saruparib (AZD5305)

In vivo, compound C16a demonstrated excellent tumor growth inhibition (TGI) in the AZD5305-sensitive/-insensitive xenograft model with TGI values of 133.6% and 71.9%, respectively. Collectively, compound C16a may be a powerful therapeutic agent not only for treating PARPi-sensitive tumors but also PARPi-resistant tumors, even HR-proficient tumors.

P1, N=113, Completed, AstraZeneca | Recruiting --> Completed

Autophagy inhibition downstream of the mTOR pathway is a mechanism of PARPi sensitivity in SCLC. This suggests that a therapeutic combination of autophagy inhibition and PARPi is a promising treatment strategy in SCLC, paving the way for the adoption of novel treatments in this disease context.

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.

P3, N=1889, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | Trial primary completion date: Jan 2028 --> Sep 2027

To explore the molecular determinants of ligand selectivity, we focus on four clinically relevant PARP inhibitors-two PARP1-selective (saruparib and NMS-P118) and two non-selective (veliparib and olaparib) inhibitors-and perform atomistic potential-of-mean-force calculations of the PARP1 catalytic binding domain in the presence of these molecules. Progressively increasing the number of mutations markedly reduces binding stability, with distinct residue combinations exerting two primary effects: destabilization of the final bound state and the emergence of energetic barriers along the ligand association pathway. Together, our results provide a coherent mechanistic framework for understanding PARP1 selectivity and informs the rational design of next-generation inhibitors with improved efficacy and safety.

This study provides a first-in-class characterization of saruparib resistance and maps a clear therapeutic path forward. By identifying these specific PARP1 mutations and their collateral DDR vulnerabilities, we provide the molecular framework necessary to monitor and treat patients who progress on next-generation PARP1-selective inhibitors.

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

Testing these cell lines for their behavior and sensitivity to different PARP inhibitors, we find that saruparib, a first-in-class PARP1-specific inhibitor, promotes the release of certain PARP1 catalytic mutants and resistance to this inhibitor. We also characterize a PARP1 catalytic mutant with intact mono(ADP-ribosyl)ation activity but devoid of poly(ADP-ribosyl)ation, enabling us to demonstrate a significant contribution of mono(ADP-ribosyl)ation toward PARP1 release from sites of DNA damage.

P1/2, N=300, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P1, N=120, Recruiting, AstraZeneca | Active, not recruiting --> Recruiting

P3, N=700, Recruiting, AstraZeneca