Safety and tolerability of olaparib, temozolomide, and pembrolizumab in a phase 2 trial in patients with progressive glioblastoma.

2055 Background: Glioblastoma is the most aggressive primary brain tumor of adults, with patients obtaining limited survival benefit from standard-of-care therapies. We are conducting a phase 2, surgical window-of-opportunity study evaluating the combination of pembrolizumab (anti-PD-1 immunotherapy), olaparib (PARP inhibitor), and temozolomide (alkylating chemotherapy) in patients with progressive glioblastoma. Olaparib and temozolomide 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 olaparib, temozolomide, and pembrolizumab combination. Methods: We enrolled patients with radiographically progressive glioblastoma, IDH-wildtype, MGMT promoter unmethylated, on 2mg daily or less of dexamethasone. Patients participating in the safety lead-in (Cohort 1) did not require surgically-resectable disease, while those enrolled in the surgical arm (Cohort 2) did. Treatment is provided in consecutive 42-day cycles with olaparib 200mg BID and temozolomide 50mg 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, with pre-specified measures to address reversible toxicities through dose adjustments. 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 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. Clinical trial information: NCT05463848 .