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Defined courses of androgen deprivation therapy (ADT) are often utilized in men undergoing treatment for prostate cancer. Previous evidence has suggested that testosterone (T) recovery can be variable after therapy, with some men never recovering their T. Recently, an oral GnRH antagonist, relugolix, has been shown to allow for more rapid T recovery than injectable GnRH agonists such as leuprolide. In this study, we sought to evaluate patient characteristics associated with T recovery in patients undergoing ADT of defined duration. The Northwestern Electronic Data Warehouse was queried for men with an established diagnosis of prostate cancer for whom ADT was prescribed from 2002 to 2022 and for whom had a recorded testosterone lab draw after completing ADT. Baseline demographics, clinicopathologic characteristics of disease, treatment history of prostate cancer (including type of ADT), and Charlson comorbidity index (CCI) were collected. The primary outcome of interest was the patient's highest recorded T level by 1 year after completion of ADT. T recovery was categorized in one of four ways: full recovery, any T level at least >300; partial recovery, maximum T level from 150 to 300, return to non-castrate levels, maximum T level from 50 to 150; and castrate, maximum T <50. 126 men who received finite courses of ADT were identified (101 receiving leuprolide and 25 receiving relugolix.; Median follow up time (from discontinuation of ADT to last T evaluation) was 213 days. Spaghetti plots for testosterone recovery by ADT type are shown in figure 1. 92% of men who were prescribed relugolix made at least a partial recovery by 1 year post-ADT, in contrast to just 56% of men who were prescribed leuprolide.; Men with partial or complete recovery also tended to be younger, had fewer comorbidities, and were on ADT for shorter courses. Men experience variable levels and timings of testosterone recovery following ADT therapy. Age, lower CCI, use of relugolix, and shorter ADT courses were associated with partial and full recovery of T. Notable limitations of this study are the lack of current guidelines regarding checking patients' T levels upon completion of ADT which affected both our study sample and design. [ABSTRACT FROM AUTHOR]

PSMA-based imaging is the preferred imaging modality recommended by NCCN guidelines for work-up of suspected recurrent or persistent prostate cancer after initial treatment with radical prostatectomy (RP) or prostate radiation and is increasingly being utilized in clinical practice. There is currently sparse data on the relative yield of PSMA PET/CT at low PSA values at biochemical recurrence. We evaluated our institutional PSMA PET/CT cohort of post-RP patients which includes 251 men with PSAs under 0.5ng/mL at the time of imaging, to identify clinical factors associated with scan positivity. We retrospectively identified men treated initially with radical prostatectomy who underwent Gallium-68 or F-18 piflufolastat (DCFPyL) PSMA PET/CT for work-up of recurrence across our eleven hospital system from July 2021-March 2023. Patient characteristics, including demographic, baseline clinical, pathologic, and imaging variables, were obtained. PSMA positivity was determined based on radiology interpretation, and equivocal or likely benign lesions considered negative. Patients with history of systemic therapy or known metastatic disease (n=216), received focal therapy only (n=4), or had bladder outlet procedures only (n=3) were excluded. Clinical variables were compared with Wilcoxon Rank Test, Chi square, and Fishers' exact test and subsequently with univariable and multivariable logistic regression. PSA was log transformed given non-normal distribution for logistic regression. Statistical significance was defined as p<0.05. Median PSA at time of PSMA PET/CT was 0.37 ng/mL (IQR 0.15, 1.29 ng/mL). 48.9% (210/429) of patients initially managed with RP were found to have PSMA positive finding suspicious for recurrence (Table 1). Rates of scan positivity among men with PSAs <0.5ng/mL and those <0.2ng/mL were 37% and 37% respectively.; Among patients with suspicious PSMA positive findings, 14% (29/210) had positivity within prostate bed only, 35% (74/210) had N1 disease, and 51% (107/210) had M1 disease. On multivariable analysis, age, PSA at PSMA scan, and RP Gleason Grade Group were significantly associated with PSMA positivity (Table 2). In a subset MVAs for men with PSAs under 0.5ng/mL at time of imaging, RP Gleason Grade group (p=0.02) and history of post-operative radiation (OR 2.12, 95% CI 1.13, 4, p=0.02) were associated with;scan positivity. PET PSMA/CT for recurrence after RP identifies locoregional or metastatic disease in 49% of patients. Though men with higher PSAs (i.e. ≥ 1ng/ml) have the highest probability of harboring PSMA positive disease, roughly 40% of men with PSAs under 0.2ng/ml had positive imaging findings concerning for recurrence.; These men harbored higher grade disease at prostatectomy and were more likely to have received post-operative radiation.; Our findings suggest PET-PSMA imaging at low PSAs can be considered in selective individuals even at low PSA to inform salvage therapies. [ABSTRACT FROM AUTHOR]

Leuprolide is an injected GnRH agonist that has been the standard of care for patients receiving androgen deprivation therapy (ADT) for advanced prostate cancer. In December of 2020, relugolix was approved as the first oral GnRH antagonist which provided patients with an alternative form of ADT. Results of the phase III HERO study associated relugolix use with faster recovery of testosterone and potentially fewer major adverse cardiovascular events (MACE). In this study, we sought to determine the clinical characteristics and cardiovascular outcomes of patients with prostate cancer treated with leuprolide or relugolix at our multi-centered academic institution. The Northwestern Electronic Data Warehouse was queried for men with an established diagnosis of prostate cancer for whom leuprolide was prescribed between January 2018-July 2022 or for whom relugolix was prescribed between December 2020-July 2022. Patients who were prescribed leuprolide were further stratified into a pre-relugolix era (January 2018-November 2020) and a post-relugolix era (December 2020-July 2022). Baseline clinicopathologic characteristics,;Charlson Comorbidity Index (CCI), and cardiac outcomes following initiation of ADT were collected. MACEs were defined as non-fatal myocardial infarction (MI), non-fatal stroke, and death from any cause. Concurrent ADT use was defined as prescription of another form of ADT (darolutamide, enzalutamide, apalutamide, abiraterone, docetaxel, cabazitaxel) during the same period. Clinical variables were compared with one-way ANOVA, t-test, Chi square and Fisher's exact test and statistical significance was defined as a p<0.05. Bonferroni correction was applied for the pairwise comparisons and statistical significance was defined as p<0.025. 403 men were prescribed leuprolide (n=225 in the pre-relugolix era, n=178 in the post-relugolix era) and 229 men were prescribed relugolix at our institution during the study period. Most patients (73%) had a history of at least one cardiovascular disease risk factor prior to initiation of therapy. Patients prescribed relugolix were overall younger, had fewer comorbidities, and were less likely to harbor metastatic disease (Tables 1,2). Following the initiation of ADT, 75 MACEs were observed. 44 occurred in the pre-relugolix leuprolide cohort, 15 occurred in the post-relugolix leuprolide cohort, and 16 occurred in the relugolix cohort. The respective incidences of major adverse cardiac events were 19.5%, 8.4%, and 7.0%. Death from any cause was the most common (n=52), followed by cerebral infarction (n=10), transient ischemic attacks (n=9), and acute MI (n=4). Of the deaths, 3, 0, and 3 were cardiac arrest or stroke for each cohort respectively. Our findings revealed similar incidences of MACEs for patients prescribed leuprolide or relugolix in the same period, however, patients who were prescribed leuprolide in the pre-relugolix era experienced a significantly greater incidence of MACEs. The higher rates observed in this cohort may be linked to the increased duration of follow-up and cumulative exposure to therapy. Due to the retrospective nature of the analysis, there were also significant limitations in regard to follow-up time and sample size for evaluation of MACEs. Ultimately, our results show a possible preference for initiation of relugolix in a younger population undergoing therapy for defined duration where rapid testosterone recovery may be favored. [ABSTRACT FROM AUTHOR]

PSMA-based PET imaging was first approved by the FDA in December 2021 for the initial staging of newly diagnosed prostate cancer and the management of biochemically recurrent disease. As a clinical aid, the Society of Nuclear Medicine and Molecular Imaging (SNMMI) provides updated appropriate use criteria for PSMA PET/CT, and these recommendations are largely mirrored by the NCCN imaging. This study aims to examine the prevalence and outcomes of PET PSMA scans ordered in scenarios where they would be considered rarely appropriate or inappropriate by the SNMMI. A retrospective analysis of 897 men who were staged with a Gallium-68 or F-18 piflufolastat (DCFPyL) PSMA PET/CT scan between July 2021 and March 2023 identified 32 men who completed a PSMA scan despite not meeting appropriate use criteria by the SNMMI. Patient clinical, pathological, and imaging characteristics were collected, including ordering provider of PSMA scan. The reference standard for a positive scan included either histopathology demonstrating prostate adenocarcinoma or a change of a bone lesion to blastic on follow-up imaging. Cases were also considered positive if they met at least three soft criteria, including a corresponding positive lesion in a different imaging modality, decrease in size or lesions following treatment, increase in size or lesions over time, clinical symptoms of malignancy, localized treatment for imaging finding, PSA increase without treatment, PSA decrease after treatment, and typical appearance of multifocal disease. Equivocal findings were considered negative. 5% (17/340) of PSMA scans performed for initial staging did not meet appropriate use criteria as they were performed on NCCN very low, low, or favorable intermediate risk patients. No patient (0/17) showed PSMA positivity from this inappropriately scanned group. Furthermore, 3% (15/557) of patients who received a PSMA for work-up of biochemical recurrence failed to meet appropriate use criteria due to an undetectable PSA preceding the PSMA scan (PSA <0.01ng/ml). 20% (3/15) of these patients had false positive findings. PSMA identified true positivity in nodal and bone metastasis in 7% (1/15) and the remainder had negative scans. Urologists (53%, 17/32) comprised the largest ordering specialty in inappropriate use, followed by hematology oncology (19%, 6/32) and radiation oncology (19%, 6/32) with the remaining scans being ordered by other specialists or internists. Inappropriate or rarely appropriate use of PSMA PET/CT occurs in a significant minority of patients within our health care system. Inappropriate scans yielded no positivity in initial staging and had significant false positivity in biochemically recurrent patients. Physicians most likely to inappropriately order PSMA PET/CT scans are urologists. Further education of providers and EMR-based interventions (such as best practice alerts) may help limit inappropriate use in the future. [ABSTRACT FROM AUTHOR]

PET PSMA imaging is a sufficient and potentially superior alternative to conventional imaging in the initial staging of newly diagnosed prostate cancer. As such, conventional imaging such as bone scan or CT is not considered a necessary pre-requisite to PET PSMA when staging patients. We investigated imaging results at our institution to better understand the contemporary role of conventional imaging. We retrospectively identified 79 patients with newly diagnosed prostate cancer who underwent initial staging with conventional imaging and Gallium-68 or F-18 piflufolastat (DCFPyL) PSMA PET/CT scan in our eleven hospital system from July 2021–December 2022. Sufficient conventional imaging was defined as a bone scan with at least one of either an MRI or CT scan. The reference standard for a positive scan included either histopathology demonstrating prostate adenocarcinoma or a change of a bone lesion to blastic on follow-up imaging. Cases were also considered positive if they met at least three soft criteria, including a corresponding positive lesion in a different imaging modality, increase in size or number of lesions over time, decrease in size or number of lesions after treatment, clinical symptoms of malignancy, localized treatment for imaging finding, PSA increase without treatment, PSA decrease with treatment, and typical appearance of multifocal disease. Equivocal findings were considered negative. PSMA PET/CT detected 93% (42/45) of total imaging positivity for patients who received both a PET scan and conventional imaging (Figure 1). PSMA PET/CT had a sensitivity of 100% and a specificity of 95% in our cohort. Comparatively, conventional imaging had a sensitivity of 76% and;specificity of 89% in our cohort. Detection rates by disease localization and imaging modality are shown in Figure 2. PSMA PET/CT falsely showed positivity for two patients, detecting both pelvic and distant nodal metastatic disease while only pelvic nodal disease was confirmed by our reference standard. Conventional imaging failed to detect cancer in 50% (9/18) of pelvic nodal disease, 60% (3/5) of distant nodal metastases, and 6% (1/16) of metastases to the bone. T99MDP bone scan only detected 63% (10/16) of metastases to the bone. When used, CT scan detected 50% (15/30) of positivity and MRI detected 50% (12/24) of positivity. PSMA PET/CT has higher specificity and sensitivity than conventional imaging for initial staging within our cohort. Real-world practice supports the omission of conventional imaging prior to PET PSMA in initial staging as it would not lead to additional detection of pelvic or metastatic cases. [ABSTRACT FROM AUTHOR]

Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate-specific enzyme human kallikrein-related peptidase 2 (hK2; KLK2). In multiple rodent models, Actinium-225-labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [225Ac]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG3, the IgG subclass with superior activation of complement and ability to mediate FC-γ-receptor binding, for immunotherapeutically enhanced hK2 targeted α-radioimmunotherapy. Second, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted α-therapy. [225Ac]hu11B6-IgG2 was a functionally enhanced alternative to [225Ac]hu11B6-IgG1 but offered no improvement of therapeutic efficacy. Progression-free survival was slightly increased with a single high activity compared to fractionated activity. Tumor-free animals succumbing after treatment revealed no evidence of treatment-associated toxicity. In addition to up-regulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS, and SCHLAP1, we also noted a significant decrease in both KLK3 (prostate-specific antigen) and FOLH1 (prostate-specific membrane antigen) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model. [ABSTRACT FROM AUTHOR]