DNA repair deficiencies and PARP inhibitors in Triple ...archives.innovationinbreastcancer.com/files/Presentations/2015/007... · DNA repair deficiencies and PARP inhibitors in Triple

DNA repair deficiencies and PARP inhibitors in Triple Negative Breast Cancer

Andrew TuttDirector

Breakthrough Breast Cancer Research CentreLondon

Overview

• Evidence for targetable DNA damage defect in TNBC

• Is platinum a probe for Homologous Recombination Deficiency?

• What are the special “+ve” populations – gBRCA / “BRCAness”

• Biomarkers of Homologous Recombination Deficiency (HRD)

Focus on Genomic Scars as biomarkers

• Potential novel combinations including targeting S-Phase Stress

Breast Cancer have variable genome

complexity reflecting DNA repair competence

Palm Baobab TreeChestnut

Risk of treatment failure ?Lee and Swanton (2011) Cancer Research; Yap and Swanton Sci Trans Med (2012)

Alexandrov et al Nature 2013

BRCA1 BRCA2 Mutation

associated

APOBEC associated

Alexandrov et al Nature 2013

Stable genome- low instability

Unstable genome- high instability

TNBCs have highly variable

Chromosome structural instability

BRCA1 BRCA2 Mutation

associated

APOBEC associated

Genomic Instability generates high tumour

heterogeneity and few recurrent targetable mutations

MYH3

LAMB3 MYH4

ITGA6

LAMB4COL7A1

ITGA8

COL11A1

LAMB2

MYOC

MYH11P53

PI3KCA

The mutator phenotypes that define the

Baobab’s shape may be “actionable” targets

BRCA1 is a genome stability “caretaker” and

is mutated in ≈15% of patients with TNBC

Roy et al Nat Rev Cancer 2012 Walsh and King Cancer Cell 2007

BRCA1 and BRCA2 share function in the DNA DSB and replication fork damage response

*

*

**

*

*

*

*

Roy et al Nat Rev Cancer 2012 Walsh and King Cancer Cell 2007

BRCA1 and BRCA2 share function in the DNA DSB and replication fork damage response

*

*

**

*

*

*

*

HR deficiency implicated

In Sporadic TNBC

Methylation

Somatic mutation

Other epigenetic mechanisms

Roy et al Nat Rev Cancer 2012

When HR fails other DNA repair processes (NHEJ) take over driving a mutator phenotype

Roy et al Nat Rev Cancer 2012

When HR fails other DNA repair processes (NHEJ) take over driving a mutator phenotype

The pattern of

rearrangements across the

genome may act as a

diagnostic tattoo for HR failure

This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute

San Antonio Breast Cancer Symposium December 9-13, 2014

DSB at DNA crosslinkpt

pt

DNA crosslink unhooked by

XPF/ERCC1 and RPA

Moynahan et al Mol Cell 2000 Tutt et al EMBO J 2001

XPFERCC1

XPFERCC1

FancJ

BRCA1

Hueng et al Nat Rev Mol Cell Biol 2012

BRCA1 / BRCA2 and HR are involved in repair of DNA platinum adducts

This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute

San Antonio Breast Cancer Symposium December 9-13, 2014

Search for homologous sequence

on identical sister chromatid

Original sequence is restored

DSB at DNA crosslinkpt

BRCA2Rad51

X-link excision and DNA resynthesis

pt

DNA crosslink unhooked by

XPF/ERCC1 and RPA

Moynahan et al Mol Cell 2000 Tutt et al EMBO J 2001

XPFERCC1

XPFERCC1

FancJ

BRCA1

Hueng et al Nat Rev Mol Cell Biol 2012

BRCA1 / BRCA2 and HR are involved in repair of DNA platinum adducts

Zander, S. A.L. et al. Cancer Res 2010;70:1700-1710

Models of BRCA1 mutated basal-likebreast cancer have specific chemo-sensitivities

BRCA1

Mutation

Carriers with

Tumors >2cm

Clinical and

Pathological

Response

Platinum for Neoadjuvant Therapy in BRCA1 Mutation Carriers

.

CISPLATIN

75mg/m2

q 3wks IV x 12

wks

•N = 25

•median age: 46

•28% with clinically positive lymph nodes

•22 pts completed 4 cycles of Cisplatin

Pathological Response 72%

Gronwald et al ASCO 2009

Copyright © American Society of Clinical OncologySilver, D. P. et al. J Clin Oncol; 28:1145-1153 2010

Biomarkers of neoadjuvant

cisplatin response in TNBC

Breast Cancer Res 2014:16,211

Birkbak et al., Cancer Discov. 2012 Apr;2(4):366-75

Breast Cancer Res 2014:16,211

Birkbak et al., Cancer Discov. 2012 Apr;2(4):366-75

Numerical and Structural Chromosomal Instability associated

with BRCA1/2 inactivation and Cisplatin Sensitivity

Popova et al., Cancer Research. 2012 Aug 72:5454-5462. Abkevich et al., Br J Cancer. 2012 Nov 6;107(10):1776-82.

High Grade Serous

Ovarian Cancer

No: LoH

> 15Mb

Basal Like Breast Cancers

& BRCA1/2 mutations

No: adjacent

> 10Mb CNA

Large State Transition

BRCA1/2 mutant

BRCA1/2 intact

Numerical and Structural Chromosomal Instability associated

with BRCA1/2 inactivation and Cisplatin Sensitivity


High Grade Serous

Ovarian Cancer

No: LoH

> 15Mb


& BRCA1/2 mutations

No: adjacent

> 10Mb CNA


BRCA1/2 mutant

BRCA1/2 intact

Platinum as a probe for HR deficiency

in metastatic TNBC?

• Very few TNBC specific trials -> mostly subsets

• Often platinum assessed in combination

• Many cross study comparisons of subgroups

• Various “triple-negative” definitions

• BRCA1/2 mutation rarely characterised

• Mostly no correction for differences in disease free interval

• Randomized data comparing platinum to standard of care

chemotherapy in first or second line

Platinum in metastatic TNBC

Unselected and gBRCAmRegimen N ORR (%) PFS

(mths)

Prior Adj

Chemo (%)

Iniparib Trials

Gem / Carbo1

1st line

2nd/3rd line

258

148

110

30% 4.1

4.6

2.9

90%

Ph II gBRCA1m2

1st line

2nd line

20

11

9

80% (TTP)

12

65%

TBCRC009

Carbo / Cis3

86

11

gBRCAm

26%

55% gBRCAm

20% gBRCAwt

2.9 86%

1. O’Shaughnessy J, et al. ASCO 2011 (abstract) 2. Byrski et al Breast Cancer Res 2012 14:R110

3. Isakoff S, et al. ASCO 2014 (abstract)

TBCRC 009 Tested Two HRD deficiency “scar”

Fingerprints in tumour DNA


Telli et al ASCO 2013

Developed in HGSOC

Tested in PrECOG 0105

No: LoH

> 15Mb


& BRCA1/2 mutations

No: adjacent

> 10Mb CNA


BRCA1/2 mutant

BRCA1/2 intact

Platinum sensitivity is associated with higher HRD scores

Presented By Steven Isakoff at 2014 ASCO Annual Meeting

TNT Trial design20

RANDOMISE

(1:1)

Docetaxel (D)

100mg/m2 q3w, 6 cycles

Carboplatin (C)

AUC 6 q3w, 6 cycles

ER-, PgR-/unknown & HER2- or known BRCA1/2

Metastatic or recurrent locally advanced

Exclusions include:

• Adjuvant taxane in ≤12 months

• Previous platinum treatment

• Non-anthracyclines for MBC

A Priori subgroup analyses:

• BRCA1/2 mutation

• Basal-like subgroups (PAM50 and IHC)

• Biomarkers of HRD

On progression,

crossover if appropriateOn progression,

crossover if appropriate

Carboplatin (C)

AUC 6 q3w, 6 cyclesDocetaxel (D)

100mg/m2 q3w, 6 cycles

59/188 (31.4%)

67/188(35.6%)

0 20 40 60 80 100

Carboplatin

Docetaxel

% with OR at cycle 3 or 6 (95% CI)

Objective response21

Absolute difference (C-D)

-4.2% (95% CI -13.7 to 5.3)

Exact p = 0.44

Randomised

treatment - all

patients (N=376)

21/92*(22.8%)

23/90*(25.6%)

0 20 40 60 80 100

Carboplatin (Crossover=Docetaxel)

Docetaxel (Crossover=Carboplatin)

% with OR at cycle 3 or 6 (95% CI)

Absolute difference (D-C)

-2.8% (95% CI -15.2 to 9.6)

Exact p = 0.73

Crossover

treatment - all

patients (N=182)

*Denominator excludes those with no first progression and

those not starting crossover treatment

17/25(68.0%)

6/18(33.3%)

0 20 40 60 80 100

Carboplatin

Docetaxel

Percentage with OR at cycle 3 or 6 (95% CI)

Objective response – BRCA 1/2 status22


34.7% (95% CI 6.3 to 63.1)

Exact p = 0.03

Germline BRCA 1/2

Mutation (n=43)

Interaction: randomised treatment & BRCA 1/2 status: p = 0.01

0 20 40 60 80 100

Carboplatin

Docetaxel


No Germline

BRCA 1/2

Mutation (n=273)


-8.5% (95% CI -19.6 to 2.6)

Exact p = 0.16

36/128

(28.1%)

53/145

(36.6%)

Bimodality

Breast & Ovarian Ca

BRCA1/2 mutation

BRCA1 methylation

Score ≥ 42 HRD High

Timms et al. Breast Cancer Res 2014, 16:475

MYRIAD Composite HRD biomarker analysis

23

Bimodality

Breast & Ovarian Ca

BRCA1/2 mutation

BRCA1 methylation

Score ≥ 42 HRD High

Timms et al. Breast Cancer Res 2014, 16:475

MYRIAD Composite HRD biomarker analysis

23

HRD score

*excluded from analyses

Tested: 220

HRD high (≥42): 81

HRD low (<42): 114

Test failed: 25*

376 patients recruited

Positive

LN143 patients

Primary

tumour309 patients

Blood

288 patients

Negative

LN112 patients

Recurrent

tumour102 patients

HRD score by BRCA 1/2 mutation25

Carboplatin Docetaxel

0

10

20

30

40

50

60

70

80

90

100

Germline BRCA1

Germline BRCA2

No Mutation

Somatic

Tumour mutation (germline unknown)

High HRD

Score ≥ 42

Low HRD

Score < 42

Myriad cut-point

19/65(29.2%)

17/49(34.7%)

0 20 40 60 80 100

Carboplatin

Docetaxel


13/34(38.2%)

20/47(42.6%)

0 20 40 60 80 100

Carboplatin

Docetaxel


Objective response – HRD score26


-4.4% (95% CI -26.0 to 17.2)

Exact p = 0.82

High HRD score

(n=81)

Low HRD score

(n=114)


-5.4% (95% CI -22.7 to 11.9)

Exact p = 0.55

Interaction: randomised treatment & dichotomised HRD score: p = 0.91

HR repair can be regained by the

evolutionary pressure of chemotherapy

Reversion of BRCA1 mutations Loss of 53BP1

Swisher et al Cancer Res 2008 vol. 68 (8) pp. 2581-6

Aly A , Ganesan S J Mol Cell Biol 2011;3:66-74

Tumours may regain

HR repair “fitness” to survive

chemotherapy S-phase stress

Adapted from Nik-Zainal et al Cell 2012

Tumours may regain




Early TNBC

Tumours may regain




Early TNBCAdvanced

TNBC

Tumours may regain




Is an old HRD “tattoo”

a good marker of

current repair

competence?

A biker can become a

Priest but can’t lose his

old “Hells Angel”

tattoos Early TNBCAdvanced

TNBC

Tumours may regain




Is an old HRD “tattoo”

a good marker of

current repair

competence?

A biker can become a

Priest but can’t lose his

old “Hells Angel”

tattoos Early TNBCAdvanced

TNBCHRD = Diagnostic filter

for Early HRD

May need measures of

current repair capability

for metastatic clones

Perhaps the HRD Scar biomarker is not sophisticated enough

• Have minimum and maximum size thresholds

• Take account of CNP and regions of LOH in the germline

• Exclude effect of very localised Chromothripsis events

• Allow better differentiation of genome instability mechanisms

Pro

po

rtio

n

S AbCNA

S AiCNA

S CnLOH

0.2

0.4

0.6

0.8

1.0

no scar

B

C

D

KCL METABRIC TCGA TNBC cell lines

0.2

P < 0.05

S AbCNA

S CnLOH

KCL TNBCs

0.4

NtAI

SCNA

SAI

SCnLOH

SAiCNA

SAbCNA

NtA

I

SCNA

SAI

SCnL

OH

SAiC

NA

0.4 0.5 0.5 0.8 0.4 0.2

0.2 0.6 0.8 0.6 0.3

0.7 0.3 0.7 0.6

0.6 0.8 0.6

0.6 0.3

0.5

0.6 0.8

0.0

Fre

qu

ency

1

Spearman’s rank correlation coefficient

non-significant P

0 20 40 60

0.00

0.01

0.02

0.03

0.04

0.05

0 20 40 60 80

0 20 40 60 80

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

Fre

qu

en

cy

0.00

0.01

0.02

0.03

0.04

0.05S AiCNA

PrECOG

BRCA1/2: mutated

0

10

20

30

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wildtype wildtype mutated

Platinum

non-responders

Platinum

responders

P = 0.0036

P = 0.083

mutated wildtype wildtype mutated

SA

i

PrECOG TNBCsG

TCGA HGSCs

P = 0.00499

S Ai

0.00

0.01

0.02

0.03

0.04

0 20 40 60 80 100

Fre

qu

en

cy

Fre

que

ncy

SLO

H

0.20.70.50.70.50.1

0.10.80.80.50.3

0.50.50.60.5

0.80.70.5

0.70.2

0.5

METABRIC TNBCs

NtA

I

SCNA

SAI

SCnL

OH

SAiC

NA

KCLTNBCs

P = 0.0019

P = 0.1

P = 0.00529

Platinum

non-responders

Platinum

responders

BRCA1/2:

Figure 2. TNBCs differ in the extent and variety of genomic scarring they exhibit

Score Score

Score Score

Allelic ImbalancedCopy Number

Aberration

SAiCNA

Copy Neutral Loss of

Heterozygosity

SCnLOH

●

●● ●

Allelic Balanced Copy Number

Aberration

SAbCNA

●●

A

0

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SC

nL

OH

SA

i


Platinum

non-responders

Platinum

responders

BRCA1/2:

P = 0.528

P = 0.271

P = 0.362

P = 0.0265

P = 0.378

P = 0.0339


Platinum

non-responders

Platinum

responders

BRCA1/2:

P = 0.0082

P = 0.161

P = 0..00356

P = 0.0181

P = 0.175

P = 0.0391


Platinum

non-responders

Platinum

responders

BRCA1/2:


Platinum

non-responders

Platinum

responders

BRCA1/2:

PrECOG TNBCsE

TCGA HGSCs

PrECOG TNBCsF

TCGA HGSCs

SLO

H

Pro

po

rtio

nS AbCNA

S AiCNA

S CnLOH

0.2

0.4

0.6

0.8

1.0

no scar

B

C

D


0.2

P < 0.05

S AbCNA

S CnLOH

KCL TNBCs

0.4

NtAI

SCNA

SAI

SCnLOH

SAiCNA

SAbCNA

NtA

I

SCNA

SAI

SCnL

OH

SAiC

NA

0.4 0.5 0.5 0.8 0.4 0.2

0.2 0.6 0.8 0.6 0.3

0.7 0.3 0.7 0.6

0.6 0.8 0.6

0.6 0.3

0.5

0.6 0.8

0.0

Fre

qu

ency

1


non-significant P

0 20 40 60

0.00

0.01

0.02

0.03

0.04

0.05

0 20 40 60 80

0 20 40 60 80

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

Fre

qu

en

cy

0.00

0.01

0.02

0.03

0.04

0.05S AiCNA

PrECOG

BRCA1/2: mutated

0

10

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wildtype wildtype mutated

Platinum

non-responders

Platinum

responders

P = 0.0036

P = 0.083


SA

i

PrECOG TNBCsG

TCGA HGSCs

P = 0.00499

S Ai

0.00

0.01

0.02

0.03

0.04

0 20 40 60 80 100

Fre

qu

en

cy

Fre

que

ncy

SLO

H

0.20.70.50.70.50.1

0.10.80.80.50.3

0.50.50.60.5

0.80.70.5

0.70.2

0.5

METABRIC TNBCs

NtA

I

SCNA

SAI

SCnL

OH

SAiC

NA

KCLTNBCs

P = 0.0019

P = 0.1

P = 0.00529

Platinum

non-responders

Platinum

responders

BRCA1/2:

Figure 2. TNBCs differ in the extent and variety of genomic scarring they exhibit

Score Score

Score Score

Allelic ImbalancedCopy Number

Aberration

SAiCNA

Copy Neutral Loss of

Heterozygosity

SCnLOH

●

●● ●

Allelic Balanced Copy Number

Aberration

SAbCNA

●●

A

0

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SC

nL

OH

SA

i


Platinum

non-responders

Platinum

responders

BRCA1/2:

P = 0.528

P = 0.271

P = 0.362

P = 0.0265

P = 0.378

P = 0.0339


Platinum

non-responders

Platinum

responders

BRCA1/2:

P = 0.0082

P = 0.161

P = 0..00356

P = 0.0181

P = 0.175

P = 0.0391


Platinum

non-responders

Platinum

responders

BRCA1/2:


Platinum

non-responders

Platinum

responders

BRCA1/2:

PrECOG TNBCsE

TCGA HGSCs

PrECOG TNBCsF

TCGA HGSCs

SLO

H

NHEJ / SSA Non-Conservative HR by GC Genome duplication

S AbCNA

S AiCNA

S CnLOH

no scar

A B

C

0.2

P < 0.05

KCL TNBCs

0.4

NtAI

SAI

SCnLOH

SAiCNA

SAbCNA

NtA

I

SAI

SCnL

OH

SAiC

NA

0.4 0.5 0.5 0.4 0.2

0.2 0.6 0.6 0.3

0.7 0.7 0.6

0.8 0.6

0.5

0.6 0.8 1


non-significant P

SLOH

0.20.70.50.50.1

0.10.80.50.3

0.50.60.5

0.70.5

0.5METABRIC TNBCs

NtA

ISA

I

S CnL

OH

SAiC

NA

KCLTNBCs

Figure 1 (A-C). The extent and nature of allelic imbalance genomic scarring differentially

associate with platinum-based chemotherapy sensitivity in TNBC and HGSC

SLOH

0

20

40

60

80

Sco

re


S AbCNA

S CnLOH

Fre

qu

en

cy

0 20 40 60

0.00

0.01

0.02

0.03

0.04

0.05

0 20 40 60 80

0 20 40 60 80

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

Fre

qu

ency

0.00

0.01

0.02

0.03

0.04

0.05S AiCNA

PrECOG

S Ai

0.00

0.01

0.02

0.03

0.04

0 20 40 60 80 100

Fre

qu

ency

Fre

que

ncy

Score Score

Score Score

ER+ cell lines

1

2

3

4

5

6

9

8

7

10

11

12

13141516171819

2021

22

X

Scores of Chromosome Instability Scarring(SCINS)

Johnathan

Watkins

Anita

Grigioradis

S AbCNA

S AiCNA

S CnLOH

no scar

A B

C

0.2

P < 0.05

KCL TNBCs

0.4

NtAI

SAI

SCnLOH

SAiCNA

SAbCNA

NtA

I

SAI

SCnL

OH

SAiC

NA

0.4 0.5 0.5 0.4 0.2

0.2 0.6 0.6 0.3

0.7 0.7 0.6

0.8 0.6

0.5

0.6 0.8 1


non-significant P

SLOH

0.20.70.50.50.1

0.10.80.50.3

0.50.60.5

0.70.5

0.5METABRIC TNBCs

NtA

ISA

I

S CnL

OH

SAiC

NA

KCLTNBCs

Figure 1 (A-C). The extent and nature of allelic imbalance genomic scarring differentially

associate with platinum-based chemotherapy sensitivity in TNBC and HGSC

SLOH

0

20

40

60

80

Sco

re


S AbCNA

S CnLOH

Fre

qu

en

cy

0 20 40 60

0.00

0.01

0.02

0.03

0.04

0.05

0 20 40 60 80

0 20 40 60 80

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

Fre

qu

ency

0.00

0.01

0.02

0.03

0.04

0.05S AiCNA

PrECOG

S Ai

0.00

0.01

0.02

0.03

0.04

0 20 40 60 80 100

Fre

qu

ency

Fre

que

ncy

Score Score

Score Score

ER+ cell lines

1

2

3

4

5

6

9

8

7

10

11

12

13141516171819

2021

22

X

Scores of Chromosome Instability Scarring(SCINS)

Johnathan

Watkins

Anita

Grigioradis

Suggestions for PARPifrom gBRCA+ platinum data

• A BRCA1 or BRCA2 mutation is associated with high pathological response to platinums in early disease

• This gBRCA+ effect persists in advanced disease and is specific to platinum rather than taxane chemotherapy

• Suggests metastatic clones of gBRCA+ BC remaining after adjuvant chemotherapy retain HR repair defect and might gain specific benefit from PARP inhibitors in advanced disease or adjuvant context

• Suggests that BRCA mutation testing of blood and possibly tumour be considered in an oncology as well as a genetics clinic in many with TNBC

Suggestions for PARPifrom gBRCA+ platinum data

• Raises Q of what standard of care comparitor regimen for PARP inhibitors should be in gBRCA+ advanced breast cancer trials

• Raises need to further assess design of trials of combination platinum and PARP inhibitor strategies particularly in gBRCA+ breast cancer

• Raises questions of trials of maintenance PARP inhibitors after platinum response in gBRCA+ mBC and platinum responsive mTNBC

• Supports trial designs of adjuvant PARP inhibitors in women with BRCA1 or BRCA2 mutations with breast cancer at high metastatic risk

• HR Deficiency or BRCAness present in early breast cancer but not associated with BRCA1 or BRCA2 mutation appears to exist

• … but this form of HR deficiency may have more reversible biological drivers such as methylation of BRCA1 that are no longer present in the metastatic clones surviving adjuvant chemotherapy

• These non-mutated HRD scar +ve tumours might be considered to be the “Biker Priests”

• in women with TNBC and no BRCA1 or BRCA2 mutation diagnostics for targetable BRCAness or HR Deficiency require further work especially in advanced recurrent breast cancer

Suggestions from the non gBRCA+ TNBC platinum data

Ramanathan et al Abst 29LBA ECCO 2013

BMN 673

PARP inhibitors in gBRCA mutated cancer

Breast

Niraparib

Ovary

Michie et al Abst 2513 ASCO 2013

Breast

PARPi monotherapy in sporadic TNBC

TNBC BRCA

TNBC non-BRCA

Non-TNBC BRCA

–100

–20

–40

–60

–80

0

20

100

80

60

40

120

Be

st

% c

ha

ng

e f

rom

ba

se

lin

e

23 treated patients with target lesions identified at baseline

22 had at least one follow-up assessment

1 patient had no follow-up tumour size assessment

– 1 due to missing / incomplete post-baseline assessments

BRCAness sufficient for

synthetic lethality uncommon in

advanced non-BRCA TNBC?

BRCA1 methylation present in

20% TNBCTimms et al Breast Cancer Res 2014, 16:475

K Gelmon et al Lancet Oncology 2011

PARP inhibition focused on gBRCA companion

diagnostic groupincluding those with TNBC

R

Potent PARP

inhibitor at MTD as

continuous

exposure

Physician Choice

within SOC options

Capecitabine

or

Vinorelbine

or

Eribulin

or

Gemcitabine

gBRCA1 / BRCA2

Carriers

Advanced

anthracycline taxane

resistant breast cancer

Primary

endpoint

PFS

Niraparib – EORTC / BIG BRAVO Trial

BMN 673 – EMBRACA - NCT01945775

OLYMPIAD – Olaparib - NCT02000622

Can we combine platinums with potent PARP inhibitors?

• Balmana et al tested 75mg/m2 cis with continuous olaparib

• Not tolerable but reduction of Cisplatin to 60mg/m2 with olaparib at 50mg BD D1-5 tolerable.

Balmana et al Ann Oncol (2014) doi: 10.1093/annonc/mdu187

• Another Phase I study found Carboplatin dose of AUC 5 Q21 could be delivered with Olaparib at 400mg BD for 14 days1

• Combination of carboplatin with paclitaxel (175 mg/m2) required lowering the doses of carboplatin (AUC 4) and olaparib (200 mg bid, days 1–10) but was then tolerable2

• Combinations with paclitaxel and carboplatin and veliparibhave been achieved in early3 and advanced4 breast cancer

• Differences in drug mechanisms of action on PARP trapping may be relevant

1. Lee et al J Clin Oncol 31, 2013 (suppl; abstr 2514)2. Oza A et al J Clin Oncol 30, 2012 (suppl abstr 5001)3. Rugo et al SABCS 2013 abst S5-024. Somlo et al ASCO 2014 (Abstr 1021)

Can we combine platinums with potent PARP inhibitors?

Can veliparib sensitized chemotherapy improve on a platinum directed chemotherapy approach?

NCT01506609

If combinations are challenging perhaps platinumsfollowed by PARP as maintenance?

R

Potent PARP

inhibitor at MTD as

continuous

maintenance

Continue

chemotherapy

while tolerable

Advanced

1. gBRCA1 / BRCA2

2. TNBC

Responding to Platinum

Regimen after 3 or 6

cycles

• Statistically significant

PFS improvement

(HR 0.35, P<0.00001)

• In gBRCA carriers

(HR=0.18 95% P<0.00001)

Ledermann J et al. N Engl J Med 2012;366:1382–1392

0

0.6

0.8

0.9

0

0.1

0.2

0.3

0.4

0.5

0.7

1.0

3 6 9 12 15 18

Pro

ba

bil

ity o

f

pro

gre

ss

ion

-fre

e s

urv

iva

l

Time from randomization (months)

Hazard ratio 0.35

(95% CI, 0.25–0.49)

P<0.00001

Randomized treatment

Placebo

Olaparib 400 mg bid monotherapy

olaparib placebo

Events: Patients (%)

60:136 (44%)

94:129 (73%)

Median (mo) 8.4 4.8

Maintenance therapy after platinum response

early in ovarian cancer management

Ledermann J et al. J Clin Oncol 2013;31(15S):abstr 5505

To avoid late resistance can we bring novel PARP inhibitor approaches in earlier in High Risk TNBC

New Diagnosis

Post-Rx residual disease

Neoadjuvant Rx Second Adjuvant

Investigational Drug Rx

Relapse

Vs

No Relapse

Definitive Surgery

TNBC

Cisplatin with or without rucaparib after preoperative

chemotherapy in patients with triple-negative breast cancer

(TNBC): Hoosier Cancer Research Network BRE09-146

Abstract 1019Sujaata Dwadasi, Yan Tong, Tom Walsh, Michael A. Danso, Cynthia X. Ma, Paula

Silverman, Mary-Claire King, Susan M. Perkins, Sunil S. Badve, Kathy Miller

Presented by: Steven Isakoff - Discussant

R

a

n

d

o

m

i

z

e

Cisplatin

X 4 cycle

Cisplatin +

Rucaparib

30mg IVx3d

X 4 cycle

Rucaparib

100mg PO q wk

X 24 weeks

• Eligibility

– TNBC (or BRCA+)

– Residual disease (RCB 2/3, M-P 0-2, node +)

– No prior cisplatin (carboallowed)

– 128 patients

– 65 cisplatin

– 63 cis/rucaparib

Median RCB 2.6 v 2.7

1 Year DFS

C 83% v C/R 83%

22/128 patients BRCA

mutation

DFS C 85% v C/R 100%

Randomise 1:1

Double blind

N=1320

IDF

S

Dis

tant D

FS

; OS

Post neoadjuvant gBRCA

TNBC,

Non-PathCR pts

Post adjuvant gBRCA

TNBC

T2 or N+

Olaparib

300 mg bd

12 month

duration

Placebo

12 month

duration

Restricted to Germline

Mutation carriers

PIK3CA pathway and PARPi synergy

Juvekar A et al. Cancer Discovery 2012;2:1048-1063

Ibrahim Y H et al. Cancer Discovery 2012;2:1036-1047

Rehman F L et al. Cancer Discovery 2012;2:982-984

PIK3CA Mutation / PTEN or INPP4 loss

PIK3CA blockade of overactive pathway

Activation of ERK

Suppression of BRCA1/2 and reduced HR

Susceptibility to a PARP inhibitor

Control

Olaparib

BKM120

BKM+Olap

Matulonis et al Abstract 2510 ASCO 2014

G1 S G2 M

Cyclin BCdk1

DNA Damage

Targeting Mutant TP53 with Platinum and

ATR inhibition

p53 ATM

G1 S G2 M

Cyclin BCdk1

DNA Damage

Wee1

Stalled DNA

replication forks

Replication

stress

(c-MYC)

Platinum adducts

Replication Inhibitors

PARPi?


ATR inhibition

ATR

Chk-1

G1 S G2 M

Normal

MitosisCyclin BCdk1

DNA Damage

Wee1

Stalled DNA

replication forks

Replication

stress

(c-MYC)

Platinum adducts


PARPi?


ATR inhibition

ATR

Chk-1

G1 S G2 M

Normal

MitosisCyclin BCdk1

DNA Damage

Wee1

Stalled DNA

replication forks

Replication

stress

(c-MYC)

Platinum adducts


PARPi?


ATR inhibition

G1 S G2 M

Normal

MitosisCyclin BCdk1

DNA Damage

Stalled DNA

replication forks

Replication

stress

(c-MYC)

Platinum adducts


PARPi?


ATR inhibition

G1 S G2 M

Normal

MitosisCyclin BCdk1

DNA Damage

Stalled DNA

replication forks

Replication

stress

(c-MYC)

Platinum adducts


PARPi?


ATR inhibition

G1 S G2 M

Normal

MitosisCyclin BCdk1

DNA Damage

Stalled DNA

replication forks

Replication

stress

(c-MYC)

Platinum adducts


PARPi?


ATR inhibition

Premature

Chromatin

Condensation

Forced Early

Mitotic Entry

Targeting p53 loss with ATR inhibition in

combination with platinum therapy

Reaper Nat. Chem. Biol. 2011

51

0.0 0.2 0.3 0.6 1.3 2.5 5.0

10

.0

20

.0

20

.0

10

.0

5.0

2.5

1.3

0.6

0.3

0.0

-50510

15202530

35404550

5560

Synergy/Antagonism

VE-821

(M)

Cisplatin

(M)

0.0 0.2 0.3 0.6 1.3 2.5 5.0

10

.0

20

.0

20

.0

10

.0

5.0

2.5

1.3

0.6

0.3

0.0

-5

0

5

10

15

20

25

30

35

40

45

50

55

60

Synergy/Antagonism

VE-821

(M)

Cisplatin

(M)

Conclusions

• Significant evidence BRCA1 and BRCA2 mutation carriers have systemic therapy clinical trial and standard of care options distinct from others

• Identification of BRCA1/2 mutation is currently the clearest diagnostic of an HRD defect that is targeted by platinum chemotherapies and PARP inhibitors

• BRCA1 and BRCA2 mutation in germline and tumour should be reported in trials testing these agents and new HRD diagnostics

• The development of tumour based diagnostics for DNA repair deficiencies to inform choice of treatment for metastatic sites of disease outside the context of BRCA1/2 mutation remains a work in progress

• Trials specific to women with uncommon but important genetic forms of DNA repair deficient BC are possible and should be conducted

Acknowledgments

Fraser Symmans

Steven Isakoff

TNT Trial TMG

BRAVO Trial Steering Group

OlympiA Trial Steering Group

Breakthrough Breast Cancer

Cancer Research UK

Documents

DNA repair deficiencies and PARP inhibitors in Triple ...archives.innovationinbreastcancer.com/files/Presentations/2015/007... · DNA repair deficiencies and PARP inhibitors in Triple