Olaparib, temozolomide and concomitant radiotherapy for partially or biopsy-only glioblastoma first-line treatment: results from the OLA-TMZ-RTE-01 phase 1 study.

in Clinical cancer research : an official journal of the American Association for Cancer Research by Dinu Stefan, Paul Lesueur, Justine Lequesne, Loic Feuvret, Charlotte Bronnimann, Marie Castéra, Pierre-Emmanuel Brachet, Ioana Hrab, Mathilde Ducloie, Joëlle Lacroix, Marie Lecornu, Grégoire Braux, François Christy, Marie-Pierre Sunyach, Elizabeth Cohen-Jonathan Moyal, William Kao, Maxime Faisant, Evelyne Emery, Jean-Michel Grellard, Francois Sichel, Carine Laurent, Maxime Fontanilles, Bénédicte Clarisse

TLDR

  • The study combined olaparib with standard radio-chemotherapy to treat unresected glioblastoma patients and determined the maximum tolerated dose (MTD) of olaparib.
  • The MTD of olaparib was 100 mg twice daily for 3 days a week, and the study showed promising outcomes with an acceptable safety profile.

Abstract

Radio-chemotherapy remains the mainstay of glioblastoma first-line treatment after extended surgery, but the prognosis is still poor. PARP inhibitors like olaparib may improve glioblastoma outcomes. We implemented a phase 1-2a trial to assess the safety and efficacy of olaparib combined with standard radio-chemotherapy as a first-line treatment in unresected glioblastoma patients. We herein present results of phase 1. Based on the Stupp regimen, two sequential dose escalations of olaparib were performed to distinguish the radiotherapy period and the maintenance period for assessing the maximum tolerated dose (MTD) of olaparib separately for each treatment period. Dose escalations were performed by a TITE-CRM (TIme-To-Event Continual Reassessment Method). A total of 30 pts were enrolled: 20 (66.7%) men, median age 59 years [range 25-70], 12 (42.9%) Eastern Cooperative Oncology Group (ECOG) performance status of 0. Among them, 16 and 11 pts were assessable for determining MTD in each period. Hematological dose-limiting toxicities were experienced by 4 and 1 patients in each sequential dose escalation, respectively. MTD was olaparib 100 mg twice daily for 3 days a week in concomitant during both the radio-chemotherapy and maintenance periods of the standard treatment. Median progression-free and overall survival was 6.2 and 19.8 months, respectively. The 2-year survival rate was 36.7% [22.9-58.7]. Intermittent dosing of olaparib at radiosensitizing concentrations in concomitant with the Stupp protocol has an acceptable safety profile with promising outcomes in unresectable glioblastoma patients. Further efficacy determination is ongoing in the phase 2a step.

Overview

  • The study investigated the safety and efficacy of combining olaparib with standard radio-chemotherapy as a first-line treatment in unresected glioblastoma patients.
  • The study used a phase 1-2a trial design with sequential dose escalations of olaparib to assess the maximum tolerated dose (MTD) during the radiotherapy and maintenance periods.
  • The primary objective was to determine the MTD of olaparib and assess the safety profile and efficacy of the treatment in unresectable glioblastoma patients.

Comparative Analysis & Findings

  • The trial determined the MTD of olaparib to be 100 mg twice daily for 3 days a week during both the radio-chemotherapy and maintenance periods.
  • The median progression-free and overall survival were 6.2 and 19.8 months, respectively, with a 2-year survival rate of 36.7%.
  • The study showed an acceptable safety profile with promising outcomes in unresectable glioblastoma patients.

Implications and Future Directions

  • The study's findings suggest that combining olaparib with standard radio-chemotherapy could improve glioblastoma outcomes.
  • Future studies should investigate the efficacy of olaparib in combination with other therapies and explore its potential in various glioblastoma subtypes.
  • Further research is needed to determine the optimal dosing schedule and duration of olaparib treatment in unresectable glioblastoma patients.
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