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

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

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

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

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

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

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

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

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

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, 0.586) 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

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, 0.903) 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, 0.628) 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, 0.922) 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

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. 19.5 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, 0.480 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

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.

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.

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.

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

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

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

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

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

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

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

We are converting ovarian cancer into a chronic disease