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Combination therapies in metastatic hormone-sensitive prostate cancer (mHSPC), which include the addition of an androgen receptor signaling inhibitor and/or docetaxel to androgen deprivation therapy, have been a game changer in the management of this disease stage. However, these therapies come with their fair share of toxicities and side effects. The goal of this observational study is to report drug-related adverse events (AEs), which are correlated with systemic combination therapies for mHSPC. Determining the optimal treatment option requires large cohorts to estimate the tolerability and AEs of these combination therapies in “real-life” patients with mHSPC, as provided in this study. We use a network of databases that includes population-based registries, electronic health records, and insurance claims, containing the overall target population and subgroups of patients defined by unique certain characteristics, demographics, and comorbidities, to compute the incidence of common AEs associated with systemic therapies in the setting of mHSPC. These data sources are standardised using the Observational Medical Outcomes Partnership Common Data Model. We perform the descriptive statistics as well as calculate the AE incidence rate separately for each treatment group, stratified by age groups and index year. The time until the first event is estimated using the Kaplan-Meier method within each age group. In the case of episodic events, the anticipated mean cumulative counts of events are calculated. Our study will allow clinicians to tailor optimal therapies for mHSPC patients, and they will serve as a basis for comparative method studies.

Abstract Background Clinical manifestation of prostate cancer (PCa) is highly variable. Aggressive tumors require radical treatment while clinically non-significant ones may be suitable for active surveillance. We previously developed the prognostic ProstaTrend RNA signature based on transcriptome‐wide microarray and RNA-sequencing (RNA-Seq) analyses, primarily of prostatectomy specimens. An RNA-Seq study of formalin-fixed paraffin-embedded (FFPE) tumor biopsies has now allowed us to use this test as a basis for the development of a novel test that is applicable to FFPE biopsies as a tool for early routine PCa diagnostics. Methods All patients of the FFPE biopsy cohort were treated by radical prostatectomy and median follow-up for biochemical recurrence (BCR) was 9 years. Based on the transcriptome data of 176 FFPE biopsies, we filtered ProstaTrend for genes susceptible to FFPE-associated degradation via regression analysis. ProstaTrend was additionally restricted to genes with concordant prognostic effects in the RNA-Seq TCGA prostate adenocarcinoma (PRAD) cohort to ensure robust and broad applicability. The prognostic relevance of the refined Transcriptomic Risk Score (TRS) was analyzed by Kaplan–Meier curves and Cox-regression models in our FFPE-biopsy cohort and 9 other public datasets from PCa patients with BCR as primary endpoint. In addition, we developed a prostate single-cell atlas of 41 PCa patients from 5 publicly available studies to analyze gene expression of ProstaTrend genes in different cell compartments. Results Validation of the TRS using the original ProstaTrend signature in the cohort of FFPE biopsies revealed a relevant impact of FFPE-associated degradation on gene expression and consequently no significant association with prognosis (Cox-regression, p-value > 0.05) in FFPE tissue. However, the TRS based on the new version of the ProstaTrend-ffpe signature, which included 204 genes (of originally 1396 genes), was significantly associated with BCR in the FFPE biopsy cohort (Cox-regression p-value

Aberrant transcriptional activity of androgen receptor (AR) is one of the dominant mechanisms for developing of castration-resistant prostate cancer (CRPC). Analyzing AR-transcriptional complex related to CRPC is therefore important towards understanding the mechanism of therapy resistance. While studying its mechanism, we observed that a transmembrane protein called neuropilin-2 (NRP2) plays a contributory role in forming a novel AR-transcriptional complex containing nuclear pore proteins. Using immunogold electron microscopy, high-resolution confocal microscopy, chromatin immunoprecipitation, proteomics, and other biochemical techniques, we delineated the molecular mechanism of how a specific splice variant of NRP2 becomes sumoylated upon ligand stimulation and translocates to the inner nuclear membrane. This splice variant of NRP2 then stabilizes the complex between AR and nuclear pore proteins to promote CRPC specific gene expression. Both full-length and splice variants of AR have been identified in this specific transcriptional complex. In vitro cell line-based assays indicated that depletion of NRP2 not only destabilizes the AR-nuclear pore protein interaction but also inhibits the transcriptional activities of AR. Using an in vivo bone metastasis model, we showed that the inhibition of NRP2 led to the sensitization of CRPC cells toward established anti-AR therapies such as enzalutamide. Overall, our finding emphasize the importance of combinatorial inhibition of NRP2 and AR as an effective therapeutic strategy against treatment refractory prostate cancer.

Cancer survivorship was recently identified as a prostate cancer (PCa) research priority by PIONEER, a European network of excellence for big data in PCa. Despite being a research priority, cancer survivorship lacks a clear and agreed definition, and there is a distinct paucity of patient-reported outcome (PRO) data available on the subject. Data collection on cancer survivorship depends on the availability and implementation of (validated) routinely collected patient-reported outcome measures (PROMs). There have been recent advances in the availability of such PROMs. For instance, the European Organisation for Research and Treatment of Cancer Quality of Life Group (EORTC QLG) is developing survivorship questionnaires. This provides an excellent first step in improving the data available on cancer survivorship. However, we propose that an agreed, standardised definition of (prostate) cancer survivorship must first be established. Only then can real-world data on survivorship be collected to strengthen our knowledge base. With more men than ever surviving PCa, this type of research is imperative to ensure that the quality of life of these men is considered as much as their quantity of life. Patient summary: As there are more prostate cancer survivors than ever before, research into cancer survivorship is crucial. We highlight the importance of such research and provide recommendations on how to carry it out. The first step should be establishing agreement on a standardised definition of survivorship. From this, patient-reported outcome measures can then be used to collect important survivorship data.

Abstract Background Prostate cancer (PCa) is one of the most prevalent cancers worldwide. The clinical manifestations and molecular characteristics of PCa are highly variable. Aggressive types require radical treatment, whereas indolent ones may be suitable for active surveillance or organ-preserving focal therapies. Patient stratification by clinical or pathological risk categories still lacks sufficient precision. Incorporating molecular biomarkers, such as transcriptome-wide expression signatures, improves patient stratification but so far excludes chromosomal rearrangements. In this study, we investigated gene fusions in PCa, characterized potential novel candidates, and explored their role as prognostic markers for PCa progression. Methods We analyzed 630 patients in four cohorts with varying traits regarding sequencing protocols, sample conservation, and PCa risk group. The datasets included transcriptome-wide expression and matched clinical follow-up data to detect and characterize gene fusions in PCa. With the fusion calling software Arriba, we computationally predicted gene fusions. Following detection, we annotated the gene fusions using published databases for gene fusions in cancer. To relate the occurrence of gene fusions to Gleason Grading Groups and disease prognosis, we performed survival analyses using the Kaplan–Meier estimator, log-rank test, and Cox regression. Results Our analyses identified two potential novel gene fusions, MBTTPS2,L0XNC01::SMS and AMACR::AMACR. These fusions were detected in all four studied cohorts, providing compelling evidence for the validity of these fusions and their relevance in PCa. We also found that the number of gene fusions detected in a patient sample was significantly associated with the time to biochemical recurrence in two of the four cohorts (log-rank test, p-value

The androgen receptor (AR) plays a central role in prostate, muscle, bone and adipose tissue. Moreover, dysregulated AR activity is a driving force in prostate cancer (PCa) initiation and progression. Consequently, antagonizing AR signalling cascades via antiandrogenic therapy is a crucial treatment option in PCa management. Besides, very high androgen levels also inhibit PCa cells’ growth, so this effect could also be applied in PCa therapy. However, on the molecular and cellular level, these mechanisms have hardly been investigated so far. Therefore, the present study describes the effects of varying androgen concentrations on the viability of PCa cells as well as localization, transactivation, and protein stability of the AR. For this purpose, cell viability was determined via WST1 assay. Alterations in AR transactivity were detected by qPCR analysis of AR target genes. A fluorescent AR fusion protein was used to analyse AR localization microscopically. Changes in AR protein expression were detected by Western blot. Our results showed that high androgen concentrations reduce the cell viability in LNCaP and C4-2 cell lines. In addition, androgens have been reported to increase AR transactivity, AR localization, and AR protein expression levels. However, high androgen levels did not reduce these parameters. Furthermore, this study revealed an androgen-induced increase in AR protein synthesis. In conclusion, inhibitory effects on cell viability by high androgen levels are due to AR downstream signalling or non-genomic AR activity. Moreover, hormonal activation of the AR leads to a self-induced stabilization of the receptor, resulting in increased AR activity. Therefore, in clinical use, a therapeutic reduction in androgen levels represents a clinical target and would lead to a decrease in AR activity and, thus, AR-driven PCa progression.

Abstract Background The analysis aimed to compare the radiotracers [68Ga]-Ga-PSMA-11 and [18F]-F-PSMA-1007 intraindividually in terms of malignant lesions, mi(molecular-imaging)TNM staging and presumable unspecific lesions retrospectively as used in routine clinical practice. Methods A retrospective analysis of 46 prostate cancer patients (median age: 71 years) who underwent consecutive [68Ga]-Ga-PSMA-11- and [18F]-F-PSMA-1007-PET/CT or PET/MRI within a mean of 12 ± 8.0 days was performed. MiTNM staging was performed in both studies by two nuclear medicine physicians who were blinded to the results of the other tracer. After intradisciplinary and interdisciplinary consensus with two radiologists was reached, differences in both malignant and presumable nonspecific tracer accumulation were analyzed. Results Differences in terms of miTNM stages in both studies occurred in nine of the 46 patients (19.6%). The miT stages differed in five patients (10.9%), the miN stages differed in three patients (6.5%), and different miM stages occurred only in one patient who was upstaged in [18F]-F-PSMA-1007 PET. Concordant miTNM stages were obtained in 37 patients (80.4%). There was no significant difference between [18F]-F-PSMA-1007 and [68Ga]-Ga-PSMA-11 in the SUVmax locally (31.5 vs. 32.7; p = 0.658), in lymph node metastases (28.9 vs. 24.9; p = 0.30) or in bone metastases (22.9 vs. 27.6; p = 0.286). In [18F]-F-PSMA-1007 PET, more patients featured presumable unspecific uptake in the lymph nodes (52.2% vs. 28.3%; p:

Life expectancy is increasing in many parts of the world. Using proportional hazard models for competing risks, we investigated whether this increase has changed outcomes after radical cystectomy in a sample of 1419 consecutive patients treated between 1993 and 2018. During the observation period, the mean age and the proportion of patients with American Society of Anesthesiologists physical status class 3 or 4 increased, whereas the proportion of patients with heart disease decreased. Competing mortality (causes other than bladder cancer) decreased in all subgroups (hazard ratios [HRs] per year ranged from 0.931 to 0.963) and after controlling for increasing age (HRs ranged from 1.018 to 1.081). In an optimal model resulting from an analysis including age (HR per year 1.048, 95% confidence interval [CI] 1.027–1.070; p