Prostate cancer remains one of the most frequently diagnosed malignancies in men worldwide, and despite favorable outcomes for localized disease, progression to castration-resistant prostate cancer (CRPC) represents a major clinical challenge associated with poor prognosis. CRPC is characterized by disease progression despite castrate levels of circulating testosterone and is most commonly diagnosed in the metastatic setting. Although the introduction of second-generation androgen receptor-targeted therapies has improved survival, resistance inevitably emerges. This review overviews the most recent findings in the field of CRPC with particular emphasis on the current understanding of the biological mechanisms of hormone-resistant cancer as well as the evidence on treatment strategies. A comprehensive literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, focusing mainly on studies published between 2015 and 2025 that investigated molecular and cellular mechanisms of resistance to androgen deprivation therapy and androgen receptor (AR)-targeted treatments. Seventy-eight relevant articles were included in the final synthesis. The reviewed evidence highlights four major categories of resistance mechanisms. First, AR-dependent alterations remain predominant, including AR gene amplification, activating mutations, dysregulation of co-regulators, and expression of constitutively active AR splice variants such as AR-V7. Second, AR-independent or bypass pathways, most notably PI3K/AKT/mTOR, Wnt/β-catenin, MAPK, and glucocorticoid receptor signaling, enable tumor survival despite AR blockade. Third, lineage plasticity and transdifferentiation to neuroendocrine prostate cancer represent a distinct and increasingly recognized resistance mechanism driven by loss of TP53 and RB1 and epigenetic reprogramming. Finally, additional contributors, including intratumoral androgen synthesis, metabolic reprogramming, and tumor microenvironment interactions, further support disease progression. Together, these interconnected mechanisms underscore the biological complexity of CRPC and emphasize the need for biomarker-guided, combination-based therapeutic strategies to overcome resistance and improve patient outcomes.
S. Riolo, G. Gallo, A. Cicione et al.· Société Internationale d'Uro...· 0 citations
This study aimed to externally validate the performance of the European Association of Urology (EAU) Guidelines Bot in neuro-urology by assessing the accuracy, completeness, and clarity of chatbot-generated answers to guideline-based questions and to compare its performance with that of a general-purpose large language model (ChatGPT 5.5). A cross-sectional validation study was conducted using 47 questions derived from the EAU Neuro-Urology Guidelines. Each question was linked to a specific recommendation and classified by recommendation strength (strong vs weak). Questions were independently submitted to both the EAU Guidelines Bot and ChatGPT 5.5 without additional prompting. Two expert urologists independently evaluated each response for accuracy, completeness, and clarity using a five-point Likert scale; discrepancies were resolved by a third reviewer. Overall, 45 questions (95.7%) were linked to strong recommendations and two (4.3%) to weak recommendations. The EAU Guidelines Bot and ChatGPT 5.5 achieved identical mean accuracy scores (4.96 ± 0.20), with all responses rated as highly accurate (Likert 4-5). ChatGPT 5.5 indicated significantly higher completeness scores than did the EAU Guidelines Bot (4.74 ± 0.44 vs 4.57 ± 0.54; p = 0.011), whereas clarity scores were not significantly different (4.83 ± 0.38 vs 4.77 ± 0.43; p = 0.083). High-quality completeness was observed in 46/47 EAU Guidelines Bot responses (97.9%) and 47/47 ChatGPT responses (100%). Score discrepancies between systems were identified in ten of 47 questions (21.3%) and were limited to completeness and clarity domains. Performance remained uniformly high across recommendation grades, with no meaningful differences observed. The EAU Guidelines Bot showed excellent accuracy, completeness, and clarity when applied to neuro-urology guideline-based questions. Its performance was comparable to that of ChatGPT 5.5, with both systems providing highly accurate guideline-concordant responses. Although ChatGPT 5.5 generated more comprehensive answers, the EAU Guidelines Bot maintained closer adherence to the original guideline recommendations. Although not a substitute for clinical judgment, the tool appears to be a reliable adjunct for rapid access to evidence-based neuro-urological guidance.
Sabrina De Cillis, Riccardo Lombardo, Daniele Amparore et al.· European Urology Focus· 0 citations
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