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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
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
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
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
Single agent: Olaparib in BRCAmutSOLO-3 trial: Ph III Olaparib vs ChT
Penson at. ASCO 2019
PFS (Intention-To-Treat Population)<br />
Penson at. ASCO 2019
Single agent: Olaparib in BRCAmutSOLO-3 trial: Ph III Olaparib vs ChT
Slide 4
Vanderstichele et at ASCO 2019
Single agent: Olaparib in all comersCLIO trial: Ph IIR
Slide 11
Vanderstichele et at ASCO 2019
Single agent: Olaparib in all comersCLIO trial: Ph IIR
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
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
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
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
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
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
Mirza et at. ASCO 2019
Combination PARPi + antiangiogenic AVANOVA2 trial: Ph IIR Niraparib +/- beva
PFS by BRCA status
Mirza et at. ASCO 2019
Combination PARPi + antiangiogenic AVANOVA2 trial: Ph IIR Niraparib +/- beva
• 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
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
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
Graciasandres.redondos@uam.es
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