1. PARP INHIBITION IN OVARIAN CANCER
Mansoor R. Mirza
Nordic Society of Gynaecological Oncology (NSGO)
&
Rigshospitalet – Copenhagen University Hospital
Denmark

2. Presenter Disclosures
Board of Directors:
Karyopharm Therapeutics Inc.
Sera Prognostics Inc.
Consultant or Advisory Role:
Advaxis
Amgen
AstraZeneca
Boehringer Ingelheim
Cerulean
Clovis Oncology
GlaxoSmithKline
Genmab
Janssen
Karyopharm Therapeutics
Merck
Novocure
Pfizer
PharmaMar
Roche
SOBI
Tesaro
Study Grants:
AstraZeneca
Boehringer Ingelheim
Eli Lilly
Pfizer
Roche
Tesaro

3. Tumour specific killing by PARP Inhibitors
Homologous Recombination Repair
PARP
DNA SSBs occur all the time in cells and PARP detects and repairs them
During the replication process unrepaired SSBs are converted into DSBs
Replicating cells
Survival
Normal cell
Repair by Homologous Recombination
No effective repair (No HR pathway)
Cell death
Cancer cell with HRD
Tumour specific killing by PARP Inhibitors

4. Sporadic Ovarian Cancer
PARP Inhibitors
Sporadic Ovarian Cancer
OC is a genetically heterogeneous disease; BRCA1/2 deleterious mutations or chromosomal damage result in similar biology
The myChoice® HRD test measures DNA damage
Telomeric allelic imbalance (TAI)
Large-scale state transitions (LST)
Loss of heterozygosity (LOH)
PARP inhibitors block DNA repair pathways in homologous recombination repair deficient (HRD) cells1
Platinum sensitivity correlates with HRD, and platinum-sensitive tumors are more responsive to PARP-inhibitors than platinum- resistant tumors2-4
BRCA1 germline
BRCA2 germline
BRCA1 somatic
Other
BRCA2 somatic
BRCA1
methylation
EMSY amplification
“Ovarian Cancer is genetically heterogeneous”. Risk associated with BRCA and HRD.
There is clinical data to show that PARP inhibitors are effective in BRCA and there is activity observed outside BRCA specifically in HRD
MMR
germline
PTEN loss
CCNE1
amplification
Other HRD
HRDneg
HRDpos
Fong PC et al. J Clin Oncol 2010; 8(15):2512-9;
Matulonis UA et al. Ann Oncol. 2016;27:1013-9;
Liu JF et al. Gynecol Oncol. 2014;133(2):362-9;
Murai J et al. Cancer Res 2012;72:5588–5599.
Levine D. The Cancer Genome Atlas, 2011

5. Data from already reported randomized trials
Phase 2: AZ Study 19 (olaparib)
Phase 3: ENGOT-OV16 / NOVA (niraparib)

6. AZ Study 19: PFS
Phase 2 randomised trial of maintenance olaparib in platinum-sensitive high-grade serous relapse OC
Subpopulation with a BRCA mutation
Whole population with HGSOC
Ledermann J et al. N Engl J Med 2012
Ledermann J et al. Lancet Oncol 2014

7. ENGOT-OV16 / NOVA
Phase 3 randomised trial of maintenance niraparib in platinum-sensitive high-grade serous relapse OC
Platinum-Sensitive Recurrent High Grade Serous Ovarian Cancer
Treatment with 4-6 Cycles of Platinum-based Therapy
Response to Platinum Treatment
553
gBRCAmut
203
Non-gBRCAmut
350
2:1 Randomization
2:1 Randomization
Script here needs to spell out the HRD test application
Point out that 100 events were needed for 90% power to detect a HR of 05 (4.8 vs 9.6 months).
Mention that PFS was by central read.
Make sure it is understood that there are 3 predefined efficacy populations: specifically state these
Niraparib 300 mg once daily
Placebo
Niraparib 300 mg once daily
Placebo
Treat until Progression of Disease
Treat until Progression of Disease
Mirza MR et al. N Engl J Med 2016; Presidential Symposium, ESMO 2016

8. ENGOT-OV16 / NOVA: PFS
Phase 3 randomised trial of maintenance niraparib in platinum-sensitive high-grade serous relapse OC
PFS: gBRCAmut
March 30 - April 2, 2014 Sheraton Sonoma County Petaluma, California
Treatment
PFS
Median
(95% CI) (Months)
Hazard Ratio (95% CI) p-value
% of Patients without Progression or Death
12 mo
18 mo
Niraparib
(N=138)
21.0
(12.9, NE)
0.27
(0.173, 0.410)
p<0.0001
62%
50%
Placebo
(N=65)
5.5
(3.8, 7.2)
16%
Mirza MR et al. N Engl J Med 2016; Presidential Symposium, ESMO 2016

9. ENGOT-OV16 / NOVA: PFS
Phase 3 randomised trial of maintenance niraparib in platinum-sensitive high-grade serous relapse OC
PFS: gBRCAmut
PFS: non-gBRCAmut
March 30 - April 2, 2014 Sheraton Sonoma County Petaluma, California
Treatment
PFS
Median
(95% CI) (Months)
Hazard Ratio (95% CI) p-value
% of Patients without Progression or Death
12 mo
18 mo
Niraparib
(N=138)
21.0
(12.9, NE)
0.27
(0.173, 0.410)
p<0.0001
62%
50%
Placebo
(N=65)
5.5
(3.8, 7.2)
16%
Treatment
PFS
Median
(95% CI) (Months)
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<0.0001
41%
30%
Placebo
(N=116)
3.9
(3.7, 5.5)
14%
12%
Mirza MR et al. N Engl J Med 2016; Presidential Symposium, ESMO 2016

10. PFS: non-gBRCAmut HRD-positive
Treatment
PFS
Median
(95% CI) (Months)
Hazard Ratio (95% CI) p-value
% of Patients without Progression or Death
12 mo
18 mo
Niraparib
(N=106)
12.9
(8.1, 15.9)
0.38
(0.243, )
p<0.0001
51%
37%
Placebo
(N=56)
3.8
(3.5, 5.7)
13% 9%
Close out that all three primary efficacy populations with consistent durable efficacy
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.
Mirza MR et al. N Engl J Med 2016; Presidential Symposium, ESMO 2016

11. ENGOT-OV16 / NOVA: PFS HRD-positive HRD-negative sBRCAmut BRCAwt
Exploratory Analysis: PFS in subgroups of Non-gBRCAmut Cohort
HRD-positive
HRD-negative
sBRCAmut
BRCAwt
Treatment
PFS
Median
(95% CI) (Months)
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, )
p=0.0248
62%
52%
Placebo
(N=12)
11.0
(2.0, NR)
19%
Treatment
PFS
Median
(95% CI) (Months)
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, )
p=0.0001
45%
27%
Placebo
(N=44)
3.7
(3.3, 5.6)
11% 6%
Treatment
PFS
Median
(95% CI) (Months)
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, )
p=0.0226
27%
19%
Placebo
(N=42)
3.8
(3.7, 5.6) 7%
Now that we have talked about primary populations, we move to exploratory analysis of the non-gBRCA cohort subgroups.
Somatic: In this subgroup, a significant treatment effect similar to that in the gBRCAmut cohort was observed with niraparib compared to placebo. Of note, the HR observed in the gBRCAmut cohort (0.27) was identical to the HR observed in this HRDpos/sBRCAmut subgroup demonstrating the consistency of the niraparib treatment effect across cohorts and in 2 independent patient populations with similar underlying tumor biology
Mirza MR et al. N Engl J Med 2016; Presidential Symposium, ESMO 2016

12. Secondary Efficacy Endpoints
Chemotherapy-free interval
gBRCAmut: HR 0.26 (22.8 mths vs 9.4 mths; 95% CI: 0.169, 0.414; p<0.0001)
Non-gBRCAmut: HR 0.50 (12.7 mths vs. 8.6 mths; 95% CI: 0.370, 0.666; p<0.0001)
Time to first subsequent treatment
gBRCAmut: HR 0.31 (21.0 mths vs. 8.4 mths; 95% CI: 0.205, 0.481; p<0.0001)
Non-gBRCAmut: HR 0.55 (11.8 mths vs. 7.2 mths; 95% CI: 0.412, 0.721; p<0.0001)
PFS 2 (data are immature)
gBRCAmut: HR 0.48 (25.8 mths vs mths; 95% CI: 0.280, 0.821; p=0.0062)
Non-gBRCAmut: HR 0.69 (18.6 mths vs.15.6 mths; 95% CI: 0.494, 0.964; p=0.0293)
Overall survival (data are immature)
26% patient deaths in either treatment arm; HR 0.73 (95% CI, to 1.125; p=0.1545)
One sentence that secondary edponints are supportive of the robustness of the overall data
Secondary endpoints, including CFI, TFST, TSST, and PFS2 demonstrated a persistent treatment effect in favor of the niraparib treatment arm in the gBRCAmut and the non-gBRCAmut cohorts consistent with the primary PFS. No detrimental impact of niraparib treatment on OS was observed and the HR was 0.73

13. Treatment-emergent Grade 3/4 Adverse Events Occurring in ≥5% of Patients
Event — no. (%)
Niraparib
(N=367)
Placebo
(N=179)
Thrombocytopeniaa
124 (33.8)
1 (0.6)
Anemiab
93 (25.3)
Neutropeniac
72 (19.6)
3 (1.7)
Fatigued
30 (8.2)
Hypertension
4 (2.2)
The most common grade ¾ TEAE are hematological abnormalities and fatigue consistent with the class effect of PARP inhibitors.
And we also observed hypertension.
MDS/AML was similar in niraparib and placebo arm.
MDS/AML occurred in 5 of 367 (1.4%) in patients who received niraparib and 2 of 179 (1.1%) in patients who received placebo.
*There were no Grade 5 events.
aThrombocytopenia=thrombocytopenia and decreased platelet count. No grade 3 or 4 bleeding events were associated with thrombocytopenia; bAnemia=anemia and decreased hemoglobin counts; cNeutropenia=neutropenia, decreased neutrophil count, and febrile neutropenia; dFatigue=fatigue, asthenia, malaise, and lethargy.

14. Dose Adjustments Due to Treatment-emergent Adverse Events
Any Grade
Grade 3/4
Any Grade
Event — no. (%)
Dose Reductions (N=367)
Events That Occurred After Cycle 3
(N=296)
Dose Discontinuations (N=367)
Thrombocytopeniaa
148 (40.3)
7 (2.4)
12 (3.3)
Anemiab
68 (18.5)
50 (16.9)
5 (1.4)
Neutropeniac
32 (8.7)
8 (2.7)
7 (1.9)
Fatigued
20 (5.4)
9 (3.0)
Hypertension - 1
The TEAE’s were managed by dose modifications. Mandatory dose reduction was required for grade 1 thrombocytopenia. Once the dose was modified based on individual patient tolerability, they continued niraparib treatment with the substantial decrease of these events beyond cycle 3. Only 3 and 1% discontinued study due to thrombocytopenia and anemia.
Mandatory dose reductions for hematology laboratory abnormalities were required for thrombocytopenia, anemia, and neutropenia
aThrombocytopenia=thrombocytopenia and decreased platelet count. No grade 3 or 4 bleeding events were associated with thrombocytopenia; bAnemia=anemia and decreased hemoglobin counts; cNeutropenia=neutropenia, decreased neutrophil count, and febrile neutropenia; dFatigue=fatigue, asthenia, malaise, and lethargy.

15. Patient-reported Outcomes
gBRCAmut: FOSI
Non-gBRCAmut: FOSI
Measured using the Functional Assessment of Cancer Therapy – Ovarian Symptom Index (FOSI) and the EQ-5D- 5L
PRO surveys were collected at:
Screening visit
Every other cycle through cycle 14
Post progression
Compliance rates were high, and similar between the two treatment arms
Niraparib: FOSI completion rate ranged from 75.0% to 97.1%
Placebo: FOSI completion rate ranged from 77.6% to 97.4%
PROs were similar for niraparib compared with placebo
gBRCAmut: EQ-5D-5L
Non-gBRCAmut: EQ-5D-5L
Patient Reported Outcomes were evaluated FOSI which looks at disease specific symptoms and EQ5D that looks at general symptoms.
No decremental effect in quality of life was observed with niraparib. The results were similar across treatments arms in the two cohorts.

16. Why do HRD negative patients respond to PARP-inhibitors?
The test may miss some HRD positive cases?
HRD tumours are more prevalent than previously believed in serous high grade?
Other non HRD DNA repair impaired mechanisms in these patients?
Courtesy of Sandro Pignata

17. Testing for HRD The myChoice® HRD test Loss of Heterozgosity (LOH)
Large-scale State Transitions (LST)
Telomeric Imbalance (TAI)
Courtesy of Tesaro/Myriad Genetics

18. Is HRD more frequent than earlier anticipated?
Konstantinopulos PA et al Cancer Discovery 2015

19. All related to response to platinum
Are there other impaired non-HRD mechanisms of DNA repair?
BER (Base excision Repair)
NER (nucleotide Ex Rep)
NHEJ (non-Homologus end Joining)
PARP inhibitors inhibit PARP-1, but also PARP2 that have different functions
(PARP2 is involved in DNA repair through NER)
All related to response to platinum
Yelamos J et al Am J Cancer Res 2011

20. Conclusions
The existing HRD test cannot split patients into responders & non-responders
The test can be complimentary to predict higher chance of response to PARPi
As we further understand the biology of DNA repair, a better test is needed
Until then the best “biomarker” for PARP-inhibitors is sensitivity to platinum based therapy

21. Who are the long-term responders?
High proportion of patients remains on treatment for a very long time
We are not able to identify these patients (other biomarkers needed?)
For “long-term responders” the natural history of the disease is changed

22. Conclusions
Niraparib significantly improved PFS in patients with platinum-sensitive recurrent ovarian cancer, regardless of BRCA mutation or HRD status. Efficacy is highest in BRCAmut population
gBRCAmut: HR 0.27
Non-gBRCAmut: HR 0.45
Non-gBRCAmut HRD-positive: HR 0.38
Non-gBRCAmut HRD-negative (exploratory): HR 0.58
Who are the long-term responders?
A better HRD test is needed to separate responders from non-responders; Until then, beyond BRCA, platinum-sensitivity remains the best “biomarker” for response to PARP inhibitors
PARP maintenance therapy should be offered to whole study population who respond to platinum-based treatment

23. We are converting ovarian cancer into a chronic disease