# 225Ac-PSMA-617 for PSMA-targeted alpha-radiation therapy of metastatic castration-resistant prostate cancer

Source: https://nuclide.cc/key-papers/paper-kratochwil-ac225-psma-jnm-2016/  
Nuclide record `paper-kratochwil-ac225-psma-jnm-2016` (Key paper). Data CC BY-NC 4.0, attribute "Data from Nuclide (nuclide.cc)"; commercial use needs a licence.

## TL;DR

The first published report of two men with very advanced prostate cancer, who had run out of other options, having their cancer disappear on scans after treatment with an alpha-emitting radioactive drug aimed at PSMA.

## Summary

This case report from Heidelberg described the first-in-human use of 225Ac-PSMA-617, an alpha-particle-emitting version of the PSMA-617 ligand used with the beta-emitter lutetium-177. Two men with metastatic castration-resistant prostate cancer in clinically critical situations - one for whom beta-emitter therapy was contraindicated by diffuse bone marrow infiltration, one who had become resistant to 177Lu-PSMA-617 - were treated with 100 kBq of 225Ac-PSMA-617 per kilogram of body weight, given roughly every two months, after 68Ga-PSMA-11 PET/CT confirmed a PSMA-positive tumour phenotype.

Both patients had PSA fall to below the detectable level and achieved a complete response on repeat 68Ga-PSMA-11 PET/CT imaging, with no relevant haematological toxicity. Xerostomia (dry mouth), from radiation to the salivary glands (which also express PSMA), was the only notable side effect.

Although based on only two patients, this report is widely cited as the proof of concept that launched clinical development of actinium-225-labelled PSMA radioligands as a next-generation, more potent alternative to beta-emitter therapy for men who fail or cannot tolerate 177Lu-PSMA-617. It also flagged salivary gland toxicity as the principal dose-limiting problem for PSMA-targeted alpha therapy, a theme followed up in the authors' subsequent dosimetry and dose-finding papers (2017, 2018).

## Fields

- Kind: Key paper
- Last checked: 2026-09-22
- Tags: alpha therapy; prostate cancer; first-in-human
- Journal: Journal of Nuclear Medicine
- Year: 2016
- DOI: 10.2967/jnumed.116.178673
- Authors: Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, et al.
- Findings: Both patients achieved a PSA decline to below the measurable level and a complete response on 68Ga-PSMA-11 PET/CT restaging.; No relevant haematological toxicity was observed at 100 kBq/kg per cycle, dosed roughly every 8 weeks.; Xerostomia was the only notable clinical side effect reported.
- What it means: This was the first evidence, in two patients, that attaching a more powerful (alpha-emitting) form of radiation to the same PSMA-seeking molecule used in lutetium-177 PSMA therapy could produce a complete response even in prostate cancer that had already stopped responding to the beta-emitter version.
- Caveats: Only two patients; no control group, no survival data, and no formal toxicity study - this is hypothesis-generating, not proof of benefit.; 225Ac-PSMA-617 remains investigational; as of this record's date it had not been approved by FDA or EMA and is used mainly under compassionate access or in trials.; Long-term xerostomia and renal toxicity risks were characterised in later, larger series, not in this initial report.

## Sources

- JNM: 225Ac-PSMA-617 first-in-human report (full text PDF): https://jnm.snmjournals.org/content/jnumed/57/12/1941.full.pdf
- PubMed record: https://pubmed.ncbi.nlm.nih.gov/27389577/

## Connected records

- drugs: [Actinium-225 PSMA agents](https://nuclide.cc/drugs/ac225-psma/)
- technologies: [Targeted alpha therapy](https://nuclide.cc/technologies/targeted-alpha-therapy/)
- targets: [PSMA](https://nuclide.cc/targets/psma/)
- indications: [Metastatic castration-resistant prostate cancer](https://nuclide.cc/indications/prostate-mcrpc/)
- people: [Clemens Kratochwil](https://nuclide.cc/people/clemens-kratochwil/), [Uwe Haberkorn](https://nuclide.cc/people/uwe-haberkorn/)
- pairings: [Beta radioligand → alpha radioligand](https://nuclide.cc/pairings/beta-then-alpha/)
- isotopes: [Actinium-225](https://nuclide.cc/isotopes/ac-225/), [Gallium-68](https://nuclide.cc/isotopes/ga-68/), [Lutetium-177](https://nuclide.cc/isotopes/lu-177/)

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