Pharmacokinetics, safety and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial

Hanna, C. et al. (2020) Pharmacokinetics, safety and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. Neuro-Oncology, 22(12), pp. 1840-1850. (doi: 10.1093/neuonc/noaa104) (PMID:32347934) (PMCID:PMC7746945)

Abstract

Background: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide chemotherapy in pre-clinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side-effects of temozolomide. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib, and assess the safety and tolerability of its combination with temozolomide. Methods: Pre-clinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose temozolomide in a 3+3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumour core and tumour margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines. Results: Olaparib was a substrate for multi-drug resistance protein-1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients, median 496nM) and 21/21 tumor margin specimens (9 patients, median 512.3nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150mg (3 days/week) with TMZ 75mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression-free at 6 months. Olaparib radiosensitized six glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. Conclusions: Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better pre-clinical models.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Carruthers, Dr Ross and Dunn, Mr Laurence and Strathdee, Mrs Karen and Williams, Dr Karin and Hanna, Catherine and Chalmers, Professor Anthony
• Authors: Hanna, C., Kurian, K. M., Williams, K., Watts, C., Jackson, A., Carruthers, R., Strathdee, K., Cruickshank, G., Dunn, L., Erridge, S., Godfrey, L., Jefferies, S., McBain, C., Sleigh, R., McCormick, A., Pittman, M., Halford, S., and Chalmers, A. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Neuro-Oncology
• Publisher: Oxford University Press
• ISSN: 1522-8517
• ISSN (Online): 1523-5866
• Published Online: 29 April 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Neuro-Oncology 22(12): 1840-1850
• Publisher Policy: Reproduced under a Creative Commons license