Ongoing Investigation and Potential Integration of Secondary Hormonal Therapy, Immunotherapy or Cytotoxic

Therapy into the Management of Earlier Stage Disease

Leonard G. Gomella, MDChairman, Department of UrologySidney Kimmel Cancer CenterThomas Jefferson University Philadelphia, PA

Disclosures

AdvisoryCommittee

AbbottLaboratories,AstraZenecaPharmaceuticalsLP,BayerHealthCarePharmaceuticals,JanssenBiotechInc,Merck,PfizerInc

NovelAgentsinEarlyStageProstateCancer

• Since2010,5newagentshavebeenapprovedinthemCRPCspace

• Increasinginterestinusingnewapproachesinearlierhighrisk,non-metastaticdisease– Existingandnewerandrogenbiosynthesispathwayinhibitors– Immunotherapy– Chemotherapy

2017ProstateCancerLandscape

UnderthecareofONCOLOGIST

CastrationSensitive

Asymptomatic

NonMetastatic

CastrationResistant

Metastatic

Symptomatic

LocalTherapies

AndrogenDeprivation+/- docetaxel

SecondaryHormonalTherapies

Docetaxel

PostChemo

Death

EnzalutamideAbirateroneCarbazitaxel

Sipuleucel-T

Abiraterone

Radium 223

Red arrows indicate new agents and indications since 2010.

PalliativeChemo

Enzalutamide

Tumor

activity

EvolvingInterestinEarlyStageHighRiskDisease

UnderthecareofONCOLOGIST

CastrationSensitive

Asymptomatic

NonMetastatic

CastrationResistant

Metastatic

Symptomatic

LocalTherapies

ADT+/- docetaxel

SecondaryHormonalTherapies Docetaxel

PostChemo

Death

EnzalutamideAbirateroneCarbazitaxel

Sipuleucel-T

Abiraterone

Radium 223

PalliativeChemo

Enzalutamide

Tumor

activity

EARLYLATE

STRIVE

IMAAGEN

RTOG0521

STANDEMBARK

PROSPER

NEOADJENZAENZARAD

LATITUDE

ATLAS

Selectedclinicaltrialscompletedandongoingin“early”disease

SelectClinicalTrialsInEarlierStageProstateCancerUsingApprovedAgents

Clinicaltrial Phase Studydescription N StatusSTRIVE

NCT01664923 2 ENZAvs. bicalutamideafterADTinM0/M1CRPC 400 Data available

NeoadjuvantEnzalutamideNCT01547299

2 Randomized,open-label ENZA neoadjtherapyforpatientsundergoingRPforlocalizedPC 52 Data available

EMBARKNCT02319837 3

Randomized,3-armtrialofENZAvs.ENZA+Leuprolidevs.Placebo+Leuprolidewithnon-metastaticprostatecancerandrapidlyrising

PSAafterinitiallocaltherapy1860 Enrolling

EnzaradNCT02446444 3 RT+AdjuvantLHRH+EnzalutamideinHigh-RiskClinicallyLocalized

ProstateCancer 800 Enrolling

PROSPERNCT02003924 3 ADT± ENZAinM0CRPCwithoutpriorchemotherapy 1560 Enrolling

RTOG0521NCT00288080 3

ADT and radiotherapy vs ADT and RT followed by chemotherapy with docetaxel and prednisone for localized,

high-risk prostate cancer 563 Data Available

LATITUDENCT01715285 3 ADTalonevsAbiraterone/prednisonenewlydiagnosedhighrisk

metastatichormonenaïve 1200 Datapending

STRIVEStudyDesign

PrimaryEndpoint:•PFS*

Secondaryendpoints:•TimetoPSAprogression•PSAresponse•Safety

Patients•Progressivechemo-naivemCRPC(n=396)

•M0:n=139•M1:n=257

•Asymptomaticormildlysymptomatic

RANDOMIZED

Enzalutamide160mgorallyoncedaily+

LHRHanalogue

Bicalutamide50mgorallyoncedaily+

LHRHanalogue

Phase 2, randomized, double-blind, parallel study

*PFS was defined as time from randomization to radiographic (bone or soft tissue) progression, PSA progression (defined by Prostate Cancer Working Group 2 criteria), or death due to any cause, whichever occurred first.31. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT01664923?term=strive+enzalutamide&rank=1. Accessed April 7, 2015.2. Penson D et al. Presented at: AUA Annual Meeting; May 15-19, 2015: New Orleans, LA.

STRIVE:Progression-FreeSurvival

Penson D et al. AUA Annual Meeting. May 15 -19, 2015; New Orleans

CI = confidence interval; HR = hazard ratio; NR = not reached

Enzalutamide 160 mgBicalutamide 50 mg

Median 19.4 months(95% CI: 16.5, NR)

HR, 0.24 (95% CI: 0.18, 0.32); P < 0.0001

Median 5.7 months(95% CI: 5.6, 8.1)

100908070605040302010

0

PFS

(%)

0 3 6 9 12 15 18 21 24 27 30

198 171 150 131 101 66 43 24 16 5 0198 138 80 51 29 17 9 5 3 1 0

Patients at RiskEnzalutamideBicalutamide

DatafromtheSTRIVEtrialindicatethatenzalutamidesignificantlyreducedtheriskofprostatecancerprogressionordeathcomparedwithbicalutamideinpatientswithnonmetastaticormetastaticCRPC.

IMAAGEN Study:IMpact ofAbirateroneAcetateinProstate-SpecificAntiGENSafety/efficacyofAA+prednisoneinnmCRPC withrisingPSAandcastratetestosterone

RyanCJ,etal.ASCOAnnualMeeting;June3-7,2016;Chicago,IL.

IMAAGENdatapresentedbyRyanCJ,etal.ASCOAnnualMeeting;June3-7,2016;Chicago,IL

87%(95%Cl:81%-93%)ofsubjectsachieveda≥50%PSAreduction• 91%ofsubjectsachieveda≥30%PSAreduction• 60%ofsubjectsachieveda≥90%PSAreduction

*Additionalanalysisincluding31confirmedand15withunconfirmedprogressionthatledtodiscontinuationfromthetrial

MaximumPSAReductionDuringCycles1-6

RadiographicEvidenceofDiseaseProgression*

IMAAGENConclusions

• Treatmentofhigh-risknmCRPC patientswithAA(1000mg)+P(5mg)resultedinamediantimetoPSAprogressionof28.7months

• Themediantimetoradiographicdiseaseprogressionwasnotreachedatthedatacut-off

• Thesafetyprofilewasconsistentwiththesafetyprofilefrompreviouslyreportedstudies

RyanCJ,etal.ASCOAnnualMeeting;June3-7,2016;Chicago,IL.

SequencingofSipuleucel-TandAndrogenDeprivationTherapy(STAND)inMenwithHormone-SensitiveBiochemically-RecurrentProstateCancer:APhaseIIRandomized

Trial

• M0followingRPorRT,PSADT<12months• Sipuleucel-Tw/12mo ADTvs12mo ADT→Sipuleucel-T• EndpointwasPA2024-specificTcellresponse• Results:responseswerehigherwithsipuleucel-T→ADTversusADT→sipuleucel-T;longertimetoPSAprogression

• Conclusions:Sipuleucel-T→ADTappearstoinducegreaterantitumorimmuneresponsesthanthereversesequence.

Antonaarakis,Clin CanResPublishedOnlineNovember10,2016

NeoadjuvantEnzalutamidePriortoProstatectomy

• Combotherapywithenza/dutasteride/LHRHa resultedinpCRandMRDratessimilartohistoricalcontrols.– 0/25enza pCR orMRD– 1/23enza/dutasteride/LHRHa pCR (4.3%)

• ContinuedARactivityinresidualtumorsuggeststhatARsignalingmaycontributetosurvival.StrategiestomoreeffectivelyablateARactivityarewarrantedtodeterminewhethermoresubstantialantitumoreffectsareobserved.

Montgomery,Betal.Clin CaResMay2017

ARantagonists:CentraltoNextPhaseofEarlyTrialsFirstGeneration Type Action FDAApproved

Flutamide Non-steroidalphenylamine

BindsARLBDandinhibitsARactivationbyandrogens

1989

Bicalutamide Non-steroidalphenylamine

BindsARLBDandinhibitsARactivationbyandrogens

1995

Nilutamide Non-steroidalphenylamine

BindsARLBDandinhibitsARactivationbyandrogens

1996

SecondGeneration Type Action FDAApproved

Enzalutamide(MDV3100) Non-steroidaldiarylthiohydantoin

BindsARLBD,inhibitsARactivationbyandrogens,inhibitsARnucleartranslocation,inhibits

ARDNAbinding

2012

Apalutamide (ARN-509) Non-steroidaldiarylthiohydantoin

BindsARLBD,inhibitsARactivationbyandrogens,inhibitsARnucleartranslocation,inhibits

ARDNAbinding

PhaseIII

Darolutamide (ODM-201) Non-steroidalcarboxamide

BindsARLBD,inhibitsARactivationbyandrogens,inhibits

ARnucleartranslocation

PhaseIII

SelectPhaseIIIClinicalTrialsinEarlier-StageProstateCancerUsingInvestigationalAgents

TrialIdentifier

TargetAccrual

EligibilitySetting

Randomization

ATLAS 1,500 High-riskclinicallylocalizedPCareceiving primaryradiationtherapy

• Apalutamide (ARN-509)x30mos +Placebo+GnRHagonistx30mos +Radiationtherapy(74-80Gy)

• Bicalutamide x30mos +Placebo+GnRHagonistx30mos +Radiationtherapy(74-80Gy)

SPARTAN 1,200 M0 CRPCathighriskofprogression(PSADT≤10mos)

• Apalutamide +ADT

• Placebo+ADT

ARAMIS 1,500 M0CRPCathighriskofprogression(PSADT≤10mosandPSA>2ng/ml)

• Darolutamide (ODM-201)

• Placebo

ARASENS 1,300 Metastatichormone-sensitivePCa

• Darolutamide +ADT+docetaxel

• Placebo+ADT+docetaxel

ManagementofEarlyStageProstateCancer:Conclusions

• RecentadvanceshavefocusedonmetastaticCRPCdisease• Renewedattentiononthemanagementofearlystagehighriskdiseaseincurrentclinicaltrials

• Newerlesstoxicagentscombinedwithadvancesingenomicandgeneticbiomarkerswillredefinetheapproachtoearlyhighriskdisease

Ongoing Investigation and Potential Integration of Secondary Hormonal Therapy, Immunotherapy or Cytotoxic

Therapy into the Management of Earlier Stage Disease

Leonard G. Gomella, MDChairman, Department of UrologySidney Kimmel Cancer CenterThomas Jefferson University Philadelphia, PA

SELECT PHILADELPHIA PROSTATE CANCER CONSENSUS 2017 CONCLUSIONS

• Factor in BRCA2 mutation status into PCA screening discussions. • Test men with suspected HPC (hereditary prostate cancer) for HOXB13, with

suspected hereditary breast and ovarian cancer (HBOC) for BRCA1/2, and suspected Lynch Syndrome for DNA mismatch repair (MMR) gene mutations.

• When considering management, BRCA2 achieved moderate consensus for factoring into early-stage management discussion, and strong consensus in high-risk/metastatic setting.

• There was moderate agreement to test all men with metastatic castration-resistant PCA, with strong agreement to test BRCA1/2 and moderate agreement to test ATM to guide targeted therapy.

Giri, et al Submitted JCO May, 2017