PSMA Imaging Research Articles

PET-CT 18F-PSMA 1007 in the staging of patients with prostate cancer prior to curative intent radiotherapy: a prospective observational study

Objective: The objective of our study was to assess whether there are staging changes in CaP with PET PSMA compared to standard diagnostic methods, and if these changes occurred, to understand how they altered the treatment of patients with an initial diagnosis of CaP and their relationship with the D'amico score. Methods: We present a prospective observational study conducted on patients initially diagnosed with prostate cancer, who underwent standard staging studies alongside PET PSMA imaging. Results: Forty patients diagnosed with prostate cancer were staged using standard diagnostic methods and PET PSMA. In 40% of the patients, initial staging changed based on the results obtained from PET PSMA. After PET PSMA, the uro-oncology committee decided to modify the initial treatment plan in 27.5% of the cases, including radiation boost targeting the extra-prostatic lesions detected by PET PSMA. When correlating the change in staging with PET PSMA versus the D'amico risk score, no changes were observed in the low-risk group, 19% in the intermediate-risk group, and 62% in the high-risk group. These differences were statistically significant (X2=9.2; df=2; p=0.01). Limitation and value: The study faced limitations in sample size and lack of long-term patient follow-up. However, it highlights key contributions: the promising evaluation of PET PSMA in staging, its influence on therapeutic decisions, and its association with the D'amico score. Conclusion: PET PSMA showed substantial changes in CaP staging, particularly in higher-risk patients, suggesting its potential utility in guiding therapeutic decisions before radiotherapy.

Real-world PET PSMA imaging patterns in a Chicago safety-net hospital.

e17009 Background: Prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging is an FDA-approved imaging modality with increased sensitivity for prostate cancer (PCa) detection. It thus can more accurately stage patients to determine optimal initial treatment. However, patients with indications for these scans can still experience significant delays in obtaining them, mainly due to insurance denials. Such delays often disproportionately affect those with healthcare disparities, representing a substantial population at University of Illinois Chicago (UIC), a safety-net hospital. We sought to identify patterns, barriers, & areas for improvement in obtaining this guideline-directed imaging modality. Methods: PCa patients with a PSMA PET scan ordered between January 2021 and June 2023 were included for analysis. Key medical and demographic data such as age, race/ethnicity, and insurance status were obtained. We also determined the time between ordering and obtaining the PSMA PET, and whether the scan led to classifying the patient’s disease as clinically localized, regional, or metastatic. We also determined whether subsequent treatment was curative or palliative intent. The dates and types of other imaging modalities, if obtained, were also recorded. Results: We identified 76 patients with PSMA PET scans ordered during the study timeframe. The mean age was 68.6 years, with a standard deviation of 7.3 years. 60.0% identified as Black or African American, 24.0% as White, 4.0% as Asian, and 1.3% as American Indian or Alaska Native. 40.8% had Illinois Medicare as their primary insurance, 27.6% had Medicaid, and 31.6% had another medical insurance. Most individuals (77.6%) had a delay in obtaining their PSMA PET scan, with a median time to scan of 23.0 days (range 6-136). All insurance types, including Illinois Medicare, Medicaid, and private insurance, had delays (74.2%, 81.0% and 79.2% of all PSMA PETs, respectively). Many delayed individuals also received conventional imaging (46.0%) within 3 months of the PSMA PET scan order as part of their workup, with 40.0% of PSMA PETs revealing new findings compared to the other scans. Ultimately, most of the imaged patients (54.0%) were determined to have regional or metastatic PCa. Delays in obtaining and receiving the results of scans affected individuals who underwent both curative (40.8%) as well as palliative intent (46.1%) treatment. Conclusions: Between January 2021 and June 2023, PCa patients had a median delay of approximately three weeks in obtaining a PSMA PET scan that was ordered urgently for the determination of their PCa treatment. Such delays can significantly impact health outcomes and often result in redundant conventional imaging. This retrospective study represents the first step in a quality improvement project to reduce delays to PSMA PETs and enable the development of a timely treatment plan to improve patient outcomes in our diverse patient population.

Lutetium-177–PSMA-617 experience in Appalachian patients with advanced prostate cancer at West Virginia University Health Science Center.

e17045 Background: Lutetium Lu-177 vipivotide tetraxetan (Lu-177) allowed for improved biochemical and radiographic response rate with relatively low toxicity for metastatic castration-resistant prostate cancer (PC) after multiple lines of therapy. In the 2021 VISION study (DOI: 10.1056/NEJMoa2107322), Lu-177 was reported to have a median overall survival (OS) of 15.3 months in patients (pts) with advanced prostate cancer (PC). We reviewed the result with Lu-177 for the treatment of advanced PC at a rural tertiary academic center at West Virginia University Health Science Center (WVU-HSC). Methods: All PC pts receiving one or more doses of Lu-177 at WVU-HSC were retrospectively reviewed. Pts were followed until death or the last clinic visit. All pts were established patients at WVU-HSC for management of the advanced PC between July 2022 and February 2024. Data was tabulated with descriptive statistics and median survival was calculated from Kaplan-Meier method. Results: Over an eighteen months period 34 pts received 126 doses of Lu-177. 26 pts were referred from outside the WVU-HSC specifically for Lu-177. Demographics from data collection showed predominantly Caucasian pts (91% Caucasian). The time from the initial PC diagnosis to the first dose of Lu-177 was a median of 67 months (range: 10 months-367 months). The median age at the first dose of Lu-177 was 65 years (range: 45-80). 18 patients (53%) remain alive as of Feb 2024. 14 pts (41%) completed 6 cycles of Lu-177 and 11 pts (32%) remain alive. The Kaplan-Meier median OS for these 34 pts starting from the first cycle of Lu-177 was 10 months. Conclusions: A 2022 estimated cost for Lu-177 was $42,500 per dose (excludes administration) so “payors” may have been charged more than $5,000,000 for the Lu-177 for these patients. Lu-177 may be of more benefit earlier in the PC disease spectrum, or perhaps pre-treatment PSMA imaging can better target patients who will benefit from Lu-177. Our observed median OS of 10 months did not match the 15.3 reported in the VISION study (DOI: 10.1056/NEJMoa2107322). Further data evaluation and collection are warranted from different communities to investigate the differences observed in the survival data reported in the literature and observed in the clinic setting. [Table: see text]

Does enzalutamide related PSMA upregulation affect outcomes of lutetium-177 PSMA radioligand therapy?

Enzalutamide is an antiandrogen drug used prior to lutetium-177 prostate specific membrane antigen (Lu-PSMA) radioligand therapy and has shown promising results for upregulating the PSMA expression on prostate cancer cells. In this study, we aim to compare prostate specific antigen (PSA) level changes in prostate cancer patients who received enzalutamide to those who did not. Prostate cancer patients who underwent Lu-PSMA between 2021 and 2023 were retrospectively included. Patients were grouped based on prior enzalutamide therapy: those who received enzalutamide (EZ+) for at least 14 days and those who did not (EZ-). PSA changes and F-18 DCFPyL SUV (Standardized Uptake Values) were compared. Thirty-seven patients were included, 18 EZ+ and 19 EZ-. The median age, Gleason score, and prior chemo/hormonal therapies were similar for EZ+ and EZ-, except for radium-223. Eleven patients (61%) in EZ+ and 13 patients (68%) in EZ- showed a decrease in PSA after the first cycle (p = 0.64). Four patients (22%) in EZ+ and seven patients (37%) in EZ- had more than 50% decrease in PSA after the first cycle (p = 0.33). The average percent decline at the end of the treatment was 23.3% in EZ+ and 50.4% in EZ- (p = 0.4). There was no difference in terms of lesion with highest SUVmax, mean SUV, total tumor volume or activity on pre-therapy PSMA imaging. Enzalutamide treatment prior to Lu-PSMA does not improve patient outcomes when applied remotely. Larger studies evaluating the combination therapies and the timing of enzalutamide are needed to assess its correlation with Lu-PSMA outcomes.

The Role of 68 Ga PSMA Imaging in Evaluating Adrenal Lesions in Prostate Cancer Patients.

Objectives Gallium-68 prostate-specific membrane antigen ( 68 Ga-PSMA) imaging is valuable for staging because an accurate diagnosis, metastatic or nonmetastatic for prostate cancer patients, is required for deciding to treatment approaches and prognostic assessment. The aim of this study was primarily to distinguish between benign and metastatic adrenal gland lesions detected during 68 Ga-PSMA positron emission tomography (PET)/CT imaging, to evaluate the presence of factors predicting its development, and then to determine the life expectancy of patients with metastatic adrenal lesions. Materials and Methods We performed a database search for PET/CT records generated from June 2016 to February 2021 for "adrenal gland" in report for patients who underwent 68 Ga-PSMA examination with prostate cancer patients. Results Twenty-three patients (10 benign and 13 metastatic) were included in this study. The total prostate-specific antigen, adrenal gland size, adrenal gland density, and maximum standardized uptake (SUVmax) values are significantly different between groups ( p < 0.05). On receiver operating characteristic curve analysis, the SUVmax cutoff value > 6.8 provided both sensitivity and specificity of 100%. However, with 29 mm as the adrenal gland size cutoff and 21.2 as Hounsfield unit, the sensitivity and specificity were 56.2 and 92.3%, and 93.8 and 92.3%, respectively. The survival of the benign and metastatic groups was compared and a statistically significant difference was found ( p = 0.006). The presence of pelvic lymph nodes was statistically negatively affected the surveillance between the groups. Conclusion The presence of atypical metastases such as adrenal gland is not insignificant in prostate cancer patients. Because of this degree of impact on patient management, accurate staging by imaging with 68 Ga-PSMA should be an integral part of prostate cancer management.

Abstract CT225: Quantitative assessment of PSMA imaging before and after 177Lu-PSMA-617 treatment in a Ph I/II trial

Abstract Background: We have previously reported that 177Lu-PSMA-617 given as a single-cycle, dose-intense regimen for patients (pts) with pretreated mCRPC is efficacious even without selection by PSMA (ESMO 2021). Quantitative analyses of pre-treatment PSMA PET may allow for better patient selection and prediction of toxicities. Analyses of sequential PET images may also provide insights that may be associated with longer term outcomes. Our previous analysis of 13 patients demonstrated association of PSMA PET signal with overall survival (OS) and PSA responses, as well as trends with adverse events (Nauseef GU ASCO 2022). Here we present long-term follow up data and expanded imaging correlatives from our completed phase I/II study. MethodsEntry criteria: progressive mCRPC after at least one prior potent AR pathway inhibitor and prior chemotherapy (excepting men ineligible for or refusing of chemotherapy) with allowance for prior radionuclides (incl. Ra223 and PSMA-TRTs). Treatment was fractionated-dose (D1 and D15) 177Lu-PSMA-617 (7.4-22.2 GBq). TRAQinform IQ (AIQ Solutions) was used to identify, track, and quantify regions of interest suspicious of cancer (lesion-ROI) on PSMA PET/CT images and quantify uptake in normal organs outside of lesion-ROI. Measurements included SUVmean across all lesion-ROI, volume of lesion-ROI, and SUVtotal (sum of SUV in all lesion-ROI), as well as changes after treatment, including in PSMA-expressing healthy tissues. Associations with survival were tested via Cox proportional hazard models in univariate analyses and associations with adverse events (AEs) and PSA responses were via assessed via Wilcoxon rank sum tests. Results32 pts (of 50 total in the study between 1/2017-2/2021) had pre- and post-treatment imaging suitable TRAQinform IQ analysis and associated survival analyses. Baseline characteristics were similar to the entire study cohort. PSA response of 50% was observed in 21/32 (66%) of which 16 were confirmed. No imaging variable predicted PSA30 or PSA50, although an association was observed in pretreatment SUVmean and lesion-ROI volume reduction. No imaging variable was significantly associated with OS (e.g., pretx SUVmean HR 0.9, p=0.10, pretx Volume HR 1.00, p=0.052). Pretx SUVmean was associated with mPFS (HR 0.85, 95% CI 0.74, 0.98, p=0.023). Among select AEs, anemia was associated with non-lesion-ROI skeleton SUVtotal in pre- (p=0.027) and post-tx (p=0.007). Higher pre-treatment salivary gland uptake (SUVmean) was associated with more xerostomia (p=0.11). Fatigue was associated with a variety of variables including salivary SUVs (mean, max, and total) and post-tx bowel SUVmax (p=0.030). ConclusionsPre-treatment and pre- to post-treatment 68Ga-PSMA11-PET data analyzed may be associated with outcome. While a strength of this study is the prospective nature of patient enrollment and fixed imaging timepoints, our associations are limited by small sample size. Expansion of this analysis to larger datasets may improve our ability to predict treatment response and toxicity by body-wide PSMA detection. Citation Format: Jones Trevor Nauseef, Charlene Thomas, Michael Sun, Nicole Jacobs, Andrés Ricaurte Fajardo, Sam Ruder, Escarleth Fernandez, Zachary Davidson, Amie Patel, A. Oliver Sartor, Shankar Vallabhajosula, Ana Molina, Cora N. Sternberg, David M. Nanus, Sandra Huicochea Castellanos, Joseph Osborne, Neil H. Bander, Timothy Perk, Scott Tagawa. Quantitative assessment of PSMA imaging before and after 177Lu-PSMA-617 treatment in a Ph I/II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT225.

Real-World Experience with 177Lu-PSMA-617 Radioligand Therapy After Food and Drug Administration Approval.

We report our initial real-world experience with 177Lu-PSMA-617 radioligand therapy. Methods: We performed a retrospective review of patients treated with 177Lu-PSMA-617. Pretreatment PSMA PET, laboratory findings, overall survival, a fall in prostate-specific antigen by 50% (PSA50), and toxicities were evaluated. Results: Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%). Conclusion: At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from 177Lu-PSMA-617 radioligand therapy.

Patterns of PSMA PET/CT scan usage for initial staging and recurrence in a multi-centered hospital system.

36 Background: PET PSMA-based imaging for prostate cancer staging has been approved since late 2020 and was widely available in our medical system by July 2021. We sought to examine the patterns of use of PSMA PET/CT and conventional imaging for staging since this time. Methods: We retrospectively identified men who were diagnosed with presumptive NCCN unfavorable intermediate risk (UIR), high risk, or very high risk (VHR) and men who underwent staging work-up for biochemical recurrence (BCR) from July 2021 – June 2023. Patient clinical, pathological, and imaging variables were collected. Sufficient conventional imaging for initial staging was defined as the use of a bone scan and one or more of an MRI or CT scan. The date of staging was determined by the initiation of staging with conventional imaging or the date of PSMA scan if used. Results: In the study period, 899 men were diagnosed with presumptive NCCN UIR-VHR disease. Among these individuals 32% (290/899) underwent no or insufficient staging, 26% (230/899) underwent staging with conventional imaging only, and 42% (379/899) underwent initial staging evaluations that included PET PSMA. The frequency of PET PSMA used for initial staging increased from 24% (20/82) to 80% (167/208) over the 2-year study period. 1173 men with biochemical recurrence who underwent a staging work-up were identified. Median PSA of these men was 1.37 ng/mL (IQR 0.23, 6.59 ng/mL). The frequency of PET PSMA imaging increased in these men from 91% (225/246) to 98% (296/303) over the 2-year study period. When ordering both PSMA and conventional imaging for initial staging, providers tended to order PSMA scans after initial conventional imaging orders (72%) rather than before (18%) or on the same day (11%). Conclusions: The use of PSMA PET/CT imaging rose since its implementation in our system in July 2021 with PSMA PET being utilized in 80% of patients being initially staged and 98% of those staged at BCR. Conventional imaging and Axumin PET are rarely used in BCR. If both PET PSMA and conventional imaging were ordered for initial staging, PET PSMA was typically performed after conventional imaging. Growing data may inform best sequencing and use of conventional imaging in the PSMA-PET era.

Predictors of PSMA positivity at initial staging of prostate cancer.

283 Background: PSMA-based imaging improves detection of metastatic disease for initial staging of men diagnosed with prostate cancer (PCa) with higher accuracy compared to conventional imaging. PSMA imaging is now being increasingly adopted for initial local and distant metastatic staging. We sought to determine the contribution of clinical and pathological factors associated with PSMA positive nodal or metastatic disease. Methods: We retrospectively identified 404 men diagnosed with PCa who underwent initial staging with Gallium-68 or F-18 piflufolastat (DCFPyL) PSMA PET/CT across our eleven-hospital system from July 2021-December 2022. Patient characteristics, including demographic, clinical, pathologic, and imaging variables were obtained. PSMA positivity representing a suspicious nodal or distant lesion was determined based on radiology reports, histopathology, and other imaging modalities, and equivocal or likely benign lesions were counted as negative. Patients with prior diagnosis (&gt;6 months) of PCa (n=42) or incomplete clinical history (n=22) were excluded. Clinical variables were compared with Wilcoxon Rank Test, Chi square, and Fishers’ exact test as well as univariable and multivariable logistic regression. Number of risk factors for patients with unfavorable intermediate or very high risk disease was also examined. PSA was log transformed. Statistical significance was defined as p&lt;0.05. Results: 103/340 patients (30.3%) had PSMA imaging findings concerning for nodal or distant metastatic disease. Patients with positive finding were less likely to be Black, and had higher PSA, biopsy Gleason Grade Group, and higher presumptive NCCN risk. Stratifying by pre-scan NCCN risk group, PSMA positivity was observed in no patients with favorable intermediate risk PCa (n=17), 9.8% (12/123) with unfavorable intermediate risk PCa, 29% (25/86) with high risk PCa, and 58% (66/114) with very high risk PCa. Stratifying by number of risk factors, there were significant differences in scan positivity comparing unfavorable intermediate risk disease with 1 vs ≥2 risk factors (4.2% vs 17%, p=0.03) and very high risk disease with 1 risk vs ≥2 risk factors (49% vs 72%, p=0.01). On multivariable analysis, NCCN classification stratified by risk factors was associated with PSMA positivity while Black race was inversely associated (OR 0.32, 95% CI 0.11, 0.82, p=0.03). Conclusions: Initial staging with PSMA PET/CT identified local regional or metastatic disease in 30% of PCa patients. A substantial proportion of unfavorable intermediate risk men were N1 or M1 based on PSMA positivity, particularly those with multiple unfavorable intermediate risk features. The clinical benefit for PSMA PET/CT in patients with favorable intermediate risk PCa is low. Limitations include retrospective design (including possible selection bias for patients with equivocal lesions on conventional imaging) and a limited number of black men in the cohort.

Prostate cancer and elective nodal radiation therapy for cN0 and pN0-anever ending story? : Recommendations from the prostate cancer expert panel of the German Society of Radiation Oncology (DEGRO).

For prostate cancer, the role of elective nodal irradiation (ENI) for cN0 or pN0 patients has been under discussion for years. Considering the recent publications of randomized controlled trials, the prostate cancer expert panel of the German Society of Radiation Oncology (DEGRO) aimed to discuss and summarize the current literature. Modern trials have been recently published for both treatment-naïve patients (POP-RT trial) and patients after surgery (SPPORT trial). Although there are more reliable data to date, we identified several limitations currently complicating the definitions of general recommendations. For patients with cN0 (conventional or PSMA-PET staging) undergoing definitive radiotherapy, only men with high-risk factors for nodal involvement (e.g., cT3a, GS ≥ 8, PSA ≥ 20 ng/ml) seem to benefit from ENI. For biochemical relapse in the postoperative situation (pN0) and no PSMA imaging, ENI may be added to patients with risk factors according to the SPPORT trial (e.g., GS ≥ 8; PSA > 0.7 ng/ml). If PSMA-PET/CT is negative, ENI may be offered for selected men with high-risk factors as an individual treatment approach.

The clinical signification and application value of [68Ga]Ga-PSMA imaging in thyroid malignancy.

Approximately 5% of differentiated thyroid cancers lose the ability to uptake iodine, leading to limited treatment options and poor prognosis due to invasion and distant metastasis. PSMA imaging probes have been proposed as a potential diagnostic and therapeutic tool for iodine-refractory thyroid cancer. However, there are limited reports and significant heterogeneity in patient selection, warranting further exploration of the application value of PSMA in thyroid cancer. We performed Western Blot, PCR, and [68Ga]Ga-PSMA uptake experiments on cell lines and conducted in vivo small animal imaging. Clinical and radiological results of included differentiated thyroid cancer patients were collected. (Trial registration number: 2021-669, Trial registration date: December 30, 2021). PSMA expression levels were significantly higher in poorly differentiated thyroid cancer (7.86 ± 1.90 vs. 1.00 ± 0, P < 0.01; 7.86 ± 1.90 vs. 0.03 ± 0.02, P < 0.01), but [68Ga]Ga-PSMA imaging correlated with tumor burden, such as 18F-FDG (8.08 ± 7.74 and 5.67 ± 4.23, P = 0.01) and Tg levels (307.1 ± 183.4 vs. 118.0 ± 116.1, P = 0.002). Our results showed that PSMA expression increased with the decrease of thyroid cancer differentiation. However, the level of [68Ga]Ga-PSMA uptake in thyroid cancer patients was not significantly associated with the degree of thyroid cancer differentiation, but also with the metabolism and burden of tumors such as 2-[18F]FDG and Tg levels. These findings provide additional clinical significance and application value for PSMA in thyroid cancer.

A Phase I Trial of Focal Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer.

Locally recurrent prostate cancer after radiotherapy (RT) is an increasingly recognized entity with no standard management. NCT03253744 was a phase I trial with a primary objective of identifying the maximally tolerated dose (MTD) of a course of image-guided, focal, salvage stereotactic body radiotherapy (SBRT) for patients with local recurrence after prior definitive RT. Additional objectives included biochemical control and imaging response on mpMRI and 18F-DCFPyL (PSMA) PET/CT. SBRT was prescribed to three dose levels (DLs): 40Gy (DL1), 42.5Gy (DL2), and 45Gy (DL3) in 5 fractions. The prescription dose was delivered to a PTV defined by mpMRI and PSMA imaging and biopsy confirmed tumor volume. Dose escalation followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities above baseline were scored using CTCAE v5.0 criteria for two years after completion of SBRT. Escalation was halted if 2 dose limiting toxicities (DLTs) were observed. DLTs were defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT, and any grade 3 GU or grade 4 GI toxicity thereafter. Imaging response was compared between baseline and 6-months by the Wilcoxon signed rank test. Between 08/2018 and 05/2022, 8 patients underwent salvage SBRT to 11 intraprostatic lesions with a median follow-up of 27 months. No DLTs were observed on DL1. Two patients were enrolled on DL2 and both experienced grade 3 GU toxicities, prompting de-escalation and expansion (n = 6) on DL1, the MTD. The most common toxicities were grade 2 GU toxicities: acute urinary urgency/frequency, acute weak urinary stream, and noninfective cystitis. One patient at DL1 had a self-limited episode of grade 2 GI toxicity (proctitis). No grade 3 GI toxicities were observed. All but two patients achieved an undetectable PSA nadir. Only one of these experienced biochemical failure (nadir + 2.0) at 33 months with suspicion of distant metastatic failure on restaging PET/CT. Imaging response was demonstrated by MRI in all lesions with heterogeneity in volumetric response (6% to 100%). A significant (p<0.01) response on PSMA PET/CT was observed for all measured parameters (SUVMax, SUVMean, GTVPSMA, Total Lesion PSMA [SUVMean × GTVPSMA]). Of the 11 lesions, 1 (9%) demonstrated a complete response (CR) by MRI and 9 (82%) by PSMA PET/CT. A single lesion increased in volume by 0.06 cc (16%) at 6-month PSMA PET/CT compared to baseline in the only patient who did not achieve an undetectable PSA nadir and did not have imaging suggestive of distant failure. On this phase I dose escalation study of salvage SBRT for isolated intraprostatic local failure after definitive RT, the MTD was 40Gy in 5 fractions. producing a 100% 24-month bPFS, with one late failure at 33 months occurring after the 24-month study period. The most frequent clinically significant toxicity was late grade 2 GU toxicity. Imaging response was demonstrated in all lesions on MRI and PSMA PET/CT with exception of a single lesion.

Phase I dose-escalation results of prostate-specific membrane antigen-targeted radionuclide therapy (PSMA-TRT) with alpha-radiolabeled antibody 225Ac-J591 and beta-radioligand 177Lu-PSMA I&amp;T.

5018 Background: PSMA may be targeted by antibodies (mAb) or small molecules (SML), with different kinetics and biodistribution. mAb with longer circulation time and marrow exposure, but decreased access to luminal PSMA expression (e.g. salivary glands, intestine, kidney). SML diffuse to all sites of PSMA expression and then excreted. Alpha radionuclides emit more energy over shorter range vs beta. Pre-clinical data combining mAb and SML supports synergy, with enhanced uptake and retention of SML. Here, we present phase I dose-escalation results of a phase I/II trial investigating combo 225Ac-J591 with 177Lu-PSMA-I&amp;T (aka PNT2002). Methods: Eligibility criteria include progressive mCRPC, ≥1 prior AR pathway inhibitor (ARPI), prior chemo (or unfit/refuse), ≥1 lesion with SUVmax &gt;liver. Doses: 177Lu-PSMA-I&amp;T (6.8 GBq); 225Ac-J591 (30, 35, or 40 KBq/kg), up to 2 doses of combo TRT 8 weeks (wks) apart with 177Lu SPECT following each dose. Primary objectives: dose-limiting toxicity (DLT) and recommended phase II dose; phase II will test the proportion of patients (pts) obtaining &gt;50% PSA decline (PSA50). DLT defined as G4 myelosuppression lasting &gt;1 wk, Gr&gt;2 non-hematologic adverse event (AE), any Gr attributed AE delaying therapy &gt;3 wks. Additional endpoints include progression-free and overall survival, radiographic response rate, safety, circulating tumor cell (CTC) changes, pt reported outcomes, PSMA imaging, blood/tissue correlatives. Results: 18 pts treated (6 at each dose level); 3 did not receive the 2nd dose due to progressive disease or withdrawal. Median age 70 (range 54-86), PSA 54.4 (2.43-9614). 13 (72%) with bone, 9 (50%) lymph node, 2 (11%) liver, 2 (11%) lung mets. 10 (56%) pts CALGB risk category high, 7 (39%) intermediate, 1 low. Previous therapies: 11 (61%) with &gt;1 ARPI, 12 (67%) chemo, 5 (28%) sip-T, 3 (17%) radium-223. 2 of 6 pts with DLT at 40 KBq/Kg (Gr 2 or 3 thrombocytopenia delaying cycle 2 by &gt;3 wk); no DLT observed in other cohorts. As submission, 7 pts (39%) remain on study, including 1 without progression at 16 months and another with undetectable PSA at 10 months. With follow up ongoing, 17 (94%) with PSA decline, 9 (50%) with PSA50. Of those with paired CTC counts, 4 of 5 (80%) converted from unfavorable to favorable CTC count, 4 of 8 (50%) from detectable to undetectable, 1 of 2 (50%) remained undetectable. AEs include 3 (17%) neutropenia (all Gr &lt;2), 12 (67%) thrombocytopenia (3 Gr 3), 10 (56%) anemia (3 Gr 3), 10 (56%) pain flare (1 Gr3 in pt with cord compression), 12 (67%) xerostomia (one Gr2), 11 (61%) nausea (all Gr 1), 9 (50%) fatigue (all Gr 1). Conclusions: The combination of dual-PSMA targeting with mAb + SML and alpha + beta is feasible with follow up ongoing. Efficacy will formally be tested in the upcoming phase II portion of the study with 225Ac-J591 at 35 KBq/Kg and 177Lu-PSMA I&amp;T at 6.8 GBq. Clinical trial information: NCT04886986 .

A study of prospective monitoring of patients with recurrent prostate cancer using serial PSMA imaging (18F-DCFPyL).

TPS5101 Background: 18F-DCFPyL PSMA PET imaging is now FDA approved for patients with high-risk prostate cancer and those with biochemically recurrent prostate cancer (BCR). BCR has been traditionally defined as a rising PSA after definitive surgery and/or radiation have not been curative in patients without tumor findings on a CT or Tc99 bone scan. There are an estimated 25,000-50,000 new cases of BCR in the US annually. BCR patients are usually managed conservatively, often with surveillance since there is no data demonstrating interventions improve survival. Although 18F-DCFPyL will be able to detect disease at the micrometastatic/subclinical level, there is limited prospective data on how these patients should be managed. While great enthusiasm exists to utilize radiation or ADT-based regimens extrapolated from a more advanced disease state, the natural history of subclinical disease seen on 18F-DCFPyL remains unclear (Madan RA et al. J Clin Oncol 2022). Methods: The primary objective of this study is to monitor patients with recurrent prostate cancer to learn about the natural history of 18F-DCFPyL PET positive disease in this patient population. Eligible patients include those who have had prior definitive surgery or radiation, current PSA ≥0.50 ng/mL, testosterone &gt; 100 ng/mL, no evidence of soft tissue disease on CT scan/MRI and no bone lesions on bone scan. Patients will undergo initial imaging with 18F-DCFPyL scans. Those with negative findings on the initial scan will have annual repeat 18F-DCFPyL scans. Patients with positive initial scans will be scanned every 6 months. All patients will have PSA testing every 3 months and will undergo annual CT and Tc99 bone scans. Up to 250 patients will be followed for 5 years or until off-study criteria is met (including new findings on CT/bone scans consistent with metastatic disease or continuous systemic prostate cancer therapy for more than 6 months). In addition to monitoring the imaging changes, we will evaluate patterns of progression on 18F-DCPyL scans over time, analyze PSA doubling time in context of 18F-DCFPyL changes and evaluate circulating biomarkers. ClinicalTrials.gov Identifier: NCT05588128. Clinical trial information: NCT05588128 .

Defining the prevalence of inherited DNA damage repair genetic variants (DDRv) in men with prostate cancer (PCa) detected by PSMA PET.

e17010 Background: Approximately 12% of patients (pts) with metastatic PCa (mPCa) identified by conventional imaging harbor DDRv. The increased use of PSMA PET has identified a group of pts with extra-prostatic PCa which is not apparent on conventional imaging and for whom the frequency of germline DDRv testing remains unknown. Methods: A single-institution retrospective analysis of patients with PCa detected by PSMA PET who had also undergone germline genetic testing was undertaken. Data collected included PSA level at time of PSMA PET imaging, stage/Gleason score at diagnosis (dx), rationale for germline testing, castration status, and whether the metastatic disease identified on PSMA PET represented de novo or recurrent mPCa. Germline sequencing results were evaluated for 16 DNA damage repair genes: ATM, ATR, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, GEN1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51C, and RAD51D. The frequency of DDRv was evaluated in groups defined by PSMA imaging results: localized (N0M0), Node-Positive (N+M0), metastatic (M+) PCa. Results: Of 795 PCa pts who underwent germline testing and 2101 PCa pts who underwent PSMA PET imaging, 386 had undergone both, and constitute the study cohort. In the study cohort the distribution of PCa extent identified by PSMA PET was: 81/386 (21.0%) N0M0; 76/386 (19.7%) N+M0; 229/386 (59.3%) M+. There were no statistically significant differences in the prevalence of DDRv with regards to age, Gleason score at dx, PSA at time of imaging, castration status at time of imaging, rationale for germline testing, or if metastatic, whether de novo or recurrent. The distribution of DDRv is shown in the table. There were no statistically significant differences between groups. Conclusions: The overall frequency of pathogenic germline DDRv in PCa pts who had undergone PSMA PET imaging was 4.66%, considerably lower than what has been reported in men with mPCa detected with conventional imaging. The presence or absence of extra-prostatic PCa detected by PSMA PET imaging did not appear to affect the frequency of DDRv. Validation of these findings in other cohorts will be important to guide recommendations for germline genetic testing in the growing group of PCa pts undergoing PSMA PET imaging. [Table: see text]

Is there more than meets the eye in PSMA imaging in prostate cancer with PET/MRI? Looking closer at uptake time, correlation with PSA and Gleason score

BackgroundIn patients with increasing PSA and suspicion for prostate cancer, but previous negative biopsies, PET/MRI is used to test for tumours and target potential following biopsy. We aimed to determine different PSMA PET timing effects on signal kinetics and test its correlation with the patients’ PSA and Gleason scores (GS).MethodsA total of 100 patients were examined for 900 s using PET/MRI approximately 1–2 h p.i. depending on the tracer used (68Ga-PSMA-11, 18F-PSMA-1007 or 18F-rhPSMA7). The scans were reconstructed in static and dynamic mode (6 equal frames capturing “late” PSMA dynamics). TACs were computed for detected lesions as well as linear regression plots against time for static (SUV) and dynamic (SUV, SUL, and percent injected dose per gram) parameters. All computed trends were tested for correlation with PSA and GS.ResultsStatic and dynamic scans allowed unchanged lesion detection despite the difference in statistics. For all tracers, the lesions in the pelvic lymph nodes and bones had a mostly negative activity concentration trend (78% and 68%, resp.), while a mostly positive, stronger trend was found for the lesions in the prostate and prostatic fossa following RPE (84% and 83%, resp.). In case of 68Ga-PSMA-11, a strong negative (Rmin = − 0.62, Rmax = − 0.73) correlation was found between the dynamic parameters and the PSA. 18F-PSMA-1007 dynamic data showed no correlation with PSA, while for 18F-rhPSMA7 dynamic data, it was consistently low positive (Rmin = 0.29, Rmax = 0.33). All tracers showed only moderate correlation against GS (Rmin = 0.41, Rmax = 0.48). The static parameters showed weak correlation with PSA (Rmin = 0.24, Rmax = 0.36) and no correlation with GS.Conclusion“Late” dynamic PSMA data provided additional insight into the PSMA kinetics. While a stable moderate correlation was found between the PSMA kinetics in pelvic lesions and GS, a significantly variable correlation with the PSA values was shown depending on the radiotracer used, the highest being consistently for 68Ga-PSMA-11. We reason that with such late dynamics, the PSMA kinetics are relatively stable and imaging could even take place at earlier time points as is now in the clinical routine.

Abstract CT014: Phase I dose-escalation study of fractionated dose 225Ac J591 for metastatic castration resistant prostate cancer

Abstract Background: PSMA-based targeted radionuclide therapy is now a standard of care for mCRPC since approval of 177Lu-PSMA-617. Use of antibodies (e.g., J591) to target PSMA with higher potency radionuclides (e.g., 225Ac) impacts kinetics, biodistribution, clinical efficacy, and toxicities. In our first-in-human ph I dose-escalation study of single dose 225Ac-J591 in patients with mCRPC, no MTD was reached (max dose 93.3 KBq/kg). Following this, we developed ph I/II parallel dose-escalation studies of fractionated (D1, D15) single cycle and multiple (q6w) dose regimens. Here we present safety data from the initial fractionated study in predominantly 177Lu-naive. Methods: Eligible patients had adequate organ function, ECOG performance status 0-2, and progressive mCRPC following potent AR pathway inhibitor (ARPI) and chemo (or unfit/refusing). Prior 177Lu-PSMA was allowed until an amendment developed a separate study for post-177Lu-PSMA. Baseline 68Ga-PSMA PET scans were performed, but not used to determine eligibility. A 3+3 dose-escalation design was used. Phase I primary objective: determination of dose-limiting toxicity (DLT) and recommended phase II dose (RP2D). DLT was defined as within 8 weeks of first dose: neutropenia (Gr 4 or febrile neutropenia), thrombocytopenia (TCP) (Gr 4, or Gr 3 with clinically significant bleeding), any Gr &amp;gt;2 non-hematologic toxicity deemed to be at least possibly related to 225Ac-J591, or any attributable toxicity precluding or delaying the second dose by &amp;gt;2 weeks. Secondary/exploratory objectives: efficacy measures (e.g., PSA decline, radiographic RR, biochemical/radiographic PFS, OS, CTCs, patient reported outcomes), safety (CTCAE v5), and correlatives (plasma and tissue genomics, PSMA imaging). Results: 24 patients were enrolled in phase I. Median age 73.5 (57-91), PSA 25.78 (3.39-2133.41); 53% (n=13) &amp;gt;1 prior ARPI, 58% (n=14) taxane chemo, 8% (n=2) anti-PSMA therapy, 12.5% (n=3) prior 223Ra. CALGB prognostic groups: Good 4 (16%), Intermediate 8 (33%), Poor 12 (50%). No DLTs were observed in Cohort 1 (n=3) or 2 (n=6). In C3, 2/6 subjects experienced DLTs (Gr 3 weakness, Gr 2 TCP with &amp;gt;2 week delay in second fraction). 8 patients were enrolled in an intermediate dose cohort (2.5) with 1 DLT (Gr 4 TCP). Two patients withdrew before the second dose (intercurrent illness; interruption of 225Ac supply). Most common low gr non-hematologic treatment emergent AEs: fatigue (95%), xerostomia (69%), and nausea (57%). Among evaluable patients for PSA change (n=22), 21 (95%) experienced PSA decline with 14 (67%) with decline of 50% and 6 (37%) with decline of 90%. 13/21 patients had CTCs samples collected at baseline and 12 wks; 5 were unfavorable at baseline (≥5/7.5 mL); 10/13 (77%) remained favorable or converted from unfavorable to favorable; 6/12 (50%) had 50% decline in CTC count; and 5/13 (38%) converted from detectable to undetectable. Conclusions: A single fractionated cycle of 225Ac-J591 was delivered with few high grade AEs and with evidence of preliminary efficacy by PSA and CTC changes across all dose levels. Citation Format: Jones T. Nauseef, Michael Sun, Charlene Thomas, Mahelia Bissassar, Escarleth Fernandez, Zachary Davidson, Amie Patel, Angela Tan, Tessa A. Chamberlain, Kara Earle, Rebecca Wunder, Sabrina Guervil, Sandra H. Castellanos, Judith Stangl-Kremser, Peter S. Gregos, Joseph R. Osborne, Karla V. Ballman, Ana M. Molina, Cora N. Sternberg, David M. Nanus, Neil H. Bander, Scott T. Tagawa. Phase I dose-escalation study of fractionated dose 225Ac J591 for metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT014.

Abstract 976: The regulation of FOLH1/PSMA in prostate cancer

Abstract Prostate Specific Membrane Antigen (PSMA) is a prominent biomarker in Prostate Cancer (PC) and has evolved into a useful target for both imaging and therapy. But how PSMA becomes overexpressed upon PC development, its modulation by androgen deprivation therapy (ADT), and its absence in neuroendocrine-differentiated PC is not well understood. The exact mechanism by which PSMA is regulated has not been defined. Understanding PSMA regulation in PC patients for diagnostic, prognostic, and treatment purposes would be extremely valuable and could be exploited for PSMA-targeted therapies. To address this, we sought to characterize the epigenetic landscape of FOLH1 (the gene for PSMA) and determine the regulatory factors involved in FOLH1 transcription. Based on histone marker and protein ChIP-Seq data sets alongside ATAC-seq, we found that FOLH1 is a Super Enhancer (SE) and is collectively bound by an array of transcription factors (TFs), including AR, FOXA1, and HOXB13. We developed a hidden Markov model (HMM) with seven chromatin states built on average TF binding in the FOLH1 landscape and trained on the FOLH1 gene and known enhancer regions. Chromatin states were annotated based on features in the FOLH1 gene. With a simple regression model and k-fold cross-validation, mean occupancy of the three TFs and H3K27Ac in each state accurately predicts FOLH1 expression (ρ &amp;gt; 0.9) across PC samples. To assess the functionality of the enhancer regions predicted by our computational HMM, we performed a CRISPR interference (CRISPRi) screen with a nuclease dead-Cas9 protein conjugated to the KRAB transcriptional repressor and directed by a pool of gRNAs that tile across the AR protein-bound regions within the FOLH1 landscape. A sliding window analysis of our CRISPRi screen revealed that the top scoring gRNAs delineate 5 Regulatory Regions (RRs) found within the SE region of FOLH1 that control FOLH1/PSMA expression. Motif identification in these RRs have provided a list of potential TF candidates involved in regulating FOLH1, and knockdown experiments are currently being conducted to evaluate individual and combinations of TF contribution to FOLH1 expression. There is evidence for a constellation of TFs responsible for regulating FOLH1, and context-specific modifications in FOLH1 regulation will need to be evaluated in various models and conditions. These results suggest FOLH1 is regulated by epigenetic control in the SE region and may be altered in progression or with ADT. Characterizing the regulation of FOLH1/PSMA will result in a deeper understanding of the meaning of alterations in uptake on PSMA imaging and may enable some degree of control over expression, thus aiding in PSMA-directed treatments. Citation Format: Margaret E. White, Thomas Pranzatelli, Xavier Moore, Joel Bowman, Jay Chiorini, Peter Choyke, Kathy Kelly. The regulation of FOLH1/PSMA in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 976.

Abstract No. 91 MRI-Guided Cryoablation of Oligo-Metastatic Prostate Cancer to the Pelvic Lymph Nodes

To demonstrate feasibility and short-term follow-up of using MR-guided cryoablation for treatment of oligo-metastatic prostate cancer to pelvic lymph nodes. Retrospective review is conducted for patient’s treated with MR-guided cryoablation from September 2018 to December 2021 for solitary prostate cancer metastasis to the pelvic lymph node as identified by PET choline and/or PET PSMA imaging. Patients underwent MR-guided cryoablation using a transperineal needle placement under general anesthesia. Cryoablation was performed with continuous MR imaging monitoring so that the iceball was grown to encompass the lesion with margins as permitted based on adjacent structures (i.e., ureter, obturator nerve, sciatic nerve). Patients were discharged the same day. PET Imaging and PSA were performed every 3 months post-ablation with MRI of the pelvis as needed. Percent change in PSA for patients without new metastatic disease at 3-month PET/CT was assessed using a paired t-test. Review demonstrated 11 patients with 12 procedures during this time frame. Baseline PSA was 1.47 ± 2.79 ng/mL. All 12 procedures had negative 3-month post-ablation PET imaging based on local response to treatment. Post-ablation gadolinium contrast T1 weighted MRI showed lack of enhancement. Among the 7 patients with no new metastatic or prostatic bed disease, there was a significant percent decrease in PSA at 3 months post-ablation (-47.2% ± 29.5%; P = 0.003). MR-guided cryoablation can be utilized for the treatment of oligo-metastatic prostate cancer to the pelvic lymph nodes with good short-term results.

68Ga-PSMA-11 patients with newly diagnosed and recurrent prostate cancer (Firefly Study): Preliminary results.

54 Background: A primary challenge facing oncologists is the accurate identification of the source of the rising PSA in the recurrent disease setting and the failure of proper staging at the time of initial therapy. PSMA imaging allows for progress in this regard, however access remains an issue. As such, we designed the Firefly study to offer PSMA imaging to patients between May 2021 and May 2022, to better characterize their disease. Methods: This is a phase II expanded access intermediate sized clinical trial using 68Ga-PSMA-11 (Telix Pharma cold kit) under Tulane’s own Investigational New Drug (IND). Clinical trial information: NCT04854369. Two cohorts are utilized, recurrent disease with a PSA &gt; 0.2 or &gt; 2.0 post-radiation, and newly diagnosed high risk or oligo-metastatic patients as assessed by conventional imaging. Between May 2021 and May 2022, a total of 90 patients were enrolled. The study was designed for a maximum of 300 patients but was terminated when access to insurance approved PSMA scans was available. Patients received 1.8–2.2 MBq/kg body weight with 68Ga-PSMA-11 (per EANM guidelines). The lower and upper limits of the dose were set to 3 to 7 mCi respectively. Primary Objective(s): Utilize 68Ga-PSMA-11 PET to define uptake location for localization of prostate cancer metastatic sites in patients prior to initial therapy, and in both local recurrences and metastatic sites in patients with recurrent disease after initial therapy. Secondary Objectives: To assess the therapeutic consequences of 68Ga-PSMA-11 PET/CT imaging in prostate cancer patients with and without prior treatment. Results: Of the 90 patients enrolled 81 were in the recurrent disease cohort and nine had newly diagnosed disease. Of the 81 patients with recurrent disease; 30 were known metastatic and were scanned with the intention of application for expanded access to 177Lu-PSMA-617, 8 received radiation for their oligometastases, 12 received a combination of radiation and initiation of hormone therapy, 13 continued surveillance, 5 were sent for salvage therapy, 13 were treated with novel hormones. Of the 9 patients with newly diagnosed disease all of them were negative for metastasis on conventional imaging. However, when scanned with 68Ga-PSMA-11, 7/9 had a positive PSMA scan. A lesion in the prostate was identified in 2/7 patients, 2/7 were found to have de novo metastatic disease to the lymph nodes and 3/7 were found to have bone metastasis. All these patients were treatment naïve and 5/7 had changes to their planned definitive treatment plan based on these results, as high-risk patients found to have previously unidentified de novo metastatic disease. Conclusions: Further analysis of the data is planned to complete secondary objectives; however, this study demonstrates the potentially meaningful impact of PSMA imaging for patient treatment planning and individualized care. Clinical trial information: NCT04854369 .