Long-term safety results and adverse event (AE) management recommendations in patients with ER+/HER2− metastatic breast cancer (mBC) receiving prifetrastat, a first-in-class KAT6 inhibitor, at the recommended phase 3 dose (RP3D) of 5 mg once-daily (QD).

Abstract

1068 Background: Prifetrastat (PF-07248144) is a first-in-class, potent, and selective inhibitor of the epigenetic modifiers KAT6A and KAT6B. In an ongoing phase 1/2a study (NCT04606446), prifetrastat has demonstrated encouraging antitumor activity and manageable safety when combined with fulvestrant (FUL) in patients with heavily pretreated ER+/HER2– mBC (Mukohara T, et al. Nat Med. 2024;30:2242-50). Here, we report comprehensive and long-term safety results and AE management recommendations after extended follow-up of patients receiving prifetrastat (± FUL) in this phase 1/2a study. Methods: This dose escalation (part 1)/expansion (part 2) study included patients with ER+/HER2– mBC whose disease progressed after prior treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and endocrine therapy. In part 1, patients received prifetrastat at varying doses as monotherapy or in combination with 500 mg FUL. In part 2, patients received prifetrastat (± FUL) at the recommended dose for expansion (RDE; 5 mg QD) identified in part 1. Primary objectives were safety/tolerability assessment and RDE selection. Results: 5 mg QD prifetrastat was previously identified as the RDE and RP3D in combination with FUL based on safety, PK/PD, and antitumor activity. As of Oct 13, 2025, a total of 92 patients were treated at the 5 mg QD dose (43 as monotherapy and 49 in combination with FUL). The most common treatment-related AEs (TRAEs) were dysgeusia (84.8%; all grade [G] 1 [66.3%] or 2 [18.5%]), neutropenia (68.5%), and anemia (50.0%). Weight loss was reported infrequently as a TRAE (5.4%). The most common G3/4 TRAEs were neutropenia (G3, 34.8%; G4, 6.5%), anemia (G3, 15.2%; no G4), and leukopenia (G3, 12.0%; no G4); no G5 TRAEs were reported. TRAEs led to dose reductions in 45 (48.9%) patients, 75.6% (n = 34/45) of whom reduced their dose due to reversible neutropenia. TRAEs led to discontinuation in 2 patients (G2 neutropenia [n = 1]; G3 myocardial injury/troponin increased [n = 1]). G3/4 neutropenia was reversible and well-managed with dose modifications and supportive care. No febrile neutropenia was reported. Dysgeusia was managed with supportive care, including patient education, weight monitoring, and nutrition consultation, as clinically indicated. Dysgeusia did not lead to any treatment discontinuations or dose reductions. Conclusions: After extended follow-up of the phase 1/2a study, the RP3D of prifetrastat (5 mg QD) maintained a manageable safety profile when dose modifications and supportive care measures were implemented for AEs such as neutropenia and dysgeusia. These AE management strategies have been incorporated into the ongoing phase 3 study (KATSIS-1; NCT07062965) in patients with HR+/HER2− mBC after progression on CDK4/6i-based therapy. Clinical trial information: NCT04606446 .