In the last decade, prostate-specific membrane antigen (PSMA) targeted PET/CT has emerged as a novel imaging modality that allows for more accurate detection of tumour lesions compared to conventional imaging (CT and bone scintigraphy). PSMA PET/CT can also provide a multitude of quantitative parameters that may reflect tumour burden and aggressiveness of the disease. Beyond prostate cancer, PSMA expression has been observed in the neovasculature of various other malignancies, raising interest in PSMA-targeted imaging and therapy in non-prostate tumours. The aim of this thesis was to evaluate the clinical value of PSMA PET/CT across different stages of prostate cancer, to assess its prognostic potential, and to explore the feasibility of PSMA-targeted approaches in non-prostate cancers.

In high-risk patients referred for radiotherapy, PSMA PET/CT resulted in substantial stage migration compared with conventional imaging, particularly in patients with multiple high-risk features, underscoring its value for accurate staging and potential treatment adaptation. In patients with synchronous metastatic hormone-sensitive and metastatic castration-resistant prostate cancer, PSMA-derived total tumour volume (PSMA-TV) consistently emerged as a strong imaging-based predictor of overall survival, outperforming conventional clinical parameters and prostate-specific antigen (PSA) levels. These findings support the integration of PSMA-TV into prognostic models and future treatment stratification. Furthermore, PSMA PET/CT-based treatment response assessment in metastatic castration-resistant disease proved superior to PSA response, revealing clinically relevant discordance and enabling earlier identification of ineffective therapy.

Beyond prostate cancer, PSMA-targeted strategies were investigated in sarcomas and gastrointestinal malignancies. While PSMA expression and tracer uptake were observed in subsets of these tumours, uptake patterns were highly heterogeneous both within and between patients. Prospective feasibility studies demonstrated that this heterogeneity currently limits the applicability of PSMA-targeted radioligand therapy in these populations, and that PSMA PET/CT offers no diagnostic advantage over [¹⁸F]FDG PET/CT in gastrointestinal cancers.