Abstract B058: Combination of the PARP1-selective inhibitor AZD5305 with the ATR inhibitor ceralasertib for the treatment of PARPi-resistant cancer

Abstract AZD5305 is a novel, selective inhibitor of PARP1 and ceralasertib (AZD6738) an inhibitor of the ATR kinase, that target distinct DNA damage response pathways. Trapping of PARP1 increases replication stress and activates ATR. Combination of PARP and ATR inhibitors enhances anti-tumour efficacy and can overcome acquired PARP inhibitor resistance. The combination of the first-in-class PARP1 selective inhibitor AZD5305 with ceralasertib was explored in preclinical models of multiple tumour types, investigating dose and schedules to optimise efficacy while minimising exposure to mitigate potential tolerability issues. AZD5305 and ceralasertib combinations were evaluated in a cell panel screen and were more effective than the respective single agents in 37/114 (~32%) cancer cell lines, including (but not restricted to) homologous recombination repair-proficient lines. Breast cancer models that have wild type BRCA, and BRCA1 hypomorphs (that re-express the BRCA1 coding sequence), were sensitive to the combination of AZD5305 + ceralasertib. Long-term 28-day in vitro colony regression assays in PARP- and ATR inhibitor resistant cell lines, were used to determine the minimum-maximum clinically relevant drug concentrations required to drive cell kill. Drug washouts were carried out to evaluate various schedules of administration. In these experiments, low concentrations (6 nM) AZD5305 were sufficient to drive combination benefit and colony regressions. Sequence-scheduling evaluation indicated that concurrent administration and 7-day exposures at the start of the cycle, were sufficient for strong combination activity. 7-day AZD5305 exposures above 6 nM were sufficient for maximum activity. Higher concentrations or longer duration of treatment provided little additional benefit. In vivo efficacy of the combination was evaluated in PARPi-resistant models of breast and ovarian cancer. Dosing 0.1 mg/kg AZD5305, with ceralasertib for 14-days in a 28-day cycle achieved maximum anti-tumour efficacy. PDX models of TNBC or ER+ breast cancer that were resistant to monotherapies achieved complete regressions after combination dosing. These data establish low-dose, short-course concurrent dosing of AZD5305 in combination with ceralasertib is sufficient for maximal efficacy in PARP inhibitor resistant models. The combination of AZD5305 and ceralasertib shows activity in a range of PARPi- and ATRi-resistant tumor models. A clinical study of the combination of AZD5305 and ceralasertib is ongoing (NCT02264678). Citation Format: Mark Albertella, Paul Wijnhoven, Annie Demin, Giuditta Illuzzi, Andrea Herencia Ropero, Violeta Serra, Ankur Karmokar, Anna Staniszewska, Alan Lau. Combination of the PARP1-selective inhibitor AZD5305 with the ATR inhibitor ceralasertib for the treatment of PARPi-resistant cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B058.