Modulation of enhancer of zeste homolog 2 (EZH2) pharmacodynamic markers and tumor gene expression by mevrometostat (PF-06821497) in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC).

146 Background: Mevrometostat (PF-06821497; M) is a potent and selective small molecule inhibitor of EZH2. Dose exploration of M in combination with enzalutamide (E) showed a manageable safety profile and promising activity in patients with mCRPC in a phase 1 study (NCT03460977). M exhibited dose-dependent pharmacokinetic (PK) exposure increases up to 1250 mg BID in combination with E (160 mg daily). We report the corresponding pharmacodynamic (PD) effects of EZH2 inhibition and tumor gene expression changes by M+E in patients with mCRPC. Methods: Serial whole blood and paired tumor biopsy samples were collected during dose escalation of M from 150 to 1250 mg BID in combination with E (160 mg QD) given on empty stomach in patients with mCRPC. Paired tumor biopsy samples were collected before the study and after 21 days of M+E or E. H3K27Me3 PD marker was evaluated in peripheral granulocytes by flow cytometry and in paired tumor biopsy samples by an immunohistochemistry assay. Tumor gene expression was profiled by whole transcriptomic RNA sequencing. Pre- and post-treatment sample gene expression levels and gene signature Gene Set Variation Analysis (GSVA) enrichment scores were analyzed by a simple linear model with transformation, if appropriate. Results: Dose-dependent H3K27Me3 PD marker reduction was observed in peripheral granulocytes and paired tumor biopsies by M+E in patients with mCRPC. Strong H3K27Me3 reduction (≥75%) in granulocytes was achieved at ≥375 mg of M+E. Tumor H3K27Me3 levels were effectively reduced from baseline in 6 patients receiving M at 1250 mg +E with a group mean change of –67% determined by H scores (95% CI: –86%, –23%; P =0.020) and –75% determined by H3K27Me3 staining (positive cells with high and medium intensity in tumor area) (95% CI: –93%, –11%; P =0.038). No significant change in tumor H3K27Me3 levels was observed in 4 patients receiving M at 500 mg +E. Consistent with strong EZH2 inhibition observed in tumor samples from patients receiving M at 1250 mg +E, M+E increased the expression of genes reported to be repressed by the PRC2/EZH2 complex (e.g., BMP7 , CPAMD8 , EYA4 , FHL1 , IGFBP3 and NOV ), and decreased expression of EZH2 and other genes involved in the E2F pathway, the G2M checkpoint, Myc responsive genes and/or cell cycle progression (e.g., AURKA , CDK1 , FOXM1 , RAD54L , TOP2A and TYMS ). Conclusions: These data indicate M at 1250 mg BID on empty stomach in combination with E effectively inhibits EZH2 in tumor tissue and may overcome drug resistance and/or enhance androgen targeting drug activity by restoring the function of tumor suppressor genes and blocking tumor cell proliferation and cell cycle progression. These data support dose recommendation for phase 3 pivotal studies and enhance understanding of mechanism of action for M+E in mCRPC. Clinical trial information: NCT03460977 .