Evaluating the role of PARP inhibitors with concurrent temozolomide in recurrent gliomas. 

Recurrent gliomas are aggressive central nervous system tumors and current therapies are inadequate. Poly-ADP-ribose polymerase (PARP) inhibitors combined with alkylating chemotherapy may be beneficial in these tumors, particularly in isocitrate dehydrogenase-mutant (IDH-mt) gliomas, which may be more susceptible to DNA damaging agents.

We retrospectively reviewed records of patients treated with concurrent olaparib and temozolomide for recurrent glioma. We explored safety, response, and survival using Kaplan-Meier methodology.

We identified 20 patients (17 men), median age 42 (range 23-76) with IDH-mt oligodendroglioma (oligo) (5), IDH-mt astrocytoma (astro) (5), IDH-mt glioblastoma (GBM) (5), IDH-wt GBM (4), or H3K27M midline glioma (1). All patients received prior temozolomide (TMZ) and 7 received prior bevacizumab. Olaparib 150mg three times/week and metronomic TMZ 50-75 mg/m²/day were administered for a median of 3 recurrences (range 0-7). Additional concurrent therapies included bevacizumab (2) and pembrolizumab (1). All patients were evaluated for toxicity. The most significant side effects included nausea/vomiting (7), diarrhea (3), fatigue (3), thrombocytopenia (2), and leukopenia (1). One patient developed PCP pneumonia. Two patients required treatment interruption/discontinuation for adverse events (PCP pneumonia, thrombocytopenia) and two required dose reduction (neutropenia, GI side effects). Five patients received RT or bevacizumab immediately prior to or concurrent with TMZ/olaparib and were therefore unevaluable for overall response (OR). Responses (n=15) included : 1 complete (CR), 4 partial (PR), 4 stable disease, 6 progressive disease. Responses were seen in 2/5 oligodendrogliomas, 2/3 astrocytomas, 1/5 IDH-mt GBM, and 0/2 IDH-wt GBM. Median progression-free and overall survival in months was: 6.8, 30.7 (oligo), 5.3, 8.6 (astro), 2.9, 7.9 (IDH-mt GBM), and 4.3, 7.5 (IDH-wt GBM), respectively.

The addition of PARP inhibitors to temozolomide may be an effective treatment for recurrent gliomas. Further investigations of this therapy, particularly in the IDH-mt population, is warranted.