PSMA and Beyond 2025: Ac225 PSMA Experience

(UroToday.com) The 2025 PSMA and Beyond annual meeting featured an alpha and other radionuclides session and a presentation by Dr. Alfred Morgenstern his group’s Ac225 PSMA experience. ²²⁵Ac-PSMA for therapy of prostate cancer is a success story for targeted alpha therapy, with the following developmental timeline:

Early clinical development of Ac-PSMA with the Joint Research Centre and partner hospitals is as follows:

• 2014: with University Hospital Heidelberg focusing on dose finding, dose de-escalation, ²²⁵Ac/¹⁷⁷Lu cocktail (PSMA-617)
• 2017: with Steve Biko Academic Hospital focusing on early treatment lines, chemotherapy-naïve patients (PSMA-617, PSMA-62)
• 2017: with the Technical University of Munich focusing on post Lu-PSMA (PSMA-617)
• 2021: with Erasmus focusing on phase I dose escalation ²²⁵Ac-PSMA I&T
• 2021: with Steve Biko Academic Hospital/St. Vincent’s Hospital focusing on the phase I dose escalation study AcTION (PSMA-617, Novartis)

To date, these partnerships have led to an experience of radioligand therapy in more than 900 patients. Dr. Morgenstern highlighted the following PSMA-targeted small molecule ²²⁵Ac trials:

The following are selected prostate antibody alpha trials:

In 2021, Feuerecker and colleagues [1] reported on the safety and activity of 225-Actinium-PSMA-617 among 26 patients that progressed after Lu-177-PSMA. The PSA50 response was 65%, and (A) median PSA-PFS was 3.5 months (95% CI 1.8–11.2), (B) median clinical PFS was 4.1 months (95% CI 3–14.8), and (C) median overall survival was 7.7 months (95% CI 4.5–12.1):

The PSA best response and the PSA best response for Lu-177-PSMA versus Ac-225-PSMA-617 is also noted:

Grade 3-4 toxicity included anemia (35%), leucopenia (27%), and thrombocytopenia (19%), with grade 1-3 xerostomia in all patients, leading to cessation of treatment in 23% of patients. Thus, the benefits and risks of Ac-225-PSMA-617 in this patient population should be weighed carefully.

In 2024, work from Dr. Morgenstern’s group looked at de-escalated ²²⁵Ac-PSMA-617 versus ¹⁷⁷Lu/²²⁵Ac-PSMA-617 cocktail therapy [2]. Among 233 patients retrospectively assessed, group 1 patients received ²²⁵Ac-PSMA as a de-escalated monotherapy (n = 104; median 6 MBq), and group 2 received ¹⁷⁷Lu-PSMA (median 4 GBq) plus ²²⁵Ac-PSMA (median 4 MBq) as a cocktail regimen (n = 129). In the ²²⁵Ac-PSMA as a de-escalated monotherapy group, the PSA50 response was 53% compared to 57% in the ¹⁷⁷Lu/²²⁵Ac-PSMA-617 cocktail group:

In contrast to high dose regimens, there was no discontinuation of therapy due to xerostomia. Looking at additional work from Dr. Morgenstern’s group, they previously assessed 53 mCRPC patients that received ²²⁵Ac-PSMA therapy immediately after receiving ADT [3]. Overall, 48 patients (91%) had a PSA decline of at least 50%, and 51 patients (96%) had any decline in PSA. The following waterfall plot shows the percentage change in PSA levels after treatment with ²²⁵Ac-PSMA-617:

In this study, the median overall survival for patients with a PSA decline > 50% was > 55 months (with the median not reached at follow-up). Side effects noted were frequent grade 1/2 xerostomia, but no severe hematologic toxicity. Renal toxicity was observed in patients with preceding renal impairment, thus medium and long term toxicity need to be carefully monitored:

In 2021, Dr. Morgenstern’s group reported the first patient with 5-year complete remission with ²²⁵Ac-PSMA-617 in the chemotherapy naïve setting.

 In 2024, ²²⁵Ac-PSMA-617 was assessed in the retrospective multicenter WARMTH Act study [4], specifically 488 patients at 7 centers (South Africa, Germany, India, Australia). ²²⁵Ac-PSMA-617 was associated with a median overall survival of 15.5 months and median progression free survival of 7.9 months. Any PSA decline was noted in 73% of patients and PSA50 response was noted in 57% of patients:

Dr. Morgenstern concluded his presentation discussing his group’s Ac225 PSMA experience with the following take home points:

• The development of ²²⁵Ac-PSMA has been the game changer for targeted alpha therapy
• ²²⁵Ac-PSMA not only offers a new treatment option for prostate cancer, but has strikingly demonstrated the potential of targeted alpha therapy with ²²⁵Ac
• Numerous novel ²²⁵Ac-radiopharmaceuticals are under development and in clinical testing
• The limited supply of ²²⁵Ac is currently slowing down R&D, and additional production methods are under implementation

Presented by: Alfred Morgenstern, PhD, Joint Research Centre, Karlsruhe, Germany

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 PSMA and Beyond Annual Meeting, Los Angeles, CA, Fri, Mar 28 – Sat, Mar 29, 2025. 

References:

1. 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 Mar;79(3):343-350.
2. Rathke H, Winter E, Bruchertseifer F, et al. De-escalated ²²⁵Ac-PSMA-617 versus ¹⁷⁷Lu/²²⁵Ac-PSMA-617 cocktail therapy: A single-center retrospective analysis of 233 patients. J Nucl Med 2024;65:1057-1063.
3. Sathekge M, Bruchertseifer F, Vorster M, et al. mCRPC patients receiving ²²⁵Ac-PSMA-617 in the post-androgen deprivation therapy setting: Response to treatment and survival analysis. J Nucl Med. 2022 Oct;63(10):1496-1502.
4. 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.