Abstract P054: RP-3500: A novel, potent and selective ATR inhibitor that is effective in pre-clinical models as a monotherapy and in combination with PARP inhibitors

Abstract

Abstract Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase is a key mediator of cellular DNA damage repair (DDR) and is activated in response to DNA replication stress. ATR is attractive as a drug target in tumors with loss-of-function alterations in complimentary DDR pathways, including ataxia-telangiectasia mutated (ATM) and BRCA. RESULTS: RP-3500 is a novel, orally bioavailable clinical-stage ATR kinase inhibitor. RP-3500 is highly potent with ATR kinase IC50 values of 1.0 and 0.33 nM in biochemical and cell-based assays, respectively. It is highly selective with >30-fold selectivity over mTOR and >2000-fold selectivity over ATM, DNA-PK and PI3Kα kinases. Preclinical tumor xenograft models harboring synthetic lethal (SNIPRx) gene mutations whose loss of function sensitizes to RP-3500 were selected for in vivo studies. RP-3500 treatment resulted in potent single-agent in vivo efficacy and/or tumor regression in multiple models at minimum effective doses (MED) of 5–7 mg/kg once daily. Pharmacodynamic assessments validated target engagement, with a proportional relationship between tumor pCHK1(Ser345) inhibition and circulating RP-3500 plasma levels (IC80 = 18.6 nM). Circulating free plasma levels of RP-3500 at the MED indicate that exposure above the in vivo tumor pCHK1(Ser345) IC80 for 10–12 hours is sufficient for efficacy and dose proportional phosphorylation of DNA damage markers γ-H2AX, pDNA-PKcs and pKAP1. In vitro, tumor cells with ATM loss exhibited increased susceptibility to RP-3500 and a 3-day compound exposure was sufficient to generate a sustained DNA damage response compared to cells with functional ATM expression. In ATM-deficient mouse models, short-duration intermittent (weekly 3 days on/4 days off or 5 days on/2 days off) dosing schedules maximized tumor growth inhibition while minimizing the impact on hematology parameters, including red blood cell depletion. These results emphasize the reversible nature of erythroid toxicity with RP-3500 and the advantage of intermittent dosing schedules to alleviate anemia. The 3 days on/4 days off intermittent treatment schedule also substantially improved the efficacy and tolerability of RP-3500 and PARP inhibitor combinations compared to continuous treatment schedules. Intermittent treatments of RP-3500 given concomitantly with reduced doses of olaparib or niraparib demonstrated synergistic efficacy in Granta-519 (ATM mutn) and SUM149PT (BRCA1mutn) models with minimal hematological adverse effects and superior efficacy to sequential treatment. CONCLUSIONS: These results provide a strong preclinical rationale to support clinical investigation of the novel ATR inhibitor RP-3500 on an intermittent schedule as a monotherapy and in combination with PARP inhibitors as a means of maximizing clinical benefit. RP-3500 is currently evaluated in the ongoing phase 1 TRESR (Treatment Enabled by SNIPRx) study (NCT04497116). Citation Format: Anne Roulston, Michal Zimmerman, Robert Papp, Alex Skeldon, Charles Pellerin, Émilie Dumas-Bérube, Valerie Dumais, Stephane Dorich, Sara Fournier, Li Li, Marie-Ève Leclaire, Shou Yun Yin, Amandine Chefson, Hunain Alam, William Yang, Chloe Fugère-Desjardins, Sabrina Hammond, Kathryn Skorey, Amina Mulani, Victoria Rimkunas, Artur Veloso, Martine Hamel, Rino Stocco, Yael Mamane, Zuomei Li, Jordan Young, Mike Zinda, Cameron Black. RP-3500: A novel, potent and selective ATR inhibitor that is effective in pre-clinical models as a monotherapy and in combination with PARP inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P054.