PSA‑Zero Radiographic Progression on PSMA PET/CT: Registry Findings

Radiographic progression on PSMA PET/CT may be seen even when prostate-specific antigen is undetectable, a discordance described by investigators from the Mayo Clinic PSMA PET Prostate Cancer Registry.

In this registry-based report spanning scans performed during 2021–2023, the authors describe how often this “PSA-zero” radiographic disease progression (rDP) occurred, where lesions appeared anatomically, what clinical features accompanied these presentations, and how progression was corroborated when serum PSA did not signal change. They also report an overall survival (OS) association tied to visceral involvement in univariate analysis. Overall, the report presents PSA-zero rDP as a registry-observed phenomenon with a defined frequency, lesion distribution, cohort context, and an OS signal, alongside author-described surveillance considerations and caveats.

Within the registry population of 2141 imaged patients, the authors identified 257 men (12%) with rDP on PSMA PET/CT despite undetectable PSA at the time of progression. Among these PSA-zero rDP cases, progression sites were reported as bone in 57%, lymph nodes in 18%, visceral organs in 15%, and local recurrence in 10%. The investigators presented these findings as an anatomic “where” description rather than a staging reclassification exercise. The distribution emphasized bone-predominant progression, with smaller subsets showing nodal, visceral, or local patterns.

The clinical context for the PSA-zero rDP cohort included disease presentations the authors characterize as high risk at diagnosis and often advanced by the time PSA-zero rDP was recognized. At initial diagnosis, median primary Gleason score was 8 (IQR 7–9) and median PSA was 11.1 ng/mL (IQR 5.6–32.7); 61% had initially localized disease with later recurrence after primary local therapy, while 39% presented with de novo metastatic disease. Median time from diagnosis to PSA-zero rDP was reported as 51.9 months (IQR 18.4–115.5) in the abstract, while the Results section reports a median of 119 months (IQR 30.8–368.5). By the time of PSA-zero rDP, 184 patients (72%) had progressed to castration-resistant prostate cancer, and most had received systemic therapy before this point. When PSA was undetectable, biopsies were obtained in 18 patients (7%), yielding adenocarcinoma in 17 and small cell/neuroendocrine features in 1; other corroboration approaches described included interval imaging evolution and treatment-response correlation. The cohort description pairs aggressive baseline features with selective tissue confirmation alongside longitudinal imaging and clinical context.

In outcomes analyses reported after PSA-zero rDP, the authors highlighted a univariate association between visceral involvement and worse OS. Specifically, in univariate Cox regression, visceral metastases were the only factor reported as significantly associated with poorer OS (hazard ratio 8.8, 95% CI 2.86–26.67; p < 0.0001), whereas other evaluated variables did not meet statistical significance in that analysis. The investigators also reported OS differences by rDP site using Kaplan–Meier comparisons, with visceral involvement described as having the poorest survival curves. In the authors’ framing, these analyses link visceral disease on imaging at PSA-zero rDP with a markedly worse OS signal in this dataset.

In discussion, the authors noted that PSA alone may not fully reflect disease activity for some patients and discussed periodic advanced imaging irrespective of PSA value in relation to earlier detection and management; they also acknowledged the retrospective design, potential selection bias, and short follow-up. They noted that imaging in the registry was performed based on clinical factors and follow-up protocols, not solely PSA triggers, which they describe as enabling detection of radiographic change during PSA suppression. Reported limitations included the retrospective nature of the analysis with potential selection bias, short follow-up, and the authors’ call for prospective studies to more definitively assess the impact of serial advanced imaging on outcomes. The report’s closing message balances the authors’ surveillance-focused interpretation with the constraints they outline for generalizing these registry findings.

Key Takeaways:

• The authors reported PSA-zero rDP in 257 of 2141 imaged patients (12%), with lesions most often in bone and smaller proportions in nodal, visceral, and local sites as detailed in their distribution.
• Reported cohort features included high-grade disease at diagnosis, frequent castration-resistant status by the time of PSA-zero rDP, and limited biopsy confirmation (18 cases) supplemented by longitudinal imaging and treatment-response correlation.
• In univariate analysis, visceral involvement was the only factor the authors reported as significantly associated with worse OS (HR 8.8). They also discussed periodic advanced imaging irrespective of PSA value in the context of detecting radiographic change during PSA suppression, while noting the study’s retrospective design, potential selection bias, and short follow-up.