Proton pump inhibitors (PPIs), commonly prescribed to prevent gastritis and peptic ulcer disease, may be associated with worse outcomes in newly diagnosed glioblastoma, according to a pooled analysis of five randomised clinical trials published in JAMA Network Open on November 25, 2025.
The meta-analysis included 2,981 patients across the ACTIV, AVAglio, CENTRIC, CORE, and EORTC 1709 trials. Researchers investigated whether PPI use affected progression-free survival (PFS) and overall survival (OS), and whether any associations differed by MGMT-promoter methylation status or steroid use.
Patients receiving potent ALDH1A1-activating PPIs (PA-PPIs), such as omeprazole and pantoprazole, had consistently shorter PFS and OS compared with those not taking PPIs. For example, at the first landmark (start of maintenance cycle 1), PA-PPI users had a hazard ratio (HR) of 1.34 (95% CI, 1.08–1.66) for OS versus non-users, indicating a 34% higher risk of death during this period. Similar associations persisted across subsequent treatment landmarks.
“In vitro studies suggested that PPIs could sensitize cancer cells to chemotherapy, but our pooled clinical data indicate that any such benefit does not translate into improved outcomes for glioblastoma patients,” the authors wrote.
The analysis found that inferior survival associated with PPI use was independent of MGMT-promoter methylation status. Median OS for patients using PA-PPIs remained shorter than for non-users, regardless of methylation status. Additionally, while steroid-treated patients were more likely to receive PPIs, the detrimental association of PPI use was observed even after adjusting for steroid use in multivariate models.
Mechanistic Insights and Preclinical Context
PPIs may affect cancer biology through multiple pathways. Omeprazole and pantoprazole are potent activators of aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme implicated in cancer stemness and cellular protection against oxidative stress. Preclinical studies suggest that PPI-induced ALDH1A1 activation could theoretically interfere with chemotherapy efficacy.
Rabeprazole, a weaker ALDH1A1 activator, has shown in vitro and in vivo activity against glioma cells, including sensitization to temozolomide. However, the clinical analysis found no evidence that weaker-activating PPIs or other antacids affected survival outcomes.
Clinical Implications
The authors noted, “These findings suggest that PA-PPI use should be discouraged in patients with glioblastoma, since alternative agents are available and a detrimental effect cannot be excluded. Translational research studies should explore whether PPI-induced activity of ALDH mediates the potential adverse effects of PPI in glioblastoma.
The authors noted several limitations, including the retrospective nature of drug-use data within prospectively conducted trials, potential confounding by tumour aggressiveness and symptom burden, and incomplete capture of over-the-counter PPI use. Despite these limitations, the findings are strengthened by the large pooled dataset and adjustment for known prognostic factors, including age, performance status, extent of resection, steroid use, and MGMT status.
This analysis provides robust evidence that PA-PPI use is associated with inferior survival in patients with newly diagnosed glioblastoma. Clinicians should carefully weigh the risks and benefits of PPI therapy in this population, especially when alternative gastric-protective strategies exist.
Paper: LeRhun, E., et al. Proton Pump Inhibitor Use and Survival in Patients With Newly Diagnosed Glioblastoma. JAMA Network Open. 2025;8(11):e2545578. Access online here.
