Culmerciclib Plus Fulvestrant for Patients With HR-Positive, HER2-Negative Advanced Breast Cancer
Key Clinical Takeaways
- Design/Population: In the phase 3, double-blind CULMINATE-2 trial (n = 432), patients with previously untreated HR-positive, HER2-negative locally advanced or metastatic breast cancer were randomized 2:1 to culmerciclib 180 mg (n = 290) or placebo (n = 142) plus fulvestrant.
- Key Outcomes: Median PFS was not reached with culmerciclib vs 20.2 months with placebo (HR 0.56; 95% CI, 0.40 to 0.78; P = .0004); ORR was 59.3% vs 42.3% (P = .0009); grade ≥3 neutropenia was the most common adverse event; discontinuations occurred in 3.5% vs 1.4%
- Clinical Relevance: Culmerciclib plus fulvestrant significantly prolonged PFS and improved response rates with manageable toxicity, supporting it as a potential new first-line option for HR-positive/HER2-negative advanced breast cancer.
Primary analysis results from the phase 3 CULMINATE-2 trial show that adding culmerciclib, a novel CDK2/4/6 inhibitor, to fulvestrant significantly improves outcomes among previously untreated patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer.
These results were presented by Erwei Song, MD, PhD, Sun Yat-sen Memorial Hospital, Guangzhou, China, at the 2025 European Society for Medical Oncology (ESMO) Congress in Berlin, Germany.
In this double-blind trial, 432 patients regardless of menopausal status were randomized on a 2-to-1 basis to receive either 180 mg of culmerciclib (n = 290) or placebo (n = 142) plus fulvestrant. The primary end point was investigator-assessed progression-free survival (PFS). Key secondary end points included objective response rate (ORR), duration of response, and safety.
At analysis, median PFS was not reached in the culmerciclib arm and was 20.2 months in the placebo arm (hazard ratio [HR] 0.56; 95% confidence interval [CI], 0.40 to 0.78; P = .0004). There was a stronger PFS risk-reduction benefit seen via independent review committee-assessment (HR 0.40; 95% CI, 0.27 to 0.59; P < .0001). Confirmed ORR was 59.3% in the culmerciclib arm and 42.3% in the placebo arm (P = .0009). Median duration of response was not reached in the culmerciclib arm and was 16.7 months in the placebo arm (P = .0064). Greater PFS benefit with culmerciclib was seen across both visceral (HR 0.57) and non-visceral (HR 0.57) metastases subgroups and the risk for disease progression dropped by 58% in patients with liver metastases. The most frequently reported grade ≥3 treatment-related adverse event was neutropenia. Treatment-related adverse events led to discontinuation in 3.5% and 1.4% of patients, respectively.
“[Culmerciclib] is the first CDK2/4/6 inhibitor to show survival benefit with [fulvestrant] in both pretreated and untreated HR+/HER2- [advanced breast cancer], positioning this combination as a promising therapeutic strategy and potentially the leading treatment among CDK inhibitors,” concluded Dr Song et al.
Source:
Song E, Yin Y, Zhao J, et al. Culmerciclib plus fulvestrant as first-line treatment for HR+/HER2- advanced breast cancer: A phase III trial (CULMINATE-2). Presented at the 2025 ESMO Congress. October 17-21, 2025; Berlin, Germany. LBA25
