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