Search Results (146)

Targeted alpha therapy (TAT) has recently emerged as a highly promising approach for the management of metastatic castration-resistant prostate cancer (mCRPC), especially in patients with disease progression despite standard treatments. Among alpha-emitter radiopharmaceuticals, actinium-225-labelled prostate-specific membrane antigen ([225Ac]Ac-PSMA) has shown remarkable potential due to its high linear energy transfer (LET), short path length, and ability to induce potent, localised cytotoxic effects. This review summarises current clinical evidence regarding [225Ac]Ac-PSMA radioligand therapy (RLT), emphasising its efficacy, safety profile, and position relative to beta-emitter therapy with lutetium-177 ([177Lu]Lu-PSMA). Data from compassionate-use programs and small clinical trials demonstrate that [225Ac]Ac-PSMA produces significant biochemical and imaging responses, including > 50% declines in prostate-specific antigen (PSA) and lesion regression on [68Ga]Ga-PSMA PET/CT, even in heavily pre-treated mCRPC cohorts. Xerostomia, renal toxicity, and haematological adverse effects remain the main safety challenges, necessitating optimisation of patient selection, dosing strategies, and salivary gland protection protocols. Compared with [177Lu]Lu-PSMA, [225Ac]Ac-PSMA appears effective even in cases of beta-refractory disease, highlighting its complementary role rather than a competitive alternative. However, limited availability, high production costs, and the lack of large-scale, randomised trials hinder widespread clinical adoption. Future directions include combination protocols, improved radiopharmaceutical design, and trials evaluating its use in earlier disease stages. This review provides a comprehensive overview of the clinical aspects of [225Ac]Ac-PSMA RLT and its evolving role in advanced prostate cancer management. Full article

Background/Objectives: ¹⁸F-PSMA-1007 is one of the more widely used radioligands in prostate cancer imaging with PET/CT. Its major advantage lies in the low urinary tracer activity due to primarily hepatobiliary clearance, but unexpectedly high tracer accumulation in the bladder can occur, potentially hindering assessment of lesions near the prostate bed. This study assesses the impact of furosemide on ¹⁸F-PSMA-1007 tracer accumulation in the bladder. Methods: In this single-center, retrospective, intra-individual comparative analysis, 18 patients undergoing two consecutive ¹⁸F-PSMA-1007 PET/CT scans for biochemical relapse (BCR) or persistence (BCP)—one with and one without prior furosemide administration—were included. Images were acquired 60 min post-injection of 250 MBq of tracer activity. Standardized Uptake Values (SUVmax, SUVpeak, SUVmean) were measured in the bladder and in tissues with physiological uptake by three readers. Differences were analyzed using Wilcoxon signed-rank tests. The inter-reader agreement was assessed using intraclass correlation coefficient. Results: Furosemide significantly decreased bladder SUVmax, SUVpeak, and SUVmean (all p < 0.001). Mean bladder SUVmax decreased from 13.20 ± 10.40 to 3.92 ± 3.47, SUVpeak from 10.94 ± 8.02 to 3.47 ± 3.13, and SUVmean from 8.74 ± 6.66 to 2.81 ± 2.56, representing a large effect size (r ≈ 0.55). Physiological tracer uptake in most organs was not significantly influenced by furosemide (all p > 0.05). Conclusions: Despite the predominantly hepatobiliary clearance of ¹⁸F-PSMA-1007, furosemide-induced forced diuresis leads to a significant reduction in tracer activity in the bladder, which in clinical practice could help in early detection of tumor recurrence. Full article

Targeted radioligand therapy (RLT) is an emerging field in anticancer therapeutics with great potential across tumor types and stages of disease. While much progress has focused on agents targeting somatostatin receptors and prostate-specific membrane antigen (PSMA), the same advanced radioconjugation methods and molecular targeting have spurred the development of numerous theranostic combinations for other targets. A number of the most promising agents have progressed to clinical trials and are poised to change the landscape of positron emission tomography (PET) imaging. Here, we present recent data on some of the most important emerging molecular targeted agents with their exemplar clinical images, including agents targeting fibroblast activation protein (FAP), hypoxia markers, gastrin-releasing peptide receptors (GRPrs), and integrins. These radiopharmaceuticals share the promising characteristic of being able to image multiple types of cancer. Early clinical trials have already demonstrated superiority to ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) for some, suggesting the potential to supplant this longstanding PET radiotracer. Here, we provide a primer for practicing radiologists, particularly nuclear medicine clinicians, to understand novel PET imaging agents and their clinical applications, as well as the availability of companion targeted radiotherapeutics, the status of their regulatory approval, the potential challenges associated with their use, and the future opportunities and perspectives. Full article

Following lung cancer, prostate cancer is the leading cause of cancer death in men. High-risk localized tumor burden or metastatic disease often progresses, refractory to initial treatment regimens. There is ongoing development of technology to appropriately identify high-risk patients, stage them correctly, and offer appropriate treatments to obtain the best clinical outcomes. Prostate cancer-specific membrane antigen (PSMA) is a transmembrane glutamate carboxypeptidase, which helps regulate folate absorption, and its overexpression is pathologically directly proportional and associated with prostate cancer. Increased PSMA expression is a known independent risk factor for poorer survival, and most metastatic lesions in CRPC are PSMA positive. Over the last decade, several PSMA-based PET radiopharmaceuticals have demonstrated superior sensitivities and specificities compared to traditional imaging methods. These outcomes have been demonstrated by several large clinical trials. As the data emerges, these diagnostics are being integrated into standard of care protocol to facilitate nuanced identification of malignant lesions. PSMA is also being targeted through several therapeutics, including radioligands and immunotherapies such as CAR-T, BiTEs, and ADCs. This review will discuss the landscape of PSMA-based theranostics in the context of prostate cancer. Full article

Background: This Phase 2 trial evaluated the efficacy, tolerability, and safety of [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) in patients with ≥1 measurable lesion and progressive prostate-specific membrane antigen-positive (PSMA+) metastatic castration-resistant prostate cancer (mCRPC) in Japan. Methods: This study comprises four parts; data from three parts are presented here. Part 1 evaluated safety and tolerability; Parts 2 (post-taxane) and 3 (pre-taxane/taxane-naive) assessed the overall response rate (ORR; primary endpoint), overall survival (OS), radiographic progression-free survival (rPFS), disease control rate (DCR), PFS, and safety; and Part 4 is the expansion part. Patients received 7.4 GBq (±10%) ¹⁷⁷Lu-PSMA-617 Q6W for up to six cycles. Results: Of the 35 patients who underwent a [⁶⁸Ga]Ga-PSMA-11 (⁶⁸Ga-PSMA-11) PET/CT scan, 30 received ¹⁷⁷Lu-PSMA-617 (post-taxane, n = 12; pre-taxane, n = 18). No dose-limiting toxicity was noted in Part 1 (n = 3). Post- and pre-taxane patients had a median of three and five cycles, respectively. The primary endpoint, ORR, met the pre-specified threshold, with the lower limit of the 90% confidence interval (CI) above the threshold of 5% for post-taxane and 12% for pre-taxane. Post- and pre-taxane patients had an ORR of 25.0% (90% CI: 7.2–52.7) and 33.3% (90% CI: 15.6–55.4), respectively. In post- and pre-taxane patients, the DCR was 91.7% and 83.3%, the median rPFS was 3.71 and 12.25 months, and the median PFS was 3.71 and 5.59 months, respectively. The median OS was 14.42 and 12.94 months in post- and pre-taxane patients, respectively. The most common adverse events were constipation, decreased appetite, decreased platelet count, anemia, and nausea. Conclusions: The primary endpoint (ORR) was met. The safety profile of ¹⁷⁷Lu-PSMA-617 was consistent with the VISION and PSMAfore studies, with no new safety signals in the Japanese patients with mCRPC. Full article

Background: Radioligand therapy with [¹⁷⁷Lu]Lu-PSMA-617 represents an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). Its clinical positioning relative to standard therapies remains under discussion. Objective: To compare overall survival (OS), radiographic progression-free survival (rPFS), PSA response, and treatment burden across randomised trials evaluating [¹⁷⁷Lu]Lu-PSMA-617 versus androgen receptor pathway inhibitors (ARTA), Cabazitaxel, or standard of care (SOC). Evidence Acquisition: We conducted a meta-analysis of five randomised controlled trials, including 2073 patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). We assessed survival endpoints, baseline comparability, and treatment intensity. Evidence Synthesis: [¹⁷⁷Lu]Lu-PSMA-617 significantly improved rPFS and PSA response. While modest overall, the OS benefit was more pronounced in taxane-naïve populations. Compared with Cabazitaxel, [¹⁷⁷Lu]Lu-PSMA-617 was associated with similar or better survival despite shorter treatment duration and potentially lower cumulative toxicity and cost. Economic modelling suggests it could offer a more sustainable therapeutic option under typical willingness-to-pay thresholds. Conclusions: [¹⁷⁷Lu]Lu-PSMA-617 shows clinical effectiveness and economic value in mCRPC, with potential advantages over Cabazitaxel and ARTA. Its use could be prioritised in early treatment lines. Patient Summary: This study suggests that PSMA-targeted radioligand therapy is at least as effective as other treatments for advanced prostate cancer, with potential benefits in terms of toxicity, duration, and overall cost. Full article

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a rising threat for immunocompromised cancer patients. The reduced immune defense may be a result of the malignancy itself or a side effect of therapy. While many chemotherapies can severely diminish the effect of vaccines against SARS-CoV-2, the effect of radioligand therapy has not yet been studied so far. Methods: In our database, 64 patient records of patients with metastatic castration-resistant prostate cancer that were treated with PSMA-directed radioligand therapy (PRLT) were randomly selected and checked for specific information (vaccination status, past corona virus disease 2019 (COVID-19) infections, the period between PRLT and vaccination, and antibody titers). A total of 30 patient records had sufficient information to examine the interference between PRLT and the vaccination against SARS-CoV-2. Results: In the analyzed cohort, 96.7% of the patients achieved seroconversion after receiving—on average—the third (booster) vaccination against SARS-CoV-2 and two PRLT cycles with average administered activities of 16.1 ± 7.2 GBq (435.1 ± 194.6 mCi) of lutetium-177 and 13.7 ± 6.6 MBq (0.37 ± 0.18 mCi) of actinium-225 (as part of ‘TANDEM therapies’) per patient. Conclusions: In the reviewed population, neither the initial response nor the maintenance of a positive immune response against the SARS-CoV-2 virus was undesirably affected by PRLT. The seroconversion rate and the absolute immune titers (in many cases >25,000 BAU/mL) are comparable to the normal population. This result implies the clinically important conclusion that neither an initial nor a booster vaccination against COVID-19 must be postponed if a PRLT is planned (and vice versa). Full article

Background/Objectives: Early treatment assessment in metastatic renal cell carcinoma (mRCC) remains challenging due to the limited accuracy of current imaging methods. Given prostate-specific membrane antigen (PSMA) overexpression in mRCC, PSMA PET is a promising approach. Despite numerous studies on PSMA imaging in mRCC, data on PSMA uptake changes during systemic therapy are scarce. We analyzed PSMA uptake on PET after treatment initiation in mRCC patients. Methods: A retrospective single-center analysis of mRCC patients who underwent [¹⁸F]PSMA-1007 PET/CT before (PET₁) and at a mean of 9.5 weeks after (PET₂) starting systemic therapy was conducted. PSMA uptake in metastatic lesions was compared by region and RCC subtype. Uptake differences between PET₁ and PET₂ were analyzed using an unpaired t-test. Results: This study included 25 patients (mean age 65.2 ± 14.7 years; 20 male) with mRCC. A total of 113 (PET₁) and 48 (PET₂) metastases were assessed. Lymph node metastases showed stable PSMA uptake (median SUV_max) after treatment (7.8 vs. 7.7, p = 0.77), while uptake by bone (6.4 vs. 12.4, p = 0.03) and lung metastases (4.5 vs. 8.1, p = 0.004) increased significantly. SUV stability in lymph nodes was independent of RCC subtype (ccRCC: p = 0.48, pRCC: p > 0.99). Bone (6.6 vs. 15.9, p = 0.008) and lung metastases (4.8 vs. 8.1, p = 0.02) had higher PSMA uptake in ccRCC, unlike pRCC (bone: 6.2 vs. 6.0, p = 0.86). Conclusions: Alterations of PSMA-radioligand uptake are seen in bone and pulmonary metastases but not in lymph node metastases after initiation of systemic treatment in patients with mRCC. ccRCC has a higher PSMA uptake than other RCC subtypes. Full article

Despite substantial improvement in the definitive management of primary prostate cancer, a significant number of patients experience biochemical recurrence—a clinical state in which serum prostate-specific antigen (PSA) levels rise prior to the development of physical signs or symptoms. The early detection and localization of biochemical recurrence may confer eligibility for salvage therapy; therefore, imaging techniques that provide accurate disease visualization are imperative. In this review, we discuss various imaging methods for localizing disease in the context of biochemical recurrence in prostate cancer. Particularly, we describe available or investigational positron emission tomography (PET) radiotracers, such as ¹⁸F-FDG, ¹⁸F-NaF, choline (both ¹⁸F and ¹¹C), the ¹⁸F-labeled amino acid derivative fluciclovine, prostate-specific membrane antigen (PSMA) radioligands, and the short peptide compound bombesin. Generally, PET radiotracers such as ¹⁸F-FDG, ¹⁸F-NaF, and ¹⁸F/¹¹C choline have fallen out of favor because of their inferior sensitivity and/or specificity in relation to more recently developed radiotracers. ¹⁸F-fluciclovine has addressed these shortcomings by exploiting the upregulation of amino acid transporters in tumors; however, PSMA-targeting agents have significantly advanced the management of biochemical recurrence of prostate cancer through their high sensitivity and specificity, enabling the identification of candidates for radionuclide therapy. Investigational agents, such as bombesin-based radiotracers, may address the shortcomings of treating prostate cancer with little to no PSMA expression. Full article

Nuclear medicine has emerged as a critical modality in the diagnostic and therapeutic management of urological malignancies, particularly prostate cancer. Advances in single-photon emission computed tomography/computed tomography (CT) and positron emission tomography/CT (PET/CT) have enhanced tumor assessment across staging, treatment response, and recurrence settings. Molecular imaging, which offers insights beyond traditional anatomical imaging, is increasingly integral in specific clinical scenarios. Theranostic nuclear medicine, which combines diagnostic imaging with targeted therapy, has become a well-established treatment option, particularly for patients with metastatic castration-resistant prostate cancer (mCRPC). The development of the prostate-specific membrane antigen (PSMA) radioligands has revolutionized clinical management by enabling precise disease staging and delivering effective radioligand therapy (RLT). Ongoing research aims to refine the role of PSMA PET imaging in staging and treatment monitoring, while optimizing PSMA-targeted RLT for broader clinical use. Given that prostate cancer remains highly prevalent, the anticipated increase in the demand for RLT presents both challenges and opportunities for nuclear medicine services globally. Theranostic approaches exemplify personalized medicine by enabling the tailoring of treatments to individual tumor biology, thereby improving survival outcomes and maintaining patients’ quality of life with minimal toxicity. Although the current focus is on advanced disease, future research holds promise for expanding these strategies to earlier stages, potentially enhancing curative prospects. This evolving field not only signifies a paradigm shift in the care of prostate cancer patients but also underscores the growing importance of nuclear medicine in delivering precision oncology. Full article

Metastatic prostate cancer (mPCa) remains a significant cause of cancer-related mortality in men. Advances in molecular profiling have demonstrated that the androgen receptor (AR) axis, DNA damage repair pathways, and the PI3K/AKT/mTOR pathway are critical drivers of disease progression and therapeutic resistance. Despite the established benefits of hormone therapy, chemotherapy, and bone-targeting agents, mPCa commonly becomes treatment-resistant. Recent breakthroughs have highlighted the importance of identifying actionable genetic alterations, such as BRCA2 or ATM defects, that render tumors sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Parallel efforts have refined imaging—particularly prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography—to detect and localize metastatic lesions with high sensitivity, thereby guiding patient selection for PSMA-targeted radioligand therapies. Multi-omics innovations, including liquid biopsy technologies, enable the real-time tracking of emergent AR splice variants or reversion mutations, supporting adaptive therapy paradigms. Nonetheless, the complexity of mPCa necessitates combination strategies, such as pairing AR inhibition with PI3K/AKT blockade or PARP inhibitors, to inhibit tumor plasticity. Immuno-oncological approaches remain challenging for unselected patients; however, subsets with mismatch repair deficiency or neuroendocrine phenotypes may benefit from immune checkpoint blockade or targeted epigenetic interventions. We present these pivotal advances, and discuss how biomarker-guided integrative treatments can improve mPCa management. Full article

Objectives: Tumor heterogeneity and acquired resistance to prostate-specific membrane antigen (PSMA) radioligand therapy (PRLT) pose significant challenges to PSMA PET-based diagnosis. This study aimed to develop an Al¹⁸F-labeled FAP-targeted tracer and explore the diagnostic value in acquired drug-resistant tumor models. Methods: To identify potential targets for imaging drug-resistant prostate cancer, bioinformatic analysis was employed to correlate FAP expression levels with genes associated with tumor progression and radiotherapy resistance. Molecular docking technology simulations were utilized to screen FAP ligands for optimal binding affinity and target specificity. The most promising ligand, FAP-2286, was radiolabeled with ¹⁸F to develop a novel PET imaging agent, Al¹⁸F-NOTA-FAP-2286 PET. To evaluate the diagnostic potential of this agent, various tumor models were established. U87 cells were used to optimize the imaging protocol and assess targeting efficiency and 22RV-1-resistant cells co-xenografted with NIH-3T3 cells were used to model acquired drug-resistant prostate cancer. The diagnostic efficacy of Al¹⁸F-NOTA-FAP-2286 PET in this acquired drug-resistant model was assessed and validated through immunohistochemical staining of tumor tissue. Results: Bioinformatic analysis confirmed the association between FAP expression and key genes involved in radiotherapy resistance, such as HIF1α, BCL2, ATM, and EGFR. Molecular docking studies demonstrated the strong binding affinity of FAP-2286 to FAPα (−10 kcal/mol). Al¹⁸F-NOTA-FAP-2286 PET/CT imaging in U87 tumor-bearing mice revealed accurate targeting of high FAP-expressing xenografts. The imaging characteristics of Al¹⁸F-NOTA-FAP-2286 were comparable to ¹⁸F-FDG and ⁶⁸Ga-FAP-2286 but with a prolonged imaging window compared to ⁶⁸Ga-FAP-2286. In acquired drug-resistant prostate cancer xenograft nude mice, Al¹⁸F-NOTA-FAP-2286 could effectively detect tumor lesions, as confirmed by immunohistochemical analysis. Conclusions: Al¹⁸F-NOTA-FAP-2286, as a PSMA-independent imaging agent, holds promise as a valuable complementary molecular imaging tool for assessing acquired resistance to PRLT. Full article

Background/Objectives: Patients with metastatic castration-resistant prostate cancer (mCRPC) who have Prostate-Specific Membrane Antigen (PSMA)-negative disease have inferior outcomes with radioligand therapy (RLT). The objective of this study is to assess the added value of whole-body (WB) diffusion-weighted imaging (DWI) to PSMA PET for identifying PSMA-negative disease, which is important for risk stratification. Methods: Consecutive PSMA PET/MRI exams at our institution, which included WB DWI in patients with mCRPC, were retrospectively reviewed. For both WB DWI and PSMA PET, two independent readers scored 14 anatomic locations, which were considered positive only if both readers identified lesions. The proportion of patients with mismatched disease was summarized descriptively for each anatomic location and overall. The inter-reader agreement was computed with intra-class correlation coefficients (ICCs). Results: The study included 41 patients (with a mean age of 71.9 years), and WB DWI identified PSMA-negative lesions in 24% of patients. PSMA PET had higher agreement than DWI, although both had good agreement (ICC: 0.87 and 0.72, respectively). The median overall survival was 442 days in those with mismatched disease vs. 523 days in those without, although this difference is not statistically significant (p = 0.49). Conclusions: The addition of WB DWI to PSMA PET can identify PSMA-negative disease, which could alter patient management. Full article

Objectives: Prostate-specific membrane antigen (PSMA)-targeted radioligands are promising diagnostic tools for the targeted positron emission tomography (PET) imaging of prostate cancer (PCa). In present work, we aimed to develop a novel PSMA tracer to provide an additional option for prostate cancer diagnosis. Methods: Our team designed a new structure of the PSMA tracer and evaluated it with cellular experiments in vitro to preliminarily verify the targeting and specificity of ⁶⁸Ga-NOTA-GC-PSMA. PET/CT imaging of PSMA-positive xenograft-bearing models in vivo to further validate the in vivo specificity and targeting of the radiotracer. Pathological tissue sections from prostate cancer patients were compared with pathological immunohistochemistry and pathological tissue staining results by radioautography experiments to assess the targeting-PSMA of ⁶⁸Ga-NOTA-GC-PSMA on human prostate cancer pathological tissues. Results: The novel tracer showed high hydrophilicity and rapid clearance rate. Specific cell binding and micro-PET imaging experiments showed that ⁶⁸Ga-NOTA-GC-PSMA displayed a high specific LNCaP tumor cell uptake (1.70% ± 0.13% at 120 min) and tumor-to-muscle (T/M) and tumor-to-kidney (T/K) ratio (13.87 ± 11.20 and 0.20 ± 0.08 at 60 min, respectively). Conclusions: The novel tracer ⁶⁸Ga-NOTA-GC-PSMA is promising radionuclide imaging of PCa. Full article

Objectives: Metastatic castration-resistant prostate cancer (mCRPC) is associated with poor prognosis, particularly in cases of liver metastases. ¹⁷⁷Lu-PSMA-617 (commercially known as Pluvicto) is an FDA-approved radioligand therapy for mCRPC patients. This study aimed to evaluate the efficacy of ¹⁷⁷Lu-PSMA-617 radioligand therapy (RLT) in mCRPC patients with liver metastases, focusing on progression-free survival (PFS), overall survival (OS), and factors influencing treatment response. Materials and Methods: This retrospective study included mCRPC patients (n = 32) with liver metastases treated with Lu-PSMA-617. Patient data, including prostate-specific antigen (PSA) levels, liver SUVmax values, Lutetium-PSMA therapy cycles, and survival outcomes, were collected. Kaplan–Meier survival analysis was used to calculate PFS and OS, while regression analysis was employed to identify factors associated with treatment response. Results: The median PFS and OS were 6 and 9 months, respectively. Partial regression was observed in patients with significantly lower PSA levels (median: 90.0 ng/mL, range: 22–699 ng/mL, p = 0.001) and liver SUVmax values (median: 17.9, range: 8.3–57.0, p = 0.008). A higher number of Lutetium-PSMA cycles correlated with improved treatment response (p = 0.010) and reduced liver SUVmax values (p = 0.043). Conclusions: Lu-PSMA-617 therapy is effective in managing mCRPC with liver metastases. Increased intensity of therapy exposure, reflected by a higher number of treatment cycles, is associated with a greater biochemical response, as indicated by reduced PSA levels, thereby supporting the rationale for personalized treatment strategies. These findings support the use of Lu-PSMA-617 in mCRPC patients with liver metastases, warranting further prospective studies. Full article