Abstract CT174: Unlocking endocrine resistance: Co-targeting KAT6 and ER with prifetrastat (PF-07248144) and fulvestrant drives tumor and ctDNA response in ER+/HER2− metastatic breast cancer

Abstract Background: Endocrine resistance is a major challenge in ER+/HER2− metastatic breast cancer (mBC). Histone lysine acetyltransferases KAT6A/B regulate lineage-specific gene transcription via H3K23 acetylation. Prifetrastat (PRIFET; PF-07248144) is a first-in-class, potent, and selective KAT6A/B inhibitor. In an ongoing phase 1/2a study, PRIFET + fulvestrant (FUL) demonstrated an acceptable safety profile and durable antitumor activity in patients with ER+/HER2- mBC after prior CDK4/6 inhibitor + endocrine therapy. Here, we report exploratory pharmacodynamic (PD) effects of KAT6 inhibition on tumor gene expression and circulating tumor DNA (ctDNA) dynamics to further support phase 3 dose selection and elucidate mechanism of action. Methods: Patients with ER+/HER2− mBC were enrolled in a phase 1/2a dose-escalation/expansion study and received PRIFET (1 mg and 5 mg QD) monotherapy or with FUL. Serial blood, plasma, and paired tumor biopsies were collected before and after PRIFET treatment. H3K23Ac was quantified in PBMCs (MSD assay) and tumor biopsies (IHC). Tumor gene expression was profiled by RNA sequencing. ctDNA mutation burden and variant allele frequency were assessed using Guardant 360 assay (74-gene panel). Early ctDNA clearance was defined as a change from detectable to nondetectable status within 9 weeks of treatment. Results: Patients received PRIFET 5 mg QD (N = 36), 1 mg QD + FUL (N = 29), and 5 mg QD + FUL (N = 43). All treatment groups achieved ≥50% reduction of H3K23Ac in PBMCs and tumor tissues, confirming target engagement. PRIFET 5 mg QD + FUL induced the strongest tumor gene expression changes, including upregulation of tumor suppressors (FOXD3, MXI1, ING4) and downregulation of proliferation/cell cycle genes (CCNE1, CCNB1, TK1, TYMS) and ER-responsive genes (TFF3). Early ctDNA clearance rates were highest with PRIFET 5 mg QD + FUL (n = 34, overall 26%, ESR1 63%, PIK3CA/AKT1/PTEN 31%) versus PRIFET 1 mg QD + FUL (n = 23, 9%, 8%, 15%, respectively) or PRIFET 5 mg QD monotherapy (n = 24, 4%, 14%, 13%, respectively). Early ctDNA clearance at 5 mg QD + FUL occurred regardless of baseline mutation status and correlated with durable clinical responses. Conclusions: PRIFET 5 mg QD + FUL robustly inhibited KAT6 and ER signaling, resulting in early ctDNA clearance, including resistance-associated ESR1 variants. These findings further support PRIFET 5 mg QD + FUL as the recommended phase 3 regimen and provide mechanistic insight into overcoming ER resistance and inhibiting cell cycle/tumor proliferation in ER+/HER2− mBC. Integration of tumor and ctDNA PD markers offers a powerful approach for dose selection, patient stratification, and real-time monitoring of molecular response in future clinical trials. ctDNA analysis limitations include small sample size and short follow-up duration; additional evaluation is ongoing. Citation Format: Li Liu, Rachel M. Layman, Xinmeng Jasmine Mu, Vinicius Bonato, Patricia M. LoRusso, Toru Mukohara, David Sommerhalder, Geoffrey J. Lindeman, Kan Yonemori, Erika Hamilton, Sung-Bae Kim, Hope S. Rugo, Toshinari Yamashita, Fengting Yan, Fumikata Hara, Gunmin Kim, Shusen Wang, Sean Kent, Karey Kowalski, Shreya Badhrinarayanan, Athanasia Skoura, Meng Li, Yeon Hee Park. Unlocking endocrine resistance: Co-targeting KAT6 and ER with prifetrastat (PF-07248144) and fulvestrant drives tumor and ctDNA response in ER+/HER2− metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT174.