Abstract 452: ORIC-944, a PRC2 inhibitor with best-in-class properties, restores luminal features and restricts adaptation in prostate cancer models, conferring synergy with AR pathway inhibitors

Abstract Polycomb repressive complex 2 (PRC2) silences transcription by tri-methylating histone H3 at lysine 27 (H3K27me3), regulating cell growth and differentiation. The EED subunit is required for chromatin recruitment and histone methyltransferase activity. PRC2 dysregulation is linked to poor prostate cancer prognosis, promotes lineage plasticity and therapeutic resistance. Combining androgen receptor pathway inhibitors (ARPI) with PRC2 inhibitors may overcome or prevent resistance, with clinical trials showing promise in metastatic castration-resistant prostate cancer. First-generation PRC2 inhibitors exhibit poor drug properties and short half-lives, requiring at least twice daily dosing at high doses. ORIC-944 is a second-generation allosteric inhibitor of PRC2 that binds EED and exemplifies best-in-class drug properties including potency, solubility, and ADME/PK, with half-life supporting once daily dosing. The mechanism of PRC2 in prostate cancer lineage plasticity was explored with RNA-seq, H3K27me3 ChIP-seq, and ATAC-seq data from in vitro and in vivo studies of ORIC-944 as a single agent and combined with ARPI. No evidence for a non-canonical EZH2 role was found comparing EZH2 and EED inhibitors by RNAseq. ORIC-944 or EZH2 inhibition led to robust PRC2 inhibition, luminal state transition, and increased AR signaling in a spectrum of AR-positive in vivo prostate cancer models. In vivo kinetic studies revealed that luminal cell state transition and increased AR signaling are early events induced by ORIC-944. The luminal cell state acquired with PRC2 inhibition was confirmed by IHC, and is highly dependent on AR signaling in vivo, indicative of a functionally relevant cell state. Continuous ORIC-944 administration was necessary to maintain the luminal state and antitumor efficacy. Surprisingly, analysis of chromatin revealed that ORIC-944 specifically restricts accessibility to lineage-associated transcription factors known to impart cellular plasticity in prostate cancer. This plasticity-restricted luminal state conferred by PRC2 inhibition is dependent on AR, leading to antitumor activity either in the hormone-depleted context or in the setting of ARPI combination. Together these data indicate that ORIC-944 reinforces a luminal cell state and, notably, restricts access to plasticity genes leading to a highly AR-dependent state in prostate models. This mechanism supports the observed preclinical synergy between PRC2 inhibition and ARPI combination in both ARPI-sensitive and ARPI-resistant settings. These results position ORIC-944 as a potential best-in-class PRC2 inhibitor that blocks prostate tumor adaptation, restores luminal features, and sensitizes tumors to ARPI. A phase 1b trial of ORIC-944 in combination with ARPIs is ongoing in metastatic prostate cancer (NCT05413421). Citation Format: Anneleen Daemen, Alexandr Pankov, Natalie Yuen, Amber Wang, Livia Ulicna, Xi Chen, Frank L. Duong, Jason E. Long, Robert Warne, Lori S. Friedman, Melissa R. Junttila. ORIC-944, a PRC2 inhibitor with best-in-class properties, restores luminal features and restricts adaptation in prostate cancer models, conferring synergy with AR pathway inhibitors [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 452.