[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-356694-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-356694-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","novel-therapeutic-strategies-for-metastatic-castration-resistant-prostate-cancer-beyond-androgen-receptor-pathway-inhibition-review","Novel therapeutic strategies for metastatic castration‑resistant prostate cancer: Beyond androgen receptor pathway inhibition (Review)","","Metastatic castration‑resistant prostate cancer (mCRPC) persists as a lethal disease largely because tumors develop broad resistance to androgen‑receptor pathway inhibitors (ARPI). Tumor progression is driven by androgen‑receptor‑independent mechanisms, including DNA‑damage repair genomic alterations, epigenetic changes enabling lineage plasticity, metabolic adaptations, and an immunosuppressive tumor microenvironment. These insights support new therapeutic development beyond AR blockade, including mechanism‑based biomarker strategies and combination sequencing.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/novel-therapeutic-strategies-for-metastatic-castration-resistant-prostate-cancer-beyond-androgen-receptor-pathway-inhibition-review/356694/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/novel-therapeutic-strategies-for-metastatic-castration-resistant-prostate-cancer-beyond-androgen-receptor-pathway-inhibition-review/356694.png","ImageObject",300,407,{"name":42,"@type":43},"Angel","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-29","2026-09-23",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",8,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why are novel strategies needed for metastatic castration‑resistant prostate cancer after ARPI?","Question",{"text":63,"@type":64},"mCRPC progression is nearly universal under androgen‑receptor blockade, and durable responses are limited with objective radiologic progression often occurring within 12–18 months.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What mechanisms underlie ARPI failure in mCRPC?",{"text":68,"@type":64},"Resistance involves androgen‑receptor‑independent drivers such as DNA‑damage repair pathway genomic alterations, epigenetic shifts promoting lineage plasticity, metabolic adaptations, and an immunosuppressive tumor microenvironment.",{"name":70,"@type":61,"acceptedAnswer":71},"Which treatment approaches are highlighted beyond androgen‑receptor pathway inhibition?",{"text":72,"@type":64},"The review emphasizes PARP inhibitors for homologous recombination repair deficiencies, PI3K/AKT‑pathway inhibition for PTEN‑loss subsets, PSMA‑targeted radioligand therapy, bispecific T‑cell engagers, antibody‑drug conjugates, and immune checkpoint inhibitors.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},356694,1790289115,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":111,"show_sort_weight":112,"slug":113},"Research & Report",30,"research-report",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},9,"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":127,"language":139,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":12,"update_tm":143,"read_time":144},687207412472,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","INTERNATIONAL JOURNAL OF ONCOLOGY 68: 69, 2026  \nNovel therapeutic strategies for metastatic castration‑resistant prostate cancer: Beyond androgen receptor pathway inhibition (Review)  \nYAQIN WANG 1 , YONGQIANG XIE2 and QIANG ZHAO2  \n1Department of Oncology, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, Gansu 730900, P.R. China; 2Department of Urology, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China  \nReceived December 26, 2025; Accepted February 26, 2026  \nDOI: 10.3892/ijo.2026.5882  \nAbstract. Metastatic castration‑resistant prostate cancer (mCRPC) remains a lethal disease due to universal resis‑ tance to androgen‑receptor pathway inhibitors (ARPI) . Tumor progression is orchestrated by a spectrum of androgen‑receptor‑independent drivers, including genomic alterations in DNA damage repair pathways, epigenetic shifts promoting lineage plasticity, metabolic adaptations and an immunosuppressive tumor microenvironment. This evolving understanding has catalyzed the development of  \nCorrespondence to: Professor Qiang Zhao or Professor Yongqiang Xie, Department of Urology, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, 222 Silong Road, Baiyin, Baiyin, Gansu 730900, P.R. China  \nE‑mail: [282986601@qq.com](282986601@qq.com)  \nE‑mail: [452062491@qq.com](452062491@qq.com)  \nAbbreviations: ADCs, antibody‑drug conjugates; ADT, androgen deprivation therapy; AI, artificial intelligence; AKT, protein kinase B; AR androgen receptor; ARPI androgen‑receptor pathway inhibitor; BiTE, bispecific T‑cell engager; CAR‑T, chimeric antigen receptor T cell; CRS, cytokine‑release syndrome; ctDNA, circulating tumor DNA; DDR, DNA‑damage response; DNR, dominant‑negative receptor; FAP, fibroblast activation protein; GRPR, gastrin‑releasing peptide receptor; HRR, homologous recombination repair; mCRPC, metastatic castration‑resistant prostate cancer; MSI‑H, microsatellite instability‑high; NEPC, neuroendocrine prostate cancer; NHEJ, non‑homologous end joining; ORR, objective response rate; OS, overall survival; PARP, poly (ADP‑ribose) polymerase; PD‑L1, programmed death‑ligand 1; PET, positron emission tomography; PI3K, phosphatidylinositol 3‑kinase; PSMA, prostate‑specific membrane antigen; PTEN, phosphatase and tensin homolog; rPFS, radiographic progression‑free survival; RLT, radioligand therapy; SOC, standard of care; TMB, tumor mutational burden  \nKey words: metastatic castration‑resistant prostate cancer, poly (ADP‑ribose) polymerase inhibitors, prostate‑specific membrane antigen theranostics, protein kinase B blockade, CDK12 loss, bispecific antibodies, antibody‑drug conjugates  \nnovel therapeutic strategies . These include PARP inhibi‑ tors for tumors with homologous recombination repair deficiencies, protein kinase B inhibitors for the phosphatase and tensin homolog‑loss subset, prostate‑specific membrane antigen (PSMA)‑targeted radioligand therapy, bispecific T‑cell engagers, antibody‑drug conjugates and immune checkpoint inhibitors. Furthermore, liquid biopsy profiling, PSMA‑positron emission tomography‑based radiomics and artificial intelligence platforms are enhancing real‑time patient selection and response assessment. The present review synthesized these recent preclinical and clinical advances to delineate biomarker‑driven, mechanism‑based therapeutic sequencing and combination strategies for mCRPC in the post‑ARPI era.  \nContents  \n1. Introduction  \n2. Precision genomics: PARP inhibitors and DNA‑damage response targeting  \n3. Immuno‑oncology revival: Checkpoint inhibitors, bispe‑ cific antibodies and cellular therapy  \n4. Radioligand therapy: PSMA‑targeted β‑ and α‑emitters  \n5. PI3K‑AKT‑PTEN axis and adjacent kinase pathways  \n6. Antibody‑drug conjugates and emerging oral molecular agents  \n7. Rational combinations and sequencing in the post‑ARPI landscape  \n8. Future directions  \n9. Conclusions  \n1. Intro","cbCaikAYeRVDKXTf","https://ap.wps.com/l/cbCaikAYeRVDKXTf","pdf",3528241,"English","# Introduction\n# Precision genomics: PARP inhibitors and DNA‑damage response targeting\n# Immuno‑oncology revival: Checkpoint inhibitors, bispecific antibodies and cellular therapy\n# Radioligand therapy: PSMA‑targeted β‑ and α‑emitters\n# PI3K‑AKT‑PTEN axis and adjacent kinase pathways\n# Antibody‑drug conjugates and emerging oral molecular agents\n# Rational combinations and sequencing in the post‑ARPI landscape\n# Future directions\n# Conclusions","[{\"question\":\"Why are novel strategies needed for metastatic castration‑resistant prostate cancer after ARPI?\",\"answer\":\"mCRPC progression is nearly universal under androgen‑receptor blockade, and durable responses are limited with objective radiologic progression often occurring within 12–18 months.\"},{\"question\":\"What mechanisms underlie ARPI failure in mCRPC?\",\"answer\":\"Resistance involves androgen‑receptor‑independent drivers such as DNA‑damage repair pathway genomic alterations, epigenetic shifts promoting lineage plasticity, metabolic adaptations, and an immunosuppressive tumor microenvironment.\"},{\"question\":\"Which treatment approaches are highlighted beyond androgen‑receptor pathway inhibition?\",\"answer\":\"The review emphasizes PARP inhibitors for homologous recombination repair deficiencies, PI3K/AKT‑pathway inhibition for PTEN‑loss subsets, PSMA‑targeted radioligand therapy, bispecific T‑cell engagers, antibody‑drug conjugates, and immune checkpoint inhibitors.\"}]","Novel therapeutic strategies for metastatic castration‑resistant prostate cancer: Beyond androgen receptor pathway inhibition (Review) | PDF",1790126826,48]