HIGHLIGHT 1: A randomized, placebo-controlled, double-blind, phase 3 clinical study to investigate the efficacy and safety of fezolinetant for treatment of moderate to severe vasomotor symptoms (hot flashes) in women with stage 0 to 3 hormone receptor–positive breast cancer who are receiving adjuvant endocrine therapy.

Abstract

TPS642 Background: Breast cancer is the most common cause of death due to malignant neoplasms in women globally. Adjuvant endocrine therapy, e.g., tamoxifen and aromatase inhibitors, can lead to premature menopause and vasomotor symptoms (VMS). Fezolinetant is a non-hormonal neurokinin 3 receptor antagonist that is an approved treatment option for moderate to severe VMS due to menopause in multiple regions worldwide, including North America, Europe, Asia, and Australia, at a dose of 45 mg once daily. The pathophysiology of VMS in women undergoing cancer treatment is not fully elucidated but is hypothesized to have similar etiology to VMS associated with menopause, i.e., rapid decline of estrogen. Methods: This global, double-blind, placebo-controlled phase 3 study (HIGHLIGHT 1 [NCT06440967]) was designed to assess efficacy and safety of fezolinetant 45 mg once daily in moderate to severe VMS associated with tamoxifen or aromatase inhibitors for hormone receptor-positive breast cancer from stage 0 (cancer cells have not spread to nearby tissue) to stage 3+ (cancer has spread from breast to lymph nodes near the breast or the chest wall). HIGHLIGHT 1 comprises screening (28 days), treatment (52 weeks), follow-up (3 weeks after final treatment), and extension follow-up (until week 104). Eligible participants will be randomized 1:1 to fezolinetant 45 mg or placebo and stratified by adjuvant endocrine therapy and prior chemotherapy. Participants will record their VMS daily on an electronic diary. The study is currently recruiting. Participants are women (target enrollment n = 540; 382 enrolled as of 24 Nov) ≥18 years with ≥7 moderate to severe VMS episodes/day receiving hormone therapy for stage 0-3 hormone receptor-positive breast cancer. Key exclusions: history/current malignancy other than hormone receptor-positive breast cancer (stage 0 to 3) or basal cell carcinoma. Co-primary endpoints: mean change from baseline to week 4 and 12 in frequency and severity of moderate to severe VMS. Key secondary endpoints: mean change from baseline to week 12 in MENQOL VMS domain score and PROMIS Total Score Sleep Disturbance–Short Form 8b. Co-primary endpoints and key secondary endpoints will be analyzed using mixed models for repeated measures. Treatment-emergent adverse events (TEAEs) assess fezolinetant safety and tolerability. The DMC last reviewed the study in November 2025 and suggested that the study continue as planned. Clinical trial information: NCT06440967 .