Does Enzalutamide Related PSMA Upregulation Affect Outcomes of Lutetium-177 PSMA Radioligand Therapy?

Background: Enzalutamide is an antiandrogen drug used prior to lutetium-177 prostate specific membrane antigen (Lu-PSMA) radioligand therapy and has shown promising results for upregulating the PSMA expression on prostate cancer cells. In this study, we aim to compare prostate specific antigen (PSA) level changes in prostate cancer patients who received enzalutamide to those who did not. Methods: Prostate cancer patients who underwent Lu-PSMA between 2021 and 2023 were retrospectively included. Patients were grouped based on prior enzalutamide therapy: those who received enzalutamide (EZ+) for at least 14 days and those who did not (EZ−). PSA changes and F-18 DCFPyL SUV (Standardized Uptake Values) were compared. Results: Thirty-seven patients were included, 18 EZ+ and 19 EZ−. The median age, Gleason score, and prior chemo/hormonal therapies were similar for EZ+ and EZ−, except for radium-223. Eleven patients (61%) in EZ+ and 13 patients (68%) in EZ− showed a decrease in PSA after the first cycle ( p = 0.64). Four patients (22%) in EZ+ and seven patients (37%) in EZ− had more than 50% decrease in PSA after the first cycle ( p = 0.33). The average percent decline at the end of the treatment was 23.3% in EZ+ and 50.4% in EZ− ( p = 0.4). There was no difference in terms of lesion with highest SUVmax, mean SUV, total tumor volume or activity on pre-therapy PSMA imaging. Conclusion: Enzalutamide treatment prior to Lu-PSMA does not improve patient outcomes when applied remotely. Larger studies evaluating the combination therapies and the timing of enzalutamide are needed to assess its correlation with Lu-PSMA outcomes.