1. Examining the relevant facts and new insights in PARP inhibition
Dr Maurizio D’Incalci, MD
Chief of Cancer Pharmacology Laboratory and Head of Dept Oncology
Mario Megri Institute
Milan, Italy
ESMO 2018
Munich, Germany

2. Outline Mode of action (canonical and not canonical)
Comparative pharmacokinetic features and preclinical anti-tumour activity
Analysis of the QUADRA study

3. Synthetic lethality
Igelhart, JD and Silver DP. N Engl J Med 2009;361(2):

4. Inhibition of PARP catalytic activity in vitro assay shows selectivity of PARP inhibitors
TNKS1
TNKS2
PARP6
PARP7
PARP8
PARP10
Niraparib
2.8 nM
0.6 nM
>1 µM
Olaparib
1.4 nM
0.8 nM
33 nM NA
722 nM
Rucaparib
0.3 nM
39 nM
201 nM
135 nM
787 nM
Talazoparib
1.0 nM
0.4 nM
29 nM
15 nM
6.7 nM
988 nM
588 nM
<10 nM nM
100 nM-1 µM
>1 µM
Results from a preclinical in vitro assay compared level of inhibition of PARP family members by various PARP inhibitors
PARP inhibitors were evaluated side-by-side in a panel of PARP assays by BPS Bioscience
PARP, Poly (ADP-ribose) Polymerase; TNKS1, tankyrase
Wang Y, et al. Presented at AACR; April 5–9, 2014: San Diego, CA; TESARO, data on file.

5. There is more than just PARP inhibition
Competitive binding to the NAD+ site
Catalytic inhibition (IC50 nM)
Cytotoxicity (IC90 µM)
PARP-trapping potency (relative to olaparib set as 1)
Olaparib 6
4.5 1
Rucaparib 21 3
Niraparib 60
2.3 ~2
Talazoparib 4
0.04
~100 +
potency
N-term
C-term
Znl
Znll
NLS
Znlll
WGR
* H
* Y
* E
DNA-binding
domain
automodification
domain
catalytic
domain
Murai J, et al. Mol Cancer Ther 2014;13(2):

6. Cellular effects of PARP1
transcriptional regulation
RNA interference
cell death
control of
cell division
inflammation
PARP1
angiogenesis
DNA repair
maintenance of telomeres
WNT signalling
formation of subnuclear bodies
mitochondrial function
Weaver, AN et al. Front Oncol
Swindal AF, et al. Cancers 2013;5(3): ; doi: /cancers

7. 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.

8. Concentration (ng/mL)
Niraparib demonstrated favourable exposure over olaparib in tumour, plasma, and brain
Mice bearing BRCA1mut tumour xenografts treated with niraparib exhibited greater AUCs in samples from tumour, plasma, and brain than those treated with olaparib 10
100
10,000
1,000
100,000 6 4 2 8 12 14 16 18 20 22 24
Time (hours)
Plasma concentration
Tumour concentration
Brain concentration
100,000
100,000
10,000
10,000
Concentration (ng/mL)
1,000
1,000
100
100
LLOQ 10 10 6 4 2 8 10 12 14 16 18 20 22 24 6 4 2 8 10 12 14 16 18 20 22 24
Time (hours)
Time (hours)
Niraparib 75 mg/kg QD ×5
Olaparib 100 mg/kg QD ×5
Studied in mice bearing BRCA1mut tumour xenografts treated with niraparib exhibited greater AUCs in samples from tumour, plasma, and brain than those treated with olaparib AUC, area under the curve; BRCA, breast cancer gene; BRCA1mut, BRCA1 mutation; Cmax, maximum concentration; LLOQ, lower limit of quantification; PK, pharmacokinetics; QD, once daily
Sun K, et al. Poster presented at AACR-NCI-EORTC 2017; Philadelphia, PA, USA, October 26–30, 2017.

9. QUADRA study design and patient eligibility
Study aim: Evaluate the efficacy of niraparib in a broad, late-line recurrent ovarian cancer population
Patients (N=463) with histologically diagnosed advanced, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received 3 or more prior chemotherapy
Niraparib 300 mg orally once daily, 28-day cycles
Endpoint assessment
Primary Endpoint
ORR by RECIST in HRD-positive patients who have received 3 or 4 lines of previous chemotherapy, platinum-sensitive, and PARPi-naïve
ORR, Objective Response Rate; HRD, homologous recombination deficiency
Moore KN, et al. ASCO 2018; abstract 5514 (poster presentation).

10. Patient characteristics
Patients enrolled in QUADRA represent a broad, late-line population
*2/3 of platinum sensitive patients were not treated with platinum in the line immediately prior to study entry
HRDpos (220)
68% platinum resistant or refractory
19% BRCAmut; 48% HRDpos
27% in 6th line or later
Plat. sens: platinum sensitive (time from last platinum until next progression ≥ 6 months), including platinum-ineligible;
Plat. res.: platinum resistant (time from last platinum until next progression between 28 days and 6 months);
Plat. ref.: platinum refractory (progression on or within 28 days from last platinum);
Plat. unk.: platinum status unknown
BRCA, breast cancer gene; BRCAwt, BRCA wild type; gBRCA, germline BRCA; sBRCA, somatic BRCA; HRD, homologous recombination deficiency; neg, negative; pos, positive; unk, unknown
Moore KN, et al. ASCO 2018; abstract 5514 (poster presentation).

11. QUADRA study met primary endpoint
Primary endpoint objective response rate (ORR) was 29% in HRDpos population
Results of overall population
ORR (CR+PR)
27% (14/51) SD
41% (21/51)
DCR (CR+PR+SD)
69% (35/51)
Median DOR
9.2 months
Median OS
19.0 months
Primary endpoint for HRDpos patients p=0.0003; 95% CI 16-44, N=45
DOR, median duration of response; DCR, disease control rate (best overall response); HRDpos, homologous recombination deficiency positive; OS, median overall survival; CR, complete response; PR, partial response; SD: stable disease.
Moore KN, et al. ASCO 2018; abstract 5514 (poster presentation).

12. QUADRA: clinical benefit rate across all patient populations
Platinum-sensitive or -ineligible
Platinum-resistant or -refractory
Plat. sens. = platinum sensitive (time from last platinum until next progression ≥ 6 months), including platinum-ineligible;
Plat. res. = platinum resistant (time from last platinum until next progression between 28 days and 6 months);
Plat. ref. = platinum refractory (progression on or within 28 days from last platinum);
CBR16, clinical benefit rate (CR + PR + SD for at least 16 weeks)
BRCAmut, breast cancer gene mutant; BRCAwt, breast cancer gene wild-type; HRDpos, homologous recombination deficiency positive;
HRDneg/unk, homologous recombination deficiency negative or unknown; CR, complete response; PR, partial response; SD, stable disease
Moore K, et al. Presented at 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Poster #241.

13. QUADRA: OS in all patients treated in 4th line or later
Population by Biomarker Status
OS (months)
BRCAmut (N=63)
26.0 (18.1, NE)
HRDpos (N=187)
19.0 (15.2, 24.6)
HRDneg or unk (N=232)
16.6 (12.6, 19.0)
All 4th or later line (N=456)*
17.2 (14.9, 19.8)
Historical CT control
Line of Therapy
OS (months)
4th Line
8.9 (95% CI 7.8 – 9.9)
5th Line
6.2 (95% CI 5.1 – 7.7)
6th Line
5.0 (95% CI 3.8 – 10.4)
*all evaluable patients
OS, overall survival; CI, confidence interval; BRCAmut, breast cancer susceptibility gene mutant; CT, chemotherapy;
HRD, homologous recombination deficiency; HRDpos, HRD positive; HRDneg, HRD negative; unk, unknown; NE, non-evaluable
Hanker LC, et al. Ann Oncol 2012;23(10):
Moore K, et al. Presented at 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Poster #241; TESARO investor & analyst briefing at ASCO 2018; Jun. 4, Available at: link

14. Take home points
Not all PARP inhibitors are the same as there are some significant differences in the mode of action
Important pharmacokinetic properties might explain the different activity and safety of PARP inhibitors
Tissue distribution, half-life, metabolism and tumour penetration differentiate niraparib from other PARP inhibitors
QUADRA shows significant anti-tumour activity and survival in late-line ovarian cancer