PARPi combinations show no significant clinical improvement in adult patients with glioblastoma.

Glioblastoma (GBM) is the most common malignant primary brain tumor in adult patients and has a poor prognosis despite current multimodal approaches that include surgery, radiation therapy, and chemotherapy. Local recurrence is almost inevitable, and treatment options for relapsed disease are limited. Poly-ADP-ribose polymerase inhibitors (PARPi) are standard of care in several advanced/metastatic solid malignancies including ovarian, breast, and prostate cancer. In GBM, PARPi could represent a novel promising class of therapeutic agents enhancing DNA repair defects present in specific GBM molecular subtypes. Indeed, these agents act by blocking DNA damage repair, amplifying the lethality of DNA-damaging therapies such as temozolomide (TMZ) and radiotherapy. Several PARPi have been investigated in combination with standard GBM therapy, without significant clinical improvement. However, their efficacy is strongly influenced by their ability to cross the blood-brain barrier and the presence of tumor resistance mechanisms. Clinical trials suggest that patient selection using molecular biomarkers and the timing of PARPi administration are crucial for maximizing therapeutic benefit. The choice of PARPi with optimal trapping and blood-brain barrier penetration capacity, together with molecular stratification based on genomic and expression profiles, appears crucial for the effective use of these agents in glioblastoma. This review investigates the biological mechanisms associated with PARPi within GBM tumor cells and assesses which patients could be the best candidates for PARPi treatment based on molecular profiling of the disease.