OVARIAN CA MEGAN INDERMAUR, MD, WOMEN’S CANCER ASSOCIATES CHERYL RYDER, ARNP, WOMEN’S CANCER ASSOCIATES

1. Ovarian Cancer and Recent
Therapeutic Advances
Megan D. Indermaur, MD
&
Cheryl Ryder, ARNP
Women’s Care Florida
Women’s Cancer Associates
St. Petersburg, FL

2. Disclosures
• Megan Indermaur, MD
– AstraZeneca – Speaker
• Cheryl Ryder, ARNP
– None

3. Objectives
• Discuss Standard of Care for Ovarian Cancer
• Understand the rationale for genetic testing in
relation to ovarian cancer
• Understand the difference between germline
and somatic mutations
• Discuss PARP Inhibitors and their role in
Ovarian cancer treatment
• Understand the potential side effects of PARP
inhibitors and how to manage them

4. Epidemiology
30% Breast
13% Lung
7% Colon
7% Uterine Corpus
5% Thyroid
4% Non-Hodgkin lymphoma
4% Melanoma
3% Pancreas/Leukemia/Kidney
2.5% Ovary (22,240)
2018 Estimated US Cancer Cases in Women (878,980)
American Cancer Society, 2018

5. Epidemiology
The Problem!
2018 Estimated US
Cancer Deaths in
Women (286,010)
25% Lung
14% Breast
8% Colon
7% Pancreas
5% Ovarian (14,070)
4% Uterine Corpus
4% Leukemia
3% Liver & Bile duct
3% Non-Hodgkin
Lymphoma
3% Brain
American Cancer Society, 2018

6. 6. MD Anderson Cancer Center website. Available from: http://bit.ly/47IhNt.
7. Goff BA, Mandel LS, Drescher CW, et al. Cancer. 2007;109(2):221-227.
Types of Ovarian Cancer

7. Who is Diagnosed with Ovarian Cancer?
• Lifetime risk of ovarian cancer in general
population:
– 1.3 %
• Incidence varies based on race & age
– Caucasians > Native Americans > Hispanics > Blacks
– Median age at diagnosis
• 63
– Incidence increases with age!
– Women with Hereditary Familial disease are usually
diagnosed at a younger.

8. Survival
Is related to the stage at Diagnosis
Stage 5 year
Survival
I 83-90%
II 66-71%
III 32-47%
IV 18.6%
Heintz, et al. Carcinomaof the ovary. Int J Gynaecol Obstet 2006

9. Overall 5-year Survival
for all stages is
46.5%
Seer 18 2007-2013

10. Clinical Manifestations
• Most women are asymptomatic (especially
with early ovarian cancer) or have ill-defined,
non-specific symptoms:
– Bloating
– Abdominal or Pelvic pain
– Increased abdominal size
– Difficulty eating or feeling “full” quickly
– Urinary frequency or urgency

11. Risk Factors
• Genetic predisposition
• Age
• Nulliparity
• Infertility
• Early age of Menarche
• Late age of Menopause
• Postmenopausal Estrogen therapy
• Environmental factors
– Talc & Cigarette smoke
• Obesity

12. Protective Factors
• Oral Contraceptives1
– 45% risk reduction without family history
– 88% risk reduction with family history
• Tubal Ligation
– 33% risk reduction
• Hysterectomy
• Breastfeeding
Am J Obstet Gynecol 2002 Jan;186(1):8-14,

13. Women with a Pelvic mass
• Evaluation & treatment dependent on age.
• Pre-menopausal women:
– Dependent on size (10 cm)
• 70% will resolve over a few menstrual cycles1
– Findings suspicious for malignancy
• Complexity of the mass
• > 10 cm
• CA-125 > 200
• OVA1 ≥ 5.0
• Ascites
• Family/personal history of cancer
****Warrant Surgical evaluation****
Gynecol Oncol. 1994;55:S42-6

14. Women with a Pelvic mass
• Postmenopausal:
– Growing mass larger than 5 cm
– Complexity
– CA-125 > 35
– OVA1 ≥ 4.4
*** Need surgical evaluation****

15. Who should do your surgery?
Gynecologist
Vs.
General Surgeon
Vs.
Gynecologic Oncologist
25% reduction in Death among women with
Stage III Ovarian cancer
If treated by a Gynecologic Oncologist
Junor et al. Br J Obstet Gynaecol. 1999; 106:1130-1136

16. Staging/surgery
• Surgical staging vs. debulking
– Hysterectomy, bilateral salpingo-oophorectomy
– Omentectomy
– Pelvic and para-aortic lymph node dissection
• Apparent early stage must have LND
– 1/3 of the patients will have microscopic involvement of LN’s
up-staging the patient1
– Peritoneal biopsies/stripping
– Bowel Resection
– Liver or Spleen Resection
1. Morice P. et al, J Am Coll Surg. 2003;197(2):198

17. Cytoreduction
• Complete cytoreduction
– No residual disease (no visible disease)
• Optimal cytoreduction
– Residual disease </= 1 cm in size
• Sub-optimal cytoreduction
– Residual disease > 1 cm in size
Tingulstad S, et al. Obstet Gynecol 2003; 101:885.

18. Adjuvant Chemotherapy
• Platinum and Taxane
– Carboplatin and Taxol
• Route of Delivery
– Dependent on Suboptimal and Optimal Surgery
– Q 3 week regiment
– “dose dense” regimen
• Suboptimal: PFS 17.6 vs 12 mo & OS 51 vs 33 mo1
• Optimal: PFS 28 vs 17.5 mo & OS 100.5 vs 62 mo1
– Intraperitoneal regimen
• Only in optimally debulked patient’s
• Best PFS & OS statistics
Katsumata K, et al.Lancet Oncol 2013:14(10);1020

19. GOG 272 Overall Survival

21. BRCA1 expression and improved survival in
ovarian cancer patients treated with IP
chemotherapy: A GOG Study
Lesnock JL, Br J Cancer 108(6):1231, 2013

22. Bevacizumab
Vascular endothelial growth factor (VEGF)-targeting agent
* FDA approved in primary treatment with maintenance

23. Genetic Testing
1. Pal T, et al. Cancer. 2005;104(12):2807-2816
2. Cancer Genome Atlas Research. Nature 2011;474:609—615.
3. Alsop K, et al. J Clin Oncol 2012;30:2654—2663.
4. Pearl LH, et al. Nat Rev Cancer 2015;15;166—180.

24. Family history does not tell the whole
story
• Genetic testing based only on family history or
age at diagnosis may miss significant percentage
of patients with a HBOC syndrome mutation
• Almost 1/3 of women with hereditary ovarian
cancer do not have a significant family history
• 35% of patients with hereditary ovarian cancer
are diagnosed over the age of 60
SGO Clinical Practice Statement: Genetic Testing for Ovarian Cancer, 2014

25. BRCA 1 and 2 do not tell the whole
story
• Study looking at other tumor suppressor genes
that predispose a woman to ovarian cancer
• Of 360 women
• 24% carried germ-line loss of function mutations
• 18% BRCA 1 or 2
• 6% BARD1, BRIP1, CHEK 2, MRE11, MSH6, NBN,
PALB2, RAD50, RAD501 or TP53
• Walsh T, et al. Proc Natl Acad Sci USA 2011;108(44):180323-18037

26. • Recommended for all patients with diagnosis
of epithelial ovarian cancer
• NCCN-National Comprehensive Cancer
Network
• SGO-Society of Gynecologic Oncology
• ASCO-American Society of Clinical Oncology
Genetic Testing

27. Purpose of genetic testing
• Guides treatment
• Gives prognostic information
• Guides recommendations for prevention of
secondary cancers
• Guides recommendations for testing family
members

28. Targeted or Panel testing
• Cost of panel testing has decreased
• Patient may have a deleterious mutation in
unexpected gene
• May be eligible for clinical trials

29. Somatic Testing
• Testing done on the tumor to look for the
presence of a mutation

30. HRD
• Recently added companion diagnostic to look
for homologous repair deficiency
• May increase number of patients who may
benefit from niraparib

31. Who Should perform Genetic
counselling
• Genetic testing should be provided by a genetic
counselor, physician or other providers with expertise
in cancer genetics.
• Pre and post test counseling recommended
• Changing landscape of germline panel and somatic
testing makes comprehensive consent a challenge
SGO

32. Recurrence

33. Recurrence
• Diagnosed typically by serologic CA 125 results
– Confirmed with radiological exams
• Classified:
– “platinum-sensitive”
• PFI > 6 months
– “platinum-resistant”
• PFI < 6 months

35. Chemotherapy in recurrent setting
• Combination chemotherapy – “platinum-sensitive”
– Carboplatin and paxlitaxel
– Carboplatin and liposomal doxorubicin
– Carboplatin and gemcitabine
• Single Agents – “platinum-resistance” or 3rd plus line
– Paxlitaxel/Docetaxel
– Liposomal doxorubicin
– Gemcitabine
– Topotecan
– Anastrozole

36. Newest Advancement in
Ovarian Cancer Treatment

37. PARP Inhibitors
• PARP = polyadenosine diphosphate (ADP)-ribose polymerase
• PARP
– superfamily of 18 protein enzymes that catalyzes the repair of single-
strand DNA breaks, leading to cell survival and replication ability
• A cancer cell that harbors a DDR (DNA damage repair)
deficiency resulting in a dependency on a particular DDR
target or pathway for survival in this way
– provides the potential for single-agent activity of an inhibitor of
that target or pathway—an approach that has been described as
synthetic lethality.
• DDR deficiency is synonymous with homologous
recombination deficiency (HRD) or base-exicion repair (BER)
deficiency.

38. DNA Damage Facts
• Cells repair up to 10,000 DNA defects per day.
• Cells with homologous recombination repair (HRR)
deficiency (HRD) accumulate DS breaks leading to cell
death through apoptosis.
• HRD cells (BRCA1/2, RAD51, others) are unable to keep up
with DNA repair also results in mutation burden that leads
to cancers (breast, ovary, prostate, pancreas).
• Up to 50% of HGS ovarian cancers have some form of HRD.

39. Mechanism of Action
As ovarian tumor cells proliferate,
they accumulate DNA damage1
Tumor cells survive by
repairing their damaged
DNA via the PARP enzyme,
among other cellular
processes2
Tumor cell
growth and
survival
Disrupting the DNA repair
process with a PARP inhibitor
may help drive tumor and
cancer cell death2-4
Tumor
cell death
PARP inhibition and trapping, which leads to an increase in DNA damage, may help drive BRCA and
non-BRCA tumor cell death4,5
References: 1. Dai H et al. Gynecol Oncol. 2013;131(1):198-206. 2. Farmer HE et al. Nature. 2005; 434(4035):917-921. 3. Bryant HE et al. Nature.
2005;434(7039):913-917. 4. LYNPARZA [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.
5. Ledermann JA et al. Eur J Cancer. 2016;60:49-58.

40. The Drugs
Niraparib Olaparib Rucaparib
Maintenance
Therapy
Maintenance treatment of
adult patients with recurrent
epithelial ovarian, fallopian
tube or primary peritoneal
cancer, with complete or partial
response to platinum-based
chemotherapy (regardless of
BRCA status). **must initiate
within 8 weeks of completing
chemotherapy
Maintenance treatment of adult
patients with recurrent
epithelial ovarian, fallopian tube
or primary peritoneal cancer,
with complete or partial
response to platinum-based
chemotherapy (regardless of
BRCA status).
Not approved
Treatment Treatment of recurrent ovarian,
primary peritoneal, or fallopian
tube cancer with germline BRCA
gene mutations, and
have received previous
treatment with 3 or more prior
chemotherapy medicines for
their cancer
Treatment of recurrent
ovarian, primary peritoneal, or
fallopian tube cancer with
either inherited (germline) or
acquired (somatic) BRCA gene
mutations, and
have received previous
treatment with 2 or more
prior chemotherapy medicines
for their cancer
Dosage 300 mg (3 capsules) Q day 300mg (2 tablets) BID 600 mg (2 tablets) BID

41. PARP Maintenance Therapy

42. Niraparib: NOVA
ZEJULA Prescribing Information. Waltham, MA: TESARO, Inc. 2017
Mirza M, et al. N Engl J Med 2016;375:2154—2164
(HR = 0.26; 95% CI, 0.17-0.41), P < 0.0001
1
(HR = 0.45; 95% CI, 0.34-0.61), P < 0.0001
1

43. Niraparib: NOVA
• Subgroup PFS analysis
Progression-Free Survival,
months
Niraparib Placebo
gBRCAm 21 5.5
HR = 0.26 (0.17—0.41), P < 0.0001
Non-gBRCAm 9.3 3.9
HR = 0.45 (0.34—0.61), P < 0.0001
HRD-positive (includes
sBRCAm)
12.9 3.8
HR = 0.38 (0.24—0.59), P = 0.02
HRD-negative 6.9 3.9
HR = 0.58 (0.36—0.92), P = 0.02
Mirza M, et al. N Engl J Med 2016;375:2154—2164

44. Olaparib – SOLO-2 (gBRCA)
Pujade-Lauraine E et al. Presentation at: SGO; March 12-15, 2017; National Harbor, MD.
43% of patients
were progression
free on Olaparib
after 2 years vs
15% on placebo1

45. Study 19: PFS by Mutation Status
Olaparib BRCAm
Olaparib BRCAwt
Placebo BRCAm
Placebo BRCAwt
74 59 34 15 5 0
57 45 18 9 2 0
62 35 13 2 0 0
61 35 10 4 1 0
*BRCAm = BRCA mutation; #BRCAwt = BRCA wild-type
Adapted from Ledermann J et al. Lancet Oncol. 2014;15:852–861.
0
Time from randomisation (months)
0
1.0
Proportionofpatients
progression-free
3 6 9 12 15
Olaparib BRCAm
Olaparib BRCAwt
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Placebo BRCAm
Placebo BRCAwt
Number at risk
13% of all patients
remained on
Olaparib therapy
for at least 5
years.
~40% of patients
who remained on
Olaparib for 5
years were BRCA
wild type

46. PARP Monotherapy

47. Olaparib – Monotherapy
Kaufman et al J ClinOncol2014

48. Rucaparib: ARIEL2, Study 10
• ARIEL 2
– Ph II, single-arm, monotherapy
– >2 prior lines of chemotherapy, platinum-sensitive
advanced ovarian cancer
– ASCO update using refined LOH cutoff
• PFS: 12.8 months (BRCAm)
• PFS: 7.2 months (BRCAwt/LOHhigh) vs. 5 months
(BRCAwt/LOHlow) [HR=0.51 (0.34—0.74), p<0.001]
Coleman R, et al. J Clin Oncol 34, 2016 (suppl; abstr 5540).

49. POTENTIAL TOXICITIES

50. Hematologic Toxicity
Toxicity Grade Olaparib (1) Rucaparib (2) Niraparib (3)
Anemia All Grades 90% 67% 85%
Grade 3 and 4 15 23 25
Neutropenia All Grades 25 35 53
Grade 3 and 4 7 10 21
Thrombocytop
enia
All Grades 30 39 72
Grade 3 and 4 3 6 35
1. Lynparza [package insert]. Wilmington DE: Astrazeneca
Pharmaceuticals LP; 2014
2. Rubraca [package insert]. Boulder CO: Clovis Oncology, Inc;
2016
3. Zejula [package insert]. Waltham, MA: Tesaro, Inc; 2017

51. GI TOXICITY

52. GI ToxicityToxicity Grade Olaparib Rucaparib Niraparib
Nausea All Grades 64% 77% 74%
Grade 3 and 4 3 5 3
Vomiting All Grades 43 46 34
Grade 3 and 4 4 4 2
Decreased
appetite
All Grades 22 39 25
Grade 3 and 4 1 3 0.3
Dyspepsia All Grades 25 9 18
Grade 3 and 4 0 <1 0
Constipation All Grades 21 40 40
Grade 3 and 4 0 2 0.8
Diarrhea All Grades 31 34 20
Grade 3 and 4 1 2 0.3
Abdominal
pain
All Grades 43 32 33
Grade 3 and 4 8 3 2
1. Lynparza [package insert]. Wilmington DE: Astrazeneca Pharmaceuticals LP; 2014
2. Rubraca [package insert]. Boulder CO: Clovis Oncology, Inc; 2016
3. Zejula [package insert]. Waltham, MA: Tesaro, Inc; 2017

53. AML/MDS: Rare Serious Adverse Event
• Olaparib 2%
• Rucaparib <1%
• Niraparib <0.9%
• Refer to hematologist if counts have not
returned to grade 1 toxicity or less after 4
weeks of holding or dose reducing drug

54. Case Study #1
• Dx: Ovarian Cancer IIC age 46 in 2010
• Optimal cytoreductive surgery
• Genetic testing BRCA 1 mutation 187delAG
• Taxol and Carboplatin IV/IP, switched to Taxol and
Cisplatin IV 6 courses
• Disease free for 4 years then recurrence
• Carboplatin Doxil 6 courses
• Disease free for 3 years
• Started on Rucaparib

55. • Patient preference
• Nausea treated with 5HT3 antagonist
• Fatigue
• Monthly labs and provider appointments

56. Case Study #2
• Dx: Ovarian Ca IIIC age 48 in 1996
• Neoadjuvant chemo followed by debulking
surgery
• Taxol and Carboplatin IV
• Disease free for 4 years
• 6 additional lines of chemotherapy
• Genetic testing initially BRCA 1 and 2
only=negative (research)

57. Case #2
• Panel testing RAD51D mutation
• Started Rubraca (rucaparib)
• Fatigue, weakness, elevated LFTs, anemia
• Dose adjusted recently due to the anemia and
weakness

58. Case #3
• Dx: Ovarian Cancer age 64 in 2014
• Optimal debulking
• Taxol and Carbo IV/IP
• Disease free 18 months
• 4 additional lines of therapy
• Testing: -gBRCA +sBRCA
• Began Lynparza (olaparib)

59. • Nausea, constipation—5HT3 antagonist,
bowel regimen
• Anemia—Procrit
• Fatigue– Plan activities
• Stayed on Lynparza for 9 months
• Now doing well on weekly paclitaxel

60. ???Questions???
Thank You!
Megan D. Indermaur, MD
&
Cheryl Ryder, ARNP
Women’s Care Florida
Women’s Cancer Associates
St. Petersburg, FL