{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T09:06:39Z","timestamp":1776071199615,"version":"3.50.1"},"reference-count":17,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The optimal combination of different cyclin-dependent kinase 4\/6 inhibitors (CDK4\/6i) with endocrine therapy (ET) for HR+\/HER2\u2212 metastatic breast cancer (MBC) remains undefined due to a lack of head-to-head comparisons. This real-world study aimed to evaluate the effectiveness and safety of three CDK4\/6 inhibitors combined with aromatase inhibitors (AI) or fulvestrant in the MBC setting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study was a retrospective, observational, single-center analysis conducted in Tianjin Medical University Cancer Institute and Hospital, China between 1 January 2019 and 1 November 2023. The eligibility criteria were as follows: age \u226518\u00a0years; histologically confirmed hormone receptor-positive, HER2-negative breast cancer; recurrent or metastatic disease; at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; and no prior systemic endocrine therapy for advanced disease. However, up to one line of prior chemotherapy in the metastatic setting was allowed. Statistical analyses were conducted using R software. Effective endpoints included progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>This study enrolled 341 patients with HR+\/HER2\u2212 MBC who received first-line CDK4\/6i-based therapy consisting of palbociclib (n = 138), abemaciclib (n = 119), or dalpiciclib (n = 84) in combination with either an AI or fulvestrant. The median follow-up durations for PFS were 15.6\u00a0months, 10.9\u00a0months, and 18.2\u00a0months in the palbociclib, abemaciclib, and dalpiciclib groups, respectively. The maximum follow-up durations were 58.0\u00a0months for the palbociclib group, 53.7\u00a0months for the abemaciclib group, and 49.3\u00a0months for the dalpiciclib group. Regarding clinical benefit rate (CBR), the values for palbociclib, abemaciclib, and dalpiciclib combined with an AI versus fulvestrant were 93.8% (95% CI: 86.2%, 97.3%) versus 93.1% (83.6%, 97.3%), 97.7% (92.1%, 99.4%) versus 96.8% (83.8%, 99.4%), and 93.3% (84.1%, 97.4%) versus 87.5% (69.0%, 95.7%), respectively. For objective response rate (ORR), the corresponding rates were 37.5% (95% CI: 27.7%, 48.5%) versus 60.3% (47.5%, 71.9%), 48.9% (38.7%, 59.1%) versus 67.7% (50.1%, 81.4%), and 45.0% (33.1%, 57.5%) versus 54.2% (35.1%, 72.1%), respectively. Median PFS was 25.3\u00a0months for the palbociclib group, not reached (NR) for the abemaciclib group, and 36.0\u00a0months for the dalpiciclib group. Statistical analysis showed that both abemaciclib and dalpiciclib combinations were associated with longer PFS compared with palbociclib (both P &amp;lt; 0.05); however, due to the shorter median PFS follow-up duration and the lower number of PFS events in the abemaciclib group, the data for this group remain immature and warrant further follow-up. The PFS following CDK4\/6i plus ET treatment was not significantly related to the status of key molecular biomarkers. The type of ET (AIs vs. fulvestrant) did not significantly affect PFS, although a consistent trend toward PFS benefit was observed in the fulvestrant-based combination group, without reaching statistical significance. Liver and bone metastases were associated with shorter PFS. Safety profiles were consistent with known spectra of each CDK4\/6i, with no new signals identified.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In this real-world analysis, dalpiciclib was associated with superior PFS compared to palbociclib as first-line CDK4\/6i-based therapy for HR+\/HER2- MBC. ET partner did not significantly impact effectiveness, supporting tailored CDK4\/6i selection based on patient and disease characteristics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1757379","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T08:24:41Z","timestamp":1776068681000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparative effectiveness of CDK4\/6 inhibitor plus endocrine therapy combinations in HR-positive, HER2-negative metastatic breast cancer: the inspiration 01 study"],"prefix":"10.3389","volume":"17","author":[{"given":"Yan","family":"Jia","sequence":"first","affiliation":[{"name":"Department of Breast Oncology, Tianjin Medical University Cancer Institute & Hospital","place":["Tianjin, China"]},{"name":"Tianjin\u2019s Clinical Research Center for Cancer","place":["Tianjin, China"]},{"name":"Key Laboratory of Breast Cancer 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