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 SUVmax > 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 (SUVmax 10.7–16.7). However, uptake across all metastatic lesions was highly heterogeneous (median SUVmax = 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.

Background
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.

Methods
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 SUVmax, total tumour volume and total lesion uptake (tumour volume * SUVmean) were calculated. PSA response was defined according to the PCWG3 criteria. Cox regression analysis identified predictors of overall survival.

Results
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.

Conclusions
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.