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The primary objective of the PARADIGM prospective cohort study was to evaluate predictors of survival in blood collected at the start of each of the first six treatment cycles from 114 patients with high-volume metastatic prostate cancer (biologically male) who were starting androgen deprivation therapy in combination with docetaxel or an androgen receptor pathway inhibitor. Here circulating tumor DNA (ctDNA) was detected in 29% of patients after 6\u201312\u2009weeks of combination therapy (compared to 70% before any treatment) and associated with 12\u2009month overall survival of 73% versus 99% for patients who were ctDNA-negative and 24\u2009month survival of 50% versus 85%. The secondary objective was to test ctDNA with serum prostate-specific antigen (PSA). In multivariable models, both were independent risk factors on combination treatment with a hazard ratio of death of 20.34 for the poorest prognosis group, but only ctDNA was associated with shorter survival on androgen deprivation before the start of combination therapy. Using ctDNA with serum PSA and clinical characteristics can improve the accuracy of survival prediction and should be evaluated for ctDNA-informed treatment modification. 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F.O., O.V., D.W., F.D. and G.A. have a second patent being considered with relevance to the submitted work (PCT\/GB2025\/051141). A.J. reports travel support from Bayer, Novartis and Merck and honoraria from Bayer. A.H.M. reports personal fees and travel support from Janssen and BMS. R.J. reports speaker and consultancy honoraria from Accord, Astellas, AstraZeneca, Bayer, BMS, Johnson and Johnson, Merck Serono and MSD. E.P. reports consulting fees from Janssen, AstraZeneca, Typharm and Merck Sharp & Dohme; financial support from Bayer; and nonfinancial support from Amgen, Janssen and Astellas. M.L. reports travel support from BMS. U.M. reports travel support from Janssen Oncology. J.S. reports a relationship with Teleflex that includes consulting or advisory; Novartis that includes consulting or advisory; Johnson and Johnson that includes speaking and lecture fees and travel reimbursement; Amgen that includes consulting or advisory; and AstraZeneca that includes lecture fees and travel reimbursement. S.J.C. reports personal fees for speaking and\/or advisory work from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer and Roche. He has received research support for clinical trials from AstraZeneca, Veracyte and Roche. He has received support for scientific meeting attendance from Bayer, BMS, Janssen, Merck and Novartis. A.B. reports personal fees from AstraZeneca, Astellas, Johnson & Johnson, MSD, Merck, Roche, Macrogenics, Bayer and Accord; speaker fees from Accord, Bayer, Roche, Astellas, Johnson & Johnson; and travel support or registration at conferences from Johnson & Johnson and Bayer. G.A. reports personal fees, grants and travel support from Janssen, Novartis and Astellas Pharma during the conduct of the study; personal fees or travel support from Pfizer, Bayer Healthcare Pharmaceuticals, AstraZeneca, Arvinas, Propella, Orion, Amgen, Merck, MSD and Sanofi-Aventis, outside the submitted work. In addition, G.A.\u2019s former employer, The Institute of Cancer Research, receives royalty income from abiraterone and G.A. receives a share of this income through the Institute\u2019s Rewards to Discoverers Scheme. G.A.\u2019s current employer (UCL) receives clinical trial costs from Novartis, Janssen, Astellas and Pfizer; licensing fees from Artera and Veracyte; equipment from Agilent; and holds the patent for \u2018Blood-based methylation markers\u2019 (GB1915469.9). The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}