{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:36:27Z","timestamp":1787506587561,"version":"build-2736575974"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T00:00:00Z","timestamp":1707264000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T00:00:00Z","timestamp":1707264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Individual trials of abemaciclib, palbociclib, and ribociclib show a similar impact on progression-free survival yet differing statistical significance for overall survival (OS). A robust comparative evaluation of OS, safety, and tolerability of the three drugs is warranted. A systematic literature search identified phase 3 randomized clinical trials reporting OS of CDK4\/6 inhibitors (CDK4\/6i) in combination with endocrine therapy in ER-positive\/HER2-negative advanced breast cancer. Trial-level data on OS and common and serious adverse events (AE) were extracted for each drug. In the absence of direct comparisons, a network meta-analysis was performed to evaluate pairwise comparative efficacy, safety, and tolerability of each of the CDK4\/6i. Seven studies comprising of 4415 patients met the inclusion criteria. Median follow-up was 73.3\u00a0months (range: 48.7\u201397.2\u00a0months). There were no statistically significant differences in OS between any of the CDK4\/6i. Compared to palbociclib, ribociclib and abemaciclib both showed significantly higher GI toxicity (grade 1\u20132 vomiting OR 1.87 [95% CI 1.37\u20132.56] and OR 2.27 [95% CI 1.59\u20133.23] respectively). Compared to palbociclib, abemaciclib was associated with more grade 3\u20134 diarrhea OR 118.06 [95% CI 7.28\u20131915.32]. In contrast, palbociclib was associated with significantly more neutropenia than ribociclib and abemaciclib but significantly lower risk of grade 3\u20134 infections. Abemaciclib had significantly less grade 3\u20134 transaminitis and grade 3\u20134 neutropenia than ribociclib. Treatment discontinuation and death due to AE were significantly higher with abemaciclib than palbociclib and ribociclib. There is no statistically significant difference in OS between CDK4\/6i despite differing statistical significance levels of individual trials. Real-world data analyses may help to identify if there is a meaningful inter-drug difference in efficacy. Significant differences between CDK4\/6i are observed for safety and tolerability outcomes.<\/jats:p>","DOI":"10.1038\/s41598-024-53151-8","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T06:02:30Z","timestamp":1707285750000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Comparative overall survival of CDK4\/6 inhibitors in combination with endocrine therapy in advanced breast cancer"],"prefix":"10.1038","volume":"14","author":[{"given":"Coralea","family":"Kappel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell J.","family":"Elliott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikaash","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle B.","family":"Nadler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Desnoyers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eitan","family":"Amir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,7]]},"reference":[{"key":"53151_CR1","doi-asserted-by":"publisher","first-page":"3959","DOI":"10.1200\/JCO.21.01392","volume":"39","author":"HJ Burstein","year":"2021","unstructured":"Burstein, H. J. et al. Endocrine treatment and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2\u2013negative metastatic breast cancer: ASCO guideline update. J. Clin. Oncol. 39, 3959\u20133977. https:\/\/doi.org\/10.1200\/JCO.21.01392 (2021).","journal-title":"J. Clin. Oncol."},{"key":"53151_CR2","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1016\/j.annonc.2021.09.019","volume":"32","author":"A Gennari","year":"2021","unstructured":"Gennari, A. et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 32, 1475\u20131495. https:\/\/doi.org\/10.1016\/j.annonc.2021.09.019 (2021).","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol."},{"key":"53151_CR3","unstructured":"NCCN Guidelines Version 4.2023 Breast Cancer. NCCN Clin. Pract. Guidel. Oncol. (2023)."},{"key":"53151_CR4","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.1056\/NEJMoa1609709","volume":"375","author":"GN Hortobagyi","year":"2016","unstructured":"Hortobagyi, G. N. et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N. Engl. J. Med. 375, 1738\u20131748. https:\/\/doi.org\/10.1056\/NEJMoa1609709 (2016).","journal-title":"N. Engl. J. Med."},{"key":"53151_CR5","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1056\/NEJMoa1607303","volume":"375","author":"RS Finn","year":"2016","unstructured":"Finn, R. S. et al. Palbociclib and letrozole in advanced breast cancer. N. Engl. J. Med. 375, 1925\u20131936. https:\/\/doi.org\/10.1056\/NEJMoa1607303 (2016).","journal-title":"N. Engl. J. Med."},{"key":"53151_CR6","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1200\/JCO.2021.39.15_suppl.1001","volume":"39","author":"DJ Slamon","year":"2021","unstructured":"Slamon, D. J. et al. Updated overall survival (OS) results from the phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+\/HER2\u2212 advanced breast cancer (ABC) treated with fulvestrant (FUL) \u00b1 ribociclib (RIB). J. Clin. Oncol. 39, 1001. https:\/\/doi.org\/10.1200\/JCO.2021.39.15_suppl.1001 (2021).","journal-title":"J. Clin. Oncol."},{"key":"53151_CR7","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1056\/NEJMoa2114663","volume":"386","author":"GN Hortobagyi","year":"2022","unstructured":"Hortobagyi, G. N. et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N. Engl. J. Med. 386, 942\u2013950. https:\/\/doi.org\/10.1056\/NEJMoa2114663 (2022).","journal-title":"N. Engl. J. Med."},{"key":"53151_CR8","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1158\/1078-0432.CCR-21-3032","volume":"28","author":"Y-S Lu","year":"2022","unstructured":"Lu, Y.-S. et al. Updated overall survival of ribociclib plus endocrine therapy versus endocrine therapy alone in pre- and perimenopausal patients with HR+\/HER2\u2212 advanced breast cancer in MONALEESA-7: A phase III randomized clinical trial. J. Am. Assoc. Cancer Res. 28, 851\u2013859. https:\/\/doi.org\/10.1158\/1078-0432.CCR-21-3032 (2022).","journal-title":"J. Am. Assoc. Cancer Res."},{"key":"53151_CR9","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1001\/jamaoncol.2019.4782","volume":"6","author":"GW Sledge Jr","year":"2020","unstructured":"Sledge, G. W. Jr. et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy\u2014MONARCH 2: A randomized clinical trial. JAMA Oncol. 6, 116\u2013124. https:\/\/doi.org\/10.1001\/jamaoncol.2019.4782 (2020).","journal-title":"JAMA Oncol."},{"key":"53151_CR10","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41523-018-0097-z","volume":"5","author":"S Johnston","year":"2019","unstructured":"Johnston, S. et al. MONARCH 3 final PFS: A randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 5, 5. https:\/\/doi.org\/10.1038\/s41523-018-0097-z (2019).","journal-title":"NPJ Breast Cancer"},{"key":"53151_CR11","doi-asserted-by":"crossref","unstructured":"Goetz, P. M. et al. 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Outcomes of older women with hormone receptor-positive, human epidermal growth factor receptor-negative metastatic breast cancer treated with a CDK4\/6 inhibitor and an aromatase inhibitor: An FDA pooled analysis. J. Am. Soc. Clin. Oncol. 37, 3475\u20133483. https:\/\/doi.org\/10.1200\/JCO.18.02217 (2019).","journal-title":"J. Am. Soc. Clin. Oncol."},{"key":"53151_CR14","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1136\/bmj.n71","volume":"372","author":"MJ Page","year":"2021","unstructured":"Page, M. J. et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 372, 71. https:\/\/doi.org\/10.1136\/bmj.n71 (2021).","journal-title":"BMJ"},{"key":"53151_CR15","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1200\/JCO.2022.40.17_suppl.LBA1003","volume":"40","author":"RS Finn","year":"2022","unstructured":"Finn, R. S. et al. Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor\u2013positive\/human epidermal growth factor receptor 2\u2013negative advanced breast cancer (ER+\/HER2\u2212 ABC): Analyses from PALOMA-2. J. Clin. Oncol. 40, 1003. https:\/\/doi.org\/10.1200\/JCO.2022.40.17_suppl.LBA1003 (2022).","journal-title":"J. Clin. Oncol."},{"key":"53151_CR16","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/S1470-2045(15)00613-0","volume":"17","author":"M Cristofanilli","year":"2016","unstructured":"Cristofanilli, M. et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 17, 425\u2013439. https:\/\/doi.org\/10.1016\/S1470-2045(15)00613-0 (2016).","journal-title":"Lancet Oncol."},{"key":"53151_CR17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2020.102086","volume":"90","author":"A Desnoyers","year":"2020","unstructured":"Desnoyers, A., Nadler, M. B., Kumar, V., Saleh, R. & Amir, E. Comparison of treatment-related adverse events of different Cyclin-dependent kinase 4\/6 inhibitors in metastatic breast cancer: A network meta-analysis. Cancer Treat. Rev. 90, 102086. https:\/\/doi.org\/10.1016\/j.ctrv.2020.102086 (2020).","journal-title":"Cancer Treat. Rev."},{"key":"53151_CR18","unstructured":"Helwick, C. Paloma-2: No overall survival benefit reported with palbociclib\/letrozole in advanced breast cancer. ASCO Post (2022)."},{"key":"53151_CR19","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1200\/JCO.2013.53.8009","volume":"32","author":"LM Ellis","year":"2014","unstructured":"Ellis, L. M. et al. American Society of Clinical Oncology perspective: Raising the bar for clinical trials by defining clinically meaningful outcomes. J. Am. Soc. Clin. Oncol. 32, 1277\u20131280. https:\/\/doi.org\/10.1200\/JCO.2013.53.8009 (2014).","journal-title":"J. Am. Soc. Clin. Oncol."},{"key":"53151_CR20","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1016\/j.ejca.2014.12.016","volume":"51","author":"AJ Templeton","year":"2015","unstructured":"Templeton, A. J. et al. Influence of censoring on conclusions of trials for women with metastatic breast cancer. Eur. J. Cancer 51, 721\u2013724. https:\/\/doi.org\/10.1016\/j.ejca.2014.12.016 (2015).","journal-title":"Eur. J. Cancer"},{"key":"53151_CR21","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/s41571-020-0368-0","volume":"17","author":"AJ Templeton","year":"2020","unstructured":"Templeton, A. J., Amir, E. & Tannock, I. F. Informative censoring: A neglected cause of bias in oncology trials. Nat. Rev. Clin. 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Diagnostics https:\/\/doi.org\/10.3390\/diagnostics13050987 (2023).","journal-title":"Diagnostics"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53151-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53151-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53151-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,10]],"date-time":"2024-11-10T12:39:47Z","timestamp":1731242387000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53151-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,7]]},"references-count":27,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["53151"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-53151-8","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-3158114\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,7]]},"assertion":[{"value":"10 July 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"E. Amir: Honoraria from Novartis, Seagen, Gilead and AstraZeneca outside the submitted work. Michelle Nadler: Honoraria from Novartis and Exact Sciences outside the submitted work.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3129"}}