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DNA copy gains that amplify the Androgen Receptor (AR) gene locus are a key driver of resistance to targeted therapy in mCRPC. Our group has recently shown that extra-chromosomal DNA (ecDNA) frequently drives this amplification. We hypothesized that ecDNA and other complex structural variants (cSVs) also affect other established drivers of therapy resistance in mCRPC and continue to evolve over time. To test this hypothesis, we reconstructed cSV profiles in 193 mCRPC tumors using whole genome and transcriptome sequencing, with matched Hi-C data for 77 tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identify ecDNA in more than half of mCRPC biopsies and show it frequently amplifies driver genes such as AR and MYC and their non-coding enhancers. The presence of ecDNA is significantly associated with whole genome doubling, chromothripsis, and inactivating TP53 alterations. Deep sequencing analysis of 53 rapid autopsy samples shows cSVs amplifying AR can arise independently within distinct tumors in a single patient. Phylogenetic analysis of tumor evolution implicates this cSV as an early event during metastatic spread. Additionally, a paired analysis of mCRPC samples as patients developed resistance to AR pathway inhibitor (ARPI) therapy demonstrates cSVs evolve in response to ARPI and can be detected in both tumor tissue and circulating tumor DNA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We conclude that cSVs, particularly ecDNA, are a pervasive contributor to intra-patient heterogeneity in late-stage mCRPC and a key driver of targeted therapy resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13059-026-04074-2","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T08:34:25Z","timestamp":1776242065000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Convergent evolution of complex structural variants drives therapy resistance in metastatic prostate cancer"],"prefix":"10.1186","volume":"27","author":[{"given":"Thaidy","family":"Moreno-Rodriguez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arian","family":"Lundberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raunak","family":"Shrestha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Sj\u00f6str\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anupama","family":"Pasam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Devereux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Foye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alana S.","family":"Weinstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna S.","family":"Trigos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander W.","family":"Wyatt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshi J.","family":"Alumkal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.","family":"Small","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul","family":"Aggarwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott M.","family":"Dehm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew L.","family":"Bootsma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang G.","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Lupien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix Y.","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahneen","family":"Sandhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Quigley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"4074_CR1","first-page":"7","volume":"71","author":"RL Siegel","year":"2021","unstructured":"Siegel RL, Miller KD, Fuchs HE, Jemal A. 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The CASCADE program was sponsored and conducted by the Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia and approved by the Human Research Ethics Committee of the Peter MacCallum Cancer Centre, Melbourne (HREC approval numbers: CASCADE 13\/122). All patients provided informed consent for research uses and publication of derived work. Experimental methods in this work comply with the Helsinki Declaration.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"A. Foye reports personal fees from Varian Medical Systems outside the submitted work. A.W. Wyatt reports personal fees from AstraZeneca, Astellas, Bayer, EMD Serono, Janssen, Merck, and Pfizer and grants from ESSA Pharma, Tyra Biosciences, and Promontory Therapeutics outside the submitted work. J. Alumkal has received consulting fees from Fortis Therapeutics and ORIC Pharmaceuticals and research support to his institution from Beactica, Zenith Epigenetics, and a National Comprehensive Cancer Network (NCCN)\/Astellas Pharma Global Development, Inc.\/Pfizer, Inc. research award outside of the submitted work. E.J. Small reports other support from Fortis, Harpoon, Teon, Janssen, Johnson & Johnson, and Ultragenyx during the conduct of the study; other support from Fortis, Harpoon, Teon, Janssen, Johnson & Johnson, and Ultragenyx outside the submitted work. R.R. Aggarwal reports grants from Janssen, Amgen, Zenith Epigenetics, and Xynomic Pharmaceuticals; grants and personal fees from AstraZeneca, Merck, and Novartis; personal fees from Dendreon, Elsevier, Exelixis, Jubilant Therapeutics, Bayer, Pfizer, and Alessa Therapeutics outside the submitted work. S.G. Zhao has patent applications with Veracyte on molecular signatures in prostate cancer unrelated to this work, and a family member employed by Artera and with stock in Exact Sciences. F.Y. Feng reports personal fees from Janssen Oncology, Bayer, PFS Genomics, Myovant Sciences, Roivant Sciences, Astellas Pharma, Foundation Medicine, Varian, Bristol Myers Squibb (BMS), Exact Sciences, BlueStar Genomics, Novartis, and Tempus; other support from Serimmune and Artera outside the submitted work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"177"}}