1. 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

2. 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. 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?

4. 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):
Coleman RL, et al. Lancet 2017;390:
Pujade-Lauraine E, et al. Lancet Oncol 2017;18:
gBRCAmut, germline breast cancer gene mutation

5. 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% % 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.

6. 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):
Niraparib
Placebo

7. 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):
Coleman RL, et al. Lancet 2017;390:
Pujade-Lauraine E, et al. Lancet Oncol 2017;18:

8. 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):

9. 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):

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

11. 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:
2. Lord R, et al. SGO 2018.

12. 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
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.

13. 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

14. 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

15. 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

16. 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

17. 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