PARP inhibitors have revolutionized ovarian cancer treatment, but recent updates to the FDA-approved indications have caused confusion and raised questions for patients. So what do these changes mean? Dr. Thomas Herzog, Deputy Director of the University of Cincinnati Cancer Center, discusses the current landscape of PARP inhibitors for ovarian cancer and what it means for you.

1. PARP Inhibition: Manipulating
Ovarian Cancer Biology
Thomas J. Herzog, MD
Paul & Carolyn Flory Professor
Deputy Director, UC Cancer Center
Vice Chair Quality & Safety, Dept Ob/Gyn
University of Cincinnati

2. Disclosures
• Scientific Advisor:
– Aravive, AZ, Caris, Clovis, Corcept, Eisai,
Genentech, Genelux, GSK, Merck, Seagen, Sutro

3. High Tumor volumes
Recurrence >70%
Why Maintenance in Advanced
Front-line Stage Ovarian Cancer?
Better therapeutic options
Patients willing
Cure?
Eliminate subclinical disease
(MRD)
Chemo-sensitive Tumor

4. Biologic Rationale for Consolidation Therapy in Ovarian Cancer
Tannock, I. Basic Science Onc.
1
103
106
109
1012
Time (months)
Number
of
Tumor
Cells
Drug Resistant Tumor
Limit of clinical
detection
“Clinical Recurrence
102
10
1.0
10-1
PFI
Tumor
Weight
(g)
Treatments
Chemosensitive Tumor

5. Biologic Rationale for Consolidation in Ovarian Cancer
Adapted from:Tannock, I. Basic Science Onc.
1
103
106
109
1012
Time (months)
Number
of
Tumor
Cells
Minimal Residual Disease
Limit of clinical detection
Initiate Consolidation Tx
102
10
1.0
10-1
Tumor
cure
Tumor
Weight
(g)
Treatments
Chemosensitive Tumor

6. PARP Plays a Role in DNA Repair Pathways &
PARP Inhibitors Disrupt DNA Repair
Konecny, et al. Br J Cancer. 2016;115(10):1157-1173.
DNA glycosylases, AP
endonucleases
BRCA1/2, RAD51, MRN
complex, ATM
FED1, NBN
Ku70, Ku80,
DNA-PKcs
PARPi is
essential for BER
PARP1 contributes to and fine-tunes
HR (recruits MRE11
and NBS1 or
ribosylates BRCA)
PARP1 prevents binding of Ku
proteins to free DNA ends (first step
to start NHEJ) and thus inhibits
NHEJ
PARP1 prevents binding of Ku proteins
and directs DSBs to this alternative
end-joining (MMEJ) repair pathway
BER HR Alt- EJ
NHEJ
7

7. 8
aTumor testing can detect both germline and somatic BRCA mutations but cannot distinguish between them.3
BRCA=breast cancer susceptibility gene; HRD=homologous recombination deficiency; HRRm=homologous recombination repair mutation.
1. Konstantinopoulos PA, et al. Cancer Discov. 2015;5(11):1137-1154. 2. da Cunha Colombo Bonadio RR, et al. Clinics (Sao Paulo). 2018;73(suppl 1):e450s. 3. Capoluongo E, et al.
Semin Oncol. 2017;44(3):187-197.
Approximate percent (%) of women “positive” by testing modality
Germline BRCA test
≈15% of women
HRD genomic instability test
(includes BRCA)
≈50% of women
Tumor BRCA testa
≈22% of women
HRRm gene panel test
(includes BRCA)
≈35% of women
Blood
sample
Tumor
sample
Ovarian
Effect
Cause
Cause
Cause
Is there one universal approach to correctly test at
Diagnosis?

8. > 50% of epithelial ovarian
cancers are likely HR
deficient1
Genetic Alterations Responsible for Homologous
Recombination (HR) Pathway in Ovarian Cancer
*Figure adapted from Konstantinopoulos et al. Cancer Discov. 2015;5:1137–54.
Genetic & epigenetic
alterations are found in the
HR pathway, including
BRCA1, BRCA2, ATM, ATR,
RAD51C, BRIP1, and other
Fanconi Anemia (FA) related
genes2
1. Konstantinopulos et al. Cancer Discov. 2015;5(11):1137-54.
2. Kristeleit, et al. Am Soc Oncol Edu Book. 2016: 35:3259-68

9. Phase I: AZD 2281 (Olaparib)
Fong et al, 2009.

10. Clinical Activity: RECIST + GCIG (cont)
Fong PC, et al. N Engl J Med. 2009;361:123-134..

11. BRCA1/2 Mutations in Ovarian Cancer:
Who Should Be Tested?
NCCN, National Comprehensive Cancer Network; SGO, The Society of Gynecologic Oncology; ASCO; American Society of Clinical Oncology.
1.NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2016.
2.Lancaster et al. Gynecol Oncol. 2015;136(1):3-7.
3.Lu et al. J Clin Oncol. 2014;32(8):833-40.
Leading oncology societies recommend testing all
women with ovarian cancer
NCCN1
Genetic counseling and
testing should be
considered in women with
a history of ovarian
carcinoma, fallopian tube
or primary peritoneal
cancer
SGO2
Women diagnosed with
epithelial ovarian, tubal,
and peritoneal cancers
should receive genetic
counseling and be offered
genetic testing, even in the
absence of family history
ASCO3
Genetic counseling and
testing should be considered
in women with epithelial
ovarian, fallopian tube or
primary peritoneal cancer
even in the absence of family
history
TEST ALL PATIENTS WITH OVARIAN CANCER

12. Clinical Value: WHY Should BRCA
Genetic Testing Be Performed?
1. SGO Clinical Practice Statement: Genetic Testing for Ovarian Cancer. Available at: https://www.sgo.org/clinical-practice/guidelines/genetic-testing-for-
ovarian-cancer/. Accessed August 1, 2016.
2. Lancaster et al. Gynecol Oncol. 2015;136(1):3-7.
Benefit
• Prognostic implications1
• Predictive implications2
• Identifies cancer risk in other organs1
• Encourages cascade testing for relatives1,2
• Avoids unnecessary screening and risk reducing
surgeries1
Test Result
Germline BRCA
mutation identified
No germline BRCA
mutation

13. Ph II Olaparib: Olaparib Monotherapy in
Patients with Advanced Cancer & a Germline
BRCA1/2 Mutation
Kaufman B et al. J Clin Oncol. 2015;33:244-250.
§ Results: A total of 298 patients received treatment and were evaluable. The
tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and
31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to
23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95%
CI, 15.7 to 84.3) in ovarian, breast, pancreatic, and prostate cancers,
respectively. Stable disease ≥ 8 weeks was observed in 42% of patients (95%
CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% CI, 34.0 to
59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with
ovarian, breast, pancreatic, or prostate cancer, respectively. The most common
adverse events (AEs) were fatigue, nausea, and vomiting. Grade ≥ 3 AEs were
reported for 54% of patients; anemia was the most common (17%).
§ Conclusion: Responses to olaparib were observed across different tumor types
associated with germline BRCA1/2 mutations. Olaparib warrants further
investigation in confirmatory studies.

14. PARP Inhibitors as Maintenance
§ Primary Therapy
§ SOLO-1–Olaparib (BRCAmut only)
§ PRIMA- Niraparib
§ PAOLA-1 Olaparib + Bevacizumab
§ Platinum-sensitive Recurrence
§ SOLO-2–Olaparib (BRCAmut only)
§ Study 19- Olaparib (Platinum-sensitive)
§ ARIEL 3–Rucaparib (Platinum-sensitive)
§ NOVA–Niraparib (BRCAmut & HGS)

15. Ph. III: SOLO-2 Maintenance
§ Relapsed Plat-
sensitive Ov
§ BRCA mutation
§ > 2 prior
platinum
treatments
• Penultimate
chemo = plat &
> 6 mo after
completion
• Last chemo with
PR/CR & > 4
cycles
§ Primary endpoint
Olaparib (PO)
300 mg tablet BID
Placebo
R
2:1
ClinicalTrials.gov Id NCT01874353
Estimated Enrollment: 264
Study Start Date: June 2013 PI: E Pujade-Lauraine
Primary endpoint:
• PFS
Secondary:
• PFS2
• OS
• QoL

16. MDS/AML Events
Agent Trial PARPi, n (%) Comparator, n (%)
Niraparib NOVA 1/367 (0.3)
(6.6) BRCA Cohort
2/179 (1.1)
Rucaparib ARIEL3 3/375 (1) 0/189
Olaparib
Study19 2/136 (1.5) 1/129 (<1)
SOLO2
(initial analysis)
4/195 (2.1) 4/99 (4)
SOLO2
(final analysis)
16/195 (8) 4/99 (4)
Risk of MDS/AML
When to worry? Counts don’t recover after interruption/discontinuation of therapy
Development of cytopenias after long duration of stability

17. SOLO3: Olaparib vs Chemo in Recurrent gBRCAmt
Penson, ASCO 2019
• 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
R
2:1
n=176
n=88
Physician’s
choice: weekly
paclitaxel,
topotecan, PLD,
or gemcitabine to
progression
• 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
FDA Indication

18. NOVA: Niraparib Maintenance in Patients with
Plat-Sens Recurrent Ovarian Cancer
• Platinum-sensitive recurrent high grade serous ovarian cancer
• ≥2 prior regimens of platinum-based chemotherapy
• Received at least 4 cycles platinum-based therapy and, following treatment, have an investigator-
defined CR or PR with no observable residual disease of <2cm and CA-125 WNL or a decrease of
>90% that was stable for at least 7 days
N=553
Phase III, multicenter, randomized, double-blind, placebo controlled study
Non-gBRCAmut gBRCAmut
2:1 Randomization 2:1 Randomization
Niraparib
300 mg QD
n=138
Placebo
n=65
Niraparib
300 mg QD
n=234
Placebo
n=116
CA-125, cancer antigen 125; CR, complete response; HRDpos, homologous recombination deficiency positive; PR, partial
response; QD, every day; WNL, within normal limits.
Mirza et al. NEJM. 2016;October 8 epub ahead of print.
Primary Endpoint: PFS by central, blinded review
Tested at 100 events to achieve p<0.05
• HRDpos population
• Tested at 100 events to achieve p<0.05
• If test was positive then:
• Test overall non-gBRCAmut cohort (p<0.05)

19. NOVA: gBRCAmut Progression-Free Survival
Treatment
PFS
Median, months
(95% CI)
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<0.0001
62% 50%
Placebo
(n=65)
5.5
(3.8, 7.2) 16% 16%
Mirza MR et al. N Engl J Med. 2016 [Epub ahead of print].

20. NOVA: Exploratory Analysis of PFS in Subgroups of
Non-gBRCAmut Cohort
BRCAwt
Treatment
PFS
Median,
months
(95% CI)
Hazard Ratio
(95% CI)
p-value
% of Patients
without
Progression or
Death
12 mo 18 mo
Niraparib
(n=71)
9.3
(5.8,
15.4)
0.38
(0.231,
0.628)
p=0.0001
45% 27%
Placebo
(n=44)
3.7
(3.3,
5.6)
11% 6%
Treatment
PFS
Median,
months
(95% CI)
Hazard Ratio
(95% CI)
p-value
% of Patients
without
Progression or
Death
12 mo 18 mo
Niraparib
(n=35)
20.9
(9.7, NR)
0.27
(0.081,
0.903)
p=0.0248
62% 52%
Placebo
(n=12)
11.0
(2.0, NR)
19% 19%
sBRCAmut
NR, Not reached.
Treatment
PFS
Median,
months
(95% CI)
Hazard Ratio
(95% CI)
p-value
% of Patients
without
Progression or
Death
12 mo 18 mo
Niraparib
(n=92)
6.9
(5.6, 9.6)
0.58
(0.361,
0.922)
p=0.0226
27% 19%
Placebo
(n=42)
3.8
(3.7, 5.6)
7% 7%
Mirza et al. ESMO, 2016.
HRD-positive HRD-negative

21. ARIEL3: Phase 3 Study Design
N=540
Primary endpoint: PFS
Secondary endpoints: OS, health-related quality of life, and safety and tolerability
Analysis will evaluate the 3 separate groups defined in ARIEL2
ClinicalTrials.gov. NCT01968213. Accessed May 31, 2016. PI = R Coleman
• Recurrent ovarian, primary peritoneal, or
fallopian tube cancer
• High-grade serous or endometrioid
histology
• 1 prior nonplatinum regimen
• Platinum sensitive
• In CR or PR at end of just-completed
platinum regimen
• No prior PARP in ≥2 prior platinum
regimens
• No more than 1 nonplatinum chemotherapy
regimen
Rucaparib
600 mg PO bid to
progression
Placebo PO bid
to progression
R
1:1

22. ARIEL3: Investigator-Assessed PFS
Ledermann JA, et al. Presented at ESMO 2017 (abstr LBA40).
25

23. Ph III Plat Sens PARP Trials
ARIEL 3 NOVA SOLO-2 Ph II Study 19

24. PARPi Transforming Front-line
Ovarian Cancer

25. 1LM Trials Leading to FDA Approval: Study Design
Study Design GOG-0218 (N=1873)1,2 SOLO-1 (N=391)3 PRIMA (N=733)4 PAOLA-1 (N=806)5
Study treatment Bev (n=623) Olaparib (n=260) Niraparib (n=487) Bev + olaparib (n=537)
Patient population
§ Newly diagnosed
§ Incompletely resectable
stage III (macroscopic ≤1 cm
or stage III >1 cm) or stage IV
§ Newly diagnosed
§ g/sBRCAmut
§ Cytoreductive surgery
§ NED, CR, or PR to 1L CT
§ Clinically high risk,
newly diagnosed
§ Stage III with residual
or inoperable disease,
stage IV, and those
who received NACT
§ CR or PR to 1L CT
§ Newly diagnosed ovarian
cancer or BRCAmut
nonmucinous EOC
§ Regardless of surgical
outcome
§ NED, CR, or PR to 1L
CT+Bev
Randomization 1:1:1 2:1 2:1 2:1
Stratification factors
GOG PS score, cancer stage, and
debulking status
Response to CT
NACT, response to CT,
and HRd status
BRCA status,
response to CT
Treatment duration 15 months Until PD or 24 months Until PD or 36 months
Olaparib: until PD or
24 months; Bev: 15 months
Primary endpoint PFS by INV PFS by INV PFS by BICR PFS by INV
Key secondary
endpoints
OS, HRQOL
PFS by BICR, PFS2, OS, HRQOL,
safety
OS, PFS2, PROs, safety
PFS by BICR, PFS2, OS, safety,
HRQOL
28
Note: No cross-trial comparisons were performed; information is presented for reference only.
1. Burger RA, et al. N Engl J Med. 2011;365(26):2473-2483. 2. Norquist BM, et al. Clin Cancer Res. 2018;24(4):777-783. 3. Moore K, et al.
N Engl J Med. 2018;379(26):2495-2505. 4. González-Martín A, et al. N Engl J Med. 2019;381(25):2391-2402. 5. Ray-Coquard I, et al. N Engl J Med.
2019;381(25):2416-2428.

26. 1LM PARP Trials with FDA Approval: Baseline Characteristics
29
Note: No cross-trial comparisons were performed; information is presented for reference only.
1. Burger RA, et al. N Engl J Med. 2011;365(26):2473-2483. 2. Norquist BM, et al. Clin Cancer Res. 2018;24(4):777-783. 3. Moore K, et al.
N Engl J Med. 2018;379(26):2495-2505. 4. González-Martín A, et al. N Engl J Med. 2019;381(25):2391-2402. 5. Ray-Coquard I, et al. N Engl J Med. 2019;381(25):2416-2428.
Trial [Treatment]
Characteristic
GOG-0218 [Bev]
(N=1873)1,2
SOLO-1 [Olaparib]
(N=391)3
PRIMA [Niraparib]
(N=733)4
PAOLA-1 [Bev + olaparib]
(N=806)5
Stage IV, % 26 17 35 30
PDS, %
R0 after PDS, %
100
Excluded stage III
63
47
33
Excluded stage III
51
30
NACT, %
R0 after IDS, %
N/A
35
29
67
Excluded
42
30
BRCAmut, %
19 (n=1195
sequenced)
100 30 30
CR to platinum, % N/A 82 69 20 (+53% NED)
HRD testing HRR (post hoc) N/A
myChoice® test
(Myriad Genetics)
myChoice®
HRD Plus assay
Median follow-up,
mo
17 41 14 23
Randomization point Before chemotherapy End of chemotherapy End of chemotherapy End of chemotherapy

27. Efficacy Summary for 1LM Trials:
Median PFS Among Patients With BRCAmut
30
1. Norquist BM, et al. Clin Cancer Res. 2018;24(4):777-783. 2. Moore K, et al. N Engl J Med. 2018;379(26):2495-2505. 3. Banerjee S, et al. Lancet Oncol. 2021;22(12):1721-1731.4.
González-Martín A, et al. N Engl J Med. 2019;381(25):2391-2402. 5. Ray-Coquard I, et al. N Engl J Med. 2019;381(25):2416-2428.
GOG-02181
(n=228)
HRD population
inclusive of BRCAmut
and BRCAwt
SOLO-1 [Olaparib]2,3
(N=391)
PRIMA [Niraparib]4
(n=223)
PAOLA-1 [Bev +
olaparib]5
(n=237)
HR 0.95
95% CI: 0.71-1.26
HR 0.33
95% CI: 0.25-0.43
HR 0.40
95% CI: 0.27-0.62
HR 0.31
95% CI: 0.20-0.47
19.6 vs 15.4 months
(Bev vs Pbo)
56.0 vs 13.8 months
(Olaparib vs Pbo)
22.1 vs 10.9 months
(Niraparib vs Pbo)
37.2 vs 21.7 months
(Bev + olaparib vs Bev
+ Pbo)

28. Efficacy Summary for 1LM Trials:
Median PFS Among Patients With BRCAwt/HRd
31
1. Norquist BM, et al. Clin Cancer Res. 2018;24(4):777-783. 2. Moore K, et al. N Engl J Med. 2018;379(26):2495-2505. 3. González-
Martín A, et al. N Engl J Med. 2019;381(25):2391-2402. 4. Ray-Coquard I, et al. N Engl J Med. 2019;381(25):2416-2428.
GOG-02181
(n=228)
HRD population inclusive of
BRCAmut and BRCAwt
SOLO-1 [Olaparib]2
N/A
PRIMA [Niraparib]3
(n=150)
PAOLA-1 [Bev + olaparib]4
(n=152)
HR 0.95
95% CI: 0.71-1.26
N/A
HR 0.50
95% CI: 0.31-0.83
HR 0.43
95% CI: 0.28-0.66
19.6 vs 15.4 months
(Bev vs Pbo)
N/A
19.6 vs 8.2 months
(Niraparib vs Pbo)
28.1 vs 16.6 months
(Bev + olaparib vs Bev + Pbo)

29. Efficacy Summary for 1LM Trials:
Median PFS Among Patients With BRCAwt/HRp
32
1. Norquist BM, et al. Clin Cancer Res. 2018;24(4):777-783. 2. Moore K, et al. N Engl J Med. 2018;379(26):2495-2505. 3. González-
Martín A, et al. N Engl J Med. 2019;381(25):2391-2402. 4. Ray-Coquard I, et al. N Engl J Med. 2019;381(25):2416-2428.
GOG-02181
(n=581)
SOLO-1 [Olaparib]2
N/A
PRIMA [Niraparib]3
(n=249)
PAOLA-1 [Bev +
olaparib]4
(n=419)
HR 0.71
95% CI: 0.60-0.85
N/A
HR 0.68
95% CI: 0.49-0.94
HR 0.92
95% CI: 0.72-1.17
15.7 vs 10.6 months
(Bev vs Pbo)
N/A
8.1 vs 5.4 months
(Niraparib vs Pbo)
16.9 vs 16.0 months
(Bev + olaparib vs Bev
+ Pbo)

30. a P<0.001 required to declares statistical significance (Haybittle boundary).
DiSilvestro P, et al. ESMO 2022. Abstract 517O.
§ 2 years of maintenance olaparib provided a
clinically meaningful improvement in OS
33
Olaparib
(n=260)
Placebo
(n=131)
Events, n (%) 84 (32.3) 65 (49.6)
Median OS,
months NR 75.2
HR 0.55 (95% CI: 0.40-0.76); P=0.0004a
73.1%
63.4%
46.5%
67.0%
Olaparib
Placebo
0 102
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Months since randomization
0
100
90
80
70
60
50
40
30
20
10
260 0
252 246 236 227 214 203 194 185 177 170 165 159 157 153 79 21
131 0
128 125 114 108 100 97 92 87 80 73 67 60 54 52 21 6
No. at risk
Olaparib
Placebo
Overall
survival
(%)
§ 44.3% of patients in the placebo
group received subsequent PARPi
therapy, compared with 14.6% of
patients in the olaparib group
Olaparib Maintenance in BRCAmut
Ovarian Cancer: OS at 7-Year Follow-Up From SOLO-1

31. a Median unstable; <50% data maturity.
HRD positive defined as a tBRCAmut and/or genomic instability score of ≥42 on the Myriad myChoice® HRD Plus assay.
Ray-Coquard I, et al. ESMO 2022. Abstract LBA29.
Olaparib + Bevacizumab Maintenance in Patients With HRd
Ovarian Cancer: 5-Year OS From PAOLA-1
34
Olaparib +
bevacizumab
(n=255)
Placebo +
bevacizumab
(n=132)
Events, n (%) 93 (36.5) 69 (52.3)
Median OS,
months
75.2
(unstable)a 57.3
5-year OS rate, % 65.5 48.4
HR 0.62 (95% CI: 0.45-0.85)
Patients receiving a PARPi
during any subsequent treatment
Olaparib + bevacizumab: 17.3% (44/255)
Placebo + bevacizumab: 50.8% (67/132)
Time from randomization (months)
255
132
No. at risk
Olaparib + bevacizumab
Placebo + bevacizumab
253
130
253
129
252
128
252
126
244
121
238
117
231
114
225
109
215
105
205
100
200
96
195
91
189
89
183
86
176
82
174
79
170
77
164
70
142
59
116
44
83
29
62
21
32
9
17
2
4
1
0
0
0 12 24 36 48 60 72 80
0
10
20
30
40
50
60
70
80
90
100
Patients
who
survived
(%)
65.5%
48.4%
5-year OS rate

32. Niraparib Maintenance in Patients With Ovarian Cancer
by Subgroup: 4-Year PFS From PRIMA
• Niraparib treatment increased PFS duration compared with placebo treatment
across biomarker subgroups at the November 17, 2021, clinical cutoff date
35
González-Martín A, et al. ESMO 2022. .
BRCAmut
HR 0.45 (95% CI: 0.32-0.64)
HRd/BRCAwt
HR 0.66 (95% CI: 0.44-1.00)
HRp
HR 0.65 (95% CI: 0.49-0.87)
0
90
80
70
60
40
30
20
10
50
100
Estimated
survival
function,
%
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60
Time since randomization, months
Patients at risk
Niraparib 152 150 145 132 128 119 109 100 95 84 81 79 78 71 70 70 68 63 60 56 50 32 30 25 13 10 9 3 2 1 0
Placebo 71 66 58 51 43 38 33 28 27 23 19 18 18 16 14 14 13 13 13 13 13 7 6 5 3 1 1 1 0
0
90
80
70
60
40
30
20
10
50
100
Estimated
survival
function,
%
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60
Time since randomization, months
Patients at risk
Niraparib 95 86 77 68 62 55 50 44 43 41 38 37 32 32 31 31 31 29 27 26 21 16 15 13 8 7 6 1 0
Placebo 55 52 44 40 33 28 24 19 19 18 17 17 16 16 14 14 13 13 12 12 11 4 4 2 2 1 1 1 1 0
0
90
80
70
60
40
30
20
10
50
100
Estimated
survival
function,
%
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60
Time since randomization, months
Patients at risk
Niraparib 169 160 128 95 87 70 56 48 44 36 31 29 27 24 23 22 19 18 16 15 14 7 7 5 0
Placebo 80 69 53 34 26 21 19 17 17 13 11 10 9 8 7 7 7 7 7 7 7 3 3 2 2 1 1 0
As of Nov 17, 2021, OS remained immature at 41.2% for the overall population

33. Safety Summary From Frontline Maintenance
Trials
36
aIn patients who received a starting dose of niraparib based on baseline weight or platelet count, anemia, thrombocytopenia, and neutropenia were reported in 23%, 22%, and 15%, respectively.
TEAE, treatment-emergent adverse event.
Note: No cross-trial comparisons were performed, information is presented for reference only.
1. Gonzalez-Martin A, et al. N Engl J Med. 2019;381(25):2391-240. 2. Ray-Coquard I, et al. Presented at ESMO Congress 2019. LBA2. 3. Moore K, et al. N Engl J Med. 2018;379(26):2495-2505.
Study Design
PRIMAb
(N=620)1
PAOLA-1
(N=612)2
SOLO-1
(N=451)3
Treatment arms vs placebo Niraparib Bevacizumab ± Olaparib Olaparib (n=260)
TEAEs (%)a
Anemia (31%) Hypertension (19%) Anemia (22%)
Thrombocytopenia (29%) Anemia (17%) Neutropenia (9%)
Neutropenia (13%) Lymphopenia (7%) Asthenia (4%)
Fatigue (2%) Neutropenia (6%) Diarrhea (3%)
Abdominal pain (1%) Asthenia (5%) Abdominal pain (2%)
Discontinuation (%) 12% 20% 12%
Dose interruption (%) 80% 54% 52%
Dose reduction (%) 71% 41% 29%

34. Common Adverse Events With
PARP Inhibitors in Ovarian Cancer
Hematologic
Neutropenia
Anemia
Thrombocytopenia
Nonhematologic
GI: Nausea/vomiting/
diarhea/constipation
Asthenia/fatigue
LFTs and HTN
Rare
AML
MDS
Pneumonitis

35. ATHENA–MONO Study Schema
1
2
Bradley J. Monk, MD, FACS, FACOG (LBA5500)
*After initiation of oral/IV combination study treatment (IV drug was initiated cycle 2 day 1; 28-day cycles). †Centrally assessed, determined by FoundationOne CDx (BRCAmut,
BRCAwt/LOHhigh [LOH ≥16%], BRCAwt/LOHlow [LOH <16%], BRCAwt/LOHindeterminate). BID, twice daily; BRCA, BRCA1 or BRCA2; CR, complete response; ECOG PS, Eastern Cooperative Oncology
Group performance status; HRD, homologous recombination deficiency; IV, intravenous; LOH, loss of heterozygosity; mut, mutant; PO, by mouth; PR, partial response; wt, wild type.
Arm A (n≈400)
rucaparib 600 mg BID PO +
nivolumab 480 mg IV
Arm B (n≈400)
rucaparib 600 mg BID PO +
placebo IV
Arm C (n≈100)
placebo PO +
nivolumab 480 mg IV
Arm D (n≈100)
placebo PO +
placebo IV
Study Analyses
Key Patient Eligibility
Randomization Stratification Factors
• Tumor HRD test status†
• Disease status post-chemotherapy
• Timing of surgery
Randomization 4:4:1:1
ATHENA–MONO
ATHENA–COMBO
Treatment for 24
months*, or until
radiographic
progression,
unacceptable toxicity,
or other reason for
discontinuation
• Newly diagnosed, stage III–IV,
high-grade epithelial ovarian,
fallopian tube, or primary
peritoneal cancer
• Completed frontline platinum-
doublet chemotherapy and surgery
– Achieved investigator-assessed
CR or PR
– Received cytoreductive surgery
(primary or interval; R0/complete
resection permitted)
• ECOG PS 0 or 1
• No prior treatment for ovarian
cancer, including any maintenance
treatment, other than frontline
platinum regimen
Arm B (n≈400)
rucaparib 600 mg BID PO +
placebo IV
Arm D (n≈100)
placebo PO +
placebo IV
Arm A (n≈400)
rucaparib 600 mg BID PO +
nivolumab 480 mg IV
Arm B (n≈400)
rucaparib 600 mg BID PO +
placebo IV

36. SOLO-1
(Olaparib)
PAOLA-1
(Olaparib+Bev)
PRIMA
(Niraparib)
PRIME
(Niraparib)
ATHENA
(Rucaparib)
ITT
22.1 vs 16.6
(HR 0.59)
13.8 vs 8.2
(HR 0.62)
24.8 vs. 8.3
(HR 0.45)
20.2 vs 9.2
(HR 0.52)
BRCAm
56.0 vs. 13.8
(HR 0.33)
37.2 vs 21.7
(HR 0.31)
22.1 vs 10.9
(HR 0.40)
NR vs 10.8
(HR 0.40)
NR vs 14.7
(HR 0.40)
HRD+
37.2 vs 17.7
(HR 0.33)
21.9 vs 10.4
(HR 0.43)
NR vs 11.0
(HR 0.48)
28.7 vs 11.3
(HR 0.47)
HRD+/Non-BRCA
28.1 vs 16.6
(HR 0.43)
19.6 vs 8.2
(HR 0.50)
24.8 vs 11.1
(HR 0.58)
20.3 vs 9.2
(HR 0.58)
HRD Negative
16.6 vs 16.2
(HR 1.0)
8.1 vs 5.4
(HR 0.68)
14.0 vs 5.5
(HR 0.41)
12.1 vs 9.1
(HR 0.65)
Median Follow-Up 4.8 years 27.4 months 13.8 months 27.5 months 26 months
PARP Inhibitors: First-Line Maintenance Ovarian Cancer

37. What Is the Standard Systemic Rx: 1st-L Advanced EOC?
40
Decision #1
NACT vs
Primary debulking
Decision #2
Bevacizumab Y/N
PRIMA
PAOLA-1
GOG 218
ICON7
Supporting Ph 3 trial
SOLO-1
PRIMA
PAOLA-1
SOLO-1
PRIMA
NCCN guidelines. Ovarian Cancer 2023

38. Ph 2 OVARIO Study of Niraparib + Bevacizumab in Advanced Ovarian
Cancer Following Frontline Plat-Based Chemo with Bevacizumab
41
Hardesty M et al SGO 2021 Annual Virtual Meeting
Treatment Emergent Adverse Events Summary
18-month landmark analysis:
62% overall population remained progression-free
76% in the HRD group
47% in the HRP group
Progression-free Survival Rates at 6, 12, and 18 Months

39. PARP Resistance Mechanisms
NHEJ recombination
- p53 BP1
DNA Methylation
-May see “Nl Test” as promoter
Methylation blocks transcription
-Case Control measuring WBC
promoter methylation
-10% in HG-SOC; 1,500+ Ov pts
-Lonning PE; Annals of Int Med 2018
Other:
-KRAS mutations
-Immune environment changes
-Micro RNA’s
Reversion mutations
-in open reading frame
-or heterogeneity in originaltumor
P glycoprotein
-Efflux pump

40. SOLO3: Post hoc subgroup analyses
43
PFS DCO: October 10, 2018; OS DCO: April 16, 2021.
Leath III CA, et al. IGCS 2022. LB001.
BICR, blinded independent central review; CI, confidence interval; OR, objective response; ORR, objective response rate; PFS, progression-free survival; PR,
partial response; SD, stable disease.
≥3 prior lines of chemotherapy
2 prior lines of chemotherapy
Olaparib
(N=90)
Chemotherapy
(N=42)
Events, n (%) 63 (70) 23 (55)
Median OS, months 29.9 39.4
HR 1.33 (95% CI 0.84–2.18)
Olaparib
Chemotherapy
56
70
26
34
0
10
20
30
40
50
60
70
80
90
100
Patients
free
from
death
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72
No. at risk
Olaparib
Chemotherapy
90
42
89
35
85
33
81
32
71
29
63
28
56
26
47
25
44
22
41
19
37
18
31
17
30
16
27
16
23
13
20
12
16
10
12
8
9
3
7
2
6
1
2
0
0
0
0
0
0
0
Months since randomization
Olaparib
(N=88)
Chemotherapy
(N=46)
Events, n (%) 53 (60) 23 (50)
Median OS,
months 37.9 28.8
HR 0.83 (95% CI 0.51–1.38)
Olaparib
Chemotherapy
41
34
80
55
0
10
20
30
40
50
60
70
80
90
100
Patients
free
from
death
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72
Months since randomization
No. at risk
Olaparib
Chemotherapy
88
46
86
41
84
39
83
38
82
36
77
30
72
26
69
23
65
19
59
18
54
17
52
16
46
15
39
14
34
12
30
11
26
9
21
8
20
7
14
5
8
4
5
3
3
1
1
1
0
0

41. DHCP Letter for Olaparib in gBRCA-Mutated Ovarian Cancer
After ≥3 Chemotherapies: Updated HCP Letter
44
AstraZeneca Letter to HCPs: IMPORTANT PRESCRIBING INFORMATION; Subject: Important Information for Lynparza (olaparib) for treatment of adult
patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more
prior lines of chemotherapy is voluntarily withdrawn in the U.S. August 26, 2022.
2. Penson RT, et al. J Clin Oncol. 2020;38(11):1164-74.
DHCP, healthcare provider.

42. Investigator-assessed PFS: Efficacy population
Trial eligibility and design
ARIEL4: PFS Improved with Rucaparib Over Chemotherapy in the ITT population
Visit cutoff September 30, 2020. HR and associated P value calculated using a stratified Cox
proportional hazards model.
Kristeleit RS, et al. SGO. 2021.; Oza AM, et al. ESMO 2022. 518MO. Slide courtesy of Dr.Shannon N. Westin.
HR, hazard ratio; PFS, progression-free survival.
45

43. OS: Platinum Resistant
ARIEL4: OS: Chemotherapy Favored Over Rucaparib
Data cutoff: 10 April 2022. HRs estimated with a Cox proportional hazards model. aWeekly paclitaxel.
bWeekly paclitaxel for patients with partially platinum-sensitive disease; single-agent platinum or platinum doublet for
patients with fully platinum-sensitive disease.
Oza AM, et al. ESMO 2022. 518MO.
HR, hazard ratio; PFS, progression-free survival. 46
OS: ITT Population OS: Platinum Sensitive

44. DHCP Letter for Rucaparib in BRCA-Mutated Ovarian Cancer After ≥2
Chemotherapies
47
Clovis Letter to HCPs: IMPORTANT PRESCRIBING INFORMATION; Subject: Rubraca® (Rucaparib) for treatment of
BRCA-mutated ovarian cancer after 2 or more chemotherapies is voluntarily withdrawn in the U.S. June 2022.
DHCP, healthcare provider.

45. QUADRA: Niraparib Improves Survival in HRD+ OC After ≥ 3 Chemotherapies
OS based on clinical benefit at 24 weeks
48
HRD-positive *
(n=189)
BRCA-mutated
(n=63)
HRD-negative or
unknown
(n=230)
Platinum-sensitive to most
recent line of platinum
therapy, n/N (%)
14/53 (26%) 7/18 (39%) 2/52 (4%)
Platinum-resistant or
refractory, n/N (%)
12/120 (10%) 10/37 (27%) 5/169 (3%)
Platinum status unknown, n/N
(%)
3/16 (19%) 1/8 (13%) 1/9 (11%)
All, n/N (%) 29/189 (15%) 18/63 (29%) 8/230 (3%)
Proportion of pts with
confirmed response by
molecular biomarker &
platinum status
Clinical benefit at 24
weeks in subgroups
defined by clinical
(platinum status) and
molecular biomarkers
The study met the primary endpoint, with 13 (28%) of 47 pts who received
3 or 4 previous anticancer therapies with HRD+ tumors that were sensitive
to the most recent Pt-based therapy and were PARPi naive (primary efficacy
population) achieving an OR (95% CI, 15.6%–42.6%, one-sided
P=0.00053); median duration of PFS was 5.5 months (95% CI, 3.5
months–8.2 months); mDOR=9.2 months (5.9 months–NE).
*Includes patients with BRCA-mutated and non-BRCA-mutated tumors.
Moore KN, et al. The Lancet. 2019.
HRD, homologous recombination deficient; NE, not estimable; OC, ovarian cancer; OR, objective response;
PARPi, Poly-ADP ribose polymerase inhibitor; pts, patients; Pt, platinum.

46. DHCP Letter for Niraparib in HRD Ov Cancer After ≥3 Chemotherapies
49
GSK Letter to HCPs: Subject: ZEJULA® (niraparib) Important Prescribing Information for the treatment of adult patients with advanced
ovarian, fallopian tube, or primary peritoneal cancer who have been treated with 3 or more prior chemotherapy regimens. September 2022.
DHCP, dear healthcare provider; HR, hazard ratio; HRD, homologous recombination deficiency; OS, overall survival.

47. PARP Inhibitor FDA Approvals
Olaparib1 Rucaparib2 Niraparib3
MOA PARP1, PARP2, and PARP3 inhibitor PARP1, PARP2, and PARP3 inhibitor PARP1 and PARP2 inhibitor
Treatment
indication
≥3 lines of chemotherapy
with deleterious
or suspected gBRCAm ovarian cancer
≥2 lines of chemotherapy
with deleterious
g/sBRCAm EOC, FTC, and PPC
≥3 lines of chemotherapy
with HRD+ ovarian cancer, FTC, and PPC
• Deleterious or suspected BRCAm, or
• Genomic instability and progression
>6 mo after response to last
platinum-based chemotherapy
Maintenance
indication
2L maintenance for recurrent
EOC, FTC, and PPC
2L maintenance
for recurrent EOC, FTC, and PPC
2L maintenance for recurrent
EOC, FTC, and PPC gBRCA only
1L maintenance regardless
of BRCAm status
1L maintenance for high-risk, advanced,
BRCAm, high-grade EOC, FTC, and PPC
1L maintenance + bevacizumab for HRD+
Recommended
dosage
300 mg PO twice daily 600 mg PO twice daily 200 or 300 mg PO once dailya
Approval
dates
December 2014, August 2017,
December 2018, and May 2020
December 2016
and April 2018
March 2017, October 2019,
and April 2020

48. PARPi Indications by Line of Therapy
After Regulatory Actions1
51
1. Summary: Revisions to FDA approvals for PARPi in the management of ovarian cancer. December 9, 2022. Accessed December 20, 2022. https://www.sgo.org/resources/revisions-to-fda-approvals-for-parp-inhibitors/ 2. Niraparib.
Package insert. GlaxoSmithKline; 2022. 3. Olaparib. Package insert. AstraZeneca; 2023. 4. Rucaparib. Package insert. Clovis Oncology; 2022. 5. GSK dear HCP Letter (niraparib). November 2022. Accessed December 19, 2022. 6. Clovis
Oncology Dear HCP Letter (rucaparib). December 2022. Accessed January 4, 2022. 7. GSK Dear HCP Letter (niraparib). September 2022. Accessed December 19, 2022. 8. AstraZeneca Dear HCP letter (olaparib). August 2022. Accessed
December 19, 2022. 9. Clovis Oncology Dear HCP Letter (rucaparib). June 2022. Accessed December 19, 2022.
Line of
therapy
PARPi
Clinical
trial
Initial indication Indication changes postregulatory actions
1LM
Niraparib2 PRIMA Regardless of biomarker status
Olaparib3
(+ bevacizumab)
PAOLA-1 HRd, including BRCAmut
Olaparib SOLO-1 g/sBRCAmut
Rucaparib4 ATHENA-
MONO
May 2023: FDA issued CRL rejecting their sNDA
≥2LM
Niraparib5 NOVA Regardless of biomarker status
November 2022: restriction of indication to gBRCAmut
only
Olaparib3 SOLO-2
Study 19
Regardless of biomarker status
September 2023: restriction of indication to g/sBRCAmut
only
Rucaparib6 ARIEL3 Regardless of biomarker status
December 2022: restriction of indication to tBRCAmut
only
Late-Line
Treatment
Niraparib7 QUADRA HRd or BRCAmut
September 2022: withdrawal of indication based on
totality of information from PARPi
Olaparib8 SOLO-3 gBRCAmut August 2022: withdrawal of indication
Rucaparib9 ARIEL4 gBRCAmut June 2022: withdrawal of indication

49. Key Ongoing Trials For Frontline or Frontline
Maintenance Treatment of Ovarian Cancer
Trial Name Setting Treatment Arms
Primary
Endpoint
NCT Number
ATHENA
Newly diagnosed
advanced EOC, FTC,
PPC
rucaparib + nivolumab vs
rucaparib vs nivolumab vs placebo
PFS NCT03522246
FIRST
Advanced non-mucinous
EOC
chemo ± bevacizumab + niraparib vs
chemo ± bevacizumab + dostarlimab
+ niraparib
PFS (All)
PFS (PD-L1+)
NCT03602859
DUO-O
Newly diagnosed,
advanced high grade
EOC, FTC, PPC
chemo ± bevacizumab + durvalumab
followed by durvalumab +
bevacizumab + olaparib
PFS
(non-tBRCAm)
NCT03737643
KEYLYNK-
001
1L maintenance in
BRCAwt EOC
pembrolizumab + chemo ± olaparib
vs chemo
PFS, OS NCT03740165
FLORA-5
Newly diagnosed EOC
after optimal debulking
Oregovomab + chemo vs chemo SOC PFS NCT04498117

50. PRESENTED BY:
DUO-O study design 53
Dr Philipp Harter
Stratified by:
• Timing and
outcomes of
cytoreductive
surgery
• Geographical
region
Arm 3
PC + bev +
durva + ola
R
1:1:1
Arm 2
PC + bev +
durva
Arm 1
PC + bev
Maintenance phase
Chemotherapy phase
Run-in phase
CTx cycle 1*
CTx†
+
bevacizumab
+
durvalumab placebo
CTx†
+
bevacizumab
+
durvalumab
CTx†
+
bevacizumab
+
durvalumab
Treatment continued until disease progression, study treatment was complete or other discontinuation criteria were met
Bevacizumab total 15 months
+
durvalumab placebo total 24 months
+
olaparib placebo total 24 months
Bevacizumab total 15 months
+
durvalumab total 24 months
+
olaparib placebo total 24 months
Bevacizumab total 15 months
+
durvalumab total 24 months
+
olaparib total 24 months
Patients
• Newly diagnosed
FIGO stage III–IV
high-grade
epithelial OC
• No prior systemic
therapy for OC
• PARP inhibitor/
immune-mediated
therapy naïve
• Primary debulking
or planned interval
debulking surgery
• Non-tBRCAm
Primary endpoints
• PFS (RECIST per investigator)
in Arm 3 vs Arm 1
– Non-tBRCAm HRD-positive‡
– ITT population
Key secondary endpoints
• PFS (RECIST per investigator)
in Arm 2 vs Arm 1
– ITT population
• OS
• Safety
Endpoints
Dosing and schedule: bevacizumab (15 mg/kg IV q3w); durvalumab (1120 mg IV q3w); olaparib (300 mg po bid); chemotherapy: paclitaxel 175 mg/m2
IV q3w and carboplatin at AUC5 or AUC6 IV q3w. PFS interim analysis DCO: December 5, 2022.
*With or without bevacizumab according to local practice; †Cycles 2–6; ‡Genomic instability score ≥42 assessed prospectively by Myriad MyChoice CDx assay.
AUC, area under the curve; bev, bevacizumab; bid, twice daily; CTx, chemotherapy; DCO, data cutoff; durva, durvalumab; FIGO, International Federation of Gynecology and Obstetrics; HRD, homologous recombination deficiency; ITT, intent-to-treat;
IV, intravenous; ola, olaparib; OS, overall survival; PC, paclitaxel/carboplatin; po, by mouth; q3w, every 3 weeks; R, randomization; RECIST, Response Evaluation Criteria for Solid Tumors.
DUO-O also included an independent,
single-arm, open-label tBRCAm cohort –
results are not presented

51. PRESENTED BY:
PFS: ITT population
Dr Philipp Harter
Arm 1
PC + bev
N=378
Arm 2
PC + bev +
durva
N=374
Arm 3
PC + bev +
durva + ola
N=378
Median follow-up,* months
25.5 23.1 23.3
Events, n (%)
259 (69) 226 (60) 193 (51)
Median PFS,†
months
19.3 20.6 24.2
HR (95% CI)
vs Arm 1 0.87
(0.73–1.04)‡
P=0.13
0.63
(0.52–0.76)‡
P<0.0001
PC + bev + durva
Arm 2
Time from randomization (months)
374 354 336 301 254 221 180 130 93 70 54 39 23 11 1
3 6 9 12 15 18 21 24 27 30 33 36 39 45
42
0
0
100
80
90
70
50
60
10
20
30
40
0
Patients
free
from
disease
progression
or
death
(%)
Patients at risk
Arm 1 378 363 341 297 260 223 189 130 87 63 51 35 23 11 0
2
Arm 3 378 366 351 323 286 266 228 163 123 84 65 52 27 9 0
PC + bev + durva + ola
PC + bev
73%
55%
81%
71%
32%§
51%§
*In censored patients; †Medians and rates were estimated by KM method; ‡HR and CI were
estimated from a stratified Cox proportional hazards model. Model stratified by timing and outcome
of cytoreductive surgery and geographical region. P value from a stratified log rank text; §24-month PFS rates unstable.
72%
56%
39%§

52. Key Trials to Address Unanswered Front-line Questions
Trial
Phas
e
Agent/Regimen ClinicalTrials.gov
Immunotherapy
GOG-
3036/KEYLYNK-001
III
Pembrolizumab + chemotherapy ± Olaparib
vs Chemo +/- Bevacizumab
NCT03740165
FIRST III Platinum-based therapy + Dostarlimab + Niraparib NCT03602859
DUO-O/GOG-3036 III
Durvalumab + Chemo + Bevacizumab followed by maintenance
durvalumab + Bevacizumab + Olaparib vs. Chemo + placebo
NCT03737643
ATHENA-
Combo/GOG-3020
III Rucaparib + Nivolumab vs. Rucaparib NCT03522246
Bevacizumab & PARP*
NIRVANA-1 II
Niraparib ± bevacizumab maintenance after complete
cytoreduction NCT04734665
AGO-OVAR 28 III
Niraparib vs niraparib + bev as maintenance after platinum + bev
NCT05009082
MITO25 I-II
Chemo ± bevacizumab followed by Rucaparib maintenance ± bev
or bev alone (3 arms) NCT03462212
*- Recall PAOLA-1 lacked Olap alone arm & PRIMA, SOLO-1 & ATHENA had no Bev Combo arm

53. Conclusions
• Maintenance has experienced a rebirth with introduction of the PARPi’s
• Clinical efficacy has placed a premium on biomarker development &
assessment
• Combinations are being studies with: I/O’s, Anti-vascular agents & Triple bio
strategies
• Combination will require assessment of cost-effectiveness & clinical value
• PARPi’s have transformed the Front-line Ovarian landscape
• Surgery and maximal removal of disease still critical
• USA FDA concern with OS pushing PARPi use to front line
• Clinical trials are cornerstone of knowledge advancement

54. Thanks!