A biopsy-free diagnostic pathway in prostate cancer (PC) is limited by the diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI). The improved accuracy of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) raises the question whether this imaging modality can complement mpMRI to safely avoid biopsy prior to radical prostatectomy (RP). In this case series, we report the feasibility of primary RP without prior biopsy based on a high suspicion of significant PC in both mpMRI (Prostate Imaging Reporting and Data System [PI-RADS] score ≥4) and PSMA-PET (PET score ≥4 on a five-point Likert scale and maximum standardized uptake value ≥4.0) in 25 patients. All patients showed International Society of Urological Pathology (ISUP) grade ≥2 PC in postoperative histopathology. We report patient- and lesion-based comparisons with histopathology of the prostate specimen. Results of our case series may trigger the discussion about RP without prior biopsy as a possible option in well-selected patients. Our case series is limited by retrospective design and small sample size. We want to emphasize clearly that this practice should not be regarded as a standard procedure at the moment. Future studies with larger cohorts only inside a prospective, ethically approved study design are necessary to confirm these results.