Gliofocus: A global, open-label, randomized phase 3 study comparing niraparib with temozolomide in newly diagnosed MGMT-unmethylated glioblastoma.

Glioblastoma (GBM) remains a fatal malignancy despite multimodality therapy. Approximately 60% of GBMs lack O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, thus associated with resistance to alkylating chemotherapy and poor survival with median OS of 12.7 months. Poly(ADP-ribose) polymerase (PARP) is a central regulator of DNA damage repair and genomic stability in GBM and represents a rational therapeutic target, particularly in the setting of radiotherapy-induced DNA damage. Niraparib is a selective PARP1/2 inhibitor that has demonstrated excellent central nervous system penetration and favorable tumor pharmacokinetic and pharmacodynamic properties in previously reported early-phase GBM studies. These findings provided the scientific rationale for Gliofocus, a global phase 3 trial designed to evaluate whether replacing temozolomide with niraparib during and after radiotherapy improves outcomes in patients with newly diagnosed, MGMT-unmethylated GBM. Gliofocus is a phase 3, open-label, randomized, two-arm study enrolling total 450 adults with newly diagnosed, MGMT-unmethylated GBM. Eligibility requires histologic diagnosis of GBM per 2021 WHO classification, Karnofsky performance status ≥70, documented MGMT promoter unmethylated status by validated local testing, and no prior GBM-directed therapy other than biopsy or resection. Patients are randomized 1:1 to receive niraparib or temozolomide concurrently with external-beam radiotherapy (60 Gy in 30 fractions using the ESTRO-EANO single-target volume approach), followed by adjuvant monotherapy of niraparib or temozolomide. Treatment continues until centrally reviewed disease progression per RANO 2.0 guidelines or completion of six cycles of temozolomide in the control arm. The primary endpoint is overall survival (HR = 0.698, 88% power). Secondary endpoints include progression-free survival, objective response rate, health-related quality of life, neurocognitive outcomes, and safety. Integrated correlative assessments include centralized imaging review, longitudinal neurocognitive testing, and patient-reported outcomes. Enrollment began in June 2024. The independent data monitoring committee last reviewed the study in January 2026, and recommended continuation as planned. The trial is sponsored by the Ivy Brain Tumor Center with funding/product support from GSK (NCT06388733). GSK was provided the opportunity to provide a courtesy review of the abstract; however, the authors are solely responsible for final content. Gliofocus study is being conducted across a minimum of 80 sites across 12 countries. .

Duke Scholars

Author Mustafa Khasraw Neurosurgery