BackgroundDespite multiple retrospective studies have demonstrated the clinical validity of molecularly-guided therapy selection in metastatic castrate-resistant prostate cancer (mCRPC), none have validated the actual clinical utility in the context of a randomised controlled trial. We hypothesise that treatment decisions based on plasma-derived cell-free DNA (cfDNA) profiling will increase progression-free survival (primary endpoint), which would result in prolonged overall survival and improved quality-of-life (secondary endpoints). Trial designThe Prostate Biomarker (ProBio) trial is a recently-initiated adaptive, multi-arm, open-label, multiple assignment randomized controlled biomarker driven phase 3 trial in men with mCRPC. Men (n=750) will be randomized to receive either standard of care or an experimental treatment with abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, or carboplatin based on molecular biomarker signatures, as inferred from our liquid biopsy profiling. Therefor a prostate-specific1.48Mb biomarker panel was designed and validated, which is capable of detecting 1) mutations in 78 genes, 2) genomic structural rearrangements in 11 prostate cancer-associated genes, 3) genome-wide copy number alterations, 4) 63 microsatellites to infer microsatellite instability, 4) tumour mutational burden and 5) estimate the circulating tumour DNA (ctDNA) fraction. The initial pre-defined biomarker signatures are defined as tumour properties or mutations in certain genes/pathways identified in the scientific literature as potentially important in prostate cancer treatment response encompassing the androgen receptor (AR), TP53, DNA-repair deficiency (DRD) and the TMPRSS2-ERG fusion. The statistical design of ProBio is novel, since the randomisation probabilities for a given experimental systemic therapy are subjective to change as the trial evolves and learns from prior experience. Secondly, ProBio implements a re-randomization of non-responding patients. Clinical trial identification2018-002350-78 (16/07/2018), NCT03903835 (29/03/2019). Legal entity responsible for the studyProBio Investigators. FundingThe Swedish Research Council, The Erling-Persson Family Foundation, The Swedish Cancer Foundation. DisclosureAll authors have declared no conflicts of interest.