Prostate-specific Membrane Antigen Positron Emission Tomography Research Articles

Comparing Magnetic Resonance Imaging and Prostate-Specific Membrane Antigen-Positron Emission Tomography for Prediction of Extraprostatic Extension of Prostate Cancer and Surgical Guidance: A Prospective Nonrandomized Clinical Trial.

Survivors of surgically managed prostate cancer may experience urinary incontinence and erectile dysfunction. Our aim was to determine if 68Ga-prostate-specific membrane antigen-11 positron emission tomography CT (PSMA-PET) in addition to multiparametric (mp) MRI scans improved surgical decision-making for nonnerve-sparing or nerve-sparing approach. We prospectively enrolled 50 patients at risk for extraprostatic extension (EPE) who were scheduled for prostatectomy. After mpMRI and PSMA-PET images were read for EPE prediction, surgeons prospectively answered questionnaires based on mpMRI and PSMA-PET scans on the decision for nerve-sparing or nonnerve-sparing approach. Final whole-mount pathology was the reference standard. Sensitivity, specificity, positive predictive value, negative predictive value, and receiver operating characteristic curves were calculated and McNemar's test was used to compare imaging modalities. The median age and PSA were 61.5 years and 7.0 ng/dL. The sensitivity for EPE along the posterior neurovascular bundle was higher for PSMA-PET than mpMRI (86% vs 57%, P = .03). For MRI, the specificity, positive predictive value, negative predictive value, and area under the curve for the receiver operating characteristic curves were 77%, 40%, 87%, and 0.67, and for PSMA-PET were 73%, 46%, 95%, and 0.80. PSMA-PET and mpMRI reads differed on 27 nerve bundles, with PSMA-PET being correct in 20 cases and MRI being correct in 7 cases. Surgeons predicted correct nerve-sparing approach 74% of the time with PSMA-PET scan in addition to mpMRI compared to 65% with mpMRI alone (P = .01). PSMA-PET scan was more sensitive than mpMRI for EPE along the neurovascular bundles and improved surgical decisions for nerve-sparing approach. Further study of PSMA-PET for surgical guidance is warranted in the unfavorable intermediate-risk or worse populations. NCT04936334.

Prostate-Specific Membrane Antigen Positron Emission Tomography Oncological Applications beyond Prostate Cancer in Comparison to Other Radiopharmaceuticals.

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein overexpressed on the surface of tumor cells in most of the patients affected by prostate adenocarcinoma (PCa). However, PSMA expression has also been demonstrated in the endothelial cells of newly formed vessels of various solid tumors, suggesting a role for PSMA in neoangiogenesis. In this scenario, gallium-68 (68Ga) or fluoro-18 (18F)-labeled PSMA positron emission tomography (PET) may play a role in tumors other than PCa, generally evaluated employing other radiopharmaceuticals targeting different pathways. This review aims to investigate the detection rate of PSMA-PET compared to other radiopharmaceuticals (especially [18F]FDG) in non-prostate tumors to identify patients who may benefit from the use of such a theragnostic agent. We performed a bibliographic search on three different databases until February 2024 using the following terms: "positron emission tomography", "PET", "PET/CT", "Prostate-specific membrane antigen", "PSMA", "non-prostate", "not prostate cancer", "solid tumor", "FDG", "Fluorodeoxyglucose", "FAPi", "FET", "MET", "DOPA", "choline", "FCH", "FES", "DOTATOC", "DOTANOC", and "DOTATATE". Only original articles edited in English with at least 10 patients were included. Out of a total of 120 articles, only 25 original articles comparing PSMA with other radiotracers were included in this study. The main evidence was demonstrated in renal cell carcinoma, where PSMA showed a higher detection rate compared to [18F]FDG PET/CT, with implications for patient management. PSMA PET may also improve the assessment of other entities, such as gliomas, in defining regions of early neoangiogenesis. Further data are needed to evaluate the potential role of PSMA-PET in triple-negative breast cancer as a novel therapeutic vascular target. Finally, unclear applications of PSMA-PET include thyroid and gastrointestinal tumors. The present review shows the potential use of PSMA-labeled PET/CT in solid tumors beyond PCa, underlining its value over other radiopharmaceuticals (mainly [18F]FDG). Prospective clinical trials with larger sample sizes are crucial to further investigate these possible clinical applications.

Comparison of discovery rates and prognostic utility of [68Ga]Ga-PSMA-11 PET/CT and circulating tumor DNA in prostate cancer-a cross-sectional study.

Circulating-tumor DNA (ctDNA) and prostate-specific membrane antigen (PSMA) ligand positron-emission tomography (PET) enable minimal-invasive prostate cancer (PCa) detection and survival prognostication. The present study aims to compare their tumor discovery abilities and prognostic values. One hundred thirty men with confirmed PCa (70.5 ± 8.0years) who underwent [68Ga]Ga-PSMA-11 PET/CT (184.8 ± 19.7MBq) imaging and plasma sample collection (March 2019-August 2021) were included. Plasma-extracted cell-free DNA was subjected to whole-genome-based ctDNA analysis. PSMA-positive tumor lesions were delineated and their quantitative parameters extracted. ctDNA and PSMA PET/CT discovery rates were compared, and the prognostic value for overall survival (OS) was evaluated. PSMA PET discovery rates according to castration status and PSA ranges did differ significantly (P = 0.013, P < 0.001), while ctDNA discovery rates did not (P = 0.311, P = 0.123). ctDNA discovery rates differed between localized and metastatic disease (P = 0.013). Correlations between ctDNA concentrations and PSMA-positive tumor volume (PSMA-TV) were significant in all (r = 0.42, P < 0.001) and castration-resistant (r = 0.65, P < 0.001), however not in hormone-sensitive patients (r = 0.15, P = 0.249). PSMA-TV and ctDNA levels were associated with survival outcomes in the Logrank (P < 0.0001, P < 0.0001) and multivariate Cox regression analysis (P = 0.0023, P < 0.0001). These findings suggest that PSMA PET imaging outperforms ctDNA analysis in detecting prostate cancer across the whole spectrum of disease, while both modalities are independently highly prognostic for survival outcomes.

Biochemical Response of

BackgroundIn a subset of patients with oligorecurrent prostate cancer (PCa), salvage surgery with prostate-specific membrane antigen (PSMA) radioguided surgery (PSMA-RGS) seems to be of value. ObjectiveTo evaluate whether a lower level of postoperative prostate-specific antigen (PSA; <0.1 ng/ml) is predictive of therapy-free survival (TFS) following salvage PSMA-RGS. Design, setting, and participantsThis cohort study evaluated patients with biochemical recurrence after radical prostatectomy and oligorecurrent PCa on PSMA positron emission tomography treated with PSMA-RGS in three tertiary care centers (2014–2022). InterventionPSMA-RGS. Outcome measurements and statistical analysisPostsalvage surgery PSA response was categorized as <0.1, 0.1–<0.2, or >0.2 ng/ml. Kaplan-Meier and multivariable Cox regression models evaluated TFS according to PSA response. Results and limitationsAmong 553 patients assessed, 522 (94%) had metastatic soft tissue lesions removed during PSMA-RGS. At 2–16 wk after PSMA-RGS, 192, 62, and 190 patients achieved PSA levels of <0.1, 0.1–<0.2, and >0.2 ng/ml, respectively. At 2 yr of follow-up, TFS rate was 81.1% versus 56.1% versus 43.1% (p < 0.001) for patients with PSA <0.1 versus 0.1–<0.2 versus >0.2 ng/ml. In multivariable analyses, PSA levels of 0.1–0.2 ng/ml (hazard ratio [HR]: 1.9, confidence interval [CI]: 1.1–3.1) and ≥0.2 ng/ml (HR: 3.2, CI: 2.2–4.6, p < 0.001) independently predicted the need for additional therapy after PSMA-RGS. The main limitation is the lack of a control group. ConclusionsFor patients after salvage PSMA-RGS, a lower biochemical response (PSA <0.1 ng/ml) seems to predict longer TFS. This insight may help in counseling patients postoperatively as well as guiding the timely selection of additional therapy. Patient summaryWe studied what happened to prostate cancer patients in three European centers who had salvage surgery using a special method called prostate-specific membrane antigen–targeted radioguidance. We found that patients who had low prostate-specific antigen levels soon after surgery were less likely to need further treatment for a longer time.

Heterogeneous PSMA ligand uptake inside parotid glands

The purpose of this investigation is to quantify the spatial heterogeneity of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) uptake within parotid glands. We aim to quantify patterns in well-defined regions to facilitate further investigations. Furthermore, we investigate whether uptake is correlated with computed tomography (CT) texture features. Methods: Parotid glands from [18F]DCFPyL PSMA PET/CT images of 30 prostate cancer patients were analyzed. Uptake patterns were assessed with various segmentation schemes. Spearman’s rank correlation coefficient was calculated between PSMA PET uptake and feature values of a Grey Level Run Length Matrix using a long and short run length emphasis (GLRLML and GLRLMS) in subregions of the parotid gland. Results: PSMA PET uptake was significantly higher (p < 0.001) in lateral/posterior regions of the glands than anterior/medial regions. Maximum uptake was found in the lateral half of parotid glands in 50 out of 60 glands. The difference in SUVmean between parotid halves is greatest when parotids are divided by a plane separating the anterior/medial and posterior/lateral halves symmetrically (out of 120 bisections tested). PSMA PET uptake was significantly correlated with CT GLRLML (p < 0.001), and anti-correlated with CT GLRLMS (p < 0.001). Conclusion: Uptake of PSMA PET is heterogeneous within parotid glands, with uptake biased towards lateral/posterior regions. Uptake within parotid glands was strongly correlated with CT texture feature maps.

Neural blind deconvolution for deblurring and supersampling PSMA PET.

Objective. To simultaneously deblur and supersample prostate specific membrane antigen (PSMA) positron emission tomography (PET) images using neural blind deconvolution.Approach. Blind deconvolution is a method of estimating the hypothetical 'deblurred' image along with the blur kernel (related to the point spread function) simultaneously. Traditionalmaximum a posterioriblind deconvolution methods require stringent assumptions and suffer from convergence to a trivial solution. A method of modelling the deblurred image and kernel with independent neural networks, called 'neural blind deconvolution' had demonstrated success for deblurring 2D natural images in 2020. In this work, we adapt neural blind deconvolution to deblur PSMA PET images while simultaneous supersampling to double the original resolution. We compare this methodology with several interpolation methods in terms of resultant blind image quality metrics and test the model's ability to predict accurate kernels by re-running the model after applying artificial 'pseudokernels' to deblurred images. The methodology was tested on a retrospective set of 30 prostate patients as well as phantom images containing spherical lesions of various volumes.Main results. Neural blind deconvolution led to improvements in image quality over other interpolation methods in terms of blind image quality metrics, recovery coefficients, and visual assessment. Predicted kernels were similar between patients, and the model accurately predicted several artificially-applied pseudokernels. Localization of activity in phantom spheres was improved after deblurring, allowing small lesions to be more accurately defined.Significance. The intrinsically low spatial resolution of PSMA PET leads to partial volume effects (PVEs) which negatively impact uptake quantification in small regions. The proposed method can be used to mitigate this issue, and can be straightforwardly adapted for other imaging modalities.

Prostate-Specific Membrane Antigen PET Response Associates with Metastasis-Free Survival After Stereotactic Ablative Radiation in Oligometastatic Prostate Cancer

PurposeEmerging data suggest metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can detect occult metastatic disease and has been proposed as a biomarker for treatment response. Herein we identify and validate a PSMA-PET biomarker for metastasis-free survival (MFS) following MDT in omCSPC. Methods and materialsWe performed an international multi-institutional retrospective study of patients with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation therapy who underwent PSMA-PET/CT prior to and after (median 6.2 months, range 2.4-10.9 months) treatment. Pre- and post-MDT PSMA-PET/CT SUVmax was measured for all lesions and PSMA response was defined as percent change in SUVmax of the least responsive lesion. PSMA response was evaluated as both a continuous variable and dichotomized as PSMA responders with a complete/partial response (at least 30% reduction in SUVmax) and PSMA non-responders with stable/progressive disease (less than a 30% reduction in SUVmax). PSMA response was correlated conventional imaging defined metastasis-free survival (MFS) with Kaplan-Meier and cox regression. ResultsA total of 131 patients with 261 treated metastases were included in the analysis, with median follow-up of 29 months (IQR 18.5-41.3). Following SABR, 70.2% of patients were classified as PSMA responders. Multivariable analysis demonstrated PSMA response as a continuous variable was associated with significantly worse MFS (HR=1.003, 95%CI 1.001-1.006; p=0.016). Patients classified as PSMA responders were found to have significantly improved median MFS of 39.9 vs 12 months (p=0.001) compared to PSMA non-responders. Our study is limited as it is a retrospective review of a heterogenous population. ConclusionsFollowing SABR, PSMA-PET response appears to be a radiographic biomarker that correlates with MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated in a prospective setting.

Multidisciplinary Team Approach in Prostate-Specific Membrane Antigen Theranostics for Prostate Cancer: A Narrative Review

In managing prostate cancer, the integration of multidisciplinary team (MDT) with prostate-specific membrane antigen (PSMA) theranostics marks a significant advancement, addressing the disease's spectrum from indolent forms to aggressive metastatic stages. MDTs, comprising urology, oncology, radiation oncology, pathology, radiology, and nuclear medicine experts, are pivotal in delivering tailored, evidence-based care, essential for the varied clinical presentations of prostate cancer. The introduction of PSMA-targeted theranostics and PSMA positron emission tomography imaging has impacted the approach to diagnosis and treatment, offering enhanced precision in disease localization and enabling more nuanced management strategies for conditions such as oligometastatic prostate cancer, metastatic hormone-sensitive prostate cancer, and metastatic castration-resistant prostate cancer. The collaborative approach of MDTs in utilizing PSMA-targeted radioligand therapy emphasizes meticulous patient selection, predictive assessment of therapy response, and careful management of therapy-related toxicities. Additionally, recent strategies, including combination therapies from ENZA-P and Lu-PARP trials, show potential for improving treatment efficacy. This unified approach showcases the critical role of MDTs in optimizing treatment outcomes, underscoring the importance of collaboration in advancing the treatment of prostate cancer with PSMAtargeted therapies, thereby setting a new paradigm in personalized prostate cancer management.

Abstract 4150: Development of a three-dimensional spatialomics map of lethal prostate cancer driven by clinical imaging

Abstract Prostate adenocarcinoma (PCa) is the most common malignancy and the second leading cause of cancer-related mortality in United States men. Following treatment for localized PCa, up to 50% of these men can experience disease recurrence, with subsequent metastasis and death. This indicates that there is suboptimal identification of lethal PCa at the time of diagnosis, despite advancements in imaging, genomics, and biomarkers. To improve the noninvasive diagnosis of lethal PCa at initial diagnosis, we have developed a novel magnetic resonance imaging (MRI) method, diffusion basis spectrum imaging (DBSI), that noninvasively measures cancer, stromal, and immune cell contributions to the prostate tumor microenvironment (TME). To validate DBSI for PCa, we have applied novel technologies to matched prostatectomy specimens that include (i) fully automated tissue section processing with serial 2-photon tomographic (STP) imaging of the sections to generate 3D volumetric structural maps of the tumor tissue and (ii) multiplex MALDI mass spectrometry imaging of untargeted glycans and extracellular matrix (ECM) peptides and of proteins targeted with novel photocleavable-mass-tagged antibodies (MALDI-IHC) to spatially resolve hundreds of biomolecules from the TME. To establish the feasibility of this approach, we recruited a patient with an unusually aggressive prostate cancer consisting of Gleason 5+4 acinar adenocarcinoma histology with intraductal growth that was locally invasive and lymph node positive at prostatectomy (stage T3bN1). This patient also had the unusual finding of low activity on prostate specific membrane antigen positron emission tomography (PSMA-PET). Following gross sectioning of the prostate with MRI-guided 3D printed molds to co-register clinical DBSI with histology, a 5-mm thick tissue cross-section containing tumor and normal prostate was imaged with high resolution ex vivo DBSI followed by 3D structural mapping with STP imaging. Selected slides in the 3D stack were subject to multiplexed MALDI imaging to identify relationships between cellular and molecular heterogeneity with tumor structure identified with DBSI and STP imaging. We discovered unique structural differences in the prostate tumor compared with the surrounding stroma based upon collagen and glycan modifications to the ECM that were recapitulated with second harmonic maps of collagen from STP imaging as well as stromal maps generated from DBSI imaging. Additional novel protein and glycan ECM components were expressed in this tumor known to be associated with poor patient outcomes. Together, these data represent the first evidence successfully linking noninvasive in vivo clinical imaging and de novo spatialomics technologies with potential to improve PCa diagnostics. This advanced imaging workflow can be applied to any tissue type, underscoring its relevance to translational cancer research. Citation Format: Joseph E. Ippolito, David H. Ballard, Karla Bergeron, Ritesh Chidambaram, Anusha Elumalai, Tyler J. Fraum, Huaping Jing, Peter Kamelin, Eric H. Kim, Catherine Kita, Aleksandra Klim, Anthony Knesis, Mark Lim, José Marcio Luna, Hani Nakhoul, Timothy Ragan, Kenneth J. Rothschild, Sheng-Kwei Song, Kainen Utt, Cody Weimholt, Gargey Yagnik, Elijah Yew, Peggi M. Angel, Richard R. Drake. Development of a three-dimensional spatialomics map of lethal prostate cancer driven by clinical imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4150.

The Role of PSMA PET Imaging in the Classification of the Risk of Prostate Cancer Patients: A Systematic Review on the Insights to Guide an Active Surveillance Approach.

active surveillance (AS) is a suitable strategy for patients with prostate cancer (PCa). Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging is an established tool used to assess PCa. The aim of this review was to evaluate the role of PSMA imaging to guide correct risk-based classification and the AS approach in PCa patients. The Scopus, Embase, Web of Science, Cochrane Library, and PubMed/MEDLINE databases were screened to find relevant published articles. 1774 articles were revealed with the literature search. A total of 1764 articles were excluded after applying exclusion criteria (data not within the field of interest, preclinical papers, conference proceedings, reviews, or editorials). Ten studies were finally included in the review, revealing that PSMA PET could have the ability to guide risk-based classification of PCa and the choice of AS, and to guide the execution of biopsies for the research of high-grade PCa, therefore precluding AS. this systematic review underlined a possible role of PSMA PET imaging in patients with PCa by correctly re-classifying them on the basis of their risk and guiding AS.

A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating "BRCAness" Genotype (ROAR).

Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms. This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600 mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle. The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI, 0-85.11 months). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen. Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946).

Lutetium-177 Labelled Anti-PSMA Monoclonal Antibody (Lu-TLX591) Therapy for Metastatic Prostate Cancer: Treatment Toxicity and Outcomes.

Whilst prostate cancer is the fourth most common cancer globally, effective therapies for patients with advanced disease are lacking. In recent years, interest in using theranostic agents to treat castrate-resistant prostate cancer (CRPC) and metastatic prostate cancer has emerged. Lu-TLX591 monoclonal antibody is a potential agent of significance; however, to date, reports on its toxicity and efficacy have been limited to small clinical trials in heavily pretreated patients. This retrospective study describes the real-world toxicity and efficacy profile of Lu-TLX591. Eighteen patients received Lu-TLX591 at two private oncology centres in Australia. Patients were eligible if they had CRPC or metastatic prostate cancer and prostate-specific membrane antigen (PSMA)-avid disease confirmed by PSMA-positron emission tomography (PET). Patients received two cycles of Lu-TLX591 monoclonal antibody (177 Lu-DOTA-rosopatamab) each dosed from 1.01-2.85 GBq, 14 days apart. Patient side effects, blood test results and radiology reports were recorded on the patient's electronic medical record (eMR). Prominent side effects included fatigue (55.6%), anorexia (16.7%), nausea (11.1%), and transfusion reactions (11.1%). All-grade haematological toxicities included lymphopenia (61.1%), anaemia (22.2%), leukopenia (27.8%), neutropenia (27.8%), and thrombocytopenia (27.8%). Grade 4 toxicity included lymphopenia (6.7%) and thrombocytopenia (6.7%). Patients' prostate-specific antigen (PSA) responses were as follows; ≥ 30% PSA decline (27.8%), ≥ 50% PSA decline (11.4%) and any PSA decline (38.9%). Follow-up radiology revealed 54.5% stable disease, 45.4% disease progression and 9.1% disease regression. Lu-TLX591 was safely administered at acceptable toxicity and its efficacy reflects previous clinical trials. Larger studies are required and are underway (NCT04786847; NCT05146973; NCT04876651) to determine Lu-TLX591 effectiveness amongst different prostate cancer populations and compare its efficacy against peptide-based radiopharmaceutical agents.

Pretherapeutic PSMA PET-Derived Semiquantitative Parameters as Predictors of PSA Response in Patients with mCRPC Receiving [177Lu]Lu-PSMA-617 Radioligand Therapy

Abstract Objective [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 radioligand therapy (RLT) shows promise for metastatic castration-resistant prostate cancer (mCRPC) patients with positive PSMA positron emission tomography (PET) imaging. Identifying high-risk patients is crucial. We evaluated pretherapeutic PSMA PET-derived parameters to predict prostate-specific antigen (PSA) response in patients undergoing [177Lu]Lu-PSMA-617 RLT. Materials and Methods We conducted a retrospective analysis among 27 patients (mean age: 71.0 ± 9.5 years; range: 52–85 years) who underwent PSMA PET/computed tomography (CT) and subsequent [177Lu]Lu-PSMA-617 RLT between March 2019 and January 2023. After excluding patients with liver metastases, the number of patients left for analysis was 21 (14 responders and 7 nonresponders). Tumors were semiautomatically delineated with calculation of total tumor volume (PSMA-TV), lesion uptake (PSMA-TLU = PSMA-TV * standardized uptake value [SUV]mean), and lesion quotient (PSMA-TLQ = PSMA-TV/SUVmean) for each patient. Semiquantitative parameters were analyzed only in patients with mCRPC and no liver metastasis. Results In total, 17/27 patients (62.96%) had a decline in PSA levels; 15/27 patients (55.56%) experienced a decline of &gt; 50%. Pretherapeutic PSMA PET/CT results revealed significant differences in PSMA-TV (p = 0.003), PSMA-TLU (p = 0.013), and PSMA-TLQ (p = 0.011) between responders and nonresponders. SUVmax was significantly correlated to the best percentage change in PSA response after 177Lu-PSMA-617 treatment (r = −0.79, p = 0.006). No association was observed between PSMA-TV (p = 0.367), PSMA-TLU (p = 0.128), and PSMA-TLQ (p = 0.556), with the best percentage change in PSA response after 177Lu-PSMA-617 therapy. Conclusion Pretherapeutic PSMA PET-derived PSMA-TV, PSMA-TLU, and PSMA-TLQ were significant negative predictors of PSA response in patients with mCRPC and no liver metastasis receiving [177Lu]Lu-PSMA-617 RLT.

Prostate-specific membrane antigen-positron emission tomography (PSMA-PET) of prostate cancer: current and emerging applications.

Prostate-specific membrane antigen-positron emission tomography (PSMA-PET) is transforming the management of patients with prostate cancer. In appropriately selected patients, PSMA-PET offers superior sensitivity and specificity compared to conventional imaging (e.g., computed tomography and bone scintigraphy) as well as choline and fluciclovine PET, with the added benefit of consolidating bone and soft tissue evaluation into a single study. Despite being a newly available imaging tool, PSMA-PET has established indications, interpretation guidelines, and reporting criteria, which will be reviewed. The prostate cancer care team, from imaging specialists to those delivering treatment, should have knowledge of physiologic PSMA radiotracer uptake, patterns of disease spread, and the strengths and limitations of PSMA-PET. In this review, current and emerging applications of PSMA-PET, including appropriateness use criteria as well as image interpretation and pitfalls, will be provided with an emphasis on clinical implications.

Metastasis-directed therapy in prostate cancer

Metastasis-directed therapy (MDT) in oligometastatic prostate cancer (omHSPC) is playing an increasingly important role in therapy with the aim of delaying disease progression, the start of systemic treatment or switching systemic treatment to improve the patient's overall prognosis. Molecular imaging as prostate-specific membrane antigen positron emission tomography (PSMA-PET) imaging allows metastases to be detected with ahigher sensitivity and specificity. This means that they can be detected early and made accessible for treatment. The standard therapy for oligo-mHSPC is androgen deprivation (ADT), which is supplemented by novel hormonal therapeutics (NHT). Afew small prospective trials have shown an extension of the ADT-free interval and progression-free survival (PFS), particularly in metachronous oligo-mHSPC, by MDT, usually radiotherapy. Additional ADT can further extend the PFS in particular. There are hardly any prospective data for synchronous oligo-mHSPC. Despite the currently still poor evidence, MDT is playing an increasingly important role. The still unclear definition of oligometastasis and the large number of influencing factors make it difficult to compare current data. Large multicenter prospective data are still pending. It is also important to clarify the effect of limited ADT in combination with NHT in the treatment of synchronous and metachronous oligo-mHSPC with MDT. In synchronous oligo-mHSPC in particular, further benefit of additional local therapy of the primary in combination with MDT should also be investigated.

Development of the quantitative PET prostate phantom (Q3P) for improved quality assurance of 18 F-PSMA PET imaging in metastatic prostate cancer.

Phantoms are commonly used to evaluate and compare the performance of imaging systems given the known ground truth. Positron emission tomography (PET) scanners are routinely validated using the NEMA image quality phantom, in which lesions are modeled using 10 to 37mm fillable spheres. The NEMA phantom neglects, however, to model focal (3-10-mm), high-uptake lesions that are increasingly observed in prostate-specific membrane antigen (PSMA) PET images. PSMA-targeting radiopharmaceuticals allow for enhanced detection of metastatic prostate cancers. As such, there is significant need to develop an updated phantom which considers both the quantitative and lesion detectability of this new paradigm in oncological PET imaging. In this work, we present the Quantitative PET Prostate Phantom (Q3P); a portable and modular phantom that can be used to improve and harmonize imaging protocols for 18 F-PSMA PET scans. A one-piece cylindrical phantom was designed effectively in two halves, which we call modules. Module 1 was designed to mimic lesions in the presence of background, and Module 2 mimicked very high contrast conditions (i.e., very low background) that can be observed in 18 F-PSMA PET scans. Shell-less radioactive spheres (3-16-mm) were cast using epoxy resin mixed with sodium-22 (22 Na), a long half-life positron emitter with positron range similar to 18 F. To establish realistic lesion contrast, the 22 Na spheres were mounted in a cylindrical chamber that can be filled with an 18 F background (module 1). Thirteen exchangeable spherical cavity inserts (3-37-mm) were machined in two parts and solvent welded together, and filled with 18 F (50 kBq/mL) to model lesions with very high contrast (module 2). Five 2.5-min PET scans were acquired on a 5-ring GE Discovery MI PET/CT scanner (General Electric, USA). Lesions were segmented using 41% of SUVmax fixed thresholding (41% FT) and recovery coefficients (RCs) were computed from 5 noise realizations. The manufactured phantom is portable (5.7kg) and scan preparation takes less than 40min. The total 22 Na activity is 250 kBq, allowing it to be shipped as an exempt package under International Atomic Energy Agency (IAEA) regulations. Recovery coefficients, computed using PSF modeling and no post-reconstruction smoothing, were 130.3% (16mm), 147.1% (10mm), 87.2% (6mm), and 7.0% (3mm) for RCmax , which decreased to 91.1% (16mm), 90.6% (10mm), 53.2% (6mm), and 3.6% (3mm) for RCmean in the 22 Na spheres. Comparatively, 18 F sphere recovery was 110.7% (17mm), 123.6% (10mm), 106.5% (7mm), and 23.3% (3mm) for RCmax , which was reduced to 76.7% (17mm), 77.7% (10mm), 66.8% (7mm), and 13.5% (3mm), for RCmean . A standardized imaging phantom was developed for lesion quantification assessment in 18 F-PSMA PET images. The phantom is configurable, providing users with the opportunity to modify background activity levels or sphere sizes according to clinical demands. Distributed to the community, the Q3P phantom has the potential to enable better assessment of lesion quantification and harmonization of 18 F-PSMA PET imaging, which may lead to more robust predictive metrics and better outcome prediction in metastatic prostate cancer.

99m TcPSMA-radioguided surgery in oligorecurrent prostate cancer: the randomised TRACE-II trial.

To investigate whether combination treatment of prostate-specific membrane antigen (PSMA)-based radioguided surgery (RGS) with short-term androgen deprivation therapy (ADT) improves oncological outcomes in men with oligorecurrent prostate cancer (PCa) as compared to treatment with short-term ADT only. The TRACE-II study is an investigator-initiated, prospective, randomised controlled clinical trial. Patients (aged >18 years) with hormone-sensitive recurrent PCa after radical prostatectomy or radiotherapy (brachytherapy or external beam radiotherapy), with involvement of ≤2 lymph nodes or local oligorecurrent disease within the pelvis as determined by PSMA positron emission tomography (PET)/computed tomography (CT) are randomly assigned in a 1:1 ratio between 6-month ADT (Arm A) or 6-month ADT plus RGS (Arm B). The primary objective is to determine clinical progression-free survival (CPFS) at 24 months. After PSMA-RGS, CPFS is defined as the time between the start of treatment and the appearance of a re-recurrence (any N1 or M1) as suggested by PSMA-PET/CT or symptoms related to progressive PCa, or death from any cause. The secondary objectives include metastasis-free survival at 2, 5 and 10 years, biochemical progression-free survival at 2 years, and patient-reported quality of life at 2, 5 and 10 years. A total of 60 patients, 30 per arm, will be included. The trial is powered (80%) to detect at least a 30% absolute difference in CPFS between the two study arms in the period 2 years after randomisation. We expect to enrol the required participants in 3 years. The study has an expected duration of 5 years in total. Combining RGS with short-term ADT might be oncologically beneficial for patients with oligorecurrent PCa. In this first randomised controlled trial, we are investigating the potential oncological benefits of this combined treatment, while also focusing on maintaining quality of life.

PSMA PET/CT as a predictive tool for subregional importance estimates in the parotid gland

Objective. Xerostomia and radiation-induced salivary gland dysfunction remain a common side effect for head-and-neck radiotherapy patients, and attempts have been made to quantify the heterogeneity of the dose response within parotid glands. Prostate Specific Membrane Antigen (PSMA) ligands have demonstrated high uptake in salivary glands, which has been shown to correlate with gland functionality. Here we compare several models of parotid gland subregional relative importance with PSMA positron emission tomography (PET) uptake. We then develop a predictive model for Clark et al's relative importance estimates using PSMA PET and CT radiomic features, and demonstrate a methodology for predicting patient-specific importance deviations from the population. Approach. Intra-parotid gland uptake was compared with four regional importance models using 30 [18F]DCFPyL PSMA PET images. The correlation of uptake and importance was ascertained when numerous non-overlapping subregions were defined, while a paired t-test was used to compare binary region pairs. A radiomics-based predictive model of population importance was developed using a double cross-validation methodology. A model was then devised for supplementing population-level subregional importance estimates for each patient using patient-specific radiomic features. Main Results. Anticorrelative relationships were found to exist between PSMA PET uptake and four independent models of subregional parotid gland importance from the literature. Kernel Ridge Regression with principal component analysis feature selection performed best over test sets (Mean Absolute Error = 0.08), with gray level co-occurrence matrix (GLCM) features being particularly important. Deblurring PSMA PET images with neural blind deconvolution strengthened correlations and improved model performance. Significance. This study suggests that regions of relatively low PSMA PET uptake in parotid glands may exhibit relatively high dose-sensitivity. We’ve demonstrated the utility of PSMA PET radiomic features for predicting relative importance within subregions of parotid glands. PSMA PET appears to be a promising quantitative imaging modality for analyzing salivary gland functionality.

Temporal and regional patterns of prostate cancer positron emission tomography imaging among commercial insurance beneficiaries in the United States.

34 Background: Prostate specific membrane antigen positron emission tomography (PSMA-PET) imaging improves prostate cancer visualization and has been proposed as a tool to guide treatment decisions. As PSMA-PET imaging agents were not approved in the United States (US) until December 2020, little is known about national patterns of PET imaging utilization. Methods: We conducted a dynamic cohort study to evaluate use of PET imaging among insurance beneficiaries aged 40-89 years with a diagnosis of prostate cancer using deidentified administrative claims from Blue Cross Blue Shield Axis. We calculated the proportions of patients undergoing PET imaging in semiannual periods from January 1, 2016, through December 31, 2022, examining tracers specific to prostate cancer, including PSMA-targeted agents as well as fluciclovine, sodium fluoride, and choline tracers. Cochran-Armitage tests were used to evaluate trends in the proportion of individuals receiving PET imaging over time. We also assessed the association between regional [hospital referral region (HRR)] level contextual sociodemographic and healthcare characteristics and regional use of PSMA-PET imaging in 2022 using chi-square tests. Results: There were 410,505 beneficiaries with prostate cancer identified in the study period. The semiannual proportion of patients undergoing PET imaging increased from 4.5 [(95% confidence interval (CI) 4.1-5.0] per 1,000 in the first half of 2016 to 41.7 (95% CI 40.6-42.9) per 1,000 in the second half of 2022, p&lt;0.001. Increases in PET imaging were driven by uptake of PSMA-PET imaging, which increased from 0.7 (95% CI 0.6-0.9) per 1000 in the second half of 2021 to 37.5 (95% CI 36.4-38.6) per 1,000 in the second half of 2022, p&lt;0.001. Following approvals of PSMA-PET agents, other forms of PET imaging rapidly decreased – from 18.2 (95% CI 17.4-18.9) per 1000 in the second half of 2021 to 4.6 (95% CI 4.3-5.0) per 1,000 in the same period of 2022, p&lt;0.001. Compared to HRRs in quartile 1 (Q1), HRRs in Q4 of PSMA-PET use in 2022 had higher levels of education (25.0% with college education or higher in Q1 versus 29.4% in Q4, p=0.005) and median household income ($50,200 in Q1 versus $60,900 in Q4, p&lt;0.001). Conclusions: In this study from a large commercial US health insurer, PSMA-PET was rapidly incorporated into clinical practice and is now the dominant prostate cancer radiotracer. However, the initial uptake of PSMA-PET may be accompanied by disparity, as our data suggests less use in areas with lower income and education measures.

Prostate-Specific Membrane Antigen: Gateway to Management of Advanced Prostate Cancer.

Prostate-specific membrane antigen (PSMA) as a transmembrane protein is overexpressed by prostate cancer (PC) cells and is accessible for binding antibodies or low-molecular-weight radioligands due to its extracellular portion. Successful targeting of PSMA began with the development of humanized J591 antibody. Due to their faster clearance compared to antibodies, small-molecule radioligands for targeted imaging and therapy of PC have been favored in recent development efforts. PSMA positron emission tomography (PET) imaging has higher diagnostic performance than conventional imaging for initial staging of high-risk PC and biochemical recurrence detection/localization. However, it remains to be demonstrated how to integrate PSMA PET imaging for therapy response assessment and as an outcome endpoint measure in clinical trials. With the recent approval of 177Lu-PSMA-617 by the US Food and Drug Administration for metastatic castration-resistant PC progressing after chemotherapy, the high value of PSMA-targeted therapy was confirmed. Compared to standard of care, PSMA-based radioligand therapy led to a better outcome and a higher quality of life. This review, focusing on the advanced PC setting, provides an overview of different approved and nonapproved PSMA-targeted imaging and therapeutic modalities and discusses the future of PSMA-targeted theranostics, also with an outlook on non-radiopharmaceutical-based PSMA-targeted therapies.