presentación de powerpoint · olaparib1 study 42 rucaparib2 study-10 & ariel-2 niraparib3...

Cáncer de ovario:Presente y futuro de los inhibidores de PARP

Andrés RedondoHospital Universitario La Paz

Madrid

Disclosures

• Consultant or Advisory Role: Roche, AstraZeneca, Tesaro, Clovis

• Research Funding: Roche

• Speaking: Roche, AstraZeneca, Tesaro

• Registration and attending scientific meetings: Roche, AstraZeneca, Tesaro

1. Predictive biomarkers and development of PARPi

2. Relapse studies:

• Single-agent

• Maintenance

3. Front line studies

4. Future

5. Approvals

PARP inhibitors in ovarian cancerAgenda

High grade serous carcinomaBRCA mutations and HRD

20% BRCA mutated

TGCA, Nature 2011

50% HRD

Yang et al. JAMA 2011Tan et al. J Clin Oncol 2008

BRCA mutationsPrognostic and predictive role

BRCA2 mut

BRCA1 mut

BRCA wildtype

61%

25%

44%

SG 5 yearsResponses to platinum in BRCA and non-BRCA-mut

Homologous Recombination Deficiency (HRD)How can we identify it?

• DNA-based measures of genomic instability reflecting underlying tumor HRD:

o Loss of heterozygosity (LOH)

o Telomeric allelic imbalance (TAI)

o Large-scale state transitions (LST)Test LOH

Foundation MedicineTest MyChoice®

Myriad

LOH LOH, LST y TAI

Rucaparib Niraparib

Survival

Normal cell

Repair by

Homologous

Recombination

DNA SSBs occur all the time

in cells and PARP detects

and repairs them

During the replication

process unrepaired SSBs are

converted into DSBs

Replicating

cells

PARP

PARP inhibitor and Homologous Recombination Repair

No effective repair

(No HR pathway)

Cell death

Cancer cell with HRD

Tumour specific

killing by PARP

Inhibitors

PARP inhibitor

Development of PARPi in recurrent ovarian cancer

Single agent

MaintenanceBRCAmut

HRD

All comers

Agent Single agent Maintenance

BRCA mut All comers BRCA mut All comers

OlaparibPh II Study 42

Ph III SOLO-3Ph IIR CLIO Ph III SOLO-2 Ph IIR Study 19

Niraparib - Ph II Quadra - Ph III NOVA

RucaparibPh II

ARIEL-2 y St. 10

Ph II

Ariel 2 Part1- Ph III ARIEL-3

PARP inhibitors in recurrent ovarian cancerClinical trials


2. Relapse studies:

• Single-agent

• Maintenance


4. Future

5. Approvals


Gelmon KA et al. Lancet Oncol 2011

Single agent: OlaparibFirst study in ovarian cancer

Olaparib1

Study 42Rucaparib2

Study-10 & ARIEL-2Niraparib3

QUADRA

Prior number of lines > 3 lines > 2 lines > 3 lines

Biomarker BRCAmut BRCAmut HRD+, Plat-S (expanded primary

population)

N 137 106(74.5% Plat-S)

51(plat-S)

ORR 34% 53.8% 27%

Median PFS (months) 7 10 -

Median DOR (months) 7.9 9.2 9.4

Approval FDA FDA and EMA (Plat-S) -

1. Kaufman B et al.. J Clin Oncol 2015; 33(3): 244–250. 2. Oza et al. Gyn Oncol 2017; 147 (2017) 267–275 3. Moore K et al. ASCO 2018

Single agent: Olaparib, Rucaparib, NiraparibPhase II studies

Study Design<br />

Penson at. ASCO 2019

Single agent: Olaparib in BRCAmutSOLO-3 trial: Ph III Olaparib vs ChT

Primary Endpoint: ORR by BICR



PFS (Intention-To-Treat Population)<br />



Vanderstichele et at ASCO 2019

Single agent: Olaparib in all comersCLIO trial: Ph IIR


2. Relapse studies:

• Single-agent

• Maintenance


4. Future

5. Approvals


Ledermann J et al. Lancet Oncol 2014

Maintenance: Olaparib in all comersStudy 19: Ph IIR PFS

SOLO 2

Olaparib

RC/RP after Plat

Only germmutant

PFS (investig-assessed)

295 germ. mutant

NOVA

Niraparib

RC/RP (< 2 cm) after Plat

Mutant and no mutant

PFS (central review)

553 (203 g mutant)

ARIEL 3

Rucaparib

RC/RP after plat

Mutant and non mutant

PFS (investig-assessed)

594 (196 g mutant)

PARPi

Population

BRCA

Primaryendpoint

n

PARPi as maintenance after platinumPhase III studies: Design

19.1 vs 5.5 monthsHR 0.3 (95% CI: 0.22-0.41)

21.0 vs 5.5 monthsHR 0.27 (95% CI: 0.17-0.41)

16.6 vs 5.4 monthsHR 0.23 (95% CI: 0.16-0.34)

1SOLO-2 2NOVA 3ARIEL-3

1. Pujade et al. Lancet Oncol 2017; 18: 1274–84 2. Mirza et al. N Eng J Med 2016;375(22):2154-2164.; 3. Coleman et al. Lancet 2017; 390: 1949–61

PARPi as maintenance after platinum in BRCAmutPhase III studies: PFS (Primary endpoint)

Treatment

PFSMedian(95% CI)

(Months)

Hazard Ratio(95% CI)p-value

Niraparib

(N=234)9.3

(7.2, 11.2)0.45

(0.338, 0.607)

p<0.0001Placebo

(N=116)

3.9(3.7, 5.5)

PFS: non-gBRCAmut PFS: HRD positive

Treatment

PFSMedian(95% CI)(months)

Hazard Ratio(95% CI)P value

Niraparib

(N=106)12.9

(8.1, 15.9)

0.38(0.243, 0.586)

P<0.0001

Placebo

(N=56)3.8

(3.5, 5.7)

Treatment

PFSMedian(95% CI)

(Months)

Hazard Ratio(95% CI)p-value

Niraparib

(N=92)6.9

(5.6, 9.6)0.58(0.361, 0.922)

p=0.0226

Placebo

(N=42)3.8

(3.7, 5.6)

PFS: HRD negative

Mirza et al. N Eng J Med 2016

Maintenance: Niraparib in gBRCAwtNOVA: PFS by biomarker cohorts

PFS: BRCAwt LOH high PFS: BRCAwt LOH low

9.7 months vs 5.4 monthsHR 0.44 (0.29–0.66); p<0.0001

6.7 months vs 5.4 monthsHR 0.58 (0.40–0.85); p=0.0049

Coleman et al. Lancet 2017

Maintenance: Rucaparib in BRCAwtARIEL-3: PFS by biomarker cohorts

Gourley et al. ASCO 2017

Maintenance: OlaparibLong-term responders

Mirza MR, et al. IGCS 2018.

Treatment arm

Number of patients on treatment, N (%)

0–3 months 3 months–1 year 1–2 years 2–4 years

Niraparib 367 (100.0%) 298 (81.2%) 143 (39.0%) 69 (18.8%)

Placebo 179 (100.0%) 145 (81.0%) 31 (17.3%) 10 (5.6%)

Maintenance: NiraparibLong-term responders

Olaparib (SOLO-2)

Niraparib (NOVA)

Rucaparib (ARIEL 3)

Discontinuation 11% 14.7% 13.4%

Dose reduction 25% 66.5% 54.6%

Related SAE 17.9% 16.9% -

Nausea/vomiting 2.6% 3% 7.8%

Fatigue 4.1% 8% 6.7%

Anemia 19.5% 25 % 18.8%

Thrombocytopenia 1% 33 % 5.1%

Neutropenia 5.1% 19% 6.7%

Hypertension - 8.2% -

GOT/GPT - - 10.5%

MDS 4 (2.1%) 5 (1.4%) 3 (0.8%)

1. Pujade et al. Lancet Oncol 2017; Mirza et al. N Eng J Med 2016.; 3. Coleman et al. Lancet 2017

Maintenance with PARP inhibitorsSafety profile (Toxicity Grade > 3 )

PARPi as maintenance after platinumQuality of life

NOVA:Niraparib vs placebo

SOLO-2:Olaparib vs placebo

There was no deterimentaleffect in quality of life


2. Relapse studies:

• Single-agent

• Maintenance


4. Future

5. Approvals


Olaparib as maintenance after front line in BRCAmutPh III SOLO-1 Trial

• Primary endpoint: PFS

• Secondary endpoints: OS, time to earliest progression by RECIST or CA-125 or death, PFS2, best ORR, health-related quality of life by TOI of the FACT-O, TDT, TFST, TSST, and safety and tolerability

• Newly diagnosed stage III-IV ovarian, primary peritoneal, or fallopian tube cancer

• Documented deleterious gBRCA mutation

• Serous or endometrioid high-grade histology

• Stage III: 1 optimal debulking attempt

• Stage IV: biopsy and/or 1 upfront or interval debulking

• In CR or PR at end of frontline platinum-based chemotherapy

Olaparib 300 mg PO bid to

ProgressionN=230

Placebo bid to progression

N=115

R2:1

Moore et al. ESMO 2018 and N Eng J Med 2018

Moore et al. ESMO 2018 and N Eng J Med 2018

Olaparib as maintenance after front line in BRCAmutPh III SOLO-1 Trial

Niraparib as maintenance after front line in all comersPh III PRIMA Trial

Endpoint assessment

Niraparib 300 mg daily (n≈413)

PlaceboDaily (n≈207)

High –Grade Stage III or IV ovarian cancer (all comers) and achieved a CR or PR following front line platinum-based chemotherapy

Hierarchical Testing for PFS (radiologic, central review)· PFS in HRD pos population (HR 0.5)

· PFS in ITT population (HR 0.65)

Primary Endpoint

· Overall Survival · Patient Reported Outcomes (FOSI, EQ-5D-5L, EORTC-QLQ-30, EORTC-QLQ-OV28) · Safety & Tolerability · PFS2 · Time to CA-125 Progression

Key Secondary Endpoints

· Population PK · PK parameters for niraparib and major metabolite· HRD Diagnostic Test

Exploratory Endpoints

2:1 Randomization Final Enrollment (N=731)

• Neoadjuvant chemotherapy administered: Yes or No • Best response to 1st platinum therapy: CR or PR• HRD status: positive or negative/not determined

Stratification Factors


2. Relapse studies:

• Single-agent

• Maintenance


4. Future

5. Approvals


Optimizing efficacy of PARPi: Combinations

Anti-angiogenic

PARPi

Olaparib Olaparib/cediranib

PFS median 9 m 17.7 m

HR 0.42 (IC 95% 0.23-0.76)

Liu et al. Lancet Oncol 2014

Combination PARPi + antiangiogenic Ph IIR Olaparib +/- Cediranib

Olaparib Olapa/cediranib

PFS median 16.5 m 19.4 m

HR 0.55 (IC 95% 0.24-1.27)

Olaparib Olapa/cediranib

PFS median 5.7 m 16.5 m

HR 0.32 (IC 95% 0.14-0.74)

BRCA mutated BRCA wildtype or unknown

Liu et al. Lancet Oncol 2014

Combination PARPi + antiangiogenic Ph IIR Olaparib +/- Cediranib

ENGOT-OV24 / NSGO-AVANOVA2 trial design

Mirza et at. ASCO 2019

Combination PARPi + antiangiogenic AVANOVA2 trial: Ph IIR Niraparib +/- beva

Primary endpoint: PFS in the ITT population



PFS by BRCA status



• Phase III randomized, placebo-controlled, double-blind, multicenter

• Olaparib tablets administered at 600 mg daily for up to 2 years.

Combination PARPi + antiangiogenic Front line PAOLA 1 trial: Ph III Beva +/- olaparib

Optimizing efficacy of PARPi: Combinations

Immuno PARPi

Combination PARPi + immunotherapyPreclinical data

PARPi upregulates PD-L1 in BC xenograftSinergy of PARPi and anti-PD-L1

Jiao et al. Clin Can Res 2017

Kostantinopoulos et al. ESMO 2017 and ASCO 2018

60 evaluable patientsORR: 25%ORR BRCAmut: 42%ORR in PR: 23%ORR in PRf: 24%

Combination PARPi + immunotherapyTopacio: Ph II niraparib + pembrolizumab in TFIp < 6 m

Time to progression or treatment discontinuation

Tumor Responses

Drew Y et al: Presented at SGO, March 24-27 New Orleans, USA

Combination PARPi + immunotherapyMediola: Ph II olaparib + durvalumab BRCAmut with TFIp > 6 m

• Recurrent high- grade serous or endometrioid, or undifferentiated ovarian, primary peritoneal or tubal carcinoma

• TFIp >6 months• ≤ 2 prior lines• Measurable disease• ECOG≤ 1

Stratification factors:•Platinum based regimen selected•PFI (6-12 months vs > 12 months)•BRCA mutation status (mutated vs.

non-mutated)

Primary Endpoint:•PFS by RECIST v.1.1Secondary endpoints:•Safety and tolerability•TFST, TSST,PFS2,OS•ORR, DOR•QoL/PRO

1:1

RA

ND

OM

IZA

TIO

N

Platinum doublet + Placebo 6 cycles

Platinum-doublet +

Atezolizumab 6 cycles

REC

IST

v1.1

CT

SCA

N

If CR, PR or SD

Niraparib + Placebo until disease progression

Niraparib + Atezolizumab until disease progression

A

B

N= 414 patients

Combination of PARPi and immunotherapyANITA study: Ph III relapse with TFIp > 6 months

PI: Dr González-Martín

Increasing efficacy of PARP inhibitors Combinations

PARPi

Anti-angiogenicImmuno

Combination PARPi / Immuno / BevaFront line trials

TRIAL Setting Patient selection Arms

AGO / DUO-OENGOT Ov46

Front line PDS or IDS Any residualLGSOC excluded

CP-BevCP-Bev-DurvalumabCP-Bev-Durvalumab-Olaparib

BGOG /ENGOT Ov43 Front line BRCA non-mut*, Any histotypePDS or IDS Any residualBev optional

CP-Placebo-PlaceboCP- Pembro-PlaceboCP- Pembro-Olaparib

GINECO/ FIRSTENGOT Ov44

Front line PDS (high risk) or IDSBev optionalMucinous excluded

CP-Placebo-PlaceboCP-Placebo-NiraparibCP-TSR042-Niraparib

ATHENA GOG3020/ ENGOT

Maintenance after front line

PDS or IDSResponse to platinum

Rucaparib-NivolumabRucaparib-PlaceboNivolumab-PlaceboPlacebo-Placebo


2. Relapse studies:

• Single-agent

• Maintenance


4. Future

5. Approvals


PARPi in relapsed BRCAmut ovarian cancerApproved indications

Indication FDA EMA

OlaparibMaintenance ✓ ✓

Single agent ✓ NO

NiraparibMaintenance ✓ ✓

Single agent NO NO

Rucaparib

Maintenance ✓ ✓

Single agent ✓ ✓(platinum-sensitive, >

2 prior lines)

Indication FDA EMA

Olaparib Maintenance ✓ ✓

Niraparib Maintenance ✓ ✓

Rucaparib Maintenance ✓ ✓

PARPi in relapsed BRCAwt ovarian cancerApproved indications

HRD status has not been considered for approvals so far

Indication FDA EMA

Olaparib Maintenance ✓ ✓

Niraparib Maintenance NO NO

Rucaparib Maintenance NO NO

PARPi in Front line BRCAmut ovarian cancerApproved indications

• BRCAmut is the best biomarker to predict the highest benefit with PARP inhibitors,but these can benefit any patient with HGSOC

• Olaparib, Niraparib and Rucaparib have clinical benefit as single agent in patientswith > 2-3 lines of chemotherapy, mainly in BRCAmut and Plat-S

• Olaparib, Niraparib and Rucaparib improve PFS significantly as maintenance afterplatinum in BRCAmut patients, and to a lesser extent in BRCAwt patients

• Olaparib has shown an impressive benefit in PFS as maintenance after front linetreatment in BRCAmut patients

• Waiting for data of other PARPi in front line, and phase III trials with combinationswith antiangiogenics and/or immunotherapy

PARP inhibitors in ovarian cancerConclusions

[email protected]

presentación de powerpoint · olaparib1 study 42 rucaparib2 study-10 & ariel-2 niraparib3...

Documents