A PHASE II STUDY EVALUATING THE EFFICACY AND SAFETY OF NIRAPARIB AND TUMOR-TREATING FIELDS IN RECURRENT GLIOBLASTOMA

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is near uniformly fatal. Only three treatments have been approved by the US FDA for GBM in the past 2 decades: temozolomide, bevacizumab, and, most recently, tumor-treating fields (TTFields). TTFields represents a novel anti-cancer modality that creates alternating electric fields delivered through transducer arrays directly applied onto the scalp of patients. The device diminishes cell proliferation primarily by perturbing mitotic spindle proteins with high dipole moments, leading to mitotic catastrophe and subsequent cancer cell death. As additional research has focused on the multiple potential mechanisms through which TTFields exert their anti-tumor effect, a recent study demonstrated that TTFields cause downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity. Thus, TTFields induce a state of BRCAness, opening the door to combination therapy with DNA-damaging agents and other agents such as PARP inhibitors. Tumors that are deficient in the homologous recombination DNA damage repair pathway are highly sensitive to blockade of the repair of single strand DNA breaks via PARP inhibition. PARP inhibitors have revolutionized the care of ovarian and breast cancers with BRCA mutations, and, in the case of niraparib, the care of women with ovarian cancer regardless of BRCA status. Based on recent advances in cancer genetics, it is now understood that cellular defects in homologous recombination repair in the absence BRCA mutations can exist de novo or can be induced therapeutically across numerous human malignancies. Tumors harboring such genomic alterations have been described as maintaining a state of BRCAness, i.e. a phenocopy of BRCA1 and BRCA2 mutation that may render the cells sensitive to treatment with PARP inhibition.