Even within a single patient, tumor lesions exhibit significant heterogeneity in PSMA expression, with some being "hot" and others "not." This ensures that a standard dose of radioligand therapy will not be delivered uniformly across all disease sites, creating an inherent mechanism for resistance and incomplete response.

The LUNAR trial's positive outcome was unexpected. Patients received SBRT for all PET-visible lesions, meaning the added Lutetium-PSMA was targeting disease that couldn't be seen. This implies the radioligand can effectively bind to and treat microscopic cancer cells, challenging the notion it only works on clearly imaged tumors.

PSMA-PET imaging at baseline can identify who benefits from adding lutetium-PSMA. In the ENZA-P trial, patients with high-volume disease saw a significant survival benefit from the combination. Conversely, those with low-volume disease derived no benefit, suggesting imaging can be used for patient selection.

Unlike traditional CT scans, PSMA-PET scans visualize the biological heterogeneity of prostate cancer, showing which lesions are target-rich and which are not. While insightful, this "shines a flashlight" on the problem, creating new clinical challenges, such as how to manage a patient whose disease largely disappears except for two resistant lesions.

Clinicians are viewing PSMA PET scans as a quantitative tool, not just a binary test. Patients with very "bright" scans (high SUV, e.g., >10) may be the ideal candidates for Lutetium-PSMA radioligand therapy, suggesting avidity predicts the magnitude of benefit.

Even if most of a patient's cancer is PSMA-avid, the presence of small liver lesions that are *not* PSMA-avid is a major red flag. This can indicate a more aggressive, PSMA-negative biology that won't respond to PSMA-targeted therapy and may instead require alternative treatments like chemotherapy, complicating patient selection.

An expert expressed disappointment with Lutetium's efficacy in the metastatic hormone-sensitive setting, suggesting its benefit is lower than expected. A potential flaw in trial design was starting hormonal agents first, which can lower PSMA expression, thereby potentially reducing the radioligand's target and diminishing its therapeutic effect.

When assessing PSMA expression on PET scans, using the average uptake across all tumors (SUVmean) provides a more stable and holistic measure of disease burden. The alternative, SUVmax, which measures the single brightest point, is analogous to a single, potentially unrepresentative biopsy of a heterogeneous cancer.

A critical limitation of PSMA PET is its inability to detect tumors that do not express the PSMA protein. In these cases, a patient may show extensive disease on a conventional bone scan that is entirely invisible on a PSMA PET scan, highlighting the risk of relying on a single imaging modality.