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Patients received afuresertib 125 mg daily with fulvestrant 500 mg on days 1, 15, and 29, then every 28 days. Thirty-one participants (median age 54; 30 women) were enrolled, including 20 with prior CDK4/6 inhibitor therapy. Investigator-assessed objective response rate was 25.8% (8/31); grade 3+ adverse events occurred in 29.0% of patients, with no deaths due to adverse events. Results supported further randomized trials.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/afuresertib-plus-fulvestrant-for-pretreated-hr-positive-her2-negative-advanced-breast-cancer-phase-ib-trial/359025/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/afuresertib-plus-fulvestrant-for-pretreated-hr-positive-her2-negative-advanced-breast-cancer-phase-ib-trial/359025.png","ImageObject",300,407,{"name":92,"@type":93},"Aurelia","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What was the main purpose of this phase Ib trial?","Question",{"text":112,"@type":113},"To evaluate the antitumor activity and safety of afuresertib plus fulvestrant in previously treated HR-positive, HER2-negative advanced breast cancer.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were afuresertib and fulvestrant administered?",{"text":117,"@type":113},"Afuresertib was given at 125 mg/day, while fulvestrant was administered 500 mg on days 1, 15, and 29, then every 28 days thereafter.",{"name":119,"@type":110,"acceptedAnswer":120},"What efficacy and serious safety results were reported?",{"text":121,"@type":113},"The investigator-assessed objective response rate was 25.8% (8/31). Grade 3 or worse adverse events occurred in 29.0% of patients, and no death due to adverse event was observed.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},359025,1790228539,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},1099514068365,"https://ap-avatar.wpscdn.com/avatar/10000253d8d9f28188e?_k=1776742907772140068","Article [https://doi.org/10.1038/s41467-026-69225-2](https://doi.org/10.1038/s41467-026-69225-2)  \nAfuresertib plus fulvestrant for pretreated HR-positive, HER2-negative, advanced breast cancer: a phase Ib trial  \nReceived: 18 April 2025  \n\n| Accepted: 28 January 2026 |\n| --- |\n| |\n| Check for updates |\n\nPin Zhang1, Tao Sun 2, Ying Wang3, Wei Li4, Zhongsheng Tong5, Sneha Phadke6, Trevor Feinstein7, Wenyue Ma 8, Pengfei Guo9, Minhua Zhang10, Yong Yue8 & Binghe Xu 1   \nThis single-arm, phase Ib trial evaluated the antitumor activities and safety of afuresertib (a pan AKT inhibitor) plus fulvestrant for previously treated HRpositive, HER2-negative advanced breast cancer. Eligible patients received afuresertib at 125 mg/day and fulvestrant at 500 mg on days 1, 15, and 29, and every 28 days thereafter during safety run-in and, in the absence of serious toxicities, subsequent 4-week cycles. The trial enrolled 31 patients (median age 54 years; 30 women); 20 received prior CDK4/6 inhibitor therapy. The primary endpoint of investigators-assessed objective response rate was 25.8%(8/31; 90% CI 13.5-41.8). Nine patients (29.0%) had grade 3 or worse adverse events. No death due to adverse event occurred. In conclusion, afuresertib plus fulvestrant was well-tolerated and had promising antitumor activities against pretreated, advanced HR-positive, HER2-negative breast cancer, supporting further studies with randomized controlled trials. This trial is registered with [ClinicalTrials.gov](ClinicalTrials.gov) (NCT04851613).  \nBreast cancer is the most frequently diagnosed cancer in women, with an estimated 2.3 million new cases, and the fourth leading cause of cancer mortality, with 665,684 deaths in 2022 globally1. The disease poses a serious health concern in China as well, with357,200estimated new cases and 75,000 deaths in China in 20222. Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) -negative tumors account for approximately 70% of breast cancer cases1. The current standard of care for women with HR-positive, HER2-negative, locally advanced, recurrent or metastatic disease consists ofendocrine therapy, often with anaromatase inhibitor, plus a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Though pivotal clinical trials have established the efficacy of CDK4/6 inhibitors (ribociclib, abemaciclib, and others)3–8, acquired CDK4/6 inhibitor  \nresistance eventually emerges and subsequent sequential single-agent chemotherapy is associated with decreasing response rates9,10, calling for a polypharmacology approach simultaneously targeting multiple kinases or an effective molecular therapy targeting critical signaling pathways that sustain endocrine resistance in breast cancer11,12.  \nThe phosphatidylinositol 3-kinase (PI3K)–AKT–PTEN signaling pathway plays a pivotal role in cell proliferation and survival, and metabolism in breast cancer and alterations ofthis pathway, including PIK3CA and AKT1 and inactivating alterations in PTEN, occur in over 50% of patients with HR-positive13,14, HER2-negative tumors15–17. These genetic alterations lead to aberrant signaling that is not only of significance in tumor development but also in shaping responses to breast cancer treatment, including the emergence of endocrine  \n1Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 2Breast Medicine, Liaoning Cancer Hospital, Shenyang, China. 3Gynecology Department, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China. 4Oncology Department, Oncology Center, The First Bethune Hospital of Jilin University, Changchun, China. 5Breast Oncology Department, Tianjin Cancer Hospital, Tianjin, China. 6Internal Medicine, University of Iowa Health Care, Holden Comprehensive Cancer Center, Iowa City, IA, USA. 7Medical Oncology, Piedmont Cancer Institute, Atlanta, GA, USA. 8Department of Me","cbCaikUyo0JkHigc","https://ap.wps.com/l/cbCaikUyo0JkHigc","pdf",601999,11,"English","# Trial overview\n## Treatment regimen and eligibility\n## Efficacy and safety outcomes\n## Clinical significance and registry","[{\"question\":\"What was the main purpose of this phase Ib trial?\",\"answer\":\"To evaluate the antitumor activity and safety of afuresertib plus fulvestrant in previously treated HR-positive, HER2-negative advanced breast cancer.\"},{\"question\":\"How were afuresertib and fulvestrant administered?\",\"answer\":\"Afuresertib was given at 125 mg/day, while fulvestrant was administered 500 mg on days 1, 15, and 29, then every 28 days thereafter.\"},{\"question\":\"What efficacy and serious safety results were reported?\",\"answer\":\"The investigator-assessed objective response rate was 25.8% (8/31). Grade 3 or worse adverse events occurred in 29.0% of patients, and no death due to adverse event was observed.\"}]","Afuresertib plus fulvestrant for pretreated HR-positive, HER2-negative, advanced breast cancer - phase Ib trial | PDF",1790135895,28]