A randomized double-blind phase II trial evaluating maintenance PARP inhibitor Olaparib versus placebo in patients with platinum-sensitive advanced non-small cell lung cancer: PIPSeN trial

Abstract

Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) have demonstrated impressive efficacy in BRCA-mutated gynaecological malignancies. Several lines of evidence now support that the DNA repair (DDR)-deficient populations that benefit from PARPi go far beyond BRCA-deficiency. Non-small cell lung cancer (NSCLC), the first cause of cancer death worldwide, displays frequent DDR defects, the most frequent being ERCC1. This defect leads to platinum and PARPi sensitivity. Beyond ERCC1, DDR defects leading to platinum sensitivity widely overlap with those underlying PARPi sensitivity. Maintenance PARPi could therefore benefit to patients (pts) with platinum-sensitive NSCLC. Olaparib (Lynparza® , Astra Zeneca), a potent and selective PARPi, was the first-in-class approved PARPi in BRCA-mutated ovarian cancer. Trial design: PIPSeN is a randomized double-blind phase II investigator-initiated study evaluating maintenanceOlaparib versus placebo in pts with platinum-sensitive advanced NSCLC. Chemonaïve ECOGPS 0-1 pts with stage III-IVNSCLC with no EGFR mutation or ALK translocation are eligible. Treatment consists of an “induction phase” of 4-6 cycles platinum-based therapy (any doublet), followed by a “randomized phase” where pts presenting with partial or complete response are randomized between Olaparib maintenance (tablets; 300mg bd) and placebo until progression or unacceptable toxicity. Primary objective is to assess the efficacy of maintenanceOlaparib asmeasured by Progression-Free Survival fromrandomisation (RECIST v1.1). Secondary objectives include comparison of overall survival, disease control rate and safety. Randomization is stratified according to age, histology and country. With an anticipatedHR=0.65 (bilateral a=0.2; b=0.2), approximately 500 enrolled pts will be required to randomize 144 pts and observe 97 events. Recruitment is ongoing since the 5th of Feb. 2016 across 21 centres in France and Spain; 95 (19) pts have been enrolled (randomised) to date. Translational studies looking notably for biomarkers of platinumand PARPi sensitivity (usingWES, RNAseq, proteomics and ctDNA) are associated.