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.

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.

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. To compare the diagnostic accuracy of ⁶⁸Ga-PSMA PET/MRI with ⁶⁸Ga-PSMA PET/CT for staging of primary PCa. 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. 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. 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. 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. 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.

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.

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Background: In 2021, the tubarial salivary glands (TSGs) were newly identified on prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) as macroscopic glands in the nasopharyngeal wall. However, the relative contribution of the TSGs to the total salivary gland function, and consequently on the development of xerostomia after external beam radiotherapy (EBRT) or PSMA-targeted radionuclide therapy (RNT) is not known. Therefore, we aimed to determine the presence of the TSGs and to quantify uptake in the TSGs on PSMA PET. Methods: Qualitative and quantitative analyses were performed on ⁶⁸Ga-PSMA-11 PET/CT scans of 100 patients with prostate cancer. The mean and maximum standardized uptake value (SUVmean and SUVmax) in the TSGs were measured and compared to the parotid, submandibular and sublingual salivary glands (PSGs, SMSGs and SLSGs, respectively). Furthermore, proportional function of the TSGs was compared to the PSGs, SMSGs and SLSGs based on the total organ PSMA (TO-PSMA). Results: The TSGs were visible on 95% of the ⁶⁸Ga-PSMA-11 PET/CT scans. The normalized median SUVmean and SUVmax was significantly higher for the PSGs (p < 0.001) and SMSGs (p < 0.001) compared to the TSGs, but not for the SLSGs (p = 0.242 and p = 0.300, respectively). The normalized median TO-PSMA was significantly higher for the PSGs (p < 0.001) and SMSGs (p < 0.001), and significant lower for the SLSGs (p < 0.001) compared the TSGs. Conclusions: The SUVmean, SUVmax and TO-PSMA of the TSGs were most comparable to the SLSGs. However, the measured PSMA uptake may be disproportional towards the saliva production. Therefore, future studies should focus on the relation between PSMA uptake and salivary function before and after PSMA therapy.