Authors: Shwetal Mehta, Nader Sanai, Tigran Margaryan, Jennifer Molloy, Hualin Zhang, William Knight, Jocelyn Harmon, Amy Hong, John Wanebo, Kelly Braun, William R. Kennedy, Michael A. Garcia, Igor J. Barani, Wonsuk Yoo, An-Chi Tien, Artak Tovmasyan
Published: 2023-06-04
DOI: 10.1200/jco.2023.41.16_suppl.2069
Source: Full article
2069 Background: Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients with O6-methylguanine methyltransferase (MGMT) unmethylated tumors into a therapeutic regimen of niraparib plus fractionated radiotherapy when high unbound drug concentrations are present in gadolinium-nonenhancing tumor. Methods: Patients with presumed newly-diagnosed GBM were enrolled in a phase 0 study receiving 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after 10 Gy ex vivo irradiation in surgical tissue compared to non-irradiated control tissue. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [niraparib] > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors exceeding this PK threshold were eligible for expansion phase dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib. Results: All patients (n=35) enrolled in the phase 0 portion of the study met the PK threshold. In non-enhancing tumor regions, the mean unbound concentration of niraparib was 253.2 nM in 32 evaluable GBM patients. The suppression of PAR levels after ex vivo radiation was observed in 75% of the patients (18/24). Eleven out of 18 patients with unmethylated tumors enrolled in phase 2. Five of the 6 initial patients enrolled in phase 2 experienced thrombocytopenia related to niraparib, and 3/5 cases were deemed serious and life-threatening. Consequently, starting dose in both phases was lowered to 200 mg, and no serious AEs were observed thereafter. At a median follow-up of 8.1 months [range: 6.0-12.9 months], PFS6 was 64% (n=11) with 4 patients remaining on treatment and 5 patients ongoing survival follow-up. Conclusions: Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor. Clinical trial information: NCT05076513 .