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We highlight design issues in the randomized controlled trials (RCTs) that bias the results of early ARSI use, suggesting that the magnitude of benefit might be overestimated and, therefore, uncertain. Issues include sub-optimal post-protocol care, inadequate control arms, and the inclusion of highly selected patients, which are increasingly characteristic of contemporary cancer RCTs. The uncertainty regarding the true magnitude of benefit of early ARSI use complicates health technology assessment (HTA). Recognition of such trial design issues with their resultant magnitude of benefit uncertainty is important not only for individual patient care but also for cancer policy decision-making in general.<\/jats:p>","DOI":"10.3389\/or.2026.1750202","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T05:45:42Z","timestamp":1778564742000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Uncertain magnitude of benefit of early second-generation androgen receptor antagonist treatment in advanced prostate cancer"],"prefix":"10.3389","volume":"20","author":[{"given":"Emma K.","family":"van de Weerdt","sequence":"first","affiliation":[{"name":"Department of Hematology-Medical Oncology, Cura\u00e7ao Medical Center","place":["Willemstad, Cura\u00e7ao"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley 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