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

Catherine Hanna, Kathreena M Kurian, Karin Williams, Colin Watts, Alan Jackson, Ross Carruthers, Karen Strathdee, Garth Cruickshank, Laurence Dunn, Sara Erridge, Lisa Godfrey, Sarah Jefferies, Catherine McBain, Rebecca Sleigh, Alex McCormick, Marc Pittman, Sarah Halford, Anthony J Chalmers

Research output: Contribution to journalArticle (Academic Journal)peer-review

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.

Original languageEnglish
JournalNeuro-oncology
Early online date29 Apr 2020
DOIs
Publication statusE-pub ahead of print - 29 Apr 2020

Bibliographical note

© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

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