An Expert Report on 177Lu-PSMA-R2: Development, Clinical Evaluation, and Strategic Evolution in PSMA-Targeted Radioligand Therapy

Executive Summary

This report provides a comprehensive analysis of 177Lu-PSMA-R2, a second-generation, urea-based radioligand therapy developed for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The agent was originated by Johns Hopkins University and advanced into clinical development by Advanced Accelerator Applications (AAA), a Novartis company, as a patent-protected successor to the first-generation agent, 177Lu-PSMA-617 (Pluvicto™).[1] The development of 177Lu-PSMA-R2 was predicated on a ligand design, PSMA-R2, that demonstrated a potentially superior safety profile, particularly with lower uptake in the salivary glands, aiming to mitigate the dose-limiting toxicity of xerostomia seen with other PSMA-targeted agents.[3]

The agent entered a Phase I/II clinical trial, known as the PROter study (NCT03490838), to evaluate its safety, radiation dosimetry, and preliminary efficacy.[6] However, after enrolling 27 patients, the trial was terminated by the sponsor in July 2022.[1] Critically, this discontinuation was not due to safety concerns but was a strategic decision reflecting the rapid technological advancements in the field of nuclear medicine.[1] Novartis pivoted its strategy to focus on a more potent, next-generation construct, 225Ac-PSMA-R2, which pairs the same promising PSMA-R2 ligand with an alpha-emitting radionuclide, Actinium-225.[9] This successor agent is now under investigation in the SatisfACtion clinical trial (NCT05983198).[10]