C15-162: Phase IB trial of radium 223 and niraparib in patients with castrate resistant prostate cancer (NiraRad).

Abstract

TPS385 Background: PARP1 is a key regulator of the transition to lethal castrate resistant prostate cancer (CRPC); niraparib is a potent and selective PARP-1 and PARP-2 inhibitor that has shown single agent clinical activity in CRPC. Radium-223 is an alpha particle emitter that causes DNA double strand breaks and is FDA approved for use in CRPC. The addition of a PARP inhibitor (niraparib) may further enhance the clinical benefit of Radium-223 through inhibition of DNA repair and modifications in the bone microenvironment. We hypothesize that targeting the PARP1/androgen receptor (AR) axis in combination with radiopharmaceutical therapy will be safe and may improve clinical outcomes for men with advanced CRPC. Furthermore, combining clinical and pathologic features with correlative studies on tumor tissue, blood, and circulating tumor cells (CTCs) may help us develop biomarkers for future use in the treatment of CRPC. Methods: This is aphase IB dose finding study of patients with metastatic CRPC using a time-to-event continual reassessment (TITE-CRM) design to identify the maximum tolerated dose (MTD) of niraparib (100, 200, or 300 mg QD) in combination with standard doses of Radium-223 in patients with and without prior chemotherapy. Niraparib dosing will continue after 6 cycles of radium-223 until disease progression or intolerable adverse events. Correlative studies include the assessment of tumor biopsy tissues using DNA and RNA next-generation sequencing to assay for the presence of DNA repair aberrations in genes; targeted gene expression profiling of serial RNA (baseline and after cycles 1 and 3) performed on whole blood using the Nanostring PanCancer panel; and evaluation of pre- and post-therapy bone marrow biopsies in a subcohort to characterize the effects of the combined therapy on the bone microenvironment. Additional correlative studies that will be performed on CTC include: assay for nuclear AR expression; immunostaining for the presence of persistent g-H2AX foci, (markers of unrepaired DNA double strand breaks); NFkB activity assayed by immunostaining for p-p65). Enrollment to Dose Level 1 began in October 2017. Clinical trial information: NCT03076203.