First-line fovinaciclib versus placebo combined with aromatase inhibitor for advanced breast cancer: A randomized, double-blind phase 3 study.

1090 Background: Endocrine therapy combined with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor is the standard first-line therapy for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Fovinaciclib is a novel CDK4/6 inhibitor that showed survival benefit when added to fulvestrant in the later-line setting. This randomized, double-blind, placebo-controlled phase 3 trial evaluated the efficacy and safety of fovinaciclib plus an aromatase inhibitor (AI) as initial therapy. Methods: Adult women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting were enrolled across 63 centers. Eligible patients were randomized in a 1:1 ratio to receive oral fovinaciclib (200 mg, once daily, days 1–21) or placebo plus an AI (letrozole 2.5 mg or anastrozole 1 mg, orally, once daily, days 1–28) in 28-day cycles. Pre- or perimenopausal patients also received goserelin (3.6 mg, subcutaneous, day 1). The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR). Secondary endpoints included other efficacy endpoints and safety. Results: A total of 417 patients were assigned to the fovinaciclib ( n = 208) or placebo arm ( n = 209) with balanced baseline characteristics. At the protocol-specified interim analysis (median follow-up 16.6 months, data cutoff date June 25, 2024), adding fovinaciclib significantly improved PFS (hazard ratio 0.55, 95% CI 0.38–0.77; p = 0.0003): median PFS was not reached in the fovinaciclib arm and 20.2 months (95% CI 16.4 months–not evaluable) in the placebo arm. The 2-year PFS rates were 65.5% (95% CI 55.3%–73.9%) and 38.9% (95% CI 27.5%–50.2%), respectively. Consistent PFS benefit was observed in investigator assessments (hazard ratio 0.49 [95% CI 0.36–0.68], p < 0.0001) and across most subgroups. Fovinaciclib also showed favorable results across secondary efficacy endpoints. OS data remain immature. Treatment-emergent adverse events (TEAEs) occurred in 207 (99.5%) and 199 (95.2%) patients in the fovinaciclib and placebo arms, respectively, with serious adverse events (SAEs) reported in 30 (14.4%) and 24 (11.5%). Discontinuation due to TEAEs was only 1.4% in both arms. The most common TEAEs were hematologic toxicities, which did not lead to SAEs or study drug discontinuation. Grade ≥3 gastrointestinal toxicities (2.4% versus 0) or renal toxicities (0 versus 0.5%) were rare. Conclusions: Adding fovinaciclib to first-line AI therapy provided a significant and clinically meaningful PFS benefit, along with consistent improvements in other survival outcomes and a manageable safety profile. These findings support fovinaciclib as a first-line treatment option for patients with HR-positive, HER2-negative advanced breast cancer. Clinical trial information: NCT05439499 .