BackgroundTo test for differences in organ-confined pathological tumor stage (pT) and intermediate International Society of Urological Pathologists (ISUP) grade vs. nonorgan confined pT stage and high ISUP grade and biochemical recurrence (BCR) after radical prostatectomy (RP). MethodsRelying on a tertiary-care database, prostate cancer patients undergoing RP between January 2014 and December 2021 were stratified according to their combination of pT stage and ISUP grade in RP specimens (pT2 ISUP4/5 vs. pT3/4 ISUP2 vs. pT3/4 ISUP3). As Active Surveillance is recommended in ISUP1, these patients were excluded. Moreover, patients with pT2 ISUP2/3 are known for their good prognosis and pT3/4 ISUP4/5 patients for their poor prognosis. Therefore, these patients were also excluded from analyses. Kaplan–Meier survival analyses and multivariable Cox regression models addressed BCR after RP. ResultsOf 215 RP patients, 29 (13%) exhibited pT2 ISUP4/5 vs. 122 (57%) pT3/4 ISUP2 vs. 64 (30%) pT3/4 ISUP3 pathology. In survival analyses, 3-year BCR-free survival rates were 95% in pT2 ISUP4/5 vs. 88% in pT3/4 ISUP2 vs. 65% in pT3/4 ISUP3 patients (P < 0.001). In multivariable Cox regression models addressing BCR, pT3/4 ISUP3 pathology was associated with higher BCR rate relative to pT2 ISUP4/5 pathology (hazard ratio 3.42, 95% confidence interval 1.07-10.94; P = 0.039), but not pT3/4 ISUP2 pathology (P = 0.6). ConclusionCompared to prostate cancer patients with pT2 ISUP4/5 pathology, the combination of pT3/4 ISUP3 pathology is associated with higher risk of BCR after RP. In consequence, patients with pT3/4 ISUP3 pathology should be considered for a closer postoperative follow-up.