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.

While many clinical trials haven't officially counted PSMA-PET only disease as metastatic, clinicians have latitude. If a PSMA-PET scan reveals aggressive, multifocal disease, especially with a rapidly rising PSA, it should be treated as incurable metastatic cancer, justifying the initiation of systemic therapy.

For on-treatment monitoring, a fixed absolute tumor volume increase (e.g., 50mL) on PSMA-PET is a superior marker of progression than a percentage-based change. Percentage metrics unfairly disadvantage patients with high-volume baseline disease, where a small relative change can represent massive, clinically significant growth.

While the landmark EMBARK study enrolled patients with no metastatic disease on conventional imaging (CT/bone scan), a similar population scanned with advanced PSMA PET imaging showed 84% had M1 disease. This suggests that treatments for this population are effective against micrometastases not visible on older scans, blurring the lines between localized and metastatic states.

The patient population in pivotal trials like EMBARK, defined as non-metastatic by conventional imaging, is being re-evaluated. A UCLA study showed that over 80% of a similar patient group would have been positive on a PSMA PET scan, suggesting the "M0" classification is largely an artifact of older imaging technology and that these patients likely have micrometastatic disease.

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.

NCCN now recommends PSMA PET as a potential replacement for traditional CT, MRI, and bone scans for initial staging of higher-risk prostate cancer and detecting recurrence. This shift is based on PSMA PET's superior sensitivity and specificity for finding micrometastatic disease, positioning it as a more effective frontline tool.

Landmark clinical trials (CONDOR, SPOTlight) demonstrate that PSMA PET imaging effectively identifies recurrent prostate cancer in a high percentage of patients even with very low PSA levels. This challenges the traditional paradigm of waiting for higher PSA thresholds before imaging, enabling earlier and more precise intervention.