Mutated Ovarian Cancer This program will include a discussion of offlabel 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 peerreviewed journa ID: 654865
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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
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