# Alpha-emitting PSMA therapy at first metastatic diagnosis

Source: https://onco.cc/ideas/idea-alpha-first-mhspc/  
OnCo record `idea-alpha-first-mhspc` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

If Pluvicto helps at first diagnosis, an alpha version might do more against microscopic disease, when tumour burden is smallest.

## Summary

This speculative idea would give alpha-emitting PSMA therapy with actinium-225 at the first metastatic diagnosis of hormone-sensitive prostate cancer, alongside hormone therapy. Short-range alpha emission suits small-volume disease and is oxygen-independent, and early treatment avoids the PSMA heterogeneity of castration resistance; PSMAddition established beta-emitter therapy here. The hypothesis is deeper PSA nadirs and longer radiographic progression-free survival than lutetium-177 PSMA-617 at equal or lower salivary dose; salivary toxicity and actinium-225 supply are limiting. The test is a randomised phase 2 with PSMA PET-based dosimetry, salivary gland protection and the undetectable-PSA rate at one year as primary endpoint.

## Fields

- Kind: Idea
- Last checked: 2026-09-06
- Hypothesis: 225Ac-PSMA added to ADT + ARPI in high-volume de novo mHSPC produces deeper PSA nadirs and longer rPFS than 177Lu-PSMA-617 at equal or lower cumulative salivary dose.
- Rationale: Short-range alpha emission suits small-volume disease; early treatment avoids PSMA heterogeneity that develops under castration resistance.
- Proposed test: Phase 2 randomised 225Ac-PSMA vs 177Lu-PSMA-617 in mHSPC with PSMA PET-based dosimetry, salivary gland protection, and undetectable-PSA rate at 12 months as primary.
- Maturity: speculative

## Sources

- ClinicalTrials.gov NCT04720157: PSMAddition: https://clinicaltrials.gov/study/NCT04720157

## Connected records

- cancers: [Prostate cancer](https://onco.cc/cancers/prostate/)
- technologies: [Radioligand therapy (beta emitters)](https://onco.cc/technologies/radioligand-therapy/), [Targeted alpha therapy](https://onco.cc/technologies/targeted-alpha-therapy/)
- drugs: [Actinium-225 PSMA agents](https://onco.cc/drugs/ac225-psma/), [Lutetium-177 vipivotide tetraxetan](https://onco.cc/drugs/pluvicto/)
- terms: [Alpha vs beta emitters](https://onco.cc/terms/alpha-vs-beta/), [Dosimetry](https://onco.cc/terms/dosimetry/)
- trials: [PSMAddition](https://onco.cc/trials/psmaddition/)
- key papers: [Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormone-relapsed metastatic prostate cancer after 2 or more treatments](https://onco.cc/key-papers/paper-lutetium-177-vipivotide-tetrax-prostate-journal-2023/), [Sequencing of Radium-223 and Lutetium-177 Vipivotide Tetraxetan: Maximizing the Benefit of Systemic Targeted Radiation Therapy in Metastatic Castration-Resistant Prostate Cancer](https://onco.cc/key-papers/paper-lutetium-177-vipivotide-tetrax-prostate-oncol-ther-2025/)

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