Join Dr. Kara Long Roche, Associate Director of the Gynecologic Oncology Fellowship Program at Memorial Sloan Kettering Cancer Center, as she breaks down new advancements in ovarian cancer research and treatment.

1. Updates in Ovarian Cancer Treatment
A 2020 research update
Kara Long Roche, MD, MSc, FACOG
Assistant Attending,
Section of Ovarian Cancer Surgery, Department of Surgery
Memorial Sloan Kettering Cancer Center

2. • Ovarian Cancer in 2020
• Challenges and considerations in research
• Upfront Treatment
• Advances in surgery and adjuvant treatment
• Maintenance therapy
• Recurrent Disease
• Surgery: the debate
• Advances in systemic treatment
• Novel Concepts
• Prevention

3. Ovarian Cancer in 2020
Ovary: 13, 940 deaths
Uterus: 12, 590 deaths
Ovary: 21,750 new cases
Uterus: 65, 620 new cases
SEER.cancer.gov/statfacts/

4. Ovarian Cancer
Cancer.gov/images
• ~1.5% risk general population
• No screening test
• No symptoms of early stage disease
• Majority of patients present with advanced disease
• Remains the most lethal Gyn malignancy
• Need for NOVEL TREATMENTS
• Need for PREVENTION

5. Ovarian Cancer is Not Just One Disease
High Grade Serous Clear Cell Endometrioid Mucinous Low Grade Serous
% of Cases
FIGO stage I-II
FIGO stage III-IV
39%
86%
33%
2%
22%
7%
5%
2%
1%
3%
Genetic Risk Factors BRCA 1/2 Lynch Lynch None known None known
Precursor Lesion Serous Tubal
Intraepithelial
Carcinoma (STIC)
Endometriosis Endometriosis Unknown Serous Borderline Tumor
Endosalpingiosis
Molecular Genetics p53, BRCA, HR Defects,
Tumor
Microenvironment
PI3K, ARID1A, MSI PTEN, beta-catenin,
ARID1A, MSI
KRAS, HER2 BRAF, KRAS, NRAS
Table courtesy of Dr C Aghajanian

6. The Importance of Outcomes
• Response to a treatment
• Response rate (RR)
• Healthy Time
• Progression free survival (PFS)
• Treatment free interval (TFI)
• All Time
• Overall survival (OS)
• Quality of Time
• Patient reported outcomes (PRO)
• Heath related Quality of Life (HRQoL)
What do we value the most?
What measure is the most useful?
What measure gets us ahead the fastest?

7. Clinical trial Endpoints
Herzog et al. Gyn Onc. 2014

8. Patient Preferences
• In surgery versus NACT:
• Patients are willing to accept a higher rate of complications and post-op
mortality in exchange for a survival benefit
• 15% increased complications and 4% increased post-op mortality for increase in survival
from 3 to 3.5 years
• For maintanance PARPi:
• Patients were willing to tolerate side effects of PARPi and risk of MDS/leukemia
for clinically observed PFS benefit
• In therapies for recurrence:
• PFS drives choice (over symptoms and side effects), however patients were
willing to trade PFS for significant reductions in treatment toxicity
Havrilesky et al. Cancer. 2014
Havrilesky et al. Cancer, 2019.
Havrilesky et al. JCO. 2019

9. Upfront Treatment

10. Debulking Surgery
Platinum/Taxane
Chemotherapy
Debulking Surgery Platinum/Taxane Chemotherapy Maintenance tx
+/- BevacizumabGoal: complete
gross resection
+/- HIPEC
PARPi vs Bev

11. Surgery or Chemo (NACT) First?
Long Roche, Gardner. Gyn Onc. 2019

12. Impact of Residual Disease Persists
Long Roche, Gardner. Gyn Onc. 2019
Surgical Effort and Quality Matters

13. Heated Intraperitoneal Chemotherapy
(HIPEC)
• Heated chemotherapy delivered directly into the
abdomen during debulking surgery
• Heat increases penetration into the tissues
• Heat increases the sensitivity of the cancer cells to
the treatment by impairing DNA repair
• Heat induces cell death, activates heat shock proteins,
inhibits angiogenesis, and has a direct cytotoxic effect
by denaturing proteins
Van Driel et al. NEJM. 2018.
Britannica.com

14. HIPEC at Interval Debulking after NACT
Van Driel et al. NEJM. 2018.
• 245 patients were randomized to IDS +/- HIPEC
• Recurrence free survival 10.7 versus 14.2 months
• Overall survival 33.9 versus 45.7 months
• Adverse events similar

15. Immune Therapy in Upfront Treatment
• Atezolizumab
• Monoclonal Antibody that binds with/inhibits PD-L1  enables T-cells
• Checkpoint Inhibitor
• IMagyn050 Trial
• Randomized to Carbo + Taxol + Bevacizumab +/- Atezolizumab
• Failed to show a PFS benefit
https://www.tecentriq-hcp.com/

16. Immune Therapy in Upfront Treatment
• Durvalumab
• PD-L1 inhibitor
• DUO-O Trial
• Carbo/Taxol/Bev +/- Durvalumab (PD-L1 inhibitor)
• Carbo/Taxol/Bev +/- PARPi
• Carbo/Taxol/Bev +/- combo (Durvalumab/PARPi)
Is the combination synergistic?

17. Maintenance Therapies: PARP Inhibitors
Delivering widespread BRCA testing and PARP inhibition to patients with ovarian cancer Nat. Rev. Clin. Oncol. 2016
• Active in pts with high grade serous
carcinoma with homologous
recombination repair deficiencies
– ~50% of patients can benefits
through germline and somatic
mutations

18. SOLO1
Moore et al, NEJM, 2018.
• Randomized trial of Olaparib
versus placebo as maintenance in
patients with BRCA mutations
who had a complete or partial
response to chemo
• 70% lower risk of death or POD

19. Maintenance Therapy: Bevacizumab
Mukherji et al. Am J Neurorad. 2010.
By inhibiting VEGF  blocks growth of tumor blood supply

20. Slide courtesy of Dr R Grisham PAOLA-1 PRIMA VELIA
Treatment: Chemo + Bev  Olaparib + Bev
Chemo + Bev  Placebo + Bev
Chemo  Niraparib
Chemo  Placebo
Chemo+Veliparib  Veliparib
Chemo+Veliparib  Placebo
Chemo+ Placebo  Placebo
Duration of Maintenance: 2 years ≥3 years 90 weeks (30 cycles)
Time of Randomization: ≥3 weeks to <9 weeks from last
chemo (4-9 cycles chemo)
≤12 weeks from day 1 last cycle chemo
(6-9 cycles chemo)
Start of upfront therapy (6 cycles
chemo)
Inclusion Criteria (primary
or interval debulking
allowed for all):
HGS/endometrioid, Stage IIIB-IV
(PDS or NACT), ≥ 3 bevacizumab
with chemo; CR or PR
HGS/endometrioid, Stage III (with
visible residual disease after PDS,
inoperable, or NACT), IV; CR or PR AND
CA125 normal or > 90% decrease;
Stage III NGR – NOT eligible
HGS, Stage III-IV (PDS or NACT);
treatment until PD (eligible for
maintenance if SD, PR, CR)
Primary Endpoint: PFS from end of chemo PFS in HRD patients & in overall
population from end of chemo
PFS for veliparib throughout vs
control from beginning of treatment
HRD Assay: Myriad MyChoice Score ≥42
and/or BRCA
Myriad MyChoice Score ≥42 and/or
BRCA
Myriad MyChoice Score ≥33 and/or
BRCA
Median PFS:
HRD+ (includes tBRCA) 37.2 vs 17.7 mos
HR 0.33 (CI; 0.25,0.45)
22.1 vs 10.9 mos
HR 0.40 (CI;0.27,0.62)
31.9 vs 20.5 mos
HR 0.57 (CI;0.43, 0.76)
HRD +(excludes tBRCA) 28.1 vs 16.6 mos
HR 0.43 (CI; 0.28,0.66)
19.6 vs 8.2 mos
HR 0.50 (CI; 0.31,0.83)
22.9 vs 19.8 mos
HR 0.74 (CI; 0.52, 1.06)
HRD- 16.9 vs 16 mos
HR 0.92 (CI; 0.72, 1.17)
8.1 vs 5.4 mos
HR 0.68 (CI; 0.49, 0.94)
15 vs 11.5 mos
HR 0.81 (CI; 0.60, 1.09)

21. Current FDA Approvals for Frontline
Maintenance
• Olaparib: approved as first line maintenance following CR or PR to chemotherapy for
patients with advanced epithelial ovarian cancer with gBRCA/sBRCA mutation
(12/19/2018)
• Olaparib in combination with bevacizumab: approved as first line maintenance
following CR or PR to chemotherapy for patients with homologous recombination
deficiency positive status defined by either a deleterious or suspected
deleterious BRCA mutation, and/or genomic instability. (5/8/2020)
• Myriad myChoice CDx approved as a companion diagnostic for olaparib
• Bevacizumab: approved as first line treatment in combination with carboplatin and
paclitaxel followed by bevacizumab maintenance for any patient with advanced
epithelial ovarian cancer (6/13/2018)
• Niraparib: approved as first line maintenance following CR or PR to chemotherapy
for any patient with advanced epithelial ovarian cancer (4/29/2020)
• Rucaparib: Not FDA approved in the first-line setting
• Veliparib: Not FDA approved
Slide courtesy of Dr R Grisham

22. Treatment of Recurrent Disease:
Platinum Sensitive

23. GOG 213
2 Questions, 1 Study
What is the role of Bevacizumab in
the treatment of platinum sensitive
recurrence?
Median overall survival in the
chemotherapy plus bevacizumab
group was 42·2 months versus 37·3
months in the chemotherapy group
Coleman et al. Lancet Oncol. 2017.

24. Eligibility for Surgical Randomization:
Treatment-free interval of at least 6 months
from completion of front-line chemotherapy
Resection deemed feasible.
Slide courtesy of Dr G Gardner
GOG 213
2 Questions, 1 Study

25. GOG 213: Surgical Outcomes
• Surgery was a safe option, but did not improve outcomes
by Randomized Surgical Treatment
Overall Survival
240 180 122 78 47 23 16
245 188 143 91 52 32 19
1
2
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
ProportionSurviving
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
ProportionSurviving
2: No Surgery
1: Cytoreductive Surgery
Treatment Group
65.724569
53.624078
Median(mos)TotalEvents
by Randomized Surgical Treatment
Progression-Free Survival
240 128 52 31 17 8 6
245 132 57 27 11 6 3
1
2
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
ProportionSurvivingProgression-Free
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
ProportionSurvivingProgression-Free
2: No Surgery
1: Cytoreductive Surgery
Treatment Group
16.5245161
18.2240142
Median(mos)TotalEvents

26. Surgery for Recurrent Ovarian Cancer
• DESKTOP I
• Establish goal of surgery
• Establish criteria for surgery (AGO score)
• DESKTOP II
• Validation of the AGO score
• Describe outcomes
• DESKTOP III
• Randomized trial of secondary debulking
versus no surgery for recurrent disease
Prof. duBois
Arbeitsgemeinschaft Gynäkologische
Onkologie (AGO)
The case for high quality surgical trials

27. Surgery for Recurrent Ovarian Cancer
• DESKTOP I
• Establish goal of surgery
• Establish criteria for surgery (AGO score)
• DESKTOP II
• Validation of the AGO score
• Describe outcomes
• DESKTOP III
• RCT of secondary debulking versus no
surgery for recurrent disease
Complete resection in 76% of the study cohort = AGO score
could predict with 95% probability A complete resection in at
least 2 out of 3 patients

28. Design: AGO DESKTOP III
(ENGOT-ov20; NCT01166737)
3rd
line
Pts. with:
• 1st relapse
• PSROC
• AGO Score +ve
Andreas du Bois
AGO & KEM Essen, Germany
PFS 18.4 months versus 14 months (P <.001)
OS 53.7 months versus 46 months (P=.02)

29. MSKCC Secondary Cytoreductive
Surgery (SCS) Selection Criteria
Disease-Free Interval
Single Site of
Recurrence
Multiple Sites of
Recurrence But No
Carcinomatosis
Carcinomatosis
6-12 months Offer SCS Consider SCS No SCS
12-30 months Offer SCS Offer SCS Consider SCS
>30 months Offer SCS Offer SCS Offer SCS
Chi DS et al, Cancer 2006

30. PARPi in Recurrent Disease
AZ LIGHT Phase II Study: Olaparib in
Patients with Platinum-Sensitive Ovarian
Cancer
gBRCA
(n=75)
sBRCA
(n=25)
HRD+
(non-
BRCA)
(n=68)
HRD-
(n=89)
≥2 prior
lines of
chemo
n (%)
35 (47) 14 (56) 37 (54) 60 (67)
ORR
n (%)
52 (69) 16 (64) 20 (29) 9 (10)
Median
PFS, mo
11.0 10.8 7.2 5.4
QUADRA Phase II Study: Niraparib for
late-line ovarian cancer: Response Rate
BRCAm
(n=63)
HRD+
BRCAm (63)
BRCAwt (126)
(n=189)
HRD - or
unknown
(n=230)
Platinum
sensitive
7/18 (39%) 14/53 (26%) 2/52 (4%)
Platinum
resistant
10/37 (27%) 12/120 (10%) 5/169 (3%)
Unknown 1/8 (13%) 3/16 (19%) 1/9 (11%)
All 18/63 (29%) 29/189 (15%) 8/230 (3%)
Moore et al, Lancet Oncology 2019;20:636-48.
Cadoo et al, J Clin Oncol38:2020(suppl; abstr 6013)

31. Treatment of Recurrent Disease:
Platinum Resistant

32. ATR inhibitor
• Interferes with the ability of cells to detect DNA damage (reduces
viability of cancer cells)
• Phase II trial
• ATR inhibitor berzosertib + Gemcitabine
• Significantly improved PFS
• Toxicity decreased WBC/platelet/anemia
Can this overcome platinum and/or PARPi resistance?
https://pubchem.ncbi.nlm.nih.gov/compound/Berzosertib
Konstantinopoulos et al. Lancet Oncol. 2020

33. WEE-1 Kinase Inhibitors
• Adavosertib
• Increases chemotherapy sensitivity
• Increases genomic instability  increases senstivity
to DNA damage from DNA damaging agent
• Phase II studies in combination with
chemotherapy
https://www.cell.com/trends/genetics/fulltext/S0168-9525(13)00038-3

34. Immune therapy
• Single agent studies have been promising
• Response rates to immune checkpoint inhibitors 6-22%
• Some disappointments
• JAVELIN 200
• 566 patients with platinum resistant disease
• Randomized to Avelumab vs Avelumab + Doxil vs Doxil alone
• Interim analysis demonstrated futility
• GY003 Nivo versus Ipi/Nivo
• Combination resulted in superior response and longer PFS
Is the key dual immune agents?
Pujade-Lauraine et al. SGO 2019.
Zamarin et al, JCO. 2020

35. Novel Concepts

36. Statins
• Finnish National Cancer Registry
• 10,062 women with ovarian cancer (1995-2015)
• Use of any statin associated with 40% reduction in ovarian cancer
mortality compared with patients who never used statins
Visvanathan et al. AACR abstract. 2020
https://www.economist.com/the-economist-explains/2018/03/26/why-is-finland-so-happy

37. Hiller et al, Nat Rev, 2017
The Impact of Stress

38. The Impact of Stress
• Perioperative Stress reduction bundles
• Beta blockers
• COX2 inhibitors
• Anesthesia modifications
• Epidural
• TIVA
• Warming
• Pre- and Post-operative Integrative Medicine
• Mind Body Relaxation
• Acupuncture

39. Prevention

40. The Importance of Identifying Risk
BRCA1
Germline
8%
BRCA2
Germline
6%
BRCA1 Somatic
4%
BRCA2 Somatic
3%
BRCA1
Methylation
11%
EMSY
Amplification
6%
PTEN Loss
6%Other HRD
5%
CCNE1
Amplification
14%RB1 Loss
4%
MMR
Germline
2%
Other
31%
• ~15-20% of ovarian cancer is
inherited through known
gene mutations
• If we identified every women
with a predisposing mutation,
we could prevent up to 4,200
of the 21,000 annual cases in
the US

41. Precursor Escape May Be the Answer
• Premalignant serous proliferations (ESP) with TP53 mutations identified in
the tubal fimbriae  Exfoliated ESPs may subsequently undergo malignant
transformation in the peritoneum
• TP53 mutation remains the precursor “event”
• Timing of dissemination uncertain
Soong et al, Gyn Oncol 2019.

42. Up to 5% risk by age 80 (compared to
~1.4% risk general population)

43. Finding the Answers

44. https://www.nytimes.com/2020/07/10/opinion/facebook-cancer-ads.html?searchResultPosition=5

47. MSK TEAM OVARY

48. Thank You
Thank you to all of the
courageous patients and
their loved ones who make
this work possible….and
who make our jobs the
best in the world.