A phase 2 study of niraparib concomitant with tumor treating fields in patients with recurrent grade 4 glioma

In preclinical models, tumor treating fields (TTFields) therapy promotes homologous repair deficiency (HRD), inducing potential sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition. The aim of this study was to determine whether TTFields combined with the brain-penetrant PARP inhibitor niraparib has clinical efficacy in patients with recurrent high-grade glioma (HGG).

We conducted a phase 2 trial of TTFields therapy concomitant with niraparib in patients with glioblastoma (n = 7) or IDH-mutant grade 4 astrocytoma (n = 2) that was recurrent after prior radiotherapy. Cohort A was a single-arm primary efficacy cohort with the Simon's 2-stage design. Cohort B was a surgical window-of-opportunity cohort in which TTFields were administered for 5-7 days prior to surgery and then resumed post-operatively with niraparib. The primary endpoint was disease control rate in cohort A, defined as objective response or stable disease (SD) lasting at least 16 weeks.

The most common treatment-related adverse events were grade 1-2 dermatologic (scalp) toxicity in 67% of patients and grade 1-2 nausea in 67% of patients. In cohort A (n = 8), there were no objective responses, and 1 patient (12.5%) achieved SD lasting over 16 weeks. The efficacy benchmark to advance to Stage 2 was not achieved, and enrollment on Cohort A was terminated for futility. Cohort B (n = 1) was closed early due to slow accrual. In the single patient in Cohort B, TTFields-treated tumor tissue was negative for HRD.

The combination of niraparib and TTFields therapy for recurrent HGG was safe and well tolerated but did not demonstrate an efficacy signal.