A randomized controlled trial of CDK7 inhibitor samuraciclib plus fulvestrant in advanced HR+/HER2− breast cancer

Abstract Resistance to CDK4/6 inhibitors remains a major challenge in HR+/HER2− metastatic breast cancer. Samuraciclib is an oral selective CDK7 inhibitor that may overcome resistance to CDK4/6 inhibitors, targeting transcriptional programs sustaining tumor growth. This study presents a 3-arm randomized comparison of samuraciclib 360 mg plus fulvestrant, samuraciclib 240 mg plus fulvestrant and fulvestrant alone in females with advanced HR+/HER2− breast cancer previously treated with a CDK4/6 inhibitor (NCT05963984). 59 patients were randomized and stratified by TP53 mutation and liver metastases status. 20, 19, and 20 patients were allocated to the samuraciclib 360 mg, 240 mg or fulvestrant arms respectively. For samuraciclib 360 mg plus fulvestrant and samuraciclib 240 mg plus fulvestrant compared with fulvestrant monotherapy, the primary endpoint of clinical benefit rate was 60.0%, 63.2% and 40.0%, respectively. Activity was enhanced in the selected secondary analysis populations of participants with no detectable TP53 mutations ( TP53 wild-type), participants with no baseline liver metastases and participants with prior CDK4/6 inhibitor duration of ≥12 months. Adverse events were predominantly gastrointestinal toxicities, manageable with prophylaxis. These results support CDK7 inhibition with samuraciclib plus fulvestrant as a potential second line strategy in HR+/HER2- breast cancer and provide a rationale for a biomarker enriched ( TP5 3 wild-type tumors) clinical evaluation.