asco 2016 gu review

ASCO 2016 GU review JonathanRosenberg,MDAssociateAttendingPhysicianEnnoErcklentzChairGenitourinaryOncologyService

Prostate cancer • #5005and5006:Initialchemotherapyinprostatecancer

• #5008:Dosingofcabazitaxel2ndline• #5004:QOLonCHAARTED• #5001:AdjuvanttherapyafterRP• #5009:GermlinefindingsinCRPC

PRINCE: Study Design

Intermi(entDocetaxel

• Weekly35mg/m2• 3-weekly70mg/m2

Con>nuousDocetaxel

• Weekly35mg/m2• 3-weekly70mg/m2

Randomized1:1

Pa#ents

decidedbytrea>ngphysician

•  ConfirmedmCRPC

•  Karnofskyscoreof≥60%

•  Lifeexpectancy>12weeks

•  sufficienthepa>c,renal,cardiacfunc>on

Presentedby:HannesCash

PRINCE: Study Design Intermittent Docetaxel

12 week sequence 3-weekly: 4 cycles Weekly: 3 cycles

Treatment Holiday until disease progression

Intermittent Docetaxel

12 week sequence 3-weekly: 4 cycles Weekly: 3 cycles

DiseaseProgression:50%PSAincrease(atleast>4ng/ml)ofPSAnadira2ercon#nuingdocetaxelRadiologicalprogression(RECIST)Symptoma>cprogression


Study Objectives Primaryoutcomemeasures:• One-yearoverallsurvivalPrimaryhypothesis

• Non-inferiorityanalysisofintermittentvs.continuoustreatment


Poor enrollment •  Expectedpatientnumber:424with247events

•  Expectedpower:80%at1-sided97.5%CI

•  Poorrecruitment:187(<45%ofplanned)patientsrandomizedbetweenAugust2005andMay2008

•  IncludedinITT-Analysis:156patients,91events•  Achievedpower:39%


Overall Survival Intermittent Continuous

Median OS (months) 18.3 19.3

Hazard ratio 1.14

95% CI 0.75-1.72

P-value .535

Non-inferiority analysis P-value (H0: HR > .25) .33

Post-hocanalysis:non-inferioritymargin1.25

Non-inferioritynotachieved


Summary: Intermittent Docetaxel

•  Outcomes:–  Non-inferiorityat1-yearsurvival–  Non-inferioritynotachievedforOS–  Nodifferencesintoxicity–  NoQoLdata

•  Significantlyunderpoweredtodrawconclusions•  However,peoplearedoingthisintherealworldandfinditavalidmanagementstrategy


Presentedby:

Docetaxelremainsfront-linestandard

Cabazitaxel 25 mg/m2 vs 20 mg/m2 in 2nd line

Cabazitaxel in prostate cancer

• Dosereductionin2nd-linesettingdoesnotworsenoutcomes

• Front-linetherapywithdocetaxelremainsstandard

E3805 – CHAARTED Treatment STRATIFICATION Extent of Mets - High vs Low Age ≥70 vs < 70yo ECOG PS - 0-1 vs 2 CAB> 30 days -Yes vs No SRE Prevention -Yes vs No Prior Adjuvant ADT ≤12 vs > 12 months

RANDOMIZE

ADT+Docetaxel75mg/m2every21daysformaximum6cycles

ADTalone

Evaluateevery3weekswhilereceivingdocetaxelandatweek24thenevery12weeks

Evaluateevery12weeks

EvaluateQOLatBaseline,3,6,9and12monthsFollowfor#metoprogressionandoverallsurvivalChemotherapyatinves#gator’sdiscre#onatprogression

Presentedby:LindaJ.Patrick-Miller,Ph.D.

•  ADTallowedupto120dayspriortorandomiza>on.•  Intermi(entADTdosingwasnotallowed•  Standarddexamethasonepremedica>onbutnodailyprednisone

QOL Endpoints •  PrimaryEndpoint:OverallQOL

–  FunctionalAssessmentofCancerTherapy-Prostate(FACT-P).Self-reportmeasureofgeneralanddisease-specificqualityoflife8.Thesumof5subscales:

1  Physical2  Social3  Emotional4  Functionalwell-being5  Concernsspecifictoprostatecancer

•  HigherscoresindicatebetterQOL.

Presentedby:LindaPatrick-Miller,Ph.D.

8Esper,P.etal.AdultUrology,1997.

Overall QOL •  Patientstreatedwithdocetaxel+ADTreportadecrementinoverallQOL(FACT-P)whileontreatment

•  HOWEVER:QOLreturnstobaselineat12months:significantlybetterthanpatientstreatedwithADTalone

•  SupportschangeinpracticebasedonSTAMPEDEandCHAARTED

•  Clinicalbenefitdemonstrated,nowsupportedbyQOLdata•  Docetaxelx6+ADTisastandardofcare

Presentedby:LindaPatrick-Miller,Ph.D.

PrimaryEndpoint:PSArecurrence>0.5ng/mL

Adjuvant docetaxel or surveillance after RP

AhlgrenASCO2016

Howearlyisearlysupposedtobe?

Adjuvant docetaxel (no steroids) does not improve bPFS: No role at this time

Twiceasmanydeathsinthedocetaxelarm(6vs3)

DNA repair in CRPC •  Nelson:

–  11.8%ofmenhadgermlinealterationsofDDRgenes

–  59%hadsomaticmutations(mutationordeletion)leadingtoLOF

–  71%ofcarriershadfamilyhistoryofcancerotherthanprostate

–  DDRalterationsmorecommoninCRPC–  Germlinegenetictestingshouldbe

consideredinCRPC

Bladder cancer •  #4502:DurvalumabphaseI•  #4501:NivolumabphaseI/II•  #LBA4500Atezolizumab1stline•  #4515Atezolizumab2ndline•  #104Atezolizumabbiomarkers•  #5011DDRgenealterationsandcisplatinresponse

Durvalumab (PD-L1 antibody) Phase 1 Expansion cohort

Durvalumab expansion cohort

•  HighORRinPD-L1posi>vetumors

•  Limited/noac>vityinPD-L1nega>vebutsmall#s

•  PossiblybestPD-L1assaybasedonhighORRinposi>vepa>ents

Nivolumab in urothelial carcinoma

Nivolumab • PFS2.78months• OS9.7months• Durableresponsesobserved

• Awaitmaturedata

Atezolizumab in cisplatin-ineligible bladder cancer • No“standard”thoughgemcitabineandcarboplatiniscommunitystandard

• MedianOS9.3monthsinphaseIIItesting• AtezolizumabisfirstFDA-approvedPD-L1inhibitor

–  Approvedforlocallyadvancedormetastaticurothelialcarcinomapreviouslytreatedwithplatinum-basedchemotherapy

Cisplatin sensitivity associated with deleterious DDR gene alterations: Results from dose dense GC study

Kidney cancer

• #4506:OverallSurvivalwithcabozantinibvs.everolimus

• #4507:Long-termsurvivalwithnivolumabphaseIandIIstudies

Cabozan>nibinhibitsVEGF,Met,andAxl

FDAapprovedforRCCbasedonPFS

Nivolumab

1/3ofpa>entsaliveat4and5years!!!

Long term survival in nivolumab phase I and II studies

Presentedby:DavidMcDermo(

Low rates of immune related AE’s with long-term nivolumab therapy

Take-home points: Kidney • CabozantinibhasOSimprovement2nd-linesetting

–  PFSadvantageinfront-linesetting(Cabo-SunAlliancetrial)

• Wenowhave5yearsurvivaldataforRCCthatisunprecedented

–  10drugs(plusIL-2)approvedforccRCCallowingsequentialtherapytoprolonglife

Sehng Paradigm1 Paradigm2

First-line,suitableforTKI

Suni>nibor

Pazopanib

Suni>nibor

Pazopanib

Second-line Nivolumab

Axi>nib,Cabozan>niborLenva>nib+Everolimus

Third-line Axi>nib,Cabozan>nib

orLenva>nib+Everolimus

Nivolumab

Treatment Paradigm for Most Clear-cell mRCC Patients

Acknowledgments

• RobDreicer• OliverSartor• JoaquimBellmunt• BobMotzer

asco 2016 gu review

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