Abstract
BACKGROUND
Olaparib, a small molecule inhibitor of poly(ADP-ribose) polymerase (PARP), has radiosensitising properties in pre-clinical GBM models. Because radiopotentiation is observed only in proliferating cells, we hypothesised that olaparib would enhance tumour control without exacerbating normal brain toxicity in GBM patients receiving radiotherapy. Having shown that olaparib penetrates GBM at radiosensitising concentrations, we studied its safety and toxicity in combination with short-course radiotherapy in GBM patients ineligible for radical chemoradiation.
METHODS
Patients aged ≥70 (WHO PS 0–1) or <70 (PS 2) with histologically confirmed GBM received oral olaparib commencing three days before and continuing throughout radiotherapy (40 Gray in 15 fractions) and for four weeks afterwards. Olaparib dose was escalated in a 3 + 3 cohort design.
RESULTS
16 patients (9 male, 7 female) were treated within four olaparib dose cohorts. Median age was 72 (range 44–78); four patients had WHO PS 0, eight PS 1 and four PS 2. Cohort 3 was expanded to six evaluable patients because one patient experienced the only dose-limiting toxicity observed in the study (agitation grade 3, CTCAE v.4). Serious adverse events were experienced by eight patients, of which only one (the DLT) was a serious adverse reaction. The recommended dose of olaparib for phase II testing in combination with short-course radiotherapy was determined to be 200 mg twice daily.
CONCLUSIONS
As predicted by pre-clinical data, olaparib is extremely well tolerated in combination with short-course radiotherapy in elderly and poorer PS patients with newly diagnosed GBM. The recommended phase II dose of 200 mg twice daily is significantly higher than has been deliverable to date in extracranial tumour sites in which acutely responding, rapidly proliferating normal tissues were within the irradiated volume. A randomised double-blind phase II study of radiotherapy plus olaparib versus radiotherapy plus placebo is underway in patients aged ≥65 with MGMT unmethylated GBM.