Abstract
BACKGROUND: We are conducting a phase 2, surgical window-of-opportunity study evaluating the combination of olaparib, temozolomide and pembrolizumab in patients with progressive glioblastoma. Temozolomide and olaparib have the potential of synergistically enhancing the tumor’s susceptibility to immune checkpoint immunotherapy through DNA damage and activation of immune pathways, potentially amplifying the efficacy of pembrolizumab. We provide a preliminary report on the safety and tolerability of the treatment combination. METHODS: We enrolled patients with progressive glioblastoma, IDH-wildtype, on 2mg or less of dexamethasone. Treatment is provided in consecutive 42-day cycles with olaparib 200mg BID and temozolomide 50mg/m2 QD given on days 1-7 and 22-29, and pembrolizumab 400mg IV given on day 1. Adverse events (AEs), dose-limiting toxicities (DLTs), and high-frequency toxicities (≥50% occurrence) were assessed, along with dose modifications or delays required to manage treatment-related toxicities. AEs were graded according to CTCAE v5.0 criteria. RESULTS: Six patients were enrolled in the safety lead-in (Cohort 1), which followed a 3 + 3 design. Grade 1–2 leukopenia, lymphopenia, and neutropenia were observed in 3 patients and resolved without intervention. Grade 4 neutropenia was observed in two patients (starting in cycle 2 for one patient, and on cycle 5 for the other). This resolved with dose delays, reduction in temozolomide dose or discontinuation of temozolomide (1 patient). In the surgical cohort (Cohort 2), which is ongoing (25 patients currently enrolled), toxicity profiles remain consistent with those observed in Cohort 1 patients. Grade 4 neutropenia has been observed in 1 (6%) of the enrolled patients, improving with dose delays and temozolomide dose reduction. CONCLUSIONS: The combination of olaparib, temozolomide, and pembrolizumab demonstrates a tolerable safety profile in patients with progressive glioblastoma. Observed hematologic toxicities are reversible with appropriate management, supporting the ongoing evaluation of this regimen to assess its efficacy and therapeutic potential.