Important Update: Actinium-225 PSMA Therapy in Advanced Prostate Cancer

 


IPCSG Newsletter - September 2025

Editor's Note: Recent research has provided important insights into the side effects and safety profile of actinium-225 (²²⁵Ac) PSMA radioligand therapy. While this therapy shows promise for advanced prostate cancer, patients need to understand both its potential benefits and toxicities, including how it compares to emerging combination approaches.

What is Actinium-225 PSMA Therapy?

Actinium-225 PSMA radioligand therapy is an experimental targeted alpha therapy that uses radioactive particles to attack prostate cancer cells. Unlike lutetium-177 PSMA (which emits beta particles - high energy electrons), actinium-225 emits more powerful alpha particles (protons) that deliver greater cancer-killing energy while traveling shorter distances through tissue. Each decay produces four alpha particles, making it roughly 1000 times more powerful than beta radiation.

Understanding the Decay Chain and Recoil Effect

The Complex Decay Process

Actinium-225 undergoes a decay chain over approximately 10 days: Actinium-225 (9.9-day half-life) → Francium-221 (4.9 minutes) → Astatine-217 (32 milliseconds) → Bismuth-213 (46 minutes) → Polonium-213 (4.2 microseconds) → stable Bismuth-209

The Recoil Effect Problem

When actinium-225 decays, the energy released (over 10,000 times stronger than chemical bonds) breaks daughter isotopes free from their targeting molecule. This means toxic daughters like francium-221 and bismuth-213 travel throughout the body independently, causing damage to healthy organs.

Key elimination timeline:

  • 90% eliminated: approximately 33 days
  • 99% eliminated: approximately 66 days
  • Critical issue: Bismuth-213 accumulates in kidneys with a 4.6-day effective half-life, explaining why kidney toxicity can worsen weeks after treatment

Latest Safety Findings

The WARMTH Act Study - Global Experience

The largest study to date (488 patients across Australia, India, Germany, and South Africa) revealed concerning toxicity patterns:

Dry mouth (xerostomia):

  • 68% after first cycle, 100% after seven or more cycles
  • Often permanent due to salivary gland damage
  • Most significant quality-of-life impact

Blood and organ toxicity:

  • Severe anemia: 13%
  • Low platelet count: 7%
  • Low white blood cell count: 4%
  • Serious kidney problems: 5%
  • Up to 25% discontinue treatment due to side effects

Timeline of Toxicity Development

Weeks 1-4: Dry mouth begins, blood count changes appear Months 1-3: Peak kidney toxicity occurs due to bismuth-213 accumulation Long-term: Xerostomia may be permanent, kidney function recovery variable

Treatment Effectiveness

Despite toxicity concerns, actinium-225 shows substantial anti-tumor activity:

  • Response rate: 72% achieve PSA decline
  • Overall survival: 15.5 months median (good responders often 2+ years)
  • Effective after lutetium-177 failure: 65% still respond
  • Best outcomes: Patients without anemia, achieving >50% PSA decline, fewer prior treatments

Alternative Approach: Converge Therapy

An important comparison is with Converge Therapy's combination approach, which uses lutetium-177-PSMA plus pembrolizumab (immunotherapy):

Converge Strategy: Combines established beta radiation with immune system activation to convert "cold" tumors into "hot" tumors that respond better to treatment.

Comparative Results:

  • Efficacy: Similar response rates (68% vs 66-72% PSA decline) but potentially better progression-free survival
  • Safety: Lower discontinuation rate (6% vs up to 25%), manageable immune-related side effects (15%), less permanent toxicity
  • Approach: Addresses both radiation resistance and immune evasion simultaneously

Patient Selection Considerations:

  • Converge may be preferable for: Patients who responded to lutetium-177 initially, good immune function, preference to avoid permanent dry mouth
  • Actinium-225 may be better for: Failed lutetium-177 therapy, treatment-resistant disease, cannot tolerate immunotherapy

Production and Access Developments

Supply Chain Reality

Current global production is described as "less than a grain of sand" annually from only four facilities. The Canadian Actineer joint venture (CNL + ITM) aims to produce 3-6 curies yearly by 2025, with commercial-scale production by 2028-2029.

Expanding Clinical Applications

Beyond prostate cancer, trials are ongoing in:

  • Brain tumors (glioblastoma patients surviving 2+ years vs weeks)
  • Neuroendocrine tumors
  • Bladder cancer
  • Leukemia and lymphoma

Key Insights for Patients

Critical Understanding Points

  1. The recoil effect is unavoidable - it's fundamental physics, not a design flaw
  2. Toxicity extends beyond treatment period due to daughter isotope circulation
  3. Kidney monitoring essential for 6-12 months post-treatment
  4. Permanent dry mouth is common with multiple treatment cycles
  5. Alternative approaches exist with different risk-benefit profiles

Treatment Decision Framework

Consider actinium-225 if:

  • Lutetium-177 has failed
  • Extensive treatment-resistant disease
  • High PSMA expression tumors
  • Access available through clinical trials or compassionate use

Consider combination approaches (like Converge) if:

  • Earlier-stage disease
  • Good performance status
  • Preference for potentially reversible side effects
  • Access to combination therapy trials

Bottom Line

Actinium-225 PSMA therapy represents a powerful but toxic treatment option for advanced prostate cancer. While it shows impressive anti-tumor activity, the near-universal occurrence of permanent dry mouth, kidney toxicity from daughter isotope accumulation, and significant treatment discontinuation rates require careful consideration.

Patients should understand that multiple innovative approaches are being developed, including combination strategies that may offer similar efficacy with better tolerability. The choice between single-agent alpha therapy and combination approaches will depend on individual circumstances, prior treatments, and access to specialized centers.

Most Important Takeaway: Both actinium-225 and combination approaches remain investigational. Patients should discuss all available options with their oncology teams, including clinical trial opportunities for both strategies.

Sources and Further Reading

  1. 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 Oncol. 2024 Feb;25(2):175-183. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00638-1/abstract
  2. Converge Therapy Announces Positive Interim Results from CONVERGE-1 Trial. https://www.convergetherapy.com/news/positive-interim-results-converge-1
  3. Biodistribution of free Francium-221 and Bismuth-213 in Tumour-bearing SCID mice. Eur J Nucl Med Mol Imaging. 2025 Jul 1. https://link.springer.com/article/10.1007/s00259-025-07427-4
  4. Renal uptake of bismuth-213 and its contribution to kidney radiation dose. https://pmc.ncbi.nlm.nih.gov/articles/PMC3034478/
  5. Canadian Nuclear Isotope Council - Actinium-225 Production Update. https://www.canadianisotopes.ca
  6. Ninatti G, Scilipoti P, Pini C, et al. Time for action: actinium-225 PSMA-targeted alpha therapy for metastatic prostate cancer. Theranostics. 2025 Feb 20;15(8):3386-3399.

This article is for educational purposes and should not replace consultation with your oncology team. Always discuss treatment options and clinical trial opportunities with your healthcare providers.Actinium-225 PSMA Therapy Newsletter - Final Version | Claude | Claude

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