Background: Castrate-resistant prostate cancer (CRPC) affects around 3,000 men in Sweden every year. New drugs are available but they have moderate effect, low response rates, are expensive, and lack predictive treatment markers. This will lead to an unsustainable situation for prostate cancer care. Our hypothesis is that treatment decisions based on molecular profiling will significantly increase the response rate at 3 months compared to current clinical care, translating into improved progression free and overall survival. The vast majority of CRPC metastasize to the bone, with low success rate in obtaining sufficient material. Therefore, we will sequence circulating tumor DNA (ctDNA) being present at high levels in plasma. Methods: ProBio-II is an adaptive, multi-arm, open-label, multiple assignment randomized biomarker driven phase 2 trial in men with CRPC . Men (n=750) will be randomized to receive either standard of care (following Swedish national guidelines) or treatment with Enzalutamide, Abiraterone, PARP inhibitors, RA-223, Cabazitaxel, or immune modulators based on molecular subtypes. The molecular subtypes are defined as tumor properties or mutations in certain genes/pathways including: Microsatellite instability; Androgen receptor alterations; DNA-repair deficiency; TP53 inactivation; PTEN inactivation etc. The molecular subtypes will be identified by ctDNA profiling. A specially designed ctDNA profile for CRPC has been developed by our group to detect: mutations, amplifications and genomic rearrangements in the androgen receptor (AR); mutations, genomic rearrangements and amplifications/deletions in 300 key genes involved in prostate cancer; and microsatellite instable and hypermutated cancers. ProBio-II’s design is novel and inspired by successful studies as I-SPY (breast cancer) and the NCI-MATCH trial (metastatic cancer). Novel aspects of the study design includes using prior probability of treatment response; re-randomization of non-responders; and adaptive design. The ProBio II study will start recruiting patients in Sweden in Q1 2018 and recruit patients during a 18 month period. All major oncology departments in Sweden will participate.