MAINTENANCE THERAPY WITH PARP INHIBITORS Prof Dr Sven Mahner, MD Chair and Director Department of Obstetrics & Gynaecology University Hospital Munich, Ludwig-Maximilians-University, Munich, Germany ESMO 2018 Munich, Germany

Maintenance therapy: Understanding the possibilities Maintenance therapy is given to sustain the disease control achieved with initial treatment Key considerations for maintenance therapy ? ? Tolerability profile of the treatment Criteria for initiating maintenance therapy ? ? Characteristics of a successful maintenance therapy Patient quality of life

Should we still do “Watch & Wait”? Fear of disease recurrence is a psychological burden Survivors (%) ∼50% women with early and advanced stage ovarian cancer fear disease recurrence2 Psychological burden may increase use of medication and health services1 Fatigue, nausea, vomiting, and poor sleep are associated with a reduction in QoL and increased fear of recurrence2 Uncertainty about and perceived risk of recurrence are two key fears in cancer survivors3 Follow-ups can trigger fear, but close and frequent monitoring can provide reassurance3 Psychological assessments of early-stage ovarian cancer survivors (N=58)1 PTSD, post-traumatic stress disorder 1. Matulonis UA, et al. Int J Gynecol Cancer 2008;18:1183-1193; 2. Mirabeau-Beale KL, et al. Gynecol Oncol 2009;114:353-359; 3. Kyriacou J, et al. Can Oncol Nurs J 2017;27:236-242.

What do patients expect from maintenance therapy? Survey of 1,954 patients Primary / Recurrence <70 / >70 Increasing the chance of cure Improvement of QoL No deterioration of QoL Delaying the tumour progression Shrinking the tumour Decrease of CA-125 Other Increasing the chance of cure Improvement of QoL No deterioration of QoL Delaying the tumour progression Shrinking the tumour Decrease of CA-125 Other ** ** * * ** * 0% 15% 30% 45% 60% 75% 0% 15% 30% 45% 60% 75% >70 Recurrence Primary 18-70 *p<0.001; **p<0.05 QoL, quality of life Sehouli J, et al. EXPRESSION IV/ESGO 2017.

What duration of maintenance therapy is acceptable? Survey of 1,954 patients Primary / Recurrence* <70 / >70 until tumour progression 48-60 months 24-36 months 18-24 months 12-18 months 6-12 months until tumour progression 48-60 months 24-36 months 18-24 months 12-18 months 6-12 months 0% 10% 20% 30% 40% 50% 0% 10% 20% 30% 40% 50% Recurrence Primary >70 18-70 *p<0.001 Sehouli J, et al. EXPRESSION IV/ESGO 2017.

The evidence: ENGOT-OV16 / NOVA Recurrent ovarian, fallopian tube or primary peritoneal cancer following CR or PR to second-line or later platinum-based chemotherapy (N=553) gBRCAmut (N=203) 2:1 Randomisation Non-gBRCAmut (N=350) 2:1 Randomisation Niraparib 300 mg QD Placebo QD Niraparib 300 mg QD Placebo QD Endpoint assessment Endpoint assessment Primary endpoint: PFS Radiologic disease progression Clinical signs and symptoms and increasing CA-125 Increasing CA-125 and additional diagnostic tests OR Progression measured by: BRCA, breast cancer gene; PFS, progression free survival; ENGOT, European Network for Gynaecological Oncological Trial groups; gBRCAmut, germline BRCA mutation Mirza MR, et al. N Engl J Med 2016;375:2154-2164.

PFS, non-gBRCA cohort (N=350) Niraparib significantly increased PFS vs placebo – in gBRCA and non-gBRCA cohorts PFS, gBRCA cohort (N=203) PFS, non-gBRCA cohort (N=350) 1.0 0.8 0.6 0.4 0.2 PFS probability Time (months) 6 12 18 24 HR = 0.27 (95% CI: 0.17–0.41) p < 0.001 1.0 0.8 0.6 0.4 0.2 PFS probability Time (months) 6 12 18 24 HR = 0.45 (95% CI: 0.34–0.61) p < 0.001 Niraparib Niraparib PFS 21.0 months PFS 9.3 months Placebo Placebo PFS 5.5 months PFS 3.9 months PFS, progression free survival; HR, hazard ratio; CI, confidence interval; BRCA, breast cancer gene; gBRCA, germline BRCA mutation; non-gBRCA, no germline BRCA mutation Mirza MR, et al. N Engl J Med 2016;375(22):2154-2164.

Published PFS results in maintenance therapy studies Anti-angiogenesis BRCA status not determined PARP inhibition gBRCA patients PARP inhibition non-gBRCA patients 21.0 months PFS 9.3 months PFS Chemotherapy 6 months Chemotherapy 6 months GOG2135 OCEANS6 Phase 3 N=337 N=242 5 10 15 Δ3.4 Δ4.0 8.4 10.4 13.8 12.4 N=377 8.8 11.8 Δ3.0 MITO16B7 Chemotherapy 6 months 21 N=138 9.3 Phase 3 NOVA1 N=234 HR 0.628 HR 0.27 HR 0.45 5.5 N=65 Δ15.5 3.9 Δ5.4 N=116 11.2 N=74 7.4 N=57 Phase 2 Study 192 HR 0.48 HR 0.18 4.3 N=62 Δ6.9 HR 0.54 5.5 Δ1.9 N=61 N=202 Phase 3 SOLO23 5.5 N=80 19.1 N=196 HR 0.51 not studied Δ13.6 N=203 HR 0.30 Phase 3 ARIEL34 16.6 N=130 5.4 N=66 not studied as a cohort HR 0.23 Δ11.2 5 10 15 20 25 5 10 15 20 Treatment Placebo PFS, progression free survival; BRCA, breast cancer gene; gBRCAmut, germline breast cancer gene mutated 1. Mirza MR, et al. N Engl J Med 2016;375:2154-164; 2. Ledermann J, et al. Lancet Oncology 2014;15:852-861; 3. Pujade-Lauraine E, et al. Lancet Oncology 2017;18:1274-1284; 4. Coleman RL, et al. Lancet 2017;390:1949-1961; 5. Coleman et al. Lancet Oncology 2017;18:779-791; 6. Aghajanian C, et al. J Clin Oncol 2012;30:2039-2045. 7. Pignata S, et al. J Clin Oncol 2018;36:(suppl; abstr 5506).