Implementing Ac-225 labelled radiopharmaceuticals: practical considerations and (pre-)clinical perspectives.

BACKGROUND: In the past years, there has been a notable increase in interest regarding targeted alpha therapy using Ac-225, driven by the observed promising clinical anti-tumor effects. As the production and technology has advanced, the availability of Ac-225 is expected to increase in the near future, making the treatment available to patients worldwide. MAIN BODY: Ac-225 can be labelled to different biological vectors, whereby the success of developing a radiopharmaceutical depends heavily on the labelling conditions, purity of the radionuclide source, chelator, and type of quenchers used to avoid radiolysis. Multiple (methodological) challenges need to be overcome when working with Ac-225; as alpha-emission detection is time consuming and highly geometry dependent, a gamma co-emission is used, but has to be in equilibrium with the mother-nuclide. Because of the high impact of alpha emitters in vivo it is highly recommended to cross-calibrate the Ac-225 measurements for used quality control (QC) techniques (radio-TLC, HPLC, HP-Ge detector, and gamma counter). More strict health physics regulations apply, as Ac-225 has a high toxicity, thereby limiting practical handling and quantities used for QC analysis. CONCLUSION: This overview focuses specifically on the practical and methodological challenges when working with Ac-225 labelled radiopharmaceuticals, and underlines the required infrastructure and (detection) methods for the (pre-)clinical application.

Evaluation of the tolerability and safety of [225Ac]Ac-PSMA-I&T in patients with metastatic prostate cancer: a phase I dose escalation study.

BACKGROUND: Life expectancy of patients with metastatic castration-resistant prostate cancer (mCRPC) is still limited despite several systemic treatments. Within five years after diagnosis of primary prostate cancer, 10-20% of the patients have mCRPC and curation is not an option. Radionuclide therapy (RNT) targeted against prostate-specific membrane antigen (PSMA) emerged as a new treatment option and showed effective results in patients with mCRPC. Survival benefit after [177Lu]Lu-PSMA RNT has already been demonstrated in several clinical trials. However, [225Ac]Ac-PSMA (225Ac-PSMA) appears to be an even more promising radiopharmaceutical for the treatment of mCRPC. The use of alpha emitting radionuclides offers advantages over beta emitting radionuclides due to the high linear energy transfer effective for killing tumor cells and the limited range to reduce the radiation effects on the healthy tissue. However, these results are based on retrospective data and safety data of 225Ac-PSMA are still limited. Therefore, a prospective trial is needed to determine the optimal amount of activity that can be administered. METHODS: The 225Ac-PSMA-Imaging & Therapy (I&T) trial is an investigator-initiated phase I, single-center, open label, repeated dose-escalation and expansion trial. Patient with PSMA-positive mCRPC after at least one line of chemotherapy and/or one line of nonsteroidal antiandrogen will be treated with 225Ac-PSMA-I&T in increasing amount of activity per cycle. Dose-escalation following an accelerated 3 + 3 design which allows to open the next dose-level cohort in the absence of dose limiting toxicity while the previous one is still ongoing. Up to 4 treatment cohorts will be explored including up to 3 dose-escalation cohorts and one expansion cohort where patients will be administered with the recommended dose. A total of up to 30 patients will be enrolled in this trial. All patients will be evaluated for safety. Additionally, dosimetry was performed for the patients in the dose-escalation cohorts after the first 225Ac-PSMA-I&T administration. DISCUSSION: This trial will assess the safety and tolerability of 225Ac-PSMA-I&T in patients with mCRPC to recommend the optimal dose for the phase II trial. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT05902247). Retrospectively registered 13 June 2023.

Liquid Biopsies for Early Response Evaluation of Radium-223 in Metastatic Prostate Cancer.

PURPOSE: Reliable biomarkers for response monitoring during radium-223 treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) are lacking. Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), obtained from liquid biopsies, are shown to have prognostic value in mCRPC. The aim of this study was to determine the value of CTCs and ctDNA for response evaluation of radium-223. METHODS: In this prospective multicenter study, longitudinal blood draws and imaging were performed in 28 patients with mCRPC and predominantly bone disease, who were treated with radium-223. CTCs were counted (CELLSEARCH CTC test), while fraction of ctDNA was estimated by measuring aneuploidy of cell-free DNA (cfDNA; modified Fast Aneuploidy Screening Test-Sequencing System). CTC counts and aneuploidy score (AS) were categorized as low (<5) and high (≥5). Primary and secondary clinical end points were failure-free survival (FFS), and overall survival (OS) and development of extraosseous metastases, respectively. Additionally, CTC count and AS were related to alkaline phosphatase (ALP) and total tumor volume in bone (TTVbone) on positron emission tomography-computed tomography with 68gallium prostate-specific membrane antigen. RESULTS: FFS was longer in patients with a low CTC count or AS either at baseline or after 12 weeks, whereas for OS, only a significant association with CTC count was observed. Liquid biopsy results correlated well with ALP and TTVbone at baseline, but not with change in both parameters after three cycles of radium-223. AS and CTC count were significantly correlated. CONCLUSION: CTC count and AS of cfDNA at baseline and during treatment predict clinical response to radium-223 in patients with mCRPC, warranting future evaluation of their value in treatment guidance.

68Ga-PSMA PET/CT for Response Evaluation of 223Ra Treatment in Metastatic Prostate Cancer.

CT and bone scintigraphy are not useful for response evaluation of bone metastases to 223Ra treatment in metastatic castration-resistant prostate cancer (mCRPC). PET using 68Ga prostate-specific membrane antigen 11 (68Ga-PSMA) is a promising tool for response evaluation of mCRPC. The aim of this study was to determine the utility of 68Ga-PSMA PET/CT for response evaluation of 223Ra treatment in patients with mCRPC. Methods: Within this prospective, multicenter, imaging discovery study, 28 patients with mCRPC, eligible for 223Ra treatment, were included between 2019 and 2022. Patients received 223Ra according to the standard of care. Study procedures included CT, bone scintigraphy, and 68Ga-PSMA PET/CT at baseline, after 3 and 6 cycles of 223Ra treatment, and on treatment failure. Response to 223Ra treatment was visually assessed on all 3 imaging modalities. Total tumor volume within bone (TTVbone) was determined on 68Ga-PSMA PET/CT. Intrapatient heterogeneity in response was studied using a newly developed image-registration tool for sequential images of PET/CT. Results were compared with failure-free survival (good responders vs. poor responders; cutoff, 24 wk) and alkaline phosphatase (ALP) response after 3 cycles. Results: Visual response assessment criteria could not distinguish good responders from poor responders on 68Ga-PSMA PET/CT and bone scintigraphy. For 68Ga-PSMA PET/CT, TTVbone at baseline was lower in good responders than in poor responders, whereas TTVbone increased in both groups during treatment. TTVbone was higher in patients with new extraosseous metastases during 223Ra treatment. Although TTVbone and ALP correlated at baseline, changes in TTVbone and ALP on treatment did not. 68Ga-PSMA response of TTVbone showed intrapatient heterogeneity in most patients. Conclusion: mCRPC patients with lower TTVbone on 68Ga-PSMA PET/CT have the best clinical outcome after 223Ra treatment. Response is highly heterogeneous in most patients. A decrease in ALP, which occurred in most patients, was not correlated with a decrease in TTVbone, which might make one question the value of ALP for disease monitoring during 223Ra treatment in clinical practice.

Advances in 177Lu-PSMA and 225Ac-PSMA Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer.

For patients with metastatic castration-resistant prostate cancer (mCRPC), the survival benefit of classic treatment options with chemotherapy and drugs targeting androgen signaling is limited. Therefore, beta and alpha radionuclide therapy (RNT) have emerged as novel treatment options for patients with mCRPC. Radioligands target the prostate-specific membrane antigen (PSMA) epitopes, which are upregulated up to a thousand times more in prostate cancer cells compared to the cells in normal tissues. For this reason, PSMA is an excellent target for both imaging and therapy. Over the past years, many studies have investigated the treatment effects of lutetium-177 labeled PSMA (177Lu-PSMA) and actinium-225 labeled PSMA (225Ac-PSMA) RNT in patients with mCRPC. While promising results have been achieved, this field is still in development. In this review, we have summarized and discussed the clinical data of 177Lu-PSMA and 225Ac-PSMA RNT in patients with mCRPC.

Comparison of 68Ga-labeled Prostate-specific Membrane Antigen Ligand Positron Emission Tomography/Magnetic Resonance Imaging and Positron Emission Tomography/Computed Tomography for Primary Staging of Prostate Cancer: A Systematic Review and Meta-analysis.

CONTEXT: In December 2020, the US Food and Drug Administration approved a 68Ga-labeled prostate-specific membrane antigen ligand (68Ga-PSMA-11) for positron emission tomography (PET) in patients with suspected prostate cancer (PCa) metastasis who are candidates for initial definitive therapy. 68Ga-PSMA PET is increasingly performed for these patients and is usually combined with computed tomography (CT). In recent years, 68Ga-PSMA PET has been combined with high-resolution magnetic resonance imaging (MRI), which is beneficial for T staging and may further enhance the staging of primary PCa. OBJECTIVE: To compare the diagnostic accuracy of 68Ga-PSMA PET/MRI with 68Ga-PSMA PET/CT for staging of primary PCa. EVIDENCE ACQUISITION: A comprehensive literature search was performed using Embase, PubMed/Medline, Web of Science, Cochrane Library, and Google Scholar up to June 24, 2021 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Risk of bias was assessed using the QUADAS-2 tool. EVIDENCE SYNTHESIS: The search identified 2632 articles, of which 27 were included. The diagnostic accuracy of 68Ga-PSMA PET/MRI, measured as the pooled natural logarithm of diagnostic odds ratio (lnDOR), was 2.27 (95% confidence interval [CI] 1.21-3.32) for detection of extracapsular extension (ECE), 3.50 (95% CI 2.14-4.86) for seminal vesicle invasion (SVI), and 4.73 (95% CI 2.93-6.52) for lymph node metastasis (LNM). For 68Ga-PSMA PET/CT, the analysis showed lnDOR of 2.45 (95% CI 0.75-4.14), 2.94 (95% CI 2.26-3.63), and 2.42 (95% CI 2.07-2.78) for detection of ECE, SVI, and LNM, respectively. The overall risk of bias and applicability concerns were assessed as moderate and low, respectively. CONCLUSIONS: 68Ga-PSMA PET/MRI shows high diagnostic accuracy equivalent to that of 68Ga-PSMA PET/CT for detection of ECE, SVI, and LNM in staging of PCa. There is an urgent need for direct comparison of the two diagnostic tests in future research. PATIENT SUMMARY: The use of radioactively labeled molecules that bind to prostate-specific membrane antigen (68Ga-PSMA) for positron emission tomography (PET) scans combined with either computed tomography (CT) or magnetic resonance imaging (MRI) is increasing for prostate cancer diagnosis. There is a need for direct comparison of the two tests to demonstrate the benefit of 68Ga-PSMA PET/MRI for determining tumor stage in prostate cancer. TAKE HOME MESSAGE: After the recent US Food and Drug Administration approval of 68Ga-labeled prostate-specific membrane antigen ligand (68Ga-PSMA) positron emission tomography (PET) for staging of primary prostate cancer (PCa), it is expected that the use of this imaging modality will increase rapidly. Our review of the literature shows that 68Ga-PSMA PET/magnetic resonance imaging has high diagnostic accuracy equivalent to that of 68Ga-PSMA PET/computed tomography in primary PCa staging. There is an urgent need for direct head-to-head comparison of the two diagnostic tests in future research.

Development of [225Ac]Ac-PSMA-I&T for Targeted Alpha Therapy According to GMP Guidelines for Treatment of mCRPC.

Recently, promising results of the antitumor effects were observed in patients with metastatic castration-resistant prostate cancer treated with 177Lu-labeled PSMA-ligands. Radionuclide therapy efficacy may even be improved by using the alpha emitter Ac-225. Higher efficacy is claimed due to high linear energy transfer specifically towards PSMA positive cells, causing more double-strand breaks. This study aims to manufacture [225Ac]Ac-PSMA-I&T according to good manufacturing practice guidelines for the translation of [225Ac]Ac-PSMA-I&T into a clinical phase 1 dose escalation study. Quencher addition during labeling was investigated. Quality control of [225Ac]Ac-PSMA-I&T was based on measurement of Fr-221 (218 keV), in equilibrium with Ac-225 in approximately six half-lives of Fr-221 (T½ = 4.8 min). Radio-(i)TLC methods were utilized for identification of the different radiochemical forms, gamma counter for concentration determination, and HPGe-detector for the detection of the radiochemical yield. Radiochemical purity was determined by HPLC. The final patient dose was prepared and diluted with an optimized concentration of quenchers as during labeling, with an activity of 8-12 MBq (±5%), pH > 5.5, 100 ± 20 µg/dose, PSMA-I&T, radiochemical yield >95%, radiochemical purity >90% (up to 3 h), endotoxin levels of <5 EU/mL, osmolarity of 2100 mOsmol, and is produced according to current guidelines. The start of the phase I dose escalation study is planned in the near future.