The Role of PARP inhibitors
in 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
Increased sensitivity of BRCA1-/- and BRCA2/- cells to PARP inhibition
BRCA1+/+
BRCA1+/BRCA1-/-
No difference in sensitivity between heterozygous
and wild-type BRCA cells
Targeted inhibition  selective and less toxic therapy
Farmer et al. Nature 2005; 434:917-21
BRCA2+/+
BRCA2+/BRCA2-/-
Olaparib (AZD2281)
Oral
AstraZeneca 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 mutation
Advanced refractory breast cancer
(stage IIIB/IIIC/IV) after failure of ≥1 prior chemotherapy for
advanced disease
Cohort 1 (enrolled first)
Cohort 2 *
Olaparib 400 mg po bid (MTD)
28-day cycles; n=27
Olaparib 100 mg po bid
28-day cycles; n=27
* 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
ITT cohort
Overall Response Rate, n (%)
Complete Response, n (%)
Partial Response, n (%)
Olaparib
400 mg bid
(n=27)
Olaparib
100 mg bid
(n=27)
11 (41)*
1 (4)
10 (37)
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
Tutt A. et al. Lancet 2010
Freedom from progression (%)
Progression-free survival
10
0
90
80
70
60
50
40
30
20
10
0
Median PFS (95% CI)
Olaparib 400 mg: 5.7 (4.6–7.4) months
Olaparib 100 mg: 3.8 (1.9–5.5) months
NB: Non-randomized sequential cohorts
0
50
100
150
200
250
300
350
400
450
6
0
5
0
1
0
0
0
PFS (days)
No. of patients at
risk 400 mg: 27
100 mg: 27
26
25
Tutt A. et al. Lancet 2010
22
17
17
10
13
4
8
0
Best % change from baseline in target
lesions by prior chemotherapy
Olaparib 400 mg bid cohort
100
Previous anthracycline, taxane and capecitabine
80
60
40
Best %
change from 20
baseline
0
–20
Increasing tumor shrinkage
*
*
**
*
–40
*
–60
–80
–100
*Prior platinum Tx
Response by BRCA mutation status and
hormonal status
Cohort: Olaparib 400mg BID
Objective
Resposne
BRCA1
(n=18)
BRCA2
(n=9)
TNBC
(n=13)
Non-TNBC
(n=14)
9 (50%)
2 (22%)
7 (54%)
4 (29%)
Tutt A. et al. Lancet 2010
Adverse events*
Olaparib 400 mg bid
(n=27)
Olaparib 100 mg bid
(n=27)
Grade 1/2
Grade 3
Grade 1/2
Grade 3
Fatigue
15 (56)
4 (15)
15 (56)
2 (7)
Nausea
11 (41)
5 (19)
15 (56)
0
Vomiting
7 (26)
3 (11)
6 (22)
0
Headache
10 (37)
0
5 (19)
1 (4)
Constipation
6 (22)
0
8 (30)
0
Diarrhea
8 (30)
0
4 (15)
0
Cough
4 (15)
0
8 (30)
0
Dyspnea
1 (4)
0
10 (37)
1 (4)
Insomnia
2 (7)
0
7 (26)
0
Pain in extremity
2 (7)
0
6 (22)
1 (4)
Patients, n (%)
*≥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)
Oral
Abbott Compound
Phase II Study of oral Veliparib Plus
Temozolomide in Metastatic Breast Cancer
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%
5.5 months
1.8 months
Median Progression-Free
Survival
a
1.9 months
P = .0042
ORR + stable disease
• Efficacy appears to be restricted to BRCA1/2 mutation carriers.
• Further evaluation of this combination is ongoing in BRCA1/2-mutated
cancers.
Isakoff et al. J Clin Oncol 2010; 28(suppl):118s (abstract 1019).
% change
Phase II Study Veliparib (ABT-888) +
Temozolamide
100
90
80
70
60
50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
* = BRCA carriers
** * **
*
p-value = 0.0042
• ORR: 7%
– All BRCA1/2+ (RR 38%)
• Toxicity:
– marrow, nausea, electrolyte, fatigue
– no gr3-4 after dose change ABT888
Isakoff et al, ASCO 2010
Carriers:
Median PFS = 5.5 Mo
Noncarriers:
Median PFS = 1.8 Mo
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 inhibitors
Reversion of BRCA2 mutations
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
Edwards et al. Nature 451: 1111-1115, 2008
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 crossresistance
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
TNBC Shares Clinical and Pathologic Features with
BRCA-1-Related Breast Cancers
Characteristics
ER/PR/HER2 status
TP53 status
BRCA1 status
Gene-expression pattern
Tumor histology
Chemosensitivity to DNAdamaging agents
Hereditary BRCA1
Triple Negative/Basal-Like1,2,3
Negative
Negative
Mutant
Mutant
Mutational inactivation*
Diminished expression*
Basal-like
Basal-like
Poorly differentiated
(high grade)
Poorly differentiated
(high grade)
Highly sensitive
Highly sensitive
*BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID44
1Perou
et al. Nature. 2000; 406:747-752
et al.Lancet Oncol 2007;8:235-44
2Cleator
3Sorlie
4
et al. Proc Natl Acad Sci U S A 2001;98:10869-74
Miyoshi et al. Int J Clin Oncol 2008;13:395-400
2
Platinum Sensitivity in BRCA1+/TNBC:
Pathologic Response to Neoadjuvant Rx
Regimen
N
pCR
CMF
14
1 (7%)
AC
23
5 (22%)
FAC
28
6 (21%)
AT
25
2 (8%)
Cisplatin
12
10 (83%)
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%)
Silver, JCO 2010
Triple negative:
• 28 TNBC
• CDDP also 75 mg/m2 x 4
• Prospective trial
• 2/2 BRCA1+ had pCR
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 CH
Trend 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
Why did she respond and so quickly to single agent
weekly cisplatin?
Case CH
Why1.did
unfortunately
Graph
Livershe
function
tests.
respond for only four
months?
1400
1200
1143
Need biopsies!
1000
823
800
AST
ALT
ASP
600
Total bilirubin
400
400
248
200
144
63
0
146
32
67
29
7
Sept-1-2009 Nov-25-2009 Dec-15-2009 Jan-21-2010 Mar-03-2010 Apr-06-2010 May-10-2010 June-07-2010
Canadian Study 20
Phase 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 Simon
Screening/e
nrolment
TNBC with
unknown
BRCA status
(n=15)
Known
BRCA +
breast
cancer
(n=10)
Known
BRCA +
ovarian
cancer
(n=10)
1
response
HGSC with
unknown
BRCA status
(n=15)
1
response
+ 40 patients
= (n=55)
+ 20 patients
= (n=35)
Olaparib 400 mg bid
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
120
Best % change from baseline
100
80
TNBC BRCA
TNBC non-BRCA
60
Non-TNBC BRCA
40
20
0
–20
–40
–60
–80
–100
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
No patient met the criteria for a confirmed RECIST response
Best change in target lesion size is maximum reduction from baseline or minimum increase in absence of reduction
Phase I safety cohort:
Olaparib plus Paclitaxel for TNBC
TN metastatic
breast Ca
≤1 prior
cytotoxic
therapy
Safety cohort
N=19
Olaparib (AZD2281)
200 mg BID po
+
Paclitaxel weekly iv 90 mg/m2
(3 of 4 weeks)
Primary objective:
Safety and tolerability
Secondary objectives:
Objective response rate (ORR)
according to RECIST
Dent R et al. ASCO 2010
CTCAE in ≥30% of patients overall
Patients with AEs, n (%)
Cohort 1 (no GCSF)
(n=9)
Grade ≥3
Grade 1/2
Grade ≥3
Overall (n=19)
6 (67)
5 (56)
3 (33)
6 (67)
6 (67)
3 (33)
4 (44)
3 (33)
0
0
4 (44)
0
0
2 (22)
0
0
6 (60)
6 (60)
2 (20)
4 (40)
3 (30)
1 (10)
2 (20)
3 (30)
0
0
2 (20)
0
1 (10)
0
0
0
12 (63)
11 (58)
11 (58)
10 (53)
10 (53)
6 (32)
6 (32)
6 (32)
1 (11)
3 (33)
0
0
5 (50)
3 (30)
0
0
6 (32)
6 (32)
Grade 1/2
Diarrhea
Nausea
Neutropenia
Alopecia
Fatigue
Anemia
Constipation
Peripheral
neuropathy
Rash
Vomiting
Cohort 2 (GCSF)
(n=10)
CTCAE, Common Terminology Criteria for Adverse Events
Phase I/II Study of Olaparib Plus Paclitaxel for TripleNegative Metastatic Breast Cancer
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
Eligibility:
Regimen:
≤ 1 prior cytotoxic regimen
olaparib 200 mg p.o., b.i.d.
paclitaxel 90 mg/m2/week 3 of 4 weeks
• 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
Dent et al. J Clin Oncol 2010; 28(suppl):118s
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
Intravenous
BiPar/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
Randomization (1:1)
Gemcitabine
Carboplatin
21 day cycles
N=62*
1000 mg/m2, IV, d 1, 8
AUC 2, IV, d 1, 8
Iniparib
5.6 mg/kg, IV, d 1, 4, 8, 11
Gemcitabine 1000 mg/m2, IV, d 1, 8
Carboplatin
AUC 2, IV, d 1, 8
21 day cycles
RESTAGING: Every 2 Cycles (RECIST)
PRIMARY ENDPOINTS:
SECONDARY ENDPOINTS:
N=61
CBR = CR + PR + SD ≥6mo, Safety
DFS, ORR, Toxicity
* 30 patients randomized to gem/carbo crossed over to receive gem/carbo + Iniparib (BSI-201) at disease progression
Iniparib: Response and Clinical
Benefit Rates (ITT Population)
Gem-Carbo
N = 62
Iniparib +
Gem-Carbo
N=61
P-value*
20 (32.3%)
32 (52.5%)
0.023
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%)
1 (1.6%)
2 (3.3%)
21 (33.9%)
34 (55.7%)
Overall response rate
Complete response
SD ≥ 6 months
Clinical benefit rate (CBR)
*P-values were not adjusted for multiple interim analyses.
0.015
Iniparib: Progression-Free and Overall
Survival
(ITT Population)
Progression Free Survival
Median PFS, months
(95% CI)
HR (95% CI)
P-value*
Iniparib +
Gem-Carbo
Gem-Carbo
N=62
N=61
3.6
5.9
(2.6, 5.2)
(4.5, 7.2)
0.59 (0.39, 0.9)
0.012
Overall Survival-Exploratory
Gem-Carbo
N = 62
Median OS, months
(95% CI)
HR (95% CI)
P-value*
PFS
+ 2.3 months
*P-values were not adjusted for multiple interim analyses.
Iniparib +
Gem-Carbo
N=61
12.3
(9.8, 21.5)
7.7
(6.5, 13.3)
0.57
0.014
(0.36, 0.90)
OS
+ 4.6 months
Safety: Hematologic Toxicity
No. of patients (%)
Adverse event
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
CANADA
Maureen Trudeau
Steven Narod
Karen Gelmon
Mark Clemons
Wedad Hanna
Janet Dancey
Kathy Pritchard
UK
Andy Tutt
Alan Ashworth
AstraZeneca
Lynn Douglas
Mark Zarenda
Ursula Lotz
Jim 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