When ovarian cancer returns, it's not uncommon to experience a range of emotions and feel overwhelmed. But it's important to remember that recurrent ovarian cancer can often be successfully treated. Dr. Shannon N. Westin, gynecologic oncologist and clinical investigator at MD Anderson Cancer Center, goes over the latest treatment options for recurrent disease.

1. Current Developments in Recurrent Ovarian Cancer
Shannon N. Westin, MD, MPH
Associate Professor
Director, Early Drug Development and Phase 1
Department of Gynecologic Oncology and Reproductive
Medicine

2. Disclosure Information
Research Support: AstraZeneca, ArQule, Bayer,
Clovis Oncology, Cotinga Pharmaceuticals,
GSK/Tesaro, Novartis, Roche/Genentech
Consultant: Agenus, AstraZeneca, Circulogene, Clovis
Oncology, Eisai, GSK/Tesaro, Merck, Novartis,
Pfizer, Roche/Genentech, Zentalis

3. Objectives
• Recurrent Ovarian Cancer Basics
• ”Platinum-sensitive” options
• Can we avoid chemotherapy?
• ”Platinum-resistant” options

4. Recurrent Ovarian Cancer Basics

5. Recurrent ovarian cancer: three biologies
Platinum-sensitive
Cured?
Primary-resistant/
-refractory

6. Considerations After Progression
• Treatment free interval
• Residual toxicity from prior therapy
• Volume of disease at the time of relapse
• Serologic relapse (Ca-125)
• Quality of life
• Patient goals

7. Platinum-Free Interval and Efficacy:
Shorter Interval, Lower Response
Platinum-Free Interval Response Rate
5-12 months 27%
13-24 months 33%
> 24 months 59%
Time to Re-challenge Response Rate
< 1 year 17%
1-2 years 27%
> 2 years 57%
1. Pujade-Lauraine E et al. Proc Am Soc Clin Oncol. 2002;21(Suppl). 2. Markman M et al. J Clin Oncol. 1991;9(3):389-393. 3. Gore ME et
al. Gynecol Oncol. 1990;36(2):207-211.
Survival
(days)
Respons
e rate (%)
Sensitive
Platinum-free interval (months)
1000
800
600
400
200
0
100
80
60
40
20
Resistant/r
efractory
Partially
sensitive
OS
Response
rate
PFS217
9
90
166
32
366
0–3/Pr 0–3 3–6 6–9 9–12 12–18 ≥18
Platinum-Free Interval and Efficacy1 Response Rate of Patients After Receiving
a Second Cisplatin-Based Regimen2
Response Rate of Patients According to
Progression-Free Interval after First Treatment3

8. • Platinum-free interval is no longer the only factor to
consider when selecting therapy
• The historical definition of using platinum-free
interval (PFI) to categorize patients as having
platinum-sensitive or resistant disease is now
replaced by therapy-free interval (TFI)
– Patients for whom platinum is an option
• formerly platinum-sensitive
– Patients for whom platinum is not an option
• formerly platinum-resistant
Platinum-Free Interval and Efficacy:
Shorter Interval, Lower Response

9. ”Platinum-sensitive” Options

10. *Carboplatin can be paired with paclitaxel, pegylated liposomal doxorubicin, or gemcitabine
Platinum-based Doublet Therapy
+/- Bevacizumab
Platinum-sensitive
Measurable
Continue until
disease progression
Carboplatin
– Doublet*
Bevacizumab until progression
Carboplatin
– Doublet*
FDA Indication

11. PLD: pegylated liposomal doxorubicin
OCEANS
Aghajanian, JCO 2012
GOG213
Coleman, SGO 2015
ENGOT-ov18
Pfisterer, ESMO 2018
Platinum-based Doublet Therapy
+/- Bevacizumab
Trial Treatment PFS (mo) HR OS (mo) HR
OCEANS
(n=484)
Gem/Carbo 8.4 0.48
P<0.0001
33.6 0.96
P=0.65
Gem/Carbo/Bev 12.3 32.9
GOG213
(n=674)
Pac/Carbo 10.4 0.61
P<0.0001
37.3 0.82
P=0.044
Pac/Carbo/Bev 13.8 42.2
ENGOT-ov18
(n=682)
Gem/Carbo/Bev 11.7 0.807
P=0.0128
28.2 0.833
P=0.787
PLD/Carbo/Bev 13.3 33.5

12. Platinum-based Doublet Therapy followed
by PARP Inhibitor Maintenance
Platinum-sensitive high-grade
ovarian cancer
PR or CR to last chemotherapy
regimen (must be platinum-based)
PARP
inhibitor
Placebo
Continue until
disease progression
1o Endpoint:
PFS
FDA Indication

13. *Primary endpoint for HRQoL was trial outcome index (TOI) of the
FACT-O (Functional Assessment of Cancer Therapy – Ovarian)
platinum therapy
Sensitivity analysis: PFS by blinded independent central review (BICR)
• Key secondary endpoints:
– Time to first subsequent therapy or death (TFST), time to second progression (PFS2),
time to second subsequent therapy or death (TSST), overall survival (OS)
– Safety, health-related quality of life (HRQoL*)
SOLO2/ENGOT-Ov2
Placebo
n=99
Olaparib
300 mg bid
n=196 Primary endpoint
Investigator-assessed
PFS
Patients
• BRCA1/2 mutation
• Platinum-sensitive relapsed
ovarian cancer
• At least 2 prior lines of
platinum therapy
• CR or PR to most recent
Randomized2:1

14. No. at risk
33 36
2 0
0 0
100
90
80
70
60
50
40
30
20
10
0
Progression-freesurvival(%)
19.1
12 15 18
Months since randomization
0 3 6 9 21 24 27 30
Olaparib
Placebo
5.5
SOLO2: PFS
Median follow-up was 22.1 months in the olaparib group and 22.2 months for placebo
Olapari
b
196 182 156 134 118 104 89 82 32 29 3
Placeb
o
99 70 37 22 18 17 14 12 7 6 0
Olaparib
(n=196)
Placebo
(n=99)
Events
(%)
107 (54.6) 80 (80.8)
Median PFS,
months
19.1 5.5
HR 0.30
95% CI 0.22 to 0.41
P<0.0001
Olaparib approved by FDA in August 2017 for maintenance therapy in
platinum-sensitive ovarian cancer

15. Niraparib: NOVA Phase 3 Maintenance Study
in Platinum-Sensitive Ovarian Cancer
Mirza MR, et al. N Engl J Med. 2016
• Platinum-sensitive ovarian, primary
peritoneal, or fallopian tube cancer
• Serous high-grade histology or known to have
gBRCAmut
• ≥2 prior platinum regimens
• In CR or PR and enrolled within
8 weeks of completion of last platinum regimen
• No prior PARP inhibitor
• Planned N=490
Niraparib 300 mg
PO daily to
progression
Placebo once
daily to
progression
R
2:1
N=490
Primary end point: PFS
Secondary end points: OS, PFS2, chemotherapy-free interval, health-related quality of life, and safety and tolerability
Analysis to include: all patients, gBRCAmut patients, and the non-gBRCAmut cohort (first as HRD+ patients and then all non-
gBRCAmut patients)
CR, complete response; gBRCAmut, germline breast cancer susceptibility gene mutation; HRD, homologous
recombination deficiency; OS, overall survival; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; PO,
by mouth; PR, partial response; R, randomization

16. Progression-Free Survival: gBRCAmut
Mirza MR, et al. N Engl J Med. 2016 Oct 7.
Treatment
PFS
Median
(95% CI), mo
Hazard Ratio
(95% CI)
P-value
% of
Patients Without
Progression or
Death
12
mo
18
mo
Niraparib
(n=138)
21.0
(12.9, NR) 0.27
(0.173, 0.410)
P<.0001
62% 50%
Placebo
(n=65)
5.5
(3.8, 7.2)
16% 16%
PFS was analyzed using a 2-sided log-rank test using randomization stratification factors, and summarized using the
Kaplan-Meier methodology. Hazard ratios with 2-sided 95% confidence intervals were estimated using a stratified Cox
proportional hazards model, with the stratification factors used in randomization.
gBRCAmut, germline breast cancer susceptibility gene mutation; NR, not reached; PFS, progression-free survival

17. Progression-Free Survival: Non-gBRCAmut
Mirza MR, et al. N Engl J Med. 2016 Oct 7
PFS was analyzed using a 2-sided log-rank test using randomization stratification factors, and summarized using the
Kaplan-Meier methodology. Hazard ratios with 2-sided 95% confidence intervals were estimated using a stratified Cox
proportional hazards model, with the stratification factors used in randomization.
gBRCAmut, germline breast cancer susceptibility gene mutation; NR, not reached; PFS, progression-free survival
Treatment
PFS
Median
(95% CI), mo
Hazard Ratio
(95% CI)
P-value
% of
Patients Without
Progression or
Death
12
mo
18
mo
Niraparib
(n=234)
9.3
(7.2, 11.2)
0.45
(0.338, 0.607)
P<.0001
41% 30%
Placebo
(n=116)
3.9
(3.7, 5.5)
14% 12%
Niraparib approved by FDA in March 2017 for maintenance therapy in
platinum-sensitive ovarian cancer

18. ARIEL3: STUDY DESIGN
18
• HRR status by NGS mutation analysis
 Mutation in BRCA1 or BRCA2
 Mutation in non-BRCA HRR gene†
 No mutation in BRCA or HRR gene
• Response to recent platinum
 CR
 PR
• Progression-free interval after
penultimate platinum
 6 to <12 months
 ≥12 months
Patient eligibility Stratification
• High-grade serous or endometrioid
epithelial OC, primary peritoneal, or
fallopian tube cancers
• ≥2 prior lines of platinum-based treatments
• No prior PARP inhibitors
• Sensitive to penultimate platinum
• Responding to most recent platinum
(CR or PR)*
 Excludes patients without assessable
disease following surgery before more
recent platinum-based therapy
• ECOG PS ≤1
• CA-125 within normal range
• No restriction on size of residual tumour Placebo
BID
n=189
Rucaparib
600 mg
BID
n=375
Randomisation2:1
Coleman Lancet Oncology 2017

19. ARIEL3: Investigator-Assessed PFS
Coleman Lancet Oncology 2017
BRCA mutant HRD
Median
(months) 95% CI
Rucaparib
(n=236)
13.6 10.9–16.2
Placebo
(n=118)
5.4 5.1–5.6
HR, 0.32;
95% CI, 0.24–0.42;
P<0.0001
Median
(months) 95% CI
Rucaparib
(n=375)
10.8 8.3–11.4
Placebo
(n=189)
5.4 5.3–5.5
HR, 0.36;
95% CI, 0.30–0.45;
P<0.0001
At risk (events)
Rucaparib 130 (0) 93 (23) 63 (46) 35 (58) 15 (64) 3 (67) 0 (67)
Placebo 66 (0) 24 (37) 6 (53) 3 (55) 1 (56) 0 (56)
Rucaparib, 48% censored Placebo, 15% censored
At risk (events)
Rucaparib 236 (0) 161 (55) 96 (104) 54 (122) 21 (129) 5 (134) 0 (134)
Placebo 118 (0) 40 (68) 11 (95) 6 (98) 1 (101) 0 (101)
Rucaparib, 43% censored Placebo, 14% censored
At risk (events)
Rucaparib 375 (0) 228 (111)128 (186) 65 (217) 26 (226) 5 (234) 0 (234)
Placebo 189 (0) 63 (114) 13 (160) 7 (164) 2 (167) 1 (167) 0 (167)
Rucaparib, 38% censored Placebo, 12% censored
Median
(months) 95% CI
Rucaparib
(n=130)
16.6 13.4–22.9
Placebo
(n=66)
5.4 3.4–6.7
HR, 0.23;
95% CI, 0.16–0.34;
P<0.0001
ITT
Rucaparib approved by FDA in April 2018 for maintenance therapy in
platinum-sensitive ovarian cancer

20. PARPi Maintenance is the Real Deal
Coleman Lancet Oncology 2018;
Mirza NEJM 2016,
Pujade-Lurain NEJM 2017
Rucaparib Niraparib
Olaparib
HR 0.30
HR 0.32
HR 0.27

21. Olaparib tablets*
Placebo
gBRCA+ or sBRCA+
(N=136)
• 1 prior PARPi treatment
• 18mo+ after 1st line CT
12 mo+ after 2nd line CT
Stratification factors
 Prior bevacizumab
 <3 vs ≥3 chemo lines
*300 mg bid or last tolerable dose
R
A
N
D
O
M
I
Z
A
T
I
O
N
OReO Study:
Olaparib Retreatment in Platinum-Sensitive Ovarian
Cancer
wtBRCA- all-comers
(N=280)
• 1 prior PARPi treatment
• 12mo+ after 1st line CT
06 mo+ after 2nd line CT
RP/RC
Platinum-based
chemotherapy
(no Bev)
PFS,TFST,FACT-O,Safety,AESI,OS
Powered 80% for PFS primary endpoint.
BRCA+ HR=0.5, 74 events.
BRCA- HR=0.65, 191 events.
416 patients
ClinicalTrials.gov : NCT03106987
2
:
1

22. Incorporating
Maintenance Therapy
• Factors to consider
– Indication
– BRCA/HRD Status
– Toxicity
– Schedule
– Type of prior therapy
– Existing adverse events
– Cost

23. Can We Avoid Chemotherapy?

24. Olaparib is active in BRCA-mutated
ovarian cancer with ≥3 prior lines
• 193 ovarian cancer
pts
– 137 pts with ≥3 prior
lines
• ORR: 31.1%
• ORR ≥3 prior lines:
34%
– Plat-sensitive: 46%
– Plat-resistant: 30%
– Plat-refractory: 14%
• PFS ≥3 prior lines:
6.7 m
– Plat-sensitive: 9.4 m
– Plat-resistant: 5.5 m
Kaufman et al., J Clin Oncol 2015
Domchek et al., Gyn Oncol 2016Olaparib approved by FDA in December 2014 for this
indication.

25. Response is related to prior lines…

26. Olaparib: SOLO-3 Phase 3 Trial
• Primary endpoint: PFS
• Secondary endpoints: OS, time to earliest progression by RECIST or CA-125 or death, PFS2, best ORR,
health-related quality of life by TOI of the FACT-O, TDT, TFST, TSST, and safety and tolerability
• Recurrent ovarian cancer after
≥2 lines of platinum therapy
• Serous or endometrioid
high-grade histology
• Measurable disease
• No prior PARP inhibitor
• Documented deleterious
BRCA mutation
Olaparib 300 mg
PO bid to
progression
Physician’s choice:
weekly paclitaxel,
topotecan, PLD, or
gemcitabine to
progression
R
2:1
n=176
n=88
~50%
entered in 4th
line or greater
Presented By Richard Penson at 2019 ASCO Annual Meeting

27. Efficacy Endpoints for SOLO 3
Presented By Richard Penson at 2019 ASCO Annual Meeting

28. Rucaparib is active in BRCA-mutated
ovarian cancer with > 2 prior lines
McNeish IA, et al. J Clin Oncol.
2015;33(suppl):abstract 5507.
HRD
Subgroup
Median PFS
(90% CI)
ORR
RECIST, n (%)
ORR
RECIST+CA-125,
n (%)
BRCAmut 9.4 mo (7.3–NR) 27/39 (69) 32/39 (82)
Rucaparib approved by FDA in May 2017 for BRCA mutant ovarian cancer
with > 2 lines of therapy
HRD
Subgroup
Median PFS
(90% CI)
ORR
RECIST, n (%)
ORR
RECIST+CA-125,
n (%)
BRCAmut 9.4 mo (7.3–NR) 27/39 (69) 32/39 (82)
BRCA-like 7.1 mo (3.7–10.8) 22/74 (30) 33/74 (45)
Biomarker-
negative
3.7 mo (3.5–5.5) 8/62 (13) 13/62 (21)

29. QUADRA: Niraparib
Moore Lancet Oncology 2019
Niraparib approved by FDA in October 2019 for HRD positive ovarian
cancer with > 2 lines of therapy

30. NRG-GY004: No improved PFS

31. AVANOVA: Niraparib + Bevacizumab
improves PFS
Mirza M, et al. ASCO 2019.
Abstract 5505.

32. “Platinum-resistant” Options

33. Agent RR (%)
Median
PFS (mths)
OS (mths)
PLD 10-20 3-4 10-12
Topotecan 12-18 3-4 10-12
Docetaxel 22 3.5 12.7
Gemcitabine 15 4-5 11.8-12.7
Pemetrexed 15-21 2.9 11.4
Etoposide 6-27 4-5 10-11
Paclitaxel
(weekly)
10-30 4-6 13
Nab-paclitaxel 23 4-5 17.4
Bevacizumab 21 4.7 17
Most Common Single-Agent Chemotherapies
In Platinum Resistant Ovarian Cancer
Coleman NatRevClinOnc 2013

34. AURELIA: Practice Changing Trial
≤2 prior lines, Exclusion: platinum-refractory, prior (sub)obstruction, or bowel involvement
N=360, randomised 1:1
Bevacizumab for Patients With Relapsed Ovarian
Cancer for Whom Platinum Is Not an Option
Improved PFS by adding bevacizumab to non-platinum based chemo + QoL benefit in symptomatic patients
60
50
40
30
0
Substantial Symptoms
at Baseline
Patientswith
≥15%Improvement(%)
20
10
Ascites at Baseline
12.7
29.6
44.0
Diff: 16.9%
95% CI, 6.1–27.6
Diff: 39.9%
95% CI, 23.9–55.9
4.1
(n=118)(n=115) (n=49) (n=50)
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24
Time (months)
Progression-FreeSurvival
(probability)
182 93 37 20 8 1 1 0 0Chemo
No. at risk
179 140 88 49 18 4 1 1 0Chemo + Bev
3.4 6.7
Progression-Free Survival1
Chemo Chemo + Bev
Median PFS, mo 3.4 6.7
HR (95% CI) 0.48 (0.38–0.60)
P value P<0.001
1. Pujade-Lauraine E et al. J Clin Oncol. 2014; 2. Stockler MR et al. J Clin Oncol. 2014
Patient-Reported Outcomes2
Chemo
Chemo + Bev

35. Anti-PDL1/PD1 single agent in OC
1. Infante et al. ESMO 2016 (abs 871P); 2. Disis et al. J Clin Oncol 2015 (abs 5509)
3. Hamanishi et al. J Clin Oncol 2015 (abs 5570); 4. Varga et al. J Clin Oncol 2015 (abs 5510)
Therapeutic agent Phase and trial name N Setting ORR, n/N (%)
Atezolizumab
Ia
(PCD4989g)1 12 PR ROC 2/8 (25)
Avelumab
Ib
(JAVELIN solid tumour)2 75 ROC 8/75 (11)
Nivolumab
II
(UMIN000005714)3 20 PR ROC 3/20 (15)
Pembrolizumab
Ib
(KEYNOTE-028)4 26 ROC 3/26 (12)
PD-L1/PD-1 inhibitors demonstrate encouraging but modest
activity in ROC, suggesting an opportunity for combinations

36. JAVELIN OVARIAN 200: PLD + Avelumab
Pujade-Lauraine, SGO 2019

37. NINJA: Nivolumab vs. Chemotherapy
Omatsu, ESMO 2020
Nivolumab Gem/PLD
PFS, mths (95% CI) 2.0 (1.9, 2.2) 3.8 (3.6, 4.2)
HR (95% CI) 1.5 (1.2-1.9); P=0.002
ORR, % (95% CI) 8% (3.5, 13.9) 13% (7.6, 20.8)

38. Zamarin JCO 2020
NRG GY003: Randomized phase II of nivolumab with or without ipilumimab for
recurrent ovarian cancer (NCT 02498600 )
Nivolumab and Ipilumimab
Nivolumab +
Ipilumimab
1mg/kg Q3wk
R
A
N
D
O
M
I
Z
A
T
I
O
N
Arm
A Nivolumab
3mg/kg Q2wk
Arm B
1:1:1
Primary Endpoint: RR n = 100
Response Rate
• Arm A: 12.2% (6/49)
• Arm B: 31.4% (16/51)
Progression Free Survival
• HR 0.528 (95% CI 0.339 – 0.821)
Grade > 3 Adverse Events
• Arm A: 55% (27/49)
• Arm B: 67% (34/51)

39. TOPACIO: Niraparib + Pembrolizumab
Konstantinopoulos, JAMA Onc 2019

40. Drew SGO 2019
N=32
44% with 1 prior regimen
25% with 2
ORR 72% (23/32)
CR 19%
PR 53%
MEDIOLA: Olaparib and Durvalumab
BRCA+

41. MEDIOLA: Olaparib, Durvalumab, Bev
BRCAwt
Drew, ESMO 2020
DCR and PFS are improved in 3 agent
combination over PARP/IO alone

42. Mirvetuximab Soravtansine (IMGN853) – Antibody-Drug
Conjugate Targeting Folate Receptor A
ASCO 2016 Moore et al

43. Efficacy of Mirvetuximab in Phase 1
Moore et al ASCO 2016 – Moore et al JCO 28Dec2016
Endpoint
All pts
(n = 46)
1-3
priors
(n = 23)
1-3 priors +
med/high
FRa
expression
(n = 16)
≥ 4 priors
or low
FRa
expressio
n
(n = 30)
ORR (%)
95% CI
26
(14, 41)
39
(20, 62)
44
(20, 70)
17
(6, 35)
PFS
(months)
Median
95% CI
4.8
(3.9, 5.7)
6.7
(3.9, 8.7)
6.7
(3.9, 11.0)
4.2
(2.6, 5.6)
DOR (weeks)
Median
95% CI
19.1
(16.1,
33.1)
19.6
(17.7,
44.1)
26.1
(17.7, -)
19.1
(13.0, 20.1)

44. STUDY DESIGN
*BIRC = Blinded Independent Review Committee;
analyzed by Hochberg procedure
6 mg/kg (adjusted ideal body weight) once
every 3 weeks
Paclitaxel: 80 mg/m2 weekly
PLD: 40 mg/m2 once every 4 weeks
Topotecan: 4 mg/m2 on Days 1, 8, and 15
every 4 weeks; or 1.25 mg/m2 on Days 1-5
every 3 weeks
• Platinum-resistant ovarian cancer
• FRα-positive tumor expression
- Medium (50-74% cells positive)
- High (≥75% cells positive)
• ECOG performance status 0 or 1
• 1-3 prior therapies
Mirvetuximab
Soravtansine
(n=248)
Investigator’s Choice
Chemotherapy
Paclitaxel, PLD†, or Topotecan
(n=118)
2:1 Randomization
Primary Endpoint
Progression-free survival (PFS; by
BIRC*) for ITT and high FRα
populations
Secondary Endpoints
Overall response rate (ORR)
Overall survival (OS)
Patient reported outcomes (PRO)
Stratification Factors:
FRα expression (medium or high)
Prior therapies (1 and 2, or 3)
Choice of chemotherapy
†Pegylated liposomal doxorubicin
ClinicalTrials.gov Identifier: NCT02631876
Statistical Assumptions
• Hochberg procedure
• α=0.05 (two-sided), power = 90%
HR=0.58; control arm mPFS 3.5 mos

45. PRIMARY ENDPOINT: PROGRESSION-FREE SURVIVAL (BY BIRC)
ITT FRα High
*not significant per Hochberg procedure
HR: 0.981 P=0.897
mPFS: 4.1 vs 4.4 months
HR: 0.693 P=0.049*
mPFS: 4.8 vs 3.3 months
PFS (by BICR) - FRα High by PFS2+ rescoring (n=116)
HR: 0.549 P=0.015
mPFS: 5.6 vs 3.2 months

46. + Bevacizumab
+ Carboplatin
Patients with
FRα-positive
ovarian cancer
FRa ≥ 25%
Plat resistant
Plat sens (carbo)
Bevacizumab
expansion cohort
Pembrolizumab
expansion cohort
+ PLD
+ Pembrolizumab
Exploration of Mirvetuximab in combination with bevacizumab

47. Maximum Tumor Change (%) in Target Lesions from Baseline
Lucy Gilbert ASCO20
Efficacy of Mirvetuximab in combination with bevacizumab

48. Conclusions
• Treatment free interval is essential in guiding
therapy choice in recurrent ovarian cancer
• Novel targeted therapies such as PARP
inhibitors and ADCs are demonstrating
exciting results
• Immunotherapy is still a work in progress…
• Assessment of rational combinations will be
essential to continue to improve outcomes

49. Thank you
@ShannonWestin
swestin@mdanderson.org