PSMA Discrepancies in Short-Course Enzalutamide for Prostate Cancer

This interview with Ravi Madan, MD, acting deputy chief of the Genitourinary Malignancies Branch at the Center for Cancer Research, National Cancer Institute, provides a fascinating look at the evolving landscape of prostate cancer treatment, specifically focusing on the utility and potential pitfalls of PSMA-PET imaging as a biomarker for treatment response.

At the 2026 Genitourinary Cancers Symposium in San Francisco, CA, Madan discusses a study investigating short-course (3-month) enzalutamide (Xtandi) monotherapy for patients with biochemically recurrent (BCR) prostate cancer.

The current research builds on a study conducted 13 years ago, prior to the landmark EMBARK trial and the widespread use of PSMA imaging. The original findings were striking: just 84 days of enzalutamide monotherapy (without androgen deprivation therapy, or ADT) resulted in PSA control for an average of over 300 days. In a population where the average PSA doubling time was 4.5 months, this 3-month "burst" of therapy provided nearly a year of disease stability.

The new iteration of this study maintains the 3-month enzalutamide window but introduces two modern variables:

1. Immunotherapy Correlation: Half of the 50-patient cohort receives an immuno-cytokine designed to enhance natural killer (NK) cells, which were previously observed to increase during enzalutamide treatment.
2. PSMA-TV Monitoring: Researchers are using PSMA scans at baseline and at the three-month mark to track Prostate Specific Membrane Antigen Tumor Volume (PSMA-TV).

Madan presents preliminary data from the first 13 patients, focusing on the correlation between PSA levels and PSMA tumor volume. While the median PSA response was a robust 98% decline, the imaging data told a far more confusing story.

The study found no correlation between changes in tumor volume on a PSMA scan and actual clinical benefit (defined as the duration of PSA control). Madan highlights a "dichotomy" through two specific cases:

• Patient A: PSA dropped to 0, and PSMA tumor volume also dropped to 0.
• Patient B: PSA dropped to 0, but PSMA tumor volume actually increased by 2–3%.

In a standard clinical setting in 2026, many clinicians might see Patient B’s increasing tumor volume as a sign of treatment failure and immediately "intensify" therapy by adding ADT or chemotherapy. However, Madan notes that Patient B actually experienced a 10–15% longer clinical benefit than the patient whose scan cleared completely.

The core message of the interview is a warning against over-reliance on PSMA imaging as an intermediate readout for treatment efficacy. Madan argues that:

• Imaging can be deceptive: An increase in PSMA tumor volume does not necessarily equate to a lack of clinical benefit or a need for more aggressive intervention.
• Risk of Over-treatment: Using PSMA-TV to "intensify or de-intensify" therapy prematurely could lead to unnecessary toxicity for patients who are actually responding well to a lighter touch.
• Hypothesis Testing: Even with a small sample size of 13, the high frequency of these discrepancies suggests that the current enthusiasm for PSMA as a definitive surrogate for response may be flawed.

Madan emphasizes that while we cannot "prove" a definitive new standard with 13 patients, these findings raise serious questions about how we interpret imaging in the BCR setting. He suggests the full data from the 50-patient trial will likely further challenge the assumption that PSMA-TV is a reliable indicator of long-term success.