Dr Axel Walther Head of Research Bristol Cancer Institute UK Practical experience with PARP inhibitors in ovarian cancer maintenance Dr Axel Walther Head of Research Bristol Cancer Institute UK ESMO 2018 Munich, Germany

PARPi? Mrs AJ – 66 years old CA125 Months Carboplatin Paclitaxel Bevacizumab Carboplatin Gemcitabine Bevacizumab Carboplatin Weekly paclitaxel Carboplatin PLD PARPi? CA125 6 12 18 24 30 36 42 48 54 Months PLD, pegylated liposomal doxorubicin

3 questions about PARPi maintenance What benefits do PARP inhibitors provide for my patient? Are the available PARP inhibitors acceptable and tolerable? Are PARP inhibitors safe to use for long-term therapy?

Efficacy comparison HR=0.27 (0.17 to 0.41)P<0.001 Progression-free survival for licensed PARP inhibitors, gBRCAmut cohorts HR=0.27 (0.17 to 0.41)P<0.001 100% HR=0.27 (0.17 to 0.41)P<0.001 80% Niraparib Rucaparib Olaparib tablets 60% 40% 20% 6 12 18 24 6 12 18 24 6 12 18 24 Months Months Months Mirza MR, et al. N Engl J Med 2016;375(22):2154-2164. Coleman RL, et al. Lancet 2017;390:1949-1961. Pujade-Lauraine E, et al. Lancet Oncol 2017;18:1274-1284. gBRCAmut, germline breast cancer gene mutation

Preferred therapy schedule Patient preferences Survey of 1,954 patients <70 / >70 Preferred therapy schedule Increasing the chance of cure Improvement of QoL No deterioration of QoL Delaying the tumour progression Shrinking the tumour Decrease of CA-125 Other Daily (oral) Every 3 weeks (infusion) Twice a day (oral) Twice a week (oral) Weekly (infusion) Other schedule 0% 5% 10% 15% 20% 25% 30% 35% 0% 15% 30% 45% 60% 75% >70 18-70 QoL, quality of life Sehouli J, et al. EXPRESSION IV. ESGO 2017 Abstract.

ENGOT-OV16 / NOVA: quality of life outcome “I have lack of energy” “I have nausea” Patients (%) Patients (%) “I have pain” “I have vomiting” Patients (%) Patients (%) Solid lines represent “Any Symptoms”; Dashed lines represent “Severe Symptoms” Size of circles corresponds to # of patients Oza A, et al. Lancet Oncol 2018;19(8):1117-1125. Niraparib Placebo

Combined side-effects across licensed PARPi All grade selected side-effects, all PARPi Comparative incidence MDS, myelodysplastic syndrome Mirza MR, et al. N Engl J Med 2016;375(22):2154-2164. Coleman RL, et al. Lancet 2017;390:1949-1961. Pujade-Lauraine E, et al. Lancet Oncol 2017;18:1274-1284.

ENGOT-OV16 / NOVA: selected adverse events Incidence for patients on niraparib (all grades) Thrombocytopenia Nausea patients (%) Anaemia Vomiting patients (%) Neutropenia Diarrhoea* patients (%) *TESARO, Inc. Data on File. Berek JS, et al. Ann Oncol 2018;29(8):1784-1792.

Timeline of thrombocytopenia Mean change in platelet levels from baseline in ENGOT-OV16 / NOVA trial (109/L ± standard error) 150 120 89 59 28 -2 -32 -63 -93 -124 -154 Niraparib Placebo First Month of Treatment Is when thrombocytopenia typically manifests1 Median time to onset of Grade 3-4 thrombocytopenia was 23 days2 Median time to resolution with dose interruption and/or dose reduction for Grade 3-4 thrombocytopenia was 10 days2 Cycle 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Day 21 Adapted from Mirza MR, et al. N Engl J Med 2016;375(22):2154-2164.

Effect of body weight on side-effect incidence Incidence for patients on niraparib Anaemia Diarrhoea Berek JS, et al. Ann Oncol 2018;29(8):1784-1792.

Dose individualisation Dose individualisation based on body weight and platelets does not impact efficacy Baseline body weight: <77 kg Baseline platelets: <150,000/µL OR Time (months) 1.0 0.8 0.6 0.4 0.2 4 8 12 16 20 24 ■ 200 mg ■ 100 mg ■ 300 mg PFS Starting dose Dose individualisation Patients <77 kg or platelets <150,000 200 mg (Two 100 mg capsules, QD) 300 mg 200 mg 100 mg Patients ≥77 kg and platelets ≥150,000 300 mg (Three 100 mg capsules, QD) From Month 4: HR (300 vs 200): 1.01 (95%CI: 0.69, 1.48) From Month 4: HR (300 vs 100): 1.05 (95%CI: 0.84, 1.31) *With dose modifications HR, hazard ratio; PFS, progression free survival; QD, once daily 1. Moore KN, et al. Gynecol Oncol 2018: https://doi.org/10.1016/j.ygyno.2018.01.011 2. Lord R, et al. SGO 2018.

Individualised dosing reduces haematological adverse events in PRIMA study Haematological toxicities Grade Pre-amendment, fixed starting dose 300 mg QD (Pooled niraparib & placebo) Post-amendment, individualised starting dose 300 + 200 mg QD N=480 N=247 Thrombocytopenia Any grade, n (%) 164 (34.2) 50 (20.2) ≥Grade 3, n (%) 110 (22.9) 22 (8.9) Grade 4, n (%) 76 (16.5) 8 (3.2) Anaemia† 229 (47.7) 77 (31.2) 101 (21.0) 27 (10.9) Neutropenia‡ 148 (30.8) 57 (23.1) 75 (15.6) 23 (9.3) *†Anaemia events included anaemia and haemoglobin decrease ‡Neutropenia events included neutropenia, febrile neutropenia, and neutrophil count decrease QD, once daily Gonzalez-Martin A, et al. PRIMA. Presented at ESMO 2018.

How to manage haematological adverse events? 1st occurrence 2nd occurrence Platelets <100,000/µL Withhold for up to 28 days and monitor blood count weekly until platelet counts ≥100,000/µL Resume at same or reduced dose based on clinical evaluation If platelet count is <75,000/µL at any time, resume at a reduced dose Withhold for up to 28 days, weekly FBC until platelet counts ≥100,000/µL Resume at reduced dose Discontinue if platelets have not returned to acceptable levels within 28 days of dose interruption, or if patient already has already undergone dose reduction to 100 mg QD Neutrophil <1,000/µL or haemoglobin <8 g/dL Withhold for up to 28 days, weekly FBC until neutrophils ≥1,500/µL or Hb ≥9 g/dL Resume at a reduced dose Discontinue if neutrophils and/or haemoglobin have not returned to acceptable levels within 28 days of dose interruption, or if patient has already undergone dose reduction to 100 mg QD If patient not recovering, MDS should be excluded FBC, full blood count; Hb, haemoglobin; QD, once daily Modified from https://www.ema.europa.eu/documents/product-information/zejula-epar-product-information_en.pdf

How to manage haematological adverse events? 1st occurrence 2nd occurrence Platelets <100,000/µL Withhold for up to 28 days and monitor blood count weekly until platelet counts ≥100,000/µL Resume at same or reduced dose based on clinical evaluation If platelet count is <75,000/µL at any time, resume at a reduced dose Withhold for up to 28 days, weekly FBC until platelet counts ≥100,000/µL Resume at reduced dose Discontinue if platelets have not returned to acceptable levels within 28 days of dose interruption, or if patient already has already undergone dose reduction to 100 mg QD Neutrophil <1,000/µL or haemoglobin <8 g/dL Withhold for up to 28 days, weekly FBC until neutrophils ≥1,500/µL or Hb ≥9 g/dL Resume at a reduced dose Discontinue if neutrophils and/or haemoglobin have not returned to acceptable levels within 28 days of dose interruption, or if patient has already undergone dose reduction to 100 mg QD If patient not recovering, MDS should be excluded FBC, full blood count; Hb, haemoglobin; QD, once daily Modified from https://www.ema.europa.eu/documents/product-information/zejula-epar-product-information_en.pdf

Mrs AJ – 66 years old, gBRCA wild-type Discuss maintenance therapy with your patient before CT start Carboplatin Paclitaxel Bevacizumab Carboplatin Gemcitabine Bevacizumab Carboplatin Weekly Paclitaxel Carboplatin PLD Niraparib CA125 6 12 18 24 30 36 42 48 54 60 66 72 CT, chemotherapy; PLD, pegylated liposomal doxorubicin Months

Personal recommendations for using PARPi based on clinical practice experience Prime the patient about intended PARP inhibitor use at the initiation of the preceding line of chemotherapy Allow patient 1 cycle length recovery after completion of chemotherapy Warn patient about the increased toxicity in the first 2-3 months, and that they tend to settle Monitor blood counts weekly for niraparib, fortnightly for other PARPi until stable for four weeks Pro-actively manage side-effects with best supportive care from day 1, cycle 1 For adverse drug reactions, including haematological toxicities, dose interruption, reduction and/or discontinuation are recommended AEs Interruption Dose reduction Discontinuation

Take home points PARP inhibitors significantly improve prognosis in patients with ovarian cancer PARP inhibitors are generally very well tolerated, permitting long-term use Pro-active management of side-effects maintains quality of life Inform patients early of intended PARP inhibitor use