The Role of PARP inhibitors in Breast Cancer QROC November 5 th, 2010 Rebecca Dent, MD FRCP(C) Sunnybrook Odette Cancer Center Toronto, Canada.

The Role of PARP inhibitorsin Breast Cancer

QROC

November 5th, 2010

Rebecca Dent, MD FRCP(C)Sunnybrook Odette Cancer Center

Toronto, Canada

Potential Conflict of Interest

• Dr. Rebecca Dent– AstraZeneca, consultant and honorariat

(2007-2010)– Roche, consultant and honorariat (2007-2010)– Sanofis-Aventis, consultant and honorariat

(2007-2010)

Why did the Scientific Committee ask the young

investigator from Sunnybrook to talk about PARP inhibitors in

breast cancer?Two Reasons:

1.Smallest study evaluating PARP inhibitors (but provocative!)

2.Large clinical practice of TNBC and BRCA mutation carriers

Achilles’ Heel:

A deadly weakness in spite of overall strength, that can

actually lead to downfall

Neoadjuvant endocrine responses in ER + disease

can be prolonged and gratifying at very little cost!

Can we do this for triple negative and BRCA related cancers?

PARP inhibitors – Finding the Achilles’ Heel in BRCA related Cancers

10 -9 10 -8 10 -7 10 -6 10 -5 10 -40-4

-3

-2

-1

0

conc (M)

BRCA2-/-

BRCA2+/+

BRCA2+/-

Increased sensitivity of BRCA1-/- and BRCA2-/- cells to PARP inhibition

10 -9 10 -8 10 -7 10 -6 10 -5 10 -40-4

-3

-2

-1

0

conc (M)

BRCA1-/-

BRCA1+/+

BRCA1+/-

No difference in sensitivity between heterozygous and wild-type BRCA cells

Farmer et al. Nature 2005; 434:917-21

Targeted inhibition selective and less toxic therapy

Olaparib (AZD2281)

OralAstraZeneca Compound

(Formerly KuDOS)

Olaparib A novel, orally active PARP inhibitor

• A phase I trial identified olaparib (AZD2281; KU-0059436) 400 mg bid as the maximum tolerated dose1 with a signal of efficacy in BRCA-mutated ovarian cancer

• Most common toxicities: CTCAE grade 1 and 2 nausea and fatigue

• Significant PARP inhibition and tumor response at olaparib doses 100–400 mg bid

1. Yap T et al. J Clin Oncol 2007;25(18S):abst 3529; 2. Fong P et al. J Clin Oncol 2008;26(15S):abst 5510.

Phase II trial of Olaparib in BRCA-deficient advanced breast cancer

• To assess the efficacy and tolerability of oral olaparib in BRCA1/ BRCA2 mutation carriers with breast cancer

• Multicenter proof-of-concept phase II study, single-arm sequential cohort design

Confirmed BRCA1 or BRCA2 mutationAdvanced refractory breast cancer

(stage IIIB/IIIC/IV) after failure of ≥1 prior chemotherapy for advanced disease

Olaparib 400 mg po bid (MTD)28-day cycles; n=27

Cohort 1 (enrolled first)

Olaparib 100 mg po bid28-day cycles; n=27

Cohort 2 *

* Following an interim review of the emerging efficacy of each cohort, patients ongoing in 100 mg bid cohort were permitted to crossover to receive the 400 mg bid dose

Tutt A. et al. Lancet 2010

Efficacy

Olaparib 100 mg bid

(n=27)

6 (22)*

0

6 (22)*An additional 1 patient in the 400 mg cohort and 3 patients in the 100 mg cohort had unconfirmed responses

Overall Response Rate, n (%)

Complete Response, n (%)

Partial Response, n (%)

11 (41)*

1 (4)

10 (37)

Olaparib400 mg bid

(n=27)ITT cohort

Tutt A. et al. Lancet 2010

Progression-free survival

Olaparib 400 mg: 5.7 (4.6–7.4) months

No. of patients at risk 27 26 17 8 5 022 13 6 1400 mg:

Median PFS (95% CI)

PFS (days)

0

Fre

edom

from

pro

gres

sion

(%

)

0

10

20

30

40

50

60

70

80

90

100

50 150 250 350 450100 200 300 400

Olaparib 100 mg: 3.8 (1.9–5.5) months

27 25 10 0 0 017 4 0 0100 mg:

NB: Non-randomized sequential cohorts

Tutt A. et al. Lancet 2010

Best % change from baseline in target lesions by prior chemotherapy

–100

–80

–60

–40

–20

0

20

40

60

80

100Previous anthracycline, taxane and capecitabine

Increasing tumor shrinkage

Olaparib 400 mg bid cohort

Best % change from

baseline

*Prior platinum Tx

* ** *

*

*

Tutt A. et al. ASCO 2009

Response by BRCA mutation status and hormonal status

Cohort: Olaparib 400mg BID

BRCA1(n=18)

BRCA2(n=9)

TNBC(n=13)

Non-TNBC(n=14)

Objective Resposne

9 (50%) 2 (22%) 7 (54%) 4 (29%)

Tutt A. et al. Lancet 2010

Adverse events*

15 (56)

11 (41)

7 (26)

10 (37)

6 (22)

8 (30)

4 (15)

1 (4)

2 (7)

2 (7)

Fatigue

Nausea

Vomiting

Headache

Constipation

Diarrhea

Cough

Dyspnea

Insomnia

Pain in extremity

Olaparib 400 mg bid(n=27)

Patients, n (%) Grade 1/2

4 (15)

5 (19)

3 (11)

0

0

0

0

0

0

0

Grade 3

Olaparib 100 mg bid(n=27)

15 (56)

15 (56)

6 (22)

5 (19)

8 (30)

4 (15)

8 (30)

10 (37)

7 (26)

6 (22)

Grade 1/2

2 (7)

0

0

1 (4)

0

0

0

1 (4)

0

1 (4)

Grade 3

*≥25% reported in either cohort; Common Terminology Criteria for Adverse Events

Olaparib Phase2 - Conclusions

• In BRCA mutation carriers: – single agent oral olaparib 400 mg bid has substantial activity with ORR 41%

and median PFS 5.7 months– well tolerated

• Not all patients with BRCA mutations responded– Are there different Homologous Recombination Repair Defects affecting

sensitivity to PARP inhibition?– Is there something else that predicts response to PARP inhibition? Likely

need functional assay!– Perhaps subtypes of sporadic breast cancer may benefit from PARP

inhibitors

Veliparib (ABT-888)

OralAbbott Compound

Phase II Study of oral Veliparib Plus Temozolomide in Metastatic Breast Cancer

• Efficacy appears to be restricted to BRCA1/2 mutation carriers.• Further evaluation of this combination is ongoing in BRCA1/2-mutated

cancers.

Total(n = 41)

(23 TNBC)

BRCA1/2 Mutant(n = 8)

BRCA1/2 Normal/Unknown

(n = 33)

Overall Response Rate 7% 37.5% 0

Clinical Benefit Ratea 17% 62.5% 6%

Median Progression-Free Survival 1.9 months

5.5 months 1.8 months

P = .0042

Isakoff et al. J Clin Oncol 2010; 28(suppl):118s (abstract 1019).

a ORR + stable disease

Phase II Study Veliparib (ABT-888) + Temozolamide

• ORR: 7%– All BRCA1/2+ (RR 38%)

• Toxicity: – marrow, nausea, electrolyte, fatigue– no gr3-4 after dose change ABT888

-80-70-60-50-40-30-20-10

0102030405060708090

100

* * * * * *

* = BRCA carriers

% c

hang

e

p-value = 0.0042

Noncarriers: Median PFS = 1.8 Mo

Carriers: Median PFS = 5.5 Mo

Isakoff et al, ASCO 2010

Proof of Concept Phase 2 trials

• Studies with Olaparib and Veliparib confirm that BRCA related cancers deficient in specific aspects of DNA repair are sensitive to agents that exploit this pathway, unless resistance occurs...

• Major mechanism of resistance ...not in PARP genes but ...re-expression of a functional form of BRCA2 and in some cases almost the full-length protein

Resistance to PARP inhibitorsReversion of BRCA2 mutations

Edwards et al. Nature 451: 1111-1115, 2008

Restoration of the open reading frame of BRCA1 or 2 by intragenic deletion

Partial function of BRCA is restored and cells become competent for HR repair

Cisplatin Resistance in tumors

• Ovarian tumors with BRCA2 mutations highly sensitive to cisplatin but resistance develops

• Analysis of resistant tumor line revealed reversion of BRCA2 mutation as with PARP inhibitors

Implications:

-Phase 2 Olaparib study showed that pts who progressed on platinum therapy rarely responded to Olaparib

=but too soon to conclude cross-resistance

Sakai et al. Nature 451:1116-1120,2008

What is the Role of PARP inhibitors

in Triple Negative Breast Cancer?

BRCA and TNBC

Theorem:

• Shared genome-wide expression array patterns between BRCA1-mutant and basal breast cancer may reflect shared defects in DNA repair processes

• Corollary:• Sporadic basal breast cancers may be especially

sensitive to DNA-damaging agents

25

Characteristics Hereditary BRCA1 Triple Negative/Basal-Like1,2,3

ER/PR/HER2 status Negative Negative

TP53 status Mutant Mutant

BRCA1 status Mutational inactivation* Diminished expression*

Gene-expression pattern Basal-like Basal-like

Tumor histologyPoorly differentiated

(high grade)Poorly differentiated

(high grade)

Chemosensitivity to DNA-damaging agents

Highly sensitive Highly sensitive

TNBC Shares Clinical and Pathologic Features with BRCA-1-Related Breast Cancers

3Sorlie et al. Proc Natl Acad Sci U S A 2001;98:10869-744 Miyoshi et al. Int J Clin Oncol 2008;13:395-400

*BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID44

1Perou et al. Nature. 2000; 406:747-7522Cleator et al.Lancet Oncol 2007;8:235-44 2

6

Regimen N pCR

CMF 14 1 (7%)

AC 23 5 (22%)

FAC 28 6 (21%)

AT 25 2 (8%)

Cisplatin 12 10 (83%)

Platinum Sensitivity in BRCA1+/TNBC:Pathologic Response to Neoadjuvant Rx

BRCA1+:• 102 BRCA1+ patients• CDDP 75 mg/m2 x 4• BUT retrospective• CDDP cohort – smaller,

more node-negative

Byrski, JCO 2009

pCR to Cisplatin 6 (22%)

Clinical CR 4 (14%)

Clinical PR 10 (36%)

Stable disease 5 (17%)

Triple negative:• 28 TNBC• CDDP also 75 mg/m2 x 4• Prospective trial• 2/2 BRCA1+ had pCR

Silver, JCO 2010

Case LG

• 51F, known BRCA1 mutation carrier– right sided LABC, TNBC– Treated with Epi/Taxotere x6 on clinical trial– Mastectomy December 2008, with residual 1cm of IDC,

2/19LN +

• Feb 2010 – Matted ipsilateral supraclavicular, cervical nodes– Brachial plexopathy due to extensive deep axillary

recurrence causing severe pain requiring extensive narcotics

LG continued• Treated as part of TRIO trial with Taxotere +/- IMCLONE

antivegf molecule– Radiological Response at 6wk CT scan– However, by clinic visit pt had extensive skin progression and pain

requiring Gabapentin 900mg TID and Hydromorphone Contin 12 TID

• April 2010: Started on Cisplatin 25mg/m2, Gemcitabine 750mg/m2 IV 3 out of 4 weeks

• After one cycle pt was off all hydromorphone and tapering gabapentin, has just completed cycle 8 with almost complete response!

Case CH• 49F previously well, BRCA negative

– 2cm, grade 3, 8/19LN+ TNBC– Treated with dd AC-paclitaxel– Completed August 2009

• November2009– Acutely unwell, fatigue, jaundice– Abdominal ultrasound confirms diffuse liver metastases

with no evidence of obstruction– Started on Cisplatin 25mg/m2 IV 3 out of 4 weeks

Pt CHTrend LFT’s

Nov 25 , 2009

Dec 2, 2009

Feb 25, 2010 March 30, 2010

ALP 1143 952 126 679

AST 400 150 33 98

ALT 248 149 25 72

Bilirubin 68 37 7 21

Case CHWhy did she respond and so quickly to single agent weekly cisplatin?

Why did she unfortunately respond for only four months?

Need biopsies!

Canadian Study 20Phase II Trial of Olaparib in BRCA and

sporadic breast and ovarian CA

• Goals – To determine markers of response and resistance

to Olaparib in four cohorts of patients– To help inform future studies in terms of patient

enrollment– To help determine activity

Gelmon K et al ASCO 2010

Study Design: 2-stage SimonScreening/enrolment

TNBC with unknown

BRCA status (n=15)

Known BRCA + breast cancer (n=10)

Known BRCA + ovarian cancer (n=10)

HGSC with unknown

BRCA status (n=15)

+ 20 patients= (n=35)

Olaparib 400 mg bid

1 response

+ 40 patients = (n=55)

1 response

TNBC, Triple-negative breast cancer; HGSC, High grade serous ovarian carcinoma

Best % Change in Target Lesion Size by Tumor Type and BRCA status: Breast Cancer

TNBC BRCATNBC non-BRCA

Non-TNBC BRCA

–100

–20

–40

–60

–80

0

20

100

80

60

40

120

No patient met the criteria for a confirmed RECIST responseBest change in target lesion size is maximum reduction from baseline or minimum increase in absence of reduction

Bes

t %

cha

nge

from

bas

elin

e

23 treated patients with target lesions identified at baseline22 had at least one follow-up assessment1 patient had no follow-up tumour size assessment – 1 due to missing / incomplete post-baseline assessments

Phase I safety cohort: Olaparib plus Paclitaxel for TNBC

Olaparib (AZD2281)200 mg BID po

+ Paclitaxel weekly iv 90 mg/m2

(3 of 4 weeks)

TN metastaticbreast Ca≤1 prior

cytotoxic therapy

Primary objective:Safety and tolerability

Secondary objectives:Objective response rate (ORR) according to RECIST

Safety cohort N=19

Dent R et al. ASCO 2010

CTCAE in ≥30% of patients overall

CTCAE, Common Terminology Criteria for Adverse Events

Cohort 1 (no GCSF)(n=9)

Cohort 2 (GCSF)(n=10)

Grade 1/2 Grade ≥3 Grade 1/2 Grade ≥3 Overall (n=19)

DiarrheaNauseaNeutropeniaAlopeciaFatigueAnemiaConstipationPeripheral neuropathyRashVomiting

6 (67)5 (56)3 (33)6 (67)6 (67)3 (33)4 (44)3 (33)

1 (11)3 (33)

00

4 (44)00

2 (22)00

00

6 (60)6 (60)2 (20)4 (40) 3 (30)1 (10)2 (20)3 (30)

5 (50)3 (30)

00

2 (20)0

1 (10)000

00

12 (63)11 (58)11 (58)10 (53)10 (53)6 (32)6 (32)6 (32)

6 (32)6 (32)

Patients with AEs, n (%)

Phase I/II Study of Olaparib Plus Paclitaxel for Triple-Negative Metastatic Breast Cancer

• Dose modifications:− Median dose intensity (total dose received/total dose planned) of paclitaxel was

57.2% (range 26–100%) in cohort 1 and 73.1% (range 29–100%) in cohort 2• Conclusions:

− Olaparib/paclitaxel is active in triple-negative MBC.− Associated neutropenia reduced paclitaxel dose intensity

Cohort 1 (No G-CSF)(n = 9)

Cohort 2 (G-CSF )(n = 10)

Overall Response Rate 33% 40%

Stable Disease ≥ 7 Weeks 33% 40%

Median Progression-Free Survival (95% CI) 6.3 (3.5-8.9) months 5.2 (3.5-NC) months

Dent et al. J Clin Oncol 2010; 28(suppl):118s

Eligibility: ≤ 1 prior cytotoxic regimenRegimen: olaparib 200 mg p.o., b.i.d.

paclitaxel 90 mg/m2/week 3 of 4 weeks

Lessons from Study 11• Other than neutropenia, well tolerated therapy

– Little to no neurotoxicity, is this related to other physiological roles of PARP?

• Other Important Observations– Patients exhibited delayed response to Olaparib

(implications for neoadjuvant studies with PARPi)– Differential response to treatment (response in lung,

progression lymph nodes) – implications for clinical trials

• Expansion cohort evaluation different schedules of Olaparib

Dent, R et al . ASCO 2010

Iniparib: BSI-201

IntravenousBiPar/Sanofi Aventis Compound

LBA11 Iniparib Study Design Multi-center, open-label, randomized Phase II

Metastatic TNBC - about 70% had prior chemotherapy for early BC

Measurable disease -median number of metastatic sites = 3

0-2 prior chemotherapy regimens for metastatic disease - no prior chemo~60%

No prior gemcitabine, carboplatin, cisplatin, PARP inhibitor Stable brain metastases allowed ECOG PS 0–1 - two thirds PS = 0

Gemcitabine 1000 mg/m2, IV, d 1, 8Carboplatin AUC 2, IV, d 1, 821 day cycles

Iniparib 5.6 mg/kg, IV, d 1, 4, 8, 11Gemcitabine 1000 mg/m2, IV, d 1, 8Carboplatin AUC 2, IV, d 1, 821 day cycles

PRIMARY ENDPOINTS: CBR = CR + PR + SD ≥6mo, SafetySECONDARY ENDPOINTS: DFS, ORR, Toxicity

* 30 patients randomized to gem/carbo crossed over to receive gem/carbo + Iniparib (BSI-201) at disease progression

Randomization (1:1)

N=62* N=61

RESTAGING: Every 2 Cycles (RECIST)

Iniparib: Response and Clinical Benefit Rates (ITT Population)

Gem-CarboN = 62

Iniparib + Gem-Carbo

N=61P-value*

Overall response rate 20 (32.3%) 32 (52.5%) 0.023

Complete response 1 (1.6%) 2 (3.3%)

Partial response 19 (30.6%) 30 (49.2%)

Stable disease 13 (21.0%) 11 (18.0%)

Progressive disease 18 (29.0%) 10 (16.4%)

SD ≥ 6 months 1 (1.6%) 2 (3.3%)

Clinical benefit rate (CBR) 21 (33.9%) 34 (55.7%) 0.015

*P-values were not adjusted for multiple interim analyses.

Iniparib: Progression-Free and Overall Survival (ITT Population)

Gem-CarboN=62

Iniparib + Gem-Carbo

N=61Median PFS, months (95% CI)

3.6 (2.6, 5.2)

5.9(4.5, 7.2)

HR (95% CI) 0.59 (0.39, 0.9)

P-value* 0.012

*P-values were not adjusted for multiple interim analyses.

Gem-CarboN = 62

Iniparib + Gem-Carbo

N=61Median OS, months (95% CI)

7.7(6.5, 13.3)

12.3 (9.8, 21.5)

HR (95% CI) 0.57 (0.36, 0.90)

P-value* 0.014

OS+ 4.6 months

PFS+ 2.3 months

Progression Free Survival Overall Survival-Exploratory

Safety: Hematologic Toxicity

Adverse event

No. of patients (%)

Gem-Carbo (N=59) Iniparib + Gem-Carbo (N=57)

All Grade 3 Grade 4 All Grade 3 Grade 4

Neutropenia 48 (81) 21 (36) 16 (27) 46 (81) 25 (44) 13 (23)

Anemia 40 (68) 9 (15) 0 38 (67) 13 (23) 0

Thrombocytopenia 30 (51) 6 (10) 10 (17) 36 (63) 10 (18) 11 (19)

Leukopenia 13 (22) 6 (10) 0 16 (28) 7 (12) 0

Summary• Proof of Concept that triple negative breast

cancers may be susceptible to PARP inhibition– Impressive improvement in ORR, CBR , PFS and

overall survival

• BSI-201 + gemcitabine/carboplatin was well tolerated and did not potentiate chemotherapy-related toxicities

Questions

• Are the platinum and PARP inhibitor effects additional or synergistic? What is the activity of single agent BSI-201 in pts with TNBC?

• Why does BSI-201 not show significant myelosuppresion compared to oral PARP inhibitors?

Development in PARP inhibitors in TN Breast Cancer

Challenges

Triple Negative Breast Cancer

Defining Triple Negative Breast Cancers

Identifying Subset with Homologous Recombination Deficiency

What are the Standards of Care for Treatment?

What should be the comparators?

PARP inhibitors

Dosing: IV vs. PO

Schedule: Intermittent vs. Continuous

Timing: Delivery before, during or after chemotherapy

Are they best combined with DNA damaging agent?

Role of Resistance

Acknowledgements and Collaborators

CANADAMaureen TrudeauSteven NarodKaren GelmonMark ClemonsWedad HannaJanet DanceyKathy Pritchard

UKAndy TuttAlan Ashworth

AstraZenecaLynn DouglasMark ZarendaUrsula LotzJim Carmicahel

2011 Triple Negative Breast Cancer Conference, March 9-11, London UK

Scientific programme committee– Alan Ashworth, Jorge Reis-

Filho, Rebecca Dent and Andy Tutt

Speakers• Charles Perou• Will Foulkes• Jos Jonkers• Gabriella Dontu• Matt Ellis

Speakers cont..• Judy Garber• Steven Narod• MikeStratton• Lajos Pusztai• Anne Vincent-Salomon, • Andrea Richardson• Max Parmar