Comprehensive Monograph on Berzosertib (DB11794): An Investigational First-in-Class ATR Kinase Inhibitor

Executive Summary

Berzosertib is a first-in-class, potent, and selective intravenous inhibitor of the Ataxia telangiectasia and Rad3-related (ATR) kinase. As a pioneer in its therapeutic class, it has been instrumental in validating the strategy of targeting the DNA Damage Response (DDR) in oncology. Its clinical development has yielded a dichotomous narrative: demonstrating significant, practice-informing efficacy in specific, biomarker-enriched populations such as platinum-resistant ovarian cancer, while simultaneously failing to meet endpoints in broader, less-selected patient groups, exemplified by the discontinuation of a pivotal trial in small cell lung cancer (SCLC).

The primary mechanism of action for Berzosertib involves the blockade of the ATR-Checkpoint Kinase 1 (Chk1) signaling pathway, a critical cell cycle checkpoint activated by replication stress. This inhibition prevents cancer cells from repairing damaged DNA, leading to mitotic catastrophe and apoptosis. This therapeutic strategy is based on the principle of synthetic lethality, which is particularly effective in tumors with pre-existing DDR defects, such as those with Ataxia-telangiectasia mutated (ATM) or TP53 mutations.

The most compelling clinical evidence for Berzosertib's efficacy comes from the randomized Phase II trial NCT02595892 in platinum-resistant ovarian cancer. In this study, the addition of Berzosertib to gemcitabine significantly improved progression-free survival compared to gemcitabine alone. Conversely, the global Phase II DDRiver SCLC 250 trial in platinum-resistant SCLC was discontinued for futility, a major setback that underscores the critical importance of patient selection for this class of agents.