ceralasertib (AZD6738)

Importantly, AZD6738 and olaparib significantly downregulated the protein expression of BRCA2, and RAD51, thereby reversing olaparib-induced activation of the DNA homologous recombination (HR) repair signaling pathways. In conclusion, dual inhibition of ATR and PARP represents a highly promising therapeutic strategy for TNBC with acquired resistance to olaparib.

P1, N=354, Active, not recruiting, AstraZeneca | Phase classification: P1/2 --> P1

P2, N=423, Completed, University of Birmingham | Active, not recruiting --> Completed

P1, N=51, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P2, N=83, Active, not recruiting, Rahul Aggarwal | Recruiting --> Active, not recruiting

Both ceralasertib plus durvalumab and ceralasertib monotherapy demonstrated low response rates in anti-PD-(L)1-resistant advanced melanoma.

This study establishes a synergistic nanotherapeutic strategy to concurrently disrupt the HIF-1α/ATR axis and augment radiodynamic ROS production. By integrating biological pathway inhibition with damage amplification, our strategy effectively overcomes hypoxia-mediated radioresistance, offering a promising and translatable paradigm for enhancing RT outcomes in LUAD.

P3, N=594, Active, not recruiting, AstraZeneca | Trial completion date: Oct 2026 --> Dec 2027

Inhibiting ATR with BAY1895344 or AZD6738 re-sensitized carboplatin-resistant PDXCs and PDXs to carboplatin, resulting in an increase in DNA damage, and apoptosis. Molecular factors associated with response to the ATR inhibitor/carboplatin combination included low RNA levels of PKMYT1. These results underscore the pivotal roles of ATR and PKMYT1 in mediating resistance to carboplatin in TNBC and support targeting these pathways to overcome carboplatin resistance in this disease.

Ceralasertib plus durvalumab was tolerated and associated with antitumour activity in advanced/metastatic NSCLC and HNSCC.

P1, N=4, Not yet recruiting, AstraZeneca AB

The formation of DNA double-strand breaks suggests replication fork collapse. Our findings demonstrates that this synthetic targeted therapy, combining a novel liposomal formulation of VitC with an ATR inhibitor, not only enhances DNA damage and the cytotoxic efficacy of ceralasertib but also effectively drives ovarian cancer cells toward cell death.