ideasIdea
Alpha-emitting PSMA therapy at first metastatic diagnosis
If Pluvicto helps at first diagnosis, an alpha version might do more against microscopic disease, when tumour burden is smallest.
PSMAddition established beta-emitter radioligand therapy in mHSPC (rPFS HR 0.72). Alpha particles kill micrometastases more efficiently and are oxygen-independent, but salivary toxicity and Ac-225 supply are limiting.
Confidence
15%–35%likelyOnCo editors (initial estimate), 2026-09-07 · Ac-225 supply and toxicity in early disease are the barriers.
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.
What would test it
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