1. Conclusion Dr Antonio González Martín Head of Medical Oncology
MD Anderson Cancer Centre, Madrid, Spain
Associate Professor of Medicine
Francisco de Vitoria University, Madrid, Spain
Adjunct Professor
University of Texas, USA
ESMO 2018
Munich, Germany

2. Ask the faculty ASK-THE-FACULTY.COM/ESMO2018
We look forward to your questions…
… ask the faculty online!

3. PARPi maintenance therapy traditional Watch & Wait
A paradigm shift with the introduction of PARP inhibitor maintenance therapy
PARPi maintenance therapy
Debulking surgery
Chemotherapy
traditional Watch & Wait
Tumour volume
Treatment-free interval
Recurrence
Symptoms
Point of decision
Maintenance
Time

4. Pharmacokinetic and -dynamic profiles of PARP inhibitors
Absorption
Distribution
Metabolism
Elimination
F (%)
Papp (10-6 cm/s)
Vd/F (L)
Major enzyme
t1/2 (h)
Niraparib
731
12-182
1,0741
CE1
48-511
Olaparib
NA3
4-84
1675
CYP3A45
11.95
Rucaparib
366
6-87
CYP2D66
17-196
Niraparib is characterised by:
High tumour penetration – largest volume of distribution
No relevant drug-drug interaction
Once daily dosing with or without food1
F, bioavailability; Papp, apparent permeability; t1/2, half-life; Vd, volume of distribution; CE, carboxyl esterase; CYP, cytochrome p450 oxidase
1. ZEJULA® Summary of Product Characteristics, Nov 2017; 2. TESARO Inc., Data on File; 3. CHMP Assessment Report: Lynparza (EMA/CHMP/789139/2014).
Available at: Accessed Jan Clinical pharmacology and biopharmaceutics review: Lynparza. Available at:
Accessed Jan 2018; 5. Lynparza Summary of Product Characteristics, July 2017; 6. Rubraca package leaflet, Dec 2016; 7. Durmus S, et al. Pharm Res 2015;32(1): Zhang ZY, et al. Oral presentation at ISSX 2015, Oct 18-22, 2015, Orlando, USA.

5. 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):

6. 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.

7. 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.

8. PRIMA patient population reflects clinical practice
SOLO 1 (olaparib)1,2
PRIMA (niraparib)3
Patient population
N=391 (randomised to olaparib [n=260] or placebo arm [n=131])
High-grade (stage III-IV) ovarian, fallopian tube, or primary peritoneal cancer
Stage III patients must have had one debulking surgery
One attempt at optimal debulking, upfront or IDS
Stage IV patients must have had either biopsy and/or debulking surgery
Biopsy and/or upfront or interval debulking
Completed 1L platinum-based chemo
6-9 cycles of front-line chemotherapy, per protocol
CR/PR or NED to 1L platinum regimen
Some patients had residual macroscopic disease
BRCAmut (mostly germline, 2 patients had somatic mutations)
Randomised within 8 weeks of last dose of chemo
N=733 (LPI 13JUN18; increase from 468)
Stage III patients required to have visible residual disease after primary surgery
Stage IV patients are eligible, irrespective of residual disease, after primary or interval debulking
Patients with inoperable Stage III or IV disease are eligible
CR/PR to 1L platinum regimen
All comers
Randomised within 12 weeks of last dose of chemo
Dosing
300 mg BID
Dose reduction to 250 mg and 200 mg permitted
200 mg QD starting dose for low body weight (<170 lb) or low baseline platelet count (<150,000 uL)
300 mg QD for all other patients
Primary endpoint
PFS; investigator-assessed RECIST [scans every 12 weeks up to 3 years; every 24 weeks thereafter until radiological disease progression]
PFS; central review RECIST [scans every 12 weeks until progression]
Hierarchical testing: HRD+; ITT
Key secondary endpoints
OS; HRQoL; time to earliest progression by RECIST or CA-125; PFS2; TFST; TSST; TDT; safety
OS; PRO (HRQoL); PFS2; Time to CA-125 progression; safety & tolerability
For reference only, cross-trial comparisons are inappropriate
ClinicalTrials.gov Identifier: NCT
Moore K, et al. N Engl J Med 2018; DOI: /NEJMoa
ClinicalTrials.gov. NCT
BID, twice daily; BRCA, breast cancer gene; CR, complete response; HRQoL, health-related quality of life; HRD, homologous recombination deficiency; ITT, intention to treat; OS, overall survival; PFS, progression free survival; PR, partial response; PRO, patient-reported outcomes; QD, once daily; TDT, time to treatment discontinuation; TFST, time to first subsequent therapy; TSST, time to second subsequent therapy

9. Stratification factors
FIRST: Phase 3, randomised, placebo-controlled comparison of platinum-based therapy with TSR-042 and niraparib vs. standard of care as first-line treatment
Concurrent bevacizumab use
BRCA/HRD status
Disease burden: Stage III with residual disease <1 cm (yes or no)
Stratification factors
Newly diagnosed stage III/IV advanced ovarian cancer
Cycle 1: Carboplatin + paclitaxel ± bevacizumab
Randomisation
Estimated enrolment: =~720 to 960
Treatment
21days cycle
x 5 cycles
Carboplatin + Paclitaxel
+ Placebo (TSR-042)
Carboplatin + Paclitaxel
+ Placebo (TSR-042)
Carboplatin + Paclitaxel
+ TSR-042
+/- Bevacizumab
Maintenance
Up to 3 years
Placebo (TSR-042) + Placebo (Niraparib)
Placebo (TSR-042) + Niraparib
TSR Niraparib
Gonzalez-Martin et al. ESMO Poster Figure 1 and Study Assessments PROs
+/- Bevacizumab (i.e., maintenance doublets and triplets)
Adaptive design anticipates evolving first-line standard of care: double-placebo maintenance arm may be transitioned to niraparib maintenance for BRCAmut (pending SOLO-1 success) and BRCAwt (pending PRIMA success) patients over time
Primary Endpoint
PFS by investigator-assessment per RECIST v1.1 criteria
Key Secondary Endpoints
Overall Survival
PFS by BICR
HRQoL
Safety & Tolerability
PFS by irRECIST
BRCA, breast cancer gene; HRD, homologous recombination deficiency; PFS, progression-free survival; RECIST, response evaluation criteria in solid tumours; BICR, blinded independent central review;
irRECIST, immune-related response criteria in solid tumours; HRQoL, health-related quality of life; OS, overall survival
1. Accessed ; 2. TESARO, Inc. Data on File.

10. THANK YOU