Abstract C032: PRC2 inhibition enhances AR inhibitor response to delay treatment relapse in castration-sensitive prostate cancer by restricting adaptation of tumor cells in preclinical studies

Abstract Background: Polycomb repressive complex 2 (PRC2) silences transcription by tri-methylating histone H3 at lysine 27, thereby regulating cell growth and differentiation. Elevated PRC2 activity promotes lineage plasticity and therapeutic resistance and has been associated with poor prostate cancer prognosis. Combining androgen receptor inhibitors (ARIs) with PRC2 inhibitors may overcome or delay resistance, with clinical trials showing promise in metastatic castration-resistant prostate cancer (mCRPC). ORIC-944 is a next-generation, potent, highly selective, orally bioavailable small molecule inhibitor of PRC2 that allosterically targets the EED subunit, with potential best-in-class drug properties including superior half-life and reduced drug-drug interaction liabilities. Methods: ORIC-944 or EZH2 inhibitors were combined with ARIs to evaluate synergy in LNCaP cells using CellTiterGlo. In vivo xenografts were dosed with ORIC-944 or EZH2 inhibitor mevrometostat, darolutamide, or the combinations. The mechanism of PRC2 inhibition was profiled using RNA- and ATAC-sequencing. Results: We previously observed in vitro and in vivo synergy between PRC2 and AR inhibition in CRPC models and established a mechanism whereby PRC2 inhibition restores luminal features and restricts lineage adaptation. Herein, we evaluated the broader applicability of this combination for castration-sensitive prostate cancer (CSPC). ORIC-944 and enzalutamide synergistically impaired LNCaP cell growth. Transcriptional effects induced by combining ORIC-944 and ARI were comparable irrespective of ARI (i.e. darolutamide, apalutamide or enzalutamide). The synergistic cell viability effects were achieved when inhibiting PRC2 either with allosteric EED inhibition or EZH2 methyltransferase inhibition. In vivo treatment with ORIC-944 and darolutamide significantly increased progression-free survival in LNCaP xenografts relative to either agent alone. Mechanistically, adding ORIC-944 to darolutamide reduced accessibility at binding sites of transcription factors (TFs) associated with lineage diversification and plasticity such as FOXA1, HNF1A and ONECUT2, demonstrating similarity between CSPC and CRPC. Moreover, treatment of LNCaP xenografts with mevrometostat decreased access for the same lineage-associated TFs, demonstrating that PRC2 activity regulates chromatin accessibility. Both in vitro and in vivo, EED and EZH2 targeting in combination with ARIs achieved similar transcriptional effects, with enhanced expression of luminal markers and down-regulation of cell cycle genes. Conclusions: These preclinical results position ORIC-944 as a potential best-in-class PRC2 inhibitor that induces luminal cell fate and restricts lineage TF accessibility in both CRPC and CSPC settings, thereby extending the duration of response to ARI treatment by disabling cellular plasticity and delaying prostate tumor adaptation. ORIC-944 is under clinical evaluation in combination with ARIs in a global Phase 1b study (NCT05413421). Citation Format: Natalie Yuen, Aleksandr Pankov, Livia Ulicna, Jason E. Long, Xi Chen, Gina Andreatta, Amber W. Wang, Lori S. Friedman, Anneleen Daemen, Melissa R. Junttila. PRC2 inhibition enhances AR inhibitor response to delay treatment relapse in castration-sensitive prostate cancer by restricting adaptation of tumor cells in preclinical studies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C032.