382MO Updated results from the phase I/II study of OP-1250, an oral complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD) in patients (pts) with advanced or metastatic ER-positive, HER2-negative breast cancer

OP-1250 is a small molecule CERAN/SERD with antitumor activity in breast cancer (BC) xenograft models, including ESR1/PIK3CA mutations and brain metastasis. OP-1250 was administered at 30–300 mg daily (qd) in the dose-escalation part of a phase 1 study. Maximum tolerated dose was not reached and no dose-limiting toxicities occurred. OP-1250 at 60 mg and 120 mg was assessed in the dose-expansion part. Based on safety, pharmacokinetics, and preliminary antitumor activity, 120 mg qd was selected as the recommended phase 2 dose. Here we present the phase 1/2 study data (phase 2 is ongoing). Pts with measurable and nonmeasurable disease were included. Eligible women (any menopausal status) and men had received ≤4 lines of endocrine therapy (ET) and ≤1 line of chemotherapy for metastatic disease. Pts with stable brain metastasis had to have ≥1 prior line of ET and ≤3 prior lines of chemotherapy (both for metastatic disease). Tumor assessment (RECIST v1.1) occurred every 8 weeks (NCT04505826). By March 17, 2023, of 86 pts on OP-1250 (120 mg), 66% had ≥2 prior lines of ET, 30% prior chemotherapy, 67% prior fulvestrant, and 98% prior cyclin-dependent kinase 4/6 inhibitors (CDK4/6i); 45% (34/75) of pts with available baseline ctDNA had ESR1 mutations. The most common (≥15% of pts) all-grade treatment-emergent adverse events (AEs) were nausea, vomiting, neutropenia, fatigue, headache, constipation, and diarrhea. The most common grade 3/4 treatment-related AEs were neutropenia (9%), nausea (3%), and vomiting (3%). Neutropenia was reversible; 3 pts with grade 4 neutropenia were rechallenged at a lower dose without recurrence. There were 4 partial responses (3 confirmed) with a clinical benefit rate of 40% (23/57). In pts with an ESR1 mutation, CBR was 50% (11/22). D[NZ1] [NZ2] ata continue to mature and updated data will be presented. OP-1250 (120 mg qd) was well tolerated with promising efficacy in heavily pretreated pts, including pts progressing on fulvestrant and CDK4/6i. A phase 3 monotherapy study in metastatic BC (second/third line) is planned in 2023.