Prostate-specific Membrane Antigen Research Articles

Intrahepatic Cholangiocarcinoma Presenting as an Incidentaloma on F-18 PYL PSMA PET/CT

AbstractCholangiocarcinoma is an aggressive malignancy arising from the biliary tract epithelium with rising incidence and mortality. Imaging commonly used for diagnostic workup includes computed tomography (CT) scan and magnetic resonance imaging (MRI). Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) scans can be used for investigating equivocal findings on radiographic imaging. Prostate-specific membrane antigen (PSMA) is known to be highly expressed in prostate adenocarcinoma, allowing it to be leveraged as a target for both imaging and radioligand therapy in prostate cancer. However, PSMA is also commonly expressed in other malignancies such as breast cancer, thyroid carcinomas, and head and neck malignancies, which increase the chances of their incidental diagnosis on PSMA PET scans. Biliary tract cancers, including cholangiocarcinoma, are not commonly expected to be incidentally diagnosed on PSMA PET imaging. Here, we describe the case of a patient with known prostate adenocarcinoma who was later incidentally diagnosed with advanced intrahepatic cholangiocarcinoma on PSMA PET/computed tomography (CT). This case highlights the unexpected finding of cholangiocarcinoma on PSMA PET/CT and suggests further investigation into the role of PSMA PET in diagnosing ambiguous cases of cholangiocarcinoma and its potential theranostic applications.

NIMG-14. HEAD-TO-HEAD COMPARISON OF18F-FET PET AND68GA-PSMA-11 PET IN DISTINGUISHING SMALL VOLUME TUMOR PROGRESSION VS TREATMENT-RELATED CHANGE IN POST-STANDARD OF CARE TREATMENT OF HIGH-GRADE GLIOMA USING DYNAMIC ACQUISITION AND KINETIC MODELING

Abstract BACKGROUND The inability to accurately distinguish between tumor progression and treatment-related changes in patients with high-grade glioma on routine imaging can negatively impact patient management and in some cases, outcome. Various imaging methods have been used to address this issue, including 18F-fluoro-ethyl-tyrosine (FET) PET and MR perfusion. However, these methods may not provide reliable results in cases of small lesion size or hemorrhage within the treatment site. The prostate-specific membrane antigen (PSMA) has been observed to be expressed by neovasculature in brain tumors. Since PSMA cannot cross the blood brain barrier, uptake of PSMA in the brain carries high-level of suspicion for residual tumor. Still, further work is needed to better understand PSMA uptake in the tumor bed following standard of care (SOC) treatment and to compare to currently available neuro-oncologic radiotracers, such as FET. We hypothesize that PSMA imaging of glioma neovasculature will provide unique diagnostic information that will aid in the differentiation of small volume tumor progression from treatment-related changes in the post-SOC treatment setting. METHODS Patients who underwent clinical Expanded Access PET/MR imaging with 18F-FET were re-imaged in a research protocol that collected a brain 68Ga-PSMA-11 PET/CT scan, as well as a repeat 18F-FET PET/CT. Kinetic modeling of dynamic radiotracer uptake was performed. Scans were assessed for correlation with subsequent imaging and changes in clinical management. RESULTS All PSMA scans that were performed were concordant with the initial clinical FET scan, subsequent imaging follow up and appropriate changes in clinical management. The PSMA-detected site was confirmed to be tumor in a single case with subsequent tissue sampling. One patient who was started on bevacizumab after their clinical FET demonstrated a significant decrease in uptake on the research FET scan, but persistent uptake on PSMA. CONCLUSION PSMA may effectively show tumor recurrence in post-SOC treatment high-grade glioma patients.

BIOM-20. EVALUATING THE POTENTIAL OF PSMA TARGETING IN CNS TUMORS: INSIGHTS FROM LARGE-SCALE TRANSCRIPTOME PROFILING

Abstract PURPOSE Prostate-specific membrane antigen (PSMA) is a well-established target in prostate cancer therapy that has shown potential as a theranostic target across non-central nervous system (CNS) and CNS tumor types. We aimed to investigate the pan-tissue expression pattern of the PSMA-encoding gene FOLH1 to assess whether transcriptome profiling can inform tumor theranostics. EXPERIMENTAL DESIGN We assessed FOLH1 expression from the Open Pediatric Cancer Project (OpenPedCan, n = 2132 specimens), The Cancer Genome Atlas (TCGA, n = 10411 specimens), and the Genotype Tissue Expression Project (GTEx, n = 17382 specimens) in relation to published reports of PSMA radionuclide uptake. RESULTS When comparing FOLH1 expression across tumor versus normal tissues, we found that non-CNS tumors exhibiting elevated expression of at least two-fold (FDR < 0.05) were reported to have successful PSMA radionuclide uptake in contrast to tumors with less than a two-fold elevation or with lower expression of FOLH1 relative to normal. Notably, CNS tumors universally exhibited lower expression of FOLH1 relative to normal brain tissue, but we observed considerable variation in the expression of blood-tumor barrier (BTB) components associated with reports of BTB integrity and uptake of PSMA radiotracers. CONCLUSIONS Large-scale transcriptomics data may help guide the application of PSMA-based radionuclide therapies in non-CNS tumors, but care should be taken to account for BTB effects in CNS tumors when assessing the potential for radionuclide success. Our analysis demonstrated that FOLH1 showed a lack of tumor-specific expression for both adult and pediatric CNS tumors when compared to normal brain tissue, suggesting that PSMA is not a desirable target in this disease type. This study highlights the utility of utilizing large-scale molecular data to guide the selection of theranostic targets.

The Quantitative Impact of Prostate Specific Membrane Antigen Positron Emission Tomography/Computed Tomography (PSMA PET/CT) staging in Newly Diagnosed Metastatic Prostate Cancer and Treatment-Decision Implications

Abstract Objectives To quantify the stage-shift with PSMA PET/CT imaging in metastatic prostate cancer and explore treatment implications. Methods Single-centre, retrospective analysis of patients with newly diagnosed [18F]PSMA-1007 or [68Ga]Ga-PSMA-11 PET/CT-detected metastatic prostate cancer who had baseline bone scintigraphy between January 2015 and May 2021. Patients were subclassified into oligometastatic and polymetastatic disease utilising the STAMPEDE2 trial (ISRCTN66357938/NCT06320067) definition. Patient, tumour, and treatment characteristics were collected. PSMA PET/CT concordance with conventional imaging (bone scintigraphy and low-dose CT of PET) was identified by number and site of metastases, and subgroup assigned. Spearman’s rank correlation and linear regression modelling determined the association between the imaging modalities. Results We analysed 62 patients with a median age was 72 years (range 48-86). On PSMA PET/CT, 31/62 (50%) patients had oligometastatic disease, and 31/62 (50%) had polymetastatic disease. Prostate radiotherapy was delivered in 20/31 (65%) patients with oligometastatic disease and 17/31 (55%) with polymetastatic disease. 23/62 (37%) patients were reclassified as M0 on conventional imaging. PSMA PET/CT had a 2.9-fold increase in detecting bone metastases. Bone metastases concordance was found in 10/50 (20%) by number and 30/33 (91%) by site. PSMA PET/CT had a 2.2-fold increase in detecting nodal metastases. Nodal metastases concordance was found in 5/46 (11%) by number and 25/26 (96%) by site. There was significant positive correlation between PSMA PET/CT and conventional imaging for detecting bone (R2= 0.25 [p < 0.001]) and nodal metastases (R2= 0.19 [p < 0.001]). 16/31 (52%) had oligometastatic disease concordance. Conclusion The magnitude of PSMA PET/CT-driven stage-shift is highly variable and unpredictable with implications on treatment decisions, future trial design and potentially clinical outcomes.

Iodinated PSMA Ligands as XFI Tracers for Targeted Cell Imaging and Characterization of Nanoparticles

Prostate cancer is the second most commonly diagnosed cancer in men worldwide. Despite this, current diagnostic tools are still not satisfactory, lacking sensitivity for early-stage or single-cell diagnosis. This study describes the development of small-molecule tracers for the well-known tumor marker prostate-specific membrane antigen (PSMA). These tracers contain a urea motif for PSMA-targeting and iodinated aromatic moieties to allow detection via X-ray fluorescence imaging (XFI). Tracers with a triiodobenzoyl moiety allowed the specific targeting and successful imaging of PSMA+ cell lines with XFI. The XFI-measured uptake of 7.88 × 10−18 mol iodine (I) per cell is consistent with the uptake of known PSMA tracers measured by other techniques such as inductively coupled plasma mass spectrometry (ICP-MS). This is the first successful application of XFI to tumor cell targeting with a small-molecule tracer. In addition, iodinated tracers were used for the characterization of quantum dots (QDs) conjugated to PSMA-targeting urea motifs. The resulting targeted QD conjugates were shown to selectively bind PSMA+ cell lines via confocal microscopy. The immobilized iodinated targeting vectors allowed the determination of the tracer/QD ratio via XFI and ICP-MS. This ratio is a key property of targeted particles and difficult to measure by other techniques.

Experience of rescue therapy with [177Lu]Lu-rhPSMA-10.1 in patients with primary or acquired resistance to [177Lu]Lu-PSMA-I&T.

Radioligand therapy is an increasingly important option for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Radiohybrid ligands targeting prostate-specific membrane antigen (PSMA) are a novel group of theranostic radioligand therapy agents for which higher tumour absorbed radiation doses have been demonstrated compared to established PSMA ligands. Here, we report data from ten patients who were treated within a compassionate use program with the radiohybrid PSMA-ligand [177Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [177Lu]Lu-PSMA-I&T. Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [177Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [177Lu]Lu-rhPSMA-10.1 (7.4-8.1 GBq per cycle). Efficacy (PSA response according to PCWG3 and RECIP) and overall survival were evaluated. Adverse events were recorded from first application. Despite progression with [177Lu]Lu-PSMA-I&T, after the first cycle of [177Lu]Lu-rhPSMA-10.1 rescue therapy, five patients (50%) showed a decrease in serum PSA level. In imaging, three of the ten patients (30%) showed a partial radiologic response. Four of the five patients with a decrease of serum PSA under [177Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [177Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [177Lu]Lu-PSMA-I&T therapy but showed an immediate response to [177Lu]Lu-rhPSMA-10.1. The additional treatment with [177Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients. Patients showing tumour progression while receiving [177Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [177Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [177Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance.

Tubarial salivary glands show a low relative contribution to functional salivary gland tissue mass.

In 2021, the tubarial salivary glands (TSGs) were newly identified on prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) as macroscopic glands in the nasopharyngeal wall. However, the relative contribution of the TSGs to the total salivary gland function, and consequently on the development of xerostomia after external beam radiotherapy (EBRT) or PSMA-targeted radionuclide therapy (RNT) is not known. Therefore, we aimed to determine the presence of the TSGs and to quantify uptake in the TSGs on PSMA PET. Qualitative and quantitative analyses were performed on 68Ga-PSMA-11 PET/CT scans of 100 patients with prostate cancer. The mean and maximum standardized uptake value (SUVmean and SUVmax) in the TSGs were measured and compared to the parotid, submandibular and sublingual salivary glands (PSGs, SMSGs and SLSGs, respectively). Furthermore, proportional function of the TSGs was compared to the PSGs, SMSGs and SLSGs based on the total organ PSMA (TO-PSMA). The TSGs were visible on 95% of the 68Ga-PSMA-11 PET/CT scans. The normalized median SUVmean and SUVmax was significantly higher for the PSGs (p < 0.001) and SMSGs (p < 0.001) compared to the TSGs, but not for the SLSGs (p = 0.242 and p = 0.300, respectively). The normalized median TO-PSMA was significantly higher for the PSGs (p < 0.001) and SMSGs (p < 0.001), and significant lower for the SLSGs (p < 0.001) compared the TSGs. The SUVmean, SUVmax and TO-PSMA of the TSGs were most comparable to the SLSGs. However, the measured PSMA uptake may be disproportional towards the saliva production. Therefore, future studies should focus on the relation between PSMA uptake and salivary function before and after PSMA therapy.

Gene expression of prostate-specific membrane antigen (FOLH1) in clear cell renal cell carcinoma predicts angiogenesis and response to tyrosine kinase inhibitors

PurposeCombination systemic therapies (CSTs) of immuno-oncologic (IO) and VEGF-inhibiting agents (VEGFi) have become the standard of care for management of metastatic clear cell renal cell carcinoma (m-ccRCC). However, treatment outcomes vary between patients, with no established biomarkers to determine optimal CST regimens (IO/IO or IO/VEGFi). Prostate Specific Membrane Antigen (PSMA), encoded by the FOLH1 gene, is a marker of tumor neovasculature in ccRCC, the downstream target of VEGFi. We evaluated the relation between FOLH1 expression and angiogenesis, as well as clinical outcomes, in 5 m-ccRCC ST trials. Materials and Methodsusing Spearman's rank correlation (SPRC) test, we assessed the correlation between FOLH1 expression and gene expression signature (GES) scores corresponding to angiogenic and immunologic features of the tumor microenvironment (TME) of m-ccRCC in our trial cohorts. Using Cox proportional hazard regression (Cox-PHR), we assessed the association between FOLH1 expression level, summarized by within-study quantiles (qFOLH1), and progression-free and overall survival (PFS, OS). ResultsIncreased FOLH1 expression was significantly associated with higher TME angiogenesis GES scores (SPRC +0.5, P < 0.001), but did not consistently correlate with immune feature GES scores. Meta-analysis of PFS in the sunitinib TKI arm of trial cohorts showed an overall positive association with qFOLH1 (HR = 0.89; 95% CI = 0.85-0.94, P < 0.0001). qFOLH1 was not significantly associated with OS in the sunitinib arms of the two trials with OS data (COMPARZ, HR 0.87, 95% CI 0.71–1.07, P = 0.17; and Checkmate-214, HR 0.89, 95% CI 0.67–1.17, P = 0.70). ConclusionsPSMA-encoding FOLH1 gene expression correlates with neoangiogenesis and predicts PFS in m-ccRCC patients treated with sunitinib TKI, suggesting that PSMA PET could be explored as a noninvasive biomarker for guiding CST choice (IO/IO or IO/VEGFi) as well as prediction of treatment response to VEGFi in m-ccRCC patients.

Engineering PSMA-targeted nanoparticles co-encapsulating mitoxantrone and indocyanine green for precise combinatory therapy in prostate cancer

Prostate cancer is the 2nd most common cancer in men worldwide. Chemotherapeutic treatment of prostate cancer with mitoxantrone (MTX) has limited efficacy due to severe side effects in which cardiotoxicity and myelosuppression are the two major causes of its dose-limiting toxicity. This study aimed to obtain a poly (lactic-co-glycolic acid) (PLGA) nanoparticle that can precisely deliver MTX to the prostate cancer cells overexpressing the Prostate-specific membrane antigen (PSMA) receptor-sparing healthy tissues and co-loading Indocyanine green (ICG) as a fluorescent photothermal/photodynamic agent for precise combinatory therapy in prostate cancer. The biocompatible polymer PLGA was covalently modified with the peptide of sequence (WQPDTAHHWATL) to actively target the PSMA receptor. Factors like the peptide-to-polymer ratio or the peptide's orientation during the polymer's chemical modification were investigated to enhance the active targeting of the nanoparticles (NPs). NPs were characterised using dynamic light scattering, scanning electron microscopy, and UV–vis spectroscopy to determine their morphological and colloidal properties and optimal MTX and ICG encapsulation efficiency. Quantitative FACS analysis of LNCaP and PC-3 cells incubated with Nile Red-labelled non-targeted PLGA or PLGA-PSMA targeted NPs was assessed to identify the best formulation that bound selectively to PSMA. The orientation of the peptide conjugated to the polymer, which has the C-terminal end of the peptide sequence accessible for interaction with the cell receptor, maximises the targeting capacity of the system. Photothermal experiments using 808 nm near-infrared laser irradiation were conducted, and cytotoxicity was assessed using the resazurin viability assay. Remarkably, our results confirmed the safety and efficacy of a targeted and activatable therapy using polymeric NPs functionalised with the peptide and co-loaded with MTX and ICG. This pioneer nanosystem opens new perspectives for exploring advanced targeted delivery in prostate cancer. It offers a straightforward methodology for functionalising drug delivery systems with bioactive peptides that can be applied to different types of cancer.

P102 First-in-human study of AB001, a prostate-specific membrane antigen (PSMA) targeted 212Pb alpha radioligand, in patients with metastatic castration resistant prostate cancer (mCRPC): Phase 0 experience

P102 First-in-human study of AB001, a prostate-specific membrane antigen (PSMA) targeted 212Pb alpha radioligand, in patients with metastatic castration resistant prostate cancer (mCRPC): Phase 0 experience

Multivariable models of outcomes with [177Lu]Lu-PSMA-617: analysis of the phase 3 VISION trial

[177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged life in patients with metastatic castration-resistant prostate cancer (mCRPC) in VISION (NCT03511664). However, distinguishing between patients likely and unlikely to respond remains a clinical challenge. We present the first multivariable models of outcomes with 177Lu-PSMA-617 built using data from VISION, a large prospective phase 3 clinical trial powered for overall survival. Adults with progressive post androgen receptor pathway inhibitor and taxane prostate-specific membrane antigen (PSMA)-positive mCRPC received 177Lu-PSMA-617 plus protocol-permitted standard of care (SoC) or SoC alone. In this post hoc analysis, multivariable Cox proportional hazards models of overall survival (OS) and radiographic progression-free survival (rPFS), and a logistic regression model of prostate-specific antigen response (≥50% decline; PSA50) were constructed and evaluated using C-index or receiver operating characteristic (ROC) analyses with bootstrapping validation. Nomograms were constructed for visualisation. Patients were randomised between June 2018 and October 2019. Data from all 551 patients in the 177Lu-PSMA-617 arm were analysed in multivariable modelling. The OS nomogram (C-index, 0.73; 95% confidence interval [CI], 0.70-0.76) included whole-body maximum standardised uptake value (SUVmax), time since diagnosis, opioid analgesic use, aspartate aminotransferase, haemoglobin, lymphocyte count, presence of PSMA-positive lesions in lymph nodes, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and neutrophil count. The rPFS nomogram (C-index, 0.68; 0.65-0.72) included SUVmax, time since diagnosis, opioid analgesic use, lymphocyte count, presence of liver metastases by computed tomography, LDH, and ALP. The PSA50 nomogram (area under ROC curve, 0.72; 95% CI, 0.68-0.77) included SUVmax, lymphocyte count and ALP. Performances of the OS and rPFS models were maintained when they were reconstructed excluding SUVmax. These models of outcomes with 177Lu-PSMA-617 are the first built using prospective phase 3 data. They show that a combination of pretreatment laboratory, clinical, and imaging parameters, reflecting both patient and tumour status, influences outcomes. These models are important for aiding treatment selection, patient management, and clinical trial design. Novartis.

Pentamethine cyanine dyes with alkynyl group as perspective structure for conjugation with targeting moiety

We report a modified carbocyanine-based asymmetric fluorescent dye, suitable for the azide-alkyne cycloaddition reaction, that possesses promising photochemical properties (Φfl = 0,49). As an example of usage of the new fluorophore, it was conjugated to a ligand targeting prostate-specific membrane antigen (PSMA), one of the widely utilized prostate cancer markers.

The Application of Prostate Specific Membrane Antigen in the Diagnosis and Treatment of Prostate Cancer: Status and Challenge

The Application of Prostate Specific Membrane Antigen in the Diagnosis and Treatment of Prostate Cancer: Status and Challenge

P058 Treatment of prostate cancer with photoimmunotherapy targeting the prostate specific membrane antigen

P058 Treatment of prostate cancer with photoimmunotherapy targeting the prostate specific membrane antigen

P104 Concordance between response on prostate-specific membrane antigen positron emission tomography/computed tomography and biochemical response in patients with metastatic hormone-sensitive prostate cancer starting on androgen deprivation therapy plus apalutamide or abiraterone acetate

P104 Concordance between response on prostate-specific membrane antigen positron emission tomography/computed tomography and biochemical response in patients with metastatic hormone-sensitive prostate cancer starting on androgen deprivation therapy plus apalutamide or abiraterone acetate

P105 Prostate-specific membrane antigen positron emission tomography/computed tomography maximum standardized uptake values as a predictor for development of castration resistant prostate cancer in patients with biochemical recurrence after radical prostatectomy

P105 Prostate-specific membrane antigen positron emission tomography/computed tomography maximum standardized uptake values as a predictor for development of castration resistant prostate cancer in patients with biochemical recurrence after radical prostatectomy

O06 Prostate-specific membrane antigen positron emission tomography before meeting the Phoenix criteria for biochemical recurrent prostate cancer after radiotherapy: Earlier detection of recurrences

O06 Prostate-specific membrane antigen positron emission tomography before meeting the Phoenix criteria for biochemical recurrent prostate cancer after radiotherapy: Earlier detection of recurrences

Clinical, Pathologic, and Imaging Variables Associated with Prostate Cancer Detection by PSMA PET/CT and Multiparametric MRI.

Multiparametric MRI (mpMRI) and prostate-specific membrane antigen (PSMA) PET/CT are complementary imaging modalities used in the presurgical evaluation of patients with prostate cancer (PCa). The purpose of this study was to characterize clinically significant PCa (csPCa) detected and not detected by PSMA PET/CT and mpMRI, focusing on tumors detected solely by PSMA PET/CT and overlooked by mpMRI. Methods: We conducted a single-center, retrospective analysis of patients who underwent both PSMA PET/CT and mpMRI within 3 mo of each other and before radical prostatectomy. Two nuclear medicine physicians and 2 radiologists, in a masked manner, independently contoured PCa lesions on PSMA PET/CT and mpMRI, respectively. A consensus read was done with a third reader for each modality, and a majority rule was applied (2:1). After centralized imaging, a pathologic review was done by a genitourinary pathologist. We assessed agreement between imaging modalities and correlation with pathology. Logistic regression models explored associations between clinicopathologic variables and tumor detection on imaging. Results: In total, 132 csPCa tumors from 100 patients were identified on surgical pathology. PSMA PET/CT showed higher lesion-level (87% vs. 80%) and patient-level (98% vs. 94%) sensitivity than mpMRI. Tumors detected on both imaging modalities were larger and had higher grade groups than those not detected by one or both imaging modalities. On multivariable analysis, csPCa tumors undetected by mpMRI but detected by PSMA PET/CT were smaller than those detected by both modalities. Most tumors showing aggressive pathologic features, such as the large cribriform pattern (94.7%) and the intraductal carcinoma (96%), were correctly detected by both imaging modalities. Limitations included selection bias in a surgical cohort. Conclusion: PSMA PET/CT tends to detect smaller csPCa not detected by mpMRI. Larger tumors on pathology with higher grade groups are more likely to be correctly detected by both imaging modalities. These findings provide insights for refining presurgical evaluation strategies in PCa.

FAP and PSMA Expression by Immunohistochemistry and PET Imaging in Castration-Resistant Prostate Cancer: A Translational Pilot Study.

Prostate-specific membrane antigen (PSMA) is a theranostic target for metastatic prostate cancer (PCa). However, castration-resistant PCa (CRPC) may lose PSMA expression after systemic therapy. Fibroblast activation protein (FAP), expressed by carcinoma-associated fibroblasts in various cancer types, including PCa, has the potential to be an alternative target. In this study, we evaluated FAP expression in CRPC to assess its potential, using PSMA as a comparison. Methods: FAP expression was assessed using immunohistochemistry in 116 CRPC tumors: 78 adenocarcinomas, 11 small cell carcinomas, and 27 anaplastic carcinomas. Correlation analysis between manual scoring and automated scoring was performed on 54 whole-slide sections of metastatic CRPC. Paired FAP and PSMA stains were assessed in tissue microarray cores of CRPC (n = 62), consisting of locally advanced CRPC (n = 9) and metastatic CRPC (n = 53). FAP and PSMA positivity was defined by an immunohistochemistry score of at least 10. To explore the correlation of PSMA and FAP inhibitor (FAPi) PET imaging and immunohistochemistry, a preliminary analysis of 4 patients included in a [68Ga]-FAPi-46 imaging trial (NCT04457232) was conducted. Results: Manual and automated scoring of FAP yielded results with strong correlations. Overall, FAP expression in CRPC was notably lower than PSMA expression (median immunoscores, 14 vs. 72; P < 0.001). Different histologic subtypes of CRPC demonstrated distinct levels of PSMA expression, whereas their FAP expression levels were comparable. Among the 19 PSMA-negative tumors, 11 (58%) exhibited FAP positivity. FAP expression levels in lymph node metastases were significantly lower than those in nonnodal metastases (P = 0.021). Liver metastases showed significant enrichment of tumors with strong FAP expression compared with nonliver lesions (P = 0.016). In the 4 clinical trial patients, the biopsied metastatic lesions showed lower uptake on FAPi PET than on PSMA PET (median SUVmax, 9.6 vs. 14.5), consistent with FAP expression that was lower than PSMA expression in the corresponding tumor biopsy samples (median immunoscores, 30 vs. 160). Conclusion: Because of the low FAP expression levels in CRPC, the utility of FAPi PET imaging may be limited. Although FAPi PET imaging may be further tested in PSMA-negative CRPC, such as small cell carcinoma, other molecular imaging modalities should be evaluated as alternative choices.

Outcomes for Patients with Metastatic Castration-Resistant Prostate Cancer and Liver Metastasis Receiving [177Lu]Lu-PSMA-617.

It is well known that patients with liver metastasis from metastatic castration-resistant prostate cancer have poor or only transient responses to many forms of systemic therapy. Data on outcomes after treatment with [177Lu]Lu-PSMA-617 (LuPSMA) are scarce. The VISION trial reports a hazard ratio for overall survival (OS) in the subgroup of patients with liver metastasis without disclosing the absolute duration of survival. Using real-world clinical data, we examined this important subgroup of patients, describing prostate-specific antigen (PSA) response and OS. Methods: A single-institution database was assembled to include all patients receiving LuPSMA at Mayo Clinic in Rochester, Minnesota, for whom treatment was initiated between March 2022 and March 2023. Baseline clinicopathologic and imaging characteristics were abstracted. Patients were then categorized by presence or absence of liver metastasis on pretreatment prostate-specific membrane antigen (PSMA) PET. PSA response and OS for the 2 groups (liver metastasis vs. no liver metastasis) were compared using χ2 testing and the Kaplan-Meier method, respectively. A multivariate Cox regression analysis was performed, including established prognostic factors. Finally, those with pretreatment circulating tumor DNA as determined in an 83-gene panel were assessed for the presence of pathogenic and likely pathogenic alterations. These findings were summarized using descriptive statistics and compared between the 2 cohorts using the Fisher exact test. Results: The overall cohort consisted of 273 patients, including 43 (15.75%) with liver metastasis on pretreatment PSMA PET/CT. The median number of cycles received was 3 (range, 1-6) for patients with liver metastasis and 5 (range, 1-6) for those without hepatic involvement. The 50% or greater reduction in PSA from baseline response rate was lower for those with liver metastasis than for those without (30.23% [13/43] vs 49.77% [106/213], P = 0.019). At a median follow-up of 10 mo (interquartile range, 9-13 mo), there was a significant difference in median OS (8.35 mo vs. not reached, P < 0.001). On multivariate analysis, the presence of liver metastasis was independently associated with shorter survival (hazard ratio, 4.06; P < 0.001). Conclusion: Our data suggest that the presence of liver metastasis predicts poorer outcomes in patients receiving LuPSMA treatment. Alternative and combination approaches should be explored to maximize the antitumor activity of radiopharmaceutical therapy in the liver.