OP-3136 (oral KAT6A/B inhibitor) shows early tumor shrinkage with low DLT signal in heavily pretreated ER+/HER2− ABC and mCRPC

OP-3136 is a potent, selective, oral small-molecule inhibitor of the histone acetyltransferases KAT6A/B, evaluated in a Phase 1 first-in-human Bayesian dose-escalation study as monotherapy in advanced solid tumors and with endocrine therapy (ET) in ER+, HER2− advanced breast cancer (ABC) (NCT06784193). As of November 26, 2025, 32 patients were treated across 2–45mg QD (monotherapy n=25; OP-3136+fulvestrant n=7); the ABC cohort (n=23) had all received prior ET and CDK4/6 inhibitors (median 3 prior systemic lines), and mCRPC patients (n=8) had all received prior AR-targeted therapy (median 5 prior lines). Safety was largely G1–2 with no DLTs, no G4–5 TRAEs, and no discontinuations due to TRAEs; common monotherapy TRAEs were dysgeusia 72% (G2 24%), anemia 40% (G3 8%), fatigue 32% (G2 16%), and neutropenia 28% (G3 20%), while the combo cohort reported one G3 neutropenia/leukopenia. Efficacy was immature but showed lesion reductions in 64% (9/14) of measurable-disease patients and 2 unconfirmed PRs (1 ABC, 1 mCRPC); 10/17 evaluable patients had stable disease—directionally interesting versus typical post-CDK4/6 ET where median PFS is often measured in only a few months even with active options like capivasertib+fulvestrant (median PFS 7.2 vs 3.6 months in CAPItello-291, overall population), though OP-3136 has not yet reported confirmed ORR/PFS to benchmark cleanly.