Patient Selection for PARP - PowerPoint Presentation

Slide1

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

Slide2

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

Slide3

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

Slide4

Kadouri L, et al.

BMC Cancer. 2007;7:14.

Identification of Unaffected Mutation Carriers

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

Slide5

BRCA1/2 Impact on Disease Behavior: Ovarian Cancer

Gourley C, et al. J Clin Oncol. 2010;28:2505-2511.

Site of Mets

Site of Mets

P

< .001

P

< .001

P = .052

P

= .153

Slide6

Tan DS, et al.

J Clin Oncol. 2008;26:5530-5536.

Impact on Patient Treatment, Platinum Sensitivity: Ovarian Cancer

Second-Line Response Rate

Chemotherapy for Relapse

BRCA

M

utant

BRCA

Wild-Type

Platinum-based

92

41

Non-platinum

20

33

Third-Line Response Rate

Platinum-based

100

14

Non-platinum

29

6

Slide7

Hollis et al., unpublished data, 2017.

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)

Rs1799950 only: 50% (3/6)

BRCA1/2

mutant (no

rs1799950-

only patients)

Slide8

Monk BJ, et al. Ann Oncol. 2015;26:914-920.

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

Slide9

Lord CJ, Ashworth A. Nature. 2012;481:287-293.O'Connor MJ. Mol Cell. 2015;60:547-560.

Cellular DNA Repair Pathways

Enzymes involved

PARP

XRCC1

LIGASE 3

BER

DSBs

SSBs

Repair Pathway

DNA-PK

KU70/80

BRCA

1/2, PALB2

CHEK1/2

,

RAD51

HRR

NHEJ

DSB repair

ATM

MSH2 MLH1

Mismatch repair

ERCC1

ERCC4

NER

Bulky

adducts

Base mismatches,

insertions and deletions

Slide10

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.

Olaparib Monotherapy

Content no longer available

Slide11

BRCA

wt 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.

Olaparib Maintenance, Study 19: PFS Analysis

Content no longer available

Slide12

19.1

5.5

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, 1274-1284, Copyright 2017, with permission from Elsevier.

Olaparib Maintenance, SOLO 2: PFS

Content no longer available

Slide13

From

N Engl J Med., Mirza MR, et al., Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer, 375, 2154-2164. Copyright ©2016 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Niraparib, NOVA: Second-Line Maintenance

Content no longer available

Slide14

Kaufman B, et al. J Clin Oncol. 2015;33:244-250.

Which Patients (Non-Ovarian)? Study 42

Olaparib monotherapy tested in gBRCA1/2 mutation carriers with advanced cancersBreast cancer with ≥ 3 prior lines of chemotherapy for metastatic diseasePancreatic cancer with prior gemcitabineProstate cancer progressed on hormone and 1 prior systemic treatmentPlatinum-resistant ovarian cancer

Tumor Response Rate (RECIST)

Breast (62 patients)

13%

Pancreatic

(23 patients)

22%

Prostate

(8 patients)

50%

Ovarian (193 patients)

31%

Slide15

From N Engl J Med., Robson R, et al., Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation, 377, 523-533. Copyright ©2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Olaparib vs Physician's Choice: Phase 3 OlympiAD Study in MBC

Content no longer available

Slide16

Mateo J, et al. N Engl J Med. 2015;373:1697-1708.

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

Slide17

Gourley C, et al. J Clin Oncol. 2017;35:5533.

Why a Breakthrough?

Clear evidence of 'super responders'

Slide18

Alsop K, et al. J Clin Oncol. 2012;30:2654-2663.

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

Slide19

(813

BRCA1

& 272 BRCA2)n = 1085

(528 BRCA1 & 176 BRCA2)n = 704

%

Histology Grade

Mavaddat N, et al. Cancer Epidemiol Biomarkers Prev. 2012;21:134-147.

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) Data

%

Slide20

Study

SerousHGSEndometrioidClear cellBorderline/MucinousRisch, 200618%7%0%Malander, 20048%13%0%Soegaard, 20085.4%5.4%9%0%Alsop, 201217%8.4%6%ExcludedSong, 20148%11%5%-

Hirsh-Yechezkel G, et al. Gynecol Oncol. 2003;89:494-498.Risch HA, et al. J Natl Cancer Inst. 2006;98:1694-1706.Malander S, et al. Eur J Cancer. 2004;40:422-428.Soergaard M, et al. Clin Cancer Res. 2008;14:3761-3767.Alsop K, et al. J Clin Oncol. 2012;30:2654-2663.Song H, et al. Hum Mol Genet. 2014;23:4703-4709.

Do Patients With Non-Serous Histology Associate With

BRCA

Mutations?

Slide21

Age?

BRCA1/2 -BRCA1+BRCA2+Alsop, 2012[a]60 y53 y60 ySoegaard, 2008[b]61 y 49 yMalander, 2004[c]59 y 57 ySong, 2014[d]59 y52 y57 y

Approximately 25% of BRCA1/2 mutation carriers are older than 60 y[e]

Family History?Frequency of BRCA in the Presence of Family HistoryFrequency of BRCA in the Absence of Family HistoryPercentage of BRCA Mutation Carriers who Lack a Family HistoryAlsop, 2012[a]39%8%44%Song, 2014[d]19%5%39%

35% to 50% of BRCA1/2 mutation carriers do not have a family history

a. Alsop K, et al. J Clin Oncol. 2012;30:2654-2663; b. Soergaard M, et al. Clin Cancer Res. 2008;14:3761-3767;c. Malander S, et al. Eur J Cancer. 2004;40:422-428; d. Song H, et al. Hum Mol Genet. 2014;23:4703-4709; e. Risch HA, et al. J Natl Cancer Inst. 2006;98:1694-1706.

Predictors of

BRCA

Mutations?

Slide22

Early

LatePrognostic informationHighLowInform 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 patientLot of other considerationsCome to terms with diseaseFamily discussion timeLess MoreGenetic counsellor timeLess More

Test Early (at Diagnosis) or Test Late

(at Relapse or Later)?

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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

Slide24

Maintenance Studies

StudyAgentsBRCA PFS HR (95% CI)gBRCA PFS HR (95% CI)Study 19[a]Olaparib vs placebo0.23 (0.04, 1.12)0.17 (0.09, 0.34)NOVA[b]Niraparib vs placebo0.27(0.08, 0.90)0.27(0.17, 0.41)

Treatment StudyStudyAgentsBRCA Response RategBRCA Response RateARIEL2[c]Rucaparib88%81%

a. Ledermann J, et al. N Engl J Med. 2012;366:1382-1392; b. Mirza MR, et al. N Engl J Med. 2016;375:2154-2164; c. Swisher EM, et al. Lancet Oncol. 2017;18:75-87; d. Hollis RL, et al. Cancer Biol Med. 2016;13:236-247; e. Patch AM, et al. Nature. 2015;521:489-494.

Germline or Somatic Sequencing?

Slide25

Germline or Somatic Sequencing? (cont)

Germline

Easy to acquire and process sample

Interpretation of sequence data straightforwardLow false negative rate (2%)False positive signals not an issueTissue heterogeneity not an issueIf 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

Slide26

Barriers to Testing

Financial

Cost of test

Cost of insurance if positive test

Genetic counsellor availability

Ethical

Technological

Cultural

Slide27

a. Risch

HA, et al.

J Natl Cancer Inst. 2006;98:1694-1706; b. Malander S, et al. Eur J Cancer. 2004;40:422-28; c. Alsop K, et al. J Clin Oncol. 2012;30:2654-2663; d. RCOG. Scientific Impact Paper No 44.

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

Slide28

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