Heterogeneous Flare in Prostate-specific Membrane Antigen Positron Emission Tomography Tracer Uptake with Initiation of Androgen Pathway Blockade in Metastatic Prostate Cancer

Background: Prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET) imaging is a highly sensitive tool for the detection of prostate cancer metastases. However, the effect of primary and secondary androgen deprivation therapy (ADT) on PSMA PET uptake has not been described. Objective: To prospectively evaluate changes in ⁶⁸Ga-PSMA-11 PET uptake on initiation of androgen receptor (AR)-targeted therapy. Design, setting, and participants: Prospective single-institution study of patients with metastatic castration-sensitive (n = 4) and castration-resistant prostate cancer (n = 4) starting treatment with ADT and enzalutamide, respectively, who underwent serial ⁶⁸Ga-PSMA-11 PET imaging before and after treatment initiation. Outcome measurements and statistical analysis: The percentage change in ⁶⁸Ga-PSMA-11 PET uptake from baseline was descriptively reported and graphically represented. Results and limitations: Early increases in PSMA PET tracer uptake in at least one metastatic lesion were observed in six out of seven patients who achieved subsequent prostate-specific antigen declines of >50% from baseline. Overall, 22 of 45 metastatic lesions (49%) exhibited early increases in PSMA uptake that were indicative of a flare effect rather than disease progression. Considerable intra- and interpatient heterogeneity was observed in the temporal pattern of PSMA uptake on treatment initiation. Study limitations include the sample size, the variable timing for scan acquisition, and limited long-term follow up. Conclusions: Tumor flare in PSMA PET tracer uptake in the absence of disease progression is variably observed on initiation of AR-targeted treatment. Further studies are needed to delineate the factors controlling PSMA expression to optimize the diagnostic yield. Patient summary: Flares of increased prostate-specific membrane antigen (PSMA) tracer uptake on positron emission tomography scans are variably observed following initiation of hormone therapy for prostate cancer and do not necessarily represent disease progression. There was considerable variability in PSMA expression between patients, and further studies are needed to understand the factors controlling PSMA expression. Serial imaging in patients starting androgen pathway blockade indicates occasional early flares in prostate-specific membrane antigen (PSMA) positron emission tomography tracer uptake that are not associated with clinical progression. Substantial heterogeneity in tracer uptake highlights the need for further mechanistic studies of factors controlling PSMA expression.