Safety and pharmacokinetics of mevrometostat (M) in combination with enzalutamide (E) in patients with metastatic castration-resistant prostate cancer (mCRPC).

5046 Background: M is a potent and selective small molecule inhibitor of enhancer of zeste homolog 2 (EZH2). In the randomized dose-expansion part of a phase 1 study, M (1250 mg BID on an empty stomach) + E (160 mg QD) improved outcomes versus E alone, with a manageable safety profile in patients (pts) with mCRPC (NCT03460977). We report safety and pharmacokinetics for M at 875 mg with food + E from this study. Methods: This was an open-label, phase 1 dose escalation and dose expansion study. Pts with mCRPC who received prior treatment with abiraterone or E, with evidence of progression per modified Prostate Cancer Working Group 3 criteria were included. Pts received M (875 mg BID with food) + E (160 mg QD) + androgen deprivation therapy. Safety and pharmacokinetics of the food effect cohort were primary and secondary endpoints, respectively. Results: As of Nov 15, 2024, 29 pts received M at 875mg with food + E. Median (interquartile range [IQR]) duration of treatment was 5.5 (4.1–7.4) months. Overall, 28 (96.6%) pts experienced a treatment-emergent adverse event (TEAE; Table). The most common TEAEs of any grade related to M were diarrhea (41.4%), thrombocytopenia (41.4%), and dysgeusia (37.9%). Serious TEAEs related to M were reported in 3 (10.3%) pts (anemia, ECG QT prolonged, and hemorrhagic enterocolitis), all were grade 3. There were no grade 4 TEAEs. TEAEs led to withdrawal from M in 4 (13.8%) pts. One patient had a fatal event of osteonecrosis of the jaw (present at baseline) that was not considered related to M. Plasma exposures of M + E after multiple doses were comparable between M 1250 mg on an empty stomach (n=51) and M 875 mg with food (n=12) (geometric mean [coefficient of variation]: AUC tau , h*ng/mL: 1250 mg, 8690 [54]; 875 mg, 8984 [48]; C max , ng/mL:1250 mg, 2371 [54]; 875 mg, 1868 [85]). Conclusions: In pts with mCRPC treated with M + E, M 875 mg with food had an improved safety profile compared with M 1250 mg on an empty stomach. M 875 mg with food has similar plasma exposures to M 1250 mg on an empty stomach. M 875 mg with food + E was selected as the recommended dose for pivotal phase 3 studies. Clinical trial information: NCT03460977 . n (%) M (875 mg with food) + E (n=29) M (1250 mg on an empty stomach) + E (n=41) † Any grade Grade ≥3 Any grade Grade ≥3 Any TEAE 28 (96.6) 10 (34.5) 40 (97.6) 22 (53.7) TEAE related to M 28 (96.6) 7 (24.1) 39 (95.1) 20 (48.8) Serious AE 8 (27.6) 6 (20.7) 14 (34.1) 13 (31.7) Most common TEAEs that occurred in ≥30% of pts ‡ Diarrhea 13 (44.8) 0 32 (78.0) 7 (17.1) Thrombocytopenia 13 (44.8) 2 (6.9) 12 (29.3) 1 (2.4) Dysgeusia 12 (41.4) 0 24 (58.5) 0 Decreased appetite 10 (34.5) 0 24 (58.5) 0 Nausea 9 (31.0) 0 17 (41.5) 0 † Data presented at ASCO-GU 2025. Data cut-off Sept 2, 2024. Median (IQR) duration of treatment: 7.6 (3.7–12.8) months. ‡ For pts treated with M (875 mg with food) + E.