Prostate-specific Membrane Antigen Research Articles

Prognostic Performance of RECIP 1.0 Based on [18F]PSMA-1007 PET in Prostate Cancer Patients Treated with [177Lu]Lu-PSMA I&T.

In metastatic castration-resistant prostate cancer (mCRPC) patients treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), the recently proposed criteria for evaluating response to PSMA PET (RECIP 1.0) based on 68Ga- and 18F-labeled PET agents provided prognostic information in addition to changes in prostate-specific antigen (PSA) levels. Our aim was to evaluate the prognostic performance of this framework for overall survival (OS) in patients undergoing RLT and imaged with [18F]PSMA-1007 PET/CT and compare the prognostic performance with the PSA-based response assessment. Methods: In total, 73 patients with mCRPC who were scanned with [18F]PSMA-1007 PET/CT before and after 2 cycles of RLT were retrospectively analyzed. We calculated the changes in serum PSA levels (ΔPSA) and quantitative PET parameters for the whole-body tumor burden (SUVmean, SUVmax, PSMA tumor volume, and total lesion PSMA). Men were also classified following the Prostate Cancer Working Group 3 (PCWG3) criteria for ΔPSA and RECIP 1.0 for PET imaging response. We performed univariable Cox regression analysis, followed by multivariable and Kaplan-Meier analyses. Results: Median OS was 15 mo with a median follow-up time of 14 mo. Univariable Cox regression analysis provided significant associations with OS for ΔPSA (per percentage, hazard ratio [HR], 1.004; 95% CI, 1.002-1.007; P < 0.001) and PSMA tumor volume (per unit, HR, 1.003; 95% CI, 1.000-1.005; P = 0.03). Multivariable Cox regression analysis confirmed ΔPSA (per percentage, HR, 1.004; 95% CI, 1.001-1.006; P = 0.006) as an independent prognosticator for OS. Kaplan-Meier analyses provided significant segregation between individuals with versus those without any PSA response (19 mo vs. 14 mo; HR, 2.00; 95% CI, 0.95-4.18; P = 0.04). Differentiation between patients with or without progressive disease (PD) was also feasible when applying PSA-based PCWG3 (19 mo vs. 9 mo for non-PD and PD, respectively; HR, 2.29; 95% CI, 1.03-5.09; P = 0.01) but slightly failed when applying RECIP 1.0 (P = 0.08). A combination of both response systems (PCWG3 and RECIP 1.0), however, yielded the best discrimination between individuals without versus those with PD (19 mo vs. 8 mo; HR, 2.78; 95% CI, 1.32-5.86; P = 0.002). Conclusion: In patients with mCRPC treated with RLT and imaged with [18F]PSMA-1007, frameworks integrating both the biochemical (PCWG3) and PET-based response (RECIP 1.0) may best assist in identifying subjects prone to disease progression.

177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer: A Review of the Evidence and Implications for Canadian Clinical Practice.

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and a therapeutic target. Lutetium-177 (177Lu)-PSMA-617 is the first radioligand therapy to be approved in Canada for use in patients with metastatic castration-resistant prostate cancer (mCRPC). As this treatment represents a new therapeutic class, guidance regarding how to integrate it into clinical practice is needed. This article aims to review the evidence from prospective phase 2 and 3 clinical trials and meta-analyses of observational studies on the use of 177Lu-PSMA-617 in prostate cancer and discuss how Canadian clinicians might best apply these data in practice. The selection of appropriate patients, the practicalities of treatment administration, including necessary facilities for treatment procedures, the assessment of treatment response, and the management of adverse events are considered. Survival benefits were observed in clinical trials of 177Lu-PSMA-617 in patients with progressive, PSMA-positive mCRPC who were pretreated with androgen receptor pathway inhibitors and taxanes, as well as in taxane-naïve patients. However, the results of ongoing trials are awaited to clarify questions regarding the optimal sequencing of 177Lu-PSMA-617 with other therapies, as well as the implications of predictive biomarkers, personalized dosimetry, and combinations with other therapies.

A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating "BRCAness" Genotype (ROAR).

Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms. This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle. The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI, 0-85.11 months). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen. Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946).

Implementation of PSMA PET/CT and alignment of ordering to SNMMI appropriate use criteria in a large network system.

The Society of Nuclear Medicine and Molecular Imaging (SNMMI) provides appropriate use criteria (AUC) for prostate-specific membrane antigen positron emission tomography/computed tomography(PSMA PET/CT) which include guidance on imaging in newly diagnosed prostate cancer and in patients with biochemically recurrent (BCR) disease. This study aims to examine trends in PSMA implementation and the prevalence and outcomes of scans ordered in scenarios deemed rarely appropriate or not meeting SNMMI AUC. We retrospectively identified patients who were diagnosed with presumptive National Comprehensive Cancer Network unfavorable intermediate, high, or very high risk prostate cancer, patients who underwent staging for BCR, and all patients staged with PSMA between July 2021 and March 2023. Positivity was validated by adherence to a predetermined reference standard. The frequency of PSMA use increased in initial staging from 24% to 80% and work-up of BCR from 91% to 99% over our study period. In addition, 5% (17/340) of PSMA scans ordered for initial staging did not meet AUC and 3% (15/557) of posttreatment scans were deemed rarely appropriate. Initial staging orders not meeting SNMMI AUC resulted in no positivity (0/17), while rarely appropriate posttreatment scans were falsely positive in 75% (3/4) of cases. Urologists (53%, 17/32) comprised the largest ordering specialty in rarely appropriate use. The frequency of PSMA use rose across the study period. A significant minority of patients received PSMA PET/CT in rarely appropriate scenarios yielding no positivity in initial staging and significant false positivity post-therapy. Further education of providers and electronic medical record-based interventions could help limit the rarely appropriate use of PET imaging.

Lutetium-177 Labelled Anti-PSMA Monoclonal Antibody (Lu-TLX591) Therapy for Metastatic Prostate Cancer: Treatment Toxicity and Outcomes.

Whilst prostate cancer is the fourth most common cancer globally, effective therapies for patients with advanced disease are lacking. In recent years, interest in using theranostic agents to treat castrate-resistant prostate cancer (CRPC) and metastatic prostate cancer has emerged. Lu-TLX591 monoclonal antibody is a potential agent of significance; however, to date, reports on its toxicity and efficacy have been limited to small clinical trials in heavily pretreated patients. This retrospective study describes the real-world toxicity and efficacy profile of Lu-TLX591. Eighteen patients received Lu-TLX591 at two private oncology centres in Australia. Patients were eligible if they had CRPC or metastatic prostate cancer and prostate-specific membrane antigen (PSMA)-avid disease confirmed by PSMA-positron emission tomography (PET). Patients received two cycles of Lu-TLX591 monoclonal antibody (177 Lu-DOTA-rosopatamab) each dosed from 1.01-2.85 GBq, 14 days apart. Patient side effects, blood test results and radiology reports were recorded on the patient's electronic medical record (eMR). Prominent side effects included fatigue (55.6%), anorexia (16.7%), nausea (11.1%), and transfusion reactions (11.1%). All-grade haematological toxicities included lymphopenia (61.1%), anaemia (22.2%), leukopenia (27.8%), neutropenia (27.8%), and thrombocytopenia (27.8%). Grade 4 toxicity included lymphopenia (6.7%) and thrombocytopenia (6.7%). Patients' prostate-specific antigen (PSA) responses were as follows; ≥ 30% PSA decline (27.8%), ≥ 50% PSA decline (11.4%) and any PSA decline (38.9%). Follow-up radiology revealed 54.5% stable disease, 45.4% disease progression and 9.1% disease regression. Lu-TLX591 was safely administered at acceptable toxicity and its efficacy reflects previous clinical trials. Larger studies are required and are underway (NCT04786847; NCT05146973; NCT04876651) to determine Lu-TLX591 effectiveness amongst different prostate cancer populations and compare its efficacy against peptide-based radiopharmaceutical agents.

A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer.

Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC). Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed. In all, 133 patients (dose exploration, n = 77; dose expansion, n = 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0-4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0-5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion. Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity.

Abstract A010: Prostate-specific membrane antigen use in glioma management: past, present, and future

Abstract Introduction: Prostate-Specific Membrane Antigen (PSMA) is a type II membrane-bound zinc metallopeptidase expressed in various tissues, including the prostate, renal tubular epithelium, small and large intestinal mucosa, and brain. It plays a role in cell proliferation pathways and folate and glutamate metabolism. PSMA has been utilized for imaging and treatment of prostate cancer and is also expressed in solid tumor neovasculature of other cancers. Gliomas, which are central nervous system neoplasms of glial tissue, represent a challenging group of tumors with limited treatment options due to their invasive nature. PSMA's ability to internalize and location makes it a promising diagnostic and therapeutic target for gliomas. This review synthesizes the literature surrounding the use of PSMA in gliomas to inform current and future directions of study. Methods: A review of the literature was conducted using PubMed and Scopus databases in June 2023. Seventy-one relevant studies, including histopathological, imaging, and therapeutic investigations, were identified. These publications were categorized by year of publication to analyze the evolution of PSMA research in glioma management. Additionally, clinicaltrials.gov was searched for ongoing clinical trials involving PSMA and gliomas. Results: Histopathological studies have demonstrated PSMA's high expression in glioma vasculature, particularly in glioblastoma (GBM), a high-grade glioma (HGG). Studies have investigated PSMA's role in tumor metabolism and its interplay with other tumor markers. Some research suggests that high PSMA expression in GBM endothelium may promote angiogenesis and correlates with poor prognosis. PSMA PET imaging has shown promise in diagnosing and differentiating HGGs and low-grade gliomas (LGGs). Studies have reported high sensitivity and diagnostic accuracy of PSMA PET for HGGs, making it a potentially useful screening tool for radioligand therapy patient selection. Mouse models have also been employed to evaluate the utility of PSMA PET imaging in GBM, with some studies suggesting its application in defining non-enhancing portions of tumors and recurrence volume. PSMA-targeted therapies, particularly PSMA-targeted radiotherapy using radionuclide agents like 177Lu-PSMA-617, have been explored for the treatment of gliomas. Case reports and preliminary studies have demonstrated potential efficacy and tumor response to such therapies, warranting further investigation. Conclusion: The evolving literature indicates that PSMA holds promise as a valuable tool in the diagnosis, prognosis, and treatment of gliomas. Studies have highlighted PSMA PET imaging's high diagnostic accuracy and its potential in patient selection for targeted therapies. However, more research is needed to fully understand the role of PSMA in glioma behavior and to optimize treatment strategies. Ongoing clinical trials and future investigations will further our knowledge of PSMA's potential in managing gliomas and improving patient outcomes. Citation Format: Joshua D. McBriar, Neeva Shafiian, Steven Scharf, A. Gabriella Wernicke. Prostate-specific membrane antigen use in glioma management: past, present, and future [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A010.

Peptide Therapeutics: Unveiling the Potential against Cancer-A Journey through 1989.

The United States Food and Drug Administration (FDA) has approved a plethora of peptide-based drugs as effective drugs in cancer therapy. Peptides possess high specificity, permeability, target engagement, and a tolerable safety profile. They exhibit selective binding with cell surface receptors and proteins, functioning as agonists or antagonists. They also serve as imaging agents for diagnostic applications or can serve a dual-purpose as both diagnostic and therapeutic (theragnostic) agents. Therefore, they have been exploited in various forms, including linkers, peptide conjugates, and payloads. In this review, the FDA-approved prostate-specific membrane antigen (PSMA) peptide antagonists, peptide receptor radionuclide therapy (PRRT), somatostatin analogs, antibody-drug conjugates (ADCs), gonadotropin-releasing hormone (GnRH) analogs, and other peptide-based anticancer drugs are analyzed in terms of their chemical structures and properties, therapeutic targets and mechanisms of action, development journey, administration routes, and side effects.

A multidisciplinary approach to address unmet needs in the management of patients with non-metastatic castration-resistant prostate cancer.

With the availability of second-generation androgen receptor inhibitors (SGARIs), the treatment landscape has changed dramatically for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). In clinical trials, the SGARIs (apalutamide, enzalutamide, darolutamide) increased metastasis-free survival (MFS), overall survival (OS), and patient quality of life compared to placebo. These drugs were subsequently integrated into nmCRPC clinical practice guidelines. With advances in radiographic imaging, disease assessment, and patient monitoring, nmCRPC strategies are evolving to address limitations related to tracking disease progression using prostate-specific antigen (PSA) kinetics. A panel of 10 multidisciplinary experts in prostate cancer conducted reviews and discussions of unmet needs in the management and monitoring of patients with nmCRPC in order to develop consensus recommendations. Across the SGARI literature, patient MFS and OS are generally comparable for all treatments, but important distinctions exist regarding short- and long-term drug safety profiles and drug-drug interactions. With respect to disease monitoring, a substantial proportion of patients using SGARIs may experience disease progression without rising PSA levels, suggesting a need for enhanced radiographic imaging in addition to PSA monitoring. Recent data also indicate that novel prostate-specific membrane antigen positron emission tomography radiotracers provide enhanced accuracy for disease detection, as compared to conventional imaging. Clinical decision-making in nmCRPC has become more complex, with new opportunities to apply precision medicine to patient care. Multidisciplinary teams can ensure that patients with nmCRPC receive optimal and individualized disease management.

A comparison study of 68gallium-prostate-specific membrane antigen positron emission tomography-computed tomography and multiparametric magnetic resonance imaging for locoregional staging of prostate cancer.

Prostate cancer (PCa) is the most common malignancy in men aged 50 years and older and the second cause of cancer death among men. Accurate staging of PCa preoperatively is of high importance for treatment decisions and patient management. Conventional imaging modalities (ultrasound, computed tomography [CT], and magnetic resonance imaging) are inaccurate for the staging of PCa. Newer modality multiparametric magnetic resonance imaging (mpMRI) and prostate-specific membrane antigen (PSMA) positron emission tomography (PET) scan show promising results for the staging of PCa. Only fewer studies are available for comparison of these modalities with histopathology as reference. The objective of our study is to evaluate the diagnostic accuracy of independent 68gallium PSMA (68Ga-PSMA) PET-CT compared with mpMRI for preoperative staging of PCa, using histopathology as the reference standard. From August 2021 to December 2022, 30 patients of biopsy-proven PCa were prospectively enrolled as per eligibility criteria. Preoperatively, 68Ga-PSMA PET scan and mpMRI were done in all the patients. Extracapsular extension (ECE), seminal vesicle invasion (SVI), and lymph node metastasis (LNM) were investigated separately. Subsequently, the patients underwent robotic-assisted radical prostatectomy with bilateral pelvic lymph node dissection. mpMRI prostate was more sensitive (66.66%) but less specific than PSMA PET-CT (55.55%) for ECE. mpMRI and PSMA PET-CT both had similar sensitivity (83.3%) and specificity (87.5%) for SVI. PSMA PET-CT was more sensitive (85.71%) and specific (95.6%) than mpMRI prostate (62.5% and 91.30%, respectively) for LNM. PSMA PET-CT is more specific for the detection of ECE and more sensitive and specific for the detection of LNM than mpMRI, and similar for the detection of SVI. mpMRI provides only local staging, while PSMA PET-CT provides information about local, regional, and distal staging. Overall, PSMA PET-CT is superior to mpMRI for locoregional staging of PCa.

Head-to-head comparison of prostate-specific membrane antigen positron emission tomography/computed tomography and multiparametric magnetic resonance imaging in the detection of biochemical recurrence of prostate cancer: a systematic review and meta-analysis

Our main goal of this meta-analytical analysis was to evaluate the diagnostic effectiveness of prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) against multiparametric magnetic resonance imaging (mpMRI) in the context of identifying biochemical recurrence in patients with prostate cancer (PCa). A thorough search covering articles published until March 2023 was carried out across major databases such as PubMed, Embase, and Web of Science. Studies examining the direct comparison of PSMA PET/CT and mpMRI in patients with PCa suffering biochemical recurrence were included in the inclusion criteria. Using the renowned Quality Assessment of Diagnostic Performance Studies-2 technique, each study's methodological rigor was assessed. We analyzed data from six eligible studies involving 290 patients in total. The combined data showed that for PSMA PET/CT and mpMRI, respectively, the pooled overall detection rates for recurrent PCa after definitive treatment were 0.69 (95% confidence interval [CI]: 0.45-0.89) and 0.70 (95% CI: 0.44-0.91). The detection rates for local recurrence were specifically 0.52 (95% CI: 0.39-0.65) and 0.62 (95% CI: 0.31-0.89), while they were 0.50 (95% CI: 0.26-0.74) and 0.32 (95% CI: 0.18-0.48) for lymph node metastasis. Notably, there was no discernible difference between the two imaging modalities in terms of the overall detection rate (P = 0.95). The detection rates for local recurrence and lymph node metastasis did not differ statistically significantly (P = 0.55, 0.23). The performance of PSMA PET/CT and mpMRI in identifying biochemical recurrence in PCa appears to be comparable. However, the meta-analysis' findings came from research with modest sample sizes. In this context, more extensive research should be conducted in the future.

Copper-mediated astatination of 211At-labelled prostate-specific membrane antigen probes in the presence of basic salts

Highly toxic alpha emitting radionuclide, astatine-211 (211At) labelled compounds have great potential as therapeutic radiopharmaceuticals in the targeted alpha therapy (TAT). Previously we have reported the usefulness of copper (Cu)-mediated radiobromination and radioiodination via boronic acid precursors for the synthesis of 77Br/125I-labelled prostate-specific membrane antigen (PSMA) inhibitors which are applicable as imaging probes. This background led us to investigate the Cu-mediated astatination of PSMA inhibitors as a therapeutic agent for TAT. 211At-labelled PSMA inhibitors [211At]mAtB-PS were synthesised from a boronic acid precursor with tert-butoxycarbonyl groups by Cu-mediated astatination in the presence or absence of NaOH and K2CO3 in order to stabilize the chemical form of At followed by deprotection of the tert-butoxycarbonyl group under acidic condition. We confirmed that [211At]mAtB-PS 1a was synthesised in 64.4–87.3% of overall radiochemical yields (RCYs). These yields are considered acceptable regardless of basic salts existed. However, RCYs of the astatination step differed depending on the base (NaOH: 22.0–31.9%; K2CO3; 69.0–82.3%; without base: 60.1%). We speculated that astatination also occurred during the deprotection of tert-butoxycarbonyl groups. This could be attributed to an electrophilic deboronation reaction involving electrophilic astatine species, resulting in compensation for the overall RCYs. Cu-mediated astatination via boronic precursors was found to be very effective for the synthesis of 211At-labelled PSMA inhibitors for the targeted alpha therapy.

Spatial Pattern of Intraprostatic Recurrence after Definitive External-Beam Radiation Therapy for Prostate Cancer: Implications for Focal Boost to Intraprostatic Dominant Lesion

Background/PurposeWe retrospectively investigated spatial pattern associations between primary and recurrent tumor sites following definitive external-beam radiation therapy (EBRT) for prostate cancer, using positron emission tomography/computed tomography (PET/CT) with a prostate-specific membrane antigen (PSMA)-targeted probe, 18F-FSU-880. MethodsAmong the patients who received PET/CT with 18F-FSU-880 in a phase 2 trial, which evaluated the tumor detection efficacy of PSMA-PET/CT for recurrent prostate cancer, patients with local intra-prostatic recurrence detected by PSMA-PET/CT following definitive EBRT were retrospectively analyzed. The prostate and seminal vesicles were divided into 14 sections in total. Two diagnostic radiologists separately re-evaluated the intra-prostatic location of the primary tumor on magnetic-resonance imaging and that of the recurrent tumor on PSMA-PET/CT, respectively, and the rate of overlap between primary and recurrent tumors was calculated. The overlap rate was defined as “the number of sections which overlapped between the primary tumor and recurrent tumor” divided by “the total number of sections of recurrent tumor”. A recurrent tumor was considered to be at the same location with an overlap rate equal to or greater than 75%, and a partial overlap was defined as an overlap rate between 25 and 74%. ResultsTwelve patients had local recurrence detected by PSMA-PET/CT. The median time to the diagnosis of local recurrence was 9.1 (range: 2.2–12.3) years after definitive EBRT.The recurrent tumor was detected at the same location in 25.0%, and a partial overlap was noted in 41.7%. ConclusionsLocal intra-prostatic recurrence after definitive EBRT often occurs at the same site or at a partially overlapping site adjacent to the primary IPDL. Our results support the merit of focal dose-escalation for intra-prostatic dominant lesions in definitive EBRT.

Re: First-in-human Evaluation of a Prostate-specific Membrane Antigen–targeted Near-infrared Fluorescent Small Molecule for Fluorescence-based Identification of Prostate Cancer in Patients with High-risk Prostate Cancer Undergoing Robotic-assisted Prostatectomy

Re: First-in-human Evaluation of a Prostate-specific Membrane Antigen–targeted Near-infrared Fluorescent Small Molecule for Fluorescence-based Identification of Prostate Cancer in Patients with High-risk Prostate Cancer Undergoing Robotic-assisted Prostatectomy

Deep Semisupervised Transfer Learning for Fully Automated Whole-Body Tumor Quantification and Prognosis of Cancer on PET/CT.

Automatic detection and characterization of cancer are important clinical needs to optimize early treatment. We developed a deep, semisupervised transfer learning approach for fully automated, whole-body tumor segmentation and prognosis on PET/CT. Methods: This retrospective study consisted of 611 18F-FDG PET/CT scans of patients with lung cancer, melanoma, lymphoma, head and neck cancer, and breast cancer and 408 prostate-specific membrane antigen (PSMA) PET/CT scans of patients with prostate cancer. The approach had a nnU-net backbone and learned the segmentation task on 18F-FDG and PSMA PET/CT images using limited annotations and radiomics analysis. True-positive rate and Dice similarity coefficient were assessed to evaluate segmentation performance. Prognostic models were developed using imaging measures extracted from predicted segmentations to perform risk stratification of prostate cancer based on follow-up prostate-specific antigen levels, survival estimation of head and neck cancer by the Kaplan-Meier method and Cox regression analysis, and pathologic complete response prediction of breast cancer after neoadjuvant chemotherapy. Overall accuracy and area under the receiver-operating-characteristic (AUC) curve were assessed. Results: Our approach yielded median true-positive rates of 0.75, 0.85, 0.87, and 0.75 and median Dice similarity coefficients of 0.81, 0.76, 0.83, and 0.73 for patients with lung cancer, melanoma, lymphoma, and prostate cancer, respectively, on the tumor segmentation task. The risk model for prostate cancer yielded an overall accuracy of 0.83 and an AUC of 0.86. Patients classified as low- to intermediate- and high-risk had mean follow-up prostate-specific antigen levels of 18.61 and 727.46 ng/mL, respectively (P < 0.05). The risk score for head and neck cancer was significantly associated with overall survival by univariable and multivariable Cox regression analyses (P < 0.05). Predictive models for breast cancer predicted pathologic complete response using only pretherapy imaging measures and both pre- and posttherapy measures with accuracies of 0.72 and 0.84 and AUCs of 0.72 and 0.76, respectively. Conclusion: The proposed approach demonstrated accurate tumor segmentation and prognosis in patients across 6 cancer types on 18F-FDG and PSMA PET/CT scans.

Development and Preclinical Evaluation of [211At]PSAt-3-Ga: An Inhibitor for Targeted α-Therapy of Prostate Cancer.

The application of prostate-specific membrane antigen (PSMA)-targeted α-therapy is a promising alternative to β--particle-based treatments. 211At is among the potential α-emitters that are favorable for this concept. Herein, 211At-based PSMA radiopharmaceuticals were designed, developed, and evaluated. Methods: To identify a 211At-labeled lead, a surrogate strategy was applied. Because astatine does not exist as a stable nuclide, it is commonly replaced with iodine to mimic the pharmacokinetic behavior of the corresponding 211At-labeled compounds. To facilitate the process of structural design, iodine-based candidates were radiolabeled with the PET radionuclide 68Ga to study their preliminary in vitro and in vivo properties before the desired 211At-labeled lead compound was formed. The most promising candidate from this evaluation was chosen to be 211At-labeled and tested in biodistribution studies. Results: All 68Ga-labeled surrogates displayed affinities in the nanomolar range and specific internalization in PSMA-positive LNCaP cells. PET imaging of these compounds identified [68Ga]PSGa-3 as the lead compound. Subsequently, [211At]PSAt-3-Ga was synthesized in a radiochemical yield of 35% and showed tumor uptake of 19 ± 8 percentage injected dose per gram of tissue (%ID/g) at 1 h after injection and 7.6 ± 2.9 %ID/g after 24 h. Uptake in off-target tissues such as the thyroid (2.0 ± 1.1 %ID/g), spleen (3.0 ± 0.6 %ID/g), or stomach (2.0 ± 0.4 %ID/g) was low, indicating low invivo deastatination of [211At]PSAt-3-Ga. Conclusion: The reported findings support the use of iodine-based and 68Ga-labeled variants as a convenient strategy for developing astatinated compounds and confirm [211At]PSAt-3 as a promising radiopharmaceutical for targeted α-therapy.

Single-Time-Point Renal Dosimetry Using Nonlinear Mixed-Effects Modeling and Population-Based Model Selection in [177Lu]Lu-PSMA-617 Therapy.

The aim of this study was to investigate the accuracy of single-time-point (STP) renal dosimetry imaging using SPECT/CT data, a nonlinear mixed-effects (NLME) model, and a population-based model selection (PBMS) in a large population for 177Lu-labeled prostate-specific membrane antigen therapy. Methods: Biokinetic data (mean ± SD) of [177Lu]Lu-PSMA-617 in kidneys at time points 1 (1.8 ± 0.8 h), 2 (18.7 ± 0.9 h), 3 (42.6 ± 1.0 h), 4 (66.3 ± 0.9 h), and 5 (160.3 ± 24.2 h) after injection were obtained from 63 patients with metastatic castration-resistant prostate cancer using SPECT/CT. Thirteen functions were derived from various parameterizations of 1- to 5-exponential functions. The function's parameters were fitted in the NLME framework to the all-time-point (ATP) data. The PBMS NLME method was performed using the goodness-of-fit test and Akaike weight to select the best function fitting the data. The best function from ATP fitting was used to calculate the reference time-integrated activity and absorbed doses. In STP dosimetry, the parameters of a particular patient with STP data were fitted simultaneously to the STP data at different time points of that patient with ATP data of all other patients. The parameters from STP fitting were used to calculate the STP time-integrated activity and absorbed doses. Relative deviations (RDs) and root-mean-square errors (RMSEs) were used to analyze the accuracy of the calculated STP absorbed dose compared with the reference absorbed dose obtained from the best-fit ATP function. The performance of STP dosimetry using PBMS NLME modeling was compared with the Hänscheid and Madsen methods. Results: The function [Formula: see text] was selected as the best-fit ATP function, with an Akaike weight of 100%. For STP dosimetry, the STP measurement by SPECT/CT at time point 3 (42.6 ± 1.0 h) showed a relatively low mean RD of -4.4% ± 9.4% and median RD of -0.7%. Time point 3 had the lowest RMSE value compared with those at the other 4 time points. The RMSEs of the absorbed dose RDs for time points 1-5 were 23%, 16%, 10%, 20%, and 53%, respectively. The STP dosimetry using the PBMS NLME method outperformed the Hänscheid and Madsen methods for all investigated time points. Conclusion: Our results show that a single measurement of SPECT/CT at 2 d after injection might be used to calculate accurate kidney-absorbed doses using the NLME method and PBMS.

Current Status of Prostate-specific Membrane Antigen-targeted Alpha Radioligand Therapy in Prostate Cancer.

Prostate cancer (PCa) is the most prevalent malignancy and leading cause of mortality in men. Despite the development of various drugs, such as novel androgen receptor signaling inhibitors and poly adenosine diphosphate-ribose polymerase inhibitors targeting homologous recombination repair-related genetic mutations, prognosis of metastatic castration-resistant prostate cancer remains unfavorable. However, recent advances in nuclear medicine have allowed for both imaging diagnostics and therapeutic interventions by targeting molecules specifically expressed in cancer cells with radioisotopes (RI). γ-rays are used in nuclear medicine imaging, whereas in therapy, α or β-emitting RIs are administered to target cells in radiation therapy. PCa, in particular, exhibits the characteristic features of radioligand therapy, as the membrane protein prostate-specific membrane antigen (PSMA) is proportionally highly expressed in malignancy compared to normal tissues. The administered RI-labeled compound binds to PSMA, enabling specific targeting of PCa for treatment. Unlike β-rays, α-rays have a shorter range and impart stronger energy to DNA, allowing α-particles to exhibit a higher linear energy transfer. Due to such characteristics, PSMA-targeted α radiotherapy is expected to have potent cytotoxic effects and fewer side effects on normal organs, making them more likely to be widely adopted in the future. However, reports on PSMA-targeted α radiotherapy differ in aspects, such as prior PSMA-targeted β radiotherapy, the administered doses, and the number of treatment cycles. Therefore, in this review, we compile the reports on treatments utilizing α-emitting isotopes targeting PSMA in patients with PCa.

"One Method to Label Them All": A Single Fully Automated Protocol for GMP-Compliant 68Ga Radiolabeling of PSMA-11, Transposable to PSMA-I&T and PSMA-617.

Prostate-specific membrane antigen (PSMA) is an ideal target for molecular imaging and targeted radionuclide therapy in prostate cancer. Consequently, various PSMA ligands were developed. Some of these molecules are functionalized with a chelator that can host radiometals, such as 68Ga for PET imaging. The 68Ga radiolabeling step benefits from process automation, making it more robust and reducing radiation exposure. To design a single automated radiolabeling protocol for the GMP-compliant preparation of [68Ga]Ga-PSMA-11, transposable to the production of [68Ga]Ga-PSMA-617 and [68Ga]Ga-PSMA-I&T. A GAIA® synthesis module and a GALLIAD® generator were used. Radio-TLC and radio-HPLC methods were validated for radiochemical purity (RCP) determination. Three [68Ga]Ga-PSMA-11 validation batches were produced and thoroughly tested for appearance and pH, radionuclide identity and purity, RCP, stability, residual solvent and sterility. Minimal modifications were made to the reagents and disposables for optimal application to other PSMA ligands. [68Ga]Ga-PSMA-11 for clinical application was produced in 27 min. The 3 validation batches met the quality criteria expected by the European Pharmacopoeia to allow routine production. For optimal transposition to PSMA-617, the solid phase extraction cartridge was changed to improve purification of the radiolabeled product. For application to PSMA-I&T, the buffer solution initially used was replaced by HEPES 2.7 M to achieve good radiochemical yields. Residual HEPES content was checked in the final product and was below the Ph. Eur. threshold. A single automated radiolabeling method on the GAIA® module was developed and implemented for 68Ga radiolabeling of 3 PSMA ligands, with slight adjustments for each molecule.

Atypical neoplastic solitary focal uptake of 18F-PSMA-1007 in PET/CT in patients with biochemically recurrent prostate cancer

It is established that prostate-specific membrane antigen (PSMA), despite its name, is expressed in many tissues other than the prostate gland, both within physiological conditions and in various pathological processes. Additionally, apart from prostate cancer, other malignant tumors are characterized by increased PSMA expression which, according to many authors, is associated with neoangiogenesis. These factors are reflected in the results of PSMA-radioligand imaging and require comprehensive approach to image interpretation including evaluation of computed tomography and magnetic resonance semiotics. In addition, rare cases of distant visceral prostate cancer metastasis in the form of solitary lesions also should be considered during interpretation of the results of radiologic imaging including positron emission tomography/computed tomography.We present two clinical cases in which positron emission tomography/computed tomography revealed solitary foci of pathological 18F-PSMA-1007 uptake outside the areas of typical metastatic spread (with exception of advanced disease) of prostate cancer, specifically in the stomach wall and the left cerebellar hemisphere. In the first case histological examination results revealed a metachronous low grade neuroendocrine tumor of the stomach, in the second case a metastatic lesion of the cerebellum was diagnosed as part of the underlying disease.