ceralasertib (AZD6738)

In conclusion, ceralasertib 160mg BID d1-7 and 15-21 was established as monotherapy dosing with a response rate of 30% in patients with R/R MDS and CMML. NCT03770429.

Yet inevitable therapeutic resistance limits durability of clinical benefit and now defines the central pharmacological challenge of the field, driving development of next-generation DDR inhibitors including saruparib, ART6043, RP-3467, ART0380/alnodesertib, ceralasertib, and peposertib. We propose a biomarker-guided adaptive treatment algorithm integrating longitudinal circulating tumor DNA monitoring, functional RAD51 foci assays, and AI-driven multi-omics integration to enable real-time resistance detection and mechanism-guided therapy switching. This framework advances DDR-targeted oncology from static biomarker selection toward a dynamic, resistance-aware, mechanism-matched therapeutic strategy for patients with metastatic solid tumors.

In vivo and in vitro studies have shown enhanced tumor cell radiosensitivity with the ATRi ceralasertib, elimusertib, and berzosertib, however, the potentiating effect of ATRi on ionizing radiation (IR) through immune-based mechanisms has only been studied with ceralasertib. ATRi elicited differential inflammatory gene induction and dose-dependent unique cytotoxicity profiles in vitro . The immune mediated antitumor effect of ATRi combined with radiation is dose and schedule dependent, and while likely a class effect, may differ between ATRi compounds.

Ceralasertib monotherapy was tolerated; however, responses were limited. Alternative patient selection and combination treatments are being explored.

We demonstrate that inhibitors against ATR (AZD6738), and particularly ATM (AZD1390) and DNA-Pkcs (AZD7648), could significantly decrease clonogenic survival of HNSCC cell lines following PBT at both low and relatively high LET (~2 keV/µm and ~8 keV/µm, respectively). We confirmed that the inhibitors in combination with PBT led to DSB persistence through neutral comet assays and monitoring γH2AX/53BP1 foci. We also show that this strategy can enhance the sensitivity of patient-derived organoids of HNSCC to PBT of both low and high LET, highlighting this as a strategy which should be exploited further.

The developed risk model based on three prognostic genes (RRM2, WDR76, and PLEKHH2) exhibited superior predictive accuracy in NSCLC. These results may provide new insights for investigating novel therapeutic targets in NSCLC.

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.