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.
PSMA expression is not a static marker but a dynamic stress response. Cancer cells increase PSMA expression when stressed by treatments like androgen receptor blockade or radiation. This model frames PSMA as a survival mechanism for the cell, explaining its association with more aggressive disease.
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.
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.
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.
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.