169 Background: Overexpression of EZH2 is associated with poor prognosis in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Inhibition of EZH2 has been reported to overcome enzalutamide (E) resistance in CRPC. Igermetostat is a highly selective, small molecule EZH2 inhibitor. Here, we report the safety and efficacy of igermetostat in combination with E in mCRPC pts from a phase 1b/2 study (NCT06702995). Methods: mCRPC pts who had received one novel hormone therapy (NHT) except E and whose disease had progressed on the received NHT per PCWG3 criteria were eligible for this multicenter, phase 1b/2 study in China. In phase1b, 3+3 design was used for dose escalation in 3 dose levels of igermetostat (800, 1200, 1600mg, p.o, BID) + E (160 mg QD) and 2 of them were selected to confirm RP2D. In phase 2, igermetostat 1200mg BID + E were selected for dose expansion. The primary endpoint was RP2D, safety, and radiographic progression-free survival (rPFS). Best overall response (BOR), ≥50% PSA decline from baseline (PSA 50 ), and pharmacokinetics (PK) were also assessed. Results: As of Sep 05, 2025, 84 mCRPC pts were treated with igermetostat at dose levels of 800mg BID (n=3), 1200mg BID (n=65), or 1600mg BID (n=16) in combination with E. Median age was 69 years. The median lines of prior systemic therapy were 2. 83.3% of the pts received abiraterone previously. 15.5 % of the pts had visceral metastasis. 10.7% of the pts had received prior taxane therapy. The most common treatment emergent AEs (TEAEs) in ≥30% pts included diarrhea (65.5%), anemia (58.3%), nausea (48.8%), vomiting (40.5%), asthenia (36.9%) and decreased appetite (34.5%), with majority of them being grade 1-2. Grade≥3 TEAEs were reported in 25% of the pts (17.9% treatment related). Serious AEs occurred in 13.1% of the pts (4.8% treatment related). No DLT was observed. 53 pts with prior abiraterone treatment were included in the efficacy analysis. Median follow-up was 13.2 months (mo). Median rPFS (mrPFS) was not reached (10.97, NC). The 12-month rPFS rate was 59.8%. Median overall survival (mOS) was not reached. In the 15 pts with baseline measurable disease, BOR rate was 26.7%, including 4 partial responses. PSA 50 occurred in 11 (31.4%) of the 35 PSA-evaluable pts. At 1200 mg BID dose group, median follow-up was 11.9 mo. mrPFS was not reached (11.01, NC). 12-month rPFS rate was 70.8%. mOS was not reached. Igermetostat exposure exhibited dose-dependent increase from 800 to 1600mg in combination with enzalutamide after multiple dose administrations at steady-state. High-fat meal had no clinically meaningful effect on igermetostat exposure. Conclusions: Igermetostat in combination with E shows promising efficacy in post-abiraterone pts with mCRPC, and has a manageable AE profile. The RP2D for igermetostat is 1200 mg BID. Clinical trial information: NCT06702995 .
Chang et al. (Sun,) studied this question.