Inhibición de PARP: Bases biológicas, aplicaciones actuales y … · 2019-05-30 · gBRCA2m n=1...

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

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


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


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)


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(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


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


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



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!

Inhibición de PARP: Bases biológicas, aplicaciones actuales y … · 2019-05-30 · gBRCA2m n=1...

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