The impact of short-term non-steroidal androgen antagonist therapy on PSMA expression and tumor cellularity studied with dynamic [68Ga]Ga-PSMA-11 PET/MR in hormone-sensitive prostate cancer patients, a preliminary longitudinal prospective study.

Abstract

Background: Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancers (PCa) and is targeted in both diagnostic and therapeutic applications. Preclinical studies suggest that short-term androgen blockade may upregulate PSMA expression, potentially enhancing lesion detectability with [⁶⁸Ga]Ga-PSMA-11 positron emission computed tomography (PET) and the therapeutic efficacy of PSMA-targeted radioligands. However, clinical data remains limited and inconsistent. The aim of this study was to assess the impact of short-term non-steroidal androgen blockade therapy (NSAA) on lesion PSMA expression and cellularity using dynamic [⁶⁸Ga]Ga-PSMA-11PET and diffusion-weighted magnetic resonance imaging (MR) for simultaneous estimation of binding potential (BP_ND) and apparent diffusion coefficient (ADC) in hormone-naïve patients with high-risk PCa without bone metastases.

Results: A significant serum prostate specific antigen (PSA) decline was observed in 7/8 patients (median PSA fold change - 88.3% at day 28), indicating positive biochemical response since the NSAA start. Among the observed eight lesions with detectable [⁶⁸Ga]Ga-PSMA-11 uptake, seven exhibited a non-linear and non-monotonic longitudinal trajectory of BP_ND, characterized by a rebound during the mid-treatment phase. In contrast, ADC values progressively increased from baseline for all lesions, suggesting reduced tumour cellularity as treatment progresses. Static SUV measurements poorly reflected these dynamic changes in PSMA expression, indicating limited sensitivity.

Conclusion: Short-term NSAA induces transient PSMA upregulation in hormone-sensitive PCa lesions despite declining cellularity, which may support its cointegration to PSMA-targeted therapies for this population.