Abstract BACKGROUND Glioblastoma (GBM) is a universally deadly disease with dismal prognosis. The O6-methylguanine methyltransferase (MGMT) promoter methylation is both predictive in response to standard chemoradiation, as well as prognosis, and unmethylated in approximately 60% of GBM. In newly diagnosed GBM patients with unmethylated MGMT, the median overall survival (OS) is 12.7 months despite combined treatments with surgical resection, temozolomide (TMZ), and fractionated radiotherapy (RT). Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response in GBM. Niraparib is an investigational PARP1/2-selective inhibitor with evidence of excellent tumor pharmacokinetic and pharmacodynamic performance in human GBM compared to other studied PARP inhibitors and an overall survival (OS) of 21.7 months noted in a phase 0/2 study in newly diagnosed GBM. A global registrational Phase 3 study (Gliofocus) will compare the clinical efficacy of niraparib compared to standard of care treatment with temozolomide. MATERIAL AND METHODS In the Phase 3, open-label, 2-arm study (NCT06388733), 450 adult participants with newly-diagnosed, MGMT-unmethylated GBM are randomized to receive niraparib or temozolomide. Participants must have a biopsied or resected GBM, per 2021 World Health Organization classification. MGMT promoter methylation status is determined locally by validated pyrosequencing or quantitative methylation-specific polymerase chain reaction assays. Other key inclusion/exclusion criteria include: (1) Karnofsky performance status of ≥70, (2) no prior treatment for GBM (including brachytherapy or BCNU wafers), (3) no tumor-treating field therapy, (4) suitability for RT of 60 Gy in 30 fractions using ESTRO-EANO ‘single phase’ targeting approach, and (5) no greater than 6 weeks from surgery to treatment initiation. Following 1: 1 randomization, niraparib (Arm A) or TMZ (Arm B) is administered concomitantly with RT and then adjuvantly as monotherapy until disease progression by Blinded Independent Central Review (BICR) or until completion of 6 cycles of TMZ for those on Arm B. The co-primary endpoints of the study are progression-free survival (PFS) (per RANO 2.0; HR = 0.612, 90% power, 1-sided alpha = 0.001) and OS (HR = 0.698, 90% power, 1-sided alpha = 0.0239). Secondary endpoints include overall response rate, health-related quality of life, neurocognitive function, and the safety and tolerability of niraparib compared to TMZ. The first patient was accrued in June 2024 and an interim futility analysis is planned in 2025 Q2. This study, supported by GSK and sponsored by the Ivy Brain Tumor Center, is expected to enroll in a minimum of 115 clinical sites across 11 countries. RESULTS NA/Trial in Progress. CONCLUSION NA/Trial in Progress.
Sanai et al. (Wed,) studied this question.