Prostate-specific Membrane Antigen Radioligand Therapy Research Articles

Prognostic Value of Tumor Volume Assessment on PSMA PET After 177Lu-PSMA Radioligand Therapy Evaluated by PSMA PET/CT Consensus Statement and RECIP 1.0.

Quantitative evaluation of prostate-specific membrane antigen (PSMA)-targeting PET/CT remains challenging but is urgently needed for the use of standardized PET-based response criteria, such as the PSMA PET/CT consensus statement or Response Evaluation Criteria in PSMA PET/CT (RECIP 1.0). A recent study evaluated the prognostic value of whole-body tumor volume using a semiautomatic method relying on a 50% threshold of lesion SUVmax (PSMATV50). In the present study, we analyzed the suitability of this approach comparing 18F-PSMA-1007 with 68Ga-PSMA-11 PET/CT scans and the potential of PSMATV50 for the prediction of overall survival (OS) in patients before 177Lu-PSMA radioligand therapy (RLT). Moreover, PSMATV50 was integrated into the PSMA PET/CT consensus statement as well as RECIP 1.0, and the prognostic value of these response classification systems was compared. Methods: This retrospective study included 70 patients with metastatic castration-resistant prostate cancer undergoing PSMA RLT. Thirty-three patients were monitored by 68Ga-PSMA-11 PET/CT, and 37 patients by 18F-PSMA-1007 PET/CT. PET/CT scans before (baseline) and at the end of PSMA RLT after 2-4 cycles (follow-up) were separately analyzed by 2 readers. PSMATV50 at baseline and its change at the time of follow-up (ΔPSMATV50, expressed as a ratio) were correlated with OS using Cox proportional-hazards regression. The results of both subgroups were compared. The integration of ΔPSMATV50 in existing response classification systems was evaluated. To assess and compare the discriminatory strength of these classification systems, Gönen and Heller concordance probability estimates were calculated. Results: PSMATV50 determination was technically feasible in all examinations. A higher PSMATV50 at baseline and a higher ΔPSMATV50 were strongly associated with a shorter OS for both 68Ga-PSMA-11 (PSMATV50: hazard ratio [HR] of 1.29 [95% CI, 1.05-1.55], P = 0.009; ΔPSMATV50: HR of 1.83 [95% CI, 1.08-3.09], P = 0.024) and 18F-PSMA-1007 (PSMATV50: HR of 1.84 [95% CI, 1.13-2.99], P = 0.014; ΔPSMATV50: HR of 1.23 [95% CI, 1.04-1.51], P = 0.03). Response assessment provided high discriminatory power for OS for the PSMA PET/CT consensus statement (concordance probability estimate, 0.73) as well as RECIP 1.0 (concordance probability estimate, 0.74). Conclusion: PSMATV50 and ΔPSMATV50 proved to be predictive of OS not only for 68Ga-PSMA-11 but also for 18F-PSMA-1007 PET/CT scans. Subsequent integration of ΔPSMATV50 into the PSMA PET/CT consensus statement and RECIP 1.0 provided equally high prognostic value for both classification systems.

Genomic characterization of metastatic castration-resistant prostate cancer patients undergoing PSMA radioligand therapy: A single-center experience.

Genomic defects in DNA-damage repair (DDR) mechanisms have been proposed to affect the radiosensitivity of prostate cancers. In this study, we intended to evaluate the prevalence of genetic alterations in a cohort of metastatic castration-resistant prostate cancer (mCRPC) patients undergoing radioligand therapy (RLT) with prostate-specific membrane antigen (PSMA)-inhibitors as well as the impact of such mutations on treatment outcomes. Data of consecutive mCRPC patients from 2017 to 2021 who were treated with PSMA-RLT and underwent next-generation sequencing (NGS) were collected and analyzed for response and survival outcomes. In 95 patients of mCRPC treated with PSMA-RLT, 15 patients (median age: 66 years, range: 50-73 years; [177 Lu]Lu-PSMA-617, n = 12; [225 Ac]Ac-PSMA-617, n = 3) underwent NGS. The median progression-free survival (PFS) of this cohort was 3 months (95% confidence interval: 1.6-4.4 months). On NGS, 21 genetic alterations were reported in 10/15 (67%) patients, of which 13 were DDR-associated alterations involving the genes: ATM (n = 3), BRCA2 (n = 3), TP53 (n = 2), PTEN (n = 2), FANCD2 (n = 1), FANCM (n = 1), and NBN (n = 1). Overall, 5/15 (33%) patients harbored six pathogenic variants (BRCA2, n = 2; ATM, n = 1; TP53, n = 1; PTEN, n = 2). No significant difference was noted for the biochemical response, radiological response, PFS, and overall survival between the patients with and without genetic alterations. Patients of mCRPC undergoing PSMA-RLT were frequently seen to harbor DDR-associated aberrations, albeit with no significant impact on treatment outcomes. Large prospective trials comparing PSMA-RLT-related outcomes in DDR-deficient and -proficient patients are required to bring out the differences, if any, in a more observable manner.

The Role of PSMA PET Imaging in Prostate Cancer Theranostics: A Nationwide Survey

Introduction: Prostate-specific membrane antigen (PSMA)-based imaging and theranostics have played an important role in the diagnosis, staging, and treatment of prostate cancer (PCa). We aimed to evaluate the acceptance and use of PSMA theranostics among German urologists. Methods: An anonymous online questionnaire was sent via survio.com to the members of the German Society of Urology (DGU). Results: Seventy-two percent of participants performed PSMA positron emission tomography (PET) imaging regularly in biochemically recurrent PCa. Overall, 61% of participants considered PSMA-radioligand therapy to be very useful or extremely useful. PSMA PET imaging in high-risk PCa is more often considered by urologists working in a university setting than in nonuniversity settings or medical practices (51% vs. 25%, p < 0.001). Most perform PSMA-radioligand therapy as an option after all approved systemic treatments for metastatic castration-resistant PCa (56%) or after cabazitaxel (14%). A total of 93.9% and 70.3% of respondents consider the lack of reimbursement by health insurance to be the main obstacle to using PSMA PET imaging or radioligand therapy, respectively. Discussion/Conclusion: PSMA-based imaging/theranostics are already widely applied but would find even more widespread use if reimbursement is clearly regulated by health insurance in Germany.

PSMA-Directed Imaging and Therapy of Salivary Gland Tumors: A Single-Center Retrospective Study.

We analyzed the diagnostic performance of prostate-specific membrane antigen (PSMA) PET/CT and the dosimetry, efficacy, and safety of 177Lu-PSMA-617 radioligand therapy (RLT) in salivary gland malignancies (SGMs). Methods: We identified 28 SGM patients with PSMA PET/CT from our database. CT and PSMA PET/CT images were evaluated separately by 3 masked readers in joint reading sessions. Pathologic findings were grouped into 6 TNM regions, and lesion-based disease extent was classified as no disease (n = 1, 4%), unifocal (n = 2, 7%), oligometastatic (n = 9, 32%), multifocal (n = 3, 11%), or disseminated (n = 13, 47%). For each region, the SUVmax of the lesion with the highest uptake was measured and the visual PSMA expression score was evaluated on a per-patient basis using PROMISE criteria. The association between PSMA expression and clinical and histopathologic markers was tested using the Student t test. Five patients underwent PSMA RLT with intratherapeutic dosimetry. Response was assessed using RECIST 1.1, and adverse events were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events. Results: Compared with CT, PSMA PET/CT demonstrated additional metastatic lesions in 11 of 28 (39%) patients, leading to upstaging of TNM and lesion-based disease extent in 3 (11%) and 6 (21%) patients, respectively. PSMA PET/CT detected CT-occult local tumor, regional lymph nodes, nonregional lymph nodes, and bone metastases in 1 (4%), 4 (14%), 2 (7%), and 4 (14%) patients, respectively; no additional lesions were detected in the other predefined regions. PSMA expression level was higher than liver in 6 patients (25%). A significantly higher SUVmax was observed in male than female patients (15.8 vs. 8.5, P = 0.007) and in bone than lung lesions (14.2 vs. 6.4, P = 0.006). PSMA RLT was discontinued after 1 cycle in 3 of 5 patients because of insufficient tumor doses. No adverse events of grade 4 or higher occurred. Conclusion: In SGMs, PSMA PET/CT demonstrated a superior detection rate and led to upstaging in about one third of patients when compared with CT. The male sex and the presence of bone metastases were associated with significantly higher PSMA expression. PSMA RLT was well tolerated, but most patients did not have more than 1 cycle because of insufficient tumor doses.

1414P Treatment efficacy and safety of 177Lu-PSMA radioligand therapy in octogenarians with metastatic castration-resistant prostate cancer

Lutetium-177 prostate-specific membrane antigen radioligand therapy (177Lu-PSMA-RLT) is an option for treatment of metastatic castration-resistant prostate cancer (mCRPC). It is increasingly used in old or comorbid patients. Purpose was to evaluate the safety and efficacy in patients ≥80 years of age.

Current Status of PSMA-Targeted Radioligand Therapy in the Era of Radiopharmaceutical Therapy Acquiring Marketing Authorization.

Prostate-specific membrane antigen (PSMA) is highly expressed in PCa, which gradually increases in high-grade tumors, metastatic tumors, and tumors nonresponsive to androgen deprivation therapy. PSMA has been a topic of interest during the past decade for both diagnostic and therapeutic targets. Radioligand therapy (RLT) utilizes the delivery of radioactive nuclides to tumors and tumor-associated targets, and it has shown better efficacy with minimal toxicity compared to other systemic cancer therapies. Nuclear medicine has faced a new turning point claiming theranosis as the core of academic identity, since new RLTs have been introduced to clinics through the official new drug development processes for approval from the Food and Drug Administration (FDA) or European Medical Agency. Recently, PSMA targeting RLT was approved by the US FDA in March 2022. This review introduces PSMA RLT focusing on ongoing clinical trials to enhance our understanding of nuclear medicine theranosis and strive for the development of new radiopharmaceuticals.

A pilot study of 68 Ga-PSMA-617 PET/CT imaging and 177Lu-EB-PSMA-617 radioligand therapy in patients with adenoid cystic carcinoma

BackgroundThis pilot study was designed to evaluate the diagnostic value of 68 Ga-PSMA-617 and 18F-FDG PET/CT in adenoid cystic carcinoma (ACC) and to assess the safety and therapeutic response to PSMA radioligand therapy (RLT) in ACC patients.MethodsThirty patients pathologically diagnosed with ACC were recruited into the cohort. Each patient underwent 68 Ga-PSMA-617 and 18F-FDG PET/CT within 1 week. The number and SUVmax of PET-positive lesions were recorded and compared. Four patients accepted RLT using 177Lu-EB-PSMA-617, in a dosage of approximately 1.85 GBq (50 mCi) per cycle for up to 3 cycles.ResultsCompared with 18F-FDG, 68 Ga-PSMA-617 revealed more PET-positive extrapulmonary tumors (157 vs. 141, P = 0.016) and higher SUVmax (8.8 ± 3.6 vs. 6.4 ± 4.2, P = 0.027). However, 68 Ga-PSMA-617 revealed less PET-positive pulmonary lesions (202 vs. 301, P < 0.001) and lower SUVmax of tumors (3.1 ± 3.0 vs. 4.2 ± 3.9, P < 0.001) than 18F-FDG. The combination of 68 Ga-PSMA-617 and 18F-FDG can detect 469 PET-positive lesions, which was superior to each alone (469 vs. 359 vs. 442, P < 0.001). Two patients achieved remarkable response after PSMA RLT, while the other two patients showed reduced tumor uptake of recurrent foci, lung and liver metastases, whereas increased SUVmax of bone metastases.Conclusions68 Ga-PSMA-617 PET/CT is a valuable imaging modality for the detection of ACC and combining with 18F-FDG PET/CT will achieve a higher detection efficiency. PSMA RLT may be a promising treatment for ACC and is worth of further investigation.Trial registration: Diagnosis of Adenoid Cystic Carcinoma on 68 Ga-PSMA-617 PET-CT and Therapy With 177Lu-EB-PSMA-617 (NCT04801264, Registered 16 March 2021, retrospectively registered).URL of registry: https://clinicaltrials.gov/ct2/show/NCT04801264.

Current role of prostate-specific membrane antigen-based imaging and radioligand therapy in castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is a therapy-resistant and lethal form of prostate cancer as well as a therapeutic challenge. Prostate-specific membrane antigen (PSMA) has been proved as a promising molecular target for optimizing the theranostics for CRPC patients. When combined with PSMA radiotracers, novel molecular imaging techniques such as positron emission tomography (PET) can provide more accurate and expedient identification of metastases when compared with conventional imaging techniques. Based on the PSMA-based PET scans, the accurate visualization of local and disseminative lesions may help in metastasis-directed therapy. Moreover, the combination of 68Ga-labeled PSMA-based PET imaging and radiotherapy using PSMA radioligand therapy (RLT) becomes a novel treatment option for CRPC patients. The existing studies have demonstrated this therapeutic strategy as an effective and well-tolerated therapy among CRPC patients. PSMA-based PET imaging can accurately detect CRPC lesions and describe their molecular features with quantitative parameters, which can be used to select the best choice of treatments, monitor the response, and predict the outcome of RLT. This review discussed the current and potential role of PSMA‐based imaging and RLT in the diagnosis, treatment, and prediction of prognosis of CRPC.

A 2022 International Survey on the Status of Prostate Cancer Theranostics.

Growing interest in PSMA imaging using [68Ga]- or [18F]-labeled ligands and PSMA-based radioligand therapy (RLT) of prostate cancer (PCa) prompted us to survey the global community on their experiences and expectations. Methods: A web-based survey was composed to interrogate areas specific to PET imaging, the clinical value chain, and RLT applications. International responses were collected in early 2022. In total, over 300 valid responses were received and evaluated. Results: Most responses (83%) were given by nuclear medicine specialists with extensive experience in PET. At 22% of sites, PCa ranked "top" in cancer-type-specific PET indications, with an average and median of 15% and 10% of all cases, respectively. The most frequently used PSMA PET tracers were [68Ga]PSMA (32%) and [18F]PSMA-1007 (31%). Users reported a steady growth in PSMA PET and RLT over the past 5 y, averaging 50% and 82%, respectively, with a further 100% median growth projected over the next 5 y. Of note, more respondents indicated cognizance of personalized dosimetry than actually used it routinely. The most commonly identified barriers to future growth in PCa theranostics were radiopharmaceutical supply, reimbursement, staff availability, and buy-in of medical oncologists. Conclusion: Despite enthusiasm, this survey indicates variable adoption of PSMA imaging and RLT globally. Several challenges need to be addressed by the medical community, authorities, and patient advocacy groups in integrating PSMA-targeted theranostics into personalized medicine.

PSMA PET Imaging and Therapy in Adenoid Cystic Carcinoma and Other Salivary Gland Cancers: A Systematic Review.

Simple SummaryAdenoid cystic carcinoma (ACC) and other salivary gland cancers (SGC) are rare conditions with limited treatment options when they recur or spread to other parts of the body. There is increasing interest in the interaction of radioactive labeled proteins 68Gallium- Prostate Specific Membrane Antigen (68Ga-PSMA) with their corresponding receptors on tumor cells (PSMA receptor) which can be detected on scans. This innovation has created diagnostic and therapeutic progress in management of metastatic prostate cancer. These interactions are also found in SGCs though studies are currently limited. Our systematic review aims to collate available published scientific information on this technology to better inform its potential use, pitfalls and its future directions as a diagnostic and therapeutic option in SGCs. We concluded that the 68Ga-PSMA scans can be useful in detecting ACC and SGC not detected on standard radioimaging and that small studies have shown the therapeutic potential of this innovation in advanced or metastatic ACC and SGC.Adenoid cystic carcinoma (ACC) and other salivary gland cancers (SGCs) are rare tumors where application of prostate specific membrane antigen (PSMA) positron emission tomography (PET) and PSMA radioligand therapy have yet to be studied extensively. This review explores the role of PSMA PET imaging and therapy as a theranostic tool for ACC and other SGCs based on current literature. A comprehensive literature search on PubMed and Embase was performed. All relevant studies containing information on PSMA PET imaging in ACC and SGC were included. Ten studies (one prospective, three retrospective, five case reports and one review paper) were included. For ACC, the mean maximum standardized uptake value (SUVmax) for local recurrence and distant metastases ranged from 2.41 to 13.8 and 2.04 to 14.9, respectively. In SGC, the meanSUVmax ranged from 1.2–12.50. Most studies observed PSMA expression positivity on immunohistochemistry (IHC) when there was PSMA PET uptake. PSMA PET was able to detect lesions not detected on standard imaging. Despite the small number of studies and wide intra-patient and inter-tumor variation of PSMA uptake in ACC and SGC, 68Gallium (68Ga)-PSMA PET has promising prospects as a diagnostic and radioligand therapeutic option. Further studies to answer the various theranostics considerations are required to guide its use in the real-world setting.

Augmented alpha-beta PSMA radioligand therapy in metastatic prostate cancer: Analysis of prognostic factors for survival.

e17025 Background: PSMA-targeted radioligand therapy (PRLT) using the alpha-emitter Ac-225 PSMA-617 is effective in metastatic prostate cancer progressing after beta-emitter-based PRLT using Lu-177 PSMA-617, and in the presence of diffuse bone marrow metastases. Xerostomia is a dose-limiting factor in PRLT using Ac-225. Augmented Alpha-Beta PRLT is a concept of concomitantly administering Lu-177 and Ac-225 PSMA in lower activities, as a trade-off between efficacy and the dose-limiting toxicity, i.e., xerostomia. The objective of this study was to compare overall survival (OS), progression-free survival (PFS), and incidence of xerostomia among metastatic prostate cancer patients who received Ac-225 PSMA-617 augmentation in the initial phase of Lu-177 PSMA-617 RLT compared to those who received it in the late phase. Initial phase is defined as first two cycles of PSMA radioligand therapy (PRLT) vs late phase as after two cycles. We also examined prognostic factors associated with OS and PFS. Methods: Kaplan Meier method was used to examine survival curves and log-rank tests were conducted to examine differences in survival by groups. Cox Proportional Hazard (CPH) model was used to examine the impact of bone marrow and visceral metastasis and age on OS and PFS. Progression was defined as an increase of ≥ 25% in prostate-specific antigen (PSA) levels. Results: 68 patients who received Ac-225 PSMA-617 by itself, or Ac-225 PSMA-617 augmentation to Lu-PSMA-617 were included in the analysis. Out of these, 15 received early augmentation, 50 received late augmentation, and 3 received Ac-225 PSMA-617 alone. Of these, 48 experienced cancer progression and 21 died due to cancer progression. Median OS was 47 months and PFS was 11 months. Those who received early augmentation had significantly better PFS (median PFS not reached during study period) compared to those who received late augmentation (median PFS: 9 months) (p = 0.02). Early augmentation was associated with lower likelihood of xerostomia (p = 0.09). CPH model suggested that visceral or bone marrow metastasis were associated with significantly worse prognosis for PFS (p = 0.04). Conclusions: In patients progressing after Lu-177 PSMA radioligand therapy and those with diffuse bone-marrow metastases, an earlier augmentation with Ac-225 PSMA-617 is associated with better PFS and lower side effects such as xerostomia. Having visceral or bone marrow metastasis is a poor prognostic indicator for PFS in augmented alpha-beta PSMA radioligand therapy.

An Albumin-Binding PSMA Ligand with Higher Tumor Accumulation for PET Imaging of Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is an ideal target for the diagnosis and treatment of prostate cancer. Due to the short half-life in blood, small molecules/peptides are rapidly cleared by the circulatory system. Prolonging the half-life of PSMA probes has been considered as an effective strategy to improve the tumor detection. Herein, we reported a 64Cu-labeled PSMA tracer conjugating with maleimidopropionic acid (MPA), 64Cu-PSMA-CM, which showed an excellent ability to detect PSMA-overexpressing tumors in delayed time. Cell experiments in PSMA-positive 22Rv1 cells, human serum albumin binding affinity, and micro-PET imaging studies in 22Rv1 model were performed to investigate the albumin binding capacity and PSMA specificity. Comparisons with 64Cu-PSMA-BCH were performed to explore the influence of MPA on the biological properties. 64Cu-PSMA-CM could be quickly prepared within 30 min. The uptake of 64Cu-PSMA-CM in 22Rv1 cells increased over time and it could bind to HSA with a high protein binding ratio (67.8 ± 1.5%). When compared to 64Cu-PSMA-BCH, 64Cu-PSMA-CM demonstrated higher and prolonged accumulation in 22Rv1 tumors, contributing to high tumor-to-organ ratios. These results showed that 64Cu-PSMA-CM was PSMA specific with a higher tumor uptake, which demonstrated that MPA is an optional strategy for improving the radioactivity concentration in PSMA-expressing tumors and for developing the ligands for PSMA radioligand therapy.

Matched-pair analysis of [177Lu]Lu-PSMA I&T and [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer

BackgroundLabelled with lutetium-177, the urea-based small molecules PSMA I&T and PSMA-617 are the two agents most frequently used for radioligand therapy (RLT) in patients with advanced metastatic castration-resistant and prostate-specific membrane antigen (PSMA) expressing prostate cancer (mCRPC). In this matched-pair analysis, we aimed to compare the toxicity and efficacy of both agents for PSMA-directed RLT.Materials and methodsA total of 110 mCRPC patients from two centres were accrued, 55 individuals treated with [177Lu]Lu-PSMA I&T, and a matched cohort of 55 patients treated with [177Lu]Lu-PSMA-617. Matching criteria included age at the first cycle, Gleason score, prostate-specific antigen (PSA) values, and previous taxane-based chemotherapy. Using common terminology criteria for adverse events (CTCAE v. 5.0), toxicity profiles were investigated (including bone marrow and renal toxicity). Overall survival (OS) between both groups was compared.ResultsToxicity assessment revealed grade III anaemia in a single patient (1.8%) for [177Lu]Lu-PSMA I&T and five (9.1%) for [177Lu]Lu-PSMA-617. In addition, one (1.9%) grade III thrombopenia for [177Lu]Lu-PSMA-617 was recorded. Apart from that, no other grade III/IV toxicities were present. A median OS of 12 months for patients treated with [177Lu]Lu-PSMA I&T did not differ significantly when compared to patients treated with [177Lu]Lu-PSMA-617 (median OS, 13 months; P = 0.89).ConclusionIn this matched-pair analysis of patients receiving one of the two agents most frequently applied for PSMA RLT, the rate of clinically relevant toxicities was low for both compounds. In addition, no relevant differences for OS were observed.

The role of PSMA radioligands in the diagnosis and treatment of prostate carcinoma

Prostate cancer (PC) is the most common tumor in men in the West and the fifth leading cause of cancer-related death. The use of PSMA radioligands has represented an important advance both in its diagnosis, through PET molecular imaging, and in its treatment in advanced stages of the disease. This article reviews the contribution of PET studies with PSMA radioligands in initial staging, in tumor detection in biochemical recurrence (elevation of PSA) after treatment with curative intent, and in the more advanced stages of the disease (castration resistant PC or CRPC). The contribution of PSMA radioligand therapy (PSMA-RLT) in CRPC patients who progress to standard therapy is also analyzed.

Utilidad de los radioligandos PSMA en el diagnóstico y tratamiento del carcinoma de próstata

Prostate cancer (PC) is the most common tumor in men in the West and the fifth leading cause of cancer-related death. The use of prostate-specific membrane antigen (PSMA) radioligands has represented an important advance in both in the diagnosis by positron emission tomography (PET) molecular imaging and the treatment of advanced stages of the disease. This article reviews the contribution of PET studies with PSMA radioligands in the initial staging, tumor detection in biochemical recurrence (elevation of PSA) after treatment with curative intent, and in the more advanced stages of the disease (castration-resistant PC [CRPC]). The contribution of PSMA radioligand therapy in CRPC patients who progress to standard therapy is also analyzed.

Predicting the outcome of mCPRC patients after Lu-177 PSMA therapy using semi-quantitative and visual criteria in baseline PSMA PET: An international multicenter retrospective study.

32 Background: The aim of this study was to assess the use of the baseline PSMA parotids uptake as a reference to determine eligibility for Lu-177 PSMA radioligand therapy (RLT) by using semi-quantitative and standardized visual criteria. Methods: We conducted a retrospective cohort study using a multicenter dataset 270 men with mCRPC treated with Lu-177 PSMA (Gafita A, Lancet Oncol 2021). For quantitative analysis, semi-automatic segmentation software (qPSMA) divided men into three groups according to the SUVmean ratio of whole-body-tumor to parotid glands: (high) &gt; 1.5; (intermediate) 0.5 - 1.5; (low) &lt; 0.5. For visual analysis, ten nuclear medicine physicians with (n = 5) and without (n = 5) clinical experience in Lu-177 PSMA RLT ( &gt; 50 cases) read each baseline PSMA PET 3D maximum intensity projection (MIP) images, and classified the patients into three groups: (high) most ( &gt; 80%) of the lesions show higher uptake than parotid glands; (intermediate) neither “low” nor “high”; (low) most ( &gt; 80%) of the lesions show lower uptake than parotid glands. In case of inter-reader disagreement, a majority vote was used. Outcome measures included PSA-progression free-survival (PSA-PFS), overall survival (OS), and PSA decline of ≥50% (PSA50). Fisher’s exact test and Kaplan–Meier analysis with the log-rank test was performed for PSA50 and survival analysis, respectively. Results: 237 men were analyzed after excluding 33 men with more than half of the parotid glands out of the PET scan field-of-view. The number of the patients in the high, intermediate, and low groups were 106/237 (44.7%), 96 (40.5%), and 35 (14.8%) for visual criteria, and 56 (23.6%), 163 (68.8%), and 18 (7.6%) for quantitative analysis, respectively. The inter- and intra-readers reproducibility of the visual scoring showed substantial (Fleiss’ weighted Kappa: 0.68) and almost perfect (Cohen's weighted Kappa (mean): 0.83) agreement, respectively. The median PSA-PFS was 6.7, 3.8, and 1.9 months (p &lt; 0.001); and 7.2, 4.0, and 1.9 months (p &lt; 0.001) in the high, intermediate, and low expression groups by visual and quantitative criteria, respectively. The PSA50 was 63.2%, 33.3%, and 17.1% (p &lt; 0.001), and 69.6%, 38.7%, and 16.7% (p &lt; 0.001) in the high, intermediate, and low expression groups by visual and quantitative criteria, respectively. OS was longer in the high PSMA expression group than in the intermediate + low (i.e., non-high) group by visual (14.3 vs.11.0 months (p = 0.038)) and quantitative criteria (15.0 vs. 11.7 months (p = 0.013)). Conclusions: Tumor-to-parotid uptake using a simple visual or semi-quantitative measure is a valuable prognostic biomarker for response in men with mCRPC treated with Lu-177 PSMA RLT.

Theragnostics in prostate cancer.

Prostate-specific membrane antigen (PSMA) is a molecular target for both imaging diagnostics and therapeutics, i.e., a theragnostics target. There has been a growing body of evidence supporting PSMA theragnostics approaches in the management of prostate cancer (PCa) for tailored precision medicine. Tumor characterization through PSMA-ligand PET imaging is crucial for assessing the molecular signature and eligibility for PSMA radioligand therapy. Recent U.S. Food and Drug Administration (FDA) approval of two new drug applications for PSMA PET imaging contribute to reinforce PSMA as an oncologic blockbuster. Additionally, relevant progress in the PSMA treatment has been made in the last five years. [177Lu]Lu-PSMA-617 radioligand therapy for patients with progressive PSMA-avid metastatic castration-resistant PCa (mCRPC) significantly increased overall survival and radiographic progression-free survival, according to the results of an international, prospective, open label, multicenter, randomized, phase III study (VISION trial). The objective of this comprehensive review is to highlight the recent advances in PCa theragnostics, focusing on actual clinical applications and future perspectives.

Prostate-Specific Membrane Antigen Radioligand Therapy Using 177Lu-PSMA I&T and 177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer: Comparison of Safety, Biodistribution, and Dosimetry.

The objective of this study was to determine the safety, kinetics, and dosimetry of the 177Lu-labeled prostate-specific membrane antigen (PSMA) small molecules 177Lu-PSMA I&T and 177Lu-PSMA-617 in a large cohort of patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing PSMA radioligand therapy (PRLT). Methods: In total, 138 patients (mean age, 70 ± 9 y; age range, 46-90 y) with progressive mCRPC and PSMA expression verified by 68Ga-PSMA-11 PET/CT underwent PRLT. Fifty-one patients received 6.1 ± 1.0 GBq (range, 3.4-7.6 GBq) of 177Lu-PSMA I&T, and 87 patients received 6.5 ± 1.1 GBq (range, 3.5-9.0 GBq) of 177Lu-PSMA-617. Dosimetry was performed on all patients using an identical protocol. The mean absorbed doses were estimated with OLINDA software (MIRD Scheme). Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 5.0, of the National Cancer Institute. Results: The whole-body half-lives were shorter for 177Lu-PSMA I&T (35 h) than for 177Lu-PSMA-617 (42 h). The mean whole-body dose of 177Lu-PSMA-617 was higher than that of 177Lu-PSMA I&T (0.04 vs. 0.03 Gy/GBq, P < 0.00001). Despite the longer half-life of 177Lu-PSMA-617, the renal dose was lower for 177Lu-PSMA-617 than for 177Lu-PSMA I&T (0.77 vs. 0.92 Gy/GBq, P = 0.0015). Both PSMA small molecules demonstrated a comparable dose to the parotid glands (0.5 Gy/GBq, P = 0.27). Among all normal organs, the lacrimal glands exhibited the highest mean absorbed doses, 5.1 and 3.7 Gy/GBq, for 177Lu-PSMA-617 and 177Lu-PSMA I&T, respectively. All tumor metastases exhibited a higher initial uptake when using 177Lu-PSMA I&T than when using 177Lu-PSMA-617, as well as a shorter tumor half-life (P < 0.00001). The mean absorbed tumor doses were comparable for both 177Lu-PSMA I&T and 177Lu-PSMA-617 (5.8 vs. 5.9 Gy/GBq, P = 0.96). All patients tolerated the therapy without any acute adverse effects. After 177Lu-PSMA-617 and 177Lu-PSMA I&T, there was a small, statistically significant reduction in hemoglobin, leukocyte counts, and platelet counts that did not need any clinical intervention. No nephrotoxicity was observed after either 177Lu-PSMA I&T or 177Lu-PSMA-617 PRLT. Conclusion: Both 177Lu-PSMA I&T and 177Lu-PSMA-617 PRLT demonstrated favorable safety in mCRPC patients. The highest absorbed doses among healthy organs were in the lacrimal and parotid glands-not, however, resulting in any significant clinical sequel. 177Lu-PSMA-617 demonstrated a higher absorbed dose to the whole-body and lacrimal glands but a lower renal dose than did 177Lu-PSMA I&T. The mean absorbed tumor doses were comparable for both 177Lu-PSMA I&T and 177Lu-PSMA-617. There was a large interpatient variability in the dosimetry parameters. Therefore, individual patient-based dosimetry seems favorable for personalized PRLT.

PSMA PET Imaging in Glioblastoma: A Preclinical Evaluation and Theranostic Outlook.

BackgroundProstate specific membrane antigen (PSMA) PET imaging has recently gained attention in glioblastoma (GBM) patients as a potential theranostic target for PSMA radioligand therapy. However, PSMA PET has not yet been established in a murine GBM model. Our goal was to investigate the potential of PSMA PET imaging in the syngeneic GL261 GBM model and to give an outlook regarding the potential of PMSA radioligand therapy in this model.MethodsWe performed an 18F-PSMA-1007 PET study in the orthotopic GL261 model (n=14 GBM, n=7 sham-operated mice) with imaging at day 4, 8, 11, 15, 18 and 22 post implantation. Time-activity-curves (TAC) were extracted from dynamic PET scans (0-120 min p. i.) in a subset of mice (n=4 GBM, n=3 sham-operated mice) to identify the optimal time frame for image analysis, and standardized-uptake-values (SUV) as well as tumor-to-background ratios (TBR) using contralateral normal brain as background were calculated in all mice. Additionally, computed tomography (CT), ex vivo and in vitro 18F-PSMA-1007 autoradiographies (ARG) were performed.ResultsTAC analysis of GBM mice revealed a plateau of TBR values after 40 min p. i. Therefore, a 30 min time frame between 40-70 min p. i. was chosen for PET quantification. At day 15 and later, GBM mice showed a discernible PSMA PET signal on the inoculation site, with highest TBRmean in GBM mice at day 18 (7.3 ± 1.3 vs. 1.6 ± 0.3 in shams; p=0.024). Ex vivo ARG confirmed high tracer signal in GBM compared to healthy background (TBRmean 26.9 ± 10.5 vs. 1.6 ± 0.7 in shams at day 18/22 post implantation; p=0.002). However, absolute uptake values in the GL261 tumor remained low (e.g., SUVmean 0.21 ± 0.04 g/ml at day 18) resulting in low ratios compared to dose-relevant organs (e.g., mean tumor-to-kidney ratio 1.5E-2 ± 0.5E-2).ConclusionsAlthough 18F-PSMA-1007 PET imaging of GL261 tumor-bearing mice is feasible and resulted in high TBRs, absolute tumoral uptake values remained low and hint to limited applicability of the GL261 model for PSMA-directed therapy studies. Further investigations are warranted to identify suitable models for preclinical evaluation of PSMA-targeted theranostic approaches in GBM.

Radioligand Therapy for Metastatic Prostate Cancer.

HomeRadiology: Imaging CancerVol. 3, No. 6 Previous Research HighlightsFree AccessRadioligand Therapy for Metastatic Prostate CancerBrian J. BurkettBrian J. BurkettBrian J. BurkettPublished Online:Nov 26 2021https://doi.org/10.1148/rycan.2021219026MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Take-Away Points■ Major Focus: Efficacy of lutetium-177 (177Lu)–prostate-specific membrane antigen (PSMA)–617 radioligand therapy with standard-of-care therapy compared to standard of care alone for castration-resistant metastatic prostate cancer.■ Key Result: 177Lu-PSMA-617, in addition to standard of care, prolongs progression-free survival and overall survival in patients with castration-resistant metastatic prostate cancer selected on the basis of PSMA-ligand PET/CT findings.■ Impact: The phase III VISION trial is the basis for U.S. Food and Drug Administration priority review of 177Lu-PSMA-617 as a new radioligand therapy for appropriately selected patients with pretreated, metastatic prostate cancer. Theranostic agent 177Lu-PSMA-617 is composed of 177Lu (a therapeutic beta-particle emitter) paired with PSMA, a cell surface glycoprotein expressed in most prostate cancer metastases. The pairing allows selective delivery of targeted radiation therapy to prostate cancer cells.The VISION trial is a phase III prospective clinical trial investigating 177Lu-PSMA-617 in the context of previously treated metastatic prostate cancer in combination with several standard-of-care options, including antiandrogen chemotherapeutic agents, external beam radiation therapy, bisphosphonates and denosumab, and steroids. Eligible patients must have progressed while receiving androgen receptor inhibitor and taxane-based chemotherapy and have undergone gallium-68–PSMA-11 PET/CT demonstrating one or more metastatic lesions with tracer uptake. Patients with PSMA-negative metastases 1 cm or larger were ineligible.Five hundred eighty-one patients were randomized to four to six cycles of 177Lu-PSMA-617 with trial-approved standard of care or only standard of care in a 2:1 ratio. 177Lu-PSMA-617 treatment significantly prolonged progression-free survival on the basis of imaging (8.7 vs 3.4 months, hazard ratio of 0.4 [95% CI: 0.29, 0.57]) and significantly prolonged median overall survival (15.3 vs 11.3 months, hazard ratio of 0.62 [95% CI: 0.52, 0.74]). 177Lu-PSMA-617 also significantly prolonged time to first symptomatic skeletal event or death, decreased prostate-specific antigen levels, and increased percentage of tumor response (complete and partial). Adverse events, most commonly fatigue, nausea, or dry mouth, happened more frequently in the group receiving 177Lu-PSMA-617. Five fatal events occurred in the 177Lu-PSMA-617 group due to pancytopenia, bone marrow failure, and intracranial bleeding.This trial complements the phase II TheraP trial that compared 177Lu-PSMA-617 alone to cabazitaxel chemotherapy. The survival benefit reported in the VISION trial ultimately may result in regulatory approval of 177Lu-PSMA-617 administered with other therapeutic options, even in heavily pretreated patients with refractory metastatic disease. PSMA-ligand PET also provides a companion diagnostic imaging marker for selecting appropriate patients and monitoring response to therapy if 177Lu-PSMA-617 receives regulatory approval.Highlighted ArticleSartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med 2021;385(12):1091– 1103. doi: https://doi.org/10.1056/nejmoa2107322Highlighted ArticleSartor O, de Bono J, Chi KN, et al. Lutetium-177EN_DASHPSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med 2021;385(12):1091–1103. doi: https://doi.org/10.1056/nejmoa2107322 Crossref, Medline, Google ScholarArticle HistoryPublished online: Nov 26 2021 FiguresReferencesRelatedDetailsRecommended Articles 177Lu–Prostate-specific Membrane Antigen Radioligand Therapy in Patients with Metastatic Castration-resistant Prostate CancerRadiology2022Volume: 306Issue: 2Prostate-specific Membrane Antigen PET in Prostate CancerRadiology2021Volume: 299Issue: 2pp. 248-260Revisiting Prostate Cancer Recurrence with PSMA PET: Atlas of Typical and Atypical Patterns of SpreadRadioGraphics2019Volume: 39Issue: 1pp. 186-212Radiotheranostics in Cancer Diagnosis and ManagementRadiology2018Volume: 286Issue: 2pp. 388-400Impact of 18F-DCFPyL PET on Staging and Treatment of Unfavorable Intermediate or High-Risk Prostate CancerRadiology2022Volume: 304Issue: 3pp. 600-608See More RSNA Education Exhibits Current Status and Future Prospects in Radioligand TherapyDigital Posters2020Peptide Receptor Radionuclide Therapy (PRRT): 2019 UpdateDigital Posters2019Advanced Prostate Cancer: Update on Evolving Concepts, Rationale, and Challenges of Imaging and Novel Therapeutic StrategiesDigital Posters2018 RSNA Case Collection Radioembolization of Liver Metastasis RSNA Case Collection2020Locally advanced, metastatic prostate adenocarcinomaRSNA Case Collection2020Parasagittal meningiomaRSNA Case Collection2022 Vol. 3, No. 6 Metrics Altmetric Score PDF download