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

Abstract

Background The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ. Methods Preclinical 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 TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor 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 multidrug 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, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. Conclusion Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.

Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

“…Grade 3/4 myelotoxicity was observed in 20% of treated patients with a median PFS of 2 months (95% CI, 1.9–2.1) for both arms and 6m-PFS of 4.4% and 17% for bevacizumab refractory and bevacizumab naïve, respectively [ 151 ]. Another phase I trial evaluated Olaparib, an oral PARP1 and PARP2 inhibitor, in combination with temozolomide in rGBM patients [ 152 ]. Grade 3/4 myelosuppression was observed in 20% overall and the median PFS was about 2 months…”

Targeting the DNA Damage Response to Overcome Cancer Drug Resistance in Glioblastoma

“…Olaparib is undergoing a Phase-I clinical trial for GBM in combination with radiation, TMZ and bevacizumab. Despite no evidence for Olaparib as a CNS available drug, it is being tested for brain tumors as well, as recent evidence has highlighted that many GBM patients show compromised integrity of the BBB and that in such cases, Olaparib may be successfully delivered to the tumor [ 90 ].…”

Advancements in PARP1 Targeted Nuclear Imaging and Theranostic Probes

“…While talazoparib, olaparib, and rucaparib show limited penetration across intact BBB as they are liable to efflux by the BBB, veliparib and niraparib were shown to have better penetration [33,34]. However, results from a Phase I clinical trial (OPARATIC trial) showed that olaparib was able to accumulate in marginal and core tumors in GBM patients who were treated with low doses of temozolomide [35].…”