inhibición de parp: bases biológicas, aplicaciones actuales y … · 2019-05-30 · gbrca2m n=1...
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Inhibición de PARP: Bases biológicas, aplicaciones actuales y perspectivas de futuro
Antonio González Martín
Clínica Universidad de Navarra, Madrid
GEICO (Grupo Español de Investigación en Cáncer de Ovario)
ENGOT (European Network of Gynecological Oncological Trials groups)
Disclosure
• Employment: NO
• Consultant or Advisory Role: AZ, TESARO. CLOVIS, MSD, ROCHE, Pfizer/MERCK, INMUNOGEN, GENMAB
• Stock Ownership: NO
• Research Funding: TESARO, ROCHE
• Speaking: ROCHE, TESARO, AZ, PHARMAMAR
• Grant support: NO
• Other: Travel and accommodation: TESARO, AZ
Agenda
• Mechanisms of action
• Clinical development update
• Mechanism of resistance
• Overcoming resistance and future directions
Mechanisms of action
DNA Damage Response
Single strand breaks
• Mismatch repair (MMR)
• Nucleotide excision repair (NER)
• Base excision repair (BER)
• PARP1/PARP 2
DNA DAMAGE
Cell death
Environmental factors
(UV, radiation, chemicals)
Normal physiology
(DNA replication, ROS)
MAJOR DNA REPAIR
PATHWAYS
Chemotherapy
(alkylating agents, antimetabolites)
Radiotherapy
Double strand breaks
▪ Nonhomologous end-joining
▪ Homologous recombination
– BRCA1/BRCA2
▪ Fanconi anemia pathway
▪ Endonuclease-mediated repair
Replication lesions
• Base excision repair
• PARP1/PARP 2
DNA adducts/base damage
• Alkyltransferases
• Nucleotide excision repair
• Base excision repair
• PARP1/PARP 2
Helleday T, et al. Nat Rev Cancer. 2008;8:193-204. O’Shaughnessy J, et al. ASCO 2009. Abstract 3. Reproduced with permission.
PARP catalytic cycle
Tens of thousands of endogenous SSBs formtransiently every day, and PARP1 and PARP2are critical for their repair
Levine D. The Cancer Genome Atlas, Molecular profiling of serous ovarian cancer, 2011
Homologous recombination (HR) deficient
Not HR deficient
BRCA1
germline
8%
BRCA2
germline
6%
BRCA1
somatic
3%BRCA2
somatic
3%
BRCA1
methylation
11%
EMSY
amplification
6%PTEN loss
5%Other HRD
7%
CCNE1
amplification 15%
MMR
germline
2%
Other
34%
20% HGSOC are BRCA 1/2 mut
• BRCA1/2 germline mutation 14%
• BRCA1/2 somatic mutation 6%
• Total 20%
Synthetic Lethality
“Phenomenon in which 2 non-lethal genetic mutations are innocuous when they occur individually, but which result in lethality to a cell in combination”
Theodosius Dobzhansky, 1946
Targeting the DNA repair defect in BRCA mutant cellsas a therapeutic strategy
Hannah farmer… Alan Ashworth. Nature 2005
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
Walsh. Gynecol Oncol 2015
PARPi MoA
PARP is needed for PARPi cytotoxic effect
Muray et al. Cancer Res 2012
PARP inhibitor Trapping
PARP inhibitors
Slide 15
Presented By Elise Kohn at 2015 ASCO Annual Meeting
Trapping potency of PARPi
Clinical development update
Clinical Development
Phase IExpansion
cohortNon-BRCA mutated
RR 50% (8/16) in
OC and BRCA mut
Dose up to 400 bidFong P et al. New Eng J Med 2009
RR 43% (23/50)
OC and BRCA mut
Fong P et al. J Clin Oncol 2010
RR 24% (11/46)
OC and BRCA wt
Gelmon KA, et al. Lancet Oncol 2011;12:852–61
PARPi as single agent in BRCAmut
Olaparib1
Study 42Rucaparib2
Study-10 & ARIEL-2Niraparib3
QUADRA
Prior number of lines > 3 lines > 2 lines > 3 lines
N 137 106(74.5% Plat-S)
63(58% plat-R/Rf)
ORR 34% 53.8% 29%
Median PFS (months) 7 10 -
Median DOR (months) 7.9 9.2 9.2
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. Lancet Oncology 2019
Platinum combination followed by iPARP maintenanceOlaparib study-19 design and results
Primary end point : PFS
Olaparib 400 mg po
bid
Randomized 1:1
Placebopo bid
• Platinum-sensitive high-grade serous ovarian cancer
• 2 previous platinum regimens
• Last chemotherapy was platinum-based to which they had a maintained PR or CR prior to enrolment
• Stable CA-125
Study-19 aim and design
265 patients
Ledermann J, et al. N Engl J Med 2012;366:1382–92
Study-19 PFS
11.2 vs 4.3 monthsHR 0.18 (95% CI: 0.10-0.31)
Ledermann et al. Lancet Oncol. 2014;15(8):852–861
Long-term outcome with olaparib in Study-19
15% 11%
Lederman et al. Lancet Oncol 2016; 17: 1579–89
gBRCA2m
n=5
gBRCA1m
n=3
gBRCA1m &
gBRCA2m
n=1
HRD +ve
n=1
HRD +ve
n=1**
HRD -ve
n=1**
HRRm*
n=1
HRRm uncertain
n=2
HRRwt
n=2
Biomarker characterisation of the 15 patients who received olaparib for ≥6 years1
• †Biomarker identification was carried out using the following: gBRCAm: case report forms after local testing or Integrated BRACAnalysis® assay (Myriad Genetics); tBRCAm: Foundation Medicine T5 panel and Myriad MyChoice® HRD test; mutations in other HRR-associated genes: Foundation Medicine T5 panel; HRD scores:; BRCA1/2m, BRCA1/2 mutation; gBRCAwt, germline BRCA wild type; HRR, homologous recombination repair; HRD, homologous recombination deficiency; HRRm, HRR mutation; HRRwt, HRR wild type; sBRCA1/2m, somatic BRCA1/2 mutation; tBRCA, tumour BRCA. DCO: May 2016
Gourley C et al. J Clin Oncol 35, 2017 (suppl; poster related to abstr 5533)
BRCAm
n=9
sBRCAm
n=3
BRCAwt
n=5
gBRCAwt;
tBRCA unknown
n=1
Foundation Medicine T5 panel result
Myriad HRD score result
Patients receiving olaparib for ≥6 years
n=15
*Myriad HRD score result, patient was found to have RAD51B mutation
**2/5 BRCAwt patients had no available Myriad HRD score result
Myriad MyChoice® HRD test (score of ≥42 was considered to be a positive HRD score)
RAD51B
mutation
*Normal CA125 required
Clinical Trials Designs and Patient’s Characteristics1SOLO-2 2ENGOT-OV16 / NOVA 3ARIEL-3
Random 2:1 withplacebo
Olaparib300 mg bid
Niraparib300 mg once daily
Rucaparib600 mg bid
BRCA status BRCAmut gBRCA Non-gBRCA All comers
Histology HGS/HGEOC HGSOC HGS/HGEOC
TFIp prior line > 6 months > 6 months > 6 months
Prior lines• 2• > 2
56%44%
51%49%
66%34%
62%38%
Best response• CR• PR
46%54%
51%49%
50%50%
34%66%*
Lesion > 2 cm 15% 0% 0% 19%
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
Efficacy of PARPi in BRCA mutant patientsPrimary endpoint: PFS
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
Efficacy of PARPi for sBRCA patients inENGOT-ov16/NOVA
Key message
Somatic BRCA testing should be determined in gBRCA wt as the benefit of maintenance with PARPi is similar to gBRCA patients
Treatment
PFSMedian(95% CI)
(Months)
Hazard Ratio
(95% CI)p-value
% of Patients without
Progression or Death
12 mo 18 moNiraparib
(N=35)20.9
(9.7, NR) 0.27(0.081, 0.903)
p=0.0248
62% 52%
Placebo(N=12)
11.0(2.0, NR)
19% 19%
Mirza et al. N Eng J Med 2016;375(22):2154-2164.
…what if gBRCA is wild-type?Is HRD a biomarker?
Hypothesis: HRD may explain long term outcome with PARPi in BRACwtConsequently: HRD may be a potential predictive biomarker beyond BRCA
myChoice HRD test (MyriadGenetics)
• HRD is a numerical score (0-100) resulting from the sum of three components scores
• LOH: loss of heterozygosity
• TAI: Telomeric Allelic Imbalance
• LST: large-scale state Transition
• A cut off point of 42 is able to capture 95% of BRCA mutand was used to identify BRCAwt HRD+ tumors
Wilcoxen et al. ASCO 2015. Poster #5532
6
LOH signature detects BRCA-like patients
Tumor genomic profiling based on NGS
• Foundation Medicine’s NGS-based comprehensive cancer genomic profiling
assay sequences BRCA and other HR genes in tumor-derived DNA
• The assay also sequences SNPs
• SNP analysis identifies and quantifies genomic LOH
mut – mutant; SNP – single-nucleotide polymorphism; wt – wild type.
Hypothesis 1:
Ovarian cancer
patients with high
genomic LOH
suggesting BRCA-
like signature will
respond to rucaparib
Hypothesis 2:
Ovarian cancer
patients who are
“Biomarker Negative”
(ie, with low genomic
LOH) will not
respond to rucaparib
BRCAmut
BRCA-like
Chromosome No.
Biomarker
Negative
BR
CA
wt
Genomic LOH HRD test (Foundation)
Efficacy of PARPi in non-gBRCAmutant patientsENGOT-ov16/NOVA
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;375(22):2154-2164.
ARIEL3: Investigator-Assessed Progression-Free SurvivalBRCA mutant HRD ITT
Median(months) 95% CI
Rucaparib(n=236)
13.6 10.9–16.2
Placebo(n=118)
5.4 5.1–5.6
HR, 0.32; 95% CI, 0.24–0.42;
P<0.0001
Median(months) 95% CI
Rucaparib(n=375)
10.8 8.3–11.4
Placebo(n=189)
5.4 5.3–5.5
HR, 0.36; 95% CI, 0.30–0.45;
P<0.0001
At risk (events)
Rucaparib 130 (0) 93 (23) 63 (46) 35 (58) 15 (64) 3 (67) 0 (67)
Placebo 66 (0) 24 (37) 6 (53) 3 (55) 1 (56) 0 (56)
Rucaparib, 48% censored Placebo, 15% censored
At risk (events)
Rucaparib 236 (0) 161 (55) 96 (104) 54 (122) 21 (129) 5 (134) 0 (134)
Placebo 118 (0) 40 (68) 11 (95) 6 (98) 1 (101) 0 (101)
Rucaparib, 43% censored Placebo, 14% censored
At risk (events)
Rucaparib 375 (0)228
(111)
128
(186)65 (217) 26 (226) 5 (234) 0 (234)
Placebo 189 (0) 63 (114) 13 (160) 7 (164) 2 (167) 1 (167) 0 (167)
Rucaparib, 38% censored Placebo, 12% censored
Median(months) 95% CI
Rucaparib(n=130)
16.6 13.4–22.9
Placebo(n=66)
5.4 3.4–6.7
HR, 0.23; 95% CI, 0.16–0.34;
P<0.0001
Visit cutoff date: 15 April 2017.
Ledermann et al. ESMO 2017
Efficacy of PARPi in BRCAwt patientsARIEL-3: investigator assesed PFS
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; 390: 1949–61
Safety Profile of PARPi
Olaparib (SOLO-2)
Niraparib (ENGOT OV-16/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, grade >3 2.6% 3% 7.8%
Fatigue, grade >3 4.1% 8% 6.7%
Anemia, grade >3 19.5% 25 % 18.8%
Thrombocytopenia, grade >3 1% 33 % 5.1%
Neutropenia, grade >3 5.1% 19% 6.7%
MDS 4 (2.1%) 5 (1.4%) 3 (0.8%)
GOT/GPT, grade >3 - - 10.5%
MDS, myelodysplastic syndrome; SAE, serious adverse event
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
SOLO-1: Study design
*Upfront or interval attempt at optimal cytoreductive surgery for stage III disease and either biopsy and/or upfront or interval
cytoreductive surgery for stage IV disease. BICR, blinded independent central review; ECOG, Eastern Cooperative Oncology
Group; FACT-O, Functional Assessment of Cancer Therapy – Ovarian Cancer; FIGO, International Federation of Gynecology
and Obstetrics; HRQoL, health-related quality of life; PFS2, time to second progression or death;
RECIST, Response Evaluation Criteria in Solid Tumours; TOI, Trial Outcome Index
• Newly diagnosed, FIGO
stage III–IV, high-grade serous
or endometrioid ovarian,
primary peritoneal or fallopian
tube cancer
• Germline or somatic BRCAm
• ECOG performance status 0–1
• Cytoreductive surgery*
• In clinical complete response or
partial response after platinum-
based chemotherapy
Olaparib 300 mg bd
(N=260)
Placebo
(N=131)
2:1 randomization
• Study treatment
continued until
disease progression
• Patients with no
evidence of disease at
2 years stopped
treatment
• Patients with a partial
response at 2 years
could continue
treatment
Primary endpoint
• Investigator-assessed PFS
(modified RECIST 1.1)
Secondary endpoints
• PFS using BICR
• PFS2
• Overall survival
• Time from randomization to
first subsequent therapy or
death
• Time from randomization to
second subsequent therapy
or death
• HRQoL (FACT-O TOI score)
Stratified by response
to platinum-based
chemotherapy
2 years’ treatment if no evidence of disease
HR 0.62
SOLO-1: Patients
September 2013 to March 2015
391 patients
260 Olaparib
131 Placebo
85% ovary
80% ECOG 0
80-85% FIGO III
2/3 PDS
75% R0
1/3 NACT (IDS)
80% R0
82% CR
18% PR
PFS by investigator assessment
0 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
0
10
20
30
40
50
60
70
80
90
100
3
Inve
stig
ato
r-as
sess
ed
pro
gre
ssio
n-f
ree
surv
ival
(%
)
Months since randomization
Olaparib
Placebo
Olaparib
(N=260)
Placebo
(N=131)
Events (%) [50.6% maturity] 102 (39.2) 96 (73.3)
Median PFS, months NR 13.8
HR 0.30
95% CI 0.23, 0.41; P<0.0001
NR, not reached
260 229 221 212 201 194 184 172 149 138 133 111 88 45 36 4 3 0 0 0240Olaparib 260 229 221 212 201 194 184 172 149 138 133 111 88 45 36 4 3 0 0 0240Olaparib
131 103 82 65 56 53 47 41 39 38 31 28 22 6 5 1 0 0 0 0118
No. at risk
Placebo
60%
27%
SOLO-1: Subgroup analysis
CR
HR 0.35
Residual
HR 0.44
FIGO III
HR 0.32
PR
HR 0.19
No-Resid
HR 0.33
FIGO IV
0.49
Summary of efficacy endpoints
0 10 20 30 40 50 60
Olaparib (N=260) Placebo (N=131)
40.7
Median not reached
15.1
41.9
51.8
51.8
41.9
Median not reached
Median not reached
13.8
41.9
Months since randomization
Median time to
second subsequent
therapy or death
Median time to
first subsequent
therapy or death
Median PFS2
Median PFS
HR 0.45
95% CI 0.32, 0.63;
P<0.0001
HR 0.30
95% CI 0.22, 0.40;
P<0.0001
HR 0.50
95% CI 0.35, 0.72;
P=0.0002
HR 0.30
95% CI 0.23, 0.41;
P<0.0001
Health-related quality of life: FACT-O TOI score*
Olaparib
Placebo
Ch
an
ge f
rom
ba
se
lin
e
in T
OI
sc
ore
Weeks since randomization
218
115
204
114
No. at riskOlaparib
Placebo
35
30
25
20
15
10
5
0
-40
-35
-30
-25
-20
-15
-10
-5
13 25 37 49 61 73 85 97
191
104
186
91
179
75
163
61
144
51
141
49
137
42
5
*TOI scores range from 0 to 100, with higher scores indicating better HRQoL and a clinically meaningful difference defined as ±10 points
The difference between
olaparib and placebo in
the mean change from
baseline in TOI score
over 24 months (−3.00;
95% CI −4.779, −1.216)
was not clinically
meaningful
Figure reproduced from: Moore K et al. N Engl J Med 2018; 379(26):2495–505
*Grouped terms. All-grade thrombocytopenia (grouped term) occurred in 11.2% of patients in the olaparib group and 3.8% of
patients in the placebo group and grade ≥3 thrombocytopenia (grouped term) occurred in 0.8% and 1.5%, respectively
Most common treatment-emergent adverse events
0.8
1.5
1.5
4.6
0.8
3.8
0.4
21.5
3.1
8.5
All grades (frequency ≥25%)
Grade ≥3 (frequency ≥5%)
All grades (frequency ≥25%)
Grade ≥3 (frequency ≥5%)
Placebo (N=130)Olaparib (N=260)
23.1
25.4
26.2
27.7
34.2
38.8
40.0
63.5
77.3Nausea
Fatigue/asthenia*
Vomiting
Anaemia*
Diarrhoea
Constipation
Dysgeusia
Arthralgia
Neutropenia* 11.5
26.9
3.8
19.2
24.6
10
41.5
37.7
14.6
100 75 50 25 0 0 25 50 75 100
Adverse events (%)
New algorithm in front line
AfterSOLO-1
AfterSOLO-1
AfterSOLO-1
SoC
CT ± BEV
BRCAmut
gBRCA
sBRCA
BRCA non-mutant
BRCA non-mutant
CT → Ola
CT ± BEV
Milestones in PFS for OC in Front-Line
GOG-47CisplatinHR 0.75
1986 1996
GOG-111Paclitaxel
HR 0.7
2006
GOG-172Intraperitoneal
HR 0.8
2011
GOG-218Bevacizumab
HR 0.71
SOLO-1OlaparibHR 0.3
2018
HRD=homologous recombination deficiency; CR=complete response; PR=partial response; PFS=progression-free survival;
ENGOT ov26 / PRIMA Study
Endpoint assessment
Niraparib 300 mg
Placebo
Platinum responsive ovarian cancer
Stage III or IV ovarian
CR or PR with front line platinum-based chemotherapy
HRDpos or HRDneg/not determined (nd) tumor
2:1 Randomization
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
pre-enrollment screening:
•centralized HRD testing for
all patients
•local sBRCA and/or gBRCA
test results are allowed
Stratification factors:
•Use of NACT: yes or no
•Best tumor response: CR or PR
•HRD status: pos or neg/nd
• Patients with sBRAC or tBRCAmut
will be stratified as HRDpos
• Patients with unknown or wild type
BRCA will be stratified based on
HRD test results
CONFIDENTIAL
Mechanisms of resistance
Mechanisms of primary resistance
• Effective (and strong) HR system
• BRCA 1 and 2
• PTEN
• PI3K
• ATM
• ….
• Defective NHEJ (40% of OC)
• miRNA (mir-9, mir-506, mir-96, mir-182 and mir-206)
Mechanisms of secondary resistance• PARPi related
• Overexpression of Pgp-1 (P-Glycoprotein) (MDR1 mechanisms): Olaparib and rucaparib are substrates of Pgp-1
• PARP related• Down-regulation of PARP1 (PARP-1 required due to the trapping mechanism
of action)
• Mutations in C-terminal domain of PARP1 (BRCT) by preventing the recruitment of protein complexes needed in the site of the damaged DNA
• HR related (“partial” restoration of HR repair) • Loss of P53-binding protein 1 (53BP1)
• Loss of REV7
• Secondary mutations restoring RAD51C and RAD51D
• Secondary mutations in BRCA 1or2 that restores the function
BRCA Reversion Mutations in Circulating Tumor DNA
Lin et al. Cancer Discovery 2018
97 patientssBRCA/gBRCA mutRucaparib treated
in ARIEL 2
cfDNAPre-rucaparib
8/97 BRCA Reversion Mutation
18% in Plat-Rf13% in Plar-R2% in Plat-S
89/97 BRCA NO Reversion Mutation
Median PFS9.0 months
Median PFS1.8 months
cfDNAPost-rucaparib
8 patientscfDNA
BRCA Reversionmutation
OReO – ENGOT-Ov38
(Olaparib Retreatment in late recurrent Ovarian cancer)
RANDOMIZATION
Eligible patients
▪ Relapsed non-
mucinous EOC
▪ Documented
BRCA1/2 status
▪ Treatment with one
course of PARPi
maintenance
therapy
▪ PR/CR after≥4
cycles of platinum-
based chemo
Olaparib tablets300 mg bid or
last tolerable dose
Placebo
PFSPrimary endpoint
(RECIST 1.1)
PF
S,
OS
, T
TP
‡,
TD
T, T
FS
T, T
SS
T,
HR
Qo
L,
Safe
ty
Stratification factors:• Prior bevacizumab• ≤3 vs ≥4 prior lines of
chemotherapy
136 patients with a germline or somatic
mutation in BCRA1/2
Exposure for ≥18 months after first-line Cx or ≥12
months after second-/later-line chemotherapy
Cohort 1
BRCAm
280 patients
Exposure for ≥12 months after first-line Cx or ≥6
months after second-/later-
line chemotherapy
Cohort 2
non-BRCAm
PR or CR to
most recent course of
platinum-based chemotherapy
(no bevacizumab)
Overcoming resistance and future directions
Optimizing PARPi efficacy: Combinations
IO
Anti-angiogenic
iPARP
Combination of PARPi and anti-angiogenic agent
Olaparib OlaparibCediranib
N 46 44
PFS all 8.2 m 16.5 m HR 0.5 p 0.007
OS all 33.3 44.2 0.64 p 0.11
PFS gBRCAwt
5.7 m 23.7 m HR p 0.002
OS gBRCAwt
23 m 37.8 m P 0.047
Liu et al. Ann Oncol 2019
Hypothesis
• Hypoxia induced byantiangiogenic agents may(re)create homologousrecombination repairdeficiency, thus enhancingthe effect of PARP inhibition
Combination of PARPi and anti-angiogenic agentSTUDY LEAD GROUP COMBINATION SETTING
ICON-9 MRC Olaparib vsCediranib - Olaparib
Maintenace 1st platinum-sensitive
relapse
GY-004 NRG Olaparib vs Cediranib - Olaparib vs
TPC
Platinum-sensitive
AVANOVA NSGO Niraparib vs Niraparib - Bevacizumab
Platinum-sensitive
GY-005 NRG Cediranib vs Olaparib vs Olaparib – Cediranib vs
Non-Platinum TPC
Platinum-resistant
ENGOT Ov24 /NSGO AVANOVA2
Mirza et al. J Clin Oncol 37, 2019 (suppl; abstr 5505)
97 patientsHGSOCHGEOC
Platinum-sensitiveAny prior lines
Niraparib 300 mg/d
Niraparib 300 mg/dBevacizumab 15 mg/kg/q3w
Median PFS5.5 months
Median PFS11.9 months
HR 0.35 (0.21-0.57)
• Phase III randomized, placebo-controlled, double-blind, multicenter
• Olaparib tablets administered at 600 mg daily for up to 2 years.
PAOLA 1 / ENGOT OV-25
Stratification factors:
First-line treatment outcome (complete resection after initial surgery and NED atscreening, complete resection at interval debulking surgery and NED at screening,incomplete resection at initial or interval debulking surgery and in CR at screening, PRat screening) & gBRCA status (yes, no, unknown)
Combination of PARPi and immunetherapyPreclinical data
PARPi upregulates PD-L1 in BC xenograft Sinergy of PARPi and anti-PD-L1
Jiao et al. Clin Can Res 2017
TOPACIO/Keynote-162 (PROC)Niraparib 200 mg/d + pembrolizumab 200 mg/21d
Kostantinopoulos et al. ESMO 2017 and ASCO 2018
60 evaluable patientsORR: 25%ORR BRCAmut: 42%ORR in PR: 23%ORR in PRf: 24%
• 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
Platinumdoublet+ Placebo 6 cycles
Platinum-doublet +
Atezolizumab6 cycles
REC
IST
v1.1
CT
SCA
N
If CR, PR or SD
Niraparib+ Placebo until disease progression,
unacceptable toxicity, death, withdrawal of consent, or
study termination by sponsor
Niraparib+ Atezolizumabdisease progression,
unacceptable toxicity, death, withdrawal of consent, or
study termination by sponsor
A
B
N= 414 patients
ENGOT-OV41/GEICO 69-O/ANITA
The addition of atezolizumab is expected to increase the median PFS of Arm A from 16 months to 22.9 months, corresponding to a 30% reduction of the risk of progression (average HR of 0.70)
PI: Gonzalez-Martin
Front line for Stage III/IV with PARPi / IO /Bev
TRIAL Setting Patient selection Arms
AGO / DUO-O ENGOT 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 OvXX
Maintenance after front line
PDS or IDSResponse to platinum
Ruca-NivoRuca-PlaceboNivo-PlaceboPlacebo-Placebo
* Clinical trial with NACT for BRACmut under discussion
Summary• PARPi therapy is one of the most important advances for ovarian
cancer patients in the last decades
• Maintenace olaparib is the new SoC in front line for BRCA mutant patients
• Maintenance with PARPi improves significantly the PFS and the time to subsequent therapy in platinum-responders patients, and we observe very long term responders (> 5 years)
• BRCA mutated patients benefit most, but no biomarker is good enough to rule out the benefit in BRCAwt patients
• Understanding mechanism of resistance is critical for optimizing the PARPi use
• Several ongoing trials are addressing different combinations in different settings
Antonio González Martín
Clínica Universidad de Navarra, Madrid
GEICO (Grupo Español de Investigación en Cáncer de Ovario)
ENGOT (European Network of Gynecological Oncological Trials groups)
Muchas Gracias!
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