Describes the emerging resistance of epithelial cancer of the ovary to current therapies and the role of PARP inhibitors in the management in view of the recent drug approvals.

1. Ovarian Cancer:
what is behind the scene?
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Asyut International Annual
Cancer Conference
Astra Zeneca Symposium
Luxor 20-22/02/2019

2. Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Pfizer, Mundipharma, MSD, Ely Lilly
Speaker Disclosures:

3. Ovarian Cancer Biography:
90%
Uptodate.com – Accessed 07/02/2019
Freimund et al. Hematol Oncol Clin N Am 32 (2018) 983-996.

4. Tumor Frequency (%)
Ovary 4.12
Cervix 1.17
Endometrium 0.62
Vagina 0.14
Vulva 0.09
Ovarian Cancer Biography:
https://seer.cancer.gov/statfacts/html/ovary.html
Ibrahim et al. Journal of Cancer Epidemiology, Volume 2014
Article ID 437971, 18 PAGES.

5. Ovarian Cancer Biography:
Voughan et al. Nature Reviews Cancer. Vol 11. 2011, 719

6. 17.7%
without
relapse
Progressoin-freesurvival
(3126patients/275events)
5.3%progression during chemotherapy
(refractory)
17.2%relapse 0-6
monthsafter chemotherapy
(resistant)
22.7% relapse within 6-12 months
after chemotherapy (partially
sensitive)
22.5%
relapse
within
6 months
59.9%
relapse after
>6 months
37.2%
after
>12 months
0 120 1322412 4836
3.7%relapse 60-120 months
after chemotherapy (second
primary?)
60 72 84 96 108
Time (Months)
100
0
70
50
30
10
90
60
40
20
80
33.5% relapse within
12-60 months
after chemotherapy (sensitive)
5 yr PFS22.6%
Median PFS18.2months
Ovarian Cancer: Course of Disease
FIGO IIB-IV: Individual patient data meta-analysis of three AGO phase 3 first-line trials (AGO Ovar 3, 5, 7)
AGO=Arbeitsgemeinschaft Gynäkologische Onkologie; FIGO=International Federation of Gynecology and Obstetrics; PFS=progression-free
survival. Proprietary data from the AGO study group
Primary
Resistance
Secondary
Resistance
Cure

7. Ovarian Cancer Biography:
Giornelli & Mando. EMJ. 2017;2[3]:128-135
Palmirotta et al. Critical Reviews in Oncology/Hematology 117 (2017) 12–29

8. Ovarian Cancer Biography:
MDR1 CTR1
Activation
Oxidative Stress
DNA Damage
Adduct Formation
Cisplatin
Cell Cycle Arrest or P53
Activation
Apoptosis
HR
NER
MMR
BRCA1/
2
Drug
Efflux
Glutathione Transferase
Glutamylcysteine Synthetase
ERCC
1/2++ DNA Repair 
Loss of Apoptosis
ATP7 A/B
Freimund et al. Hematol Oncol Clin N
Am 32 (2018) 983-996.

9. DNA in Cells Is Constantly Damaged and Repaired
Double-strand
Breaks (DSBs)
Single-strand
Breaks (SSBs)
Bulky Adducts
Nucleotide mutations,
substitutions, deletions,
insertions
Base Excision
Repair (BER)
Homologous
Recombination
Repair (HRR)
Nucleotide
Excision Repair
and Trans-Lesion
Synthesis
Mismatch Repair
(MMR)
O’Connor M. Mol Cell. 2015
DNA Damage Mechanism
DNA Repair Mechanism
Ovarian Cancer Biography:

10. Ovarian Cancer Biography:
R. Palmirotta et al. / Critical Reviews in Oncology/Hematology 117
(2017) 12–29

11. Ovarian Cancer Biography:
Freimund et al. Hematol Oncol Clin N Am 32 (2018) 983-996.

12. Ovarian Cancer Biography:
Freimund et al. Hematol Oncol Clin N Am 32 (2018) 983-996.

13. Ovarian Cancer Biography:

14. Ovarian Cancer Biography:

15. Line of Therapy Progression-Free Survival
Firstline 18.2months
Secondline 10.2months
Thirdline 6.4months
Fourthline 5.6months
Fifthline 4.4months
Characterizationof the secondto sixth lines of therapy and their effectsonsurvival wascarried out based on
data from 1620patients with advancedepithelial ovarian cancerfrom three, large,randomized Phase3
trials investigatingprimary therapy with different combination chemotherapyregimens.2
Patients Often Receive Multiple Treatment Lines
with Decreasing Periods of Remission Between
Regimens1,2
Table adapted from Hanker LC, et al. Ann Oncol. 2012;23(10):2605-2612.
1. Markman, M. et al. The Oncologist. 2000. 2. Hanker LC, et al. Ann Oncol. 2012
Overcome Resistance ++ Time Between Lines

16. PARP inhibitors exploit synthetic lethality in tumour cells with
dysfunctional HRR1-4
1. Helleday et al. Molecular Oncology 2011 2. Aly A et al. J Mol Cell Biol. 2011 3. Girolimetti et al. Biomed Research International. 2014; 4.
O’Connor MJ. Mol Cell 2015
Single strand break
PARP
Normal cell
Repair by base
excision repair
Double strand break
Normal cell
Repair by homologous
recombination

17. PARP inhibitors exploit synthetic lethality in tumour
cells with dysfunctional HRR1-4
1. Helleday et al. Molecular Oncology 2011 2. Aly A et al. J Mol Cell Biol. 2011 3. Girolimetti et al. Biomed Research International. 2014; 4.
O’Connor MJ. Mol Cell 2015
Single strand break
PARP
Double strand breaks
Homologous recombination
deficient cancer cell
Increase in double
strand breaks
Cell death
Non-functioning HR e.g.
BRCAmut
PARP inhibitor

19. PARPi sensitivity and HRD
• The relationship between sensitivity to PARPi and HRD is likely to be more
akin to a continuous rather discrete variable
• For example, patients with a BRCAm are highly sensitive to PARP inhibition,
but lack of a BRCA mutation does not preclude sensitivity to PARPi1,2
High level of HRD Low level of HRD
BRCAm
Likelihood of
clinical benefit
High grade serous ovarian
cancer Level of platinum
resistance
1. Ledermann J, et al. Lancet Oncol. 2014 2. Ledermann J, et al. Lancet Oncol. 2016

20. Olaparib Monotherapy in Ovarian Cancer:
A Non-randomized Phase II Trial
BRCAmt BRCA
wt
ORR*
*RECIST
41% 24%
Platinum- BRCAstatus ORR(%) N=
Sensitive
wt 50% (10/20)
mt 60% (3/5)
Resistant
wt 4% (1/26)
mt 33% (4/12)
BRCAmt=BRCA mutant; BRCAwt=BRCA wild type; CA-125=cancer antigen-125; ORR=objective response rate; RECIST=response evaluation criteria
in solid tumors. Gelmon KA, et al. Lancet Oncol. 2011.

21. Maintenance trial design
1. Ledermann J et al. N Engl J Med 2012. 2. Mirza et al. N Engl J Med 2016. 3. Pujade-Lauraine et al. Lancet Oncol 2017. 4. Coleman et al. Lancet
2017
Randomised trials of PARP inhibitors in platinum-sensitive high-grade relapsed ovarian cancers
PARP inhibitor
Randomised
Placebo
• Platinum-sensitive relapsedhigh-
grade ovarian cancer
• ≥ 2 previous platinum regimens
• Last chemotherapy was platinum-
based, to which they had a maintained
PR or CR prior to enrolment
• Stable CA-125
Treatment
until
disease
progression
Primary
endpoint
:
PFS
Olaparib
Niraparib
Rucapari
b

22. Key demographics of maintenance
trials with PARP inhibitors
One patient received two regimens of platinum-based chemotherapy that were not recorded because the data were not entered into the databased before it was locked. This patient
was therefore classified as having received no chemotherapy regimens
Study 191
(ITT – PSR OC)
SOLO-22
(ITT – BRCAm PSR OC)
NOVA3
(gBRCAm PSR OC / non-gBRCAmPSR
OC)
ARIEL34
(ITT – PSR OC)
Olaparib
(n=136)
Placebo
(n=129)
Olaparib
(n=196)
Placebo
(n=99)
Niraparib
(n=138) /(n=234)
Placebo
(n=65) / (n=116)
Rucaparib
(n=375)
Placebo
(n=189)
Prior lines ofplatinum-
based chemotherapy,
median
3* 3 2 2 2 / 2 ≥3 / 2 2 2
PR to platinum-based
chemotherapy (%)
58 51 54 53 49 / 50 49 / 48 66 66
CR to platinum-based
chemotherapy (%)
42 49 46 47 51 / 50 51 / 52 34 34
Platinum-free interval,
6-12 months (%)
39 42 40 40 39 / 39 40 / 38 40 40
Platinum-free interval >
12 months (%) 61 58 60 60 61 / 62 60 / 62 60 60
1. Ledermann J et al. N Engl J Med 2012. 2. Mirza et al. N Engl J Med 2016. 3. Pujade-Lauraine et al. Lancet Oncol 2017. 4. Coleman et al. Lancet
2017

23. Study 19: Olaparib maintenance
Ledermann J et al. N Engl J Med 2012; Ledermann J et al. Lancet Oncol 2014.
Progression-free survival
Subpopulation with BRCA mutationWhole population with HGSOC
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Proportionofpatients
progression-free
3 15 180 6 9 12
Time from randomisation(months)
Number at risk:
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
3 6
9
120
Time from randomisation(months)
Olaparib 136 104 51 23 6 0 0 Olaparib 74 59 34 15 5 0
Placebo 129 72 23 7 1 0 0 Placebo 62 35 13 2 0 0
Number at risk:
Olaparib
(n=74)
Placebo
(n=62)
Events/N [%]
60/13
6
[44.1]
93/12
9
[72.1]
MedianPFS,
months
8.4 4.8
HR=0.35
95% CI: 0. 25, 0.49;
P<0.001
Olaparib
(n=74)
Placebo
(n=62)
Events/N [%] 26/74 [35] 46/62 [74]
MedianPFS,
months
11.2 4.3
HR=0.18
95% CI: 0. 10, 0.31;
P<0.0001
Proportionofpatients
progression-free

24. A PFS benefit was also observed in patients
without a BRCAm
Adapted from Ledermann J, et al. Lancet Oncol. 2014
*Pre-specified, p-values not adjusted for multiplicity.
N=254 patients with known BRCA mutation status. DCO: June 2010; Median overall PFS FU: 5.6 months
Analysis performed after 154 progression events had occurred (in 58% of patients)
46% reduction in risk of progression or death
Non-BRCAm (n=118)
Olaparib Placebo
Events/N [%] 32/57 [56] 44/61 [72]
Median
PFS,
months
7.4 5.5
HR=0.54
95% CI: 0.34–0.85;
P=0.0075*
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Olaparib non-BRCAm
Placebo non-BRCAm
0 3 6 9 12 15
Number at risk
Time from
randomisation
(months)
Olaparib non-
BRCAm
57 45 18 9 2 0
Placebo non-
BRCAm
61 35 10 4 1 0
Proportionofpatients
progressionfree

25. Study 19: Olaparib maintenance
Ledermann J et al. N Engl J Med 2012; Ledermann J et al. Lancet Oncol 2014.
Overall survival

26. Study 19: Olaparib maintenance
Ledermann J et al. N Engl J Med 2012; Ledermann J et al. Lancet Oncol 2014.
Time to First Subsequent Therapy

27. Study 19: Olaparib maintenance
Ledermann J et al. N Engl J Med 2012; Ledermann J et al. Lancet Oncol 2014.
Time to Second Subsequent Therapy

34. Moore et al. N Engl J Med. 2018;379:2495-505
60.4%
26.9%

35. Solo 1: 2ry Endpoints
Kathleen Moore et al. ESMO 2018 Presidential
Symposium

36. FDA Official Website: Accessed 20th
December 2018

37. is the first Phase III study to evaluate the efficacy of single agent
treatment with a PARP inhibitor (olaparib tablets) in BRCAm OC patients
who have progressed at least six months after last platinum treatment
and have received at least 2 prior platinum treatments1
High level results from the SOLO-3 trial demonstrated that olaparib improved the primary endpoint of
objective response rate compared to physician’s choice of chemotherapy in platinum-sensitive relapsed
OC patients with BRCA mutations. The key secondary endpoint of progression free survival was also
significantly improved
Can we get rid of chemotherapy?
www.astrazeneca.com: last acessed 20th
December 2018

38. Safety profiles of the different PARP inhibitors
Note: In the absence of head to head data between PARPi efficacy and safety comparisons between PARPi are not to be made or communicated
MDS, myelodysplastic syndrome; SAE, serious adverse event
Olaparib
(SOLO-2)
Niraparib
(NOVA)
Rucaparib
(ARIEL3)
Discontinuation 10.8% 14.7% 13%
Dose reduction 25.1% 66.5% 55%
Related SAE 18% 16.9% 21%
Nausea/vomiting, Grade ≥3 2.6% 3% 4%
Fatigue, Grade ≥3 4.1% 8.2% 7%
Anaemia, Grade ≥3 19.5% 25.3% 19%
Thrombocytopenia, Grade ≥3 1% 33.8% 5%
Neutropenia, Grade ≥3 5.1% 19.6% 7%
MDS 1 (0.5%) 5 (1.4%) 3 (1%)
GOT/GPT, Grade ≥3 - - 10%
1. Pujade-Lauraine E, et al. Lancet Oncol. 2017. 2. Mirza MR, et al. N Engl J Med. 2016. 3. Coleman RL, et al. Lancet. 2017.

39. Resistance to PARP Inhibitors
• Reversion of BRCA mutations
detected in tumor and cfDNA
• Increase P-Glycoprotein efflux pump
• Increased expression of RAD51
• Loss of 53BP1 restores HR
• Increased miR-622 supresses NHEJ
and leads to increased DSB repair
Fojo & Bates Cancer Disc 2013

40. Strategies for the Future!
Reduce PARP resistance
• ? Earlier treatment
• Additional DDR inhibition
Combination therapies
• Anti-angiogenic therapy
• Immune checkpoint
inhibition

41. Strategies for the Future!
Reduce PARP resistance
• ? Earlier treatment
• Additional DDR inhibition
Hamilton EP, et al. J Clin Oncol 2016;34(suppl;
abstr 5562)

42. Randomised Phase II Trial Combining Cediranib and Olaparib
in Platinum-Sensitive Recurrent Ovarian Cancer
Liu JF, et al. Lancet Oncol. 2014

43. Rationale for combining PARPi and PDL1/PD1
inhibitors
Immunologically
active
Immunologically
paused
Immunologically
absent
PARP
inhibito
r
It is hypothesised that PARPI induces DNA damage and genomic instability in HRD mutated tumours
which results in enhanced immunogenicity and response to durvalumab1-2
1. Hartlova A et al. Immunity 2015; 2. Nolan E et al. Sci Transl Med 2017 3. Angell et al. SITC 2017

44. Combination Therapy: Ongoing Trials
Anti-Angiogenesis Combination Immune Checkpoint Inhibitor Combination
Clinicaltrials.gov
Proposed Strategy Trials
Maintenance combinations • PAOLA 1:
(olaparib/bevacizumab)
first-line
• ICON9:
cediranib/olaparib v
olaparib
• AVANOVA: Niraparib +
bevacizumab
Combinations versus
chemotherapy
NRG-GYN 004: olaparib +
cediranib v platinum-based
chemotherapy
Trial name Phase N Treatment arms Population
NCT02657889
(TOPACIO)
I/II 114
Pembrolizumab +
Niraparib
Recurrent ovarian
or TNBC
NCT02520154 II 30
Pembrolizumab +
paclitaxel + carboplatin
Newly diagnosed
ovarian
NCT02853318 II 40
Pembrolizumab +
bevacizumab +
cyclophosphamide
Recurrent ovarian,
fallopian tube or
primary peritoneal
NCT02873962 II 38
Nivolumab +
bevacizumab
Relapsed epithelial
ovarian, fallopian
tube or peritoneal

45. Biomarkers for PARPi sensitivity
• There are several biomarkers that already exist to identify PARPi sensitivity
BRCA mutations: ~20% of high grade serous cancers have a BRCA mutation
Homologous recombination deficiency (HRD)
Laboratory biomarkers1,2
Clinical biomarkers1,3
Degree of platinum sensitivity
Number of lines of previous treatments
High-grade serous histology
1. Benafif S, Hall M. Onco Targets Ther. 2015 Feb 26;8:519-28; 2. Konstantinopoulos PA et al. Cancer Discov. 2015 Nov;5(11):1137-54; 3. Hanker
LC et al. Ann. Oncol. 2012;23(10):2605-2612

46. • Olaparib FDA Approvals:
1. Rec. gBRCAmut following > 3 lines.
2. Maintenance in Rec. Platinum Sensitive EOC (CR – PR), Upfront
(SOLO1).
3. Rec. Breast Cancer gBRCAmut – Her 2 Negative previously received
chemotherapy.
• Increase in progression-free survival across all groups of patients
with high grade ovarian cancer that respond to platinum
– Greatest effect in germline or somatic BRCAm
– Significant but lesser benefit in BRCAw
– Benefit present irrespective of HRD status
Don’t Forget:

47. Thank You