A pilot study of prostate-specific membrane antigen (PSMA) dynamics in men undergoing treatment for advanced prostate cancer

Abstract

Background: Prostate-specific membrane antigen (PSMA) is a rational target for noninvasive detection of recurrent prostate cancer (PCa) and for therapy of metastatic castration-resistant prostate cancer (mCRPC) with PSMA-targeted agents. Here we conducted serial measurements of PSMA expression on circulating tumor cells (CTCs) to evaluate patterns of longitudinal PSMA dynamics over the course of multiple sequential therapies.

Methods: A retrospective investigation of men with mCRPC undergoing evaluation at medical oncology clinics at our institution assessed the dynamics of PSMA expression in the context of different systemic treatments administered sequentially. Eligibility included patients who began systemic therapies with androgen receptor (AR)-directed agents or taxane agents for whom peripheral blood samples were tested for CTC mRNA of AR splice variant-7 (AR-V7), prostate-specific antigen (PSA), and PSMA (with >2 CTC + results) in a CLIA-accredited laboratory.

Results: From August 2015 to November 2017, we identified 96 eligible men. Fifteen had greater than or equal to 2 sequential therapies and evaluable CTC samples, greater than or equal to 1 expressing PSMA (PSMA+). Among the 15 patients included in this analysis, a total of 54 PSMA status evaluations were performed in the context of 48 therapies during a median follow-up of 18 months. At baseline, PSMA signal was detected ("positive") in 11 of 15 (73.3%) patients, while for 4 of 15 (26.7%) patients PSMA signal was undetectable ("negative"). In all but two patients, the baseline collection corresponded with a change in treatment. On the second assessment, PSMA increases were detected in all 4/4 (100%) PSMA-negative patients and 8 of 11 (72.7%) PSMA-positive patients. PSMA significantly decreased in a patient treated with ¹⁷⁷ Lu-PSMA-617. Serum PSA declines were seen in 7 of 8 (88%) of the treatment periods where PSMA decreased.

Conclusions: PSMA expression in CTCs is a dynamic marker. PSMA transcript declines appear to be associated with concurrent decreases in serum PSA. Sequential CTC sampling could provide a noninvasive response assessment to systemic treatment for mCRPC.

Keywords: PSA; PSMA; circulating tumor cells; metastatic prostate cancer; prostate-specific membrane antigen.

FIGURE 1

CONSORT diagram for patient exclusion. CTC, circulating tumor cell; CTC⁻, CTC negative; CTC⁺, CTC positive; mCRPC, metastatic castration-resistant prostate cancer; PSMA, prostate-specific membrane antigen

FIGURE 2

Swimmer plot indicating treatments that patients received, along with timing (and PSMA status) of CTC sampling, and whether or not PSA responses occurred during each therapy. Patients had greater than 2 CTC⁺ evaluations; the first was the baseline. Percentage values indicate the best PSA response. Daggers indicate deceased patient [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

Association between PSA change and PSMA change by treatment type. A, abiraterone; Ac,²²⁵-Ac-PSMA-617; Ap, apalutamide; C, cabazitaxel; D, docetaxel; E, enzalutamide; K, KEYNOTE (pembrolizumab + enzalutamide); Lu,¹⁷⁷-Lu-PSMA-617; R, RESTORE (bipolar androgen therapy: testosterone); S, STARVE-PC (Ipilimumab + nivolumab) [Color figure can be viewed at wileyonlinelibrary.com]