Search Results (904)

Backgrounds: High-volume (HV) metastatic castration-sensitive prostate cancer (mCSPC) is an aggressive disease. Despite this, we aimed to assess the metastatic patterns associated with a favorable prognosis in HV disease with bone metastasis (BM), including BM’s coexistence with lung metastasis (LM). Methods: We retrospectively analyzed 379 patients with synchronous mCSPC. They were categorized using the CHAARTED criteria as low-volume (LV) or HV with BM, classified based on extent of the disease from 1 to 4 (HV-EOD1–4) with or without LM. Multivariate Cox models for overall survival and castration-resistance-free survival assessed the prognostic values of HV-EOD1–4 compared with LV disease and the presence of LM. Site-specific radiographic progression at the time of castration-resistant prostate diagnosis was assessed in patients with BM and LM. Results: Multivariate analyses for overall survival showed no prognostic value of HV-EOD1 (hazard ratio [HR] 0.90; 95% confidence interval [CI] 0.43–1.85; p = 0.77), HV-EOD2 (HR 1.17; 95% CI 0.69–1.99; p = 0.57), and LM (HR 1.29; 95% CI 0.80–2.07; p = 0.29). In the analyses, HV-EOD ≤ 2 and LM did not influence castration resistance-free survival. LM showed a significantly lower incidence of radiographic progression to castration-resistant prostate cancer than BM (6.0% vs. 29.9%, p < 0.001). Conclusions: This study indicates the prognostic heterogeneity of HV disease considering BM and LM. These findings may aid in determining the treatment intensity for mCSPC. Full article

Background: Prostate cancer is the second most common malignant cancer among men, and according to the predictions, the estimated number of new cases will substantially grow in the coming years. Therefore, the costs of the disease will increase as well. Methods: We conducted a literature review of the state of knowledge about the costs of treatment and the economic burden of prostate cancer. The vast majority of studies were focused on direct costs only, which clearly shows the literature gap. Results: We focused on the estimates of direct costs, i.e., treatment of prostate cancer, adjuvant and neoadjuvant treatment, and supportive and palliative care, and indirect costs. Cost-effectiveness analyses indicated that docetaxel combined with androgen deprivation therapy (ADT) was the most cost-effective strategy for metastatic hormone-sensitive prostate cancer (incremental cost-effectiveness ratio (ICER): USD 13,647). In contrast, novel therapies such as PARP inhibitors and whole-genome-sequencing-guided treatments were not cost-effective unless drug prices were reduced by 47–70%. In the United States, 5-year cumulative treatment costs ranged from USD 48,000 for conservative management to over USD 91,000 for radiotherapy, while out-of-pocket expenses averaged AUD 1172 in Australia. Indirect costs were also considerable, with Slovakia reporting an increase in sick leave costs from EUR 1.2 million in 2014 to EUR 2.1 million in 2022. Conclusions: Metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer were the most frequent categories for various treatment cost evaluations. A few specific combinations of drugs were cost-effective only under the condition of dropping the unit prices of a medication. Further summarizing, reviewing, and developing a methodology for standardized comparisons are needed. Full article

Elevated cholesterol levels play important mitogenic roles. Pseurotin A (PsA) is a fermentation product that has recently been reported as a dual inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) secretion and protein-protein interaction (PPI) with the LDLR. PsA showed a high acute safety profile and therapeutic potential against metastatic castration-resistant prostate cancer (mCRPC). The study aims to uncover the chronic safety, distribution, and anti-mCRPC genomic and molecular mechanistic insights of PsA. A 90-day chronic safety assessment of PsA up to 80 mg/kg in Swiss albino mice showed no signs of hematological, biochemical, or major organ toxicity. PsA demonstrated rapid intravenous distribution and elimination in Swiss albino mice. PsA is biodistributed to multiple key organs but was not detected in the brain, indicating its inability to cross the blood-brain barrier. PsA effectively suppressed the recurrence of nude mice xenografted mCRPC, which was subjected to a neoadjuvant docetaxel and enzalutamide regimen, followed by surgical excision. Collected PsA and vehicle control-treated recurrent tumors were subjected to RNA-sequencing and pathway enrichment analysis (PEA) of differentially expressed genes (DEGs). PsA-treated tumors revealed multiple significantly enriched pathways associated with promoting tumor apoptosis and inhibiting both invasion and migration. The PPI network analyses for the downregulated DEGs displayed prominent networks of genes associated with the ubiquitin-proteasome system. Results provide comprehensive mechanistic and preclinical validations for PsA’s potential as a novel PC recurrence suppressive lead entity. Full article

A group of Spanish experts of different specialties participated in the ENFOCA2 project, promoted by the Spanish Oncology Genitourinary Group (SOGUG), which was designed to provide updated information on current and novel aspects contributing to the optimal care of prostate cancer (PCa) patients. In localized disease, it is important to implement strategic alliances with other institutions for improving adherence to active surveillance in low-risk groups and to explore genetic testing for a better indication of focal therapy. Local control of the disease should be maximized to prevent local failure and biochemical recurrence. In patients with locally advanced disease, with PSMA PET/CT-positive lesions in M0 staging on conventional imaging techniques, therapeutic decisions should be carefully evaluated due to insufficient evidence regarding the gold standard in this setting. In patients with metastatic castration-resistant PCa (mCRPC), assessment of BRCA somatic and germline mutations provides prognostic information and familial cancer risk and informs treatment decisions. Combinations of androgen receptor signaling inhibitor (ARSi) agents and poly-ADP ribose polymerase inhibitors (PARPi) are emerging alternatives for advanced PCa. The oldest segment of PCa patients (>70 years of age) may require geriatric assessment to evaluate physical and functional reserves, tailoring treatment to their individual characteristics and circumstances. The concept of a comprehensive multidisciplinary approach together with inter-center and/or inter-specialty therapeutic alliances should be implemented in the routine care of patients with PCa. Full article

Although multimodal therapeutic management has significantly improved outcome in prostate cancer (PCa) patients, treatment options for castrate-resistant disease remain challenging. Plant-derived mistletoe extracts have supported cancer patients and are, therefore, widely used as complementary medicine. However, mechanisms behind possible mistletoe benefits to PCa patients remain to be explored. The present study was designed to evaluate the effect of mistletoe extracts from four different host trees (Tiliae, Populi, Salicis, and Crataegi) on the growth and proliferation of PCa cell lines in vitro. PC3, DU145, and LNCaP cells were used to evaluate tumor cell growth (MTT assay) and proliferation (BrdU incorporation assay). Clonogenicity, apoptosis, cell cycle, and cell-cycle-regulating proteins (cyclin-dependent kinases (CDKs) and cyclins) were investigated, as was CD44 standard and splice variant expression and integrin α and β receptors. SiRNA knockdown studies were employed to investigate the functional relevance of integrins. All mistletoe extracts significantly inhibited cell growth in a dose-dependent manner and cell proliferation and clonogenicity were suppressed. Populi and Salicis induced cell-cycle arrest in the G2/M phase and increased apoptosis. Both extracts down-regulated CDK1 and cyclin A and altered CD44 expression. Integrins α5 in all cell lines and α6 in DU145 and LNCaP were particularly diminished. Knocking down α5 and α6 induced cell growth inhibition in DU145. Mistletoe extracts block the growth and proliferation of PCa cells in vitro and therefore qualify for use in future animal studies to evaluate mistletoe as an adjunct to standard PCa treatment. Full article

Background: Treatment with androgen receptor (AR) signaling inhibitors, such as enzalutamide, can induce neural lineage plasticity in prostate cancer, potentially progressing to t-NEPC. However, the molecular mechanisms underlying this enzalutamide-driven plasticity, particularly the contribution of immune signaling pathways, remain poorly understood. Methods: We analyzed transcriptomic profiles of patient samples and prostate cancer cell lines to investigate changes in immune signaling pathways. Interferon gamma (IFNγ), interferon alpha (IFNα), and interleukin 6 (IL6)-Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling were assessed in enzalutamide-sensitive and -resistant prostate cancer cells. Functional assays were conducted to examine cell responsiveness to cytokine stimulation and susceptibility to STAT1 inhibition using fludarabine. Results: Immune-related pathways, including IFNγ, IFNα, IL6-JAK-STAT3, and inflammatory responses, were significantly suppressed in NEPC patient samples compared to those with castration-resistant prostate cancer (CRPC). Enzalutamide-resistant and NEPC cells exhibited markedly impaired IFNγ and IL6 signaling. In contrast, early-stage enzalutamide treatment paradoxically enhanced IFNγ and IL6 responsiveness. Transcriptomic profiling revealed coordinated upregulation of E2F target genes and activation of IFNα/IFNγ and JAK/STAT signaling pathways during early treatment. Importantly, these early-stage cells remained highly sensitive to IFNγ and IL6 stimulation and showed increased susceptibility to STAT1 inhibition by fludarabine, a sensitivity that was lost in resistant cells. Conclusions: Early enzalutamide treatment enhances immune responsiveness, while the development of resistance is associated with suppressed immune signaling and increased lineage plasticity. These results suggest a therapeutic window where combining enzalutamide with STAT inhibitors may delay or prevent lineage plasticity and resistance. Full article

The androgen receptor (AR) signaling pathway is the primary driver of prostate cancer initiation and progression, including the development of castration-resistant prostate cancer (CRPC). Because current AR-targeted therapies inevitably encounter drug resistance, novel strategies to suppress AR signaling are urgently needed. Natural products represent a rich and structurally diverse source of bioactive compounds capable of targeting AR at multiple regulatory levels. This review overviews the interactions between natural products and the AR signaling axis through distinct mechanisms, including inhibition of testosterone production and 5α-reductase activity, direct antagonism of AR, and induction of AR degradation. In addition, several compounds disrupt AR nuclear translocation, downregulate AR splice variants, or suppress AR signaling indirectly through epigenetic regulation, microRNA modulation, or interference with co-regulator networks. Preclinical studies provide compelling evidence that these agents can effectively interrupt AR signaling, thereby suppressing prostate cancer growth. However, challenges remain, particularly the limited pharmacokinetic characterization, lack of in vivo validation, and scarcity of clinical studies. Future research should focus on improving bioavailability, exploring synergistic combinations with existing therapies, and advancing well-designed in vivo and clinical investigations. Collectively, these efforts may establish natural products as lead compounds to modulate AR signaling for prostate cancer prevention and treatment. Full article

Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor approved for treating metastatic castration-resistant prostate cancer (mCRPC) with BRCA mutations, has significant clinical benefits. However, evidence suggests an increased risk of venous thromboembolism, including pulmonary embolism (PE), particularly in patients with PC. However, no case reports of olaparib-associated PE in mCRPC have been published. Here, we report the case of a 70-year-old man with mCRPC harboring a BRCA2 mutation, who developed PE during olaparib therapy. Diagnostic evaluations included contrast-enhanced computed tomography and serum D-dimer level measurement. Clinical decision tools, such as the Wells score and the Khorana score, were used to support the diagnosis and risk assessment. The patient developed acute dyspnea and chest pain 7 months after olaparib initiation. Imaging confirmed multiple pulmonary emboli; laboratory testing revealed markedly elevated D-dimer levels. Anticoagulation therapy with apixaban led to rapid clinical and radiological improvement. However, mCRPC eventually progressed after olaparib discontinuation, and the patient died 15 months after olaparib initiation. This is the first reported case of olaparib-associated PE in mCRPC. It underscores the importance of vigilance for thromboembolic complications during PARP inhibitor therapy. The integration of clinical scoring systems and biomarkers may facilitate timely PE diagnosis and management, potentially improving patient outcomes. Full article

Objectives: The objective of this study was to investigate the prognostic value of systemic inflammatory markers (SIMs)—namely, the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR)—on survival outcomes and treatment responses in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone (ABI) or enzalutamide (ENZA) therapy. Methods: In this two-center retrospective observational study, researchers analyzed clinical data from 106 patients diagnosed with mCRPC. The cut-offs for NLR and PLR were determined to be 2.83 and 156, respectively, and their effects on progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan–Meier and Cox regression analyses. Changes in SIMs before and after ABI/ENZA treatment were assessed using the Wilcoxon signed-rank test. Results: Lower NLR (≤2.83) and PLR (≤156) were significantly associated with longer PFS and OS; however, in multivariate analysis, only high PLR emerged as an independent adverse prognostic factor for OS (HR: 2.01; p = 0.026). Meanwhile, treatment response was an independent predictor of PFS, and no significant changes were observed in the mean platelet volume (MPV), platelet distribution width (PDW), or platelet–large cell ratio (P-LCR) after treatment. Conclusions: SIMs, such as NLR and especially PLR, may serve as practical and accessible tools for predicting survival in mCRPC patients; however, further prospective studies are warranted. Full article

Purpose: Accurate survival prediction is essential for optimizing the treatment planning in patients with castration-resistant prostate cancer (CRPC). However, the traditional statistical models often underperform due to limited variable inclusion and an inability to account for complex, multidimensional data interactions. Methods: We retrospectively collected 46 clinical, laboratory, and pathological variables from 801 patients with CRPC, covering the disease course from the initial disease diagnosis to CRPC progression. Multiple machine learning (ML) models, including random survival forests (RSFs), XGBoost, LightGBM, and logistic regression, were developed to predict cancer-specific mortality (CSM), overall mortality (OM), and 2- and 3-year survival status. The dataset was split into training and test cohorts (80:20), with 10-fold cross-validation. The performance was assessed using the C-index for regression models and the AUC, accuracy, precision, recall, and F1-score for classification models. Model interpretability was assessed using SHapley Additive exPlanations (SHAP). Results: Over a median follow-up of 24 months, 70.6% of patients experienced CSM. RSFs achieved the highest C-index in the test set for both CSM (0.772) and OM (0.771). For classification tasks, RSFs demonstrated a superior performance in predicting 2-year survival, while XGBoost yielded the highest F1-score for 3-year survival. The SHAP analysis identified time to first-line CRPC treatment and hemoglobin and alkaline phosphatase levels as key predictors of survival outcomes. Conclusion: The RSF and XGBoost ML models demonstrated a superior performance over that of traditional statistical methods in predicting survival in CRPC. These models offer accurate and interpretable prognostic tools that may inform personalized treatment strategies. External validation and the integration of emerging therapies are warranted for broader clinical applicability. Full article

Background: The outgrowth of castration-resistant prostate cancer (CRPC) dictates patient morbidity and mortality. Recurrence of prostate cancer (PC) following androgen-deprivation therapy (ADT) often occurs due to constitutively active androgen receptor (AR) splice variants (AR-Vs), primarily AR-V7. Therefore, safe and effective therapies enabling the suppression of both full-length AR (AR-FL) and AR-Vs are urgently needed. The natural compound dimethyl sulfoxide (DMSO) has negligible cytotoxicity at concentrations below 5% and has anticancer potential. DMSO has been broadly used in biomedical research as a solvent for pharmaceuticals, as a cryoprotectant for cells, and as a topical treatment to suppress pain and inflammation. We investigated the effect of low-dose DMSO on AR expression, cell viability, and metastatic ability in PC cell lines expressing both AR-FL and AR-V7 (e.g., 22Rv1) and those expressing only AR-FL (e.g., C4-2B). Methods: MTT cell viability assays were performed to measure DMSO-induced cytotoxicity. Wound-healing assays were conducted to monitor the effect of DMSO on the migratory phenotype of cancer cells. Western blot analyses were performed to study the efficacy of DMSO in suppressing the protein levels of AR-FL and AR-V7, and expression of heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) was measured as a possible mechanism. Results: At concentrations of 0.1–1% (v/v), DMSO treatment showed minimal cytotoxicity, whereas the highest concentration used (2.5%) showed approximately 20% cytotoxicity at 96 h. Interestingly, however, DMSO treatment at concentrations of 1.0 and 2.5% significantly inhibited the migration of PC cells. Treatment with DMSO led to a dose-dependent inhibition of both AR-FL and AR-V7. Notably, in 22Rv1 cells, DMSO potently downregulated the expression of hnRNPH1, a splicing factor often associated with AR expression and signaling. Conclusions: Our findings suggest that low concentrations of DMSO may have potential as an effective anticancer agent, both at the initial and later stages when PC cells become castration resistant. Full article

Introduction and Aims: Androgen deprivation therapy (ADT) with systemic anti-cancer treatment (SACT) ± palliative radiotherapy (pRT) is the current standard of care for Oligo-metastatic hormone-sensitive prostate cancer (o-mHSPC). Cytoreductive radical prostatectomy (cRP) has gained interest in this group of patients, with potential benefits including reduced tumour burden and a lower risk of local events from disease progression. In this review, we compare both survival outcomes and local event rates between cRP and upfront ADT ± SACT. Methods: All randomised trials and observational studies comparing cRP with standard treatment (ST), which we defined as ADT ± SACT for o-mHSPC, were included in the review. The study protocol was registered in PROSPERO (CRD42024516586), and the review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The databases searched included Embase, Medline, Cochrane Library, PubMed, and Web of Science. A risk of bias assessment was performed for the included studies as recommended by the Cochrane Handbook of Systematic Reviews and Interventions. The primary outcome measures were Overall Survival (OS), Cancer-Specific Survival (CSS), Progression-free Survival (PFS), Castrate-resistant Prostate Cancer-free Survival (CRPC-FS), and local complication rates. The secondary outcome measures were complication rates and functional outcomes post-cRP. Results: A total of 5130 studies were identified for this review (5119 by database searching and 11 through manual searching). Eight studies were included in the review, comprising 611 patients. cRP was identified to have superior OS (HR: 0.56 (95% CI: 0.34–0.92), I² = 0%, p = 0.02 (very low certainty)) and CSS (HR: 0.27 (95% CI: 0.15–0.47), I² = 0%, p < 0.0001 (very low certainty)). The PFS (HR: 0.67 (95% CI: 0.34–1.33), I² = 58%, p = 0.25 (very low certainty)) and CRPC-FS (HR: 0.67 (95% CI: 0.32–1.43), I² = 57%, p = 0.30 (very low certainty)) were similar between the two groups. The rates of local events were significantly lower in patients undergoing cRP (RR 0.27 (95% CI: 0.13–0.59), I² = 17%, p = 0.001 (low certainty)). The rates of Clavien–Dindo (CD) grade 3 or higher complications ranged from 0% to 13.1%. Additionally, the reported continence rates ranged from 81.5% to 91.3%. The review is limited by the lack of a uniform definition for o-mHSPC and the predominance of low-quality, heterogeneous studies. Despite mitigation strategies, the overall certainty of evidence remains very low per GRADE assessment. Conclusion: cRP significantly reduces local event rates compared with ST and offers comparable PFS and CFPC-FS, with superior OS and CSS in the cRP arm compared to the ST arm in patients with o-mHSPC. However, there is a paucity of high-quality literature on this subject. Ongoing randomised controlled trials may soon clarify the role of cRP in the context of o-mHSPC concerning survival benefits. Full article

Background/objectives: Multiple systemic treatments are available for metastatic castration-resistant prostate cancer (mCRPC), with unclear safety profiles. This study seeks to describe the safety determined in randomized clinical trials of a systemic treatment for mCRPC and whether safety differs by age. Methods: We utilized individual patient data from industry-funded phase 2/3 trials in mCRPC on abiraterone acetate (AA). Vivli, a clinical trial repository site, was used. One investigator independently performed screening. Relative effects of treatment were assessed with frequencies and odds of serious adverse events (SAEs). The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used. Subgroup analysis measured odds of SAEs as modified by age. Results: We identified 14 trials with 4296 patients. The median age of participants was 69 years. Nearly all participants experienced at least one adverse event (98.4% abiraterone, 97.3% standard of care [SOC]). More serious adverse events (grade 3 or 4) and deaths (grade 5) occurred in those receiving SOC (71.8%) compared to abiraterone (64.1%). The most frequent adverse event category was “Musculoskeletal and Connective Tissue Disorders”. The most frequent event types included anemia, back pain, hypertension, fatigue, hypokalemia, and bone pain. The odds of all events were lower in those receiving abiraterone compared to SOC. Odds of a serious musculoskeletal event were lower in older subjects by 22% (OR 0.78; 95% CI 0.63, 0.96). Conclusions: In this IPD meta-analysis, abiraterone acetate provides no greater risk of SAE in those receiving abiraterone than those receiving SOCs. Patients in the RCTs are younger and healthier than those in the general population; consequently, the results of RCTS might not be applied to the general population, especially those under-represented in the RCTs. There is a need to further evaluate abiraterone-related fractures and neuromuscular toxicities (NMTs) as key outcomes to gain insight into risk factors related to these adverse events. A real-world prospective study is warranted to examine the overall risks and benefits associated with treatment. Full article

Background: Despite advances in prostate cancer treatment, castration-resistant prostate cancer (CRPC) remains clinically challenging due to inherent therapy resistance and a lack of durable alternatives. Although traditional Chinese medicine offers untapped potential, the therapeutic role of paeoniflorin (Pae), a bioactive compound derived from Paeonia lactiflora, in prostate cancer has yet to be investigated. Methods: Using an integrative approach (network pharmacology, molecular docking, and experimental validation), we identified Pae key targets, constructed protein–protein interaction networks, and performed GO/KEGG pathway analyses. A Pae-target-based prognostic model was developed and validated. In vitro and in vivo assays assessed Pae effects on proliferation, migration, invasion, apoptosis, and tumor growth. Results: Pae exhibited potent anti-CRPC activity, inhibiting cell proliferation by 60% and impairing cell migration by 65% compared to controls. Mechanistically, Pae downregulated SRC proto-oncogene, non-receptor tyrosine kinase (SRC) mRNA expression by 68%. The Pae-target-based prognostic model stratified patients into high- and low-risk groups with distinct survival outcomes. Organoid and xenograft studies confirmed Pae-mediated tumor growth inhibition and SRC downregulation. Conclusions: Pae overcomes CRPC resistance by targeting SRC-mediated pathways, presenting a promising therapeutic strategy. Our findings underscore the utility of network pharmacology-guided drug discovery and advocate for further clinical exploration of Pae in precision oncology. Full article

Targeted alpha therapy (TAT) has recently emerged as a highly promising approach for the management of metastatic castration-resistant prostate cancer (mCRPC), especially in patients with disease progression despite standard treatments. Among alpha-emitter radiopharmaceuticals, actinium-225-labelled prostate-specific membrane antigen ([225Ac]Ac-PSMA) has shown remarkable potential due to its high linear energy transfer (LET), short path length, and ability to induce potent, localised cytotoxic effects. This review summarises current clinical evidence regarding [225Ac]Ac-PSMA radioligand therapy (RLT), emphasising its efficacy, safety profile, and position relative to beta-emitter therapy with lutetium-177 ([177Lu]Lu-PSMA). Data from compassionate-use programs and small clinical trials demonstrate that [225Ac]Ac-PSMA produces significant biochemical and imaging responses, including > 50% declines in prostate-specific antigen (PSA) and lesion regression on [68Ga]Ga-PSMA PET/CT, even in heavily pre-treated mCRPC cohorts. Xerostomia, renal toxicity, and haematological adverse effects remain the main safety challenges, necessitating optimisation of patient selection, dosing strategies, and salivary gland protection protocols. Compared with [177Lu]Lu-PSMA, [225Ac]Ac-PSMA appears effective even in cases of beta-refractory disease, highlighting its complementary role rather than a competitive alternative. However, limited availability, high production costs, and the lack of large-scale, randomised trials hinder widespread clinical adoption. Future directions include combination protocols, improved radiopharmaceutical design, and trials evaluating its use in earlier disease stages. This review provides a comprehensive overview of the clinical aspects of [225Ac]Ac-PSMA RLT and its evolving role in advanced prostate cancer management. Full article