OS09.3.A FINAL RESULTS OF THE MGMT UNMETHYLATED ARM OF PARADIGM-2: A PHASE I STUDY OF OLAPARIB AND RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)
Authors: Derby S J , Sweeting L , Shad S , Paterson L , Stobo J , Nowicki S , Williamson A , James A , Short S C , McBain C , Herbert C , Powell J , Kelly C , Chalmers A J 
Published: September 2023

Abstract

BACKGROUND
The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib has radio and chemosensitizing effects in preclinical models and penetrates GBM in patients at radiosensitizing concentrations. PARP inhibitors sensitize proliferating cells to temozolomide (TMZ) but exacerbate haematological toxicity. Patients with MGMT unmethylated tumours do not benefit from TMZ so it can be withheld, enabling continuous olaparib dosing with radiotherapy (RT). Patients with MGMT methylated tumours benefit from TMZ so olaparib must be combined with chemoradiation (CRT) in an intermittent, low-dose manner. PARADIGM-2 is a clinical trial comprising two parallel phase I studies of olaparib/RT or olaparib/RT/TMZ in newly diagnosed GBM patients stratified by MGMT status.

MATERIAL AND METHODS
GBM patients aged &lt;70 with WHO performance status 0-1 were eligible. Tumour tissue underwent central pyrosequencing testing for MGMT promoter methylation. MGMT unmethylated patients received daily oral olaparib throughout RT (60 Gray in 30#) and for four weeks afterwards. MGMT methylated patients received intermittent olaparib during CRT (60 Gray plus TMZ 75mg/m2 daily) and for four weeks after. In both arms, olaparib dose was escalated in a 3 + 3 cohort design. ISRCTN 51253312.

RESULTS
By January 2023, 24 MGMT methylated patients and 43 MGMT unmethylated patients had been recruited. Dose escalation in MGMT unmethylated patients was completed with no dose-limiting toxicities and the recommended phase II dose (RP2D) of olaparib was established at 300 mg twice daily (the full single agent dose). Maximum tolerated dose was not reached. The RP2D cohort was expanded to 30 patients of whom one was excluded because the diagnosis was revised to anaplastic oligodendroglioma. Median overall survival (OS) of the 42 eligible patients was 14.1 months (80% confidence intervals (CI) 12.2 - 15.9), with 12- and 24-month OS estimates of 64.3% (54.0-72.9) and 16.7% (10.1-24.7) respectively. In the dose expansion cohort, 6 of 29 patients are alive with median follow-up time of 22.9 months. Median OS is 14.2 months (12.2-16.9); 12- and 24-month OS estimates are 69.0% (56.5-78.5) and 24.1% (14.8-34.8) respectively. Updated survival data will be presented at the conference. Dose escalation in MGMT methylated patients continues with the current cohort receiving olaparib 150 mg daily 4 days per week.

CONCLUSION
Pre-treatment stratification by MGMT status in a phase I study in GBM is feasible and enables optimisation of olaparib dosing and scheduling with RT and TMZ. In MGMT unmethylated patients, olaparib can be combined with RT at the full single agent dose (300 mg twice daily) if TMZ is withheld. Of 29 patients receiving this dose, a quarter have survived more than 2 years. In MGMT methylated patients, olaparib can be safely combined with radical CRT when given at lower doses on an intermittent basis (currently 150 mg four days per week).