Objective: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with varying survival outcomes. This study investigated whether baseline PSMA PET/CT parameters are associated with survival and treatment response. Methods: Sixty mCRPC patients underwent [¹⁸F]PSMA-1007 PET/CT before treatment with androgen receptor-targeted agents (ARTAs) or chemotherapy. Intensity-based parameters, volumetric parameters, metastatic sites and DmaxVox (distance between the two outermost voxels) from baseline PSMA PET/CT were collected, as well as age, Gleason score and laboratory parameters. Cox regression analysis evaluated their prognostic value for overall survival (OS). Additionally, a preliminary lesion-level analysis was done (n = 241 lesions) with lesion location and twelve radiomic features selected from previous literature. Logistic regression evaluated their association with PSMA PET/CT-based lesion progression after 3–4 months of treatment. Results: Total tumour volume (PSMA-TV) (HR = 1.41 per doubling [1.17–1.70]), total lesion uptake (TL-PSMA) (HR = 1.40 per doubling [1.16–1.69]) and DmaxVox (HR = 1.31 per 10 cm increase [1.07–1.62]) were prognostic for OS, each independent of baseline PSA level (HR = 0.82 per doubling [0.68–0.98]), haemoglobin level (HR = 0.68 per mmol/L increase [0.49–0.95]) and line of treatment. On lesion-level, location (prostate vs bone OR = 0.23 [0.06–0.83]) and SUV_mean (OR = 1.72 per doubling [1.08–2.75]) were independent prognostic markers for lesion progression, morphological and texture-based radiomic features were not. Conclusion: Baseline PSMA PET/CT scans have prognostic value in mCRPC patients and can potentially aid in treatment decision-making. DmaxVox can serve as a simpler alternative to PSMA-TV when automated segmentation software is not available. When combined with PSMA-TV, lower PSA levels indicated worse OS, which may be a marker of tumour dedifferentiation. Further research is needed to validate these models in larger patient cohorts. Key Points: Question mCRPC is a highly heterogeneous disease, requiring good prognostic markers. Findings PSMA-TV was the best independent prognostic marker for OS; maximum distance between lesions (DmaxVox) can be used as a simpler alternative. Clinical relevance Baseline PSMA PET/CT parameters representing tumour burden were independently associated with OS in mCRPC patients, providing prognostic insights for clinical decision-making. Although PSMA-TV was the best prognostic marker, DmaxVox can serve as an easier to obtain alternative.

In metastatic castration-resistant prostate cancer (mCRPC), using serum prostate-specific antigen (PSA) levels to evaluate treatment response is not always accurate. This study aimed to assess the efficacy of PSMA PET/CT at specific time points for evaluating treatment response and predicting survival in mCRPC patients, compared to PSA. Sixty mCRPC patients underwent [¹⁸F]PSMA-1007 PET/CT at baseline and for treatment response evaluation of either androgen receptor-targeted agents (after 3 months) or chemotherapy (after completion), and were retrospectively analysed. Visual assessment categorised overall response and response of the worst responding lesion as partial response, stable disease, or progressive disease, using the EAU/EANM criteria. Additionally, percentage changes in SUV_max, total tumour volume and total lesion uptake (tumour volume * SUV_mean) were calculated. PSA response was defined according to the PCWG3 criteria. Cox regression analysis identified predictors of overall survival. PSMA PET/CT and PSA response were discordant in 47 % of patients, and PSMA PET/CT response was worse in 89 % of these cases. Overall response on PSMA PET/CT independently predicted overall survival (progression versus non-progression: HR = 4.05, p < 0.001), outperforming PSA response (progression versus non-progression: HR = 2.53, p = 0.010) and other PSMA PET/CT parameters. Among patients with a PSA decline of > 50 %, 31 % showed progressive disease on PSMA PET/CT, correlating with higher mortality risk (progression versus non-progression: HR = 4.38, p = 0.008). No flare in PSMA uptake was observed in this cohort. PSMA PET/CT for assessing treatment response at predefined time points was superior to PSA-based response for predicting overall survival in mCRPC patients treated with androgen receptor-targeted agents and chemotherapy. PSMA PET/CT showed the ability to detect disease progression earlier than PSA levels, which can affect treatment decisions and has the potential to improve patient outcomes. We recommend further research to validate these findings in larger patient cohorts, to extend the number of treatments, and to evaluate cost-effectiveness and impact on patient outcomes.

Current imaging modalities frequently misjudge disease stage in colorectal, gastric and pancreatic cancer. As treatment decisions are dependent on disease stage, incorrect staging has serious consequences. Previous preclinical research and case reports indicate that prostate-specific membrane antigen (PSMA)-targeted PET/CT imaging might provide a solution to some of these challenges. This prospective clinical study aims to assess the feasibility of [¹⁸F]DCFPyL PET/CT imaging to target and visualize primary colon, gastric and pancreatic cancer. In this prospective clinical trial, patients with colon, gastric and pancreatic cancer were included and underwent both [¹⁸F]DCFPyL and [¹⁸F]FDG PET/CT scans prior to surgical resection or (for gastric cancer) neoadjuvant therapy. Semiquantitative analysis of immunohistochemical PSMA staining was performed on the surgical resection specimens, and the results were correlated to imaging parameters. The results of this study demonstrate detection of the primary tumor by [¹⁸F]DCFPyL PET/CT in 7 out of 10 patients with colon, gastric and pancreatic cancer, with a mean tumor-to-blood pool ratio (TBR) of 3.3 and mean SUV_max of 3.6. However, due to the high surrounding uptake, visual distinction of these tumors was difficult, and the SUV_max and TBR on [¹⁸F]FDG PET/CT were significantly higher than on [¹⁸F]DCFPyL PET/CT. In addition, no correlation between PSMA expression in the resection specimen and SUV_max on [¹⁸F]DCFPyL PET/CT was found. In conclusion, the detection of several gastrointestinal cancers using [¹⁸F]DCFPyL PET/CT is feasible. However, low tumor expression and high uptake physiologically in organs/background hamper the clear distinction of the tumor. As a result, [¹⁸F]FDG PET/CT was superior in detecting colon, gastric and pancreatic cancers.

Bone and soft tissue sarcomas are a group of rare malignant tumours with major histological and anatomical varieties. In a metastatic setting, sarcomas have a poor prognosis due to limited response rates to chemotherapy. Radioligand therapy targeting prostate-specific membrane antigen (PSMA) may offer a new perspective. PSMA is a type II transmembrane glycoprotein which is present in all prostatic tissue and overexpressed in prostate cancer. Despite the name, PSMA is not prostate-specific. PSMA expression is also found in a multitude of non-prostatic diseases including a subgroup of sarcomas, mostly in its neovascular endothelial cells. On PET/CT imaging, multiple sarcomas have also shown intense PSMA-tracer accumulation. PSMA expression and PSMA-tracer uptake seem to be highest in patients with aggressive and advanced sarcomas, who are also in highest need of new therapeutic options. Although these results provide a good rationale for the future use of PSMA-targeted radioligand therapy in a selection of sarcoma patients, more research is needed to gain insight into optimal patient selection methods, PSMA-targeting antibodies and tracers, administered doses of radioligand therapy, and their efficacy and tolerability. In this review, mRNA expression of the FOLH1 gene which encodes PSMA, PSMA immunohistochemistry, PSMA-targeted imaging and PSMA-targeted therapy in sarcomas will be discussed.

In high-risk prostate cancer, the proPSMA trial showed upstaging with prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) in 14% of patients. We hypothesised that the probability of stage migration in a patient population referred for curative-intent radiotherapy would be higher. Here we report stage migration results according to PSMA PET/CT in the first year of inclusion in the phase 2/3 THUNDER trial (NCT06282588). Patients with high-risk prostate cancer screened between December 2023 and December 2024 in the THUNDER trial with both conventional imaging (CT, bone scintigraphy) and PSMA PET/CT within 16 weeks before screening were included (n = 142). Stage migration according to the TNM classification versus the molecular imaging (miTNM) classification (PROMISE v2 criteria) was assessed using descriptive statistics. PSMA PET/CT led to stage migration in 43 patients, of whom 42 (30%) were upstaged and one (1%) was downstaged. Upstaging to miN1-2 disease occurred in 32 patients (23%), and to miM1a-c disease in 19 patients (13%). The probability of upstaging increased with the number of high-risk features. In the subgroup meeting the STAMPEDE M0 high-risk criteria (n = 73), PSMA PET/CT upstaged 27 patients (37%), including upstaging to miM1a-c disease in 14 (19%). Limitations include the absence of central review of the imaging procedures. One-third of patients with high-risk prostate cancer referred for curative-intent radiotherapy were upstaged on PSMA PET/CT. This finding supports the use of PSMA PET/CT for staging, especially in patients with multiple high-risk features, and suggests a need for treatment adaptations accordingly, which will be further investigated in the THUNDER trial.

Purpose: Prostate-specific membrane antigen (PSMA) expression has been observed in a subset of soft tissue sarcomas, mainly in the neovascular endothelial cells. This feasibility study aimed to evaluate PSMA expression and PSMA PET/CT imaging in metastatic soft tissue sarcoma, providing important insights for potential future exploration of PSMA-targeted radioligand therapy. Methods: This prospective single-center study included adult patients with metastatic soft tissue sarcoma, with measurable disease (lesion diameter > 1 cm), available biopsy/resection material, ECOG/WHO performance status of 0–2 and either no prior systemic treatment, progressive disease during/after treatment, or stable disease/partial response with the last dose > 8 weeks prior. Immunohistochemical PSMA staining was performed on previously obtained biopsy or resection material. In case of high PSMA expression, a [¹⁸F]-JK-PSMA-7 PET/CT scan evaluated tracer uptake, with adequate uptake defined as SUV_max > 8. Results: Of 25 included patients, 11 (44%) had high PSMA expression: 4/11 leiomyosarcomas, 3/4 dedifferentiated liposarcomas, 2/5 undifferentiated pleomorphic sarcomas, 1/2 myxofibrosarcomas and 1/1 malignant peripheral nerve sheath tumour. Five of 11 patients agreed to a [¹⁸F]-JK-PSMA-7 PET/CT, of which 3 had lesions that showed adequate tracer uptake (SUV_max 10.7–16.7). However, uptake across all metastatic lesions was highly heterogeneous (median SUV_max = 3.8; range 0.5–16.7), indicating that these patients are unlikely to benefit sufficiently from PSMA-targeted therapy. The study was therefore terminated prematurely. Conclusion: PSMA expression and PSMA tracer uptake in metastatic soft tissue sarcoma were highly heterogeneous. A deeper understanding of PSMA biology and improved patient selection criteria are essential for future application of PSMA-targeted radioligand therapy in this disease. Trial registration: : clinicaltrials.gov, NCT05522257. Registered 31-08-2022.