Unlike traditional chemotherapy, radioligand therapy's toxicity may be inversely correlated with tumor volume. In low-burden disease, fewer cancer cells act as a 'sink' for the drug, potentially leading to higher radiation exposure and side effects in healthy, PSMA-expressing tissues like salivary glands.

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.

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 PSMA PET scans are more sensitive, they create a clinical dilemma because pivotal trials defining treatment efficacy were based on conventional imaging (CT/bone scans). This forces oncologists to either re-image patients with older technology to match trial criteria or make treatment decisions based on PET data that lacks a clear evidence-based framework for response assessment.

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.

The primary benefit of combining an androgen receptor inhibitor with lutetium-PSMA is a complementary, additive effect. The drugs target different cancer cell populations: the AR-inhibitor targets low-PSMA disease, while lutetium targets high-PSMA disease. This is more significant than any minor synergistic effect from PSMA upregulation.

Blocking the androgen receptor with enzalutamide can increase PSMA expression. In patients on enzalutamide alone, this predicts a poor outcome. However, for patients receiving combination therapy, this increased expression creates a better target for lutetium-PSMA, effectively mitigating the negative prognosis and improving survival.

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.