Abstract 254: The PARP1-selective inhibitor and trapper saruparib achieves extended PARP1 target engagement in vitro , in vivo and in the clinic.

Abstract Saruparib (AZD5305) is a potent and selective inhibitor and trapper of PARP1 which is currently in ph3 clinical development. Initial preclinical characterisation highlighted nanomolar PARP1 inhibition potency and differentiated PARP1 binding profile with longer residence time kinetics compared with approved non-selective PARP inhibitors (PARPi). Here we describe the consequences of this in pre-clinical and clinical studies where we analysed PARP1 inhibition duration and phenotypic effects after different exposure times to saruparib. Surface plasmon resonance (SPR) of purified PARP1 showed that saruparib has a very slow dissociation rate, Koff, and extended residence time on purified PARP1 protein (5 days) compared to approved PARP1/2 inhibitors (hours). In cellular assays, saruparib treatment followed by wash-off resulted in sustained suppression of Poly ADP Ribose (PAR) over several days, whereas PAR levels recovered within 24 hours after olaparib exposure. We explored the duration of in vivo pharmacodynamic effects by monitoring PAR levels after steady state dosing of saruparib to mice bearing BRCA1-mutant MDA-MB-436 tumours, for up to 7 days after cessation of dosing. Saruparib at 0.01, 0.03 or 0.1mg/kg maintained PAR inhibition of 90% for up to 7 days, although the drug levels were not detectible in plasma after 2 days, confirming this extended duration of action in vivo. In contrast, PAR levels were substantially recovered by 24 hours after olaparib dosing. The functional consequences of the extended duration of action of saruparib were evaluated for in vivo efficacy. Multiple intermittent schedules of saruparib, compared to olaparib or talazoparib were evaluated in the BRCA1m-MDA-MB-436 model. Strong regressions were observed with saruparib on intermittent schedules where even 1 wk on, 2 wk off schedule at 1mg/kg (equivalent to the clinical RP2D dose of 60mg) gave durable regressions. A reduced dose of saruparib of 0.1mg/kg was still effective on an intermittent schedule, but lost significant activity compared to the higher dose. Intermittent dosing schedules of saruparib were clearly superior to the same schedules of olaparib or talazoparib at clinically equivalent doses. The long duration of activity of saruparib observed in preclinical studies were also observed in the PETRA clinical study (NCT04644068). A single dose of saruparib resulted in 90% PAR inhibition for up to 7 days, despite no drug being detected in plasma after 48 hours. These data suggest that short-term dose interruptions are unlikely to result in reduced efficacy, in contrast to approve non-selective PARPi where dose interruptions have been shown to reduce efficacy. These data also suggest that intermittent scheduling may be effective for saruparib in circumstances where minimising exposure may provide an optimal risk-benefit - for example cancer prevention. Citation Format: Mark Robert Albertella, Giuditta Illuzzi, Anna D. Staniszewska, Domenic Pilger, Sophie Cooke, Spiros Linardopoulos, Anna Beckett, Christopher Stubbs, Ganesh Moorthy, Mark J. O'Connor. The PARP1-selective inhibitor and trapper saruparib achieves extended PARP1 target engagement in vitro, in vivo and in the clinic abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 254.