# 177Lu-PSMA-617 then 225Ac-PSMA rescue therapy

Source: https://nuclide.cc/pairings/beta-psma-then-alpha-psma-rescue/  
Nuclide record `beta-psma-then-alpha-psma-rescue` (Pairing). Data CC BY-NC 4.0, attribute "Data from Nuclide (nuclide.cc)"; commercial use needs a licence.

## TL;DR

When the standard radioactive prostate cancer treatment (177Lu-PSMA) stops working, some clinics switch to a more powerful alpha-particle version (225Ac-PSMA) as a rescue option. It can bring PSA down in about half of patients, but people who have already failed the beta treatment tend to respond less well and for a shorter time than those who have never had it.

## Summary

225Ac-PSMA-617 or 225Ac-PSMA-I&T alpha-particle radioligand therapy is used, mainly outside the United States where actinium-225 is more accessible (for example in Germany), as salvage treatment for metastatic castration-resistant prostate cancer that has progressed after beta-emitting 177Lu-PSMA radioligand therapy (such as Pluvicto) plus prior androgen-receptor pathway inhibitors and taxane chemotherapy. Zacherl et al. (J Nucl Med 2021) reported the first dedicated series: of 14 patients treated with 225Ac-PSMA-I&T, 11 (79%) had previously received 177Lu-PSMA; 50% achieved a PSA decline of 50% or more, with median progression-free survival of 3.1 months and median overall survival of 7.7 months.

A subsequent meta-analysis of retrospective 225Ac-PSMA-617 series (largely post-177Lu-PSMA patients) found pooled rates of 87% for any PSA decline and 66% for a PSA50 response, with pooled median overall survival of 12.5 months and progression-free survival of 9.1 months, and a molecular imaging response in 54% of patients — activity that the authors describe as clinically meaningful in a population that has exhausted other options, achieved with relatively low toxicity (xerostomia is the dominant, often dose-limiting, side effect; haematological toxicity is generally milder than with 177Lu-PSMA). A larger, more recent single-centre series (2025) similarly reported a median overall survival around 7 months in a mixed population, ranging up to 39 months in favourable cases.

Importantly, multiple groups note that patients who progressed on 177Lu-PSMA before starting 225Ac-PSMA have inferior outcomes compared with alpha-therapy-naive patients (a 2022 series found a 45% versus 50% PSA50 rate, and a 2021 Ezziddin group series used 225Ac-PSMA as an 'augmentation' added to, rather than purely after, 177Lu-PSMA cycles, reporting median PSA-progression-free survival of 9.1 months and overall survival of 14.8 months). 225Ac-PSMA remains investigational (not FDA- or EMA-approved) and randomised trials comparing it against other post-177Lu-PSMA options are still needed; it is generally reserved for salvage use in patients with adequate marrow reserve who have exhausted approved options.

## Fields

- Kind: Pairing
- Last checked: 2026-09-22
- Tags: prostate cancer; alpha therapy; salvage therapy
- Pairs: Lutetium-177 vipivotide tetraxetan + Actinium-225 PSMA agents
- Type: sequence
- Rationale: Alpha particles deposit far more energy per track than beta particles and can still kill tumour cells that have become less responsive to 177Lu-PSMA, making 225Ac-PSMA a mechanistically plausible salvage option after beta-emitter progression.
- Evidence: In a series of 14 patients (79% previously treated with 177Lu-PSMA), 225Ac-PSMA-I&T produced a PSA50 response in 50%, with median progression-free survival 3.1 months and overall survival 7.7 months (Zacherl et al., J Nucl Med 2021); a pooled meta-analysis of mostly post-177Lu-PSMA series found 66% PSA50 response and 12.5-month median overall survival, but response is consistently inferior to alpha-therapy-naive patients.

## Sources

- Zacherl et al., first clinical results for 225Ac-PSMA-I&T in advanced mCRPC, J Nucl Med 2021;62:669-674: https://jnm.snmjournals.org/content/64/10/1574
- Meta-analysis of efficacy and safety of 225Ac-PSMA-617 targeted alpha therapy (PMC8852230): https://pmc.ncbi.nlm.nih.gov/articles/PMC8852230/
- Long-term safety and survival outcomes of 225Ac-PSMA (PMC11816130, 2025): https://pmc.ncbi.nlm.nih.gov/articles/PMC11816130/

## Connected records

- indications: [Metastatic castration-resistant prostate cancer](https://nuclide.cc/indications/prostate-mcrpc/)
- technologies: [Targeted alpha therapy](https://nuclide.cc/technologies/targeted-alpha-therapy/)
- targets: [PSMA](https://nuclide.cc/targets/psma/)
- people: [Clemens Kratochwil](https://nuclide.cc/people/clemens-kratochwil/), [Uwe Haberkorn](https://nuclide.cc/people/uwe-haberkorn/)
- isotopes: [Actinium-225](https://nuclide.cc/isotopes/ac-225/), [Lutetium-177](https://nuclide.cc/isotopes/lu-177/)
- drugs: [Actinium-225 PSMA agents](https://nuclide.cc/drugs/ac225-psma/), [Lutetium-177 vipivotide tetraxetan](https://nuclide.cc/drugs/pluvicto/)

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