2025/10/14 by David Schiff, Xiaobu Ye, Jing Li +12 · 1 voice
Medicine · #Glioma Diagnosis and Treatment #PARP inhibition in cancer therapy #Brain Metastases and Treatment
paper · doi:10.1093/neuonc/noaf246
openalex publication_date 2025/10/14 · openalex created_date 2025/10/17 · openalex updated_date 2026/07/27
BACKGROUND: Preclinical studies demonstrate activity of poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors in isocitrate dehydrogenase (IDH) mutant gliomas. We investigated safety, tolerability, pharmacokinetics, and efficacy of the PARP inhibitor pamiparib in conjunction with metronomic low-dose temozolomide in patients with recurrent IDH mutant (IDHmt) gliomas in a multicenter Phase I/II/window of opportunity study. METHODS: Patients received pamiparib in conjunction with daily temozolomide. Following Phase I determination of maximum tolerated dose (MTD), we enrolled 2 patient cohorts (Arm A, multiple prior chemotherapy regimens; Arm B, single prior regimen) in a 2-stage design. Exploratory cohorts examined grade 4 IDHmt patients and intratumoral pharmacokinetics of pamiparib. The primary endpoint was objective radiographic response (ORR) by RANO criteria. RESULTS: Sixty-six subjects were enrolled. We established pamiparib 60 mg twice daily with temozolomide 20 mg daily as the phase II dose. In non-enhancing and enhancing tumor, pamiparib exhibited an unbound tumor/plasma ratio of 0.92 and 0.98, respectively. 0/15 Arm A and 1/24 Arm B patients achieved a centrally confirmed partial response. Median progression-free survival for Arm A was 5.9 months (95% CI, 1.2-14.8 months), and for Arm B was 9.7 months (95% CI, 5.7-21.7 months). Grade 3+ anemia and neutropenia affected 24% and 33% of patients, respectively. Twenty-two of 66 patients (33.3%) discontinued study treatment for reasons other than tumor progression. CONCLUSIONS: Pamiparib appeared to achieve sufficient pharmacologically active concentrations in both enhancing and non-enhancing tumors. While some patients achieved prolonged progression-free survival, combination with temozolomide did not produce a meaningful ORR in IDHmt recurrent gliomas. Cumulative hematologic toxicity was substantial and impacted long-term tolerability.