Abstract 7182: EZH2 inhibition as a therapeutic strategy for castration resistant prostate cancer in combination with AR-antagonist enzalutamide

Abstract The histone methyltransferase EZH2 is an epigenetic transcriptional repressor which mediates gene silencing through methylation of H3K27 residues. EZH2 is overexpressed in castration-resistant prostate cancer (CRPC) and has been associated with prostate cancer progression and resistance to anti-androgen therapies. We have developed a potent, selective, SAM-competitive EZH2 inhibitor, PF-06821497 (Mevrometostat). Using genetic and pharmacological approaches, we demonstrate an epigenetic dependency in CRPC to EZH2 inhibition. EZH2 was identified as a hit in a genome-wide CRISPR screen in AR-positive, but not in AR-negative, CRPC models and was further confirmed in independent CRISPR-competition assays. Consistent with genetic data, long-term PF-1497 treatment showed selective anti-tumor activity in AR-positive CRPC cell lines. Anti-tumor activity of PF-1497 was further validated in vivo with dose-dependent tumor growth inhibition observed in correlation with H3K27me3 biomarker inhibition in CRPC xenograft models. EZH2 inhibition induced cell cycle arrest concomitant with transcriptional upregulation of tumor suppressor genes. Interestingly, we found a subset of genes induced upon enzalutamide treatment are also upregulated upon PF-1497 treatment. Transcriptional and epigenetic profiling revealed that genes repressed by AR show enrichment for H3K27me3 indicating a co-repressor function for EZH2. Combination in vitro treatment of PF-1497 with enzalutamide showed synergistic upregulation of such co-repressed genes associated with robust inhibition of proliferation, survival, cell cycle and stem cell pathways. This transcriptional synergy was associated with robust in vivo anti-tumor combination activity of PF-1497 with enzalutamide inducing durable tumor regressions. Similar combination benefit of PF-1497 and enzalutamide was observed across a panel of CRPC PDXs with anti-tumor activity enriched in AR-positive prostate cancer models, including tumors from patients who were refractory to anti-androgen therapies. Taken together, these data highlight the promise of EZH2 inhibition in treating prostate cancer and provide support for ongoing clinical study of PF-06821497 in combination with enzalutamide in mCRPC. Citation Format: Shikhar Sharma, Jelena Petrovic, Sara Linker, Whijae Roh, Joan Cao, Sean Uryu, Zhenxiong Wang, Yong Zhang, Colin A. Flaveny, Conglin Fan, Tao Xie, Kimberly H. Kim, Xiaoli Wang, Robert A. Rollins, Gail P. Risbridger, Renea A. Taylor, Mitchell G. Lawrence, Thomas A. Paul, Pei-Pei Kung. EZH2 inhibition as a therapeutic strategy for castration resistant prostate cancer in combination with AR-antagonist enzalutamide [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 7182.