Recent advances in PSMA-targeted radioligand therapy (RLT) highlight its expanding role in eradicating occult micrometastatic disease in prostate cancer.

Lutetium-177: Winning Early Battles Against Limited Recurrences

The phase II LUNAR trial in a few-site recurrent hormone-sensitive prostate cancer demonstrated that adding two cycles of ¹⁷⁷Lu-PNT2002 before high-dose external radiation (stereotactic ablative body radiotherapy or SABR) to the visible metastases significantly extended progression-free survival versus SABR alone (from about 7 months to over 17 months). It was very well tolerated, with hardly any extra side effects. Such success is attributed to the comprehensive targeting of PSMA-expressing micrometastases undetected by conventional imaging.

Terbium-161: The Next-Gen Supercharged Radionuclide

Building on this foundation, emerging data with ¹⁶¹Tb-PSMA radioligands—led by ongoing phase I/II (VIOLET) and pilot/registry studies at Saarland University—reveal superior radiation action profile of Terbium-161 over Lutetium-177. ¹⁶¹Tb emits comparable medium-energy beta particles but adds abundant high-linear-energy-transfer conversion and Auger electrons, depositing markedly higher absorbed radiation doses in single cells and micrometastatic clusters (up to several-fold greater nuclear doses in preclinical models). This enhanced cytotoxicity is particularly potent against small-volume, undetectable disease, yielding promising response and tumor control even in heavily pretreated mCRPC patients progressing after standard ¹⁷⁷Lu-PSMA RLT.

The 1-2 Knockout: Lu-177 + Tb-161

Collectively, these developments position PSMA RLT as a cornerstone for micrometastasis-directed therapy across disease stages, with Terbium-161 representing a next-generation upgrade. A smart early-stage combination plan —such 1–2 cycles of ¹⁷⁷Lu-PSMA followed by ¹⁶¹Tb-PSMA—could use Lutetium-177 to target the larger tumor sites, while leveraging ¹⁶¹Terbium’s augmented potency to eliminate resistant micrometastatic reservoirs more thoroughly and potentially achieve longer-lasting results.

At our clinic, we apply this precise combination protocol to give patients the best chance of targeting both visible and hidden cancer sites.