Presented July 10, 2016 at the Ovarian Cancer National Conference in Washington, DC

1. Targeting BRCA for Therapeutic Benefit:
Update on PARP inhibitors as a treatment for all
subtypes of ovarian cancer
Ursula Matulonis, M.D.
Director and Program Leader
Gynecologic Oncology Program
Dana-Farber Cancer Institute
Associate Professor of Medicine
Harvard Medical School
Boston MA

2. Pertinent Conflicts of Interest:
Consultant: Astrazeneca, Clovis
Steering committee membership: Astrazeneca (Study
19), Tesaro (NOVA study)

3. What are PARP inhibitors?
• PARP = poly (ADP ribose) polymerase
• PARP is an enzyme that helps repair damaged DNA.
Damage to DNA is caused by many events (UV light,
radiation, etc).
• Inhibiting the PARP enzyme with a PARP inhibitor
prevents the DNA from repairing itself; cell then dies.
• Cancer cells with underlying vulnerabilities in repairing
DNA such as those with an abnormal BRCA gene are
more susceptible to PARP inhibitors

4. Spectrum of the degree of cancer cell susceptibility
to PARP inhibitors; (i.e. definitions of “BRCAness”)
• BRCA positive:
Presence of a BRCA mutation (either germline or
tumor)
• HRD positive:
HRD = Homologous recombination deficiency
(Underlying defects in DNA repair are present in
the cancer) positive as defined by testing the
tumor’s DNA
• HRD negative:
No BRCA mutation and the HRD test is negative

5. High grade serous cancers:
Homologous recombination deficiency
(HRD) is common and thus displays
high rate of platinum and PARP
inhibitor sensitivity
Serous
Endometrioid
Mucinous
Clear cell
Low grade High grade
PARP inhibitors exploit HRD presence in different
types of ovarian cancer

6. High grade serous cancers:
Homologous recombination deficiency
(HRD) is common and thus displays
high rate of platinum and PARP
inhibitor sensitivity
Serous
Endometrioid
Mucinous
Clear cell
Low grade High grade
PARP inhibitors exploit HRD presence in different
types of ovarian cancer

7. High grade serous cancers:
Homologous recombination deficiency
(HRD) is common and thus displays
high rate of platinum and PARP
inhibitor sensitivity
Serous
Endometrioid
Mucinous
Clear cell
Low grade High grade
Important!
Other histologies of ovarian
cancer also have DNA repair
defects making them
susceptible to PARP
inhibitors or PARP inhibitor
combinations
PARP inhibitors exploit HRD presence in different
types of ovarian cancer

8. 2005: first evidence in the lab that PARP inhibitors work in
BRCA+ cancer cells
2007-08: First patients showing benefit from PARP
inhibitors and phase II trials of olaparib launched
2009: Combination trials are launched
2012: Olaparib shows benefit as maintenance therapy
following platinum based chemotherapy (study 19)
2013: Other Phase III PARP inhibitor trials are launched
2014: FDA gives accelerated approval to olaparib
Timeline of PARP inhibitor development

9. Olaparib in germline BRCA+
Recurrent Ovarian Cancer: FDA approval based on
ORR and DOR and not based on platinum sensitivity
Response N = 137
Response rate 34%
Median Duration of response 7.9 months
Olaparib FDA approval on 12/20/14:
Olaparib as monotherapy in pts with deleterious/suspected
deleterious gBRCA recurrent ovarian cancer treated with ≥3
lines of chemotherapy.
Study 42: Kaufman B, et al. J Clin Oncol. 2015;33:244-250.

10. PARP inhibitors in clinical trials
for ovarian cancer
PARP inhibitors
Olaparib
Veliparib
Rucaparib
Niraparib
Talazoparib
(BMN673)

11. PARP inhibitors in clinical trials
for ovarian cancer
PARP
inhibitor
Key Studies Ongoing or Completed
Olaparib Phase III
SOLO1: new diagnosis, maintenance, BRCA+ (NCT01844986)
SOLO2: maintenance post-platinum, BRCA+ (NCT01874353)
GY004: olap/cediranib vs platinum for sensitive relapse
(NCT02446600)
GY005: olap/cediranib vs single agents for resistant relapse
(NCT02502266)
Veliparib Phase III:
newly diagnosed ovarian cancer: still accruing (NCT02470585)
Rucaparib Phase III: ARIEL3 (still accruing) (NCT01968213)
Phase II: ARIEL2 given FDA breakthrough status in 2015
(NCT01891344)
Niraparib Phase III: NOVA (NCT01847274)
Reported positive results on June 28, 2016

12. Presented by: Joyce Liu,
MD, MPH
• Randomized multi-center Phase 3 study, international study, double
blinded study
• Stratified for BRCA mutation and HRD test done retrospectively
• Eligibility criteria included:
– Platinum-sensitive relapsed high grade ovarian cancer
Dx platinum-
sensitive
recurrent
ovarian cancer,
received
platinum and
there is an anti-
cancer
response
Randomize 2:1
(niraparib
vs.placebo)
Placebo
Niraparib 300
mg every day
orally
Disease
progression by
radiographic
imaging
NOVA study (niraparib): phase III study
1www.tesarobio.com
Matulonis et al, ASCO 2014NCT01847274

13. Presented by: Joyce Liu,
MD, MPH
• Randomized multi-center Phase 3 study, international study, double
blinded study
• Stratified for BRCA mutation and HRD test done retrospectively
• Eligibility criteria included:
– Platinum-sensitive relapsed high grade ovarian cancer
Dx platinum-
sensitive
recurrent
ovarian cancer,
received
platinum and
there is an anti-
cancer
response
Randomize 2:1
(niraparib
vs.placebo)
Placebo
Niraparib 300
mg every day
orally
Disease
progression by
radiographic
imaging
NOVA study (niraparib): phase III study
NOVA Results released in a press release on June
28, 20161:
Increased time in remission for women receiving
niraparib compared to placebo who have a
BRCAm as well as for the group of women whose
cancers were HRD positive. Some benefit too
from niraparib versus placebo for the women
whose cancers were HRD negative
1www.tesarobio.com
Matulonis et al, ASCO 2014NCT01847274

14. Can PARP inhibitors be used in ovarian cancer
without abnormalities of BRCA?
• Single agent PARP inhibitors in BRCA
negative cancers (niraparib, rucaparib)
• Combinations of PARP inhibitors and other
biologic agents (GY004 and GY005)

15. Figure 6 Therapeutic Targeting of the Hallmarks of Cancer Drugs that interfere with each of
the acquired capabilities necessary for tumor growth and progression have been developed
and are in clinical trials or in some cases approved for clinical use.
Cell, Volume 144, Issue 5, 2011, 646 - 674
Cancer is complex

16. Figure 6 Therapeutic Targeting of the Hallmarks of Cancer Drugs that interfere with each of
the acquired capabilities necessary for tumor growth and progression have been developed
and are in clinical trials or in some cases approved for clinical use.
Cell, Volume 144, Issue 5, 2011, 646 - 674
Cancer is complex

17. Phase 1 study of cediranib (Oral VEGFR1, 2, and 3
inhibitor) and olaparib demonstrated
activity in ovarian cancer patients: NCT01116648
Presented by: Joyce Liu,
MD, MPH

18. • Dose escalation study of cediranib and olaparib in
recurrent ovarian and triple negative breast cancer
• This study:
--Showed significant anti-cancer activity of the
combination
--Established the dosing for both drugs so that the
randomized phase II could begin
Presented by: Joyce Liu,
MD, MPH
Liu et al., Eur J Cancer 2013
Phase 1 study of cediranib (Oral VEGFR1, 2, and 3
inhibitor) and olaparib demonstrated
activity in ovarian cancer patients: NCT01116648

19. Presented by: Joyce Liu,
MD, MPH
Phase 2 Study Design
• Randomized multi-center open-label Phase 2 study
• Eligibility criteria included:
– Platinum-sensitive relapsed ovarian cancer
– High-grade serous or endometrioid histological subtype
– Other high-grade histological subtypes with known germline BRCA mutation allowe
Dx platinum-
sensitive
recurrent
ovarian
cancer
Randomize 1:1
Cediranib
30mg daily +
Olaparib
200mg BID
Olaparib
400mg BID
Disease
progression by
radiographic
imaging
PI: Liu
Liu et al,
Lancet Oncology 2014 NCT01116648

20. Primary Outcome: Cediranib/olaparib significantly
increased the time the cancer stayed in remission
for compared to olaparib alone
Benefit for the combination was much more
pronounced for BRCA negative cancers than
BRCA positive cancers
Why? Perhaps the anti-angiogenic effect of
cediranib makes the cancer cell more susceptible
to the effects of a PARP inhibitor
Presented by: Joyce Liu,
MD, MPH
Liu et al,
Lancet Oncology 2014 NCT01116648

21. Phase III NCI-sponsored olaparib and
cediranib studies in recurrent ovarian cancer
• NRG-GY004 (platinum sensitive)
olaparib vs olaparib/cediranib vs platinum
doublet (PI’s: Liu/UAM) (NCT02446600)
• NRG-GY005 (platinum resistant)
olaparib (or cediranib) vs
olaparib/cediranib vs single agent
chemotherapy
(PI’s: Lee/Secord) (NCT02502266)

22. Novel PARP inhibitor
combinations
• HSP90 + PARP inhibitors:
Heat shock protein 90 inhibitors: Preclinical data
generated by Panos Konstantinopoulos using patient
derived mouse xenograft models
In development.
• Immuno-oncology agents and PARP inhibitors:
Phase I Pembrolizumab and Niraparib
SU2C ovarian cancer grant
NCT02657889,
Phase I Olaparib and MEDI4736 (NCI) (NCT02484404)

23. Other combinations
• PARP and PI3K inhibitors
(NCT01623349)
• Wee1 and PARP inhibitors (Astrazeneca, Dana-
Farber, and MDAnderson)
• Anti-BCL2 and MEK inhibitors
(Joan Brugge lab HMS)
Combination development needs to be driven by
rationale, expected side effects, and cancer pre-
selection

24. Next steps
• PARP inhibitor roles in:
New diagnoses of ovarian cancer
Combinations with other agents that interfere
with DNA repair, immunotherapy agents, etc.
• Why are certain cells more sensitive or
resistant to PARP inhibitors?
• How does a cancer cell eventually become
resistant to a PARP inhibitor and what is the
treatment strategy then?
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