Actinium-225 PSMA sends alpha radiation into prostate cancer cells and can work after lutetium-177 has stopped. In 488 heavily treated men, median survival was 15.5 months. It is not yet approved, and dry mouth affects two thirds of patients. This guide covers who may be considered, the approved alternative, a treatment cycle and questions to ask.
About This Department
Nuclear Medicine
Actinium-225 PSMA delivers alpha radiation, far more powerful over a far shorter distance than the approved lutetium-177 treatment. For now it remains an experimental option, used after approved treatments have run out.
Actinium-225 PSMA targets the same protein on prostate cancer cells as lutetium-177 PSMA, the radioligand approved after the VISION trial. In a pooled series of 488 men with advanced prostate cancer, most already treated with chemotherapy and a third with lutetium, median survival was 15.5 months. No major regulator has approved it. Randomized trials are running, and a dry mouth affects two thirds of patients. Send us your PSMA PET/CT, PSA history and every treatment so far, and a nuclear medicine physician will tell you whether an approved option still fits, whether actinium-225 could be considered, and what it would involve.
15.5 months
Median survival, 488 men treated with actinium-225 PSMA
68%
Dry mouth after the first cycle
15.3 vs 11.3
Months of survival with approved lutetium-177 PSMA, VISION
Targeted alpha-therapy with 225Ac-PSMA-617, although still experimental, obviously has strong potential to significantly benefit advanced-stage prostate cancer patients.
First report of actinium-225 PSMA in two patients, Journal of Nuclear Medicine, 2016
Actinium-225 PSMA sits late in the sequence of treatments for prostate cancer that no longer responds to hormone therapy.
Hormone therapy, lowering testosterone, with or without newer drugs such as abiraterone or enzalutamide.
Taxane chemotherapy, docetaxel and then cabazitaxel.
Lutetium-177 PSMA, approved for PSMA-positive disease after hormone therapy and chemotherapy.
Actinium-225 PSMA, experimental.
Clinical trials, including newer targeted drugs and combinations, at any point in the sequence.
1
The target
PSMA, prostate-specific membrane antigen, covers the surface of most prostate cancer cells in large amounts. A PSMA PET/CT scan shows how much of the cancer carries it.
2
The alpha particle
Actinium-225 releases four alpha particles as it decays. Each travels only a few cell widths but deposits a large dose, causing breaks in both strands of DNA that cancer cells find hard to repair.
3
The salivary glands
The same molecule also collects in the salivary and tear glands, which carry PSMA. That is the source of the dry mouth, the side effect that limits how many cycles a patient can receive.
An experimental treatment
Actinium-225 PSMA has not been approved by the United States Food and Drug Administration or the European Medicines Agency. Where it is given, it is used under national rules for unapproved treatments or within trials, with written consent that explains what is and is not known. Lutetium-177 PSMA, which is approved, should be considered first where it fits.
Alpha against beta
How actinium differs from lutetium
Lutetium-177 emits beta particles that travel up to two millimeters in tissue, reaching cells near those that absorbed the drug, useful in larger tumor deposits. Actinium-225 emits alpha particles that travel less than a tenth of a millimeter and carry many times more energy. The alpha dose stays in the cells that took up the molecule and their immediate neighbors.
For this reason actinium can work in cancer that has become resistant to lutetium, and it can reach small deposits in the bone marrow. The same concentration makes the salivary glands more vulnerable, since they take up PSMA ligands avidly and alpha radiation damages them more. Doctors therefore keep doses small, measured in kilobecquerels per kilogram, and limit the number of cycles.
What the evidence shows
2016, first patients. Two men in Heidelberg with extensive disease had a complete response, with PSA falling below measurable levels.
2016 to 2023, growing experience. Centers in Germany, South Africa, India and Australia treated hundreds of patients, many where lutetium was unavailable.
2024, the pooled analysis. WARMTH Act gathered 488 patients from seven centers, the largest series so far.
Now, prospective trials. Randomized studies of actinium-225 PSMA ligands are running, and their results will decide approval.
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WARMTH Act, 488 men treated with actinium-225 PSMA
68 percent of those assessed, all patients after more than seven cycles
Severe anemia, low platelets, kidney toxicity
13, 7 and 5 percent. No treatment-related deaths recorded
Reading those numbers
WARMTH Act looked back at patients treated at different centers under different selection rules, with no comparison group. Its survival figure encourages hope for men with advanced, heavily treated disease. A randomized trial is a different kind of evidence, and the two cannot be set side by side.
The approved alternative, lutetium-177 PSMA
What VISION and TheraP showed
VISION randomized 831 men with PSMA-positive metastatic castration-resistant prostate cancer, already treated with hormone drugs and taxane chemotherapy. Adding lutetium-177 PSMA-617 to standard care lengthened median survival from 11.3 to 15.3 months and imaging-based progression-free survival from 3.4 to 8.7 months, without harming quality of life.
TheraP compared lutetium with cabazitaxel chemotherapy in 200 men. PSA fell by half or more in 66 percent with lutetium against 37 percent with cabazitaxel, and severe side effects were less common, 33 against 53 percent. Regulators in the United States and Europe have approved lutetium-177 PSMA.
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Randomized trials of lutetium-177 PSMA
Trial
Patients
Comparison
Main result
VISION, 2021
831
Lutetium plus standard care against standard care
Median survival 15.3 against 11.3 months
TheraP, 2021
200
Lutetium against cabazitaxel
PSA response 66 against 37 percent. Severe side effects 33 against 53 percent
Who may be considered for actinium-225
Candidates have metastatic castration-resistant prostate cancer with strong uptake on PSMA PET throughout the disease. Deposits visible on FDG PET and absent on the PSMA scan would go untreated, so they rule a patient out. Kidney function and blood counts must be adequate. Existing dry mouth weighs against it.
Most have received hormone drugs and chemotherapy, and many have received lutetium-177. Lutetium comes first wherever it is available and untried. Doctors consider actinium-225 when lutetium has stopped working, when it cannot be obtained, or when bone marrow involvement makes the shorter-range alpha radiation more attractive.
Tandem and combined approaches
Some centers combine a low dose of actinium-225 with lutetium-177 in the same cycle, aiming for the effect of both with fewer salivary side effects. These tandem schedules remain experimental, and results come from small series.
Availability and access
A Lancet Oncology Commission published in 2024 surveyed radiopharmaceutical therapy worldwide and found its use highly variable, limited by isotope supply chains, trained staff and regulation. A handful of facilities produce actinium-225 in small quantities. Availability and price therefore vary between countries and over time.
A recent PSMA PET/CT.
PSA results over the past year and every treatment with dates, including any lutetium-177 cycles and the response to each, which tells the team how the cancer has behaved and whether alpha therapy is likely to add anything.
Recent blood count, kidney function and a note of any dry mouth.
Questions to ask any center
Ask where the actinium-225 comes from and how its purity is tested, which ligand is used, how many patients the center has treated, how it measures response, what happens if the salivary glands are damaged, and what the legal basis for the treatment is in that country. A center that cannot answer clearly is not the right one. A second opinion from an independent nuclear medicine physician costs little compared with a treatment whose supply, quality and legal status all need to be sound before the first infusion.
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Timing of one actinium-225 PSMA cycle
Step
Timing
PSMA PET/CT and blood tests
Before the first cycle
Infusion
30 minutes, with a short observation afterward
Blood tests
Every two to four weeks
Next cycle
Eight weeks later, if blood counts and response allow
Response scan
After two cycles
What does a treatment cycle involve?
1
Assessment
Consultation, blood tests and a review of the PSMA PET/CT by the tumor board. If lutetium-177 is the better choice, the plan says so.
2
The infusion
A 30-minute drip. Fluids run alongside, and in some centers the salivary glands are cooled with ice packs to reduce uptake. Alpha radiation hardly leaves the body, so the stay is one night or less for the majority, and the precautions at home are simple.
3
Between cycles
Blood tests every few weeks at home, PSA after each cycle, and a PSMA PET/CT after two cycles to decide whether to continue. Most patients receive two to four cycles.
How many days in Istanbul, and what decides the cost?
Each cycle is a short trip.
Plan three to four days for each cycle, covering assessment, infusion and discharge. Eight weeks separate the cycles, so patients return home between them and have their blood tests locally. Fly home the day after discharge. Close contact with pregnant women and small children is limited for a few days.
Cost depends above all on the actinium-225 itself, whose supply is scarce and whose price varies over time, and on the number of cycles. The PSMA PET/CT, blood tests and hospital stay make up the rest. Your own figure follows the free review of your file.
One coordinator handles your visit. The team works in seven languages, with interpreters for the rest. Ten days before travel, an invitation letter naming the hospital and the physician goes out, and the international patients office books the transfer and a hotel for you and a companion. Halal, vegetarian and diabetic meals are served on request, a prayer room is on site, and a request for a female doctor is passed to the department and met wherever the rota allows. Back home, the coordinator stays reachable on the same WhatsApp number between cycles, collects the blood results from your local laboratory, passes them to the physician who treated you, and books the next cycle only once the counts and the PSA allow it, so that the decision to continue always rests on your latest results and never on a date fixed months in advance.
Actinium-225 PSMA therapy FAQ
Is actinium-225 PSMA therapy approved?
No. It is not approved by the United States or European regulators and is given under national rules for unapproved treatments or within trials. Lutetium-177 PSMA is the approved radioligand.
How effective is actinium-225 PSMA?
In 488 heavily treated men, median survival was 15.5 months and progression-free survival 7.9 months. These are retrospective results without a comparison group.
What are the side effects?
Dry mouth, in 68 percent after the first cycle, is the most common. Severe anemia occurred in 13 percent, low platelets in 7 percent and kidney toxicity in 5 percent.
Can it work after lutetium-177 has failed?
In many patients, yes. A third of the 488 men in the pooled series had already received lutetium.
How many cycles are given?
Most patients receive two to four cycles, eight weeks apart, depending on response and side effects.
Can my family come with me?
Yes. The international patients office arranges a hotel for you and a companion for each cycle.
References
Kratochwil C, Bruchertseifer F, Giesel FL, et al. 225Ac-PSMA-617 for PSMA-Targeted alpha-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer. Journal of Nuclear Medicine. 2016;57(12):1941-1944.
Sathekge MM, Lawal IO, Bal C, et al. Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicentre, retrospective study. Lancet Oncology. 2024;25(2):175-183.
Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2021;385(12):1091-1103.
Hofman MS, Emmett L, Sandhu S, et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804.
Abdel-Wahab M, Giammarile F, Carrara M, et al. Radiotherapy and theranostics: a Lancet Oncology Commission. Lancet Oncology. 2024;25(11):e545-e580.
Editor's note
Written by the Biruni Hospital medical editorial team. Reviewed by Prof. Dr. Burçak YILMAZ, Nuclear Medicine.
