The Prognostic Value of Posttreatment68Ga-PSMA-11 PET/CT and18F-FDG PET/CT in Metastatic Castration-Resistant Prostate Cancer Treated with177Lu-PSMA-617 and NOX66 in a Phase I/II Trial (LuPIN)

Pathmanandavel, Sarennya; Crumbaker, Megan; Nguyen, Andrew; Yam, Andrew O.; Wilson, Peter; Niman, Remy; Ayers, Maria; Sharma, Shikha; Eu, Peter; Martin, Andrew; Stockler, Martin R.; Joshua, Anthony M.; Emmett, Louise

doi:10.2967/jnumed.122.264104

Cited by 16 publications

(11 citation statements)

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“…The majority of patients receiving PSMA-targeted peptide receptor radionuclide therapy will get a drop in PSMA intensity, which is not predictive of OS. 12,17 However, these results suggest the depth of the reduction in SUVmax and SUVmean may be a proxy marker of radiation sensitivity and depth of cell death achieved. Currently, while we can measure PSMA characteristics at baseline to predict treatment response, we do not have an easy measure of radiation sensitivity, which is a significant factor in treatment resistance with 177 LuPSMA.…”

Section: Discussionmentioning

confidence: 94%

“…Currently, while we can measure PSMA characteristics at baseline to predict treatment response, we do not have an easy measure of radiation sensitivity, which is a significant factor in treatment resistance with 177 LuPSMA. 17,18 Treatment failure in RG 3 is likely due at least in part to a combination of both baseline PSMA heterogeneity/intensity and low radiation sensitivity. We can measure PSMA heterogeneity and expression at baseline (SUVmean), but the Δ Lu-SPECT parameters at 6 weeks may give some additional indication of radiation sensitivity, and this warrants further evaluation.…”

Section: Discussionmentioning

confidence: 99%

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Patient outcomes following a response biomarker-guided approach to treatment using 177Lu-PSMA-I&T in men with metastatic castrate-resistant prostate cancer (Re-SPECT)

et al. 2023

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Background: 177LuPSMA is an effective treatment in metastatic castrate-resistant prostate cancer with trials adopting a standardised dose interval. Adjusting treatment intervals utilising early response biomarkers may improve patient outcomes. Objective: This study evaluated progression-free survival (PFS) and overall survival (OS) based on treatment interval adjustment utilising 177LuPSMA 24-h SPECT/CT (177Lu-SPECT) and early prostate-specific antigen (PSA) response. Design: Retrospective analysis of a clinical 177Lu-PSMA-I&T treatment programme. Methods: In all, 125 men were treated with 6-weekly 177LuPSMA-I&T [median 3 cycles, interquartile range (IQR): 2–4], median dose 8.0 GBq [95% confidence interval (CI): 7.5–8.0]. Imaging screening involved 68GaPSMA-11 PET/diagnostic CT. 177Lu-SPECT/diagnostic CT was acquired following each therapy, and clinical assessments 3-weekly. Following dose 2 (week 6), a composite PSA and 177Lu-SPECT/CT imaging response [partial response (PR), stable disease (SD), and progressive disease (PD)] determined ongoing management. Response group (RG) 1 (marked reduction in PSA/imaging PR) break in treatment until subsequent PSA rise, then re-treatment. RG 2 (stable or reduced PSA and/or imaging SD) 6-weekly treatments until six doses, or no longer clinically benefitting. RG 3 (rise in PSA and/or imaging PD) recommended for an alternative treatment. Results: Overall PSA50% response rate (PSARR) was 60% (75/125), median PSA-PFS 6.1 months (95%CI: 5.5–6.7), and median OS 16.8 months (95%CI: 13.5–20.1). 35% (41/116) were classified as RG 1, 34% (39/116) RG 2, and 31% (36/116) RG 3. PSARRs by RG were 95% (38/41), 74% (29/39), and 8% (3/36); median PSA-PFS rates were 12.1 months (95%CI: 9.3–17.4), 6.1 months (95%CI: 5.8–9.0), and 2.6 months (95%CI: 1.6–3.1); and OS rates were 19.2 months (95%CI: 16.8–20.7), 13.2 months (95%CI: 12.0–18.8), and 11.2 months (95%CI: 8.7–15.6) for RG 1, 2, and 3, respectively. The median months of ‘treatment holiday’ for RG 1 was 6.1 months (IQR: 3.4–8.7). Nine men had received prior 177LuPSMA-617 and were retreated with 177LuPSMA-I&T, with a PSARR of 56% on re-treatment. Conclusion: Personalising dosing regimens using early response biomarkers with 177LuPSMA has the potential to achieve similar treatment responses to continuous dosing while allowing treatment breaks or intensification. Further evaluation of early response biomarker-guided treatment regimens in prospective trials is warranted. Plain Language Summary Lutetium-PSMA therapy is a new therapy for metastatic prostate cancer that is well tolerated and effective. However, not all men respond equally, with some responding very well and others progressing early. Personalising treatments require tools that can accurately measure treatment responses, preferably early in the treatment course, so adjustments to treatment can be made. Lutetium-PSMA can measure tumour sites after each therapy by taking whole body 3D images at 24 h using a small radiation wave from the treatment itself. This is called a SPECT scan. Previous work has shown that both prostate-specific antigen (PSA) response and changes in tumour volume on a SPECT scan can predict how patients will respond to treatment as early as dose 2. This study demonstrates that stratifying how men are treated based on the results of the 6-week SPECT scan and PSA response potentially allows a third of men to have break in treatment and that these men have both longer time to disease progression and OS. Men with an increase in tumour volume and increase in PSA early in treatment (6 weeks) had shorter time to disease progression and OS. Men with early biomarker disease progression were offered alternative treatments early in an attempt to allow the opportunity to allow a more effective potential therapy, if one was available. The study is an analysis of a clinical programme, and was not a prospective trial. As such, there are potential biases that could influence results. Hence, while the study is encouraging for the use of early response biomarkers to guide better treatment decisions, this must be validated in a well-designed clinical trial.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Patient outcomes following a response biomarker-guided approach to treatment using 177Lu-PSMA-I&T in men with metastatic castrate-resistant prostate cancer (Re-SPECT)

et al. 2023

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“…the FPQ, predicted lesional response to PSMA-targeted RLT, aligns with the findings of a number of studies suggesting predictive and prognostic power in prostate cancer of the [ 18 F]FDG SUV max of a lesion or of the total tumor burden. These studies showed these variables to be associated with negative disease characteristics and poor patient outcomes [19][20][21][38][39][40] , including in men with mCRPC 18,22,41,42 , and those undergoing PSMA-targeted RLT 25,29 . Table 2.…”

Section: Discussionmentioning

confidence: 99%

“…As on many other malignant cell types, GLUT1 overexpression on prostate cancer cells is reflected by uptake of the fluorine-18-conjugated glucose analogue fluorodeoxyglucose ([ 18 F]FDG), shown on PET 19 . Higher [ 18 F]FDG uptake now is well-recognized to correlate with prognosticallyunfavorable pathological factors in prostate cancer in general 20,21 , and with poor outcomes in men receiving systemic treatment of mCRPC, including PSMA-targeted RLT 18,[22][23][24][25] . As a result, [ 18 F]FDG PET/computed tomography (CT) increasingly is being applied in mCRPC, to provide prognostic and/or predictive data 3,16,[26][27][28][29] .…”

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confidence: 99%

Dual FDG/PSMA PET imaging to predict lesion-based progression of mCRPC during PSMA-RLT

Rosar,

Burgard,

David

et al. 2024

Sci Rep

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Candidates for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) frequently have “mismatch” lesions with pronounced 18-fluorodeoxyglucose ([18F]FDG) but attenuated PSMA ligand uptake on positron emission tomography (PET). However, no quantitative criteria yet exist to identify mismatch lesions and predict their response to RLT. To define such criteria, we retrospectively analyzed 267 randomly-selected glucometabolic mCRPC metastases from 22 patients. On baseline PET, we determined [18F]FDG and [68Ga]Ga-PSMA-11 maximum standardized uptake value (SUVmax), and calculated the [18F]FDG SUVmax/[68Ga]Ga-PSMA-11 SUVmax quotient (FPQ). From follow-up [18F]FDG PET after two lutetium-177-PSMA-617 RLT cycles, we evaluated the treatment response and categorized the lesions into three subgroups (partial remission, stable disease, progression) based on change in [18F]FDG SUVmax. Lastly, we compared the baseline PET variables in progressing versus non-progressing lesions. Variables differing significantly, and a score incorporating them, were assessed via receiver operator characteristic (ROC) curve analysis, regarding ability to predict lesional progression, with area under the curve (AUC) as metric. Cut-offs with optimal sensitivity and specificity were determined using the maximum value of Youden's index. Fifty-one of 267 lesions (19.1%) progressed, 102/267 (38.2%) manifested stable disease, and 114/267 (42.7%) partially responded after two RLT cycles. At baseline, median [68Ga]Ga-PSMA-11 SUVmax was significantly lower (p < 0.001), median FPQ significantly higher (p < 0.001), and median [18F]FDG SUVmax similar in progressing versus non-progressing lesions. [68Ga]Ga-PSMA-11 SUVmax and FPQ showed predictive power regarding progression (AUCs: 0.89, 0.90). An introduced clinical score combining both further improved predictive performance (AUC: 0.94). Optimal cut-offs to foretell progression were: [68Ga]Ga-PSMA-11 SUVmax < 11.09 (88.2% sensitivity, 81.9% specificity), FPQ ≥ 0.92 (90.2% sensitivity, 78.7% specificity), clinical score ≥ 6/9 points (88.2% sensitivity, 87.5% specificity). At baseline, a low [68 Ga]Ga-PSMA-11 SUVmax and a high FPQ predict early lesional progression under RLT; [18F]FDG SUVmax does not. A score combining [68 Ga]Ga-PSMA-11 SUVmax and FPQ predicts early lesional progression even more effectively and might therefore be useful to quantitatively identify mismatch lesions.

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“…Ga-68-PSMA-11 (Ga 68 PSMA-11) was FDA-approved in 2020, followed by F-18-piflufolastat (Pylarify) in 2021. Subsequently, Lu-177-PSMA-617 (Pluvicto) was approved in March 2022 for therapeutic applications [18,19]. PSMA-617 targets PSMA and becomes internalized into cancer cells [20].…”

Section: Radiotheranosticsmentioning

confidence: 99%

Intra-Arterial Delivery of Radiopharmaceuticals in Oncology: Current Trends and the Future of Alpha-Particle Therapeutics

Kauffman

Morrison²,

O’Brien

et al. 2023

Pharmaceutics

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A paradigm shift is underway in cancer diagnosis and therapy using radioactivity-based agents called radiopharmaceuticals. In the new strategy, diagnostic imaging measures the tumor uptake of radioactive agent “X” in a patient’s specific cancer, and if uptake metrics are realized, the patient can be selected for therapy with radioactive agent “Y”. The X and Y represent different radioisotopes that are optimized for each application. X–Y pairs are known as radiotheranostics, with the currently approved route of therapy being intravenous administration. The field is now evaluating the potential of intra-arterial dosing of radiotheranostics. In this manner, a higher initial concentration can be achieved at the cancer site, which could potentially enhance tumor-to-background targeting and lead to improved imaging and therapy. Numerous clinical trials are underway to evaluate these new therapeutic approaches that can be performed via interventional radiology. Of further interest is changing the therapeutic radioisotope that provides radiation therapy by β- emission to radioisotopes that also decay by α-particle emissions. Alpha (α)-particle emissions provide high energy transfer to the tumors and have distinct advantages. This review discusses the current landscape of intra-arterially delivered radiopharmaceuticals and the future of α-particle therapy with short-lived radioisotopes.

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The Prognostic Value of Posttreatment⁶⁸Ga-PSMA-11 PET/CT and¹⁸F-FDG PET/CT in Metastatic Castration-Resistant Prostate Cancer Treated with¹⁷⁷Lu-PSMA-617 and NOX66 in a Phase I/II Trial (LuPIN)

Cited by 16 publications

References 20 publications

Patient outcomes following a response biomarker-guided approach to treatment using 177Lu-PSMA-I&T in men with metastatic castrate-resistant prostate cancer (Re-SPECT)

Patient outcomes following a response biomarker-guided approach to treatment using 177Lu-PSMA-I&T in men with metastatic castrate-resistant prostate cancer (Re-SPECT)

Dual FDG/PSMA PET imaging to predict lesion-based progression of mCRPC during PSMA-RLT

Intra-Arterial Delivery of Radiopharmaceuticals in Oncology: Current Trends and the Future of Alpha-Particle Therapeutics

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