Ceralasertib (AZD6738): A Comprehensive Monograph on a Leading ATR Kinase Inhibitor in Oncology

Executive Summary

Ceralasertib (AZD6738) is an investigational, orally bioavailable, small molecule inhibitor of the Ataxia Telangiectasia and Rad3-related (ATR) kinase, under development by AstraZeneca. As a central component of the DNA Damage Response (DDR) pathway, ATR is critical for maintaining genomic stability, particularly in response to replication stress—a hallmark of many cancers. Ceralasertib functions as a potent and highly selective ATP-competitive inhibitor of ATR, leading to the abrogation of cell-cycle checkpoints, disruption of DNA repair, and ultimately, selective apoptosis in cancer cells. Its therapeutic rationale is twofold: inducing synthetic lethality in tumors with pre-existing DDR defects (such as ATM loss) and sensitizing tumors to DNA-damaging agents and other therapies.

The preclinical profile of Ceralasertib is robust, demonstrating significant antineoplastic activity both in vitro across numerous cancer cell lines and in vivo in xenograft models. This activity is particularly pronounced in tumors with ATM deficiency and is enhanced when combined with chemotherapy, radiotherapy, and PARP inhibitors. The clinical development program for Ceralasertib is extensive and multifaceted, evaluating the agent as both a monotherapy and a versatile combination partner. The Phase I PATRIOT trial established its monotherapy safety profile and recommended Phase II dose (RP2D), revealing durable responses in biomarker-selected patients with advanced solid tumors, particularly those with ARID1A mutations.