Targeting DNA damage response in oesophagogastric cancers

Abstract

A subset of patients with oesphophagogastric (OG) adenocarcinomas are characterised by homologous recombination repair deficiency (HRD), providing the rationale for poly (ADP-ribose) polymerase inhibitor (PARPi) therapy in these tumours. Low dose olaparib, a first in class PARPi, signalled potential activity in patients with gastric cancer in combination with paclitaxel second line. However, the efficacy of olaparib monotherapy at optimal dosing, alongside a comprehensive analysis of biomarkers of response, has not been established. Pre-specified interim results from the phase II Solar trial (a translational phase II study of single agent olaparib in patients with advanced OG cancer) demonstrate olaparib monotherapy is safe and well-tolerated at 300mg twice daily, achieving a meaningful disease control rate at 8 weeks of 37% - passing the pre-specified threshold to continue recruitment into stage 2. In a post-hoc analysis, a high proportion (90%) of patients with prior platinum response experienced disease control by Response Evaluation Criteria in Solid Tumours 1.1 at 8 weeks, warranting further assessment of platinum sensitivity as a surrogate clinical biomarker of PARPi sensitivity in the final study dataset. In stage 1 of the Solar study, the sensitivity and specificity of PET/CT to predict RECIST response was 70% and 75% respectively, demonstrating the potential utility of metabolic response assessment in determining PARPi response in OG adenocarcinomas. A comprehensive biomarker analysis plan was devised to evaluate HRD and PARPi sensitivity. Discovery analyses show a proportion of patients with OG adenocarcinoma exhibit loss of ATM and ARID1A protein expression, putative biomarkers of PARPi sensitivity. Assessment of the tumour immune microenvironment reveals a higher proportion of patients achieved disease control with high CD3 and PD-L1 compared to low level expression. Finally, assessment of somatic DDR mutations reveals somatic BRCA2 mutation associated with prolonged duration of olaparib disease control of more than 6 months.