1. Patient Selection for PARP Inhibitors:
Purpose and Practicalities
Presenter
Charlie Gourley, MBChB, PhD, FRCP
Professor of Medical Oncology
University of Edinburgh
Edinburgh, Scotland, United Kingdom
Abbreviations:
BRCA = breast cancer gene 1

2. Topics for Discussion
Rationale for BRCA testing to inform decision making in patients with cancer
Who should be tested and when?
Germline or somatic testing?
Barriers to testing 2

3. BRCA1/2 Mutation Status in Ovarian Cancer
Identification of unaffected mutation carriers
Prognostic importance
Tells us how the disease might behave
Impact on patient treatment
Platinum sensitivity
Sensitivity to intraperitoneal chemotherapy
Sensitivity to other chemotherapy
Pegylated liposomal doxorubicin
Trabectedin
PARP inhibition
Abbreviations:
PARP = poly (ADP-ribose) polymerase 3

4. Identification of Unaffected Mutation Carriers
Abbreviations:
BBC = bilateral breast cancer
ca = cancer
OS = overall survival
Patients with BRCA1 and BRCA2 mutations had a better survival vs patients with wild-type BRCA until ~5 years
At around 5 years, OS between patients with BRCA1 mutations and patients with wild-type BRCA was similar
However, patients with BRCA2 mutations continue to have improved OS at 10 years
Kadouri L, et al. BMC Cancer. 2007;7:14. 4

5. BRCA1/2 Impact on Disease Behavior: Ovarian Cancer
Abbreviations:
hered = hereditary
met = metastasis
P = .153
Site of Mets
Site of Mets
Gourley C, et al. J Clin Oncol. 2010;28: 5

6. Impact on Patient Treatment, Platinum Sensitivity: Ovarian Cancer
Second-Line Response Rate
Chemotherapy for Relapse
BRCA Mutant
BRCA Wild-Type
Platinum-based 92 41
Non-platinum 20 33
Third-Line Response Rate
100 14 29 6
Tan DS, et al. J Clin Oncol. 2008;26: 6

7. BRCA1/2 Status: Impact on PLD Sensitivity
87 Edinburgh patients evaluable for PLD response
83 HGS, 4 non-HGS
19.3% response rate in HGS (16/83)
BRCA1/2 wild-type: 12.1% (7/58)
BRCA1/2 aberrant: 36% (9/25)
Rs only: 50% (3/6)
BRCA1/2 mutant (no rs only patients)
Abbreviations:
HGS = high-grade serous
PLD = pegylated liposomal doxorubicin
Hollis et al., unpublished data, 2017. 7

8. BRCA1/2 Status: Impact on Trabectedin Sensitivity
Ova-301 phase 3 study
In patients with recurrent ovarian cancer
PLD ± trabectedin
The PFS and OS benefit of the combination appears to be confined to the BRCA1-mutant population
Abbreviations:
PFS = progression-free survival
Monk BJ, et al. Ann Oncol. 2015;26: 8

9. Cellular DNA Repair Pathways
Enzymes involved
PARP
XRCC1
LIGASE 3
BER
DSBs
SSBs
Repair Pathway
DNA-PK
KU70/80
BRCA1/2, PALB2
CHEK1/2, RAD51
HRR
NHEJ
DSB repair
ATM
MSH2 MLH1
Mismatch repair
ERCC1
ERCC4
NER
Bulky
adducts
Base mismatches, insertions and deletions
Abbreviations:
DSB = double-strand break
SSB = single-strand break
BER = base excision repair
NER = nucleotide excision repair
NHEJ = non-homologous end joining
HRR = homologous recombination repair
Lord CJ, Ashworth A. Nature. 2012;481:
O'Connor MJ. Mol Cell. 2015;60: 9

10. Olaparib Monotherapy Content no longer available Abbreviations:
bid = twice daily
gBRCAm = germline breast cancer gene mutation
Reprinted from Lancet, 376 /9737, Audeh MW, et al., Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial, 245–251, Copyright 2010, with permission from Elsevier.
Reprinted from Lancet Oncol., 12 /9, Gelmon KA et al., Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study, 852–861, Copyright 2011, with permission from Elsevier. 10

11. Olaparib Maintenance, Study 19: PFS Analysis
Content no longer available
Abbreviations:
BRCAm = breast cancer gene mutation
BRCAwt = breast cancer gene wild-type
CI = confidence interval
HR = hazard ratio
BRCAwt includes patients with no known BRCAm or a mutation of unknown significance
Reprinted from Lancet Oncol., 15 /8, Ledermann J, et al., Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial, 852–861, Copyright 2014, with permission from Elsevier. 11

12. Olaparib Maintenance, SOLO 2: PFS
Content no longer available
5.5
19.1
Median follow-up was 22.1 months in the olaparib group and 22.2 months for placebo
Reprinted from Lancet Oncol., 18 /9, Pujade-Lauraine EA, et al., Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial, , Copyright 2017, with permission from Elsevier. 12

13. Niraparib, NOVA: Second-Line Maintenance
Content no longer available
Abbreviations:
HRD = homologous recombination deficiency
From N Engl J Med., Mirza MR, et al., Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer, 375, Copyright ©
2016 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 13

14. Which Patients (Non-Ovarian)? Study 42
Olaparib monotherapy tested in gBRCA1/2 mutation carriers with advanced cancers
Breast cancer with ≥ 3 prior lines of chemotherapy for metastatic disease
Pancreatic cancer with prior gemcitabine
Prostate cancer progressed on hormone and 1 prior systemic treatment
Platinum-resistant ovarian cancer
Tumor Response Rate (RECIST)
Breast (62 patients)
13%
Pancreatic (23 patients)
22%
Prostate (8 patients)
50%
Ovarian (193 patients)
31%
Abbreviations:
RECIST = Response Evaluation Criteria In Solid Tumors
Kaufman B, et al. J Clin Oncol. 2015;33: 14

15. Olaparib vs Physician's Choice: Phase 3 OlympiAD Study in MBC
Content no longer available
Abbreviations:
MBC = metastatic breast cancer
No. = number
From N Engl J Med., Robson R, et al., Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation, 377, Copyright ©
2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 15

16. Which Patients (Prostate Cancer)? TOPARP Study
Olaparib monotherapy in metastatic, castration- resistant prostate cancer (49 evaluable patients):
Heavily pre-treated
33% response rate (16/49) by RECIST 1.1, PSA response, or fall in circulating tumor cells
16 patients found to have aberrations in DNA repair genes; 88% response rate (14/16) in these patients
All 7 patients with BRCA2 loss had a PSA response and all 5 with measurable disease had a RECIST response
PSA = prostate-specific antigen
Mateo J, et al. N Engl J Med. 2015;373: 16

17. Clear evidence of 'super responders'
Why a Breakthrough?
Clear evidence of 'super responders'
Gourley C, et al. J Clin Oncol. 2017;35:5533.

18. Non mucinous ovarian cancer patients (n = 1001)
Australian Population-Based Study of BRCA Mutations in Patients With Ovarian Cancer
Non mucinous ovarian cancer patients (n = 1001)
BRCA mutations:
14% overall
16.6% of serous cancer
22.6% of HGS
Alsop K, et al. J Clin Oncol. 2012;30: 18

19. Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) Data
(528 BRCA1 & 176 BRCA2)
n = 704
(813 BRCA1 & 272 BRCA2)
n = 1085 % %
Histology Grade
Mavaddat N, et al. Cancer Epidemiol Biomarkers Prev. 2012;21: 19

20. Do Patients With Non-Serous Histology Associate With BRCA Mutations?
Study
Serous
HGS
Endometrioid
Clear cell
Borderline/
Mucinous
Risch, 2006
18% 7% 0%
Malander, 2004 8%
13%
Soegaard, 2008
5.4% 9%
Alsop, 2012
17%
8.4% 6%
Excluded
Song, 2014
11% 5% -
Hirsh-Yechezkel G, et al. Gynecol Oncol. 2003;89:
Risch HA, et al. J Natl Cancer Inst. 2006;98:
Malander S, et al. Eur J Cancer. 2004;40:
Soergaard M, et al. Clin Cancer Res. 2008;14:
Alsop K, et al. J Clin Oncol. 2012;30:
Song H, et al. Hum Mol Genet. 2014;23: 20

21. Predictors of BRCA Mutations?
Age?
BRCA1/2 -
BRCA1+
BRCA2+
Alsop, 2012[a]
60 y
53 y
Soegaard, 2008[b]
61 y
49 y
Malander, 2004[c]
59 y
57 y
Song, 2014[d]
52 y
Approximately 25% of BRCA1/2 mutation carriers are older than 60 y[e]
Family History?
Frequency of BRCA in the Presence of Family History
Frequency of BRCA in the Absence of Family History
Percentage of BRCA Mutation Carriers who Lack a Family History
Alsop, 2012[a]
39% 8%
44%
Song, 2014[d]
19% 5%
35% to 50% of BRCA1/2 mutation carriers do not have a family history
a. Alsop K, et al. J Clin Oncol. 2012;30: ; b. Soergaard M, et al. Clin Cancer Res. 2008;14: ;
c. Malander S, et al. Eur J Cancer. 2004;40: ; d. Song H, et al. Hum Mol Genet. 2014;23: ; e. Risch HA, et al. J Natl Cancer Inst. 2006;98: 21

22. Test Early (at Diagnosis) or Test Late (at Relapse or Later)?
Prognostic information
High
Low
Inform first-line therapy decision ☑ ☒
Inform access to first-line PARP inhibitor trials
Identification for PARP inhibitor at relapse
Identification of family carriers
☑ (early and complete)
☑ (late and less complete)
Timing for patient
Lot of other considerations
Come to terms with disease
Family discussion time
Less
More
Genetic counsellor time 22

23. Ideal Scenario
All women with non-mucinous epithelial ovarian cancer (or at least HGS ovarian cancer) know their BRCA status shortly after a diagnosis of ovarian cancer
This information is used to:
Guide therapeutic decisions
Reduce the morbidity and mortality from BRCA-associated cancer for the patient and their family members 23

24. Germline or Somatic Sequencing?
Maintenance Studies
Study
Agent
sBRCA PFS HR (95% CI)
gBRCA PFS HR (95% CI)
Study 19[a]
Olaparib vs placebo
0.23
(0.04, 1.12)
0.17
(0.09, 0.34)
NOVA[b]
Niraparib vs placebo
0.27
(0.08, 0.90)
(0.17, 0.41)
Treatment Study
Study
Agent
sBRCA Response Rate
gBRCA Response Rate
ARIEL2[c]
Rucaparib
88%
81%
Abbreviations:
gBRCA = germline breast cancer gene mutation
sBRCA = somatic breast cancer gene mutation
a. Ledermann J, et al. N Engl J Med. 2012;366: ; b. Mirza MR, et al. N Engl J Med. 2016;375: ; c. Swisher EM, et al. Lancet Oncol. 2017;18:75-87; d. Hollis RL, et al. Cancer Biol Med. 2016;13: ; e. Patch AM, et al. Nature. 2015;521: 24

25. Germline or Somatic Sequencing? (cont)
Easy to acquire and process sample
Interpretation of sequence data straightforward
Low false negative rate (2%)
False positive signals not an issue
Tissue heterogeneity not an issue
If want to detect all BRCA patients, will need to sequence 100% of germline and 85% of somatic (if do germline first)
In some countries, patients required to see a genetic counsellor before testing can be done
Somatic
More samples processing required
Interpretation of sequence data complicated
False negative rate unclear
False positive signals are an issue (FFPE artefact)
Tissue heterogeneity may be an issue
If want to detect all BRCA patients, will need to sequence 100% of somatic and 15% of germline (if do somatic first)
In many countries, patients not required to see a genetic counsellor before the testing is done
Abbreviations:
FFPE = formalin-fixed paraffin-embedded 25

26. Barriers to Testing Financial Genetic counsellor availability Ethical
Cost of test
Cost of insurance if positive test
Genetic counsellor availability
Ethical
Technological
Cultural 26

27. Summary
Approximately 10% of invasive epithelial non-mucinous ovarian cancers are associated with germline BRCA1/2 mutations[a-c]
BRCA germline mutations are not restricted to serous histology, but it is the most frequent type[d]
Around one-third of BRCA carriers with ovarian cancer do not have a family history of breast/ovarian cancer, or have been diagnosed > 60 y
BRCA germline testing should be considered in all patients with epithelial invasive non-mucinous ovarian cancer
Knowledge of BRCA status informs therapeutic decisions including access to PARP inhibitors
RCOG = Royal College of Obstetricians and Gynaecologists
Royal College of Obstetricians and Gynaecologists. The distal fallopian tube as the origin of non-uterine pelvic high-grade serous carcinomas (Scientific Impact Paper No. 44). Published November Accessed November xx , 2017.
a. Risch HA, et al. J Natl Cancer Inst. 2006;98: ; b. Malander S, et al. Eur J Cancer. 2004;40:422-28; c. Alsop K, et al. J Clin Oncol. 2012;30: ; d. RCOG. Scientific Impact Paper No 44. 27

28. Thank you for participating in this activity.
To proceed to the online CME test, click on the Earn Credit link on this page. 28