Abstract 1374: The novel PARP1-selective inhibitor AZD5305 has reduced hematological toxicity when compared to PARP1/2 inhibitors in pre-clinical models

Abstract

Current clinical poly (ADP-ribose) polymerase (PARP) inhibitors target both PARP1 and PARP2 and they all cause clinical cytopenias with varying severity. Understanding the mechanism underlying the hematological toxicity of these agents is key for the rational design of a best-in-class molecule with greater therapeutic potential, both as monotherapy and in combination with chemotherapy. We validated the rat as a physiologically competent translational model to investigate PARP inhibitor-driven hematological toxicity. Here we demonstrate that in comparison with a representative PARP1/2 inhibitor, olaparib, the novel highly potent PARP1-selective inhibitor and trapper, AZD5305, does not cause hematological toxicity as a monotherapy in pre-clinical rat models at predicted clinically efficacious exposures. Thus, monotherapy toxicity of PARP1/2 inhibitors likely depends on PARP2 inhibition. Next, we proceeded to investigate whether PARP1-selective inhibition would be better tolerated in chemotherapy combinations than PARP1/2 inhibition. We performed a rat in vivo study comparing daily olaparib or daily AZD5305 at matched exposures in combination with one cycle of intravenous carboplatin for 14 days. We show that olaparib and PARP1-selective AZD5305 cause comparable exacerbation of carboplatin-induced peripheral blood effects implicating PARP1 inhibition in combination-driven hematological toxicity. Importantly however, AZD5305+carboplatin showed improved hematological tolerability over olaparib+carboplatin because peripheral reticulocytes and bone marrow erythroid precursor cells recover in the presence of continuous AZD5305 but not in the presence of continuous olaparib. Importantly, this differentiation was maintained in a subsequent rat in vivo study, where daily olaparib or daily AZD5305 were combined with two three-weekly cycles of a higher dose of carboplatin to more closely mimic clinical protocol. AZD5305+carboplatin was associated with a more rapid recovery of reticulocytes, red blood cells and hemoglobin following both cycles of carboplatin. In contrast, olaparib+carboplatin was associated with a slower recovery resulting in a more sustained reduction in red cells and hemoglobin during both the first and second cycle of carboplatin. Thus, in rodents the novel potent PARP1-selective inhibitor AZD5305 has improved hematological tolerability over dual PARP1/2 inhibitors, both as a monotherapy and in carboplatin combinations. Citation Format: Sonja J. Gill, Ruth Macdonald, Carmen Pin, Rob Collins, Emilyanne Leonard, Gareth Maglennon, Andy Pike, Peter Cotton, Glen Hawthorne, Jordan Pugh, Rebecca Sargeant, Daniel Sutton, James Atkinson, Stewart Jones, Sarah Chinery, Mark Anderton. The novel PARP1-selective inhibitor AZD5305 has reduced hematological toxicity when compared to PARP1/2 inhibitors in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1374.

Current status and future promise of next-generation poly (ADP-Ribose) polymerase 1-selective inhibitor AZD5305

“…Notably, this differentiation was maintained and confirmed again in a more closely mimic clinical protocol with two-weekly cycles and higher dose of carboplatin ( Gill et al, 2021 ). Thus, regardless of monotherapy or in carboplatin combinations, AZD5305 has improved hematological tolerability over dual PARP1/2 inhibitors in rodents ( Gill et al, 2021 ). Findings above has confirmed the pathogenic role of PARP2-associated hematologic toxicity, thus targeting only PARP1 can retain the therapeutic benefit of non-selective PARPi, while reducing potential for hematotoxicity ( Illuzzi et al, 2022 ).…”

“…In rat models as a monotherapy, in comparison with olaparib, AZD5305 does not cause hematological toxicity at predicted clinically efficacious exposures, however, olaparib causes up to 50% reduction in hemoglobin ( Leo and Johannes, 2021 ), again demonstrating that monotherapy toxicity of PARP1/2 inhibitors may be dependent on PARP2 inhibition. Furthermore, according to a subsequent rat in vivo study of combination chemotherapy, AZD5305 + carboplatin showed improved serologic tolerance compared with olaparib + carboplatin, as peripheral reticulocytes and myeloid erythroid precursor cells recover with continuous AZD5305 administration but not in the presence of continuous olaparib ( Gill et al, 2021 ). Notably, this differentiation was maintained and confirmed again in a more closely mimic clinical protocol with two-weekly cycles and higher dose of carboplatin ( Gill et al, 2021 ).…”

“…Furthermore, according to a subsequent rat in vivo study of combination chemotherapy, AZD5305 + carboplatin showed improved serologic tolerance compared with olaparib + carboplatin, as peripheral reticulocytes and myeloid erythroid precursor cells recover with continuous AZD5305 administration but not in the presence of continuous olaparib ( Gill et al, 2021 ). Notably, this differentiation was maintained and confirmed again in a more closely mimic clinical protocol with two-weekly cycles and higher dose of carboplatin ( Gill et al, 2021 ). Thus, regardless of monotherapy or in carboplatin combinations, AZD5305 has improved hematological tolerability over dual PARP1/2 inhibitors in rodents ( Gill et al, 2021 ).…”

Development of Next-Generation Poly(ADP-Ribose) Polymerase 1–Selective Inhibitors

“…Furthermore, bone marrow examination at day 14 revealed a similar level of erythroid bone marrow precursors and bone marrow cellularity for rats treated with AZD5305 plus carboplatin compared with those treated with carboplatin alone. 39 Similar red blood cell and platelet nadir-to-recovery patterns for AZD5305 and first-generation PARP inhibitors were demonstrated when rats were dosed with daily AZD5305 plus carboplatin at a higher dose for two thrice-weekly cycles to mimic the clinical conditions of treatment. Even at increased carboplatin dose and duration of combination therapy, red blood cell and platelet recovery was significantly more rapid for AZD5305 compared with other PARP inhibitors.…”

“…34 In rat models, olaparib dosed daily for 2 weeks led to a 50% reduction in hemoglobin, consistent with the anemia often observed among patients in the clinic. 39 Yet, when AZD5305 was dosed under identical experimental conditions, using a dose predicted to be clinically efficacious, no cytopenias were noted. 39 Peripheral blood reticulocyte levels were also maintained in rats treated with AZD5305 throughout the 2-week period of treatment, compared with rats treated with first-generation PARP inhibitors, which suffered significant reductions both in peripheral reticulocytosis, as well as in intramedullary erythroid precursor cells measured using flow cytometry.…”