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Radioligand Therapy Hormone Combinations and the ENZA-p Trial
1Theranostics and Nuclear medicine, St Vincent's Hospital, Sydney, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia; Garvan Institute of Medical Research.
Abstract:
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.
Insights
Combining androgen blockade with PSMA radioligand therapy improves survival in metastatic prostate cancer. Understanding the androgen and PSMA receptor relationship is key to optimizing treatments for prostate cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Radiopharmaceutical Therapy
Background:
- The androgen axis is a critical driver in prostate cancer progression.
- Androgen blockade is a standard treatment for metastatic prostate cancer.
- Prostate-specific membrane antigen (PSMA) radioligand therapy is emerging for metastatic castration-resistant prostate cancer (mCRPC).
Purpose of the Study:
- To investigate the relationship between androgen receptor signaling and PSMA expression in mCRPC.
- To understand the clinical impact of androgen blockade on PSMA expression.
- To explore the potential of combining androgen blockade with PSMA-targeted therapies.
Main Methods:
- Review of preclinical data on androgen/PSMA receptor interactions.
- Analysis of translational data from the ENZA-p randomized phase 2 trial.
- Discussion of PSMA receptor genetics and expression changes in response to enzalutamide.
Main Results:
- Preclinical studies show a strong link between androgen and PSMA receptors in prostate cancer.
- The ENZA-p trial demonstrated improved survival and quality of life with enzalutamide plus [177Lu]Lu-PSMA-617 compared to enzalutamide alone.
- Androgen blockade influences PSMA expression, with implications for treatment efficacy.
Conclusions:
- The combination of androgen blockade and PSMA radioligand therapy offers significant benefits for mCRPC patients.
- Understanding the interplay between androgen and PSMA receptors is crucial for refining treatment strategies.
- Further research into PSMA expression dynamics under androgen deprivation is warranted.
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