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New insights in the paradigm of upregulation of tumoral PSMA expression by androgen receptor blockade: Enzalutamide induces PSMA upregulation in castration-resistant prostate cancer even in patients having previously progressed on enzalutamide

Abstract

Purpose

There is preliminary evidence for prostate-specific membrane antigen (PSMA) upregulation effects of androgen receptor blockade in prostate cancer. In an attempt to find the best condition for PSMA radioligand therapy in metastatic castration-resistant prostate cancer (mCRPC) patients, we evaluated the effect of oral enzalutamide in patients, predominantly having previously progressed on enzalutamide treatment.

Methods

Ten patients with advanced mCRPC scheduled for PSMA radioligand therapy were examined with 68Ga-PSMA-11 PET/CT before and after a mean of 11.8 days of enzalutamide 160 mg/day. Imaging results were compared using total PSMA tumor burden quantification. We assessed whole-body total lesion PSMA (TLP), defined as SUVmean × tumor volume and calculated TLP-to-liver ratio (TLP-LR), TLP-to-parotid gland ratio (TLP-PR), and TLP-to-kidney ratio (TLP-KR).

Results

The mean (median) increase of TLP-LR, TLP-PR, and TLP-KR in the cohort was 49.3% (38.8%), 45.1% (23.5%), and 54.9% (37.6%), respectively. These increases were statistically significant (p = 0.002, p = 0.014, and p = 0.014), while PSA values did not change significantly (p = 0.846). Seven of the 10 patients had previously undergone enzalutamide treatment with eventual progression, formally classified as treatment failure. No side effects were noted in the short term.

Conclusions

Our results suggest that enzalutamide could be considered as a PSMA radioligand treatment enhancing primer medication, which may increase PSMA expression by a dimension of 50% in mCRPC. The effect was shown even in patients having previously failed enzalutamide treatment for arrest of progression in the mCRPC setting. Our observation deserves evaluation in a prospective setting.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ADT:

androgen deprivation therapy

AR:

androgen receptor

mCRPC:

metastatic castration-resistant prostate cancer

MIP:

maximum intensity projection

OSEM:

ordered subset expectation maximization

PET:

positron emission tomography

PSA:

prostate-specific antigen

PSMA:

prostate-specific membrane antigen

RLT:

radioligand therapy

SUV:

standardized uptake volume

SUVmax :

maximum standardized uptake volume

SUVmean :

mean standardized uptake volume

mSUV70 :

mean standardized uptake volume within a 70% isocontour of SUVmax

TLP:

total lesion PSMA

TLP-KR:

total lesion PSMA-to-kidney ratio

TLP-LR:

total lesion PSMA-to-liver ratio

TLP-PR:

total lesion PSMA-to-parotid gland ratio

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Author information

Florian Rosar, Sebastian Dewes, Carsten Ohlmann, and Samer Ezziddin contributed to the design of the study. Martin Ries and Fadi Khreish performed data acquisition with support from Stephan Maus and Hendrik Bohnenberger. Andrea Schaefer-Schuler reconstructed the images. Florian Rosar, Sebastian Dewes, and Johannes Linxweiler analyzed the data. Florian Rosar and Sebastian Dewes drafted this paper, which was revised by Mark Bartholomä and Samer Ezziddin. All authors approved the final manuscript.

Correspondence to Samer Ezziddin.

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The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

All procedures performed in the patients described herein were in accordance with the ethical standards of the Institutional and/or National Research Ethics Committees and with the 1964 Helsinki Declaration and its later amendments, or with comparable ethical standards. This report does not include any animal studies. Written informed consent was obtained from all study participants.

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All patients have given written consent to publication.

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Rosar, F., Dewes, S., Ries, M. et al. New insights in the paradigm of upregulation of tumoral PSMA expression by androgen receptor blockade: Enzalutamide induces PSMA upregulation in castration-resistant prostate cancer even in patients having previously progressed on enzalutamide. Eur J Nucl Med Mol Imaging 47, 687–694 (2020). https://doi.org/10.1007/s00259-019-04674-0

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Keywords

  • Metastatic castration-resistant prostate cancer
  • PSMA radioligand therapy
  • Androgen deprivation therapy
  • Enzalutamide
  • Upregulation of PSMA expression