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

Abstract Background: 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. Methods: 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). Results: 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]. Conclusions: 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.