# New Drugs for Targeted Radionuclide Therapy in Metastatic Prostate Cancer

Kévin Hébert, Paul Bodin-Cufi, Cyril Fersing, Emmanuel Deshayes

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Kévin Hébert, Paul Bodin-Cufi, Cyril Fersing, Emmanuel Deshayes. New Drugs for Targeted Ra-dionuclide Therapy in Metastatic Prostate Cancer. European Urology Focus, 2024, 10 (4), pp.514 - 517. 10.1016/j.euf.2024.07.016. hal-05080188

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Submitted on 22 May 2025

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Mini Review

# New Drugs for Targeted Radionuclide Therapy in Metastatic Prostate Cancer

Kévin Hébert<sup>a</sup>, Paul Bodin-Cufi<sup>a</sup>, Cyril Fersing<sup>a,b</sup>, Emmanuel Deshayes<sup>a,c,*</sup>

**Article info**

**Article history:**

Accepted July 31, 2024

Available online 13 August 2024

Associate Editor: Derya Tilki

**Keywords:**

Metastatic prostate cancer

Targeted radionuclide therapy

Prostate-specific membrane

antigen

**Abstract**

Metastatic prostate cancer is a frequent and fatal disease. Targeted radionuclide therapy (TRT) has become a readily available therapeutic option since the approval of [¹⁷⁷Lu]Lu-PSMA-617. Various molecules are currently being studied for TRT in prostate cancer. We review various combinations of isotopes and vectors being used to target prostate cancer cells and optimize pharmacokinetics. Promising innovations include chemical modifications to improve biodistribution, identification of new targets, and the use of novel radioisotopes such as α emitters.

**Patient summary:** Our mini review summarizes research on targeted radioactive drugs for treatment of metastatic prostate cancer. Several promising radioactive pharmaceuticals are being evaluated in clinical trials, but more studies are necessary before these can be used in routine clinical practice.

© 2024 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)).

# 1. Introduction

Metastatic castration-resistant prostate cancer (mCRPC) is an advanced form of prostate cancer and is the second leading cause of cancer-related death among men. Targeted radionuclide therapy (TRT) is a promising new treatment approach for mCRPC. TRT uses radiopharmaceuticals composed of a radioactive isotope linked to a vector molecule. The radioisotope emits radiation that induces cancer cell death. The vector specifically targets tumor cell receptors or the tumor microenvironment. The theranostic concept is an essential aspect of TRT and involves the use of a single vector to detect the molecular target (most frequently using

positron emission tomography [PET]/computed tomography [CT]) and to perform therapy. In the pivotal phase 3 VISION study, [¹⁷⁷Lu]Lu-PSMA-617, targeting prostate-specific membrane antigen (PSMA), which is overexpressed in metastatic prostate cancer, improved both overall survival (OS) and progression-free survival (PFS) in comparison to the standard of care in a cohort of patients with mCRPC who had previously received at least one taxane regimen and androgen receptor pathway inhibitor [1]. Several radio-pharmaceuticals similar to [¹⁷⁷Lu]Lu-PSMA-617 are in development, some of them at premarketing stages, such as [¹⁷⁷Lu]Lu-PSMA-I&T (also known as PNT2002 or PSMA-1). Apart from these well-known drugs, The aim of this

<footnote><sup>a</sup>Nuclear Medicine Department, Institut Régional du Cancer de Montpellier, University of Montpellier, Montpellier, France; <sup>b</sup>Institut des Biomolécules Max Mousseron, University of Montpellier, Montpellier, France; <sup>c</sup>INSERM U1194, Institut de Recherche en Cancérologie de Montpellier, University of Montpellier, Montpellier, France</footnote>

<footnote>* Corresponding author. Nuclear Medicine Department, Institut du Cancer de Montpellier, 34298 Montpellier, France. Tel. +33 4 67613190. E-mail address: emmanuel.deshayes@icm.unicancer.fr (E. Deshayes).</footnote>
short review is to focus on innovative radiopharmaceuticals besides these well-known radioligands. We summarize ongoing clinical trials (Table 1) and recent results from studies of significant clinical and pharmacological interest according to the nature of the vector or radionuclide (Table 2).

## 2. Lutetium radioligands

Lutetium-177 is the radionuclide most commonly used for therapeutic purposes in prostate cancer TRT, mainly linked to small PSMA ligands ([¹⁷⁷Lu]Lu-PSMA-617 or [¹⁷⁷Lu]Lu-PSMA-I&T). These are cleared quickly from the circulation, and require either a high dose or frequent administration. Conjugation to an albumin-binding group can increase the circulatory half-life, tumor uptake, and absorbed dose, and can potentially reduce the activity needed to be injected, the number of injections, or the frequency of administration (Fig. 1). [¹⁷⁷Lu]Lu-EB-PSMA, which bears a truncated Evans blue albumin-binding moiety, was tested in a prospective trial (up to 3 cycles of 2 GBq at 8-wk intervals) involving 30 patients with mCRPC. Among these patients, 80% developed grade 2 hematologic toxicity and 33% experienced grade 3 toxicity; no grade 4 toxicity events occurred. Median PFS and OS were 4.6 mo and 12.6 mo, respectively, and 57% of the patients achieved a prostate-specific antigen (PSA) reduction > 50% [2]. A phase 1 trial of another derivative, [¹⁷⁷Lu]Lu-LNC1003 (EB-PSMA-01), in a cohort of 13 patients with mCRPC showed that myelosuppression was the dose-limiting toxicity at 2.6 GBq, with 1.85 GBq determined to be the maximum tolerable activity [3]. A phase 1 trial of [¹⁷⁷Lu]Lu-Ludotadipep, another PSMA ligand functionalized with a 4-phenylbutyrate albumin binder, evaluated a single dose (ranging from 1.9 to 5.6 GBq) in 24

patients with mCRPC. According to the results, 38% achieved a PSA reduction ≥50% at 12 wk and 50% experienced a reduction ≥30%, while 28% experienced PSA progression ≥25%; no dose-limiting toxicity was observed [4]. An ongoing phase 1/2 trial (NCT05458544) of this radio-pharmaceutical is investigating up to six injections of 3.7 GBq at 8-wk intervals. In another study, ten patients who received mean [¹⁷⁷Lu]Lu-PSMA-ALB-56 activity of 3.4 GBq received a higher tumor absorbed dose in comparison to those with conventional small PSMA radioligands and experienced no severe adverse events [5]. Lastly, ¹⁷⁷Lu-labeled radiohybrid PSMA ligands have been developed that allow either fluorination or radiometal binding. Initial data for four men treated with [¹⁷⁷Lu]Lu-rhPSMA-10.1 (up to 6 cycles of 7.4 GBq each) showed a mean PSA reduction of 81% without grade 3–4 toxicity [6]. A phase 2 trial is currently under way (NCT05413850).

## 3. Other radioligands

Beyond lutetium-177, other β⁻ emitters such as terbium-161 and copper-67 are attracting increasing interest for clinical use. In addition to its β⁻ decay, terbium-161 emits numerous Auger electrons, which increase local cellular damage. In a clinical study involving six patients with mCRPC with head-to-head individual comparison, the dose delivered to tumors was significantly higher with [¹⁶¹Tb]Tb-PSMA-617 than with [¹⁷⁷Lu]Lu-PSMA-617 for the same injected activity [7]. The PROGNOSTICS trial (NCT06343038) of [¹⁶¹Tb]Tb-SibuDAB, a long-circulating PSMA ligand bearing an ibuprofen moiety as a weak albumin binder, is also exploring the potential benefits of terbium-161.

The ⁶⁴Cu/⁶⁷Cu pair allows both diagnosis with copper-64 (a β⁺ emitter for PET/CT imaging) and therapy with copper-67.

<table><caption>Table 1 – Clinical trials of novel targeted radionuclide therapeutics for metastatic castration-resistant prostate cancer a</caption><thead><tr><th>Trial</th><th>Vector</th><th>Isotope</th><th>Target</th><th>Phase</th><th>ECD</th><th>Sponsor</th></tr></thead><tbody><tr><td>NCT05458544<br>LUCIDA</td><td>Ludotadipep</td><td><sup>177</sup>Lu</td><td>PSMA</td><td>1/2a</td><td>June 2025</td><td>FutureChem</td></tr><tr><td>NCT03822871</td><td>CTT1403</td><td><sup>177</sup>Lu</td><td>PSMA</td><td>1</td><td>Completed</td><td>Cancer Targeted Technology</td></tr><tr><td>NCT05413850</td><td>Radiohybrid-PSMA-10.1</td><td><sup>177</sup>Lu</td><td>PSMA</td><td>1/2</td><td>Oct 2026</td><td>Blue Earth Therapeutics</td></tr><tr><td>NCT06343038<br>PROGNOSTICS</td><td>Sibu-DAB</td><td><sup>161</sup>Tb</td><td>PSMA</td><td>1</td><td>June 2028</td><td>University Hospital Basel</td></tr><tr><td>NCT04868604<br>SECURE</td><td>SAR-bis-PSMA<br>(Abefolastat)</td><td><sup>67</sup>Cu</td><td>PSMA</td><td>1/2a</td><td>Sept 2026</td><td>Clarity Pharmaceuticals</td></tr><tr><td>NCT05633160<br>COMBAT</td><td>SAR-BBN</td><td><sup>67</sup>Cu</td><td>GRPR</td><td>1</td><td>May 2026</td><td>Clarity Pharmaceuticals</td></tr><tr><td>NCT04597411<br>ACTION</td><td>PSMA-617</td><td><sup>225</sup>Ac</td><td>PSMA</td><td>1</td><td>Jan 2027</td><td>Endocyte</td></tr><tr><td>NCT05983198<br>SATISFACTION</td><td>PSMA-R2</td><td><sup>225</sup>Ac</td><td>PSMA</td><td>1/2</td><td>Aug 2026</td><td>Novartis</td></tr><tr><td>NCT06217822<br>PANTHA</td><td>PSMA-Trillium (BAY3563254)</td><td><sup>225</sup>Ac</td><td>PSMA</td><td>1, FIH</td><td>June 2027</td><td>Bayer</td></tr><tr><td>NCT06052306</td><td>Macropa-pelgifatamab<br>(BAY3546828)</td><td><sup>225</sup>Ac</td><td>PSMA</td><td>1, FIH</td><td>June 2027</td><td>Bayer</td></tr><tr><td>NCT05219500<br>TATCIST</td><td>FPI-2265<br>(PSMA-I&T)</td><td><sup>225</sup>Ac</td><td>PSMA</td><td>2</td><td>Dec 2025</td><td>Fusion Pharmaceuticals</td></tr><tr><td>NCT06402331<br>ALPHABREAK</td><td>FPI-2265<br>(PSMA-I&T)</td><td><sup>225</sup>Ac</td><td>PSMA</td><td>2/3</td><td>Jan 2031</td><td>Fusion Pharmaceuticals</td></tr><tr><td>NCT05725070</td><td>NG001</td><td><sup>212</sup>Pb</td><td>PSMA</td><td>0/1</td><td>July 2023</td><td>ARTBIO</td></tr><tr><td>NCT03724747</td><td>BAY2315497</td><td><sup>227</sup>Th</td><td>PSMA</td><td>1, FIH</td><td>Nov 2024</td><td>Bayer</td></tr></tbody></table>

ECD = estimated completion date; FIH = first in human.

<footnote>a Ongoing trials and trials that have completed recruitment complete with results pending, excluding trials at the most advanced clinical stage such as for [¹⁷⁷Lu]Lu-PSMA-617 and [¹⁷⁷Lu]Lu-I&T. Data retrieved from ClinicalTrials.gov in May 2024.</footnote>
<table><caption>Table 2 – Main characteristics of radioisotopes in clinical use for innovative TRT of metastatic prostate cancer</caption><thead><tr><th>Parameter</th><th>Lutetium-177</th><th>Terbium-161</th><th>Copper-67</th><th>Actinium-225</th><th>Lead-212</th><th>Thorium-227</th></tr></thead><tbody><tr><td>Half-life (d)</td><td>6.7</td><td>6.9</td><td>2.5</td><td>9.9</td><td>10.6/24</td><td>18.68</td></tr><tr><td>Mean tissue range (µm)</td><td>β: 160-670</td><td>β: 200<br>Auger: &lt;1-5</td><td>β: 190-200</td><td>α: &lt;85</td><td>α: &lt;100</td><td>α: &lt;80</td></tr><tr><td>Mean energy, keV (intensity)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>β<sup>-</sup></td><td>134 (100%)</td><td>154 (100%)</td><td>145 (100%)</td><td>435 (98%)<br>198 (100%)</td><td>569</td><td>569</td></tr><tr><td>γ</td><td>208 (10%)</td><td>75 (10%)<br>45-53 (39%)</td><td>186 (44%)</td><td>218 (11.4%)<br>440 (25.9%)</td><td>238 (43%)</td><td>236 (41%)<br>256 (7%)</td></tr><tr><td>Auger electrons</td><td>3-50 (14%)</td><td>3-50 (224%)</td><td>&gt;7 (120%)</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Mean PDP α energy (MeV)</td><td>-</td><td>-</td><td>-</td><td>5.8<br>8.4</td><td>6.1<br>8.8</td><td>5.9<br>6.1</td></tr></tbody></table>

PDP = predominant decay path.

<figure><img src="image_2.png" /><figcaption>Fig. 1 – Chemical structures of the various targeted radionuclide therapeutic agents for metastatic castration-resistant prostate cancer discussed in this review, arranged by radionuclide type (blue background, ¹⁷⁷Lu; purple background, other β⁻ emitters; green background, α emitters). Nearly half of these derivatives contain an albumin-binding moiety in their structure, shown in color (blue, truncated Evans blue in [¹⁷⁷Lu]Lu-EB-PSMA; brown, 4-phenylbutyric acid-derived structure in [¹⁷⁷Lu]Lu-PSMA-ALB-56, [¹⁷⁷Lu]Ludotadipep, and [²²⁵Ac]Ac-PSMA-Trillium; purple, S-ibuprofen in [¹⁶¹Tb]Tb-SibuDAB). Of note, only [⁶⁷Cu]Cu-SAR-BBN binds to GRPR rather than prostate-specific membrane antigen (PSMA) as the target.</figcaption></figure>

Two ongoing early-phase studies are exploring the therapeutic use of copper-67 in mCRPC. SECURE (NCT04868604) investigates the dimeric PSMA-targeting agent [⁶⁷Cu]Cu-SAR-Bis-PSMA (abefolstat), which provides superior binding in comparison to conventional monomeric PSMA ligands. COMBAT (NCT05633160) tests the bombesin analog [⁶⁷Cu]Cu-SAR-BBN, which is a GRPR antagonist. This distinct target could open a path for TRT in prostate cancer cases that lack PSMA expression but express GRPR.

Radioligands that emit α particles have the potential to cause more significant DNA damage via a greater number of double-strand breaks in comparison to β⁻ emitters. Actinium-225 was recently tested in an international mCRPC cohort comprising 488 patients treated with [²²⁵Ac]Ac-PSMA-617. The disease control results are encouraging, with median OS of 15.5 mo (95% confidence interval 13.4-18.3) and median PFS of 7.9 mo (95% confidence interval 6.8-8.9) [8]. The safety profile was accept-

able, with grade ≥3 anemia in 13% of patients, leukopenia in 4%, and thrombocytopenia in 7%; 68% patients reported xerostomia after the first cycle of treatment [8]. The anti-PSMA monoclonal antibody J591 labeled with actinium-225 was tested in a dose-escalation protocol involving 32 patients. No PSMA selection was performed. The recommended phase 2 dose was the highest dose level of 93.3 kBq/kg. Severe toxicities were mainly hematological. At any given time, 46.9% of patients presented with a PSA decline of at least 50% [9].

Several noteworthy studies are currently investigating various ²²⁵Ac-labeled radiopharmaceuticals in mCRPC. These include a phase 1 study (NCT06052306) of the anti-PSMA monoclonal antibody [²²⁵Ac]Ac-macropa-pelgifatamab (BAY3546828); the PANTHA trial (NCT06217822) of ²²⁵Ac-PSMA-Trillium, an albumin-binding PSMA ligand; the SATISFACTION trial of ²²⁵Ac-PSMA-R2, a small PSMA ligand with minimal uptake in salivary glands (NCT05983198); and the
phase 2 TATCIST (NCT05219500) and phase 2/3 ALPHABREAK (NCT06402331) trials exploring $^{225}$Ac-PSMA-I&T (FPI-2265).

Ongoing phase 1 trials are also exploring novel α emit-
ters that include lead-212 linked to the PSMA-targeting
ligand NG-001 (NCT05725070) and thorium-227 coupled
to a PSMA-targeted immunoconjugate (BAY2315497), alone
or in combination with darolutamide.

4. Conclusions

The development of TRT targeting metastatic prostate can-
cer is progressing rapidly. TRT innovations involve modula-
tion of the vector and/or radioisotope to achieve optimal
combinations that improve the pharmacokinetics, enhance
efficacy, and/or reduce side effects. These advances should
pave the way for integration of TRT with other treatment
modalities such as chemotherapy and external beam radio-
therapy. Further research and clinical trials will be crucial to
identify the most effective combinations and optimize the
treatment of mCRPC.

**Conflicts of interest:** KH received honoraria and travel expenses from AAA/Novartis and Astrellas. ED received honoraria from Janssen and AAA/Novartis and travel expenses from AAA/Novartis and GE Healthcare. Other authors have nothing to disclose.

References

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[2] Wang G, Zang J, Jiang Y, et al. A single-arm, low-dose, prospective study of 177Lu-EB-PSMA radioligand therapy in patients with metastatic castration-resistant prostate cancer. J Nucl Med 2023;64:611–7.

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[7] Schaefer-Schuler A, Burgard C, Blickle A, et al. [161Tb]Tb-PSMA-617 radioligand therapy in patients with mCRPC: preliminary dosimetry results and intra-individual head-to-head comparison to [177Lu]Lu-PSMA-617. Theranostics 2024;14:1829–40.

[8] 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;25:175–83.

[9] Tagawa ST, Thomas C, Sartor AO, et al. Prostate-specific membrane antigen-targeting alpha emitter via antibody delivery for metastatic castration-resistant prostate cancer: a phase I dose-escalation study of 225Ac-J591. J Clin Oncol 2024;42:842–51.