Ongoing Investigation and Potential Integration of...
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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
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Disclosures
AdvisoryCommittee
AbbottLaboratories,AstraZenecaPharmaceuticalsLP,BayerHealthCarePharmaceuticals,JanssenBiotechInc,Merck,PfizerInc
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NovelAgentsinEarlyStageProstateCancer
• Since2010,5newagentshavebeenapprovedinthemCRPCspace
• Increasinginterestinusingnewapproachesinearlierhighrisk,non-metastaticdisease– Existingandnewerandrogenbiosynthesispathwayinhibitors– Immunotherapy– Chemotherapy
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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
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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
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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
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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.
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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
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DatafromtheSTRIVEtrialindicatethatenzalutamidesignificantlyreducedtheriskofprostatecancerprogressionordeathcomparedwithbicalutamideinpatientswithnonmetastaticormetastaticCRPC.
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IMAAGEN Study:IMpact ofAbirateroneAcetateinProstate-SpecificAntiGENSafety/efficacyofAA+prednisoneinnmCRPC withrisingPSAandcastratetestosterone
RyanCJ,etal.ASCOAnnualMeeting;June3-7,2016;Chicago,IL.
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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*
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IMAAGENConclusions
• Treatmentofhigh-risknmCRPC patientswithAA(1000mg)+P(5mg)resultedinamediantimetoPSAprogressionof28.7months
• Themediantimetoradiographicdiseaseprogressionwasnotreachedatthedatacut-off
• Thesafetyprofilewasconsistentwiththesafetyprofilefrompreviouslyreportedstudies
RyanCJ,etal.ASCOAnnualMeeting;June3-7,2016;Chicago,IL.
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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
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NeoadjuvantEnzalutamidePriortoProstatectomy
• Combotherapywithenza/dutasteride/LHRHa resultedinpCRandMRDratessimilartohistoricalcontrols.– 0/25enza pCR orMRD– 1/23enza/dutasteride/LHRHa pCR (4.3%)
• ContinuedARactivityinresidualtumorsuggeststhatARsignalingmaycontributetosurvival.StrategiestomoreeffectivelyablateARactivityarewarrantedtodeterminewhethermoresubstantialantitumoreffectsareobserved.
Montgomery,Betal.Clin CaResMay2017
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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
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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
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ManagementofEarlyStageProstateCancer:Conclusions
• RecentadvanceshavefocusedonmetastaticCRPCdisease• Renewedattentiononthemanagementofearlystagehighriskdiseaseincurrentclinicaltrials
• Newerlesstoxicagentscombinedwithadvancesingenomicandgeneticbiomarkerswillredefinetheapproachtoearlyhighriskdisease
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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
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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