A phase 1, first-in-human study of OP-3136, a novel oral selective KAT6A/B inhibitor, as monotherapy in advanced solid tumors and in combination with endocrine therapy in ER+, HER2− advanced breast cancer (ABC): Preliminary results.

Abstract

3088 Background: Histone lysine acetyltransferases (KATs) control oncogenic transcription and are frequently dysregulated in cancer. OP-3136 is a potent, selective, oral small-molecule inhibitor of KAT6A/B with preclinical antitumor activity, including in combination with endocrine therapy (ET) (Palanisamy et al, 2024). This phase 1 study evaluates the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of OP-3136 as monotherapy in advanced solid tumors and in combination with fulvestrant or palazestrant (a novel oral complete estrogen receptor antagonist [CERAN] and selective estrogen receptor degrader [SERD]) in ER+, HER2− ABC (NCT06784193). Methods: Patients (pts) with ABC, metastatic castration-resistant prostate cancer (mCRPC), or non-small cell lung cancer (mNSCLC) received OP-3136 once daily (QD) as monotherapy (no limit on prior lines of therapy), and a separate cohort of ABC pts received OP-3136 + fulvestrant in a phase 1 study using a Bayesian Optimal Interval dose-escalation. Results: As of 26 November 2025, 32 pts ABC, n=23; mCRPC, n=8; and mNSCLC, n=1) received OP-3136 (monotherapy, n=25; in combination with fulvestrant, n=7) across doses of 2–45 mg QD. All ABC pts received prior endocrine therapy and CDK4/6 inhibitors, all mCRPC pts received prior androgen receptor–targeted therapy. The median (min – max) of prior anticancer systemic therapy lines was 3 for ABC (1–5) and 5 (1–8) for mCRPC pts. The median time on treatment was approximately 2 months (max 47 months). In the monotherapy cohort, treatment-related adverse events (TRAEs) were mostly grade (G)1–2. The most common (≥25%) TRAEs included dysgeusia (72%; G2, 24%), anemia (40%; G3, 8%), fatigue (32%; G2, 16%), and neutropenia (28%; G3, 20%). In the combination cohort, TRAEs were predominantly G1–2 with one G3 neutropenia and leukopenia. No dose-limiting toxicities (DLTs), G4-5 TRAEs or treatment discontinuations due to TRAEs were reported. Across monotherapy dose levels, among 14 pts with measurable disease, reduction of target lesions occurred in 64% (9/14) and 2 pts (1 with ABC and 1 with mCRPC) had partial responses (unconfirmed). Among 17 pts with evaluable disease,10 had stable disease. PK analyses showed dose-proportional exposure of OP-3136 with rapid absorption and sustained systemic exposure over the dosing interval supporting QD administration. Conclusions: OP-3136 demonstrated a manageable safety profile and favorable PK, both as monotherapy and in combination with fulvestrant. Preliminary evidence of antitumor activity in ER+ HER2- ABC and mCRPC was observed in these heavily pretreated pts. Dose escalation and enrollment in combination with fulvestrant or palazestrant are ongoing and updated data will be presented. Clinical trial information: NCT06784193 .