Pembrolizumab and Olaparib in Homologous-recombination Deficient (HRD) Advanced Colorectal Cancer (CRC).

ABSTRACT: Colorectal Cancer (CRC) is a leading cause of cancer-related death. Around 30% of patients present with advanced disease and 50% of those that attempt curative surgery will eventually relapse. The potential synergism of combining PARP inhibitor and PD-L1 is based on the hypothesis that pharmacological inhibition of PARP by olaparib will result in enhanced immunogenicity which can be further enhanced with an immune checkpoint inhibitor such as pembrolizumab. This may occur through a number of mechanisms, such as increased production of cytokines and chemokines that have the potential to promote antitumour immunity, upregulation of surface receptors which render tumour cells more visible to detection by cytotoxic T cells thereby leading to death of tumour cells and release of neoantigens, that help promote antigen presentation and immune priming. This hypothesis is supported by preclinical studies in mouse models of cancer, demonstrating that administration of a PARP inhibitor to sensitive tumour types resulted in increased T cell infiltration and immune activation within tumours. The primary hypothesis is that Olaparib and pembrolizumab combination will lead to an increase in objective response rate in patients with refractory metastatic colorectal cancer (mCRC) with DNA homologous-recombination-repair deficiency (HRD) from 1.5% in benchmark studies to up to >10%. The primary objective of the study is to determine the objective response rate (ORR) of pembrolizumab in combination with olaparib, assessed by the investigator per RECIST criteria version 1.1. Secondary objectives include efficacy in terms of disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and duration of response (DOR); safety and an exploratory study of biomarkers associated with treatment efficacy and disease prognosis.

DISEASE(S): Metastatic Colorectal Cancer,Cáncer Colorrectal Avanzado (ccr) Con Reparación De Recombinación Homóloga Deficiente (hrd).,Colorectal Neoplasms,Colorectal Cancer Metastatic,Homologous-recombination Repair Deficient (hrd) Advanced Colorectal Cancer (crc)

PROVIDER: 2401742 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR