Prostate-specific Membrane Antigen Biology in Lethal Prostate Cancer and its Therapeutic Implications

Context Prostate-specific membrane antigen (PSMA) is a promising, novel theranostic target in advanced prostate cancer (PCa). Multiple PSMA-targeted therapies are currently in clinical development, with some agents showing impressive antitumour activity, although optimal patient selection and therapeutic resistance remain ongoing challenges. Objective To review the biology of PSMA and recent advances in PSMA-targeted therapies in PCa, and to discuss potential strategies for patient selection and further therapeutic development. Evidence acquisition A comprehensive literature search was performed using PubMed and review of American Society of Clinical Oncology and European Society of Medical Oncology annual meeting abstracts up to April 2021. Evidence synthesis PSMA is a largely extracellular protein that is frequently, but heterogeneously, expressed by PCa cells. PSMA expression is associated with disease progression, worse clinical outcomes and the presence of tumour defects in DNA damage repair (DDR). PSMA is also expressed by other cancer cell types and is implicated in glutamate and folate metabolism. It may confer a tumour survival advantage in conditions of cellular stress. PSMA regulation is complex, and recent studies have shed light on interactions with androgen receptor, PI3K/Akt, and DDR signalling. A phase 2 clinical trial has shown that 177 Lu-PSMA-617 causes tumour shrinkage and delays disease progression in a significant subset of patients with metastatic castration-resistant PCa in comparison to second-line chemotherapy. Numerous novel PSMA-targeting immunotherapies, small molecules, and antibody therapies are currently in clinical development, including in earlier stages of PCa, with emerging evidence of antitumour activity. To date, the regulation and function of PSMA in PCa cells remain poorly understood. Conclusions There has been rapid recent progress in PSMA-targeted therapies for the management of advanced PCa. Dissection of PSMA biology will help to identify biomarkers for and resistance mechanisms to these therapies and facilitate further therapeutic development to improve PCa patient outcomes. Patient summary There have been major advances in the development of therapies targeting a molecule, PSMA, in PCa. Radioactive molecules targeting PSMA can cause tumour shrinkage and delay progression in some patients with lethal disease. Future studies are needed to determine which patients are most likely to respond, and how other treatments can be combined with therapies targeting PSMA so that more patients may benefit.