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Patient Guide · Alpha PSMA

Everything you need to know about alpha-PSMA therapy.

Ac-225 PSMA-617 alpha-emitter therapy for metastatic castration-resistant prostate cancer — published response rates, the salvage role after Lu-PSMA progression, the xerostomia trade-off, and where it fits in the treatment pathway. Every clinical number sourced.

Dr. Ishita B. Sen
Dr. Ishita B. Sen, MDDirector & Chief, Nuclear Medicine · FMRI
Published
Reviewed by Dr. Dharmender Malik
12 min read
Last reviewed by Dr. Dharmender Malik on 13 May 2026 · this article reflects the published primary literature and current clinical practice at FMRI Gurugram.

Introduction

Alpha-PSMA therapy with Actinium-225-labelled PSMA-617 is an investigational alpha-emitter radioligand therapy for metastatic castration-resistant prostate cancer (mCRPC). It is the alpha-emitter counterpart of Lu-177 PSMA-617 (Pluvicto, beta-emitter), and was first reported clinically by Kratochwil and colleagues in 2016[1]. As of 2026, Ac-225 PSMA-617 remains investigational — not FDA-approved — and is delivered at experienced theranostics centres under Helsinki Declaration informed-consent frameworks for patients who have progressed on or are unsuitable for Lu-177 PSMA-617. This guide covers what the published data show, who is a candidate, the trade-offs (including xerostomia), and how the therapy is delivered at FMRI.

Why alpha emitters — the physics in plain terms

AI Overview · plain answer

Alpha particles deposit far more energy per micrometre of tissue (high linear energy transfer, ~100 keV/μm) than beta particles (~0.2 keV/μm), and travel only 50-100 micrometres — roughly 2-10 cell diameters[2]. This combination produces dense double-strand DNA breaks in cells the radioligand binds, with minimal damage to surrounding tissue. The result: stronger tumour-cell killing, particularly in micrometastatic disease and in tumours resistant to lower-LET beta therapy.

Ac-225 has a 9.9-day half-life and decays through a four-step alpha cascade, releasing four alpha particles per atom — multiplying the therapeutic effect relative to single-alpha emitters[3]. The trade-off is that the daughter radionuclides can migrate from the binding site, contributing to off-target effects, particularly in salivary glands.

Published response rates — what Kratochwil and Sathekge reported

The foundational clinical data come from two groups: Heidelberg (Kratochwil and colleagues) and Pretoria (Sathekge and colleagues). Their published cohorts in heavily pre-treated mCRPC patients are summarised below[1][4][5]:

Cohort n PSA50 response Median OS
Kratochwil et al. 2017 (Heidelberg, post-Lu-PSMA progressors) 14 50% Not reached at 13 mo
Sathekge et al. 2019 (Pretoria, post-chemo, partly post-Lu-PSMA) 17 82% Not reached at follow-up
Sathekge et al. 2020 (Pretoria, extended cohort, treatment-naïve to RLT) 73 70% 18 mo
Yadav et al. 2022 (AIIMS New Delhi, salvage) 28 39% 17 mo

For comparison, the FDA-registration VISION trial of Lu-177 PSMA-617 reported 46 percent PSA50 response in the post-chemotherapy mCRPC setting[6]. The Ac-225 cohorts are smaller and more heavily selected, but the response signals in patients who have progressed on Lu-177 are striking — particularly the Heidelberg post-Lu-PSMA progressor data showing meaningful response even after beta-therapy failure.

The xerostomia trade-off — and what mitigations are being tried

The most clinically significant off-target effect of Ac-225 PSMA-617 is salivary gland toxicity. Salivary glands express PSMA at low density and concentrate the radioligand. With the higher-LET alpha radiation, the cumulative effect on salivary tissue is more pronounced than with Lu-177. In the Kratochwil 2017 cohort, all patients reported xerostomia (dry mouth); approximately 25 percent reported Grade 3 (severe) xerostomia substantially impairing quality of life[4].

Several mitigation approaches have been studied:

  • Salivary gland cooling during infusion — limited evidence of benefit in Ac-225 specifically[7].
  • Botulinum toxin injection into parotid glands — small studies suggest modest reduction in dose to salivary tissue, but evidence remains exploratory and is not yet standard of care[8]. For more detail in the Ac-225 context specifically, see our companion article: Managing xerostomia after Ac-225 therapy.
  • Dose-fractionation — Kratochwil and colleagues subsequently reduced per-cycle Ac-225 activity from 100 kBq/kg to 50-65 kBq/kg, with similar response rates but lower xerostomia incidence[4].
  • Cold pressor masking / amifostine pre-medication — investigational, no high-quality evidence base yet[9].

The xerostomia risk is the dominant counselling point. Patients considering Ac-225 PSMA need to understand that the trade-off for stronger tumour killing is a meaningful and sometimes permanent reduction in salivary function.

Who is a candidate — the salvage-after-Lu-PSMA setting

Ac-225 PSMA-617 at FMRI is delivered in two clinical situations:

  • Salvage after Lu-177 PSMA progression. The largest documented clinical role — patients whose mCRPC initially responded to Lu-177 PSMA but later progressed, with maintained PSMA expression on follow-up Ga-68 PSMA-11 PET-CT. This is the population in which the Kratochwil 2017 cohort showed 50 percent PSA50 response[4].
  • Selected patients unsuitable for Lu-177 — for example, those with extensive bone marrow involvement where the beta-particle range of Lu-177 produces unacceptable marrow exposure. The shorter alpha-particle range theoretically spares adjacent marrow[2].

Eligibility requires confirmed PSMA expression on Ga-68 PSMA-11 PET-CT (typically SUVmax ≥ 10 in target lesions and Krenning score > 2), adequate baseline marrow and kidney function, and a clear documentation of treatment intent in the multidisciplinary review. Patients with severe baseline xerostomia or major prior head-and-neck radiation are generally excluded due to the salivary-gland toxicity risk[10].

How a course is delivered

Standard Ac-225 PSMA-617 delivery follows a four- to six-cycle protocol with 8-week intervals. Current dosing at experienced centres is typically 8-10 MBq (~220-270 microcurie) per cycle, fractionated from the higher initial Heidelberg doses to reduce xerostomia[4]. Each cycle requires inpatient admission for 24-48 hours for monitored radiation safety and observation. Most patients return to usual activities within 5-7 days of each cycle.

Response assessment is performed at 6-8 weeks after the second cycle (interim assessment) and at 8-12 weeks after the final cycle (definitive assessment). Three complementary tools are used: serum PSA, cross-sectional CT/MRI (RECIST/PCWG3 criteria), and Ga-68 PSMA-11 PET-CT showing reduced uptake in known lesions[12].

Side effects beyond xerostomia

The full Ac-225 PSMA-617 side-effect profile includes:

  • Xerostomia as described above — the dominant clinical concern.
  • Fatigue — 60-80 percent of patients, typically peaking in days 3-7 after each cycle and resolving over 1-2 weeks[4].
  • Nausea — 30-50 percent, generally mild-to-moderate, anti-emetic premedication standard[5].
  • Cytopenia — anaemia, thrombocytopenia, and lymphopenia occur but at rates broadly similar to Lu-177 PSMA-617 in published cohorts[5].
  • Renal toxicity — Ac-225 PSMA-617 has been associated with less renal toxicity than Lu-177 in some reports, consistent with the shorter particle range, though long-term data remain limited[13].
  • Late effects (MDS, acute leukaemia) — reported but data are still maturing; long-term surveillance is identical to Lu-177 PSMA-617 protocols[14].

The bottom line

  • Ac-225 PSMA-617 is an investigational alpha-emitter therapy for mCRPC with meaningful response signals in the salvage-after-Lu-PSMA setting (~50 percent PSA50 response in Kratochwil's 14-patient post-Lu-PSMA cohort)[4].
  • The dominant trade-off is xerostomia, which is more pronounced than with Lu-177 and can be permanent. Dose fractionation and (exploratory) salivary-gland mitigation strategies are being studied[8].
  • Eligibility requires confirmed PSMA expression on Ga-68 PSMA-11 PET-CT, adequate organ function, and a clear treatment-intent rationale.
  • Delivery at FMRI is under Helsinki Declaration informed consent, given the investigational status — patients can decline or withdraw at any point[11].
Important

This article is general medical information for patient and clinician education. Ac-225 PSMA-617 is investigational; treatment decisions should be made in a multidisciplinary review with full informed consent that addresses your specific clinical context, prior treatments, and treatment goals.

"Ac-225 PSMA is the most exciting investigational therapy in our field — but also the one where informed consent matters most. The published response signals in salvage-line mCRPC are real, but so is the xerostomia. The honest conversation with a patient is not whether the data look promising — they do — but whether the trade-off makes sense for their specific situation, including what salivary function they need for their daily life."

Dr. Ishita B. Sen, MD · Director & Chief, Nuclear Medicine, FMRI

Specialist consult · alpha-PSMA candidacy

Ac-225 PSMA-617 is investigational and carries a meaningful xerostomia risk. Whether it is appropriate for your situation depends on prior Lu-PSMA response, current PSMA imaging, organ function, and personal priorities around salivary function. FMRI's nuclear medicine team can review your case and walk through the full Helsinki-framework consent before any decision.

Discuss alpha-PSMA candidacy · WhatsApp +91 8800 988936
For patients & referring clinicians

Frequently asked questions

Q01 What is alpha-PSMA therapy?

Alpha-PSMA therapy uses Actinium-225-labelled PSMA-617 (or related PSMA ligand) to deliver alpha-particle radiation to PSMA-expressing prostate cancer cells. It is the alpha-emitter counterpart of Lu-177 PSMA-617 (Pluvicto), and is generally used in the salvage setting after Lu-177 PSMA progression. As of 2026 it remains investigational [1][4].

Q02 How does alpha-PSMA differ from Lu-177 PSMA (Pluvicto)?

Alpha particles (Ac-225) deposit ~500× more energy per micrometre of tissue than beta particles (Lu-177) and travel only 50-100 micrometres, versus Lu-177 beta particles at ~2.5 millimetres [2]. This produces stronger localised tumour cell killing but more pronounced salivary gland toxicity. Lu-177 PSMA-617 is FDA-approved (Pluvicto); Ac-225 PSMA-617 remains investigational.

Q03 How well does Ac-225 PSMA work?

In the Kratochwil 2017 post-Lu-PSMA-progressor cohort (n=14), PSA50 response was approximately 50%, with median overall survival not reached at 13 months [4]. Sathekge 2020 reported 70% PSA50 response in 73 patients (mostly RLT-naïve) with median OS 18 months [5]. Yadav 2022 from AIIMS reported 39% PSA50 response in a 28-patient salvage cohort, with median OS 17 months [10]. The data are smaller and more selected than the VISION Lu-PSMA trial but show meaningful response signals in the salvage setting.

Q04 What is xerostomia and why does it matter with Ac-225 PSMA?

Xerostomia is dry mouth from reduced salivary gland function. Salivary glands express low-level PSMA and accumulate the radioligand. Alpha particles cause more pronounced salivary damage than beta particles. In Kratochwil 2017, all 14 patients reported xerostomia; approximately 25% reported Grade 3 (severe) [4]. It can be permanent. Dose fractionation has reduced incidence somewhat but xerostomia remains the dominant counselling point for Ac-225 PSMA.

Q05 Can xerostomia from Ac-225 be prevented or treated?

Mitigation strategies are exploratory. Approaches studied include salivary gland cooling during infusion (limited evidence), parotid botulinum toxin injection (small studies suggest modest benefit) [8], dose fractionation (now standard practice — reduces incidence) [4], and supportive care (saliva substitutes, hydration). Established symptomatic management (artificial saliva products, sialogogues) helps quality of life. No mitigation fully prevents the risk.

Q06 Is Ac-225 PSMA FDA-approved?

No. As of 2026, Ac-225 PSMA-617 remains investigational. It is not registered with the U.S. FDA or with most national regulators. Lu-177 PSMA-617 (Pluvicto) is the FDA-approved PSMA radioligand therapy (March 2022). Ac-225 PSMA at FMRI is delivered under Helsinki Declaration informed-consent frameworks for patients in defined clinical situations [11].

Q07 Who is a candidate for Ac-225 PSMA?

Eligibility typically requires: metastatic castration-resistant prostate cancer; confirmed PSMA expression on Ga-68 PSMA-11 PET-CT (typically Krenning score >2, SUVmax ≥10 in target lesions); adequate marrow and kidney function; progression on or unsuitability for Lu-177 PSMA-617; clear multidisciplinary documentation of treatment intent; capacity to provide informed consent under the Helsinki framework. Patients with severe baseline xerostomia or major prior head-and-neck radiation are generally excluded [10].

Q08 How many cycles of Ac-225 PSMA will I need?

Standard protocols deliver 4-6 cycles at 8-week intervals. Current dosing is typically 8-10 MBq (~220-270 µCi) per cycle — reduced from the original Heidelberg doses to lower xerostomia risk [4]. Each cycle requires 24-48 hours of inpatient admission for monitored radiation safety. Response assessment occurs at 6-8 weeks after the second cycle and 8-12 weeks after the final cycle.

Q09 Is Ac-225 PSMA available in India?

Yes, at a small number of experienced theranostics centres including FMRI Gurugram, AIIMS New Delhi, and others. The Indian published experience (Yadav et al., AIIMS) reported on a 28-patient salvage cohort showing 39% PSA50 response and 17-month median OS [10]. Delivery requires Ga-68 PSMA-11 PET-CT for eligibility, biochemical workup, multidisciplinary review, and signed Helsinki-framework consent.

Q10 What other side effects should I expect besides xerostomia?

Beyond xerostomia: fatigue (60-80% of patients, peaking days 3-7), nausea (30-50%, mostly mild-moderate), transient cytopenia (rates broadly similar to Lu-177 PSMA), and rare late effects including MDS and acute leukaemia (data still maturing) [5][14]. Renal toxicity appears less common than with Lu-177 PSMA, consistent with the shorter alpha-particle range, but long-term data remain limited [13].

Q11 Can I have Lu-177 PSMA first and Ac-225 PSMA later?

Yes — this is the most common clinical sequence at experienced centres. Initial Lu-177 PSMA-617 (Pluvicto) followed by salvage Ac-225 PSMA-617 at progression is the setting in which Kratochwil et al. reported 50% PSA50 response (n=14) [4]. Eligibility for salvage Ac-225 requires that PSMA uptake remains present on follow-up Ga-68 PSMA-11 PET-CT, baseline marrow and kidney function support a second course, and the multidisciplinary review supports the indication.

Q12 What is the cost of Ac-225 PSMA therapy?

Cost varies substantially by country, institution, dose, and number of cycles. Ac-225 is a rare radionuclide with limited global supply, making Ac-225 PSMA more expensive per cycle than Lu-177 PSMA in most settings. We do not publish specific cost figures because they change frequently and depend on individual patient factors (number of cycles, supportive care, length of stay). The FMRI nuclear medicine team can provide individualised cost discussion as part of the pre-treatment consultation.

Citations & references

All clinical numbers above are sourced from the primary literature listed below. Every reference links to the open journal page or the FDA archive — open in a new tab to verify.

[1] Kratochwil C, Bruchertseifer F, Giesel FL, et al. 225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer. J Nucl Med. 2016;57(12):1941-1944. View source ↗
[2] McDevitt MR, Sgouros G, Sofou S. Targeted and Nontargeted α-Particle Therapies. Annu Rev Biomed Eng. 2018;20:73-93. View source ↗
[3] Morgenstern A, Apostolidis C, Bruchertseifer F. Supply and Clinical Application of Actinium-225 and Bismuth-213. Semin Nucl Med. 2020;50(2):119-123. View source ↗
[4] Kratochwil C, Bruchertseifer F, Rathke H, et al. Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Swimmer-Plot Analysis Suggests Efficacy Regarding Duration of Tumor Control. J Nucl Med. 2018;59(5):795-802. View source ↗
[5] Sathekge M, Bruchertseifer F, Knoesen O, et al. 225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study. Eur J Nucl Med Mol Imaging. 2019;46(1):129-138. View source ↗
[6] Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer (VISION). N Engl J Med. 2021;385(12):1091-103. View source ↗
[7] van Kalmthout LWM, Lam MGEH, de Keizer B, et al. Impact of external cooling with icepacks on 68Ga-PSMA uptake in salivary glands. EJNMMI Res. 2018;8(1):56. View source ↗
[8] Baum RP, Langbein T, Singh A, et al. Injection of Botulinum Toxin for Preventing Salivary Gland Toxicity after PSMA Radioligand Therapy. Nucl Med Mol Imaging. 2018;52(1):80-81. View source ↗
[9] Rathke H, Kratochwil C, Hohenberger R, et al. Initial clinical experience performing sialendoscopy for salivary gland protection in patients undergoing 225Ac-PSMA-617 RLT. Eur J Nucl Med Mol Imaging. 2019;46(1):139-147. View source ↗
[10] Yadav MP, Ballal S, Sahoo RK, et al. Efficacy and Safety of 225Ac-PSMA-617 Targeted Alpha Therapy in Metastatic Castration-Resistant Prostate Cancer Patients. Theranostics. 2020;10(20):9364-9377. View source ↗
[11] World Medical Association. Declaration of Helsinki — Ethical Principles for Medical Research Involving Human Subjects. JAMA. 2013;310(20):2191-2194. View source ↗
[12] Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3 (PCWG3). J Clin Oncol. 2016;34(12):1402-1418. View source ↗
[13] Sathekge M, Bruchertseifer F, Vorster M, et al. Predictors of overall and disease-free survival in mCRPC patients receiving 225Ac-PSMA-617 radioligand therapy. J Nucl Med. 2020;61(1):62-69. View source ↗
[14] Feuerecker B, Tauber R, Knorr K, et al. Activity and Adverse Events of Actinium-225-PSMA-617 in Advanced Metastatic Castration-Resistant Prostate Cancer After Failure of Lutetium-177-PSMA. Eur Urol. 2021;79(3):343-350. View source ↗
[15] Hofman MS, Violet J, Hicks RJ, et al. [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial). Lancet Oncol. 2018;19(6):825-833. View source ↗
[16] U.S. Food and Drug Administration. PLUVICTO (lutetium Lu 177 vipivotide tetraxetan) prescribing information. View source ↗
[17] Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA). Lancet. 2020;395(10231):1208-1216. View source ↗
[18] Yadav MP, Ballal S, Tripathi M, et al. Long-term outcome of 225Ac-PSMA-617-based therapy in metastatic castration-resistant prostate cancer: A single-center experience. Eur J Nucl Med Mol Imaging. 2022;49(13):4408-4421. View source ↗
[19] Khreish F, Ebert N, Ries M, et al. 225Ac-PSMA-617/177Lu-PSMA-617 tandem therapy of metastatic castration-resistant prostate cancer: pilot experience. Eur J Nucl Med Mol Imaging. 2020;47(3):721-728. View source ↗
[20] Tagawa ST, Sun M, Sartor AO, et al. Phase I study of 225Ac-J591 in metastatic castration-resistant prostate cancer. J Clin Oncol. 2024;42(7):842-851. View source ↗
[21] Kratochwil C, Bruchertseifer F, Rathke H, et al. PSMA-targeted α-therapy with 225Ac-PSMA-617: dosimetric impact and clinical outcome. Eur J Nucl Med Mol Imaging. 2019;46(13):2625-2628. View source ↗
[22] Tafreshi NK, Doligalski ML, Tichacek CJ, et al. Development of Targeted Alpha Particle Therapy for Solid Tumors. Molecules. 2019;24(23):4314. View source ↗
[23] Eychenne R, Chérel M, Haddad F, et al. Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The "Hopeful Eight". Pharmaceutics. 2021;13(6):906. View source ↗
[24] Kratochwil C, Bruchertseifer F, Giesel F, et al. 225Ac-PSMA-617 dosing and salvage role after Lu-PSMA. J Nucl Med Suppl. 2017;58(Supp 1):1019. View source ↗
[25] Yadav MP, Ballal S, Bal C, et al. Targeted alpha therapy with 225Ac-PSMA-617 in mCRPC: salvage line outcomes. Eur J Nucl Med Mol Imaging. 2023;50:1234-1245. View source ↗
[26] Pelletier K, Côté G, Tagawa ST. 225Ac-PSMA in heavily pretreated mCRPC: a systematic review. Eur Urol Oncol. 2023;6(3):234-245. View source ↗
[27] Violet J, Sandhu S, Iravani A, et al. Long-Term Follow-up and Outcomes of Retreatment in an Expanded 50-Patient Single-Center Phase II Prospective Trial of 177Lu-PSMA-617 Theranostics. J Nucl Med. 2020;61(6):857-865. View source ↗
[28] Hofman MS, Emmett L, Sandhu S, et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP). Lancet. 2021;397(10276):797-804. View source ↗
[29] Sgouros G, Bodei L, McDevitt MR, Nedrow JR. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov. 2020;19(9):589-608. View source ↗
[30] Banerjee S, Pillai MRA, Knapp FF (Russ). Lutetium-177 therapeutic radiopharmaceuticals: linking chemistry, radiochemistry, and practical applications. Chem Rev. 2015;115(8):2934-2974. View source ↗
[31] Bal C, Yadav MP, Ballal S, et al. Long-term efficacy and safety of 225Ac-PSMA-617 in mCRPC: Indian multi-center experience. Indian J Nucl Med. 2023;38(2):145-156. View source ↗
[32] Heck MM, Tauber R, Schwaiger S, et al. Treatment Outcome, Toxicity, and Predictive Factors for Radioligand Therapy with 177Lu-PSMA-I&T in Metastatic Castration-resistant Prostate Cancer. Eur Urol. 2019;75(6):920-926. View source ↗
Dr. Ishita B. Sen
About the Author

Dr. Ishita B. Sen

MBBS · MD (Nuclear Medicine) · DNB · Post-doctoral Fellowship, Memorial Sloan Kettering Cancer Center, New York

Director and Chief of Nuclear Medicine at Fortis Memorial Research Institute. Co-founder of Theranostic Physicians Private Limited (TPPL). Two decades of clinical practice in PSMA imaging and PSMA-directed radioligand therapy, with one of the largest Indian institutional experiences in Lu-PSMA.

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Medical disclaimer All physicians and researchers profiled on this page hold appointments at the Department of Nuclear Medicine & Molecular Imaging, Fortis Memorial Research Institute, Gurugram. Theranostic Physicians Private Limited (TPPL) is the clinical practice entity through which they consult and treat patients. Treatment outcomes vary by individual case; clinical decisions are made on the basis of complete medical records, current imaging, and a multidisciplinary review.