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FACULTY
Thomas J. Herzog, MD – Chair
University of Cincinnati
Michael J. Birrer, MD, PhD
Harvard Medical School
Susan M. Domchek, MD
University of Pennsylvania
Kristin K. Zorn, MD
University of Arkansas for Medical Sciences
Welcome, Introduction, and Updates in
Guideline Recommendations for Advanced
Ovarian Cancer and Unmet Needs
Thomas J. Herzog, MD – Chair
University of Cincinnati
Objectives
• Identify and select appropriate genetic testing/companion
diagnostics to evaluate the tumor profiles of patients with ovarian
cancer to aid in therapy individuation and ultimately the delivery of
high quality care
• Review and summarize the concept of synthetic lethality in ovarian
cancer and value of PARP inhibition in patients with BRCA
mutations
• Compare and contrast clinical outcomes from clinical trials
evaluating the safety and efficacy of PARP inhibitors in the treatment
of BRCA-driven ovarian cancer and how these may be safely and
effectively integrated into practice when available
• Increase awareness of recent and ongoing clinical trials evaluating
PARP inhibitors in patients with ovarian cancer
Ovarian Cancer Landscape
The Case for No Residual
% Progression-Free Survival
100%
75%
0 mm
HR
1-10 mm vs 0 mm:
(95%CI)
2.52 (2.26;2.81)
50%
> 10 mm vs 1-10 mm: 1.36 (1.24;1.50)
Log-rank: P < 0.0001
1-10 mm
25%
> 10 mm
0%
0
12
24
36
48
60
72
84
96
108
120
132
144
Generated from 3
prospective phase III trials
(OVAR 3, 5, & 7)
N = 3126 pts
100%
0 mm
% Overall Survival
75%
HR
(95%CI)
50%
1-10 mm vs 0 mm:
1-10 mm
2.70 (2.37; 3.07)
> 10 mm vs 1-10 mm: 1.34 (1.21; 1.49)
25%
Log-rank: P < 0.0001
> 10 mm
0%
0
12
24
36
48
60
72
84
96
108
120
132
144
du Bois A, et al. Cancer. 2009;115(6):1234-1244.
Shaping Current Standard
Study
PI/Author
Results
Pub
GOG 111
N = 384
McGuire
PFS = 18 vs 13 mos
OS = 38 vs 24 mos
NEJM,
1996
EORTC-OV10
N = 680
Piccart
PFS = 16 vs 12 mos
OS = 43 vs 44 mos
JNCI,
2000
AGO
N = 798
du Bois
PFS = 17 vs 19 mos
OS = 43 vs 44 mos
JNCI,
2003
GOG 158
N = 792
Ozols
PFS = 19 vs 21 mos
OS = 49 vs 57 mos
JCO,
2003
McGuire WP, et al. N Engl J Med. 1996;334(1):1-6.
Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708.
du Bois A, et al. J Natl Cancer Inst. 2003;95(17):1320-1329.
Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200.
When is the Recurrence?
0 months
6 months
12 months
Primary
Treatment
Resistant
Refractory
End of
Frontline
Therapy
Sensitive
How to Treat:
Platinum-Resistant Disease
Surgery
Rarely
Benefits;
Sxs?
Combination
Therapy
Increased
Toxicity
Radiation
Isolated Cases
Clinical Trials
Eligibility limited
Balance Hope vs
Efficacy
?
PsychoSocial
Support
&
Hospice
Hormonal
Low Toxicity
Single Agent
Chemo
Best Therapeutic
Index
How to Treat:
Platinum-Sensitive Disease
Surgery
Benefit in
Selected
Patients
Single Agent
Therapy
Best Therapeutic
Index?
Radiation
Isolated Cases
Clinical Trials
Eligibility Limited
Balance Hope vs
Efficacy
?
PsychoSocial
Support &
Hospice
Hormonal
Low Toxicity
Combination
Therapy
Phase III
Evidence
What About Histology?
Months
Winter WE, 3rd, et al. J Clin Oncol. 2007;25(24):3621-3627.
FDA-Approved Drugs for
Ovarian Cancer
For 1st-line therapies both RR and OS have been the basis of drug approvals
For 2nd- and 3rd-line therapy, RR, PFS, and OS have been the basis of approvals
Carboplatin
(1989)
Paclitaxel
(1992, 1998)
PLD-Accelerated
(1999)*
Gemcitabine
Carboplatin
(2006)
1978
Cisplatin
(1978)
Olaparib
(2014)
2015
Altretamine
(1990)
Topotecan
(1996)
Objective response (RR)
“Clinical” benefit (RR, no PFS, no OS)
PLD-Full
(2005)^
Chemo +
Bevacizumab
(2014)
“Clinical” benefit (no PFS, no OS*, OS^)
“Clinical” benefit (RR, PFS, no OS)
State-of-the-Science Updates on the
Molecular Genetics of Ovarian Cancer
and Implications on Management
Michael J. Birrer, MD, PhD
Harvard Medical School
Case 1
• 53-year-old woman presents with 6 weeks of abdominal
bloating and early satiety
• Her CT scan shows a large pelvic mass, ascites, and
peritoneal carcinomatosis
• She undergoes staging laparotomy, which reveals optimally
debulked stage III high-grade endometrioid ovarian cancer
• She undergoes initiation of adjuvant chemotherapy with
carboplatin and taxol. While under treatment she arranges to
have her peripheral blood cell DNA tested for mutations in
BRCA1/2 and her tumor for a “complete genomic analysis”
• The results show no mutation in BRCA1/2, a mutation in PI3
Kinase, no methylation of BRCA1/2 and a gene expression
signature for improved survival
Which of the Following Molecular
Analyses is the Most Valuable for
Treating Patients With Ovarian Cancer?
1. Gene expression profiling
2. BRCA 1/2 mutation testing
3. Somatic mutation testing
4. BRCA 1/2 methylation
Are There Clinically Relevant
Predictors for the Treatment of
Ovarian Cancer?
TCGA Analysis of HGSOC
Lots of CNV and low
mutation rate
Methylation, expression
microRNA subsets?
HGSOC, high grade serous ovarian cancer.
The Cancer Genome Atlas Network. Nature. 2011;474(7353):609-615.
1
2
6
3
7
12
8
13
19
3
4
5
15
10
16
20
2
13
14
19
20
1
2
12
13
9
10
16
21
5
11
15
12
17
18
22
3
X
4
15
X
4
8
14
18
22
3
7
11
17
21
6
2
5
9
14
1
1
4
16
5
17
18
In a tumor with genomic chaos are
there predictors of tumor behavior?
Prognostic Gene Expression Signatures
Prognostic Gene Signatures
of Ovarian Cancer
Meta-Analysis Overview
Literature review
Prognostic models
Database of curated gene expression
101 candidate papers
5 review papers
Standardized clinical annotation and gene ID
23 studies, 2,908 samples
Inclusion Criteria
Training sample size > 40
Focus on late-stage serous
Multivariate model
Continuous risk score
Claims to predict survival
Possible to reproduce model
14 prediction models implemented
100 pages documentation
survHD Bioconductor package
Waldron L, et al. J Natl Cancer Inst. 2014;106(5).
Inclusion Criteria
Sample size > 40
Primary tumors
Overall survival available
Events (deaths) > 15
Late stage, high-grade tumors
Serous subtype
10 datasets, 1,455 samples
curatedOvarianData Bioconductor package
Assessment of Prognostic
Signatures
14 Prognostic Signatures
C-Index = Pr(g(Z1)>g(Z2) | T2>T1)
T1,T2 = times to death of two patients
g(Z1,g(Z2) = predicted risk scores
C = 0.5 expectation for random prediction
C = 1 if the exact order of all deaths is
predicted
Survival
Kaplan-Meier estimate
10 Microarray Datasets
Time
Waldron L, et al. J Natl Cancer Inst. 2014;106(5).
Assessment of Prognostic
Signatures
14 Prognostic Signatures
C-Index = Pr(g(Z1)>g(Z2) | T2>T1)
T1,T2 = times to death of two patients
g(Z1,g(Z2) = predicted risk scores
C = 0.5 expectation for random prediction
C = 1 if the exact order of all deaths is
predicted
Study
Forest plot
10 Microarray Datasets
C-Index
Waldron L, et al. J Natl Cancer Inst. 2014;106(5).
14 Prognostic Signatures
Assessment of Prognostic Models
Cancer Genome Atlas Research
Network. Nature. 2011;
474(7353):609-615. Integrated
genomic analyses of ovarian
carcinoma.
Bonome et al. Cancer Res. 2008;
68(13):5478-5486. A gene signature
predicting for survival in
suboptimally debulked patients
with ovarian cancer.
10 Microarray Datasets
Waldron L, et al. J Natl Cancer Inst. 2014;106(5).
Assessment of Prognostic Models
14 Prognostic Signatures
Dressman et al. J Clin Oncol. 2007;
25(5):517-525. An integrated
genomic-based approach to
individualized treatment of
patients with advancedstage ovarian cancer.
Baggerly et al. J Clin Oncol.
2008;26(7):1186-1187. Run batch
effects potentially compromise the
usefulness of genomic signatures
for ovarian cancer.
Dressman et al. J Clin Oncol. 2012;
30(6):678. Retraction.
10 Microarray Datasets
Waldron L, et al. J Natl Cancer Inst. 2014;106(5).
Assessment of Prognostic Models
Conclusions:
• Most models make better
predictions than random
• Large, consortium
studies performed best
• Validation datasets can
be biased
• None of these models
are ready for the clinic
Waldron L, et al. J Natl Cancer Inst. 2014;106(5).
Are there predictors which are
clinically useful?
Establishment of Debulking
Signature
• Based upon the biologic basis of disease spread
• Analyzed 1525 microarrays of primary ovarian
cancers
• 22% suboptimal (> 1 cm)
• Supervised analysis/signature identification
• Generate pathway
Riester M, et al. J Natl Cancer Inst. 2014;106(5).
Riester M, et al. J Natl Cancer Inst. 2014;106(5).
Expression of Three Proteins Provides
93% Accuracy for Determining
Suboptimal Debulking Status
Riester M, et al. J Natl Cancer Inst. 2014;106(5).
Gynecologic Cancer Oral Abstract Session
Abstract #5505 9:24 AM - 9:36 AM
Retrospective analysis of candidate
predictive tumor biomarkers (BMs) for
efficacy in the GOG-0218 trial
evaluating frontline carboplatin–
paclitaxel (CP) ± bevacizumab (BEV)
for epithelial ovarian cancer (EOC).
However, these are experimental
and require validation!
Genomic Instability/HRD
Does it provide prognostic or predictive
biomarkers?
PARP Inhibition and Tumor-Selective
Synthetic Lethality
DNA damage (SSBs)
PARP
PARP inhibition
DNA replication
(accumulation of DNA DSBs)
Normal cell
with functional HR
pathway
HR-deficient tumor
cell (eg, BRCA 1/2-/-)
HR-mediated
DNA repair
No HR-mediated
DNA repair
Cell survival
Cell death
Tumor-selective cytotoxicity
Farmer H, et al. Nature. 2005;434(7035):917-921.
Bryant HE, et al. Nature. 2005;434:913-917.
McCabe N, et al. Cancer Res. 2006;66:8109-8115.
DSB, double-strand break; HR, homologous
recombination; SSB, single-strand break.
Best % Change From Baseline
in Target Lesions
100
Olaparib 400 mg bid cohort
Best % Change From Baseline
80
BRCA1
BRCA2
60
*
40
Increasing tumor shrinkage
20
0
*
*
-20
-40
*
-60
-80
-100
*Platinum-sensitive patients. Figure includes 3 unconfirmed responses.
Audeh MW, et al. Lancet. 2010;376(9737):245-251.
*
Background: GOG-0218 and GOG0262
GOG-218
GOG-262
Chemotherapy Arms
Carbo/Taxol +/- Bev,
Bev maint
Carbo/Taxol q 3wk vs
Dose-dense, + Bev
< 40
22 (2.8%)
19 (2.7%)
40 - 49
108 (13.9%)
86 (12.4%)
50 - 59
242 (31.1%)
210 (30.3%)
60 - 69
262 (33.7%)
233 (33.7%)
70 - 79
136 (17.5%)
120 (17.3%)
> 80
8 (1.0%)
24 (3.5%)
White
688 (88.4%)
592 (85.5%)
Black
28 (3.6%)
38 (5.5%)
Hispanic
32 (4.1%)
27 (3.9%)
Stage IV
184 (23.7%)
217 (31.4%)
Optimal
333 (42.8%)
0 (not allowed)
Neoadjuvant
0 (not allowed)
88 (12.7%)
High-Grade Serous Histology
632 (81.2%)
556 (80.3%)
Age
Race
Stage/Debulking
Norquist BS, et al. SGO Annual Mtg. 2014. Abstract 10.
There is More to DNA-Repair Than
BRCA1/2
Meindl A, et al. Nat Genet. 2010;42(5):410-414.
Loveday C, et al. Nat Genet. 2011;43(9):879-882.
Rafnar T, et al. Nat Genet. 2011;43(11):1104-1107.
Casadei S, et al. Cancer Res. 2011;71(6):2222-2229.
Walsh T, et al. Proc Natl Acad Sci U S A. 2011;108(44):18032-18037.
Summary of Mutation-Carriers:
GOG-0218 and GOG-0262
• 258/1346 (19.2%) with loss of function mutations
BRCA1
8.7%
BRCA2
5.1%
Cancerassociated
(non-BRCA)
5.3%
Wild-Type
81%
N = 1346
Norquist BS, et al. SGO Annual Mtg. 2014. Abstract 10.
28% of mutation-carriers
had mutations in nonBRCA1/2 genes
Summary of Cancer-Associated
Mutations:
GOG-0218
and
GOG-0262
ATR, 0.8% XRCC2, 0.4%
FAM175A,
0.4%
SLX4, 0.4%
MRE11A, 0.4%
BARD1, 0.8%
LYNCH, 1.9%
RAD51C, 2.3%
CHEK2, 2.6%
TP53, 0.8%
RAD51D, 2.6%
NBN, 2.6%
ATM, 3.0%
PALB2, 3.4%
BRIP1, 7.5%
N = 20
BRCA2, 26.0%
N = 69
Norquist BS, et al. SGO Annual Mtg. 2014. Abstract 10.
BRCA1, 44.2%
N = 117
N = 265 mutations
in 258 women
Summary of Cancer-Associated
Mutations:
GOG-0218 and GOG-0262
ATR, 0.8% XRCC2, 0.4%
BARD1, 0.8%
LYNCH, 1.9%
RAD51C, 2.3%
CHEK2, 2.6%
FAM175A,
0.4% SLX4, 0.4%
MRE11A, 0.4%
TP53, 0.8%
RAD51D, 2.6%
NBN, 2.6%
ATM, 3.0%
PALB2, 3.4%
BRIP1, 7.5%
N = 20
BRCA1, 44.2%
N = 117
BRCA2, 26.0%
N = 69
N = 265 mutations
in 258 women
Norquist BS, et al. SGO Annual Mtg. 2014. Abstract 10.
Summary of Cancer-Associated
Mutations:
GOG-0218 and GOG-0262
ATR, 0.8% XRCC2, 0.4%
BARD1, 0.8%
LYNCH, 1.9%
FAM175A,
0.4% SLX4, 0.4%
RAD51C, 2.3%
MRE11A, 0.4%
TP53, 0.8%
CHEK2, 2.6%
RAD51D, 2.6%
NBN, 2.6%
ATM, 3.0%
PALB2, 3.4%
BRIP1, 7.5%
N = 20
BRCA1, 44.2%
N = 117
BRCA2, 26.0%
N = 69
N = 265 mutations
in 258 women
Norquist BS, et al. SGO Annual Mtg. 2014. Abstract 10.
Genomic Instability/HRD
This prognostic signature may be
predictive
Diagnostic Development
Cutoff Defined for BRCA-Like Signature,
Being
Tested
and
Refined
TCGA and AOCS Overall Survival Data Used to Develop LOH Cutoff to Identify
High-Grade Ovarian Cancer Patient Tumors With BRCA-Like Signature
0.30
Log-rank P Value
(high vs low LOH
groups)
0.25
0.20
0.15
0.10
Optimal LOH cutoff
0.05
Overall Survival
(% probability)
100
High genomic LOH (n = 97)
Low genomic LOH (n = 212)
80
Log-rank: P = 0.0047
Hazard ratio = 0.62
60
Independent
predictor from
BRCAmut status
40
20
Median overall survival:
56.4 vs 38.2 months
0
0
0
Genomic LOH Cutoff
25
50
75
100 125
Overall Survival (months)
Prospective testing of prespecified cutoff in ARIEL2 and ARIEL3
The Cancer Genome Atlas (TCGA) Research Network. Nature. 2011;474:609-615; Wang ZC, et al; Australian
Ovarian Cancer Study (AOCS). Clin Cancer Res. 2012;18:5806-5815.
ARIEL2 Goal: Assess Rucaparib
Sensitivity in Prospectively Defined
Molecular Subgroups
Primary Endpoint
Key Eligibility
• High-grade serous or
endometrioid ovarian
cancer
• ≥ 1 prior platinum
chemotherapy
• Platinum-sensitive,
relapsed, measurable
disease
• Adequate tumor tissue
(screening biopsy and
archival)
• No prior PARPi
600 mg bid
rucaparib
continuously until
progression by
RECIST
• PFS (RECIST) in:
– BRCAmut
– BRCA-like
(excludes BRCAmut)
– Biomarker negative
N = 180
Cap on known
germline BRCAmut
Secondary Endpoints
• ORR (RECIST & CA-125)
• Safety
• Pharmacokinetics
CA-125, cancer antigen 125 test; ORR, overall response rate; PFS, progression-free survival;
RECIST, Response Evaluation Criteria In Solid Tumors.
Swisher EM. 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. 2014.
Abstract 215.
The Majority of BRCAwt Patient
Tumors Exhibit BRCA-Like Signature
Tumor BRCA/BRCA-like status as determined
by HRD Test (N = 121)
• 17 germline
BRCAmut
• 12 somatic
BRCAmut
• 1 indeterminate
•
High genomic LOH
LOH, loss of heterozygosity.
Swisher EM. 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. 2014.
Abstract 215.
Greatest Rucaparib Activity
Observed in BRCAmut Patients …
– 61% ORR
(RECIST)
– 70% ORR (RECIST
& CA-125)
– 83% of patients
continuing on
treatment (+)
• Responses
observed in germline
and somatic
BRCAmut tumors
Best Target Lesion Response
120
Germline
Somatic
Indeterminate
100
80
Change From Baseline
(%)
• Robust clinical
activity observed in
BRCAmut patients
(n = 23)
60
40
20
0
-20
-40
+ +
+
+ +
+
-60
+ +
+ + + +
+ + +
+ + +
-80
-100
+
+=ongoing
Swisher EM. 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. 2014.
Abstract 215.
… and Differential Rucaparib Activity
Seen in Patients With/Without BRCA-Like
Signature
• Clinical activity observed in
BRCAwt patients with
BRCA-like signature (n = 25)
• Few responses observed in
BRCAwt patients without
BRCA-like signature (n = 13)
Change From Baseline (%)
– 32% ORR (RECIST)
– 40% ORR (RECIST & CA-125)
– 52% of patients continuing
on treatment (+)
Best Target Lesion Response
120
100
80
60
40
20
0
-20
-40
-60
-80
-100
BRCA-like
+ +
+ +
+
+ +
+
+
+
+
+
120
Biomarker
100
80
negative
– 8% ORR (RECIST)
60
40
– 8% ORR (RECIST & CA-125)
20
+
0
– 38% of patients continuing
+
+ +
+=ongoing
on treatment (+)
20
-40
-60
-80
-100
+
Swisher EM. 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.
2014.
Abstract 215.
+
Genomic Assays
• Multiple different companies
• Multiple genomic platforms
– Sequencing
– Expression profiling
– IHC
• Accurate assessments but clinical correlations
not validated
• Could be used to identify appropriate clinical trial
Conclusions
• High-grade serous ovarian cancer is a disease
of genomic chaos
• BRCA/Fanconi pathway/HRD testing is
reasonable for all patients with ovarian cancer
• Mutational analysis of tumors can be considered
but will not alter initial management and can be
used only for clinical trial identification
• Gene expression profiling remains experimental
PARP Inhibitor Sensitivity in Ovarian
Cancer: Rationale and Proof of
Concept
Susan M. Domchek, MD
University of Pennsylvania
Case
• 62-year-old woman presents for second opinion about
treatment options for recurrent ovarian cancer
• Review of her path report shows stage IIIC high-grade
serous ovarian cancer at the time of diagnosis
• She has received 2 courses of chemotherapy
– First with carboplatin/paclitaxel with an 18-month disease-free
interval
– Second with carboplatin/paclitaxel with a 5-month disease-free
interval
• She underwent genetic testing and is found to have a
germline mutation in BRCA1
Is she eligible for a PARP inhibitor
based on FDA approved indication?
1. No, because her ovarian cancer is cisplatin resistant
2. Yes, because she has a germline mutation in BRCA1
3. No, because she has received only 2 prior courses of
chemotherapy
4. No, because the drug is approved for maintenance
therapy only
Objectives
• Review the mechanism of action of PARP
inhibitors
• Proof of concept studies
• Challenges for development
Clinical Trials of PARP Inhibitors
Proof of principle of synthetic
lethality in BRCA1/2
mutation carriers
(NEJM 2009)
Unselected triple negative
breast cancer (TNBC) with
iniparib/chemo
(NEJM 2011)
Phase III study in TNBC did not meet primary
endpoint
December 2014: Approval of olaparib for ovarian cancer
by FDA and EMA (although for different indications)
Fong PC, et al. N Engl J Med. 2009;361(2):123-134; O'Shaughnessy J, et al. N Engl J Med. 2011;364(3):205-214.
Targeting BRCAness for Tumor Selective
Killing
BRCA1 or BRCA2 Carrier BRCA1 or BRCA2
Normal tissues
Carrier Tumor tissue
DNA DAMAGE
HR NHEJ SSA BER NER etc
x
DNA DAMAGE
HR NHEJ SSA BER NER etc
x
x
Tumor specific lethality
Tutt A, et al. Cold Spring Harb Symp Quant Biol. 2005;70:139-148; McCabe N, et al. Cancer Res. 2006;66:8109-8115.
Mechanisms of PARPi
Shah GM, et al. Front Oncol. 2013;3.
Scott CL, et al. J Clin Oncol. 2015;33(12):1397-1406.
Farmer H, et al. Nature. 2005;434(7035):917-921; Bryant HE, et al. Nature. 2005;434(7035):913-917.
PARP Inhibitors in BRCA1/2 Mutation
Carriers
• Olaparib
• Phase I trial
– Established favorable toxicity profile
– Proof of principle with responses seen only in BRCA1
and BRCA2 mutation carriers
– PARP inhibition
– Breast, ovarian, prostate
• Using why a person developed cancer against it
Fong PC, et al. N Engl J Med. 2009;361(2):123-134.
Confirmed BRCA1 or BRCA2 mutation
Advanced refractory breast cancer
Failure of ≥ 1 prior chemotherapy
Cohort 1 (enrolled first)
Cohort 2
Olaparib 400 mg po bid
28-day cycles; 27 patients
Olaparib 100 mg po bid
28-day cycles; 27 patients
Tutt A, et al. Lancet. 2010;376(9737):235-244.
Best % Change From Baseline by
Genotype
Best % Change From Baseline
100
Olaparib 400 mg bid cohort
BRCA status
1
2
80
60
40
Increasing tumor shrinkage
20
0
-20
-40
-60
-80
-100
Tutt A, et al. Lancet. 2010;376(9737):235-244.
Best % Change From Baseline by Prior
Chemotherapy
Olaparib 400 mg bid cohort
Best % Change From Baseline
100
80
60
40
20
0
–20
–40
–60
–80
–100
Previous anthracycline, taxane, and capecitabine
Increasing tumor shrinkage
Tutt A. ASCO Annual Meeting. 2009. Abstract CRA501.
Confirmed BRCA1 or BRCA2 mutation
Recurrent ovarian cancer
Cohort 1 (enrolled first)
Cohort 2
Olaparib 400 mg po bid
28-day cycles; 33 patients
Olaparib 100 mg po bid
28-day cycles; 24 patients
Audeh MW, et al. Lancet. 2010;376(9737):245-251.
Best % Change From Baseline by
Genotype
Audeh MW, et al. Lancet. 2010;376(9737):245-251.
Other PARP Inhibitors
•
•
•
•
•
•
•
•
Olaparib (AZD-2281, KU-0059436)
Veliparib (ABT-888)
Rucaparib (AG014699/PF01367338/CO288)
Niraparib (MK-4827)
Talazoparib (BMN-673)
CEP-9722
E7016
Iniparib (BSI-201)
BRCA1/2 Associated Ovarian Cancer:
Doxorubicin vs Olaparib
• Multicenter open label phase II trial
• Recurrence within 12 months of platinum therapy
• Germline BRCA1 or BRCA2 mutation
Olaparib
200 mg bid
N = 32
Olaparib
400 mg bid
N = 32
Pegylated
liposomal
doxorubicin
(PLD)
50 mg/m2 q 28 days
N = 33
Kaye SB, et al. J Clin Oncol. 2012;30(4):372-379.
Progression-Free
Survival
•
•
•
•
Response rates
25% 200 mg olaparib
31% 400 mg olaparib
18% PLD
PLD, pegylated liposomal doxorubicin.
Kaye SB, et al. J Clin Oncol. 2012;30(4):372-379.
BRCA1/2 Cancer: Chemosensitivity
• General chemosensitivity
• Improved prognosis in ovarian cancer with standard
chemotherapy
– Bolton et al. JAMA. 2012
• Improved response rates in ovarian cancer to PLD
– Adam et al. Gyn Onc. 2011
• Improved response rates to chemotherapy in breast
cancer
– Kriege et al. JCO. 2009
– Arun et al. JCO. 2011
Bolton KL, et al. JAMA. 2012;307(4):382-390; Adams SF, et al. Gynecol Oncol. 2011;123(3):486-491; Kriege M,
et al. J Clin Oncol. 2009;27(23):3764-3771; Arun B, et al. J Clin Oncol. 2011;29(28):3739-3746.
Best % Change From Baseline by Prior
Chemotherapy
Olaparib 400 mg bid cohort
*
*
*
*
*
*
Best % Change From Baseline
100Phase Ib olaparib study in advanced ovarian cancer
Previous anthracycline, taxane and capecitabine
80
Cisplatin sensitive:
Clinical benefit 69%
60Cisplatin resistant:
Increasing tumor
shrinkage
Clinical
benefit 45%
Clinical benefit 23%
40Cisplatin refractory:
20
0
–20
–40
–60
–80
–100
*Prior platinum Tx
Tutt A. ASCO Annual Meeting. 2009. Abstract CRA501; Fong PC, et al. J Clin Oncol. 2010;28(15):2512-2519.
More Than BRCA1/2?
• The concept of “BRCA-ness”
• Basal phenotype of breast cancer
– Triple negative as an imperfect surrogate
• Ovarian cancer
• Particularly high-grade serous
• Many of these may have dysregulation of BRCA1 or
BRCA2
• The Cancer Genome Atlas – defect in the HR pathway in
half of 489 tumors
The Cancer Genome Atlas Network. Nature. 2011;474(7353):609-615.
Best % Change From Baseline
Gelmon KA, et al. Lancet Oncol. 2011;12(9):852-861.
Ledermann J, et al. N Engl J Med. 2012;366(15):1382-1392.
Progression-Free Survival
Ledermann J, et al. N Engl J Med. 2012;366(15):1382-1392.
Ledermann J, et al. Lancet Oncol. 2014;15(8):852-861.
Kaufman B, et al. J Clin Oncol. 2015;33(3):244-250.
Ovarian
(n = 193)
Breast
(n = 62)
Other
(n = 12)
All
(n = 298)
148 (76.7)
44 (22.8)
1 (0.5)
37 (59.7)
25 (40.3)
0
5 (21.7)
17 (73.9)
1 (4.3)
1 (12.5)
7 (87.5)
0
7 (58.3)
5 (41.7)
0
198 (66.4)
98 (32.9)
2 (0.7)
Median (SD) prior
regimens for
advanced disease
4.3 (2.2)
4.6 (2.0)
2.0 (1.6)
2.0 (1.0)
2.2 (1.3)
4.0 (2.2)
Tumor response rate
60 (31.1)
8 (12.9)
5 (21.7)
4 (50)
1 (8.3)
78 (26.2)
Complete response
6 (3.1)
0
1 (4.3)
0
0
7 (2.3)
Partial response
54 (28)
8 (12.9)
4 (17)
4 (50)
1 (8.3)
71 (23.8)
Stable (> 8 wks)
Stable disease
Unconfirmed PR
78 (40)
64 (33)
12 (6)
29 (47)
22 (36)
7 (11)
8 (35)
5 (22)
3 (13)
2 (25)
2 (25)
0
7 (58)
6 (50)
1 (8.3)
124 (42)
99 (33)
25 (9)
BRCA status, n (%)
BRCA1 mutation
BRCA2 mutation
Both
Kaufman B, et al. J Clin Oncol. 2015;33(3):244-250.
Pancreas Prostate
(n = 23)
(n = 8)
Who Will Respond?
• BRCA1/2 germline mutation status is at this time the
best predictor of response to PARP inhibitors
• Not all BRCA1/2 mutation carriers respond to PARP
inhibitors
• Determining primary and secondary resistance
• Will the germline or the tumor genetic testing be most
important?
• Specific genes or evidence of homologous
recombination?
• Studies are ongoing
PARP Inhibitors in BRCA-Driven
Cancers: Current Status and Future
Promise
Kristin K. Zorn, MD
University of Arkansas for Medical Sciences
Case
• 62-year-old woman presents for second opinion about
treatment options for recurrent ovarian cancer
• Review of her path report shows stage IIIC high grade
endometrioid ovarian cancer at the time of diagnosis
What additional information is
needed to decide if genetic
counseling and testing
is appropriate?
1. Family cancer history
2. Ancestry, especially Ashkenazi Jewish descent
3. None – already appropriate with current info
4. None – already inappropriate since not serous histology
Objectives
• Summarize the current approvals for olaparib in ovarian
cancer
• Review the options for germline and somatic testing of
tumors
• Review the ongoing clinical trials of PARP inhibitors in
ovarian cancer
Study 19
• Phase II trial of olaparib vs placebo maintenance in
recurrent, platinum-sensitive HGSOC
• Objective complete or partial response to last platinumbased regimen required at study entry
•
•
•
•
Platinum
sensitive
relapsed
HGSOC
≥ 2 platinum
regimens
PR or CR on
most recent
platinum
regimen
N = 265
Olaparib
400 mg bid
continuous
n = 136
1:1
PD
R
Primary endpoint
PFS
Placebo
n = 129
Randomized within 8 weeks
of last regimen dose
Ledermann J, et al. N Engl J Med. 2012;366(15):1382-1392.
HGSOC, high grade serous ovarian cancer; PR,
partial response; CR, complete response; PD,
progressive disease.
Study 19: PFS by BRCA Mutation
Status
ODAC Sponsor Briefing Book.
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/oncologicdrugsadvisoryco
mmittee/ucm402209.pdf.
European Approval of Olaparib
• Approval granted to olaparib Dec 2014 based on Study
19 PFS data
• First approval for maintenance treatment in women with
recurrent, platinum-sensitive ovarian, fallopian tube, or
peritoneal cancer
– Requires germline and/or somatic BRCA mutations
– Requires complete or partial response to platinum-based chemo
– Genetic testing should be done in an appropriate laboratory
• Dose 400 mg by mouth twice daily (8 x 50 mg capsules)
with reductions to 200 mg or 100 mg twice daily if
needed
• Treatment to be continued until progression of disease
Study 42
• Phase II trial of olaparib in patients with germline BRCA
mutation and recurrent ovarian, breast, pancreatic,
prostate, or other cancer
• 193 heavily pretreated OC patients with platinum
resistance
– 31% ORR (3% CR, 28% PR)
– Median time to response 56 days
OC, ovarian cancer; ORR, objective response rate, CR, complete response; PR, partial response.
Kaufman B, et al. J Clin Oncol. 2015;33(3):244-250.
FDA Approval of Olaparib
• Accelerated approval of olaparib in Dec 2014 based on
Study 42 objective response rate and duration of
response
• Indication granted for treatment of recurrent OC patients
with deleterious or suspected deleterious germline
BRCA mutations
– ≥ 3 lines of prior chemotherapy
– Companion diagnostic also approved
• Maintenance therapy not granted accelerated approval
• Dose 400 mg by mouth twice daily (8 x 50 mg capsules)
with reductions to 200 mg or 100 mg twice daily if
needed
FDA Approval of Olaparib
• 2% of patients developed myelodysplastic syndrome
(MDS) or acute myeloid leukemia (AML)
• 17/22 cases of MDS/AML were fatal
• Duration of olaparib therapy in those who developed
secondary MDS/AML varied from < 6 months to > 2
years
• Recommended to monitor for heme toxicity monthly
• Pneumonitis, sometimes fatal, in < 1%
• Recommended to avoid concomitant use of CYP3A
inhibitors and inducers
• Teratogenic – category D
Package insert. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf.
Objectives
• Summarize the current approvals for olaparib in ovarian
cancer
• Review the options for germline and somatic testing of
tumors
• Review the ongoing clinical trials of PARP inhibitors in
ovarian cancer
NCCN Guidelines for Germline
Testing
• Personal history of epithelial ovarian, fallopian tube, or
primary peritoneal cancer suffices to recommend genetic
counseling and testing
• Not dependent on family history
• Not dependent on ethnicity (ie, Ashkenazi descent)
• Not dependent on tumor pathology (ie, serous histology)
Version 1.2011, www.nccn.org.
Beyond BRCA1/2:
Ovarian Cancer Predisposition
Genes
Syndrome/Gene
Clinical Mutation
Positivity Rate
Lifetime OC
Risk
Other Features
BRCA11
11%
35-46%
OC at earlier age (50)
BRCA21
6%
13-23%
OC at same age as
general population (60)
Lynch Syndrome2,3
< 1%
3-14%
OC at earlier age (43-50);
endometrial and colon
cancer risks are higher
RAD51C4,7
1.3% (RR 6-8)
10-15%
RAD51D5,7
0.6% (RR 6-9)
10-15%
BRIP16
1.4% (RR 8)
10-15%
1. Walsh T, et al. Proc Natl Acad Sci U S A. 2011;108(44):18032-18037.
2. Koornstra JJ, et al. Lancet Oncol. 2009;10(4):400-408.
3. Barrow E, et al. Clin Genet. 2009;75(2):141-149.
4. Meindl A, et al. Nat Genet. 2010;42(5):410-414.
5. Loveday C, et al. Nat Genet. 2011;43(9):879-882.
6. Rafnar T, et al. Nat Genet. 2011;43(11):1104-1107.
7. Pelttari LM, et al. J Med Genet. 2012;49(7):429-432.
History of BRCA1/2 Mutation Testing
• Previously patented
• Baseline testing involves full sequencing and analysis for
5 large BRCA1 rearrangements
• Additional testing possible for other large
rearrangements in BRCA1 and BRCA2 (BART)
• Ashkenazi Jewish panel
• Specific mutation
Genetic Testing Debate
• Single gene testing
– Traditional Sanger
sequencing approach
– Low throughput
– High cost if assessing
multiple genes
– Misses structural
rearrangements
VUS, variants of uncertain significance
www.cancer.gov/cancertopics/pdq/genetics/overview.
• Multigene panel
– Recent development
due to advent of
massively parallel
sequencing
– Lower cost to assess
multiple genes
– Better assessment of
rearrangements
– Large number of VUS
Current HBOC Genetic Testing
• Multiple commercial providers of genetic testing with cost
approximately halved
• Evolving use of BRCA1/2 testing vs panel tests with
expanded number of genes
• Only BRCA1/2 mutation carriers eligible for olaparib
outside of clinical trial
• Evolving landscape of insurance coverage
– To date, coverage for unaffected patients has been poor
– Some insurers are using only 1 testing provider
– Many insurers only allow 1 shot at genetic testing
HBOC, hereditary breast and ovarian cancer.
50% of Serous OC Cases
Have Germline or Somatic HR Defects
BRCA1/2
mutations,
21%
No HR defect
Germline
15%
Somatic 6%
BRCA1 promoter
methylation
11%
EMSY
amplification, 8%
RAD51C
hypermethylation, 3%
Mutation of
PTEN mutation, 7%
Fanconi Anemia Mutation of ATM
genes, 5%
or ATR, 2%
The Cancer Genome Atlas Network. Nature. 2011;474(7353):609-615.
Tumor Testing for Somatic Mutations
• Options include institutional research protocols and
commercial testing
• Result interpretation needs to factor in potential for
germline mutation
• Somatic mutation carriers not eligible for olaparib
therapy in US outside of clinical trial
Objectives
• Summarize the current approvals for olaparib in ovarian
cancer
• Review the options for germline and somatic testing of
tumors
• Review the ongoing clinical trials of PARP inhibitors in
ovarian cancer
PARPi Under Development
PARPi
Treatment
Population
Phase
Olaparib
Monotherapy
Combo w/Chemo
Combo w/Biologic
Combo w/RT
BRCA1/2 mut
BRCA-like tumors
Maintenance
I/II/III
Veliparib
Monotherapy
Combo w/Chemo
Combo w/Biologic
Combo w/RT
BRCA1/2 mut
BRCA-like tumors
I/II
Rucaparib
Monotherapy
Combo w/Carbo
BRCA1/2 mut
Recurrent OC
Maintenance (ongoing)
I/II/III
Niraparib
Monotherapy
Combo w/temozolomide
BRCA1/2 mut
Maintenance (ongoing)
I/III
Talazoparib
Monotherapy
All solid tumors
I
CEP-9722
Monotherapy
Combo w/chemo
All solid tumors
I
Lee JM, et al. Ann Oncol. 2014;25(1):32-40.
Liu JF, et al. Gynecol Oncol. 2014;133(2):362-369.
PARPi, PARP inhibitor; BRCA1/2mut, BRCA1/2
mutations; OC ovarian cancer.
Challenges in PARPi Development
• Other PARPi compared to olaparib?
• Monotherapy or combination treatment with
chemotherapy, targeted therapy, and/or radiation?
• Appropriate dose and schedule? Escalate PARPi or
chemo dose if in combination?
• Frontline, maintenance, and/or recurrent setting?
• Appropriate population? Only HGS? Only platinumsensitive? Only mutation carriers?
Zorn KK. Oncology. 2012;26(2):128-136.
Liu JF, et al. Gynecol Oncol. 2014;133(2):362-369.
GOG 3004/SOLO-1
• Randomized phase III trial of olaparib vs placebo as
maintenance after frontline chemo in BRCA-mutated,
high-grade serous or endometrioid ovarian cancer,
fallopian tube cancer, or peritoneal cancer
• 300 mg tablets twice daily
GOG 3005
• First frontline trial in ovarian cancer in cooperative group
setting
• Randomized phase III trial of carboplatin/paclitaxel +/concurrent and maintenance veliparib in women with
HGSOC, FTC, or PPC
• Neoadjuvant treatment allowed
Olaparib + Cediranib
• Phase I of olaparib + cediranib in recurrent OC or
metastatic TNBC
– RP2D olaparib 200 mg twice daily + cediranib 30 mg daily
– ORR in OC 44%
• Randomized phase II with olaparib +/- cediranib in
platinum-sensitive, BRCA-mutated or high-grade
serous/endometrioid OC
– ORR 56% for olaparib vs 84% for combination
– Median PFS 9 months for olaparib vs 17.7 months for
combination
Liu JF, et al. Eur J Cancer. 2013;49(14):2972-2978.
Liu JF, et al. Lancet Oncol. 2014;15(11):1207-1214.
OC, ovarian cancer, TNBC, triple negative breast cancer.
ARIEL2: Rucaparib for Relapsed,
Platinum-Sensitive, High-Grade
Ovarian Cancer
Primary EP:
Key Eligibility:
• High-grade ovarian
cancer
• ≥ 1 prior platinum
• Platinum-sensitive,
relapsed disease
• Adequate tumor
tissue (archival and
fresh biopsy)
• No prior PARPi
Courtesy Kathleen Moore, MD
N = 180
600 mg bid rucaparib
continuously until
disease progression
by RECIST
 ORR by RECIST
and GCIG CA-125
criteria in HRD
subgroups
Secondary EPs:
 DOR
 PFS
 Safety
 Steady state PK
ARIEL3: Rucaparib Maintenance in
Patients Who Respond to PlatinumBased Treatment for Relapsed
Disease
N = 540 pts
Rucaparib
 PFS
Key Eligibility:
• High-grade ovarian
cancer
• Received ≥ 2 prior
platinum-based
regimens
• Platinum-sensitive
disease
• Response to last
platinum
• Available archival
tumor tissue
Courtesy Kathleen Moore, MD
Primary EP:
Secondary EPs:
2:1
Stratify:
• HRD classification
• Response to
platinum regimen
• Progression-free
interval after
penultimate platinum
R
A
N
D
O
M
I
Z
A
T
I
O
N
Placebo
 PFS by IRR
 PRO
 OS
 Safety
Key Exploratory EP:
 PFS2
Selected Ongoing PARPi Trials
• Ovarian cancer
– Quadra: niraparib in
recurrent disease
– AVANOVA: Niraparib +/bev in platinum-sensitive
• Other sites
– Olympiad: olaparib vs chemo
in HER2-negative, BRCAmutated metastatic BC
– EMBRACA: talazoparib in
locally advanced or metastatic
BRCA-mutated BC
– Bravo: niraparib in HER2negative, BRCA-mutated BC
– Veliparib combination therapy
vs chemo in metastatic,
BRCA-mutated BC
BC, breast cancer, bev, bevacizumab.
Summary
• Olaparib is the first PARP inhibitor to be approved for
clinical use
– EU: maintenance setting, germline and/or somatic BRCA
mutation
– US: ≥ 3 prior therapies, germline mutation
• Genetic testing landscape is rapidly evolving
Summary
• Many gaps in our knowledge of how to best implement
PARPi therapy exist
• Ongoing clinical trials are testing additional PARPi,
frontline setting, and drug combinations to help fill those
gaps
Thoughts From the Chair: Practical
Guidance for an Evolving Clinical
Practice
Thomas J. Herzog, MD – Chair
University of Cincinnati
Future of PARP Inhibition
When?
Who?
BRCAg
BRCAs
HDR
Other
Frontline
Maintenance
Second-line
Third-line
Which?
Different PARPs
Efficacy
Toxicity
Where?
Single agent
Chemo combo
Biologic combo
Evolving PARP MOA’s: How?
Rouleau M, et al. Nat Rev Cancer. 2010;10(4):293-301.
Conclusions
• Novel agents now available to treat ovarian cancer
patients
– Olaparib approved 12/19/14
• Competitive landscape with multiple PARP inhibitors
• Unclear as to true differences between PARPs
• Genetic testing becoming more prevalent
• Basic science & clinical trials will answer many questions