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The recent approval of [[sup.177]Lu]Lu-prostate-specific membrane antigen (PSMA) for managing metastatic castration-resistant prostate cancer (mCRPC) has catalyzed the innovation of various PSMA-targeted radiopharmaceuticals. In our retrospective study, we explored both safety and efficacy of two beta-emitting PSMA radioligands, [[sup.177]Lu]Lu and [[sup.161]Tb]Tb, for mCRPC therapy. Our study included 53 patients and reinforced prior evidence validating the clinical safety and efficacy of these radioligands. Our research suggested that these treatments are characterized by a favorable safety profile with negligible toxicity. Moreover, [[sup.161]Tb]Tb-PSMA recipients, though trialed in a smaller patient sample, yielded concordant outcomes on par with those receiving [[sup.177]Lu]Lu-PSMA, highlighting its promise as an alternative therapy and warrants additional investigation. The objective of this retrospective study is to assess the effectiveness and safety of two beta-emitting prostate-specific membrane antigen (PSMA) radioligands, [[sup.177]Lu]Lu and [161Tb]Tb, in heavily treated patients with metastatic castration-resistant prostate cancer (mCRPC). A total of 148 cycles of beta-emitting PSMA radioligand therapy were given to 53 patients at a specialized cancer care center in Amman, Jordan. This treatment was offered following the exhaustion of all prior treatment modalities. Approximately half of the cases (n = 26) demonstrated an initial partial response to PSMA radioligand therapy. Moreover, roughly one-fourth of the patients (n = 13) exhibited a sustained satisfactory biochemical response, which qualified them to receive a total of six PSMA radioligand therapy cycles and maintain continued follow-up for additional treatment cycles. This was reflected by an adequate prostate-specific antigen (PSA) decline and a concomitant partial response evident on [[sup.68]Ga]Ga-PSMA positron emission tomography/computed tomography imaging. A minority of patients (n= 18; 34%) experienced side effects. Generally, these were low-grade and self-limiting toxicities. This study endorses previous research evidence about PSMA radioligand therapy’s safety and efficacy. It also provides the first clinical insight from patients of Arab ethnicity. This should facilitate and promote further evidence, both regionally and internationally.

In the past decade, a growing body of literature has reported promising results for prostate-specific membrane antigen (PSMA)-targeted radionuclide imaging and therapy in prostate cancer. First clinical studies evaluating the efficacy of [177Lu]Lu-PSMA radioligand therapy (PSMA-RLT) demonstrated favorable results in prostate cancer patients. [177Lu]Lu-PSMA is generally well tolerated due to its limited side effects. While PSMA is highly overexpressed in prostate cancer cells, varying degrees of PSMA expression have been reported in other malignancies as well, particularly in the tumor-associated neovasculature. Hence, it is anticipated that PSMA-RLT could be explored for other solid cancers. Here, we describe the current knowledge of PSMA expression in other solid cancers and define a perspective towards broader clinical implementation of PSMA-RLT. This review focuses specifically on salivary gland cancer, glioblastoma, thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, lung cancer, and breast cancer. An overview of the (pre)clinical data on PSMA immunohistochemistry and PSMA PET/CT imaging is provided and summarized. Furthermore, the first clinical reports of non-prostate cancer patients treated with PSMA-RLT are described.

IntroductionPSMA-targeted radionuclide therapy with lutetium-177 has emerged as an effective treatment option for metastatic, castration-resistant prostate cancer (mCRPC). Recently, the concept of modifying PSMA radioligands with an albumin-binding entity was demonstrated as a promising measure to increase the tumor uptake in preclinical experiments. The aim of this study was to translate the concept to a clinical setting and evaluate the safety and dosimetry of [177Lu]Lu-PSMA-ALB-56, a novel PSMA radioligand with albumin-binding properties.MethodsTen patients (71.8 ± 8.2 years) with mCRPC received an activity of 3360 ± 393 MBq (120–160 μg) [177Lu]Lu-PSMA-ALB-56 followed by whole-body SPECT/CT imaging over 7 days. Volumes of interest were defined on the SPECT/CT images for dosimetric evaluation for healthy tissue and tumor lesions. General safety and therapeutic efficacy were assessed by measuring blood biomarkers.Results[177Lu]Lu-PSMA-ALB-56 was well tolerated, and no severe adverse events were observed. SPECT images revealed longer circulation of [177Lu]Lu-PSMA-ALB-56 in the blood with the highest uptake in tumor lesions at 48 h post injection. Compared with published data for other therapeutic PSMA radioligands (e.g. PSMA-617 and PSMA I&T), normalized absorbed doses of [177Lu]Lu-PSMA-ALB-56 were up to 2.3-fold higher in tumor lesions (6.64 ± 6.92 Gy/GBq) and similar in salivary glands (0.87 ± 0.43 Gy/GBq). Doses to the kidneys and red marrow (2.54 ± 0.94 Gy/GBq and 0.29 ± 0.07 Gy/GBq, respectively) were increased.ConclusionOur data demonstrated that the concept of albumin-binding PSMA-radioligands is feasible and leads to increased tumor doses. After further optimization of the ligand design, the therapeutic outcomes may be improved for patients with prostate cancer.

RationaleThe development of consensus guidelines for interpretation of Prostate-Specific Membrane Antigen (PSMA)-Positron Emission Tomography (PET) is needed to provide more consistent reports in clinical practice. The standardization of PSMA-PET interpretation may also contribute to increasing the data reproducibility within clinical trials. Finally, guidelines in PSMA-PET interpretation are needed to communicate the exact location of findings to referring physicians, to support clinician therapeutic management decisions.MethodsA panel of worldwide experts in PSMA-PET was established. Panelists were selected based on their expertise and publication record in the diagnosis or treatment of PCa, in their involvement in clinical guidelines and according to their expertise in the clinical application of radiolabeled PSMA inhibitors. Panelists were actively involved in all stages of a modified, nonanonymous, Delphi consensus process.ResultsAccording to the findings obtained by modified Delphi consensus process, panelist recommendations were implemented in a structured report for PSMA-PET.ConclusionsThe E-PSMA standardized reporting guidelines, a document supported by the European Association of Nuclear Medicine (EANM), provide consensus statements among a panel of experts in PSMA-PET imaging, to develop a structured report for PSMA-PET in prostate cancer and to harmonize diagnostic interpretation criteria.

Radioligand therapy (RLT) with (177)Lu-DKFZ-617 PSMA (Lu-PSMA) (prostate-specific membrane antigen) is a novel targeted therapy of metastatic prostate cancer. We analysed retrospectively the early side effects and the response rate in the first patients, who received a therapy with Lu-PSMA in our departments. RLT was performed in ten hormone- and/or chemo-refractory patients with distant metastases and progressive disease (mean age 73.5 years). (68)Ga-PSMA HBED-CC PET/CT was performed in all patients prior to RLT. The median PSA level prior to the therapy was 298.5 ng/ml (range 5-853 ng/ml). All patients received CBC, renal and liver function tests the day before and 2 days after application (mean administered activity 5.6 GBq, range 4.1-6.1 GBq), followed by further tests every 2 weeks. All patients were contacted by telephone every week regarding side effects or any positive and negative changes. Eight weeks after the therapy, seven patients (70 %) experienced a PSA decline, of whom six experienced more than 30 % and five more than 50 %. Three patients showed a progressive disease according to the PSA increase. No patient experienced any side effects immediately after injection of Lu-PSMA. Relevant hematotoxicity (grade 3 or 4) occurred 7 weeks after the administration in just one patient. The same patient showed a leucopenia grade 2. Two patients showed a disturbance of only 1 hematologic cell line, whereas one patient showed a reduction of grades 1 and 2 in leucocytes and thrombocytes, respectively. Six patients did not show any hematotoxicity during the 8 weeks after therapy. There was no relevant nephrotoxicity (grade 3 or 4). Our initial results indicate that RLT with Lu-PSMA is safe and seems to have low early side-effect profile. A relevant PSA decline was detected in 70 % of patients.

Androgen deprivation therapy (ADT) alone has been the standard of care for many years in men with metastatic prostate cancer. Due to the limited survival under this monotherapy, many new treatment options have been developed in the last few years. Regarding hormone-sensitive prostate cancer, combination therapies of two or three agents of ADT, androgen receptor signaling inhibitors (ARSI) and chemotherapy have been established and led to a significant benefit in overall survival. Additionally, in patients with metastatic castration-resistant prostate cancer, there are many new therapeutic approaches. Chemotherapy alone has been the standard of care in this situation. In the last years, some new therapeutic options have been developed, which led to an improved survival after progression under chemotherapy. These therapies include ARSI, PARP inhibitors and Lu-PSMA radioligand therapy. The use of a bispecific T-cell engager (BiTE) in this setting is a new promising therapeutic approach, which has not been established as standard of care yet. The role of immunotherapy in prostate cancer is still under investigation. Overall, many new treatment options make prostate cancer therapy a challenging and promising field.

Prostate-specific membrane antigens (PSMAs) are frequently overexpressed in both tumor stromal endothelial cells and malignant cells (stromal/tumor cells) of various cancers. The RGD (Arg-Gly-Asp) peptide sequence can specifically detect integrins involved in tumor angiogenesis. This study aimed to preclinically evaluate the cytotoxicity, biokinetics, dosimetry, and therapeutic efficacy of [sup.225]Ac-iPSMA-RGD to determine its potential as an improved radiopharmaceutical for alpha therapy compared with the [sup.225]Ac-iPSMA and [sup.225]Ac-RGD monomers. HEHA-HYNIC-iPSMA-RGD (iPSMA-RGD) was synthesized and characterized by FT-IR, UV-vis, and UPLC mass spectroscopy. The cytotoxicity of [sup.225]Ac-iPSMA-RGD was assessed in HCT116 colorectal cancer cells. Biodistribution, biokinetics, and therapeutic efficacy were evaluated in nude mice with induced HCT116 tumors. In vitro results showed increased DNA double-strand breaks through ROS generation, cell apoptosis, and death in HCT116 cells treated with [sup.225]Ac-iPSMA-RGD. The results also demonstrated in vivo cytotoxicity in cancer cells after treatment with [sup.225]Ac-iPSMA-RGD and biokinetic and dosimetric properties suitable for alpha therapy, delivering ablative radiation doses up to 237 Gy/3.7 kBq to HCT116 tumors in mice. Given the phenotype of HCT116 cancer cells, the results of this study warrant further dosimetric and clinical studies to determine the potential of [sup.225]Ac-iPSMA-RGD in the treatment of colorectal cancer.

Introduction[177Lu]Lu-PSMA-617 (Lu-PSMA) radioligand therapy is an emerging treatment option for patients with end-stage prostate cancer. However, response to Lu-PSMA therapy is only achieved in approximately half of patients. It is clinically important to identify patients at risk of poor outcome. Therefore, the aim of this study was to evaluate pretherapeutic PSMA PET derived total tumor volume and related metrics as prognosticators of overall survival in patients receiving Lu-PSMA therapy.MethodsA total number of 110 patients form the Departments of Nuclear Medicine Münster and Essen were included in this retrospective analysis. Baseline PSMA PET-CT was available for all patients. Employing a previously published approach, all tumor lesions were semi-automatically delineated in PSMA PET-CT acquisitions. Total lesion number, total tumor volume (PSMA-TV), total lesion uptake (PSMA-TLU = PSMA-TV * SUVmean), and total lesion quotient (PSMA-TLQ = PSMA-TV / SUVmean) were quantified for each patient. Log2 transformation was used for regressions.ResultsLesion number, PSMA-TV, and PSMA-TLQ were prognosticators of overall survival (HR = 1.255, p = 0.009; HR = 1.299, p = 0.005; HR = 1.326, p = 0.002). In a stepwise backward Cox regression including lesion number, PSMA-TV, PSA, LDH, and PSMA-TLQ, only the latter two remained independent and statistically significant negative prognosticators of overall survival (HR = 1.632, p = 0.011; HR = 1.239, p = 0.024). PSMA-TLQ and LDH were significant negative prognosticators in multivariate Cox regression in contrast to PSA value.ConclusionPSMA-TV was a statistically significant negative prognosticator of overall survival in patients receiving Lu-PSMA therapy. PSMA-TLQ was an independent and superior prognosticator of overall survival compared with PSMA-TV.

PurposeProstate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) is used for (re)staging prostate cancer (PCa) and as a biomarker for evaluating response to therapy, but lacks established response criteria. A panel of PCa experts in nuclear medicine, radiology, and/or urology met on February 21, 2020, in Amsterdam, The Netherlands, to formulate criteria for PSMA PET/CT-based response in patients treated for metastatic PCa and optimal timing to use it.MethodsPanelists received thematic topics and relevant literature prior to the meeting. Statements on how to interpret response and progression on therapy in PCa with PSMA PET/CT and when to use it were developed. Panelists voted anonymously on a nine-point scale, ranging from strongly disagree (1) to strongly agree (9). Median scores described agreement and consensus.ResultsPSMA PET/CT consensus statements concerned utility, best timing for performing, criteria for evaluation of response, patients who could benefit, and handling of radiolabeled PSMA PET tracers. Consensus was reached on all statements. PSMA PET/CT can be used before and after any local and systemic treatment in patients with metastatic disease to evaluate response to treatment. Ideally, PSMA PET/CT imaging criteria should categorize patients as responders, patients with stable disease, partial response, and complete response, or as non-responders. Specific clinical scenarios such as oligometastatic or polymetastatic disease deserve special consideration.ConclusionsAdoption of PSMA PET/CT should be supported by indication for appropriate use and precise criteria for interpretation. PSMA PET/CT criteria should categorize patients as responders or non-responders. Specific clinical scenarios deserve special consideration.

Purpose[68 Ga]Ga-PSMA-11 is a promising radiopharmaceutical for detecting tumour lesions in prostate cancer, but knowledge of the pharmacokinetics is limited. Dynamic PET-CT was performed to investigate the tumour detection and differences in temporal distribution, as well as in kinetic modelling of [68 Ga]Ga-PSMA-11 by tissue type.MethodsDynamic PET-CT over the lower abdomen and static whole-body PET-CT 80–90 min p.i. from 142 patients with biochemical recurrence were retrospectively analysed. Detection rates were compared to PSA levels. Average time-activity curves were calculated from tumour lesions and normal tissue. A three-compartment model and non-compartment model were used to calculate tumour kinetics.ResultsOverall detection rate was 70.42%, and in patients with PSA > 0.4 ng/mL 76.67%. All tumour lesions presented the steepest standardised uptake value (SUV) incline in the first 7–8 min before decreasing to different degrees. Normal tissue presented with a low uptake, except for the bladder, which accumulated activity the steepest 15–16 min. p.i.. While all tumour lesions continuously increased, bone metastases showed the steepest decline, resulting in a significantly lower SUV than lymph node metastases (60 and 80–90 min). Transport rate from the blood and tracer binding and internalisation rate were lower in bone metastases. Heterogeneity (fractal dimension) and vascular density were significantly lower in bone metastases.ConclusionEven at low PSA between 0.51 and 0.99 ng/mL, detection rate was 57%. Dynamic imaging showed a time window in the first 10 min where tumour uptake is high, but no bladder activity is measured, aiding accuracy in distinction of local recurrence. Kinetic modelling provided additional information for tumour characterisation by tissue type.