Prostate cancer represents one of the most prevalent malignancies among men. Despite the growing array of therapeutic options available across the various stages of disease, effective disease control remains a significant clinical challenge, largely due to the intrinsic heterogeneity of the malignancy. Optimization of clinical outcomes in patients with prostate cancer requires not only precise diagnostic assessment and accurate localization of disease sites, but also reliable risk stratification strategies capable of guiding personalized therapeutic interventions.1

Conventional imaging modalities, particularly computed tomography (CT) and bone scintigraphy (BS), have historically constituted the cornerstone of both initial staging and biochemical recurrence. However, in recent years, prostate-specific membrane antigen positron emission tomography (PSMA-PET) has emerged as a superior imaging technique,2 offering enhanced diagnostic accuracy and more reliable detection of disease (Table 1).

Conventional imaging, indeed, frequently underestimates disease burden3,4 and is associated with a higher incidence of indeterminate or false-positive findings, particularly in the context of bone scans.2 This diagnostic limitation is especially critical in the current therapeutic landscape, where metastasis-directed therapies are demonstrating encouraging outcomes in terms of disease control and progression-free survival.5

Prostate-specific membrane antigen (PSMA), first identified in 1987,6 is a type II transmembrane glycoprotein encoded by the FOLH1 (folate hydrolase 1) gene, also known as glutamate carboxypeptidase II (GCPII). PSMA is physiologically expressed at low levels in various tissues, including the salivary glands, kidneys, and small intestine, but it is highly expressed in the epithelial tissue of the prostate.7 Crucially, PSMA is significantly overexpressed in the vast majority (85-100%) of primary PCa lesions, as well as in lymph node and bone metastases. Its expression levels often correlate positively with tumor aggressiveness, higher Gleason scores, advanced stage, and the development of metastatic castration-resistant prostate cancer (mCRPC).8 Beyond serving as an imaging biomarker, PSMA possesses biological functions implicated in PCa progression, including roles in folate metabolism, cell signaling, extracellular matrix degradation, neoangiogenesis (supported by coexpression with VEGF), and tumor invasiveness. This high and relatively specific overexpression on PCa cells, coupled with its presence on the cell surface and internalization upon ligand binding, makes PSMA an ideal target for molecular imaging and therapy. This dual utility underpins the concept of “theranostics,” where the same molecular target is used for both diagnostic imaging (e.g., PSMA-PET) and targeted radionuclide therapy (e.g., PSMA-targeted radioligand therapy, RLT).9

Several PSMA-targeting PET tracers have been developed and are used clinically. The most extensively used for diagnostic purpose are [68Ga]Ga-PSMA-11, [18F]F-DCFPyL (Pylarify) and [18F]F-PSMA-1007. Fluorine-18 offers logistical advantages over gallium-68, including a longer half-life (∼110 minutes vs. ∼68 minutes) allowing for centralized production and distribution, and potentially higher spatial resolution due to its lower positron energy.10

The rapid development and clinical adoption of multiple PSMA-PET tracers ([68Ga]Ga-PSMA-11, [18F]F-DCFPyL, [18F]F-PSMA-1007) underscores the significant clinical need for improved PCa imaging. However, this also introduces complexities. While all these tracers target PSMA and are widely used in clinical practice, they showed slightly different pharmacokinetic and biodistribution profiles.10 For instance, [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL show significant urinary excretion, which can sometimes obscure lesions near the bladder, whereas [18F]F-PSMA-1007 has predominantly hepatobiliary excretion but may exhibit higher nonspecific uptake in bone potentially leading to false positives if not interpreted cautiously.11

The enhanced diagnostic capabilities of PSMA-PET have significant implications for the planning and delivery of radiotherapy (RT), a cornerstone treatment for localized and recurrent PCa. By providing more accurate information on disease extent and location, PSMA-PET facilitates more precise RT strategies, potentially improving efficacy while minimizing toxicity.12

PSMA-PET/CT has demonstrated superior accuracy over conventional imaging (CI) for initial staging of high-risk prostate cancer, as shown in the proPSMA trial.2 It offers higher sensitivity and specificity, fewer equivocal findings, and leads to more frequent changes in management. These advantages have led to its inclusion in major clinical guidelines (NCCN,13 EAU1,14) for staging intermediate- to high-risk patients.

However, its higher sensitivity results in stage migration, complicating the interpretation of historical data and necessitating updates to existing risk models and treatment strategies.15

In radiotherapy planning, PSMA-PET, often combined with mpMRI, enhances identification of dominant intraprostatic lesions (IPLs) for focal dose escalation16 and focal boost stereotactic body radiotherapy (SBRT).17,18

While PSMA-PET may improve patient selection and enable more precise radiotherapy, its ultimate impact on survival and long-term outcomes remains to be confirmed through ongoing prospective trials.