Radioligand Therapy Hormone Combinations and the ENZA-p Trial.

The androgen axis is an important growth driver in prostate cancer, with androgen blockade a cornerstone treatment for metastatic prostate cancer. Prostate-specific membrane antigen (PSMA) radioligand therapy is also playing an increasingly important role in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Both clinical and preclinical research have shown a strong relationship between the androgen and PSMA receptors in metastatic prostate cancer. Gaining a full understanding of the drivers of the inter-receptor interactions and consequent clinical impact is important in order to maximally exploit the relationship for better treatment outcomes. The ENZA-p trial is a randomized phase 2 trial of enzalutamide versus enzalutamide ± lutetium-177 ([177Lu])Lu-PSMA-617 in mCRPC, which demonstrated a significant improvement in overall survival and quality of life with this combination compared to enzalutamide monotherapy [1,2]. Transational endpoints of the trial embedded at inception were designed to better understand the relationship between androgen blockade and PSMA expression and its potential impact on clinical outcomes. This mini-review will discuss the genetics of PSMA receptor expression, the preclinical evidence for androgen/PSMA receptor interaction, and the frequency, magnitude, and clinical significance of PSMA expression change in response to androgen blockade with enzalutamide.