In this prospective study including nine patients with metastatic castration-resistant prostate cancer (mCRPC) initiating a new drug modulating the androgen receptor signaling (ARSi), we evaluated changes in serum PSA levels and PSMA expression during the initial 3-months after exposure to the new treatment. The goal of our study was to assess whether there is a significant modulation of PSMA expression in response to the androgen receptor pathway inhibition.

At 1-week after ARSi initiation, the whole-body PSMA SUVmean and whole-body tumor volume were stable (changes ≤ 10%) in 6/9 and 5/9 patients, respectively. In our cohort, the average % change of SUVmean, SUVmax, and tumor volume was 3%, 10% and 5%, respectively. This suggests that no significant modulation of PSMA expression induced by ARSi occurs at 1-week in mCRPC.

It was suggested by clinical studies and case reports that a heterogeneous increase in PSMA ligand uptake on PET can be observed in PCa lesions early after initiation of androgen receptor modulating treatments [9, 11, 12]. However, this “PSMA flare” phenomenon has significant inter- and intra-patient variability and was almost exclusively described in castration-sensitive prostate cancer. The mechanism behind this phenomenon is not well understood. A prospective study by Emmet et al. [8] showed that 6 CRPC patients initiating ARSi had a median increase in WB-SUVmax of 45% (IQR: 12.7–66) 9 days after treatment initiation, and a subsequent plateau at later time-points. The authors suggested that the increased PSMA expression may result in a synergistic effect of ARSi and PSMA-targeted radioligand treatments (PSMA RLT). However, in our cohort there was a more heterogeneous response: 1/9 patient had a 47% decrease, 1/9 patient had minimal decrease of 2% (considered stable), and 6/9 had a > 10% increase in SUVmax at 1-week, highlighting patient variability in response to androgen receptor modulation and the need for larger cohorts to demonstrate a significant trend.

While other groups have investigated the effects of ARSi treatments on PSMA expression in patients with prostate cancer and different castration status [8, 9], the novelty of our study was the assessment of PSA kinetics and changes in whole-body PSMA PET quantitative measures in relation to clinical outcome at 1-year after the initiation of the AR modulating treatments. In 6/9 patients, PSA changes at 1-week were discordant with clinical outcome at 1-year, while PSMA PET was concordant. In the remaining 3/9 patients, PSMA PET and PSA kinetics were concordant with each other, and with clinical outcome. Our results show that early PSA monitoring after ARSi initiation is likely not a good prognosticator. While PSMA PET was more often concordant with 1-year outcome than serum PSA levels in our cohort, suggesting the use of serial PET imaging after initiation of ARSi as a prognostic marker appears unrealistic because of cost considerations.

Previous studies have prospectively assessed the effects of ARSi on PSMA expression in mCRPC patients at the whole-body-level [8] and at a lesion-level [9], in 7 and 4 CRPC patients, respectively. The main inherent limitation of doing such analysis is the rigid protocol requiring multiple visits at pre-specified and strict time-points, which interferes with patient compliance. The goal for our study was to prospectively enroll 30 consecutive mCRPC patients initiating a new ARSi treatment, but we were forced to close it early due to recruitment difficulties. Additionally, patients were not encouraged to participate in our study after FDA approval of 68Ga-PSMA-11 in December 2020, which allowed easier access to PSMA PET. Despite the recruitment difficulties, our cohort including 9 mCRPC patients was larger than the previously published studies with similar design.

Another intended endpoint of our study was the clinical and imaging assessment of these patients at later time-points, as well as at time of BCR. While all patients underwent PSMA PET at 1-week, 4/9 patients from the initial cohort, all of which had unfavorable outcome, did not undergo PSMA PET at 3-months, leaving the cohort at this time-point skewed toward patients with favorable outcome, and limiting our ability to interpret the 3-months data.

Lastly, we included patients undergoing types of ARSi which may have affected the androgen receptor function, and thus, PSMA expression, differently.

This study contributes to the small body of knowledge on the effects of ARSi on PSMA expression as measured by PSMA PET imaging. We showed that the early impact of these treatments on PSMA modulation is heterogeneous, and likely negligible. Therefore, the manipulations of PSMA levels prior to RLT may not be warranted early after ARSi.