Observational Management for Patients with Biochemical Recurrence Following Radical Prostatectomy, in the Absence of Detectable Disease on Restaging PSMA PET/CT Imaging

<b>Background/Objectives:</b> In men with biochemical recurrence (BCR) after a radical prostatectomy (RP), salvage radiotherapy (SRT) is commonly recommended when imaging shows no metastases. The optimal management for patients with negative prostate-specific membrane antigen (PSMA) PET/CT findings at BCR remains uncertain. This study evaluated outcomes of patients with BCR and negative PSMA PET/CT to identify who may be safely observed and who may benefit from early SRT. <b>Methods:</b> This retrospective multicentre cohort study included 89 patients with BCR and negative PSMA PET/CT findings after a RP (2015-2022) who were managed with observation. The exclusion criteria were PSA levels ≥ 0.8 ng/mL at baseline, prior SRT, or prior or ongoing hormonal therapy. Minimum follow-up was 3 years. Biochemical progression (PSA rise > 0.2 ng/mL above baseline or initiation of additional treatment) and radiological progression (local or metastatic disease on follow-up PSMA PET/CT) were assessed. Patients were stratified by EAU BCR-risk classification. Multivariable Cox regression included age, biochemical persistence (BCP) after a RP, pathological tumour stage (pT), pathological ISUP grade group (pISUP), node status (pN), margin status (R), and PSA doubling time (PSAdt). <b>Results:</b> The median age was 66 years (IQR 60-69) and the median PSA measurement at BCR was 0.2 ng/mL (IQR 0.2-0.3). A total of 27/89 (30%) patients were EAU BCR low-risk and 62/89 (70%) were high-risk. At three years, biochemical progression occurred in 14/27 (52%) low-risk vs. 51/62 (83%) high-risk patients, with time to progression being 21 vs. 12 months (<i>p</i> = 0.01). A pISUP grade group ≥ 4 (HR 2.04 [95%-CI 1.11-3.74]; <i>p</i> = 0.022) and a PSAdt < 20 months (HR 5.72 [95%-CI 2.41-13,56]; <i>p</i> < 0.01) independently predicted biochemical progression. Radiological progression occurred in 43/68 (66%) rescanned patients, with 32/43 (74%) showing disease outside the prostatic fossa. <b>Conclusions:</b> Nearly half of patients with BCR and negative PSMA PET/CT findings who were classified as EAU BCR low-risk remained progression-free at three years. These results support a risk-adapted approach, indicating that SRT may be deferred in selected low-risk patients.