicHealthImportance

Prostatecanceristhesecondleadingcauseofcancerdeathsinmen,with26,000deathsprojectedintheUSin2016.7SincetheadventofPSAscreeningin1991,a45%declineinoverallprostatecancermortalityhasbeenobserved,withmuchofthisdeclineattributabletoPSAscreening.8In2009,theEuropeanRandomizedStudyofScreeningforProstateCancer(ERSPC)reporteda29%reductionindeathfromprostatecancerinmenundergoingroutinePSAscreening.9However,nobenefittoscreeningwasobservedintheU.S.basedProstate,Lung,Colorectal,andOvarianCancerScreeningTrial(PLCO),10butthiswaslikelyduetocontaminationofthecontrolgroup(whoweretohavenoPSAscreening)withPSAtesting.Areviewofthestudydeterminedthat80%ofthemeninthePLCOcontrolgrouphadatleastonePSAtestduringthetrial.11Nevertheless,becauseofthePLCOstudyresults,thenetphysicalandpsychologicalharmsthatresultfromunnecessaryprostatebiopsies,theuncertaintyofprostatebiopsiesundergradingormissingprostatecancer,andtheovertreatmentofnon‐lifethreateningprostatecancer,in2012theUSPSTFadvisedagainstusingthePSAtestforroutineprostatecancerscreeninginmen.12

A2012systematicanalysisofavailableliteratureonactivesurveillanceofprostatecancersuggestedthatupto60%ofprostatecancersdiagnosedincontemporarystudiesmightbesafelyobservedwithoutaneedforimmediateintervention.13Currently,about40%oflowriskpatientsareonactivesurveillance,whiletherestundergomoreaggressivetherapy.14

Theharmsassociatedwithunnecessaryprostatebiopsyandovertreatmentoflow‐gradeprostatecancerarewelldocumented.Apopulation‐basedstudyrevealedafour‐foldincreasefrom1996to2005intheincidenceofhospitaladmissionsafter

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prostatebiopsy,toanoverallrateof4.1%,with72%oftheseadmissionsduetobiopsy‐relatedbacterialsepticemia.5Theprimarypostsurgicalandpost‐radiationtherapycomplicationsincludeerectiledysfunction,urinaryincontinence,anddeclineinhealth‐relatedqualityoflifeinthedomainsofsexual,urinary,andpsychologicalfunction.6,15‐18

TheimpactoftheUSPSTFhasbeenadecreaseinoverallbiopsyrates,andasaconsequence,adecreaseinthedetectionoftheaggressiveGleasonscore7‐10prostatecancers.19EvidenceisnowmountingthatwithreducedlevelsofPSAscreening,menwhowouldhavebeenfoundtohaveaggressiveprostatecancerfollowinganabnormalPSAlevel,andsubsequentlyreferredtoaurologist,areremainingundetectedlonger,andpresentingwithmoreadvanceddiseaseandwithreducedlikelihoodforcure.20‐22

Insummary,thereisaneedtoaddressthelimitationsofPSAscreeningwithoutabandoningthisveryeffectivetoolfortheearlyidentificationofmenatriskforprostatecancer.The4KscoretestoffersaseconddecisionpointafteranabnormalPSAtestand/orDRE,usinganon‐invasivebloodsample,toreducethenumberofunnecessaryprostatebiopsiesinmenatalowerriskforaggressiveprostatecancer(Gleasonscore7andhigher).Theuseofthe4Kscoretestwilldistinguishthosemenatriskforaggressivediseasefrommenatlowrisk,therebyreducingunnecessaryprostatebiopsies,unnecessarytreatment,andtheharmsthatresultfromboth.

ThresholdPSAValueof1.5ng/mLforFurtherEvaluation

The4KscoreisafollowuptestafteranabnormalPSAand/orDRE.OneofthedifficultiesofusingPSAasascreeningtoolforprostatecanceristhelackofconsensusonwhatPSAthresholdisappropriateforfurtherevaluation.Severalstudieshaveexaminedtheriskofprostatecanceratathresholdof1.5ng/mL,showinganincreasedriskabovethisvalue.

Aprospectivestudyof5,855menexaminedthecancerdetectionrateatvariousPSAvaluestodetermineatwhatpointmorefrequentPSAtestingcouldberecommended.23Ofthesemen,539(9.2%)developedprostatecancer,withamedianfollowupof7.6years.TheyfoundaverylowriskofdetectionformenwithaPSAbelow1.0ng/mL(0‐0.9%).TherateshowedasignificantriseformenwithaPSAof1.50‐1.99ng/mL(12.3%)versusfor1.00‐1.49ng/mL(4.7%).Regular,shorterintervalswererecommendedforPSAtestinginmenwithaPSAgreaterthan1.5ng/mL.

Aretrospectivestudyof21,502menwithPSAof0‐4ng/mL,whoinmanycaseswillbeconsiderednormalrisk,evaluatedtheprostatecancerriskoverafour‐yearperiod.24Prostatecancerrateswere15‐foldhigher(19‐foldforAfricanAmericanmen)inpatientswithaPSAof1.5‐4.0ng/mLversusthosewithaPSA<1.5ng/mL.MenwithabaselinePSAof<1.5ng/mLshowedlittleprogressionoverthestudyperiod,withastartingPSAmeanof0.70ng/mLandanendingmeanof0.88ng/mL.MenwithaPSAbetween1.5‐4.0ng/mL,however,progressedfromameanof2.44

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ng/mLto3.24ng/mL.TheauthorsconcludedthatmenwithaPSAof1.5‐4.0ng/mLshouldbeconsideredinanEarly‐WarningPSAZone,withanincreasedriskasopposedtomenwithalowerPSA.

ArecentdiscussionofhowtoapproachmenwithaPSAgreaterthan1.5ng/mLdiscussedtheuseoffollowuptests,includingthe4Kscoretobetterstratifymen.25RecognizingthedifficultieswithPSAscreening,especiallyinminimizingunnecessaryprocedures,theauthorsproposedutilizingnextgenerationtestsfollowinganabnormalPSA,toimprovethespecificityofdetectinghigh‐riskdisease.Thiscombinationreducestheunnecessaryevaluationoflow‐riskmen,whileprovidingasimplealgorithmthatidentifieshigherriskmenforfurtherworkup,includingaprostatebiopsy.

EvidenceSupportingtheIntendedUseofthe4KscoreTest

AnalyticalValidityofthe4KscoreTest

Thedifferentmolecularformsofprostatespecificantigen(PSA)andhumankallikreinrelatedpeptidase2(hK2)arederivedfromtheprostate.26Inmenwithnoorbenignconditionsoftheprostate,mostPSAisfoundastheenzymaticallyinactiveformsofeithercomplexedPSAordegraded(nicked)freePSA,withverylowlevelsofhK2andtheenzymaticallyactiveintactPSAform(iPSA).27AsignificantincreaseinlevelsofhK2andiPSAinserumisassociatedwithaggressivecancerpathologyatbiopsyandradicalprostatectomy.28‐30

The4Kscoretestutilizesthelaboratoryresultsoffourbloodbiomarkers:totalPSA(tPSA),freePSA(fPSA),intactPSA(iPSA)andhumankallikrein‐relatedpeptidase2(hK2).ThetPSAandfPSAassaysareFDA‐approvedandpurchasedfromRocheDiagnostics(Indianapolis,IN).ThespecifickitsusedaretheElecsys®totalPSA(FDAPMAP990056)andtheElecsys®freePSA(FDAPMAP000027).BothassaysareperformedontheRochecobas®analyzerinaccordancewiththeinstructionsprovidedbyRocheDiagnostics.TheplasmaorserumconcentrationsofiPSAandhK2,whichare1/100thto1/1000thoftPSA,aredeterminedusinglaboratorymethodsdevelopedbyOPKOHealth,anddesignedtorunonthePerkinElmerDiagnostics(Waltham,MA)AutoDELFIA®instrument.31TheAutoDELFIAimmunoassaysystem,whichutilizestime‐resolvedfluorescencetechnology,isFDAclearedforuseinseveralIVDkitssoldintheU.S.byPerkinElmer.

TheanalyticalvalidationforiPSAandhK2assayswasperformedatBioReferenceLaboratoriesandincludedtheanalyticallimitofquantitation(LoQ),reportingrange,precision(intra‐labandinter‐lab),referencerangeforeachinbenignprostateconditionsversusprostatecancer,invitrostability,invivostabilityoftheanalytes,andinterferingsubstances(exclusioncriteria).

TheRochecobasinstrumentandthePerkinElmerAutoDELFIAinstrumentarevalidatedforusewiththe4KscoretestaccordingtotheBioReferenceLaboratories“4KscoreAnalyticalPerformanceVerificationPlan”,whicharedesignedtobein

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substantialcompliancewithFDAstandardsaswell.AppropriatevalidationreportsaremaintainedatBioReferenceLaboratories.

Insummary,thelaboratorymeasurementofthefourkallikreinbiomarkersthatarepartofthe4Kscoretesthavebeenfullyvalidatedandarerobustlaboratoryassaysforuseundertheconditionsemployedforthe4Kscoretest.

ClinicalValidityintheDecisiontoPerformProstateBiopsy

2015USValidationStudy:

The2015U.S.validationtrialfor4Kscorewasadoubleblinded,prospectivestudythatassessedtheaccuracyofthe4Kscoretesttopredictthepresenceofhigh‐grade(Gleasonscore7andhigher)prostatecancerpriortoprostatebiopsy.1Patientswereenrolledintheclinicaltrialat26sitesacrosstheUnitedStatesfromOctober2013toApril2014.Theclinicaltrialwasdesignedtotargettheintendedusepopulationofmenaged40to80yearsoldwhowerescheduledtoreceiveadiagnosticprostatebiopsy,andassuch,placednorestrictiononPSAlevelsorDREresults.Furthermore,thestudyenrolledmenregardlessofwhetherthiswastheirfirstprostatebiopsy,orarepeatprostatebiopsyafterpreviousbiopsieswerebenign(negative)forprostatecancer.AsthiscohortrepresentedacontemporaryU.S.populationofmen,atleasta10‐coretransrectalultrasoundguided(TRUS)prostatebiopsywasperformedonallpatientsandcurrentGleasongradingcriteriawereusedforthehistology.

Thestudywasadouble‐blindeddesign,i.e.OPKOperformedthefourkallikreinimmunoassaysandgeneratedthe4Kscoreresultblindedtothebiopsyoutcome,theurologistandpatientdidnotknowthe4Kscoretestresultspriortothebiopsy,andtheanatomicpathologistgradingthebiopsyspecimenwasblindedtothe4Kscoretestresult.AnindependentbiostatisticianthenanalyzedthecombineddatatoassesstheAUC,sensitivity,specificity,negativepredictivevalue(NPV),positivepredictivevalue(PPV),riskcalibrationandclinicalutilitybydecisioncurveanalysisofthe4Kscoretestinthispopulation.

ThestudywasIRB‐approvedandallmenwerepreviouslyscheduledforandreceivedbothaprostatebiopsyanda4Kscoretestresult.The4Kscoretestwasperformedwithin30dayspriortotheprostatebiopsy.Thestudywasconductedintwoparts:first,a300patientcalibrationcohortconfirmedthediscriminationandcorrelationoftheOPKO4Kscoretestresultagainsttheactualbiopsydataobtainedforthese300patients.Thestatisticalalgorithmusedtoestimatetheriskofhigh‐gradecanceronthebasisofthekallikreinmarkerswas“lockeddown”beforeanalysisofthe1012patientvalidationcohort.The4Kscoretestresultshowedanearperfectcorrelationwiththeactualbiopsydataforthe1012patientclinicalvalidationcohort(Figure1).

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Figure1.The4KscoretestisaccuratelycalibratedtopredicttheriskforGleasonscore7andhigherprostatecancer.XAxis:Eachpointonthecurverepresents10%ofthe1012men(rankedbydecilesaccordingtotheir4Kscoreresult),YAxis:HeightonYaxisshowsthefrequencyofGleasonscore7andhigherprostatecancerfounduponbiopsy.

Table1AsummarizestheAUC,sensitivityandspecificity,NPVandPPVforthe4KscoretestcomparedwithtotalPSA,%freePSA,andageadjustedPSAforhigh‐grade(Gleasonscore7andhigher)prostatecancer,determinedintheU.S.validationstudy.TheAUCofthe4Kscoretestforhigh‐gradeprostatecancer(Gleasonscore7andhigher)was0.821,andsuperiorcomparedtoPSAalone(AUC=0.694)or%freePSA(AUC=0.712).The4KscoretestalsoshowedthesuperiorspecificityandnegativepredictivevalueatsensitivitiesthatwerecomparableorsuperiortoPSA,%freePSA,orageadjustedPSA.1Asubanalysisinmenaged45‐75yearswithaPSAbetween1.5‐10ng/mLshowedthe4Kscoreretainedhighaccuracyandoutperformedcomparativetests(Table1B)inthisgroup.

Thestudyalsofoundthatthepotentialreductioninbiopsieswouldhavebeen30%to58%dependingonthe4Kscoretestthresholdchosentoperformaprostatebiopsy.Thedecisionanalysisforclinicalutility(seeFigure3below)showedthe4Kscoretesttobesuperioracrossalltherelevant4Kscoreresultriskthresholdscomparedtothestandardofcare(allmenreceiveabiopsy),oraPSA‐basedriskmodel.

Furthersub‐analysisofthiscohortexaminedthepathologyofradicalprostatectomyspecimensforthe51menwithGleason6prostatecanceronprostatebiopsy.Theradicalprostatectomyspecimenwasupgraded(Gleason7‐10)in67%(22/33)ofthosemenwitha4Kscoregreaterthan7.5%.Ofthosewitha4Kscorebelow7.5%,only33%(6/18)hadahighergradeintheprostatectomyspecimen.

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Table1:TheAUC,andsensitivity,specificity,NPV,andPPVofpatientsenrolledintheOPKO4KscoreU.S.validationstudy.1A)Thedatacomparesthe4Kscore,totalPSA,%freePSA,andageadjustedPSAatthecutpointlistedfortheentirecohortof1,012men.B)Asimilarcomparisonformenaged45‐75yearswithaPSAof1.5‐10ng/mL.

A)

TestandCutPoint Subgroup NNGleasonScore≥7 AUC Sens. Spec. NPV PPV

4Kscore7.5% AllPatients 1012 231(22.8%) 0.821 93% 44% 95% 33%

PSA3.0ng/mL AllPatients 1012 231(22.8%) 0.694 93% 24% 92% 27%

PSA4.0ng/mL AllPatients 1012 231(22.8%) 0.694 84% 40% 89% 29%

%fPSA25% AllPatients 1012 231(22.8%) 0.712 91% 26% 91% 27%

AgeadjustedPSA AllPatients 1012 231(22.8%) NA 66% 49% 83% 28%

B)

TestandCutPoint Subgroup NNGleasonScore≥7 AUC Sens. Spec. NPV PPV

4Kscore7.5% 45‐75YearsPSA1.5‐10

784 159(20.3%) 0.774 91% 42% 95% 28%

PSA3.0ng/mL 45‐75YearsPSA1.5‐10

784 159(20.3%) 0.607 92% 17% 89% 22%

PSA4.0ng/mL 45‐75YearsPSA1.5‐10

784 159(20.3%) 0.607 80% 35% 87% 24%

%fPSA25% 45‐75YearsPSA1.5‐10

784 159(20.3%) 0.676 92% 21% 91% 23%

AgeadjustedPSA 45‐75YearsPSA1.5‐10

784 187(23.9%) NA 59% 46% 81% 21%

Insummary,thisprospective,double‐blindedvalidationstudyreportsanearperfectcalibrationof4Kscoreriskpredictionofhighgradecancertoprostatebiopsyresults,asuperioraccuracyof4Kscoreforpredictinghighgradecancervs.PSA,%freePSA,orageadjustedPSA;andapotentialreductioninunnecessarybiopsiesby30‐58%.

VeteransAffairsValidationStudy:

Tofurtherevaluatethevalidityofthe4Kscore,especiallyinAfricanAmericanmen,arecentmulti‐institutionalstudyintheVeteransAffairsHealthSystemprospectivelyenrolled403menwhowerereferredforprostatebiopsy.32Ofthese,366receiveda

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4Kscoretestandhadcompletedataavailableforanalysis.Therewere205(56%)AfricanAmericanmen,ofwhich82(40%)hadhighgradeprostatecancer.Therewere161(44%)non‐AfricanAmericanmen,ofwhom49(31%)hadhighgradeprostatecancer.

The4KscorewascomparedtoabasemodelconsistingofPSA,age,andDREfindings.Theperformanceof4KscorewasalsocomparedinAfricanAmericanmenandnon‐AfricanAmericanmen.TheAUCof4Kscoreinthecohortwas0.81vs0.74forthebasemodel(p=0.011),and4Kscoredemonstratedhigherutilityondecisioncurveanalysisthanthebasemodel.Therewasnosignificantdifferencebetweendiscriminationof4KscoreforaggressiveprostatecancerbetweenAfricanAmericanmen(0.80)versusnon‐AfricanAmericanmen(0.84)(p=0.32).Thecalibrationplotforthecohortdemonstratedthat4Kscoreriskcloselymatchesprostatebiopsyfindingsforhighgradecancer(Figure2).

Figure2:The4KscoretestisaccuratelycalibratedtopredicttheriskforGleasonscore7andhigherprostatecancerinacohortwithsignificantAfricanAmericanrepresentation.

The4Kscorehaspreviouslybeenshowntoaccuratelyprovidetheriskofaggressiveprostatecancerinlargemulti‐institutionalstudies.ThisstudyshowsthatinacohortwithhighrepresentationofAfricanAmericans,thetestremainshighlycorrelatedwithprostatebiopsyresults,andretainshighdiscriminationforaggressiveprostatecancer.

ClinicalUtilityintheDecisiontoPerformaProstateBiopsy

The4Kscoretestimproveshealthcareoutcomesbyprovidingriskinformationthatleadstoachangeinbehaviorofthephysicianutilizingthetest.The2015Konetyetal.study33isaretrospectivedecision‐impactstudythatexaminedprostatebiopsyreductionat35clinicalpracticesthatwereusingthe4Kscoretest.Thestudy

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involvedatotalof611menwithanabnormalPSAtestand/orDRE.Eachurologistusedthe4Kscoretestandhisorherownclinicaljudgmenttodecidehowbesttomanage(i.e.toproceedwithaprostatebiopsyornot)thepatient.Theurologistswereaskedviaaquestionnairetoevaluatetheimpactofthe4Kscoretestontheirpatientmanagementdecisions.

Theoverallresultsshoweda64.6%reductioninprostatebiopsies.Whenthepatientswerestratifiedintogroupsbasedonthe4Kscoretestresults(Table2),thebiopsyreductionrangedfrom19%to94%.Thethreegroupsare:LowRisk(4Kscorelessthan7.5%),IntermediateRisk(4Kscore7.5%‐19.9%),andHighRisk(4Kscore20%andhigher).Ahigher4Kscoretestwasassociatedwithagreaterlikelihoodofhavingaprostatebiopsy(p<0.001).Only6.0%ofmenwithalow‐risk4Kscoretest(lessthan7.5%)optedforprostatebiopsy,representinga94%biopsyreduction.Intheintermediateriskgroup47.1%ofmenhadaprostatebiopsy,and81.0%ofmenwithahigh‐risk4Kscoretestresultgroupunderwentaprostatebiopsy.

Table2.BiopsyutilizationinallpatientsenrolledinKonetyetal.4Kscoreclinicalutilitystudy.

Theauthorsconcludedthatacrossthe35urologypracticesettings,the4Kscoretesthadsignificantlyimpactedprostatebiopsydecisions,andreducedtherateofprostatebiopsiesby64.6%overall,andnotably,amongmenwithalowriskresult(4Kscore7.5%orless),a94.0%reductioninprostatebiopsyratewasobserved.

ClinicalUtilitybyDecisionCurveAnalysis(DCA)

Adecisioncurveanalysis(DCA)allowsphysiciansandpatientstodeterminethenetclinicalbenefit(orharm)theuseofaparticulartestorprocedurewillhavewhencomparedtostandardofcareattheirownacceptablethresholdforrisk.Asappliedtothe4Kscoretest,theDCAestimatesanetbenefitforthe4Kscoretestandotherpredictionmodelsbysummingthebenefits(truepositives)andsubtractingtheharms(falsepositives)wherethelatterisweightedbyafactorsoastoreflecttherelativeharmofamissedcancercomparedwithanunnecessarybiopsy.Figure3showstheDCAfromthe4KscoreU.S.validationstudy.1Atallrelevantthresholdslikelytobeutilizedwiththe4Kscoretest,theDCAshowedafavorablenetbenefitwhencomparedtostandardofcare(biopsyall)oraPSApredictivemodelknownastheProstateCancerPreventionTrialRiskCalculator2.0(PCPTRC2.0).34

4Kscore Test CategoryNo Biopsy (Reduction)

(n = 395; 64.7%)Received Biopsy(n = 216; 35.4%)

Total (n = 611)

Low Risk(4Kscore test less than 7.5%)

Intermediate Risk(4Kscore test 7.5% ‐ 19.9%)

High Risk(4Kscore test 20% and higher)

283 (94.0%) 18 (6.0%) 301

83 (52.9%) 74 (47.1%) 157

29 (19.0%) 124 (81.0%) 153

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Figure3:Decisioncurveanalysiscomparingthe4Kscoretootherstrategies.1Redline,biopsynopatients;orangeline,biopsyallpatients;greenline,aPSA‐basedriskpredictor(PCPTRC2.0)ascriterionforbiopsy;andblueline,4Kscoreascriterionforbiopsy.Thelinewiththehighestnetbenefit(y‐axis)atanyparticularthresholdprobabilityforbiopsy(x‐axis)willresultinthebestclinicalresults.

ReviewsinMedicalLiterature

Asystemicreviewofthefourkallikreinpanelin2016byMcDonaldandParsonsexaminedthebenefitsandlimitationsofPSAscreening,andthepotentialutilityofthe4KscoretesttoimprovethespecificityofPSAfordetectingclinicallysignificantprostatecancer.35Thereviewdetailedtheimprovementsinhealthoutcomes,includinga45%reductioninprostatecancermortalitysincethewidespreaduseofPSAscreening,butalsotheassociatedhighcostofoverdiagnosisandovertreatmentofindolentprostatecancer.Theauthorsdescribeseveralstudieswherethe4KscoretestwasevaluatedindifferingpopulationsandwasshowntohavesuperiordiscriminationversusPSAandPSAriskcalculators.ThereviewalsopointedoutthatiPSAandhK2assaysrequiresophisticatedexpertisetoperformandarenotwidelyavailable.Theauthorsstressthegoalofprostatecancerscreeningis“…tomaximizetheearlydiagnosisofpotentiallyaggressivebutcurablediseasewhileminimizingboththedetectionofindolentdiseaseandthenumberofinvasiveconfirmatorytests.However,therelativelypoorspecificityofPSAhas

15


contributedtotheoverdetectionofindolentdisease.Onepotentialsolutionistofocusonthedetectionofclinicallysignificantprostatecancerbyusingtestswithenhancedspecificity.”Theauthorsfoundthatthe4Kscoretestiseffectiveby“…providinganindividualizedpredictionofclinicallysignificantcancerregardlessofpriorscreeningorpreviousbiopsy.”Theyconcludedthatitwouldhaveutilityintheprocessofshareddecisionmakingforprostatebiopsiesandintheearlydetectionofprostatecancer.Thiscouldleadtoa41‐71%reductioninprostatebiopsies,withaminimalriskfordelayeddiagnosisofsignificantprostatecancer.

Inanothersystematicreviewofthe4Kscoretest,theauthorsreviewedthe

clinicalstudiesfortencohortsconsistingofover15,000menfrompeer‐reviewedmedicaljournals.36Theauthorsfoundthatthe4Kscoretestiseffectiveforaccuratelyidentifyingmenathighriskforaggressivediseaseandisappropriatetoselectthosemenwhowouldbenefitfromaprostatebiopsyandpreventapotentiallylethaloutcomefromprostatecancer.Theauthorsconcludethat30‐58%ofmenwithalow4Kscoretestresultcouldsafelydeferprostatebiopsybecauseofhavinganegligibleriskofhavingmissedaggressiveprostatecancer.

ArecentreviewbyBrattetal.37examinedthepotentialforblood‐based

biomarkerstodetectprostatecancer.TheauthorshighlightedtheimportanceofPSAscreeningfollowedbyafourkallikreinpanelformenwithevenmodestlyelevatedPSAvaluespriortoconsideringabiopsy.Theauthorsnotedthatstatisticalmodelsbasedonthebiomarkersinthe4KscoretestimprovethespecificityofelevatedPSA(2.0‐10.0 ng/mL),reduceunnecessaryprostatebiopsies,andbetteridentifymenatriskofaggressiveprostatecancerwhoshouldhaveabiopsyoradditionalimaging.

Filellaetal.publishedacomprehensivereviewofemergingbiomarkersfor

detectionofaggressiveprostatecancerinbloodandurine.38Thereviewincludedadiscussionoftheclinicalworkunderlyingthe4KscoreaswellasotherbloodandurinetestsincludingPCA3andphi.ItconcludedthatthesebiomarkersoutperformthespecificityoftPSAandpercentfPSA.

IndependentRecommendationsandGuidelines

NCCNGuidelinesforProstateCancerEarlyDetection

The4Kscoretestisincludedinthemostrecent2016NCCNGuidelinesforProstateCancerEarlyDetectionbasedonlevel2Aevidence,andisindicatedasatesttobeusedafterafindingofanabnormalPSAtestorDRE:39ThespecificNCCNpanelrecommendationshighlightthe4Kscoretestinthefollowingway,consistentwith

16


itsintendeduseinbiopsynaïvepatientsorinpatientswithpreviousbenign(negative)biopsies:

“Biomarkersthatimprovethespecificityof(prostatecancerearly)detectionarenotrecommendedasfirstlinescreeningtests.However,theremaybesomepatientswhomeeteitherPSAstandardsforconsiderationofprostatebiopsy,butforwhomthepatientand/orthephysicianwishtofurtherdefinetheprobabilityofhigh‐gradecancer.4Kscore(whichprovidesanestimateoftheprobabilityofprostatecancer)ispotentiallyinformativeinpatientswhohaveneverundergonebiopsyorafteranegativebiopsy”.

TheNCCNguidelinesgoontofurthercommentonthemanagementofbiopsyresults:

“Itiswellknownthatanegativeprostatebiopsydoesnotprecludeadiagnosisofprostatecanceronsubsequentbiopsy.ThosepatientswithnegativebiopsiesshouldbefollowedwithDREandPSA.Testswhichimprovespecificityinthepost‐biopsystate—including4Kscoreshouldbeconsideredinpatientsthoughttobeatahigherriskdespiteanegativebiopsy.”

EuropeanAssociationofUrology(EAU)ProstateCancerGuidelines

The4Kscoreisincludedinthe2016EAU‐ESTRO‐SIOGGuidelinesonProstateCancer,40withthefollowingrecommendation:

“UsetheadditionaldiagnosticoptionsinasymptomaticmenwithanormalDREandaPSAbetween2.0and10ng/mL(riskcalculator,oranadditionalserumorurine‐basedtest[4Kscore]orimaging).”

Theguidelinesalsomentionthat4Kscorehasbeenshowntoout‐performfree/totalPSAprostatecancerdetection,“withanimprovedpredictionofclinicallysignificantprostatecancer,inmenwithaPSAbetween2‐10ng/mL.”

RegulationandCPTCode

FederalLaboratoryRegulation

The4KscoretesthasbeendevelopedandvalidatedatBioReferenceLaboratories,Inc.,awhollyownedsubsidiaryofOPKOHealth,Inc.The4KscoretestwasvalidatedinstrictcompliancewithCLIAregulations,andisperformedinasinglefacilityinaccordancewiththefederalregulationsregardingLaboratoryDevelopedTests(LDTs).

StatePermits

InadditiontoNewJersey,BioReferenceLaboratoriesislicensedbyallstatesrequiringout‐of‐statediagnosticlabstohavepermits,includingCalifornia,Connecticut,Florida,Maryland,NewYork,Pennsylvania,RhodeIsland,Vermont,andWestVirginia.

17


The4KscoretestalsohasconditionalapprovalbyNewYorkStateunderitsClinicalLaboratoryEvaluationProgram.MostclinicalpathologistsconsiderthisprogramasrepresentingthehigheststandardforevaluatingtheperformanceofnewLDTs.

LaboratoryAccreditation

BioReferenceLaboratoriesislicensedbyCMSandisCLIAcertifiedasahighcomplexitylaboratoryunderCLIA88regulations.TheBioReferenceLaboratoriesteamofboard‐certified,fellowship‐trainedpathologistsislicensedinall50states.TheBioReferenceLaboratoriesfacilityisalsoaCollegeofAmericanPathologists(CAP)‐accreditedlaboratory.

4KscoreTestCategoryICPTCode

InOctober2015,theAmericanMedicalAssociation(AMA)determinedthatthe4KScoremettherequirementsforaCategoryICPTcode.BelowistheCPTcodeassignedandthedescriptionofthetestinthe2017AMACPTbookeffectiveJanuary2017.Thetestdescriptorisasfollows:

81539‐Oncology(high‐gradeprostatecancer),biochemicalassayoffourproteins(TotalPSA,FreePSA,IntactPSAandhumankallikrein‐2[hK2]),utilizingplasmaorserum,prognosticalgorithmreportedasaprobabilityscore

Discussion

Developmentofthe4KscoreTest

ScientistsandcliniciansfromMemorialSloanKetteringCancerCenterledtheinitialclinicalresearchonthefourkallikreinbiomarkers,andthedevelopmentofalgorithmsthatcombinedthebiomarkerswithclinicalinformation,laterfinalizedasthe4Kscoretest.Thisteampublishedaseriesofarticles41‐45thatdemonstratedtherepeatedabilityofafourkallikreinbiomarkerandclinicalinformationalgorithmtopredicttheriskofhigh‐grade(Gleasonscore7andhigher)prostatecancerandreduceunnecessaryprostatebiopsies.ThemenwereallenrolledintheEuropeanRandomizedStudyofScreeningforProstateCancer(ERSPC)andunderwentprostatebiopsyduetoanelevatedPSAlevel(3.0ng/mLandhigher)detectedbyPSAscreening.Multiplecohortswerestudied,includingmenwithnopriorPSAscreening,priorPSAscreening,andmenwhohadapriorbenign(negative)prostatebiopsy.ThispioneeringeffortservedasthescientificbasisforthedevelopmentofthecommerciallyavailableOPKO4Kscoretest.

IntheyearsfollowingthecollectionoftheERSPCsamples,theprostatebiopsystandardprocedurechangedfroma6‐core(sextant)biopsytoa10‐corebiopsyandnewcriteriaforGleasongradingwerealsointroducedthatbroadenedthecriteriaforinclusionintoGleasongrade4.46Also,therewasgrowingevidencethatGleasonscore6prostatecancer,thoughhavingthehistopathologicalfeaturesofadenocarcinoma,wasunlikelytometastasizeandcausedeath.2,3Thesechangesinclinicalpracticewerereflectedinthedevelopmentofthecommercialized4Kscore

18


test,validatedbyOPKO1inadoubleblinded,prospectivestudyofacontemporaryU.S.populationof1012menat26urologycentersacrosstheU.S.in2013‐14,anddescribedindetailbelow.

TheProstateTestingforCancerandTreatment(ProtecT)study,anongoingprospective,randomized,controlledclinicaltrial,providedanadditionalopportunitytoevaluatethediagnosticaccuracyandbiopsyreductionpotentialofthe4Kscoretestina2015publishedreport.47Allavailablecryopreservedbloodsamplesfromthosemenwhoagreedtoundergoprostatebiopsywereretrieved,resultinginasamplesetconsistingofEDTAplasmafrom4765men,serumfrom1860men,andbothplasmaandserumfrom496menwhohadundergoneaprostatebiopsy.Thelaboratoryperformingthetestingofthefourkallikreinsbiomarkerswasblindedtothebiopsypathologydataandviceversa.

Theplasmasamplesassessedwiththe4KscoretestagainstprostatebiopsyhistologyhadanAUC=0.820fordiscriminationofhigh‐grade(Gleasonscore7andhigher)prostatecancerandsuperiorperformancecomparedtoaPSA‐basedmodel(AUC=0.738).TheAUCinthiscohortwasvirtuallyidenticalcomparedwiththeU.S.validationstudyofParekhetal.1(discussedabove),andtheauthorsreportedthattheplasmaandserumsamplesprovidedequivalentAUCperformanceforthe4Kscoretest.Adecisioncurvedemonstratedclinicalutilityacrossrelevantriskthresholdsforhigh‐grade(Gleasonscore7andhigher)prostatecancer,withabiopsyreductionpotentialof43%ata6%riskthreshold.

The4Kscorewasfurthershowntoaccuratelypredictriskofhigh‐gradediseaseinapopulationscreenedwithfreetototalPSAratio.Braunetal.48studiedthe4Kscoretestinacohortof749whoallreceivedaprostatebiopsyduetoalowfreetototalPSAratio(<20%)orasuspiciousDRE.Theauthorsanalyzedarangeof4Kscorecutpoints(4‐12%)andprojectedthatupto38%ofprostatebiopsiescouldbeavoided.

TheAbilityofthe4KscoreTesttoPredicttheRiskofDistantMetastasis

The4KscoretestwasalsoevaluatedbyStattinetal.49inalong‐termclinicaloutcomesstudypublishedin2015,withanendpointofdistantprostatecancermetastasis.PSAand4Kscoretestresultswereobtainedfrombankedplasmasamplesinagroupofmenwhohadmorethan15yearsoffollowup.Duringthistimeframe,themenwerenotsubjecttoPSAscreening,thusthisstudyexaminedthenaturalhistoryofmetastaticprostatecanceroccurrenceobservedinmenasafunctionoftheirPSAandthe4Kscoretestresultsmeasuredover15yearsearlier.

Theplasmasamplesfromthesemenweretestedwiththe4KscoretestinadditiontoPSA.Thedatashowedthatafter20years,a4Kscoretestperformedatage50or60onamanwithaPSAlevelof2.0ng/mLandhigherprovidedclearriskstratificationforsubsequentdevelopmentofmetastaticprostatecancer(seeFigure4).

19


The50and60‐yearoldmenwithalow4Kscoretest(lessthan7.5%)hada1.3%and3.0%risk,versus10.7%and14.2%riskofmetastaticprostatecancerformenwithahigh4Kscoretestresult(7.5%andhigher).TheshorttermriskforbeingdiagnosedwithmetastaticprostatecancerinmenwithanelevatedPSAandalow4Kscoretestresults(lessthan7.5%)was0.3%forbothgroupsat10years,meaningadecisionnottobiopsytheprostateatthetimeofperformingthe4Kscoretestissafeandreasonable.Thisisespeciallytruebecausethisstudydesignwasanaturalhistorystudy.MeninthisstudywithelevatedPSAhadnofollowupforprostatecancer.Inpractice,amanwithanelevatedPSAandalow4KscorewouldbesubjectedtoregularmonitoringwithPSAtestingthatwouldverylikelydiagnosethepresenceofprostatecancerthatwasdestinedtobecomemetastaticatanearly,successfullytreatablestage.

Figure4.The4Kscoretestata7.5%cutpointprovides20‐yearpredictiveriskstratificationfor50and60‐year‐oldmenwithelevatedPSAof2.0ng/mLandhigher.

Theresultofthisstudyshows:1)the4KscoretestcandiscriminatethelongtermoutcomeofprostatecancermetastasisinmenwithanelevatedPSA2)adecisiontoavoidaprostatebiopsyinamanwithanelevatedPSA,butlow4Kscoretestresultwouldbeasafeandreasonableclinicaljudgment.

Conclusions

WidespreadPSAscreeningforprostatecancerhasledtoa45%declineinprostatecancermortality.However,thishascomeatahighcostintermsofthenumberofmensubjecttoprostatebiopsyandovertreatmentofindolentdiseasewithsurgeryandradiationtherapy.ThereisaneedforanoninvasivetestthatcanprovidebettersensitivityandspecificitythanPSAasadecisionpointpriortoprostatebiopsy.The4Kscoretesthasbeendevelopedtofillthismedicalneed,andisintendedtobeusedasaseconddecisiontestbyprovidingaccurateinformationontheriskforamanto

Age 50, PSA 2.0 ng/mL and higher Age 60, PSA 2.0 ng/mL and higher

1.1%

2.4%

8.3%

10.7%

0.0% 0.3% 0.9%

1.3%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

5 Year Risk 10 Year Risk 15 Year Risk 20 Year Risk

Risk of D

istant P

rostate Can

cer Metastases

4Kscore 7.5% and higher N = 318 (19%)

4Kscore less than 7.5% N = 1374 (81%)

1.8%

4.8%

9.1%

14.2%

0.0% 0.3%

1.3%

3.0%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

14.0%

16.0%

5 Year Risk 10 Year Risk 15 Year Risk 20 Year Risk

Risk of D

istant P

rostate Can

cer Metastases

4Kscore 7.5% and higher N = 2005 (46%)

4Kscore less than 7.5% N = 2313 (54%)

20


beharboringhigh‐grade(Gleasonscore7andhigher)prostatecancerbeforeproceedingtoaprostatebiopsy.

The4Kscoretest:

Isanon‐invasive,blood‐basedtest,offeredasanLDTbyBioReferenceLaboratories,awhollyownedsubsidiaryofOPKOHealth

Intendedtobeusedasaseconddecisiontoolbeforeperformingaprostatebiopsyinmenaged45‐75yearswithaPSAbetween1.5‐10ng/mLand/oranabnormalDRE.

Providesthenecessarydiscriminationforhigh‐grade,GleasonScore7andhigherprostatecancer(AUC=0.821)determinedinaprospective,doubleblinded,26‐centerclinicaltrialof1012menintheU.S.

HassuperioraccuracytoPSA,%fPSA,andPSAbasedriskcalculatorsforpredictinghighgradeprostatecancer

Hasbeenshowntominimizetheriskofover‐diagnosisandovertreatmentofprostatecancerbyreducingunnecessaryprostatebiopsiesasmuchas64.6%

Isincludedinthe2016NCCNguidelinesforprostatecancerearlydetectioninbothbiopsynaïveandmenwithapriorbenign(negative)biopsy

IsapprovedforaCategoryICPTcodebytheAMA

21


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The 4Kscore Test Accurately Identifies Risk for Aggressive ...4kscore.com/wp-content/uploads/2017/09/4Kscore-Dossier_0917.pdf · 6 BioReference Laboratories, Inc. (an OPKO Health