PSA Zero Radiographic Disease Progression on PSMA PET/CT

<b>Background and Objective:</b> Radiographic progression in prostate cancer (PCa) can occur even when prostate-specific antigen (PSA) levels are undetectable. We aimed to determine the frequency and characteristics of radiographic disease progression (rDP) on PSMA PET/CT in patients with undetectable PSA, referred to as PSA zero rDP. <b>Methods:</b> We analyzed the Mayo Clinic PSMA PET Prostate Cancer Registry to identify patients with rDP on PSMA PET/CT despite undetectable PSA levels. Disease progression was confirmed via biopsy or treatment response. The cohort included patients with non-metastatic and metastatic hormone-sensitive disease, as well as those with castration-resistant prostate cancer at the time of imaging. Overall survival (OS) was estimated using the Kaplan-Meier method. Group comparisons were performed with the log-rank test. Univariate Cox regression was used to identify factors associated with poor OS. <b>Key findings and Limitations:</b> Among 2141 patients imaged between 2021 and 2023, 257 (12%) had PSA zero rDP. Sixty-one percent had initially localized disease; 39% had de novo metastatic disease. Median (IQR) time from diagnosis to PSA zero rDP was 51.9 (18.4-115.5) months. A total of 184 patients (72%) progressed to castration-resistant PCa. Sites of rDP included bone (57%), visceral (15%), lymph node (18%), and local recurrence (10%). During median follow-up of 8.1 (3.5-11.9) months, 5% of patients died. Only visceral metastases were significantly associated with poorer OS (<i>p</i> < 0.0001). <b>Conclusions and Clinical Implications:</b> Prostate cancer patients frequently develop metastatic disease with undetectable PSA values. Our findings suggest the use of periodic advanced imaging techniques, irrespective of PSA value, for more prompt detection and early management of disease progress.