ESTRO 2024 - Abstract Book

S877

Clinical - CNS

ESTRO 2024

Patients aged <70 with newly diagnosed GBM and WHO performance status 0-1 were eligible for the study. In a two stage consent process, patients authorised central, quantitative pyrosequencing analysis of MGMT promoter methylation in tumour samples prior to registration. MGMT unmethylated patients (mean methylation <12%) received daily oral olaparib throughout RT (60 Gray in 30#) and for four weeks afterwards. MGMT methylated patients (mean methylation ≥12%) received intermittent olaparib during CRT (60 Gray plus TMZ 75mg/m2 daily) and for four weeks after. Only MGMT methylated patients received adjuvant TMZ. In both arms, olaparib dose was escalated in a 3+3 cohort design. Where available, tumour samples underwent gene expression analysis using a bespoke Nanostring panel that included DDR and TGFb genes. PARADIGM-2 was registered with ISRCTN (reference 51253312).

Results:

By January 2023, 24 MGMT methylated 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 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 their diagnosis was revised to grade 3 oligodendroglioma. Median overall survival (OS) of the 42 eligible MGMT unmethylated 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, 3 of 29 patients remain alive with median follow-up time 27.4 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 [Figure 1]. These data compare favourably with historical controls. Dose escalation in MGMT methylated patients continues with the current cohort receiving olaparib 150 mg daily 4 days per week. Within the MGMT unmethylated population, quantitative analysis of CpG island promoter methylation revealed a modest correlation between mean percentage methylation and overall survival. However, longer-term survivors (≥24 months, n=7) exhibited a range of methylation percentages encompassing unmethylated -high (8-12%, n=3), unmethylated-intermediate (4-8%, n=3) and unmethylated-low (0-4%, n=1) categories. Unsupervised hierarchical clustering analysis of Nanostring gene expression data from 37 samples, including MGMT methylated and unmethylated tumours, identified groups of patients with different DDR characteristics. Stratification by this method revealed that these groups exhibited significantly different overall survival outcomes following Kaplan Meier analysis [Figure 2]. Additional tumour samples are awaiting analysis, so this dataset will be expanded and updated results presented at the conference.