Prostate-specific Membrane Antigen Positron Emission Tomography Research Articles

Determination of the optimal imaging protocol for [18F]PSMA-PET-CT for the detection of bone metastases in prostate cancer patients.

Prostate-specific membrane antigen-positron emission tomography (PSMA-PET) is a widely used diagnostic tool in patients with prostate cancer (PC).However, due to the limited availability of PET scanners and relevant acquisition costs, it is important to consider the indications and acquisition time.The aim of this investigation was to determine whether a PET scan from the skull base to the proximal thigh is sufficient to detect the presence of bone metastases. A retrospective analysis was conducted on 1050 consecutive [18F]PSMA-1007-PET-CT scans from the head to the proximal lower leg.The PET scans were categorised according to the presence and amount of bone metastases: (1) 1-5, (2) 6-19 and (3) ≥20. Additionally, the PET scans were evaluated for the presence of bone metastases below the proximal thigh as well as bone metastases above the skull base.Imaging results were compared to patients PSA values. Of the 391 patients with bone metastases, 146 (37.3%) exhibited metastases located below the proximal thigh and 104 (26.6%) above the skull base.The majority of bone metastases located below the proximal thigh (145, 99.3%) and above the skull base (94, 90.4%) were identified in patients with more than five bone metastases. No solitary distal metastasis was detected.The PSA value correlated significantly with number of bone metastases (e. g., 1-5 vs. ≥20 bone metastases, P < 0.001) and was significantly higher in patients with distal bone metastases (P < 0.001).ROC analysis showed that a PSA value of 11.15 ng/mL is the optimal cut-off for detecting bone metastases located below the proximal thigh, with an AUC of 0.919 (95% CI: 0.892-0.945, sensitivity 87%, specificity 86%).Similarly, the PSA value of 12.86 ng/mL is the optimal cut-off for detecting bone metastases above the skull base with an AUC of 0.904 (95% CI: 0.874-0.935, sensitivity 87%, specificity 83%). CONCLUSION: PSMA-PET acquisition protocols from the skull base to the proximal femur may be sufficient to accurately detect bone metastatic disease in PC. PSA values can provide decision support for individual PET acquisition protocols.

Fluorine-18 Prostate-Specific Membrane Antigen–1007 PET/CT vs Multiparametric MRI for Locoregional Staging of Prostate Cancer

Prostate-specific membrane antigen (PSMA) demonstrates overexpression in prostate cancer and correlates with tumor aggressiveness. PSMA positron emission tomography (PET) is superior to conventional imaging for the metastatic staging of prostate cancer per current research but studies of second-generation PSMA PET radioligands for locoregional staging are limited. To determine the accuracy of fluorine-18 PSMA-1007 PET/computed tomography (18F-PSMA-1007 PET/CT) compared to multiparametric magnetic resonance imaging (MRI) in the primary locoregional staging of intermediate-risk and high-risk prostate cancers. The Next Generation Trial was a phase 2 prospective validating paired cohort study assessing the accuracy of 18F-PSMA-1007 PET/CT and MRI for locoregional staging of prostate cancer, with results of histopathologic examination as the reference standard comparator. Radiologists, nuclear medicine physicians, and pathologists were blinded to preoperative clinical, pathology, and imaging data. Patients underwent all imaging studies and radical prostatectomies at 2 tertiary care hospitals in Alberta, Canada. Eligible participants included men with intermediate-risk or high-risk prostate cancer who consented to radical prostatectomy. Participants who underwent radical prostatectomy were included in the final analysis. Patients were recruited between March 2022 and June 2023, and data analysis occurred between July 2023 and December 2023. All participants underwent both 18F-PSMA-1007 PET/CT and MRI within 2 weeks of one another and before radical prostatectomy. The primary outcome was the correct identification of the prostate cancer tumor stage by each imaging test. The secondary outcomes were correct identification of the dominant nodule, laterality, extracapsular extension, and seminal vesical invasion. Of 150 eligible men with prostate cancer, 134 patients ultimately underwent radical prostatectomy (mean [SD] age at prostatectomy, 62.0 [5.7] years). PSMA PET was superior to MRI for the accurate identification of the final pathological tumor stage (61 [45%] vs 38 [28%]; P = .003). PSMA PET was also superior to MRI for the correct identification of the dominant nodule (126 [94%] vs 112 [83%]; P = .01), laterality (86 [64%] vs 60 [44%]; P = .001), and extracapsular extension (100 [75%] vs 84 [63%]; P = .01), but not for seminal vesicle invasion (122 [91%] vs 115 [85%]; P = .07). In this phase 2 prospective validating paired cohort study, 18F-PSMA-1007 PET/CT was superior to MRI for the locoregional staging of prostate cancer. These findings support PSMA PET in the preoperative workflow of intermediate-risk and high-risk tumors.

Quality metrics analysis in patients who received Lutetium-177 PSMA-617 (177Lu–PSMA) therapy in a real-world practice setting.

e17049 Background: 177Lu–PSMA is a radiolabeled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA). It has been approved for use in metastatic castration-resistant prostate cancer (mCPRC) in 3/2022, based on VISION study. The Food and Drug Administration (FDA) label for 177Lu–PSMA requires prior therapy with an androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy as well as presence of at least one PSMA-positive tumor with uptake greater than normal liver and no PSMA-negative lesions on a PSMA positron emission tomography (PET) scan. In the VISION study, PSMA PET was performed within 4 weeks of therapy start. Further, patient received either 177Lu–PSMA plus protocol permitted standard of care (SOC), including ARPI, or SOC alone. Given the relatively recent approval of this therapy, real-world familiarity with administration of this agent may not be optimal. Methods: A retrospective analysis of 25 patients with mCRPC who received 177Lu–PSMA therapy since 3/2022 at the University of California Irvine (24/25) and Hoag Hospital (1/25) was performed. Multiple variables were analyzed and compared to the FDA label for this agent as well as design of the VISION study. Results: All patients in this study had received an ARPI and at least one taxane chemotherapy prior to 177Lu–PSMA. A PSMA-PET scan was obtained prior to 177Lu–PSMA therapy in all patients. The timing of the scan was within 4 weeks of starting 177Lu–PSMA therapy in only 5/25 (20.0%) patients. The average time from PSMA PET scan to 177Lu–PSMA therapy start was 66 days [range: 18 - 326 days]. None of the PSMA PET scan reports included a baseline liver standardized uptake value (SUV) or mentioned whether any lesions were non PSMA-avid. All reports provided SUV values for some, but not all, PSMA-avid lesions. The average maximum SUV of the most PSMA-avid lesion noted on the reports was 34.7. All PSMA PET scans were retrospectively reviewed by a nuclear medicine specialist and the average maximum SUV of the most PSMA-avid lesion on re-review was 42.0 (p &lt;0.05). During 177Lu–PSMA therapy, co-administration of ARPI occurred in 10/24 (23.8%) of patients. Conclusions: This study highlights the differences in quality metrics between patients who received 177Lu–PSMA therapy in a real-world practice setting compared to the FDA label for this agent and VISION study design. Differences included lack of uniform PSMA PET scan reporting, timing of obtaining pre-treatment PSMA PET imaging, and co-administration of ARPI. Development of institutional algorithms around administration of 177Lu–PSMA therapy may be needed.

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.

Role of Ga68 Prostate-Specific Membrane Antigen Positron Emission Tomography-Computed Tomography in Prostate Cancer Imaging

Role of Ga68 Prostate-Specific Membrane Antigen Positron Emission Tomography-Computed Tomography in Prostate Cancer Imaging

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

BackgroundCirculating-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.MethodsOne hundred thirty men with confirmed PCa (70.5 ± 8.0 years) who underwent [68Ga]Ga-PSMA-11 PET/CT (184.8 ± 19.7 MBq) 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.ResultsPSMA 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).ConclusionThese 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.Graphical

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.

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.

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.

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 18F-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 18F-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 18F-PSMA PET scans. Shell-less radioactive spheres (3-16-mm) were cast using epoxy resin mixed with sodium-22 (22Na), a long half-life positron emitter with positron range similar to 18F. To establish realistic lesion contrast, the 22Na spheres were mounted in a cylindrical chamber that can be filled with an 18F background (module 1). Thirteen exchangeable spherical cavity inserts (3-37-mm) were machined in two parts and solvent welded together, and filled with 18F (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 22Na 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 22Na spheres. Comparatively, 18F 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 18F-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 18F-PSMA PET imaging, which may lead to more robust predictive metrics and better outcome prediction in metastatic prostate cancer.