# Fractionation gives therapeutic benefit in animal model of [177Lu]Lu-PSMA-617 therapy of prostate cancer

## TL;DR

Splitting prostate cancer radionuclide therapy into smaller doses improves tumor control and survival in mice.

## Contribution

Demonstrates that fractionated [177Lu]Lu-PSMA-617 therapy improves outcomes in a mouse model of prostate cancer.

## Key findings

- Fractionated therapy with a 24-hour window significantly improved survival compared to single-dose treatment.
- Tumor regrowth was slower in mice receiving fractionated therapy with a 24-hour interval.
- A 6-day fractionation window showed similar trends but did not significantly outperform single-dose treatment.

## Abstract

The clinical standard practice of [177Lu]Lu-PSMA-617 therapy is a single injection per treatment cycle, with 6 weeks between cycles. While clinical schedules currently utilize single-bolus cycles, splitting a treatment cycle into multiple smaller injections has demonstrated benefits in other radionuclide therapies, preclinically and in clinical studies. Potential mechanisms for improved therapeutic efficacy include receptor recycling, receptor upregulation, or targeting new cell growth between fractions. This study aims to investigate the effects on tumor size and animal survival, in a mouse model of prostate cancer, of fractionating [177Lu]Lu-PSMA-617 therapy compared to the same total activity in a single injection.

BALB/c mice bearing subcutaneous LNCaP prostate cancer tumors, below 650 mm3 in volume, were treated with either 1 × 30 MBq, 2 × 15 MBq (24-hour window), or 2 × 15 MBq (6-day window). SPECT/CT imaging showed a higher, but not significantly so, tumor uptake in the 24-hour window group than in the unfractionated one. Differences in tumor sizes were primarily visible during regrowth after therapy, with significantly smaller relative tumor sizes in the 24-hour window group compared to the unfractionated group day 89–95 post inoculation. The median survival for the 24-hour group (71.5 days) was significantly longer than that of the unfractionated group (46 days; p = 0.024). The 6-day group tumor sizes and survival came close to the 24-hour one, but was not significantly better than the unfractionated group.

This study demonstrates that fractionation gives therapeutic benefit in an animal model of [177Lu]Lu-PSMA-617 therapy of prostate cancer for tumors in this size range. A shorter 24-hour window outperformed a longer of 6 d between fractions. The outlook for clinical translation will depend on if the mechanism is relevant at conditions, blood ligand concentration etc., that differs between the animal model and human patients.

The online version contains supplementary material available at 10.1186/s13550-026-01417-9.