The Evolving Role of Prostate-Specific Membrane Antigen-Based Diagnostics and Therapeutics in Prostate Cancer

Prostate-specific membrane antigen (PSMA)-based imaging seeks to fill some critical gaps in prostate cancer staging and response assessment, and may select patients for treatment with radiolabeled PSMA conjugates. In biochemical recurrence, at prostate-specific antigen (PSA) levels as low as 0.2 ng/dL, ⁶⁸Ga-PSMA imaging has demonstrated a 42% detection rate of occult metastatic disease, and detection has been greater than 95% when PSA levels are higher than 2 ng/dL. This may facilitate novel approaches, including salvage lymphadenectomy or metastasis-directed radiation therapy, in patients with oligometastatic disease. PSMA-based imaging has shown promise in evaluating treatment response in hormone-sensitive and castration-resistant disease; however, additional longitudinal assessment is needed given the heterogeneity in uptake changes after the initiation of androgen-deprivation therapy. Changes in uptake must be taken in context of RECIST measurements and other response parameters, given the potential for growth of PSMA-negative lesions and persistent uptake in treated bone lesions of uncertain significance. For selecting patients to receive PSMA-targeted radioconjugate therapy, standardized uptake value thresholds remain to be established. Nevertheless, preliminary data from ¹⁷⁷Lu-PSMA theranostic trials have yielded PSA responses in up to 57% of patients, as well as pain relief and improved quality of life. Thrombocytopenia was the most common grade 3 or greater toxicity; however, grade 1 xerostomia occurred frequently and was cited as the most common reason for treatment discontinuation.