Abstract 4201: Combination of the PARP1-selective inhibitor saruparib with androgen receptor pathway inhibition provides combination benefit in preclinical models of prostate cancer with or without homologous recombination repair deficiency

Abstract Recent phase 3 clinical trial readouts have shown benefit of the combination of poly(ADP-ribose) polymerase inhibitors (PARPi) with androgen receptor (AR) pathway inhibitors (ARPi) in metastatic, castration-resistant prostate cancer (mCRPC). While benefit was particularly evident in patients with tumors harboring mutations in homologous recombination repair (HRRm) genes, improved outcomes were also observed in patients with no such alterations in their cancers (non-HRRm). We evaluated the activity of the PARP1-selective inhibitor and trapper saruparib (AZD5305) in combination with the ARPi enzalutamide in a range of preclinical models in vitro and in vivo. Combination treatment of clinically relevant doses of 1mg/kg saruparib and 60mg/kg enzalutamide led to regressions or tumor control in BRCA2-mutant PDX models of prostate cancer, C901 and G266, and in the CDK12-mutant HRRm model PCU-012. Importantly, enhanced in vivo combination efficacy was also observed in non-HRRm prostate models LNCaP and C4-2, on treatment with saruparib and enzalutamide. Saruparib led to enhanced DNA damage after treatment in these models. We explored the mechanisms of action contributing to this observed combination benefit, focusing on the non-HRRm models where this was observed. The cell line C4-2 was not sensitive to saruparib alone, as expected, but showed enhanced sensitivity to the combination of enzalutamide with saruparib. Strikingly, this was not observed with the weaker PARP1 trapper veliparib, suggesting a requirement for trapping-induced DNA damage. The combination of enzalutamide and saruparib led to increased DNA double strand break formation, and enhanced accumulation of micronuclei, suggesting that this combination benefit is driven by an increase in unrepaired DNA damage. Enzalutamide treatment of C4-2 cells reduced the soluble nuclear fraction of the AR, as expected. Importantly, inhibition of PARP1 by saruparib reduced AR recruitment to chromatin in the presence of DNA damage. Combined treatment led to maximal reduction in AR recruitment, which may help explain the increased efficacy. These preclinical data demonstrate combination activity of saruparib and ARPi in HRRm as well as non-HRRm prostate cancer models and provide mechanistic evidence that combination benefit is driven by PARP1 trapping inducing DNA damage, and PARP1 inhibition and ARPi inhibiting the repair of this damage, leading to accumulation of cytotoxic genomic instability to the cancer cells. A clinical study ASCERTAIN (NCT05938270) has been initiated, where the focus is on collection of pre- and post- treatment biopsies from monotherapy and combinations of saruparib, and the ARPi darolutamide, with the aim of increasing further understanding of mechanisms of action between PARPi and ARPi. Citation Format: Mark R. Albertella, Giuditta Illuzzi, Anna D. Staniszewska, Sophie Cooke, Mark J. O'Connor, Josep V. Forment. Combination of the PARP1-selective inhibitor saruparib with androgen receptor pathway inhibition provides combination benefit in preclinical models of prostate cancer with or without homologous recombination repair deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4201.