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The Journal of Urology Aug 2023
Point-Counterpoint: Staging Prostate-specific Membrane Antigen Positron Emission Tomography/Computerized Tomography for Detecting Clinically Node Positive Prostate Cancer.
Topics: Male; Humans; Prostate; Prostatic Neoplasms; Positron-Emission Tomography; Positron Emission Tomography Computed Tomography; Neoplasm Staging; Prostate-Specific Antigen
PubMed: 37194136
DOI: 10.1097/JU.0000000000003495 -
European Urology Oct 2023
Prostate-specific Membrane Antigen Imaging Remains True to its Name in Primary Staging of Prostate Cancer: The Time To Characterize its Impact on Clinical Outcomes Is Now.
Topics: Male; Humans; Prostate; Prostatic Neoplasms; Neoplasm Staging; Gallium Radioisotopes; Prostate-Specific Antigen
PubMed: 37517942
DOI: 10.1016/j.eururo.2023.07.007 -
Lakartidningen Apr 2024Prostate-specific antigen (PSA) based screening is controversial, even though randomised trials show that screening can reduce prostate cancer mortality. The main reason... (Review)
Review
Prostate-specific antigen (PSA) based screening is controversial, even though randomised trials show that screening can reduce prostate cancer mortality. The main reason is that screening leads to overdiagnosis of indolent cancers that would never have surfaced clinically in the absence of screening. Recently, several large studies have shown that magnetic resonance imaging (MRI) improves prostate cancer diagnostics. With MRI, up to half of all men with elevated PSA values can be spared a biopsy. When a biopsy is needed, the needles can be directed towards the suspicious area in the prostate, which increases the detection of clinically significant tumors. In Sweden, regional programmes with organised prostate cancer testing were introduced in 2020. These programmes aim to make prostate cancer testing more standardized, efficient, and equitable. In the future, biomarkers and AI-based systems will likely be important to further improve prostate cancer diagnostics.
Topics: Humans; Prostatic Neoplasms; Male; Prostate-Specific Antigen; Early Detection of Cancer; Magnetic Resonance Imaging; Sweden; Mass Screening; Biopsy; Biomarkers, Tumor
PubMed: 38647107
DOI: No ID Found -
Frontiers in Immunology 2023In oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and...
INTRODUCTION
In oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy. These drugs whose mode of action is expected to potently stimulate anti-tumor immunity, may potentially induce ADAs as an unintended corollary due to an overall augmentation of the immune response. ADA formation is therefore emerging as an important determinant in the successful clinical development of such biologics.
METHODS
Here we describe the immunogenicity and its impact observed to pasotuxizumab (AMG 212), a prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) molecule in NCT01723475, a first-in-human (FIH), multicenter, dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). To explain the disparity in ADA incidence observed between the SC and CIV arms of the study, we interrogated other patient and product-specific factors that may have explained the difference beyond the route of administration.
RESULTS
Treatment-emergent ADAs (TE-ADA) developed in all subjects treated with at least 1 cycle of AMG 212 in the subcutaneous (SC) arm. These ADAs were neutralizing and resulted in profound exposure loss that was associated with contemporaneous reversal of initial Prostate Surface Antigen (PSA) responses, curtailing durability of PSA response in patients. Pivoting from SC to a continuous intravenous (CIV) administration route remarkably yielded no subjects developing ADA to AMG 212. Through a series of stepwise functional assays, our investigation revealed that alongside a more historically immunogenic route of administration, non-tolerant T cell epitopes within the AMG 212 amino acid sequence were likely driving the high-titer, sustained ADA response observed in the SC arm.
DISCUSSION
These mechanistic insights into the AMG 212 ADA response underscore the importance of performing preclinical immunogenicity risk evaluation as well as advocate for continuous iteration to better our biologics.
Topics: Male; Humans; Prostate; Root Cause Analysis; Prostate-Specific Antigen; Antibodies; Antigens, Surface; T-Lymphocytes; Biological Products
PubMed: 37942314
DOI: 10.3389/fimmu.2023.1261070 -
European Urology Oncology Jun 2024The European Association of Urology guidelines include the lutetium-177 (Lu) PSMA-617 prostate-specific membrane antigen (PSMA) ligand as a therapy option for metastatic... (Observational Study)
Observational Study
Real-world Outcomes and Predictive Biomarkers for Lutetium Prostate-specific Membrane Antigen Ligand Treatment in Metastatic Castration-resistant Prostate Cancer: A European Association of Urology Young Academic Urologists Prostate Cancer Working Group Multi-institutional Observational Study.
BACKGROUND
The European Association of Urology guidelines include the lutetium-177 (Lu) PSMA-617 prostate-specific membrane antigen (PSMA) ligand as a therapy option for metastatic castration-resistant prostate cancer (mCRPC). A major challenge in clinical practice is to pursue a personalized treatment approach based on robust predictive biomarkers.
OBJECTIVE
To assess the performance of Lu PSMA in real-world practice and to elaborate clinical biomarkers for evaluating treatment responses.
DESIGN, SETTING, AND PARTICIPANTS
We conducted a retrospective observational study including 233 patients with mCRPC treated with Lu PSMA in eight high-volume European centers.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Baseline characteristics and clinical parameters during and after Lu PSMA treatment were documented. Correlations to treatment response were analyzed using χ and log-rank tests, with differences between groups with and without disease progression calculated using a Mann-Whitney U test. Univariate and multivariate-adjusted hazard ratios (HRs) were measured using Cox proportional hazards models.
RESULTS AND LIMITATIONS
A prostate-specific antigen (PSA) decrease of ≥30% was observed in 41.7%, 63.5%, and 77.8% of patients after the first, second, and third treatment cycle, respectively. Restaging performed via PSMA positron emission tomography-computed tomography revealed that 33.7% of patients had an imaging-based response, including two patients with a complete response, while 13.4% had stable disease. The median time to progression was 5 mo and the median time until the start of a consecutive antineoplastic therapy was 8.5 mo. Of importance, a PSA decrease ≥30% after the first two cycles of Lu PSMA (1 cycle: p = 0.0003; 2 cycles: p = 0.004), absolute PSA after the first three cycles (1 cycle: p = 0.011; 2 cycles: p = 0.0005; 3 cycles: p = 0.002), and a PSA doubling time >6 mo (p = 0.009) were significantly correlated to treatment response. Furthermore, gamma-glutamyl transferase ≤31 U/L at the start of Lu PSMA therapy was correlated with 1.5 times higher risk of progression for patients without but not with visceral metastases (p = 0.046).
CONCLUSIONS
Lu PSMA is an effective treatment option in mCRPC in the real-world setting. A PSA decrease ≥30% after the first two cycles is an early marker of response that can be easily implemented in clinical practice.
PATIENT SUMMARY
Lu PSMA is a radioactive agent approved for treatment of advanced prostate cancer. We reviewed its use outside of clinical trials for patients treated at eight European centers. We found that Lu PSMA is an effective treatment option in real-world practice. A PSA (prostate-specific antigen) decrease of ≥30% after the first two therapy cycles is an early indicator of response to treatment and can be used in personalizing treatments for patients.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Aged; Lutetium; Treatment Outcome; Biomarkers, Tumor; Middle Aged; Europe; Radioisotopes; Glutamate Carboxypeptidase II; Antigens, Surface; Aged, 80 and over; Prostate-Specific Antigen; Ligands; Neoplasm Metastasis
PubMed: 37604763
DOI: 10.1016/j.euo.2023.07.018 -
Urologie (Heidelberg, Germany) Nov 2023Prostate-specific membrane antigen (PSMA) hybrid imaging is a promising new technique gaining importance in the field of prostate cancer (PCa) diagnosis and treatment... (Review)
Review
Prostate-specific membrane antigen (PSMA) hybrid imaging is a promising new technique gaining importance in the field of prostate cancer (PCa) diagnosis and treatment planning. By combining PSMA radioligands and computed tomography (CT) or magnetic resonance imaging (MRI), PSMA hybrid imaging opens up new diagnostic opportunities. PSMA-PET/CT (PET: positron-emission tomography) is already well established in high-risk PCa for primary staging and tumor localization when biochemical recurrence occurs. Further potential indications for PSMA-PET/CT include tumor detection in the initial work-up before a rebiopsy with improved accuracy, the identification of target structures for precise local treatment in recurrent PCa (salvage radiotherapy or radio-guided surgery) as well as a prediction of response to PSMA radioligand therapy. This narrative review is based on a recent literature search and aims to highlight the opportunities of PSMA imaging in different disease stages of PCa.
Topics: Male; Humans; Prostate; Positron Emission Tomography Computed Tomography; Prostatic Neoplasms; Prostate-Specific Antigen; Positron-Emission Tomography
PubMed: 37702749
DOI: 10.1007/s00120-023-02189-z -
The Science of the Total Environment Jul 2024The presence of perfluoroalkyl and polyfluoroalkyl substances (PFAS) in various everyday products has raised concerns about their potential impact on prostate health....
The presence of perfluoroalkyl and polyfluoroalkyl substances (PFAS) in various everyday products has raised concerns about their potential impact on prostate health. This study aimed to investigate the effects of different types of PFAS on prostate health, including PFDeA, PFOA, PFOS, PFHxS, and PFNA. To assess the relationship between PFAS exposure and prostate injury, machine learning algorithms were employed to analyze prostate-specific antigen (PSA) metrics. The analysis revealed a linear and positive dose-dependent association between PFOS and the ratio of free PSA to total PSA (f/tPSA). Non-linear dose-response relationships were observed between the other four types of PFAS and the f/tPSA ratio. Additionally, the analysis showed a positive association between the mixture of PFAS and prostate hyperplasia, with PFNA having the highest impact followed by PFOS. These findings suggest that elevated serum levels of PFDeA, PFOA, PFOS, and PFNA are linked to prostate hyperplasia. Therefore, this study utilized advanced machine learning techniques to uncover potential hazardous effects of PFAS exposure on prostate health, specifically the positive association between PFAS and prostate hyperplasia.
Topics: Male; Fluorocarbons; Humans; Prostatic Hyperplasia; Environmental Exposure; Environmental Pollutants; Machine Learning; Alkanesulfonic Acids; Prostate-Specific Antigen
PubMed: 38729377
DOI: 10.1016/j.scitotenv.2024.173085 -
International Journal of Molecular... Aug 2023Prostate-specific membrane antigen (PSMA)-based imaging improved the detection of primary, recurrent and metastatic prostate cancer. However, in certain patients, a low...
Prostate-specific membrane antigen (PSMA)-based imaging improved the detection of primary, recurrent and metastatic prostate cancer. However, in certain patients, a low PSMA surface expression can be a limitation for this promising diagnostic tool. Pharmacological induction of PSMA might be useful to further improve the detection rate of PSMA-based imaging. To achieve this, we tested dutasteride (Duta)-generally used for treatment of benign prostatic enlargement-and lovastatin (Lova)-a compound used to reduce blood lipid concentrations. We aimed to compare the individual effects of Duta and Lova on cell proliferation as well as PSMA expression. In addition, we tested if a combination treatment using lower concentrations of Duta and Lova can further induce PSMA expression. Our results show that a treatment with ≤1 μM Duta and ≥1 μM Lova lead to a significant upregulation of whole and cell surface PSMA expression in LNCaP, C4-2 and VCaP cells. Lower concentrations of Duta and Lova in combination (0.5 μM Duta + 0.5 μM Lova or 0.5 μM Duta + 1 μM Lova) were further capable of enhancing PSMA protein expression compared to a single compound treatment using higher concentrations in all tested cell lines (LNCaP, C4-2 and VCaP).
Topics: Male; Humans; Dutasteride; Prostate; Lovastatin; Glutamate Carboxypeptidase II; Antigens, Surface; Prostatic Neoplasms; Prostate-Specific Antigen; Cell Line, Tumor
PubMed: 37569712
DOI: 10.3390/ijms241512338 -
Irish Journal of Medical Science Dec 2023To investigate the value of serum free prostate-specific antigen density (fPSAD) in the diagnosis of prostate cancer (PCa).
PURPOSE
To investigate the value of serum free prostate-specific antigen density (fPSAD) in the diagnosis of prostate cancer (PCa).
METHODS
The data of 558 patients who underwent transrectal ultrasound-guided prostate biopsy were retrospectively analyzed. According to the pathological results, the patients were divided into a PCa group and a benign prostatic hyperplasia (BPH) group. Receiver operating characteristic curves were plotted, based on which the sensitivity, specificity, Youden index, concordance, and kappa values of free prostate-specific antigen (fPSA), the free-to-total f/tPSA, prostate-specific antigen density (PSAD), the free-to-total (f/t)/PSAD ratio, and fPSAD were compared. The patients were divided into three groups by PSA levels (PSA < 4 ng/mL, PSA = 4-10 ng/mL, and PSA > 10 ng/mL), into three groups by age (age < 60 year, age = 60-80y, and age > 80 years), and into two groups by prostate volume (PV) (PV ≤ 80 mL and PV > 80 mL) to compare the sensitivity, specificity, and concordance of indicators.
RESULTS
tPSA, PSAD, (f/t)/PSAD, and fPSAD had high accuracy in predicting PCa with AUC values of 0.820, 0.900, 0.846, and 0.867. fPSAD showed lower diagnostic sensitivity but significantly higher specificity and concordance for PCa than tPSA, f/tPSA, (f/t)/PSAD, or PSAD. Thus, fPSAD had the highest accuracy in the diagnosis of PCa. In the groups with different PSA, age, and PV stratification, the concordance of fPSAD was significantly higher (88.61%, 90.74%, and 90.38%) than that of other indicators.
CONCLUSION
With the optimal cutoff value of 0.062, fPSAD has a higher diagnostic value for PCa than tPSA, f/tPSA, (f/t)/PSAD, and PSAD, and can well predict the risk of PCa, significantly improve the clinical diagnostic rate of PCa, and reduce unnecessary biopsy.
Topics: Male; Humans; Middle Aged; Prostate-Specific Antigen; Retrospective Studies; Prostatic Neoplasms; Prostate; Prostatic Hyperplasia; ROC Curve; Sensitivity and Specificity
PubMed: 37414978
DOI: 10.1007/s11845-023-03448-w -
European Urology Jun 2024Previously, we demonstrated that prostate-specific membrane antigen positron emission tomography (PSMA-PET) revealed distant metastases in 109/200 patients (39% distant...
Prostate-specific Membrane Antigen Positron Emission Tomography-detected Disease Extent and Overall Survival of Patients with High-risk Nonmetastatic Castration-resistant Prostate Cancer: An International Multicenter Retrospective Study.
Previously, we demonstrated that prostate-specific membrane antigen positron emission tomography (PSMA-PET) revealed distant metastases in 109/200 patients (39% distant nodes, 24% bone, and 6% visceral organ) with nonmetastatic castration-resistant prostate cancer (nmCRPC) and high-risk features (International Society of Urological Pathology score ≥4 and/or prostate-specific antigen doubling time ≤10 mo) without metastases by conventional imaging. However, the impact of disease extent determined by PSMA-PET on patient outcomes is unknown. We followed these 200 patients for a median of 43 mo after PSMA-PET and retrospectively assessed the association between patient characteristics, PSMA-PET findings, treatment management, and outcomes using a Kaplan-Meier model and Cox multivariable regressions. Among assessed disease characteristics, polymetastatic disease (five or more distant lesions on PET) was independently associated with shorter overall survival (OS; median 61 mo vs not reached; hazard ratio [95% confidence interval], 1.81 [1.00-3.27]; p = 0.050) and time to new metastases (median 38 vs 60 mo; 1.80 [1.10-2.96]; p = 0.019), and initial pN1 status with shorter OS (55 mo vs not reached; 1.94 [1.12-3.37]; p = 0.019). Following PSMA-PET, locoregional salvage therapies were used most commonly in no/local disease (58%), and androgen receptor signaling inhibitors were used in distant metastatic disease (51%). PSMA-PET provides additional risk stratification for patients with nmCRPC. Polymetastatic disease (five or more distant lesions) is associated with worse outcomes. PATIENT SUMMARY: A novel sensitive imaging technology, called prostate-specific membrane antigen positron emission tomography (PSMA-PET), allows doctors to detect the spread of prostate cancer, known as distant metastases, earlier and more accurately than in the past. In our study, PSMA-PET detected none to many metastases in patients who were considered free of distant metastasis by conventional imaging. These findings predicted outcomes and were used to select appropriate treatment.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Aged; Positron-Emission Tomography; Middle Aged; Glutamate Carboxypeptidase II; Antigens, Surface; Prostate-Specific Antigen; Aged, 80 and over
PubMed: 38490855
DOI: 10.1016/j.eururo.2024.01.019