Abstract PR024: Circulating tumor DNA methylation captures epigenetic changes in patients induced by the PRC2 inhibitor ORIC-944

Abstract Androgen Receptor Pathway Inhibition (ARPI) is a cornerstone of prostate cancer treatment; however, therapeutic resistance often arises due to an AR-independent cell state emerging as a result of tumor plasticity. Dysregulation of epigenetic reprogramming factors, including Polycomb Repressive Complex 2 (PRC2), creates an environment conducive to lineage plasticity. Thus inhibiting PRC2 offers a promising strategy to overcome ARPI therapeutic resistance in prostate cancer. ORIC-944 is a potent, orally bioavailable, allosteric PRC2 inhibitor with potential best-in-class drug properties that is currently in Phase 1b clinical development. In preclinical studies, ORIC-944 in combination with ARPI demonstrated efficacy across various models including AR-mutant and -wildtype, ARPI-resistant and -sensitive, and castration-resistant and -sensitive prostate cancers. Despite the spectrum of resistance mechanisms in these AR positive models, ORIC-944 consistently enhanced signatures of luminal cell state and AR signaling. These preclinical observations reveal the potential for ORIC-944 to block prostate tumor adaptation and re-sensitize tumors to ARPI. In this study of clinical samples from the ORIC-944-01 Phase 1b clinical trial, we aimed to evaluate the mechanism of ORIC-944 in patients with prostate cancer. DNA methylation profiling from liquid biopsies was chosen as a non-invasive method for investigating the epigenetic landscape of circulating tumor DNA. We identified CpG-rich regions associated with prostate tumorigenesis and transcriptional subtypes based on publicly available DNA methylation data from 100 metastatic castration-resistant prostate cancer (mCRPC) tumors, 35 healthy blood samples, and 150+ normal tissues. These selected regions became the foundation of a custom panel utilized on liquid biopsies to profile the epigenetic states of tumors from mCRPC patients treated with single-agent ORIC-944. A new methodology for cell-free DNA methylation was established to detect and quantify changes in subtype-associated regions independently of tumor burden. This approach and the clinical DNA methylation data showed that following treatment with ORIC-944, tumors from most patients experienced a shift in methylation pattern that suggests an increase in AR signaling. Notably, this shift was detectable after one treatment cycle of single agent ORIC-944, consistent with preclinical studies. Conversely, no patients showed an increase in neuroendocrine-associated signals after one cycle of treatment. These findings suggest that a selected set of informative methylation regions evaluated in plasma can identify epigenetic-driven changes in transcriptional activity during the treatment of patients with advanced prostate cancer. This approach is a key step towards enabling non-invasive epigenomic profiling of transcriptional states of prostate cancer. Furthermore, this analysis confirms our preclinical mechanistic data and hypothesis that ORIC-944 treatment enhances AR signaling in prostate cancer. Citation Format: Amber W. Wang, Michal Pawlak, Eric Ariazi, Livia Ulicna, Anne Page, Rupal Patel, Edna Chow Maneval, Pratik S. Multani, Lori S. Friedman, Anneleen Daemen, Aleksandr Pankov. Circulating tumor DNA methylation captures epigenetic changes in patients induced by the PRC2 inhibitor ORIC-944 abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr PR024.