# PSMA-Based Radiopharmaceuticals in Prostate Cancer Theranostics: Imaging, Clinical Advances, and Future Directions

## TL;DR

This paper reviews recent advances in PSMA-based imaging and therapy for prostate cancer, highlighting improved diagnostics and targeted treatments that are enhancing patient outcomes.

## Contribution

The paper provides a comprehensive overview of the clinical translation of PSMA-based theranostics and emerging strategies to optimize prostate cancer care.

## Key findings

- PSMA PET imaging has shown superior accuracy compared to conventional imaging methods for prostate cancer detection.
- Targeted radioligand therapy with [177Lu]Lu-PSMA-617 has been approved and is improving survival for metastatic castration-resistant prostate cancer patients.
- Integration of AI and radiomics is enhancing diagnostic precision and treatment planning in prostate cancer theranostics.

## Abstract

Significant advancements have been made since the approval of the Prostate-Specific Antigen (PSA) test in 1986 and the identification of Prostate-Specific Membrane Antigen (PSMA) in 1987, leading to the introduction of the first-in-human [68Ga]Ga-PSMA-11 PET imaging. Despite these developments, prostate cancer continues to be a leading cause of cancer-related mortality among men worldwide. This ongoing challenge largely stems from the limitations of current PSMA imaging techniques, which can miss a subset of malignant lesions, resulting in variable patient outcomes. However, recent innovations in theranostic and chemotherapeutic agents, along with the implementation of immunotherapy, are improving patient outcomes and survival rates. Additionally, advancements in imaging technologies—including hardware improvements, the integration of artificial intelligence (AI), and radiomics—are significantly enhancing the diagnostic and therapeutic landscape. This review article aims to summarize recent progress in both diagnostic and therapeutic domains while discussing relevant ongoing clinical trials. It is important to note that this summary may not cover all recent developments, as the rapid pace of advancements in multimodal approaches within this field may have led to some progress being overlooked.

Prostate cancer remains one of the most common malignancies in men worldwide, with incidence and mortality steadily increasing across diverse populations. While early detection and radical prostatectomy can achieve durable control in a subset of patients, approximately 40% of men will ultimately experience biochemical recurrence often in the absence of clinically detectable disease. Conventional imaging approaches—CT, MRI, and bone scintigraphy—have limited sensitivity for early relapses, frequently leading to delayed diagnosis and suboptimal treatment planning. The discovery of prostate-specific membrane antigen (PSMA) in 1987 and its subsequent clinical translation into positron emission tomography (PET) imaging with [68Ga]Ga-PSMA-11 in 2012, followed by U.S. FDA approval in 2020, has transformed the landscape of prostate cancer imaging. PSMA PET has demonstrated superior accuracy over conventional imaging, as highlighted in the landmark proPSMA trial and now serves as the foundation for theranostic approaches that integrate diagnostic imaging with targeted radioligand therapy. The clinical approval of [177Lu]Lu-PSMA-617 (Pluvicto®: (lutetium Lu 177 vipivotide tetraxetan, Advanced Accelerator Applications USA, Inc., a Novartis company) has established targeted radioligand therapy as a viable option for men with metastatic castration-resistant prostate cancer, extending survival in patients with limited alternatives. Emerging strategies, including next-generation ligands with improved tumor uptake and altered clearance pathways, as well as the integration of artificial intelligence for imaging quantification, are poised to further refine patient selection, dosimetry, and treatment outcomes. This review highlights the evolution of PSMA-based imaging and therapy, discusses current clinical applications and limitations, and outlines future directions for optimizing theranostic strategies in prostate cancer care.