OS04.7.A RESULTS OF THE MGMT METHYLATED SUBSTUDY OF PARADIGM: A PHASE I STUDY OF OLAPARIB WITH RADIOTHERAPY AND TEMOZOLOMIDE IN ELDERLY PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND Older patients with glioblastoma (GBM) experience very poor outcomes, with median overall survival (OS) 9.3 months (all patients) and 13.5 months (MGMT methylated patients) in a recent randomized trial. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib has radio and chemosensitizing effects in preclinical models and penetrates GBM at sensitizing concentrations. Olaparib can be combined with radiotherapy for GBM without increasing toxicity, but combination with temozolomide (TMZ) exacerbates haematological toxicity. Since patients with MGMT methylated tumours benefit from radiotherapy-TMZ, addition of olaparib must be intermittent and low dose to avoid compromising standard of care. As part of the PARADIGM trial, we undertook a phase I dose escalation study of olaparib-RT-TMZ in newly diagnosed, elderly patients with MGMT methylated GBM. MATERIAL AND METHODS GBM patients aged ≥70, WHO performance status (PS) 0-1; aged 65-69, PS 0-2; or aged 18-64, PS 2 were eligible. Tumour tissue underwent central pyrosequencing testing for MGMT status. Patients with mean CpG island methylation >12% were eligible and received intermittent olaparib during RT (40 gray in 15 fractions) plus TMZ 75 mg/m2 and for four weeks afterwards. Olaparib dose was escalated in a 3 + 3 cohort design. Patients were permitted to receive up to 12 cycles of adjuvant TMZ but this was not part of study treatment. ISRCTN 51253312. RESULTS By April 2025, 19 patients had been treated at 5 different dose levels of olaparib. One patient is currently on treatment and is not included in this analysis. One patient was deemed non-evaluable for safety having missed an evaluation in week 3. Median age was 71 (range 55-77); 4 patients had WHO PS 0, 12 PS 1 and 2 PS 2. No dose-limiting toxicities (DLTs) have been recorded and 5 patients have completed treatment at the highest olaparib dose level: 150 mg daily, 5 days per week. Treatment was extremely well tolerated with one patient experiencing grade 3 neutropenia and 2 patients experiencing grade 3-4 lymphopenia during the treatment period. Of 7 serious adverse events and 1 serious adverse reaction, none was attributed to olaparib and one to TMZ. Median OS of the 18 eligible patients is 22.8 months (80% confidence intervals (CI) 14.8 - 24.2), with 12- and 24-month OS estimates of 80.4% (63.1 - 90.1) and 40.1% (22.4 - 57.2) respectively. Updated survival data will be presented at the conference. Eight patients remain alive plus the patient still on treatment. CONCLUSION Pre-treatment stratification of elderly GBM patients by MGMT status is feasible in a phase I study. In elderly MGMT methylated patients, olaparib can be safely combined with short course RT-TMZ at doses up to 150 mg once daily, 5 days per week. The combination was extremely well tolerated in this vulnerable patient population, with no DLTs, no haematological complications and very promising survival.