Oral Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2023

Differentiation of Niraparib and Olaparib Brain Penetration in a Mouse Brain Metastatic Tumor Model (#78)

Ashish Banerjee 1 , Reid M Groseclose 2 , Jeremy A Barry 2 , Tinamarie Skedzielewski 2 , Gerald McDermott 2 , Chakravarthi Balabhadrapatruni 2 , William Benson 2 , Yongle Pang 2 , David K Lim 2 , Hoang Tran 2 , Mike Ringenberg 2 , Keyur Gada 3 , Amine Aziez 4 , Elaine Paul 5 , Hasan Alsaid 2
  1. GSK, Melbourne, Australia
  2. GSK, Collegeville, PA, USA
  3. GSK, Waltham, MA, USA
  4. GSK, Basel, Switzerland
  5. GSK, Raleigh, NC, USA

Aims: There remains an unmet need to provide effective treatments for patients with primary and metastatic brain tumors; lack of drug penetration across the blood brain barrier is a key factor. Here, we evaluated brain penetration and distribution of niraparib and olaparib in a mouse brain tumor model.

Methods: Female mice (CrTac:NCr-Foxn1nu; 6 w/o) received 2.5E5 luciferase-transfected human breast cancer line (MDA 231-BRM2-831) via intracardiac injection. Mice were imaged twice/week using bioluminescence imaging (BLI) to monitor tumor growth. On day 35, mice with brain metastases (BM) were treated via oral gavage once daily for 5 days with niraparib (35 mg/kg, n=4 BM, n=3 control), olaparib (50 mg/kg, n=3 BM, n=3 control), or vehicle (n=3 control). Terminal blood samples and brains were collected 2 hours post final dose. Serial brain sections were collected for MALDI-IMS, H&E and IHC staining from 5 distinct horizontal planes. Tissue between imaging planes was homogenized for LC-MS bioanalysis.

Results: Tumor presence was confirmed using ex vivo IHC. Quantitative MALDI-IMS of coronal brain sections from niraparib-administered mice showed consistent concentrations distributed throughout the parenchyma with locally higher concentrations detected from tumor regions. LC-MS and MALDI-IMS detected concentrations are summarized in Table 1. The estimated mean unbound brain-to-plasma partition coefficient (Kp,uu,brain) was 3.0x and 4.7x higher for niraparib compared to olaparib in control and BM mice, respectively.

Conclusions: Herein, we demonstrated that niraparib has a higher brain penetration and distribution compared with olaparib in both control mice and mice with BM.

Compound

Group

LC-MS terminal plasmaa (ng/mL)

LC-MS bulk brain homogenatea (ng/g)

MADLI-IMS brain sectiona (ng/g)

Kp,uu,brain

Niraparib

Control

3847 (595)

658 (71)

314 (54)

0.18

BM

2535 (414)

543 (27)

397 (100)

0.14

Vehicle

BLQ

BLQ

–

Olaparib

Control

226 (75)

6 (5)

BLQ

0.06

BM

119 (63)

5 (4)

BLQ

0.03

Vehicle

BLQ

BLQ

–

aData are mean (standard deviation)

  1. Encore statement: Data presented on behalf of the original authors with their permission. Data previously presented at the American Association for Cancer Research (AACR) Annual Meeting; April 14–19, 2023; Orlando, FL, USA. This abstract reports data from AACR poster #3582, which uses updated data relative to the associated abstract.
  2. Disclosures: This study was funded by GSK, Waltham, MA, USA.
  3. Third-party medical writing support: This study was funded by GSK (Philadelphia, PA, USA). Writing and editorial support, funded by GSK and coordinated by Hasan Jamal, MSc, and Prudence L. Roaf, MPH, of GSK, were provided by David M. Jensen, PhD, and Jennifer Robertson, PhD, of Ashfield MedComms, an Inizio company.