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Antibody‐drug conjugates (ADCs) represent a novel type of targeted cancer therapy combining the specificity of monoclonal antibodies with the cytotoxicity of conventional chemotherapy. Recently, ADCs have demonstrated practice‐changing efficacy across diverse solid cancers. The anti‐NECTIN‐4 ADC enfortumab vedotin (EV) has just been approved for patients with urothelial cancer and is currently under investigation for patients with castration‐resistant prostate cancer (CRPC e.g. Phase II ENCORE trial). Our objective was to evaluate the efficacy of EV in established prostate cancer (PCa) cell lines and to examine the membranous NECTIN‐4 expression in primary tumours (PRIM) and distant metastases (MET). NECTIN‐4 was heterogeneously expressed in the panel of PCa cell lines. EV led to growth inhibition in NECTIN‐4 expressing PCa cells (22Rv1 and LNCaP), whereas the NECTIN‐4‐negative PC‐3 cells were significantly less responsive to EV, emphasizing the dependence of EV response on its target expression. Immunohistochemical staining revealed moderate membranous NECTIN‐4 expression only in a small subgroup of CRPC patients with lung and peritoneal MET [n = 3/22 with H‐score ≥100, median H‐score 140 (IQR 130–150)], while 100% of PRIM (n = 48/48) and 86.4% of common MET sites (n = 19/22), including lymph node, bone and liver MET, were NECTIN‐4 negative. In summary, EV may be effective in NECTIN‐4‐positive PCa. However, our findings demonstrate that the tumoural NECTIN‐4 expression is predominantly low in metastatic PCa, which suggests that EV may only be effective in a biomarker‐stratified subgroup. [ABSTRACT FROM AUTHOR]

Purpose: Improved survival rates have been observed in castration‐resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody‐drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop‐2 and NECTIN‐4 in cerebral metastasized CRPC (mCRPC). Methods: Immunohistochemical staining of Trop‐2 and NECTIN‐4 with evaluation of H‐score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop‐2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti‐Trop‐2 ADC Sacituzumab govitecan (SG) in vitro. Results: Our analysis revealed that most patients exhibited moderate to strong Trop‐2 expression [n = 27/31 with H‐score ≥100, median H‐score 220 (IQR 180–280)], while NECTIN‐4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop‐2 expression levels in vitro. Overexpression of Trop‐2 in Trop‐2‐negative PC‐3 cells led to sensitization to SG, whereas CRISPR‐Cas9‐mediated knockdown of Trop‐2 in Trop‐2‐expressing DU‐145 cells conferred resistance to SG. Conclusion: The substantial expression of Trop‐2 in cerebral metastases, along with our preclinical in vitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases. [ABSTRACT FROM AUTHOR]

Objective: Utilizing personalized risk assessment for clinically significant prostate cancer (csPCa) incorporating multiparametric magnetic resonance imaging (mpMRI) reduces biopsies and overdiagnosis. We validated both multi- and univariate risk models in biopsy-naïve men, with and without the inclusion of mpMRI data for csPCa detection. Methods: N = 565 men underwent mpMRI-targeted prostate biopsy, and the diagnostic performance of risk calculators (RCs), mpMRI alone, and clinical measures were compared using receiver operating characteristic curve (ROC) analysis and decision curve analysis (DCA). Subgroups were stratified based on mpMRI findings and quality. Results: csPCa was detected in 56.3%. PI-RADS score achieved the highest area under the curve (AUC) when comparing univariate risk models (AUC 0.82, p < 0.001). Multivariate RCs showed only marginal improvement in csPCa detection compared to PI-RADS score alone, with just one of four RCs showing significant superiority. In mpMRI-negative cases, the non-MRI-based RC performed best (AUC 0.80, p = 0.016), with the potential to spare biopsies for 23%. PSA-density and multivariate RCs demonstrated comparable performance for PI-RADS 3 constellation (AUC 0.65 vs. 0.60–0.65, p > 0.5; saved biopsies 16%). In men with suspicious mpMRI, both mpMRI-based RCs and the PI-RADS score predicted csPCa excellently (AUC 0.82–0.79 vs. 0.80, p > 0.05), highlighting superior performance compared to non-MRI-based models (all p < 0.002). Quality-assured imaging consistently improved csPCa risk stratification across all subgroups. Conclusion: In tertiary centers serving a high-risk population, high-quality mpMRI provides a simple yet effective way to assess the risk of csPCa. Using multivariate RCs reduces multiple biopsies, especially in mpMRI-negative and PI-RADS 3 constellation. [ABSTRACT FROM AUTHOR]

This article discusses the relevance of circular RNAs (circRNAs) in the serum of patients undergoing prostate biopsy. circRNAs are a type of stable non-coding RNA that are associated with various diseases, including cancer. The study enrolled 96 patients scheduled for prostate biopsy and found that the levels of circulating circRNAs were not significantly different in patients with prostate cancer compared to those without cancer. However, the levels of serum circZMIZ1 were significantly increased in patients with metastatic prostate cancer. The study suggests that circZMIZ1 could serve as a prognostic biomarker and a potential treatment target for metastatic prostate cancer. [Extracted from the article]

Simple Summary: FBXO45 plays a role in the regulation of apoptosis through the ubiquitylation and degradation of specific target proteins. While FBXO45 has been suggested to have prognostic potential in various cancers, its specific role in prostate carcinoma (PCA) remains unclear. Transcriptome data concerning FBXO45 were analysed using The Cancer Genome Atlas (TCGA) and a publicly available Gene Expression Omnibus (GEO) progression PCA cohort. In addition, FBXO45 protein expression was evaluated using immunohistochemistry in a large cohort of PCA tissue microarrays. It was demonstrated that high FBXO45 expression was associated with advanced stages of PCA and biochemical recurrence. Shortened progression-free survival was associated with strong FBX045 staining, especially in TMPRSS2–ERG-positive PCA. In vitro experiments demonstrated that FBXO45 knockdown led to a significant reduction in migration capacity in the PC-3, DU-145 and LNCaP cell lines. These findings suggest that FBXO45 may serve as a promising biomarker for PCA and exhibit oncogenic properties. Background: F-box/SPRY domain-containing protein 1 (FBXO45) plays a crucial role in the regulation of apoptosis via the ubiquitylation and degradation of specific targets. Recent studies indicate the prognostic potential of FBXO45 in several cancers. However, its specific role in prostate carcinoma remains unclear. Methods: A systematic analysis of FBXO45 mRNA expression in PCA was performed using The Cancer Genome Atlas database and a publicly available Gene Expression Omnibus progression PCA cohort. Subsequently, FBXO45 protein expression was assessed via immunohistochemical analysis of a comprehensive tissue microarray cohort. The expression data were correlated with the clinicopathological parameters and biochemical-free survival. The immunohistochemical analyses were stratified according to the TMPRSS2–ERG rearrangement status. To assess the impact of FBXO45 knockdown on the tumour proliferation capacity of cells and metastatic potential, transfection with antisense-oligonucleotides was conducted within a cell culture model. Results: FBXO45 mRNA expression was associated with adverse clinicopathological parameters in the TCGA cohort and was enhanced throughout progression to distant metastasis. FBXO45 was associated with shortened biochemical-free survival, which was pronounced for the TMPRSS2–ERG-positive tumours. In vitro, FBXO45 knockdown led to a significant reduction in migration capacity in the PC3, DU145 and LNCaP cell cultures. Conclusions: Comprehensive expression analysis and functional data suggest FBXO45 as a prognostic biomarker in PCA. [ABSTRACT FROM AUTHOR]

Purpose: Additive systematic biopsy (SB) contributes to prostate cancer (PCA) detection in MRI-targeted biopsy (TB). However, the reasons for this are not yet clear. We compared the performance of TB, SB and the combined approach (CB) in biopsy-naive men to determine the added value of SB for tumor grading and spatial tumor distribution. Methods: Two hundred and fifty-nine men with PI-RADS 3–5 graded lesions who underwent CB were enrolled. Data were prospectively collected, and cancer detection rates (CDR) were compared at patient and lesion level. Gleason grade up- and down-grading from biopsy to prostatectomy specimens (n = 56; 21.6%) were determined. Clinically significant cancer (csPCA) was defined as Gleason grade ≥ 2. Results: CDR by CB based on PI-RADS categories 3, 4 and 5 for PCA were 24%, 72% and 98% and 17%, 64% and 96% for csPCA. CB detected more PCA and csPCA than TB (p < 0.001). However, TB showed higher efficiency, defined as CDR per biopsy core, for PCA and csPCA in PI-RADS 4–5 rated patients (p < 0.001). Concordance between biopsy and prostatectomy grading was highest in CB with misdiagnosis of csPCA in 25% of men. TB missed cancer attributed to the index lesion in 10.2% and underestimated csPCA in 7%. In these cases, 76% of csPCA were detected and 85% were upgraded to csPCA by SB in adjacent sectors. Conclusion: SB cannot be safely abundant without increased diagnostic uncertainty. When TB missed csPCA, SB detected it close to the MRI-target lesion. Therefore, perifocal biopsies could potentially replace 12-core SB with increased efficiency in taking manageable risks. [ABSTRACT FROM AUTHOR]

Purpose: Multiparametric magnetic resonance imaging fusion targeted prostate biopsy (MR-TB) has emerged to the biopsy technique of choice for evaluation of patients with suspected prostate cancer (PCA). The study aimed to determine expected and experienced pain during MR-TB depending on patients' psychological state. Methods: We prospectively enrolled 108 men with suspicion of PCA who underwent MR-TB. All patients completed self-reported validated questionnaires assessing pain, stress, self-efficacy, anxiety and study-specific questionnaires on expected and experienced pain before, during and after MR-TB. Patient characteristics and survey scores were obtained. Results: Overall, pain levels during MR-TB were low (mean 2.8/10 ± 2.5 Numerical Rating Scale, NRS). 10/86 (11.6%) participants reported severe pain (≥ 7/10 NRS). Pain correlated significantly with anxiety (r = 0.42), stress (r = 0.22) and pain expectancy (r = 0.58). High self-efficacy did not show increased pain resilience. Participants anticipated more pain than experienced during each step of MR-TB with significant differences concerning local anesthesia and core sampling (both p < 0.001), among others. Expectancy and actual pain did not match regarding severity and impact of the total amount of cores taken (p < 0.05). Independent predictors of increased pain at biopsy were prostate volume > 50 ml (p = 0.0179) and expected pain during rectal manipulation (p < 0.001). Conclusion: Pain during MR-TB can be positively influenced by reducing men's anxiety, stress and pain expectancy. To meet the needs of the audience, clinicians should address concrete pain levels of each procedural step and consider special treatment for patients with prostate volume > 50 ml and men reporting on increased rectal sensitivity. [ABSTRACT FROM AUTHOR]