Abstract PS5-08-19: Randomized phase 3 trial evaluating KAT6 inhibitor PF-07248144 plus fulvestrant in HR+HER2− advanced/metastatic breast cancer after progression on CDK4/6 inhibitor-based therapy

Abstract Background: Patients with HR+HER2− advanced/metastatic breast cancer (ABC) who have tumors that progressed after CDK4/6 inhibitor and endocrine therapy (ET) represent a high unmet medical need. Histone lysine acetyltransferases KAT6A and KAT6B regulate lineage-specific gene transcription via H3K23 acetylation. PF-07248144 is a selective inhibitor of KAT6A and KAT6B. PF-07248144 (5 mg QD) in combination with fulvestrant (FUL) has demonstrated encouraging and durable antitumor activity with a manageable safety profile in patients with heavily pretreated HR+HER2− ABC in a phase 1/2 study. The phase 3 study is designed to evaluate and confirm the efficacy and safety of PF-07248144 plus FUL in patients with HR+HER2− ABC after tumor progression on CDK4/6i -based therapy, when compared to standard of care therapy. Methods: This open-label, randomized phase 3 trial is comparing PF-07248144 plus FUL versus everolimus (EVE) plus ET FUL or exemestane (EXE)) in patients with HR+HER2− ABC. Key inclusion criteria are: age ≥ 18 years; histologically confirmed HR+HER2− ABC; progression after prior CDK4/6i-based therapy; available tumor tissue; measurable disease or non-measurable bone-predominant disease, defined by RECIST v1.1; Adequate organ function; ECOG PS 0 or 1. Key exclusion criteria are: presence of detectable PIK3CA/AKT1/PTEN alterations; prior chemotherapy or therapy targeting PIK3CA/AKT1/PTEN in ABC; 2 prior lines post-CDK4/6i of systemic anticancer therapy in ABC and no more than one line of chemotherapy; systemic anticancer therapy or radiation within 2 weeks of randomization. Up to 400 patients will be randomized (1:1) to receive either PF-07248144 plus FUL versus EVE plus ET (FUL or EXE). Patients will be stratified by ET (FUL vs EXE), prior systemic lines of therapy in metastatic setting (1 vs 2), and disease site (visceral vs non-visceral). The primary endpoint is progression-free survival by blinded independent central review. Overall survival is a key secondary endpoint; other secondary endpoints include objective response, duration of response, clinical benefit rate, safety, and pharmacokinetics of PF-07248144. Citation Format: K. M. Kalinsky, R. M. Layman, A. Giordano, T. Mukohara, Y. Park, G. J. Lindeman, G. Bianchini, A. Nonneville, V. Diéras, S. Kuemmel, S. Wang, Z. Shao, S. Kent, M. Li, M. Oliveira. Randomized phase 3 trial evaluating KAT6 inhibitor PF-07248144 plus fulvestrant in HR+HER2− advanced/metastatic breast cancer after progression on CDK4/6 inhibitor-based therapy abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-19.