State of the Art in BRCA - PowerPoint Presentation

Slide1

State of the Art in BRCA-Mutated Ovarian Cancer

Lessons for Practitioners

Moderator

Robert L. Coleman, MD

Professor

The University of Texas

MD Anderson Cancer Center

Houston, TexasSlide2

Panelists

Robert A. Burger, MDProfessor, Obstetrics and Gynecology

University of PennsylvaniaPhiladelphia, Pennsylvania

Beth Y. Karlan, MD

Professor

Cedars-Sinai Medical Center

Los Angeles, California

Slide3

This program will include a discussion of off-label treatment and investigational agents not approved by the FDA for use in the United States and data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal.Slide4

SEER website.

Ovarian Cancer

11.7 new cases per 100,000 women/y; 7.4 deaths per 100,000/y1.3% lifetime chance of diagnosis

In 2014, > 222,000 women living with ovarian cancer in the United StatesSlide5

Case 1

Susan

58-year-old Korean woman diagnosed with

high-grade serous ovarian cancer

Presented with a large pelvic mass, intermittent abdominal pain, and obstructive symptoms

CT imaging confirmed bilateral 9-cm adnexal lesions and multiple peritoneal nodules

CA125 = 5157

Family historyOlder sister with breast cancer at age 40 and recent diagnosis of primary peritoneal cancerNo other known cancers in either maternal or paternal pedigrees.Slide6

Case 1

Susan (cont)

Susan

underwent optimal cytoreduction with exploratory laparotomy, TAH-BSO, right ureterolysis, appendectomy, omentectomy and tumor debulking to

< 0.5

cm

disease

She was treated with 6 cycles of carboplatin and dose-dense paclitaxel and completed treatment with no evidence of disease and normalization of her

CA125

Germline

BRCA

testing was performed and revealed a deleterious

BRCA1

mutation (1041del3insT

)Slide7

Norquist BM, et al. JAMA Oncol; 2016;2:482-490.

Frequency of Germline

BRCA1 and

BRCA2

Mutations in Ovarian Cancer

Approximately 15% of patients have

BRCA1

or BRCA2 mutations

The incidence is higher in some subpopulations such as Ashkenazi Jewish patients

Frequency by

BRCA

:

©Medscape, LLC

MUTATED

BRCA1

9.5%

MUTATED

BRCA2

5.1%Slide8

a. SGO website.b. NCCN

Guidelines®. Genetic/familial high-risk assessment: breast and ovarian. Version 2.2017.

Genetic Testing of Ovarian Cancer

All

patients diagnosed

with

invasive epithelial ovarian

, fallopian

tube,

or peritoneal carcinoma,

regardless

of age of onset or family history, should receive

genetic

counseling and be offered genetic

testing

[a,b]Slide9

Norquist BM, et al. JAMA Oncol; 2016;2:482-490.

Mutation Status by Histology

Serous, high-grade, n = 1498

Serous, low-grade, n = 70

Carcinoma, n = 165

Endometrioid, low-grade, n = 13

Endometrioid, high-grade, n = 64

Clear cell, n = 58

Carcinosarcoma, n = 22

Transitional cell, n = 9

0

.2

.15

.1

.05

BRCA1

BRCA2

Other

MMRSlide10

NCCN Guidelines®. Genetic/familial high-risk assessment: breast and ovarian. Version 2.2017.

Single-Gene vs Multigene (Panel) TestingSlide11

a. NIH website.

Cascade Testing and Genetic Counseling

Patients should receive a genetic referral at the time of diagnosis

[a]

Genetic counseling is recommended before and after any genetic test and should

[a

:Include a hereditary cancer risk assessment and explanation of specific tests that might be used

Genetic counselors will discuss the appropriateness of genetic testing, medical implications of a positive or negative test result, the possibility that a test result might not be informative, psychological risks and benefits of genetic test results, and the risk of other family members

Cascade testing

:

Genetic tests

performed on blood relatives of the person diagnosed with a

BRCA

mutation

Cascade testing is important to identify relatives who may be at greater risk for cancer so they can employ available preventative measures

Genetics counseling should not be a barrier for testing of patients with ovarian cancerSlide12

Childers CP, et al. J Clin Oncol. 2017;35.

[Epub ahead of print]

Genetic Testing Rates

Content no longer availableSlide13

a. Hosoya N, et al. Cancer Sci.

2014;105:370-388.b. NCCN Guidelines®. ®). Ovarian cancer including fallopian tube cancer and primary peritoneal cancer. Version 3.2017.

Effect of BRCA

Mutations in the Front Line

BRCA

mutations cause defects in DNA repair

[a]

Generally, patients with BRCA1

or

BRCA2

mutations should receive platinum-based chemotherapy

[b]

Knowledge of mutation

Allows treatment planning in recurrence

[b

]

Helps to understand prognosis

[b

]Slide14

Germline vs Somatic Mutations

Germline mutations are

inherited and found in all cells.

Somatic

mutations are

not inherited and are found

within the

tumor.

Germline Mutation

Half of gametes carry mutation

Acquired

Somatic Mutation

Mutation only in affected area

Embryo

Parental gametes

Organism

Offspring gametes

None of gametes carry mutation

Embryo

Parental gametes

Entire organism carries mutation

Organism

Offspring gametes

©Medscape, LLC

©Medscape, LLCSlide15

Case 2Angela

71-year-old black woman initially presented

with a large bowel

obstruction

She

underwent an emergent diverting colostomy and biopsy, which revealed high-grade serous adenocarcinoma consistent with ovarian primaryFamily history

was negative for breast or

ovarian cancer

Genetics

evaluation

found

a pathogenic mutation in

BRCA1

(c.2110_2111delAA

)

Referred

for

evaluation

Neoadjuvant chemotherapy: dose-dense paclitaxel/carboplatin × 3

D

ebulking was

aborted

because of disease

distribution

Completed

6 more cycles of

dose-dense paclitaxel/carboplatin but had progressionSlide16

Case 2

Angela (cont)

Regimen was changed to pegylated liposomal doxorubicin (PLD)

CR by imaging and normalized CA125

She underwent surgical exploration with no visible residual disease and colostomy reversal

Pathology was microscopically positive

4 more cycles of PLD

After 1 y of surveillance postcomplete remission, CA125 started to rise and her imaging revealed small-volume, multifocal recurrenceShe was started on single-agent olaparib

400 mg bidSlide17

*As indicated by an FDA-approved companion diagnostic test. a. LynparzaTM

PI 2017; b. RubracaTM PI 2017; c. ZejulaTM

PI 2017; d. Myriad Genetics Laboratories, Inc. website ; e. Foundation Medicine website.

FDA-Approved PARP Inhibitors

Companion diagnostics (nonmaintenance setting)

Olaparib has a companion diagnostic that detects germline

BRCA1

and

BRCA2

mutations in blood

[d]

Rucaparib has a companion diagnostic that tests the tumor to detect somatic and germline

BRCA1

and

BRCA2

mutations via NGS

[e]

.

PARP Inhibitor

FDA

Approval

FDA Indication

Olaparib

[a]

December 2014

August 2017

Deleterious

or suspected deleterious germlin

e

BRCA

-mutated

* advanced

ovarian cancer,

≥ 3

prior

treatments

Maintenance treatment of adult

patients with

recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer with CR or PR to platinum-based chemotherapy

Rucaparib

[b]

December

2016

Deleterious

BRCA

-mutated*

(germline

and/or

somatic)

advanced

ovarian cancer,

≥

2

prior treatments

Niraparib

[c]

March

2017

Maintenance treatment for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer with CR or PR to platinum-based chemotherapySlide18

2:1

Placebo

Olaparib

Treatment until progression

R

*or fallopian tube or primary peritoneal

cancer.

a. Pujade-Lauraine E, et al.

Lancet Oncol.

2017;18:1274-1284; b. Mirza MR, et al.

N Engl J Med

. 2016;375:2154-2164; c. Ledermann

JA,

et al.

ESMO

2017.

Abstract LBA40_PR.

Phase 3 PARP Inhibitor Maintenance Studies

SOLO2/ENGOT-OV21

[a]

ENGOT-OV16/NOVA

[b]

ARIEL3

[c]

Platinum-sensitive relapsed OC;

BRCA1/2

MUT+

, ≥2 lines of prior tx; CR or PR to most recent platinum-based therapy

Primary endpoint:

investigator-assessed PFS

non-g

BRCAmut

n = 350

2:1

Niraparib

Placebo

g

BRCAmut

n = 203

2:1

Niraparib

Placebo

R

R

2:1

Placebo

Rucaparib

Treatment until progression

R

Platinum-sensitive recurrent high-grade serous or endometrioid OC*; ≥ 2

lines of

prior platinum-based Tx: ≤1 prior nonplatinum regimen; no prior PARPi, CR, or PR; N = 564

Screening

High-grade, platinum-sensitive relapsed OC; CR or PR to most recent platinum treatment

Primary endpoint:

PFS

Primary endpoint:

PFS

Treatment until progressionSlide19

*Primary endpoint.

†Sensitivity analysis by blinded independent central review (BICR). a. Pujade-Lauraine E, et al. Lancet Oncol.

2017;18:1274-1284; b. Mirza MR, et al. N Engl J Med.

2016;375:2154-2164

;

c.

Ledermann JA, et al. ESMO 2017. Abstract LBA40_PR. PARP Inhibitors as Maintenance Therapy

Platinum-Sensitive Recurrent Ovarian Cancer, Phase 3

SOLO2/ENGOT-OV21

(

All patients were

BRCA

mut+

)

[a

]

Olaparib, n = 196

Placebo, n

= 99

HR

Median PFS (investigator-assessed)*, mo

19.1

5.5

0.30

Median PFS† (BICR), mo

30.2

5.5

0.25

ARIEL3

[c]

Rucaparib, n = 375

Placebo, n

= 189

HR

Median PFS ITT (Investigator-assessed)*, mo

10.8

5.4

.36

Median PFS ITT (BICR),

mo

13.7

5.4

.35

Median PFS all

BRCA

mut+

(investigator-assessed),

mo

16.6

5.4

.23

Median PFS all

BRCA

mut+

(BICR),

mo

26.8

5.4

.20

Median PFS all

BRCA

mut+

+ HRD

+

(investigator-assessed),

mo

13.6

5.4

.32

ENGOT-OV16/NOVA

[b]

Niraparib, n = 372

Placebo, n = 181

HR

Median PFS ITT cohort (BICR)*, mo

11.3

4.7

NR

Median PFS

g

BRCA

cohort (BICR), mo

21.0

5.5

0.27

Median PFS non-

g

BRCA

cohort (BICR), mo

9.3

3.9

0.45

Median PFS non-g

BRCA

cohort with HRD+ (BICR), mo

12.9

3.8

0.38Slide20

a. Pujade-Lauraine E, et al. Lancet Oncol. 2017;18:1274-1284; b. Mirza MR, et al. N Engl J Med

. 2016;375:2154-2164; c. Ledermann JA, et al. ESMO 2017. Abstract LBA40_PR.

Maintenance StudiesPatients in PR vs CR

SOLO2/ENGOT-OV21

[a]

ENGOT-OV16/NOVA

[b]

CR

46%

PR

54%

CR

47%

PR

53%

Olaparib, n = 196

Placebo, n = 99

CR

51%

PR

49%

CR

51%

PR

49%

Niraparib, n = 372

Placebo, n = 181

ARIEL3

[c]

CR

34%

PR

66%

CR

34%

PR

66%

Rucaparib, n = 375

Placebo, n = 189Slide21

BRCA

mutation

BRCA1

BRCA2

Germline

Somatic

BRCA

WT

LOH high

LOH low

LOH indeterminate

BRCA

Mutation

Status

known

Status unknown

a. Ledermann JA, et al.

N Engl J Med

. 2012. b. Mirza MR, et al.

N Engl J Med

. 2016;375:2154-2164; c. Ledermann JA, et al. ESMO 2017. Abstract LBA40_PR.

PFS Hazard Ratio by Mutation Status

Study 19

[a]

NOVA

[b]

ARIEL3

[c]

Placebo Better

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.00

Olaparib Better

Germline

BRCA

HRD+/No

BRCA

No germline

BRCA

(WT)

Placebo Better

0.01

0.10

1.00

Niraparib Better

Placebo Better

Rucaparib Better

0.0625

1.00

2

0.5

0.25

0.125Slide22

Case 2

Angela (cont)

After 12 mo on olaparib, she

is disease-free by

imaging

and CA125

Still, on single-agent therapy, she continued to have 3 bothersome

AEs that required attentionNauseaDiarrhea

Anemia, grade 3Slide23

a. Lynparza® PI 2017; b. Rubraca®

PI 2017; c. Zejula ® PI 2017.

PARP InhibitorsSafety Overview

Agent

Warnings/Precautions

Most

Common AE or Lab Abnormality

Olaparib

[a]

MDS/AML (<1.5%), pneumonitis, embryo-fetal toxicity

AE

≥20%,:

anemia, n

ausea, fatigue (including asthenia), vomiting, nasopharyngitis/URTI/ influenza,

diarrhea, arthralgia/myalgia, dysgeusia, headache, dyspepsia, decreased appetite, constipation, stomatitis.

Lab abnormality

≥35%:

decrease in: hemoglobin, lymphocytes, leukocytes, ANC, platelets;

Increase in: MCV

Rucaparib

[b]

MDS/AML,

embryo-fetal toxicity

AE ≥20%:

n

ausea, fatigue (including asthenia), vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, dyspnea.

Lab abnormality

≥35%

: increase in: creatinine, ALT, AST, cholesterol; Decrease in: hemoglobin, lymphocytes, platelets, ANC

Niraparib

[c]

MDS/AML, bone marrow suppression, cardiovascular effects, embryo-fetal toxicity

AE ≥20%:

thrombocytopenia, anemia, neutropenia, nausea, constipation, vomiting, abdominal pain/distention, mucositis/stomatitis, diarrhea, fatigue/asthenia, decreased appetite, headache, insomnia,

nasopharyngitis

, dyspnea, rash, hypertension.

Lab abnormality

≥35%:

decrease

in: hemoglobin, platelet count, WBC count, absolute neutrophil count; increase in AST.Slide24

a. Pujade-Lauraine E, et al. Lancet Oncol. 2017;18:1274-1284; b. Mirza MR, et al.

N Engl J Med. 2016;375:2154-2164; c. Ledermann JA, et al. ESMO 2017. Abstract LBA40_PR.

ToxicityGI and Fatigue

Trial

Drug

Grade

SOLO2

[a]

NOVA

[b]

ARIEL3

[c]

Olaparib,

n = 195

Placebo,

n = 99

Niraparib,

n = 367

Placebo,

n = 179

Rucaparib

n = 372

Placebo

n = 189

Any, %

≥3,

%

Any, %

≥ 3,

%

Any, %

≥ 3,

%

Any, %

≥ 3,

%

Any, %

≥ 3,

%

Any, %

≥ 3,

%

Nausea

76

3

33

0

74

3

35

1

75

4

37

< 1

Vomiting

38

3

19

1

34

2

16

< 1

37

4

15

1

Diarrhea

33

1

20

0

19

< 1

21

1

32

0.5

22

1

Constipation

21

0

23

3

40

< 1

20

< 1

37

2

24

1

Fatigue/asthenia

66

4

39

2

59

8

41

< 1

69

7

44

3Slide25

a. Pujade-Lauraine E, et al. Lancet Oncol. 2017;18:1274-1284; b. Mirza MR, et al. N Engl J Med

. 2016;375:2154-2164; c. Ledermann JA, et al. ESMO 2017. Abstract LBA40_PR.

ToxicityHematologic

Trial

Drug

Grade

SOLO2

[a]

NOVA

[b]

ARIEL3

[c]

Olaparib,

n = 195

Placebo,

n = 99

Niraparib,

n = 367

Placebo,

n = 179

Rucaparib

n = 372

Placebo

n = 189

Any, %

≥3,

%

Any, %

≥ 3,

%

Any, %

≥ 3,

%

Any, %

≥ 3,

%

Any, %

≥ 3,

%

Any, %

≥ 3,

%

Anemia

43

19

8

2

50

25

7

0

37

19

6

< 1

Neutropenia

19

5

6

4

30

20

6

2

18

7

5

1

Thrombo-cytopenia

14

1

3

1

61

34

6

< 1

28

5

3

0Slide26

a. Pujade-Lauraine E, et al. Lancet Oncol. 2017;18:1274-1284; b. Mirza MR, et al. N Engl J Med

. 2016;375:2154-2164; ZejulaTM PI 2017; d.

Ledermann JA, et al. ESMO 2017. Abstract LBA40_PR. Toxicity

Other

Any grade ≥ 3

AE

36%

olaparib vs 18% placebo

AE leading to

discontinuation

11%

vs 2

%

AE

leading to dose

reduction

25% vs

3

%

MDS/AML

2%

vs 4

%

Trial

Drug

Grade

SOLO2

[a]

NOVA

[b,c]

ARIEL3

[d]

Olaparib,

n = 195

Placebo,

n = 99

Niraparib,

n = 367

Placebo,

n = 179

Rucaparib

n = 372

Placebo

n = 189

Any, %

≥3,

%

Any, %

≥ 3,

%

Any, %

≥ 3,

%

Any, %

≥ 3,

%

Any, %

≥ 3,

%

Any, %

≥ 3,

%

↑

ALT or AST

4

0

4

< 1

10

4

5

2

34

11

4

0

↑

s

erum creatinine

11

0

1

0

15

< 1

2

0

Any grade ≥ 3 AE

74

% niraparib vs 23% placebo

AE leading to discontinuation

15

% vs 2%

AE leading to dose reduction

67

% vs

15%

MDS/AML

1.4

% vs

0.5%

Any grade ≥ 3 AE

56% rucaparib

vs

15%

placebo

AE

leading to discontinuation

13% vs 2%

AE leading to dose reduction

55% vs 4%

MDS/AML

0.8% vs 0%

Not ReportedSlide27

Future Directions

Combinations

PARPi + antiangiogenic agents Published ongoing trials with olaparib and cediranib

PARPi + checkpoint inhibitors agents

Combined with PD-1 and PD-L1

PARPi + other DNA

damage response pathwaysAdditive or synergistic effect with PARP agents

Best practice for combination therapyAdminister in sequence or upon resistance? Slide28

Key Takeaways

Genetic testing of all patients with ovarian cancer and family members is criticalPARP inhibitors represent the f

irst molecular targeted therapy for patients with ovarian cancer based on the genetics of the tumor Several treatment options available with

different toxicities

Become familiar with the AEs and how best to

ameliorate them

This will ensure patient adherence and maximize benefit Slide29

You may now revisit those questions presented at the beginning of

the activity to see what you’ve learned by clicking on the Earn Credit link. The CME posttest will follow. Please also take a moment to complete the program evaluation at the end.

Thank you for participating in this activity

.