Quantifying the Renal Impact of [177Lu]Lu-PSMA-617: A Longitudinal Analysis of Real-World Data from the LUMEN Registry

The success story of [177Lu]Lu-PSMA-617 is one of the most exciting developments in modern GU oncology. For patients with pre-treated metastatic castration-resistant prostate cancer (mCRPC), this targeted radioligand therapy has provided a crucial last-line option. However, debate has emerged regarding its collateral adverse events—specifically, to the kidneys. While landmark clinical trials initially painted a picture of near-perfect renal safety, real-world post-market observations have hinted at more concerning nephrotoxic properties.

In this longitudinal analysis, we aimed to clarify the impact on estimated glomerular filtration rate (eGFR), modelling the long-term renal trajectories of our institutional LUMEN cohort. The findings suggest the truth lies somewhere in the middle. We identified a significant downward trend in eGFR, slow and modest at an estimated annual decline of -1.8 mL/min/1.73m2. Importantly, though, we noted that the established nephrological risk factors of vascular damage—such as advancing age, hypertension, and diabetes—do not seem to accelerate this radiotoxic decline. Instead, the real driver could be cumulative exposure: the more therapeutic radioactivity administered, the steeper the functional drop was observed.

For a patient in late-stage mCRPC, a modest, slow loss of renal function seems acceptable, weighted against extended survival. A slight annual eGFR will rarely outpace the disease itself. However, the landscape of PSMA-targeted radioligand therapy is rapidly shifting toward earlier stages of the disease. The PSMAfore trial has already successfully pushed the therapy ahead of chemotherapy for taxane-naive mCRPC patients.¹ But the therapeutic timeline is moving even further forward:

The UpFrontPSMA trial is exploring its use in metastatic hormone-sensitive prostate cancer (mHSPC), a setting where life expectancy can stretch well beyond a decade.²
The LUNAR investigated the therapy alongside stereotactic body radiotherapy (SBRT) for oligorecurrent disease with even better life expectancy.³
Most aggressively, trials like PRELUDE (NCT06798558) are placing Lu-PSMA into the localized, high-risk setting, evaluating it as a neoadjuvant treatment prior to curative surgery.

This is where the LUMEN cohort’s findings become important. If we start administering radioligand therapy to men who are expected to live for > 10 years, even a modest eGFR decline could eventually translate into clinically significant kidney disease, warranting monitoring as well as further validation of these signals.

Written by: Thomas Büttner,¹ Christian Hoffmann,¹ Markus Essler,² Florian Gärtner,² Barbara Kreppel,² Jim Küppers,² Manuel Ritter,¹ Leander Fritzsche,¹ Milka Marinova,² Philipp Krausewitz,¹

Department of Urology and Pediatric Urology, University Hospital Bonn, Bonn, Germany
Department of Nuclear Medicine, University Hospital Bonn, Bonn, Germany.

References:

Morris MJ, Castellano D, Herrmann K, de Bono JS, Shore ND, Chi KN, et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. The Lancet. 2024;404(10459):1227-39.
Azad AA, Bressel M, Tan H, Voskoboynik M, Suder A, Weickhardt AJ, et al. Sequential [177Lu]Lu-PSMA-617 and docetaxel versus docetaxel in patients with metastatic hormone-sensitive prostate cancer (UpFrontPSMA): a multicentre, open-label, randomised, phase 2 study. The Lancet Oncology. 2024;25(10):1267-76.
Kishan AU, Valle LF, Wilhalme H, Felix C, Nabong R, Juarez-Casillas JE, et al. 177Lu-Prostate-Specific Membrane Antigen Neoadjuvant to Stereotactic Ablative Radiotherapy for Oligorecurrent Prostate Cancer (LUNAR): An Open-Label, Randomized, Controlled, Phase II Study. Journal of Clinical Oncology. 2025;43(36):3812-21.

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