Reference Detail

Ref Type

Journal Article

PMID

(32347934)

Authors

Hanna C, Kurian KM, 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, Chalmers AJ

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Neuro-oncology			2020 Apr 29	1840-1850	Neuro Oncol

URL

Abstract Text

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.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.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.Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better pre-clinical models.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References