TIP-06. A global, open-label, randomized Phase 3 trial evaluating niraparib compared to standard temozolomide therapy in patients with newly diagnosed, MGMT-unmethylated glioblastoma

Glioblastoma (GBM) carries a uniformly poor prognosis. Lack of methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter, present in around 60% of GBM tumors, is associated with limited benefit from standard chemoradiation and a median overall survival (OS) of just 12.7 months despite maximal therapy with combination of surgery, radiotherapy (RT), and chemotherapy. Niraparib, a selective PARP1/2 inhibitor, has demonstrated strong pharmacokinetic and pharmacodynamic performance in human GBM and yielded a median OS of 21.7 months in a previous phase 0/2 trial (NCT05076513). Gliofocus, a global Phase 3 trial (NCT06388733), investigates whether niraparib improves clinical outcomes compared to the current standard of care, temozolomide (TMZ), in newly diagnosed, MGMT-unmethylated GBM. In this open-label, randomized, two-arm study, 450 adult patients are assigned to receive either niraparib or TMZ concurrent to RT and continued as monotherapy. Key eligibility includes histologically confirmed GBM per the 2021 WHO classification, KPS ≥70, and no prior GBM-directed therapies including tumor-treating fields. Radiation is administered as 60 Gy in 30 fractions using ESTRO-EANO ‘single target volume’ approach, with treatment starting within 6 weeks post-surgery. Niraparib or TMZ is taken concurrently with RT and then as maintenance until disease progression (per Blinded Independent Central Review guided by RANO 2.0 guidelines) or completion of 6 cycles of TMZ in the control arm. Dual primary endpoints are progression-free survival (PFS) and OS, powered to detect HRs of 0.612 and 0.698, respectively. Secondary endpoints include objective response rate, quality of life, neurocognitive outcomes, and safety profiles. This trial is sponsored by the Ivy Brain Tumor Center with support from GSK for the study drug and funding. Gliofocus began enrolling in June 2024 and targets at least 115 sites across 12 countries. A futility interim analysis is scheduled in 2025.

Duke Scholars

Author Mustafa Khasraw Neurosurgery