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Concurrent CDK2\/4\/6 blockade may be effective in treating HR-positive, HER2-negative advanced breast cancer (ABC). This randomized, double-blind, parallel-controlled, phase 3 trial (ClinicalTrials.gov, NCT05375461) assessed the efficacy of culmerciclib, a CDK2\/4\/6 inhibitor, plus fulvestrant in ABC. Patients with HR-positive, HER2-negative, locally recurrent or metastatic breast cancer were randomized (2:1) to receive culmerciclib plus fulvestrant or matching placebo plus fulvestrant. Between March 18, 2022 and March 3, 2023, 293 pretreated patients (median age 53.0 years; pre- or perimenopausal 42.3%; bone metastasis 65.2%) were randomized to assigned treatments. At this prespecified interim analysis, culmerciclib plus fulvestrant extended the median investigator-assessed progression-free survival (PFS) significantly, the primary endpoint, as compared with placebo plus fulvestrant (16.6 months, 95% CI 13.8 to not evaluable\n                    <jats:italic>versus<\/jats:italic>\n                    7.5 months, 95% CI 5.3 to 11.0; hazard ratio 0.36, 95% CI 0.26\u20130.51; stratified log rank test\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001). Consistent effects were observed across diverse subgroups of patients. At a median follow-up duration of 13.8 months, overall survival was immature. The investigators-assessed objective response rate was 40.2% (95% CI, 33.3\u201347.5) for culmerciclib compared to 12.1% (95% CI 6.4\u201320.2) for placebo (stratified Mantel-Haenszel \u03c7\n                    <jats:sup>2<\/jats:sup>\n                    test\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001). Diarrhea (87.1%) and neutropenia (80.4%) were the most common toxicities with culmerciclib plus fulvestrant. In conclusion, this randomized clinical trial met its primary outcome. Culmerciclib plus fulvestrant is well tolerated and leads to a significant gain in PFS of pretreated HR-positive HER2-negative ABC patients.\n                  <\/jats:p>","DOI":"10.1038\/s41392-025-02475-6","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T05:38:26Z","timestamp":1766036306000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Novel CDK2\/4\/6 inhibitor culmerciclib (TQB3616) plus fulvestrant in previously treated, HR-positive, HER2-negative advanced breast cancer: a randomized, double-blind, phase 3 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