ceralasertib (AZD6738)

P3, N=630, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

P1, N=51, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027 | Trial primary completion date: Mar 2026 --> Mar 2027

The study failed to meet its primary end point of ORR. DDR and homologous recombination repair defects are not consistently actionable with olaparib as monotherapy or in combination with other targeted therapies in a histology-agnostic manner.

These results demonstrate that ATR blockade concurrently enhances the efficacy of genotoxic agents and immune checkpoint inhibitors, thus paving the way for combination therapies in NSCLC.

P2, N=273, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2025 --> Sep 2026

P1/2, N=357, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2025 --> Jun 2026

P2, N=174, Active, not recruiting, Institute of Cancer Research, United Kingdom | Recruiting --> Active, not recruiting | Trial completion date: Apr 2026 --> Aug 2026 | Trial primary completion date: Apr 2026 --> Aug 2026

Mechanistically, 38a arrested cell cycle progression, induced apoptosis, inhibited colony formation and migration, and suppressed DNA damage repair pathways, outperforming combined Niraparib and AZD6738. These findings underscore the therapeutic potential of PARP1/ATR dual inhibitors for breast cancer and support further investigation.

Ceralasertib monotherapy demonstrated promising anti-tumor activity in ARID1A-deficient gynecologic malignancies. Tumor molecular and immune correlates may inform the further development of ATR inhibitors in this patient population.

Preclinical studies demonstrate that ATR inhibition disrupts replication stress tolerance, impairs homologous recombination, and disables checkpoint control, enhancing cytotoxicity from standard therapies including gemcitabine, FOLFIRINOX, fluoropyrimidines, and radiotherapy...Early-phase clinical trials of ATR inhibitors (ART0380, AZD6738, BBI-355) alone or in combination show promising safety, tolerability, and preliminary efficacy. In this review, we summarize current literature on targeting the ATM-CHK2 and ATR-CHK1 pathways in PC, highlighting preclinical evidence, clinical developments, and strategies for biomarker-driven, precision oncology approaches.

CD8+ T cell depletion completely abrogates the anti-tumor effects, suggesting their essential role in mediating therapeutic responses. These findings establish Gal-9 upregulation as a critical adaptive immune resistance mechanism constraining ATRi efficacy, providing a compelling rationale for clinical translation of ceralasertib/Gal-9 blockade combinations.

We provide a detailed analysis of the structure-activity relationships (SAR) of leading clinical candidates, including berzosertib, ceralasertib, and elimusertib, focusing on strategic chemical modifications such as scaffold hopping and sulfoximine substitution to optimize selectivity and druggability. Critical challenges, specifically dose-limiting hematological toxicities and acquired resistance, are analyzed alongside the search for robust predictive biomarkers. By synthesizing current pharmacological and clinical data, this work outlines the trajectory for next-generation ATR-targeted precision medicine.