Fovinaciclib versus placebo combined with fulvestrant for advanced breast cancer after endocrine therapy: A randomized, double-blind phase 3 trial.

Abstract

1101 Background: Approximately 70% breast cancer (BC) patients have hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative disease. Fovinaciclib is a novel, potent, oral selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. A multicenter, randomized, double-blind, placebo-controlled phase 3 trial was conducted to compare fovinaciclib versus placebo plus fulvestrant in patients with advanced BC that relapsed or progressed on previous endocrine therapy. Methods: Eligible patients were randomly assigned (1:1) to receive 200 mg fovinaciclib (fovinaciclib arm) or placebo (placebo arm) orally once daily on days 1–21 in 28-day cycles. All patients also received intramuscular fulvestrant 500 mg (cycle 1: days 1 and 15; subsequent cycles: day 1). Premenopausal or perimenopausal patients also received subcutaneous goserelin 3.6 mg (day 1). The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival (PFS). Secondary endpoints included other efficacy endpoints and safety. Exploratory endpoints included patient-reported outcomes. Results: A total of 319 patients were randomized to the fovinaciclib ( n = 160) or placebo arm ( n = 159). Baseline characteristics were balanced. Interim analysis at 9-month median follow-up (data cutoff date May 11, 2023) showed significant PFS benefit from adding fovinaciclib (p = 0.0001). Sustained PFS benefit of greater extent (median 14.0 months versus 5.6 months, hazard ratio 0.48, 95% confidence interval 0.36–0.65) was observed at updated analysis at 23-month follow-up (data cutoff date August 30, 2024). Trends of the PFS benefit were observed in all subgroups. Consistent improvements were observed in investigator-assessed PFS and objective response rate, disease control rate, clinical benefit rate, duration of response, and time to progression according to BICR or investigator's assessments. At updated analysis, all patients in the fovinaciclib arm and 148 (93.7%) in the placebo arm reported at least 1 treatment-emergent adverse event (TEAE). The most common TEAEs were hematological toxicities. TEAEs leading to study drug discontinuation were reported in 9 (5.6%) and 2 (1.3%) patients in the respective arms. No grade ≥3 venous thromboembolism or interstitial lung disease was reported. The two arms showed similar overall longitudinal profiles of global health status, function domains and symptom domains assessed with the European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire. Conclusions: Adding fovinaciclib to fulvestrant conferred statistically significant and clinically meaningful PFS benefit and consistent improvements in other survival outcomes, along with manageable safety. These findings support fovinaciclib as a later-line option. Clinical trial information: NCT05438810 .