the break.

Maintenance Therapy for Recurrent Platinum-Sensitive

Ovarian Cancer

Robert L. Coleman, MD Professor & Executive Director, Cancer Network Research

M.D. Anderson Cancer CenterHouston, TX

Disclosures Related to This Presentation

• Research Funding:• NCI-SPORE, AstraZeneca, Clovis, Roche/

Genentech, V-Foundation, Janssen, Merck,Novartis

• Scientific Steering Committee:• Abbvie, AstraZeneca, Biomarin, Clovis, GamaMab,

Genmab, Immunogen, Janssen, Merck, Pfizer,Roche/Genentech, Tesaro

Symptoms

Diagnosis

Chemo#1

Staging/debulking

Evalua;on?SLL

Progression

Chemo#2

Chemo#3

Suppor;vecare

Chemo#4+

Maintenance M MConcomitant Concomitant

OvarianCancerNaturalHistory

Symptoms

Diagnosis

Chemo#1

Staging/debulking

Evalua;on?SLL

Progression

Chemo#2

Chemo#3

Chemo#4+

Maintenance M MConcomitant Concomitant

OvarianCancerNaturalHistory

Symptoms

Diagnosis

Chemo#1

Staging/debulking

Evalua;on?SLL

Progression

Chemo#2

Chemo#3

Chemo#4+

Maintenance M MConcomitant Concomitant

OvarianCancerNaturalHistory

?

CurrentUSFDAApprovalsforMaintenance

• Primary– Bevacizumab(2018)

• Concomitantwithchemotherapy• NorestricFonsonpaFentpopulaFon

• Exposurelimited:21cycles

– Olaparib(2018)• Followingchemotherapyresponse

• Restrictedtog/sBRCA• Exposurelimited:24months

• Recurrent(Pla;num-Sensi;ve)– Bevacizumab(2016)

• Concomitantwithchemotherapy• NorestricFonsonpaFentpopulaFon

• Exposurenotlimited

– PARPinhibitors(niraparib[2017],olaparib[2017],rucaparib[2018])

• Followingchemotherapyresponse

• NorestricFonsonpaFentpopulaFon

• Exposurenotlimited

ClinicalDebate

VS.

Anti-angiogenesis PARPi

PlaFnum-SensiFveMaintenance:Bevacizumab

PFS

Aghajanian, J Clin Oncol 2012 Coleman, Lancet Onc 2017

OCEANS GOG-213

PlaFnum-SensiFveMaintenance:PARPi

PFS(invReview–Primary) Rucaparib Placebo HR PtBRCA 16.8 5.4 0.23 P<0.000

1tBRCA+HRD 13.6 5.4 0.32 P<0.000

1ITT 10.8 5.4 0.37 P<0.000

1PFS(BICR–Primary) Niraparib Placebo HR PtBRCA 21.0 5.5 0.26 P<0.000

1Allnon-gBRCA(sBRCA+HRD+HRC)

9.3 3.9 0.45 P<0.001

ITT(FDAanalysis) 11.3 4.7 0.42 NotGiven

PFS(InvReview-Primary) Olaparib Placebo HR PgBRCA 19.1 5.5 0.30 P<0.000

1

ARIEL3

NOVA

SOLO2

Coleman, Lancet Oncol 2017; Mirza, N Eng J Med 2016; Pujade-Lauraine, Lancet Onco

2017

Key Issues to Understand the Data • The strategies for bevacizumab and PARPi are

different

• While both bevacizumab and PARPi’s are approved inbiomarker unrestricted populations, PARPi’s primarilyfunction under a predictive biomarker (g/sBRCA)

• Cross trial comparisons are particularly hazardous, notonly because they differ in design and primaryendpoints but also how those endpoints are measuredand patient enrichment

• Impact of front-line maintenance approval will bedifferent in the recurrent setting

ClinicalTrialDesignConsidera;ons

y

Symptoms

Diagnosis

Chemo#1

Staging/debulking

Evalua;on?SLL

Progression

Chemo#2

Chemo#3

Progression

Maintenance M MConcomitant Concomitant

Bevacizumab

PFS

y

Symptoms

Diagnosis

Chemo#1

Staging/debulking

Evalua;on?SLL

Progression

Chemo#2

Chemo#3

Maintenance M MConcomitant Concomitant

ClinicalTrialDesignConsidera;ons

Progression

PARPi

PFS

• PFS – Assessment

• Trials of concomitant/maintenance assignedtreatment start the PFS clock at pre-treatmentrandomization

• Trials of “switch maintenance” used in the PARPiphase III trials start the PFS clock at pre-treatmentrandomization but AFTER induction therapy

ClinicalTrialDesignConsidera;ons

y

Symptoms

Diagnosis

Chemo#1

Staging/debulking

Evalua;on?SLL

Progression

Chemo#2

Chemo#3

Maintenance M MConcomitant Concomitant

Progression

ProgressionPARPi

Bevacizumab

PFS

• Pre-randomization trial eligibility:

• In trials supporting bevacizumab, only patients withPD before completing chemotherapy wereexcluded

• Phase III PARPi trials required a response toplatinum-doublet therapy

ClinicalTrialDesignConsidera;ons

y

Symptoms

Diagnosis

Chemo#1

Staging/debulking

Evalua;on?SLL

Progression

Chemo#2

Chemo#3

Maintenance M MConcomitant Concomitant

Progression

ProgressionPARPi

Bevacizumab

PFS

502-891-4575 info@igcs.org www.igcs.org

• Whenismaintenanceconsidered• Sincebevacizumabaccompanies

chemotherapy,thedecisiontouseornotusebevacizumaboccursatrecurrence

• SincePARPiareconsideredwhenaresponsehasbeenachieved,discussioncanbedelayedunFlacerchemotherapy

• However,bevacizumabimprovedobjecFveresponse(anenrollmentrequirementforPARPi)from60%to80%

• PotenFallymissing10%ofPARPieligiblepaFentsbynotusingbevacizumabwithchemotherapy

y

Progression

Platinum- Based

Chemo Bevacizumab

y

Progression

Platinum- based Chemo

PARP

Bev

PARPi

Decision time – 100% of patients

Decision time - ~60% of patients

If response

ClinicalTrialDesignConsidera;ons

GO G

-213

• Pre-randomization trial eligibility:

• Platinum-sensitive recurrenttrials enrich for patients withBRCA-mutated and HRDcancers

• PARPi trials enrich for patientswith BRCA-mutated and HRDcancers

ClinicalTrialDesignConsidera;ons

y

Symptoms

Diagnosis

Chemo#1

Staging/debulking

Evalua;on?SLL

Progression

Chemo#2

Chemo#3

Maintenance M MConcomitant Concomitant

Progression

ProgressionPARPi

Bevacizumab

PFS

Trial BRCA-mt BRCA-wtHRD-pos

Total HRD

NOVA 203

(37%) 162 (29%) 66%

ARIEL3 196

(35%) 158 (28%) 63%

SOLO2 295

(100%) 100%

Double ovarian cancer population

prevalence

y

Symptoms

Diagnosis

Chemo#1

Staging/debulking

Evalua;on?SLL

Progression

Chemo#2

Chemo#3

Maintenance M MConcomitant Concomitant

Progression

ProgressionPARPi

Bevacizumab

PFS

• Stratification Variables

• In trials supporting bevacizumab, prognostic considerationswere PFI, prior bevacizumab (GOG-213), secondarycytoreduction (OCEANS) were considered

• In trials supporting PARPi, prognostic considerations were PFI,BRCA-mutation status (not SOLO2), best response toplatinum, prior second-line bev (NOVA)

ClinicalTrialDesignConsidera;ons

y

Symptoms

Diagnosis

Chemo#1

Staging/debulking

Evalua;on?SLL

Progression

Chemo#2

Chemo#3

Maintenance M MConcomitant Concomitant

Progression

ProgressionPARPi

Bevacizumab

PFS

• Interpretation of the data

• GOG-213 primary endpoint was OS; 8% of patients randomized to surgery, priorbevacizumab 10%

• OCEANS primary endpoint was PFS; 10% had surgery but were still measurable/assessable

• NOVA primary endpoint was BICR-PFS; two isolated cohorts (gBRCA and non-gBRCA(included sBRCA);final analysis included a merged ITT population

• SOLO2 primary endpoint was investigator-PFS but 100% gBRCA; Study 19 data used for ITT

• ARIEL3 primary endpoint was investigator-PFS but the ITT analysis specified a ”step-down”which included g/sBRCA, then HRD (included g/sBRCA), then ITT (included HRD)

ClinicalTrialDesignConsidera;ons

CurrentUSFDAApprovalsforMaintenance

• Recurrent(Pla;num-Sensi;ve)– Bevacizumab(2016)

• Concomitantwithchemotherapy• Norestric;onsonpa;entpopula;on• Exposurenotlimited

– PARPinhibitors(niraparib[2017],olaparib[2017],rucaparib[2018])• Followingchemotherapyresponse• Norestric;onsonpa;entpopula;on• Exposurenotlimited

VS.

MaintenanceTherapy:Concepts• Maintenance therapy is

TREATMENT

Tumor genetic data – N=121 Efficacy data – N=61

gBRCAmut15%

sBRCAmut10%

ORR:8%(RECIST)8%(RECIST&

CA-125)

ORR:32%(RECIST)40%(RECIST&

CA-125)

ORR:61%(RECIST)70%(RECIST&

CA-125)

BRCA-like42%

BiomarkerNega;ve33%

ARIEL2

100

80

60

40

20

0

79%

57% PR = 61

PR = 48

CR = 17 CR = 9

Difference: 21% p<0.0001

CG + PL (n=242)

CG + BV (n=242)

OCEANS

MaintenanceTherapy:Concepts• Prior exposure is likely IMPORTANT for

PARPi

Symptoms

Diagnosis

Chemo#1

Evalua;on?SLL

Progression

Chemo#2

Chemo#3

Chemo#4+M M

Bevacizumab Concomitant

BevacizumabPARPi(BRCA+)

?

MaintenanceTherapy:Concepts• Prior exposure is likely IMPORTANT for

PARPi

0.0

00

.25

0.5

00

.75

1.0

0

Pro

ba

bili

ty o

f P

FS

202 179 83 30 9 3 0 0 0Experimental203 137 35 10 5 1 0 0 0Control

Number at risk

0 6 12 18 24 30 36 42 48months

Control Experimental

Kaplan-Meier survival estimates

MITO-16B – Bev after Bev: no deteriment Deficient NHEJ Resista

nt Sensitive

McCormick,ClinCancerRes2017Aghajanian,JClinOncol2012

MaintenanceTherapy:Concepts• Prior exposure is likely IMPORTANT for

PARPi

0.0

00

.25

0.5

00

.75

1.0

0

Pro

ba

bili

ty o

f P

FS

202 179 83 30 9 3 0 0 0Experimental203 137 35 10 5 1 0 0 0Control

Number at risk

0 6 12 18 24 30 36 42 48months

Control Experimental

Kaplan-Meier survival estimates

MITO-16B – Bev after Bev: no deteriment

Olaparibtablets*

Placebo

gBRCA+orsBRCA+(N=136)

• 1priorPARPitreatment• 18mo+acer1stlineCT

12mo+acer2ndlineCT

Stra;fica;onfactorsü  Prior

bevacizumabü  <3vs≥3chemo

lines

*300 mg bid or last tolerable dose

R A N D O M I Z A T I

O N

wtBRCA-all-comers(N=280)

• 1priorPARPitreatment

• 12mo+acer1stlineCT06mo+acer2ndlineCT

RP/RC

Pla;num-basedchemotherapy

(noBev)

PFS,

TFS

T, F

AC

T-O

, Saf

ety,

AES

I, O

S

Powered80%forPFSprimaryendpoint.BRCA+HR=0.5,74events.BRCA-HR=0.65,191events.

416pa;ents

2:1

OREO Trial

ENGOT-ov26(PRIMA)StudyDesignNiraparib maintenance in First-line therapy

High Risk patients: Stage IV; residual Stage III

Stratification factors: • Use of NACT: yes or no• Best tumor response: CR or PR• HRD status: pos or neg/nd

• Patients with sBRCA or tBRCAmutwill be stratified as HRDpos

• Patients with unknown or wild typeBRCA will be stratified based onHRD test results

PFS in HRDpos patients; hierarchical analysis for all patients regardless of HRD status Primary Endpoint

Overall survival (OS), patient reported outcomes (PRO’s), time to first subsequent treatment, progression- survival-2 , time to CA-125 progression, safety and tolerability of study therapy

Key Secondary Endpoints

ClinicalTrials.gov Identifier: NCT02655016

PARPi Combination With Anti-Angiogenesis

ClinicalTrials.gov.NCT02477644.AccessedMay31,2019.

PAOLA-1

Primaryendpoint:PFS

Secondaryendpoints:OS,post-progressionsurvival,health-relatedqualityoflifebyTOIoftheFACT-O,andsafetyandtolerability

Veliparib:VELIA/GOG3005

•High-gradeseroustumors,StageIII,IV•ElecFonforNACT-ICSandschedulingofpaclitaxel(noIPtherapy)•PrimaryendpointPFS(ARMIvsArmIII):(1)g/sBRCA1/2PopulaFon;(2)HRD;(3)EnFrePopulaFon•StraFficaFons:Stage,ResidualDisease,NACT-ICS,Region,gBRCAstatus

III Veliparib 400 mg PO BID

Paclitaxel (standard or dose-dense) Carboplatin AUC 6 (IV)* Veliparib 150 mg PO BID

x6

IPaclitaxel (standard or dose-dense) Carboplatin AUC 6 (IV)* Placebo PO BID

Placebo PO BID

R

Open: Jul 2015 Closed: May 2017 Target Accrual: ~1100 pts (264 BRCA1/2 +)

x6

II Placebo PO BID

Paclitaxel (standard or dose-dense) Carboplatin AUC 6 (IV)* Veliparib 150 mg PO BID

1:1:1

ClinicalTrials.gov Identifier:NCT02470585

x6

Ovarian Cancer: Emerging Paradigm

• Maintenance therapy appear tobe of value in patients withplatinum-sensitive recurrentdisease

• Clinical pathway will likelychange:

• Exposure in earlier lines oftherapy

• With combinations that makesense in biomarkerunrestricted patients

• With new dynamic biomarkers of HRD

Progression

Chemo#2 Chemo#3 Chemo#4+M MConcomitant

PARPinhibitorsAnF-AngiogenesisInhibitors

CombinaFons

Thanks!