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. 2025 Jan 2;8(1):e2452971.
doi: 10.1001/jamanetworkopen.2024.52971.

PSMA-PET/CT Findings in Patients With High-Risk Biochemically Recurrent Prostate Cancer With No Metastatic Disease by Conventional Imaging

Adrien Holzgreve  1   2 , Wesley R Armstrong  1   3 , Kevyn J Clark  1 , Matthias R Benz  1   4   5   6 , Clayton P Smith  7 , Loïc Djaileb  1 , Andrei Gafita  1 , Pan Thin  1 , Nicholas G Nickols  6   7 , Amar U Kishan  6   7 , Matthew B Rettig  6   8   9 , Robert E Reiter  6   9 , Johannes Czernin  1   6 , Jeremie Calais  1   6
Affiliations

PSMA-PET/CT Findings in Patients With High-Risk Biochemically Recurrent Prostate Cancer With No Metastatic Disease by Conventional Imaging

Adrien Holzgreve et al. JAMA Netw Open. .

Abstract

Importance: The phase 3 randomized EMBARK trial evaluated enzalutamide with or without leuprolide in high-risk nonmetastatic hormone-sensitive prostate cancer. Eligibility relied on conventional imaging, which underdetects metastatic disease compared with prostate-specific membrane antigen-positron emission tomography (PSMA-PET).

Objective: To describe the staging information obtained by PSMA-PET/computed tomography (PSMA-PET/CT) in a patient cohort eligible for the EMBARK trial.

Design, setting, and participants: This post hoc, retrospective cross-sectional study included 182 patients from 4 prospective studies conducted from September 15, 2016, to September 27, 2021. All patients had recurrent prostate cancer after radical prostatectomy (RP), definitive radiotherapy (dRT), or salvage radiotherapy (SRT). Analysis was performed from January 2023 to July 2024.

Exposures: Patients included had increasing prostate-specific antigen (PSA) levels greater than 1.0 ng/mL (after RP and SRT) or 2.0 ng/mL above the nadir value (after dRT), PSA doubling time of 9 months or less, and a serum testosterone level of 150 ng/dL or greater. Exclusion criteria were distant metastatic disease on radiographic imaging and prior hormonal or systemic therapy.

Main outcomes and measures: Staging information obtained by PSMA-PET/CT in patients with nonmetastatic disease according to conventional imaging.

Results: From 2002 patients screened, 182 (median age at PET/CT scan, 69 years [IQR, 64-73 years]) were included. Median prescan PSA levels were 2.4 ng/mL (IQR, 1.4-4.8 ng/mL) after RP (n = 91), 6.9 ng/mL (IQR, 3.5-18.5 ng/mL) after dRT (n = 39), 2.6 ng/mL (IQR, 1.6-5.2 ng/mL) after RP and SRT (n = 52), and 2.8 ng/mL (IQR, 1.7-6.6 ng/mL) overall (n = 182). Results of PSMA-PET were positive in 80% of patients (73 of 91) after RP, 92% of patients (36 of 39) after dRT, 85% of patients (44 of 52) after RP and SRT, and 84% of patients (153 of 182) overall. PSMA-PET detected any distant metastatic disease (miTxNxM1) in 34% of patients (31 of 91) after RP, 56% of patients (22 of 39) after dRT, 60% of patients (31 of 52) after RP and SRT, and 46% of patients (84 of 182) overall. Polymetastatic disease (≥5 lesions) was found in 19% of patients (17 of 91) after RP, 36% of patients (14 of 39) after dRT, 23% of patients (12 of 52) after RP and SRT, and 24% of patients (43 of 182) overall.

Conclusions and relevance: In a cohort of patients with high-risk hormone-sensitive prostate cancer without evidence of metastatic disease by conventional imaging, PSMA-PET results were positive in 84% of patients, detected M1 disease stage in 46% of patients, and found polymetastatic disease (≥5 lesions) in 24% of patients, suggesting that patients' high-risk nonmetastatic hormone-sensitive prostate cancers are understaged by conventional imaging. The results challenge the interpretation of previous studies, such as the EMBARK trial, and support the evolving role of PSMA-PET for patient selection in clinical and trial interventions in prostate cancer. Further studies are needed to assess its independent prognostic value and use for treatment guidance.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Holzgreve reported receiving personal fees from ABX advanced biochemical compounds outside the submitted work. Dr Nickols reported receiving grants from Lantheus and Janssen to institution outside the submitted work. Dr Kishan reported receiving personal fees from Varian, Novartis, and Boston Scientific; and grants from Lantheus and Janssen outside the submitted work. Dr Rettig reported receiving personal fees from Bayer, Johnson & Johnson, AVEO, Amgen, Novartis, and INmune Bio; and grants from Bayer, Johnson & Johnson, Amgen, Merck, Lantheus, Novartis, and INmune Bio outside the submitted work; in addition, Dr Rettig had a patent issued for NA Inhibitors of the N-teminal Domain of the Androgen Receptor. Dr Czernin reported receiving grants from the Prostate Cancer Foundation during the conduct of the study; being founder of Sofie Biosciences, founder of Trethera Corporation; and serving on the medical advisory board for Aktis Oncology outside the submitted work. Dr Calais reported receiving personal fees from Amgen, Astellas, Bayer, Blue Earth Diagnostics, Curium Pharma, Coretag, DS Pharma, Fibrogen, GE Healthcare, Isoray, IBA Radiopharma, Janssen Pharmaceuticals, Lantheus, Progenics, EXINI, Monrol, Novartis, Advanced Accelerator Applications, Nucleus Radiopharma, Pfizer, POINT Biopharma, Radiomedix, Radiopharm Theranostics, Siemens, SOFIE, and Telix; and grants from Progenics, Novartis, POINT Biopharma, and Lantheus outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow Diagram
ADT indicates androgen deprivation therapy; dRT, definitive radiotherapy; DT, doubling time; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; RP, radical prostatectomy; and SRT, salvage radiotherapy. To convert PSA to micrograms per liter, multiply by 1.0.
Figure 2.
Figure 2.. Disease Distribution by Primary Treatment
dRT indicates definitive radiotherapy; RP, radical prostatectomy; and SRT, salvage radiotherapy.
See this image and copyright information in PMC

Comment in

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