PSMA-targeted radioligand therapy with beta emitters in prostate cancer: current evidence, emerging indications, combination strategies, and future directions

Abstract

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) has emerged as a major therapeutic advance in metastatic castration-resistant prostate cancer (mCRPC), The phase III VISION trial demonstrated that [ 177 Lu]Lu-PSMA-617 significantly improves overall survival and radiographic progression-free survival (rPFS) establishing PSMA-targeted RLT as a key treatment option in advanced disease. Prostate-specific Membrane Antigen (PSMA) positron emission tomography/computed tomography (PET/CT) plays a central role in patient selection, treatment monitoring, and prognostic stratification, thereby supporting a precision oncology approach. More recently, the clinical development of PSMA-targeted radioligand therapy (RLT) has expanded in several directions, including its use in earlier disease stage, such as metastatic hormone-sensitive prostate cancer (mHSPC), and in the neoadjuvant and oligometastatic settings, as well as its integration into multimodal treatment strategies. These include combination approaches with androgen receptor pathway inhibitors (ARPIs), chemotherapy, immunotherapy, and radiation therapy. This review provides a comprehensive overview of the major developments in the field, including advances in molecular imaging, emerging therapeutic indications, combination approaches, and future directions in PSMA-targeted theranostics according to recent clinical trial data. Collectively, these developments highlight the evolving role of beta-emitting RLT across the prostate cancer disease.