Objectives

This review summarizes the current literature and ongoing clinical trials on the use of PSMA-based radioligand therapy (RLT) in hormone-sensitive prostate cancer (HSPC).
It covers the application of PSMA-based RLT in various settings, including neoadjuvant, de-novo/synchronous metastatic, adjuvant, and early biochemical recurrence (BCR).
The review highlights the potential benefits of early PSMA-based RLT in HSPC, such as improved treatment efficacy due to lower tumor burden, more frequent exclusive nodal involvement, and higher organ reserve.

Methodology

The review is based on a systematic literature search on PubMed/MEDLINE/EMBASE and clinicaltrials.gov databases.
The search included terms related to PSMA, HSPC, and RLT.
Inclusion and exclusion criteria were applied to select relevant studies and protocols.
Data extracted from selected papers included clinical setting, study design, number of participants, radiopharmaceuticals used, imaging modality, study status, and main endpoints/results.

Multiple studies and ongoing trials are presented, providing preliminary data on the efficacy and safety of early PSMA-based RLT in HSPC.
Golan et al. reported a PSA median reduction of 17% and 34% after 2 and 3 cycles of [177Lu]Lu-PSMA-I&T, respectively, in the neoadjuvant setting.
Eapen et al. (LuTectomy study) showed that 45% of patients achieved >50% PSA decline with neoadjuvant [177Lu]Lu-PSMA-617.
Satapathy et al. observed undetectable PSA in 50% of de-novo mHSPC patients treated with [177Lu]Lu-PSMA-617 plus ADT.
Privé et al. reported a PSA 50% reduction in 5/10 BCR patients and PSMA PET response in 6/10 patients treated with [177Lu]Lu-PSMA-617.
Sathekge et al. reported any PSA decline in 95% and PSA decline ≥50% in 86% of mHSPC patients treated with [225Ac]Ac-PSMA-617.
Most studies reported no G3 or higher toxicities, except for one case of G3 anemia and G4 thrombocytopenia in a patient treated with a combination of [177Lu]Lu-PSMA-617/I&T and [225Ac]Ac-PSMA-I&T.

The review provides a comprehensive overview of the current landscape of PSMA-based RLT in HSPC, but it primarily focuses on summarizing existing studies rather than providing a critical appraisal.
The rationale for early RLT is presented, but further discussion on patient selection criteria is needed. Specifically, which HSPC patients are most likely to benefit from early RLT, beyond simply stating they are 'unfit for or refuse standard therapy'?
The review mentions the potential impact of hormone therapy on PSMA expression, which is crucial. However, it could benefit from a more in-depth discussion of how this interaction might influence the timing and sequencing of RLT and hormone therapy.
While several ongoing trials are listed, the review lacks a critical comparison of their designs and endpoints. A table directly comparing key aspects (e.g., inclusion criteria, treatment regimens, primary endpoints) would be valuable.
The discussion of alpha-emitters is brief. Given the increasing interest in alpha-RLT, a more detailed analysis of the potential benefits and risks of combining alpha- and beta-emitters in HSPC is warranted.
The conclusion emphasizes the potential of early RLT but lacks specific recommendations for future research directions. What are the most pressing unanswered questions that need to be addressed in future trials?