Precision medicine expands the treatment options for metastatic castration-resistant prostate cancer (mCRPC) by targeting druggable genetic aberrations. Aberrations can be identified following molecular analysis of metastatic tissue. Bone metastases, commonly present in mCRPC, hinder precision medicine due to a high proportion of biopsies with insufficient tumor cells for next-generation DNA sequencing. We aimed to investigate the feasibility of incorporating advanced target planning and needle guidance in bone biopsies and whether this procedure increases biopsy tumor yield and success rate of molecular analysis as compared to the current standards, utilizing only CT guidance. In a pilot study, ten mCRPC patients received Fusion target planning and CBCT needle guidance were feasible. Nine out of ten biopsies contained prostate cancer cells, with a median of 39% and 40% tumor cells by two different sequencing techniques. Molecular analysis was successful in eight of ten patients (80%). This exceeds previous reports on CT-guided biopsies that ranged from 33 to 44%. In two patients, important druggable aberrations were found. A biopsy procedure using advanced target planning and needle guidance is feasible and can increase the success rate of molecular analysis in bone metastases, thereby having the potential of improving treatment outcome for patients with mCRPC. Level 4, case series.