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Actinium-225 PSMA Therapy for Prostate Cancer

Angelina Popel image
Written by
Angelina Popel
Dr. Farrukh Ahmed image
Reviewed by
Dr. Farrukh Ahmed

Prostate cancer is often treatable when it is found early.[1] But for many men, the disease does not stay “local.” It can spread to bones or other organs. This later stage is where patients and families feel the biggest gap: treatments still help, but the cancer can outsmart one option after another.[2]

This is where targeted Actinium-225 PSMA therapy becomes relevant. At the same time, it’s important to be clear about where this therapy sits today.[3] Actinium PSMA therapy is still under investigation in many countries and is being evaluated in ongoing clinical trials.[4]

In this article, we’ll break down what the prostate cancer treatment with Actinium is, who it is used for, what results the research has shown so far, what results are expected, and future prospects.

What is Actinium-225 PSMA Therapy?

Actinium 225 PSMA therapy is a type of targeted radiotherapy in which a radioactive atom, Actinium-225 (Ac-225), is attached to a small “seeking” molecule that binds to PSMA on prostate cancer cells.[5] The PSMA-targeting component functions like a homing device, directing radiation to areas where PSMA is present rather than dispersing it throughout the entire body.[6]

Actinium-225 PSMA Therapy

What distinguishes this approach from other radioligand therapies is the type of radiation emitted by actinium PSMA. It is an alpha particle emitter.[5] Alpha radiation is extremely powerful at the cellular level, but it travels only a tiny distance in tissue.[7]

That combination is why this method is called “precision radiation,” even though it is administered via the bloodstream rather than from an external device.

Understanding Alpha-Particle Therapy

Alpha-Particle TherapyTargeted alpha therapy is built around two physical facts. First, alpha particles dump a very high amount of energy into a very short path.[7] Their typical tissue thickness is only about 40–100 micrometers, roughly a few cell diameters.[5] Second, their energy deposition is dense. Reported linear energy transfer (LET) values are around ~80–100 keV per micrometer, which is far higher than beta radiation (used in Lu177 PSMA therapy).[5][8]

Ac-225 is appealing due to its decay properties. It has a half-life of approximately 9.9 days, which is sufficient to allow for shipping, preparation, and circulation within the body. As the product decays, it generates a cascade, resulting in the release of four alpha particles for each atom of Ac-225 that breaks down. In simpler terms, one delivered atom can produce multiple impactful interactions at its destination.[5]

The Role of PSMA Actinium Targeting

PSMA stands for prostate-specific membrane antigen. It is a membrane protein that is strongly overexpressed in many prostate cancer cases compared with normal prostate tissue.[9]

Some reviews describe expression that can be roughly 100–1000 times higher in prostate adenocarcinoma than in normal prostate cells, which is why it became such a useful target for imaging and therapy.[10]

This is where the whole PSMA binding logic comes from because PSMA-targeted drugs like Actinium-225 cancer treatment can interact precisely at the place where it is needed.[11] The exact areas where any malignant prostate cells are located in a certain patient.[12]

Mechanism of Action

Once the PSMA-targeting molecule binds to PSMA on the surface of a prostate cancer cell, the complex can be taken into the cell.[13] Then Ac-225 begins its decay process.[14]

The primary damage arises from the alpha particles examined earlier. Because alpha radiation has such a short range, most of its energy is delivered very locally, close to where the radioligand is sitting.[15]

Mechanism of Action for Ac225

Alpha particles create dense tracks of ionization. This produces clustered DNA damage, especially double-strand breaks. These breaks are hard for cells to repair correctly.[15][16] That is one reason alpha therapy can be harmful to targeted cancer cells and lead to cancer destruction.

Who is a Candidate for Actinium PSMA Therapy?

For Actinium PSMA therapy, the diagnosis in most scenarios and clinical trials is PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).[17]

PSMA-positive metastatic castration-resistant prostate cancer (mCRPC)The treatment is generally considered when a prostate tumor is clearly “PSMA-driven” on imaging and the disease still needs control after established options have been used.[18]

The core idea is simple: the therapy can only work well if the cancer cells express sufficient PSMA for the radioligand to bind, and if the body has a good reserve to tolerate radiation-based therapy.[18]

Because the PSMA Actinium procedure is still evolving in research, and protocols can vary by center and country, candidacy is typically determined by a multidisciplinary team that includes nuclear medicine, medical oncology, and urology, using imaging, laboratory values, and the overall clinical picture.

Eligibility Criteria: PSMA PET-CT Scans

For Actinium 225 PSMA therapy, the first and most important step is the PSMA PET-CT scan. This scan shows whether your cancer spots “light up” because they carry enough PSMA for the medicine to attach to them.

PSMA PET-CT ScansThe process is referred to as PSMA PET/CT selection. Doctors want to see clear, strong uptake in the tumors. If the spots are only faintly visible, the treatment has less to “grab onto,” so it is less likely to work.[19][20]

To make this decision more objective, many centers don’t just say “it looks positive.” They often compare tumor brightness with that of normal organs on the same scan. A common practical rule is that the important tumor lesions should look at least as bright as the liver. If the cancer is weaker than the liver on the scan, it can be a sign that the cancer is not strongly PSMA-driven, and doctors may recommend a different approach instead of Ac-225.[21]

This “compare to the liver” idea was originally widely adopted in Lutetium-177 PSMA studies, and many teams apply the same logic to Actinium 225 therapy because the target is the same.[20][21]

When Standard Treatments Fail

Actinium PSMA is most often discussed in the setting where the cancer has continued to progress despite standard systemic treatment.[14] For many patients, “standard” includes androgen deprivation therapy plus one or more modern androgen-axis drugs (like abiraterone or enzalutamide), and often chemotherapy with a taxane.[22]

When a disease continues to progress despite the standard evidence-based treatments, physicians explore alternative therapies that can more directly target metastatic lesions e.g in bones, liver, or LNs.[23]

After Lutetium-177 PSMA Therapy

A common real-world scenario is using Ac-225 PSMA after progression on Lutetium-177 PSMA therapy.[24] Several published series and reviews describe Actinium PSMA therapy as a “salvage” approach in men with prior failure of Lu 177.[6] Meaning whose disease progressed after Lutetium-based radioligand therapy (RLT).

This is relevant because alpha radiation can deliver very high energy over a very short distance, which may help in tumors that did not respond sufficiently to Lu177 (beta-emitting therapy).[7]

A recent clinical analysis examined the use of Ac-225 PSMA-617 following Lu-177 PSMA therapy. The results showed that more than half of patients experienced a PSA decline of at least 50%.[24] However, the median progression-free survival was short, indicating that this remains a challenging disease setting, even with advanced radioligand therapies available.

Find out more about the difference between Ac225 vs Lu177 here.

Contraindications

“Not a good fit at the moment” situations typically fall into two categories: insufficient target on imaging or inadequate normal-tissue reserve to safely tolerate the therapy.

If PSMA PET-CT shows low uptake in key lesions or there is concern for aggressive disease that is not PSMA-avid, treatment is less likely to benefit, and alternative strategies are often prioritized.[29][30]

On the safety side, the main organs doctors watch are the salivary glands, bone marrow, and kidneys.[28] Xerostomia (dry mouth) is repeatedly reported as the most common side effect of Ac-225 PSMA therapy and can be severe enough to stop treatment in some patients.[31]

Bone marrow and kidney toxicities have been reported, with a smaller percentage of patients experiencing severe side effects.[32] Because of this, significant issues such as chronic dry mouth, weak bone marrow reserve (for example, very low blood counts or a history of previous treatments that suppress bone marrow), and notable kidney impairment may lead to decisions to avoid therapy, delay treatment, or modify the plan.[32]

Actinium-225 Success Rate: Studies & Results

In research papers, “success” is most often reported as a major PSA drop after treatment. A common benchmark is PSA50, defined as PSA level 50% or more below baseline. It’s a useful signal that the treatment is targeting the cancer, but it does not guarantee longer survival for every patient.

Across studies, response rates vary substantially because some patients are treated very late (after multiple therapies), whereas others receive Actinium 225 cancer treatment earlier in the disease course.

Actinium 225 PSMA Therapy Efficiency

Explore what the Actinium-225 success rate looks like in a comprehensive table below.

StudyYearPSA50What scans showedOverall survival
Systematic review & meta-analysis[3]202565%Imaging results not pooled8–31 months
M. Sathekge et al.[25]202070%Complete disappearance of PSMA-PET lesions in 29%18 months
M. P. Yadav et al.[6]202039%Complete PSMA-PET response in 9%, and partial in 45%17 months
J. Ma et al.[26]202562.1%PSMA-PET response in 61.1%18 months
Z. Rao et al.[24]202655.6%Disease control by PSMA-PET progression criteria in 38.9%17 months
S. T. Tagawa et al.[27]202346.9%Partial response 18.2%10.7 months

Interpretation

Across studies, Actinium-225 PSMA therapy often leads to a strong PSA drop in a large share of patients. In the largest summary of research, approximately 65% of patients had a PSA decline of 50% or more, and reported overall survival across studies ranged from 8 to 31 months.

In individual clinical reports, PSA50 results were commonly in the 55%–70% range (e.g., 70% in Sathekge 2020 and 55.6% in Rao 2026), indicating that many patients had a meaningful PSA decline.

Scans also improved in a noticeable number of patients. Some studies reported that cancer spots on PSMA PET became much smaller or less active, and in a smaller group, the scan could even look “clear” after treatment. For example, Sathekge 2020 reported the complete disappearance of PSMA-PET lesions in 29%, while Yadav 2020 reported complete response in 9% and partial response in 45%.

Overall survival in several of these reports was around 17–18 months, while the antibody-based study (Tagawa 2023) reported a median overall survival of 10.7 months.

Actinium-225 Side Effects & Safety Profile

When evaluating a cutting-edge treatment like Actinium-225, it is vital to understand its safety profile.

How to Understand the Data

The statistics in the table below are synthesized from the most significant global studies on targeted alpha therapy to date. This includes the WARMTH Act Study from 2024–2025. Additionally, the data incorporates 2025 meta-analyses from peer-reviewed systematic reviews in journals that pooled data from multiple first-in-human trials. All likelihood percentages are based on the Common Terminology Criteria for Adverse Events (CTCAE), the global standard for grading the severity of side effects in cancer research.

To read the following table accurately, note that the group column categorizes side effects by the bodily system or organ affected. The likelihood (%) represents the percentage of patients who reported this symptom in clinical settings.

Complication Table

GroupSide Effects & ReactionsLikelihood in %
GlandularDry mouth (xerostomia)75-85%
Dry eyes (xerophthalmia)2-6%
HematologicalAnemia (all grades)30-58%
Severe anemia7-13%
Low white cells (leukopenia)15-19%
Low platelets (thrombocytopenia)15-21%
SystemicFatigue25-50%
Loss of appetite15-30%
Weight loss25-27%
Nausea6-13%
Organ-specificKidney impairment3-7%
Liver stress< 2%
RareSecondary myelofibrosis< 1%
Toxicity5-13%

Safety Precautions

The main safety topic patients hear about with the Actinium procedure is xerostomia (salivary gland toxicity).[31] Because salivary glands can also take up PSMA-targeted agents, dry mouth can appear early and may become the dose-limiting side effect.[33] Clinics usually monitor this closely and may adjust dosing or cycle spacing if symptoms build.

Doctors also track hematologic toxicity, which means the treatment can lower blood counts.[34] This matters because a low white blood cell count increases infection risk, a low platelet count increases bleeding risk, and a low hemoglobin level can worsen fatigue. Regular blood tests before and after each cycle are standard so the team can pause, reduce dose, or support recovery when needed.

Finally, renal monitoring is part of routine safety because the kidneys help clear many radioligand therapies and can be exposed to radiation.[35] Patients typically undergo kidney function tests (e.g., creatinine and eGFR) over time, and treatment plans may be adjusted if kidney function declines.

The Future of Actinium PSMA Therapy

Actinium-225 PSMA therapy is moving from “promising early results” into a more organized, evidence-building phase. The primary goal now is to demonstrate, in larger trials, which dose is most effective, how often it should be administered, and how to minimize side effects. At the same time, the world is racing to solve a practical problem: making enough Ac-225 so more patients can access it.

Here, we review the current status of Actinium-225 treatment, discuss its availability, and outline perspectives on this radioligand therapy.

Breakthrough Trials

The most important change is that Ac-225 is no longer being studied only in small, single-center reports. Several international trials are now testing it systematically.

  • ACTION study (NCT04597411). The ACTION study is a Phase 1, open-label, international dose-escalation trial designed to identify a safe dose of 225Ac-PSMA-617 and to evaluate side effects and early antitumor activity. Notably, it includes people with and without prior exposure to Lu-177 PSMA radioligand therapy, which helps answer a real-world question: how Ac-225 behaves after other PSMA-targeted treatments.[19]
  • PSMAcTION (NCT06780670). What feels especially “breakthrough” is that the field is already pushing into bigger, later-phase studies. Novartis lists PSMAcTION as a Phase II/III study comparing AAA817 (their name for an Ac-225 PSMA program) versus standard treatment options in adults with PSMA-positive disease who progressed on or after Lu-177 PSMA therapy. This kind of design is what you need to move from “it looks effective” to “it’s proven against standard care.”[36]
  • AcTFirst (NCT06855277). Another major step is moving Ac-225 earlier in the treatment timeline and combining it with other modern drugs. For example, Novartis describes AcTFirst as a Phase III trial evaluating 225Ac-PSMA-617 combined with an androgen receptor pathway inhibitor (ARPI) versus other standard approaches, with the aim of improving radiographic progression-free survival (the time on study during which scans remain stable).[37]
  • 225Ac-PSMA-Trillium BAY 3563254 (NCT06217822). Beyond PSMA-617, other next-generation Ac-225 PSMA agents are also entering first-in-human testing. Bayer announced the initiation of a Phase I, first-in-human dose-escalation study of 225Ac-PSMA-Trillium to evaluate safety, tolerability, and early efficacy signals.[38]

FDA Status

FDA Status of Ac-225 PSMACurrently, Ac-225 PSMA therapies are not FDA-approved for routine use. In the United States, access is typically through clinical trials (or very limited special-access tracks, depending on the situation and local rules).

For Actinium 225 PSMA therapy, the most “FDA-facing” updates so far are development signals, not approvals.[39] For example, the FDA granted Fast Track designation to 225Ac-FL-020 (an investigational PSMA-targeting radiopharmaceutical) and cleared an IND to support clinical trial activities that can expedite development, but this does not mean the treatment is approved.[40]

Global Availability

Worldwide availability is uneven, mainly because Ac-225 supply is limited and regulations differ by country.[41][42] Some highly specialized nuclear medicine centers have offered Ac-225 PSMA therapy under research programs for years, but even in places with experience, it may still be considered not formally approved and used only with special permissions and consent.

In parallel, access is expanding through multinational trials. Large programs such as AcTION and later-phase studies such as PSMAcTION and AcTFirst are designed as international studies, which is one of the main ways global availability grows.[19][36][37]

For example, international patients can privately receive Actinium-225 alpha therapy for cancer in countries such as Germany, Austria, South Africa, Turkey, and India.

Advancements in Ac-225 Radioisotope Production

Even the best clinical trial cannot scale if the isotope is scarce. Ac-225 has been in “short supply” partly because traditional production routes are complex and limited by isotope availability. The good news is that this is changing.

The U.S. Department of Energy reports that it established a scalable accelerator-based production method using particle accelerators at Brookhaven and Los Alamos and described a milestone in which accelerator-produced Ac-225 would support a U.S. clinical trial for human care.[43]

Commercial supply is also expanding. TerraPower Isotopes announced commercial-scale Ac-225 production with weekly runs, aiming to provide drug developers with steadier access.[44]

In Europe, the production of Actinium-225 is closely linked to public research infrastructure and coordination within the European Union. The PRISMAP program identifies JRC Karlsruhe in Germany as a production site that utilizes thorium-229 generators.[45] It also mentions Ac-225 production at CERN’s MEDICIS facility in Geneva, which uses high-energy proton irradiation and mass-separation techniques.[46]

Europe is simultaneously exploring new production methods to enhance supply scalability. The European Commission’s Joint Research Centre has outlined a patented approach for producing Ac-225. This method involves irradiating a liquid radium-226 target within a closed-loop system.[47] This design aims to improve both safety and scalability by recycling the radium and minimizing contamination risks.

Dual-Isotope Therapy

One of the most interesting directions is dual PSMA therapy, sometimes called tandem therapy. The idea is simple: beta radiation (Lu-177) and alpha radiation (Ac-225) behave differently in tissue, so combining them may help cover different tumor sizes and resistance patterns while allowing lower Ac-225 doses that could reduce toxicity.[48][49]

Clinical research in this area remains in its early stages, but there is real-world data. As clinical trials advance, dual-isotope strategies may become more standardized. These strategies may be implemented as planned combinations or as "step-up" approaches, in which Lu-177 is administered first, with Actinium-225 treatment added as needed.

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