Abstract 1270: The novel PARP1-selective inhibitor, AZD5305, is efficacious as monotherapy and in combination with standard of care chemotherapy in the in vivo preclinical models

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown efficacy in homologous recombination deficient (HRD) tumours, such as those with BRCA mutations (BRCAm). In this setting PARPi treatments lead to accumulation of DNA damage and cancer cell death. PARPi currently in clinical use inhibit both PARP1 and PARP2, as well as other members of the PARP family. Here, we report for the first time in vivo profiling of AZD5305, a potent and highly selective PARP1 inhibitor and trapper, currently in Ph1 clinical trials. Dose response efficacy of AZD5305 was evaluated in the BRCA1m triple-negative breast cancer (TNBC) xenograft model MDA-MB-436. AZD5305 dosed at 0.1mg/kg QD or higher for 35 days delivered about 90% regression, compared with 83% regression caused by treatment with 100mg/kg QD olaparib. Anti-tumour effects of AZD5305 continued after cessation of treatment and complete responses were achieved which were sustained for the whole duration of the study, over 100 days after treatment withdrawal, in contrast to the olaparib-treated group where regrowth of tumours was observed from day 63 after treatment withdrawal. Investigation of the PK/PD/efficacy relationship in MDA-MB-436 showed that maximum efficacy of AZD5305 was achieved when unbound plasma concentrations were maintained above the IC95 estimated from an in vitro DLD-1 BRCA2-/- cell growth assay. Similar results were obtained in a BRCA1m patient-derived explant (PDX) model, HBCx-17. Anti-tumour efficacy of AZD5305 was also tested in the DLD-1 BRCA2-/- and wild-type (WT) isogenic xenograft models. In the DLD-1 BRCA2-/- model, AZD5305 dosed at 10mg/kg QD and 1mg/kg QD delivered 78% and 63% tumour regression, respectively. AZD5305 at 0.1mg/kg QD resulted in responses similar to those observed in the olaparib 100mg/kg QD group (40-54% tumour growth inhibition, TGI). As expected, AZD5305 and olaparib showed no anti-tumour efficacy in the DLD-1 WT tumour model. Due to improved PARP1 selectivity, AZD5305 has the potential to show improved efficacy and tolerability in combination with standard of care chemotherapy when compared to non-selective PARPi. Hence, we investigated the anti-tumour effects of AZD5305 in combination with carboplatin or paclitaxel in a BRCA1m TNBC xenograft, SUM149PT, and BRCA WT TNBC PDX model, HBCx-9. In both models, combination of AZD5305 with carboplatin was well tolerated and demonstrated clear benefit compared to each monotherapy treatment. The effects of adjusted dosing and scheduling of the combination on the anti-tumour efficacy will be presented. Citation Format: Anna D. Staniszewska, James W. Yates JWT, Andy Pike, Christine Fazenbaker, Kimberly Cook, Emily Bosco, Aaron Smith, Joanne Wilson, Elisabetta Leo. The novel PARP1-selective inhibitor, AZD5305, is efficacious as monotherapy and in combination with standard of care chemotherapy in the in vivo preclinical 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 1270.

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

“…Along with its good potency, AZD5305 was expected to drive low efficacious doses, reflecting its high therapeutic potential. Another investigation of the PK/PD relationship in BRCA1m triple-negative breast cancer (TNBC) xenograft model MDA-MB-436 indicated that the maximum efficacy of AZD5305 was achieved when unbound plasma concentrations were maintained above the IC95 ( Staniszewska et al, 2021 ).…”

“…AZD5305 was tested for efficacy in BRCA1m TNBC patient-derived explant (PDX) model HBCx17, MDA-MB-436 model, DLD-1 BRCA2−/− and wild-type isogenic xenograft model respectively ( Staniszewska et al, 2021 ). Similar results were obtained in the first three models, as it showed excellent potency compared with olaparib, enabled anti-tumor effects and tumor regression under a low-level dosage.…”

“…As expected, AZD5305 showed no efficacy in the last model, again confirming its selectivity for HRD cells. Moreover, an investigation in BRCA1m TNBC xenograft model SUM149PT and BRCA WT TNBC PDX model HBCx-9 indicated that, comparing to each monotherapy treatment, AZD5305 was well tolerated and showed significant benefit when combined with carboplatin ( Staniszewska et al, 2021 ). Likewise, another investigation in ovarian cancer xenografts (OC-PDXs) model had come to a conclusion that combined with carboplatin, AZD5305 stabilized the growth of tumours at doses as low as .1 mg/kg that on its own was not effective ( Dellavedova et al, 2021 ).…”

Expanding the Use of PARP Inhibitors as Monotherapy and in Combination in Triple-Negative Breast Cancer

“…Toxicity was a significant concern with continuous and concomitant dosing of talazoparib in combination with carboplatin. However, it will be interesting to observe the efficacy and toxicity of the newly developed selective PARP-1 inhibitor that has demonstrated promising preclinical results and is currently in a Phase I trial [138].…”

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

“…While significant tumor growth inhibition was observed with AZD5305 monotherapy compared with vehicle ( P ≤ 0.01), significant tumor regression was observed only with combination treatment of AZD5305 plus carboplatin ( P ≤ 0.001). 38 Interestingly, despite limited monotherapy response for AZD5305 in BRCA-wild-type HBCx-9 xenografts, combinations of oral AZD5305 at dose ranges of 0.1 to 1 mg/kg daily with either carboplatin or paclitaxel dosed intraperitoneally led to significant tumor growth inhibition. 38 Remarkably, significant tumor regression was observed from doses of AZD5305 as low as 0.01 mg/kg daily when combined with carboplatin or AZD5305 0.1 mg/kg daily when combined with paclitaxel (both P ≤ 0.001).…”