Citations

TPS5116 Background: Prostate cancer (PC) is common and despite recent advances in treatment options, patients with metastatic disease still have poor outcomes, warranting the development of new effective therapies in this setting. Prostate-specific membrane antigen (PSMA) is expressed in benign and malignant prostate tissues and luminal surface of salivary/lacrimal glands, small intestine and renal tubules. The double PSMA binding moiety of SAR-bisPSMA in 64Cu-SAR-bisPSMA (imaging) and 67Cu-SAR-bisPSMA (therapy) may offer advantages compared to currently used single-target PSMA agents. Clinical evidence demonstrated 2-3 times higher uptake of 64Cu-SAR-bisPSMA compared to the single-target PSMA agent, 68Ga-PSMA-11. Pre-clinical efficacy data of 67Cu-SAR-bisPSMA in mice showed statistically significant tumor growth inhibition compared to the control group as well as a dose-dependent delay in eventual tumor regression in a PC xenograft study. These results led to the development of this clinical study, which aims to assess safety and anti-tumor efficacy of 67Cu-SAR-bisPSMA in patients with metastatic castrate resistant PC (mCRPC). Methods: SECuRE is a phase I/IIa multi-center, open-label, non-randomized, dose-escalation and cohort expansion study of 64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA (NCT04868604). mCRPC patients with progression, prior exposure to at least one androgen receptor pathway inhibitor, and positive 64Cu-SAR-bisPSMA PET may be treated with 67Cu-SAR-bisPSMA. This study is being conducted in 3 phases: a 64Cu-SAR-bisPSMA Dosimetry Phase (n=6), a 67Cu-SAR-bisPSMA Dose Escalation Phase (n=up to 24), and a 67Cu-SAR-bisPSMA Cohort Expansion Phase (n=14). The primary and key secondary objectives include assessment of 64Cu- and 67Cu-SAR-bisPSMA safety and dosimetry, determining the maximum tolerated dose (MTD) or maximum feasible dose (MFD) and anti-tumor efficacy of 67Cu-SAR-bisPSMA. The 67Cu-SAR-bisPSMA dose levels investigated in the escalation phase include: 4 GBq (cohort 1, single dose), 8 GBq (cohort 2, single dose), 12 GBq (cohort 3, single dose) and up to 24 GBq across two doses (cohort 4, two doses at MTD or MFD). The Dose Expansion Phase of the study will allow the administration of up to 4 doses of 67Cu-SAR-bisPSMA at the MTD/MFD. Response measurements include reduction in PSA levels, radiological progression-free survival, duration of response and overall survival. Radiological response will be assessed by RECIST V1.1 and PCWG3. At the time of submission of this abstract, no dose limiting toxicities have been observed to date in the first 3 cohorts. In the United States, 4 sites are active with additional sites in planning. Additional sites in the US and Australia are currently in start-up. Clinical trial information: NCT04868604 .

Abstract A 78-year-old man receiving bicalutamide for prostate cancer was referred for a PSMA PET/CT scan to evaluate his gradually rising prostate-specific antigen level. The PSMA PET/CT revealed gynecomastia with radiotracer uptake in bilateral breast parenchyma, a known but rarely reported effect of bicalutamide monotherapy. This scan also demonstrated metastatic progression of his disease in bone and lymph nodes, and he was started on leuprolide injections. Three months after a decrease in his testosterone level, the radiotracer uptake in his breast tissue had resolved, demonstrating that PSMA-avid bicalutamide-induced gynecomastia is reversible.

TPS246 Background: Prostate cancer (PC) is common and despite recent advances in treatment options, patients with metastatic disease still have poor outcomes, warranting the development of new effective therapies in this setting. Prostate-specific membrane antigen (PSMA) is expressed in benign and malignant prostate tissues and luminal surface of salivary/lacrimal glands, small intestine and renal tubules. The double PSMA binding moiety of SAR-bisPSMA in 64Cu-SAR-bisPSMA (imaging) and 67Cu-SAR-bisPSMA (therapy) may offer advantages compared to currently used single-target PSMA agents. Clinical evidence demonstrated 2-3 times higher uptake of 64Cu-SAR-bisPSMA compared to the single-target PSMA agent, 68Ga-PSMA-11. Pre-clinical efficacy data of 67Cu-SAR-bisPSMA in mice showed statistically significant tumor growth inhibition compared to the control group as well as a dose-dependent delay in eventual tumor regression in a PC xenograft study. These results led to the development of this clinical study, which aims to assess safety and anti-tumor efficacy of 67Cu-SAR-bisPSMA in patients with metastatic castrate resistant PC (mCRPC). Methods: SECuRE is a phase I/IIa multi-center, open-label, non-randomized, dose-escalation and cohort expansion study of 64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA. mCRPC patients with progression, prior exposure to at least one androgen receptor pathway inhibitor, and positive 64Cu-SAR-bisPSMA PET may be treated with 67Cu-SAR-bisPSMA. This study is being conducted in 3 phases: a 64Cu-SAR-bisPSMA Dosimetry Phase (n=6), a 67Cu-SAR-bisPSMA Dose Escalation Phase (n=up to 24), and a 67Cu-SAR-bisPSMA Cohort Expansion Phase (n=14). The primary and key secondary objectives include assessment of 64Cu- and 67Cu-SAR-bisPSMA safety and dosimetry, determining the maximum tolerated dose (MTD) or maximum feasible dose (MFD) and anti-tumor efficacy of 67Cu-SAR-bisPSMA. The 67Cu-SAR-bisPSMA dose levels investigated in the escalation phase include: 4 GBq (cohort 1, single dose), 8 GBq (cohort 2, single dose), 12 GBq (cohort 3, single dose) and up to 24 GBq across two doses (cohort 4, two doses at MTD or MFD). The Dose Expansion Phase of the study will allow the administration of up to 4 doses of 67Cu-SAR-bisPSMA at the MTD/MFD. Response measurements include reduction in PSA levels, radiological progression-free survival, duration of response and overall survival. Radiological response will be assessed by RECIST 1 V1.1 and PCWG3. At the time of submission of this abstract, cohort 3 is open for recruitment and no dose limiting toxicities have been observed to date. Clinical trial information: NCT04868604 .

49 Background: Ductal carcinoma (DC) is the second most commonly encountered histologic variant of prostate cancer. Previous studies have described its molecular features and aggressive behavior, but few have explored the performance of PSMA PET/CT in the initial staging and follow-up of DC. Methods: To address this gap, we performed a single-institution retrospective analysis using the Mayo Clinic PSMA PET database. All patients receiving a PSMA PET/CT scan in the interval of January 1, 2021, to December 31, 2022, were eligible for inclusion. Cases were filtered and categorized by histology at the time of diagnosis to select for pure DAC and mixed ductal variants. Trained research personnel annotated disease- and treatment-related variables. A board-certified radiologist performed tumor burden segmentation with calculations of SUV max, total lesion SUV mean and volume, and total lesion uptake, and ascribed a miPSMA expression score. Results: We queried 1792 patients from our PSMA PET/CT registry and identified 32 (1.8%) patients with a pathologically confirmed DC, including 8 (25%) patients with pure ductal and 25 (75%) patients with mixed histology. The indication for PSMA PET/CT was biochemical progression or restaging for 29 (91%) patients and initial staging for 3 (9%) patients. The median (IQR) time from prostate cancer diagnosis to PSMA PET scan was 41.6 (11.5-64.7) months, during this time 50% (n= 16) of patients developed CRPC. At the time of the PSMA PET/CT scan, the median age was 70 years, the median (IQR) PSA was 0.5 ng/mL (0.2-2.6). The distribution of metastatic spread and quantitative imaging parameters from PSMA PET are shown in the Table. Conclusions: Despite low PSA at the time of imaging, PSMA PET/CT frequently detected high volume osseous and/or visceral metastases in patients with DC. However, it is noteworthy that more than 50% of patients with DC had a low miPSMA score (0-1). Additional studies are needed to better understand the performance of novel imaging modalities when evaluating variant prostate cancers. [Table: see text]

220 Background: There is a critical need to identify biomarkers of response and resistance to 177Lu-PSMA-617. Post-hoc analyses of VISION have explored the prognostic and predictive value of select clinical parameters. However, we are still in the early stages of deciphering which molecular changes are associated with favorable or adverse treatment outcomes. Methods: We conducted a retrospective analysis of patients with metastatic castration-resistant prostate cancer (mCRPC), who received 177Lu-PSMA-617 at Mayo Clinic in Rochester, Minnesota, in the interval of March 2022 to March 2023. We included patients who provided research authorization, had a baseline PSA of at least 2 ng/mL, received at least 2 cycles of treatment, and had circulating tumor DNA (ctDNA) genomic profiling performed by Guardant (83 gene panel) within 60 days of treatment initiation. Clinical, laboratory, genomic, and radiomic parameters were abstracted by trained research personnel. Two independent analyses of “response” and “resistance” were performed. Response to treatment was defined as 50% or greater decrease in PSA from baseline (PSA50 response: dichotomized yes versus no), and resistance was defined as non-decreasing or rising PSA during treatment (PSA non-response: dichotomized yes versus no). Associations between gene alterations and response and resistance were evaluated via Fisher’s exact tests. Results: Between March 2022 and March 2023, 273 patients received cycle 1 of 177Lu-PSMA-617. A total of 108 patients met the inclusion criteria. The median number of cycles at data cutoff was 6 (IQR: 4,6) with 57 (53%) patients receiving all 6 planned cycles. The median PSA at baseline was 16.65 ng/ml (IQR: 5.20, 66.12). A total of 65 patients (60%) experienced a PSA50 response. No molecular alterations were associated with a higher rate of PSA50 response; however, alterations in ARID1A, AR, and CHEK2 were associated with lack of PSA50 response (Fisher’s exact p < 0.05). Of the 108 evaluable patients, 20 (19%) met criteria for PSA non-response. Alterations in AR, ARID1A, MYC, TP53, CHEK2, ATM, EGFR, and NOTCH1 were significantly associated with PSA non-response (Fisher’s exact p < 0.05); in each case, the presence of the alteration was positively associated with resistance (i.e., more instance of PSA non-response). No biomarkers were found to be inversely associated with PSA non-response. Conclusions: ctDNA assessed by commercially available, targeted sequencing panels prior to treatment may be useful in identifying the patients least likely to benefit from 177Lu-PSMA-617. Further work is ongoing to integrate ctDNA findings with clinical parameters in the hopes of understanding the factors mediating response and resistance to therapy.

175 Background: It is well-known that patients with liver metastases from metastatic castration resistant prostate cancer (mCRPC) have poorer or transient responses to many forms of systemic therapy. Data on outcomes following treatment with Lutetium-177–PSMA-617 is scarce. The VISION trial reports hazard ratios for overall survival in the subgroup of patients with liver metastases without disclosing the absolute duration of survival. Using real-world clinical data, we examine this important subgroup of patients, describing their PSA response rates and survival. Methods: A single institution database was assembled to include all patients receiving 177-Lu-PSMA-617 at Mayo Clinic Rochester, MN, and starting treatment in the interval of March 2022 to March 2023. Baseline clinicopathologic and imaging characteristics were abstracted. Patients were categorized based on the presence or absence of measurable liver metastases on their baseline PSMA PET scan. Best PSA response while on treatment was annotated and reported as percent decline from baseline. Survival was calculated from date of first cycle of 177-Lu-PSMA-617. PSA50 response and overall survival (OS) outcomes for the two groups (liver metastases versus no liver metastases) were compared using Chi square test and Kaplan-Meier method, respectively. Those with available pre-treatment circulating tumor DNA (ctDNA) genomic profiling, performed by Guardant (83 gene panel), were assessed for the presence of pathogenic and likely pathogenic alterations. Findings are summarized using descriptive statistics. Results: The overall cohort consisted of 212 patients, including 29 (14%) with liver metastases on pre-treatment PSMA PET/CT. The median number of cycles received was 4 (range, 1-6) for patients with liver metastases and 6 (range, 1-6) for those without hepatic involvement. The observed PSA50 response trended lower for those with liver metastases (34.5% [10/29] versus 51% [94/183], p= 0.091). At median (IQR) follow-up of 10 (8-12) months, there was a numerical but not statistically significant difference in median OS (11.28 months versus NR, p=0.066). In the exploratory analysis of baseline ctDNA, BRCA2 copy number loss was relatively enriched among patients with liver metastases (4 of 19, 21%) versus patients without liver disease (5.7%, 9/158). Conclusions: Our data suggest that the presence of liver metastases predict poorer outcomes in patients receiving Lutetium-177–PSMA-617 treatment, which is similar to data reported with other forms of systemic therapy for mCRPC. To maximize the anti-tumor activity of radioligand therapy in the liver, combination approaches should be explored.

592 Background: The introduction of peptide receptor radionuclide therapy (PRRT) using Lutetium-177 (177Lu) DOTATATE has led to a paradigm shift in the treatment of neuroendocrine tumors (NETs). Hematological toxicity is a well-recognized adverse effect (AE) of 177Lu DOTATATE. Most cytopenias are transient, with an estimated incidence of 10-25%, typically mild to moderate in severity (grade G1-2). The most dreaded AE of PRRT is therapy-related myeloid neoplasm (t-MN), with an estimated 2-8% incidence and a higher incidence reported in patients who also received prior chemotherapy. We sought to evaluate the hematological safety of 177Lu PRRT in the setting of NETs with extensive (i.e., innumerable) bone metastases. Methods: We retrospectively reviewed the medical records of all Mayo Clinic patients (pts) with extensive/innumerable osseous metastases, defined as >50% skeletal involvement by positron emission tomography (PET) DOTATATE, who were treated with 177Lu DOTATATE. Pts characteristics and laboratory results were collected before, during, and after 177Lu DOTATATE treatment. Hematotoxicity was graded according to the NCI-CTCAE v5. Results: Out of 27 pts, 13(48%) developed cytopenia(s) of any grade after treatment with one or more cycles of 177Lu DOTATATE. In total, there were 13(48%) pts with anemia, 13(48%) with thrombocytopenia, and 6(22%) with neutropenia. Six (22%) pts had severe hematological toxicity (G3-4). Twelve months post-PRRT, 7(26%) pts continued to experience cytopenia(s) of any grade, of whom 4(15%) had G3-4 hematotoxicity. One pt developed t-MN, and two pts had myelophthisis on bone marrow biopsy from infiltrating NET. 16(59%) pts received cytotoxic chemotherapy before PRRT, and 7(25.9%) developed subsequent cytopenia(s). Overall, 15(55%) pts completed four cycles, while 3 pts didn’t complete four cycles of 177Lu DOTATATE due to hematotoxicity. Conclusions: Pts with advanced NETs and extensive/innumerable bone metastases treated with PRRT could be at higher risk for myelosuppression than historical controls. Our study highlights the importance of carefully monitoring and assessing hematological parameters in pts being considered for 177Lu DOTATATE with extensive/innumerable bone metastasis. [Table: see text]

Major advances in prostate cancer diagnosis, staging, and management have occurred over the past decade, largely due to our improved understanding of the technical aspects and clinical applications of advanced imaging, specifically magnetic resonance imaging (MRI) and prostate-cancer-specific positron emission tomography (PET). Herein, we review the established utility of these important and exciting technologies, as well as areas of controversy and uncertainty that remain important areas for future study. There is strong evidence supporting the utility of MRI in guiding initial biopsy and assessing local disease. There is debate, however, regarding how to best use the imaging modality in risk stratification, treatment planning, and assessment of biochemical failure. Prostate-cancer-specific PET is a relatively new technology that provides great value to the evaluation of newly diagnosed, treated, and recurrent prostate cancer. However, its ideal use in treatment decision making, staging, recurrence detection, and surveillance necessitates further research. Continued study of both imaging modalities will allow for an improved understanding of their best utilization in improving cancer care.

Abstract Background: Many patients use artificial intelligence (AI) chatbots as a rapid source of health information. This raises important questions about the reliability and effectiveness of AI chatbots in delivering accurate and understandable information. Purpose: To evaluate and compare the accuracy, conciseness, and readability of responses from OpenAI ChatGPT-4 and Google Bard to patient inquiries concerning the novel 177Lu-PSMA-617 therapy for prostate cancer. Materials and Methods: Two experts listed the 12 most commonly asked questions by patients on 177Lu-PSMA-617 therapy. These twelve questions were prompted to OpenAI ChatGPT-4 and Google Bard. AI-generated responses were distributed using an online survey platform (Qualtrics) and blindly rated by eight experts. The performances of the AI chatbots were evaluated and compared across three domains: accuracy, conciseness, and readability. Additionally, potential safety concerns associated with AI-generated answers were also examined. The Mann-Whitney U and chi-square tests were utilized to compare the performances of AI chatbots. Results: Eight experts participated in the survey, evaluating 12 AI-generated responses across the three domains of accuracy, conciseness, and readability, resulting in 96 assessments (12 responses x 8 experts) for each domain per chatbot. ChatGPT-4 provided more accurate answers than Bard (2.95 ± 0.671 vs 2.73 ± 0.732, p=0.027). Bard's responses had better readability than ChatGPT-4 (2.79 ± 0.408 vs 2.94 ± 0.243, p=0.003). Both ChatGPT-4 and Bard achieved comparable conciseness scores (3.14 ± 0.659 vs 3.11 ± 0.679, p=0.798). Experts categorized the AI-generated responses as incorrect or partially correct at a rate of 16.6% for ChatGPT-4 and 29.1% for Bard. Bard's answers contained significantly more misleading information than those of ChatGPT-4 (p = 0.039). Conclusion: AI chatbots have gained significant attention, and their performance is continuously improving. Nonetheless, these technologies still need further improvements to be considered reliable and credible sources for patients seeking medical information on 177Lu-PSMA-617 therapy.

AbstractBackgroundProstate cancer (PCa) parenchymal brain metastases are uncommon and troubling observations in the course of the disease. Our study aims to evaluate the prevalence of brain metastases among PCa patients while reporting various therapeutic modalities, clinical features, and oncological outcomes.MethodsWe retrospectively identified 34 patients with parenchymal brain metastasis out of 4575 patients using a prospectively maintained database that contains clinicopathologic characteristics of PCa patients between January 2012 and December 2021. Based on the three treatment modalities used, the patients were divided into three groups: stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), and systemic therapy alone. The Kaplan–Meier curve was used to calculate overall survival [OS] probability and the Cox proportional hazards regression model was used to compare between groups.ResultsAt the time of brain metastasis diagnosis, the median age was 66 years, the median (interquartile range [IQR]) prostate‐specific antigen (PSA) was 2.2 (0.1–26.6) ng/ml and the median (IQR) months from initial PCa diagnosis to brain metastasis development was 70.8 (27.6–100.9). The median (IQR) primary Gleason score was 8 (7–9) and over a median (IQR) follow‐up time of 2.2 (1.2–16.5) months, 76.5% (n = 26) of the patients died. Thirteen (38.2%) patients had solitary lesion, whereas 21 (61.8%) had ≥2 lesions. The lesions were supratentorial in 19 (55.9%) patients, infratentorial in six (17.6%), and both sides in nine (26.5%). Among all 34 patients, 10 (29.4%) were treated with SRS, seven (20.6%) with WBRT, and 17 (50%) with systemic therapy alone. OS varied greatly between the three treatment modalities (log‐rank test, p = 0.049). Those who were treated with SRS and WBRT had better OS compared with patients who were treated with systemic therapy alone (hazard ratio: 0.37, 95% confidence interval: 0.16–0.86, p = 0.022).ConclusionsIn our single‐institutional study, we confirmed that PCa brain metastasis is associated with poor survival outcomes and more advanced metastatic disease. Furthermore, we found that SRS and WBRT for brain metastasis in patients with recurrent PCa appear to be associated with improved OS as compared with systemic therapy alone and are likely secondary to selection bias.