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High levels of YAP1 and ferroptosis activation in castration-resistant prostate cancer (CRPC) can inhibit CRPC progression and improve its sensitivity toward chemotherapeutics drugs. However, whether YAP1 regulates ferroptosis in CRPC cells and the underlying mechanisms are unknown. The protein levels of YAP1, SLC1A5, and GLS1 in benign prostatic hyperplasia (BPH), prostate cancer (PCa) that did not progress to CRPC, and CRPC tissue samples were evaluated using western blotting. In PC-3 and DU-145 cells, YAP1 overexpression vector, small-interfering RNA, specific inhibitor verteporfin, ferroptosis-inducer RSL3, SLC1A5-inhibitor V-9302, and GLS1-inhibitor CB-839 were used. Immunofluorescence, flow cytometry, dual-luciferase reporter gene, and related kits were used to investigate the effect of YAP1 on the ferroptosis activity in CRPC cells and its underlying mechanisms. YAP1 promoted extracellular glutamine uptake and subsequent production of glutamate and glutathione (GSH), and increases the GPX4 activity. For the activation of ferroptosis by RSL3, YAP1 decreased the levels of reactive oxygen species, malondialdehyde, and lipid peroxidation, and the proportion of dead cells. Mechanistically, YAP1 promoted the expression of SCL1A5 and GLS1 and further increased the GSH levels and GPX4 activity. Thus, inhibiting SLC1A5 or GLS1 activity could alleviate the antagonistic effect of YAP1 on the ferroptosis of RSL3-induced CRPC cells. In CRPC, the YAP1 level is high, which enters the nucleus and promotes the expressions of SLC1A5 and GLS1, thereby promoting cellular glutamine uptake and metabolism to generate glutamate and further synthesizing GSH, increasing GPX4 activity, improving cellular antioxidant capacity, and inhibiting cell death. [ABSTRACT FROM AUTHOR]

Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for prostate cancer, yet dynamic molecular changes from hormone-sensitive to castration-resistant states in patients treated with ADT remain unclear. Methods: In this study, we combined the dynamic network biomarker (DNB) method and the weighted gene co-expression network analysis (WGCNA) to identify key genes associated with the progression to a castration-resistant state in prostate cancer via the integration of single-cell and bulk RNA sequencing data. Based on the gene expression profiles of CRPC in the GEO dataset, the DNB method was used to clarify the condition of epithelial cells and find out the most significant transition signal DNB modules and genes included. Then, we calculated gene modules associated with the clinical phenotype stage based on the WGCNA. IHC was conducted to validate the expression of the key genes in CRPC and primary PCa patients Results:Nomograms, calibration plots, and ROC curves were applied to evaluate the good prognostic accuracy of the risk prediction model. Results: By combining single-cell RNA sequence data and bulk RNA sequence data, we identified a set of DNBs, whose roles involved in androgen-associated activities indicated the signals of a prostate cancer cell transition from an androgen-dependent state to a castration-resistant state. In addition, a risk prediction model including the risk score of four key genes (SCD, NARS2, ALDH1A1, and NFXL1) and other clinical–pathological characteristics was constructed and verified to be able to reasonably predict the prognosis of patients receiving ADT. Conclusions: In summary, four key genes from DNBs were identified as potential diagnostic markers for patients treated with ADT and a risk score-based nomogram will facilitate precise prognosis prediction and individualized therapeutic interventions of CRPC. [ABSTRACT FROM AUTHOR]

Introduction: Prostate cancer most commonly metastasizes to the bone and lymph nodes. Gastrointestinal metastasis has been noted in the literature but appears to be an exceedingly uncommon phenomenon. Large intestinal involvement in particular has been reported on only a few occasions, and never concomitantly with small intestinal metastatic involvement. Case Report: We report the case of a 69-year-old gentleman with metastatic castrate-resistant prostate cancer with development of gastrointestinal symptomatology with extensive investigation eventually revealing small and large intestinal polyps subsequently confirmed to be representative of metastatic prostate cancer. Conclusion: This case demonstrates the importance of maintaining a wide differential diagnosis in the context of gastrointestinal symptomatology in malignancy. Thorough endoscopic evaluation may be necessary in such cases in order to identify potential metastatic malignancy in otherwise relatively unremarkable appearing polyps.

Introduction: Prostate cancer most commonly metastasizes to the bone and lymph nodes. Gastrointestinal metastasis has been noted in the literature but appears to be an exceedingly uncommon phenomenon. Large intestinal involvement in particular has been reported on only a few occasions, and never concomitantly with small intestinal metastatic involvement. Case Report: We report the case of a 69-year-old gentleman with metastatic castrate-resistant prostate cancer with development of gastrointestinal symptomatology with extensive investigation eventually revealing small and large intestinal polyps subsequently confirmed to be representative of metastatic prostate cancer. Conclusion: This case demonstrates the importance of maintaining a wide differential diagnosis in the context of gastrointestinal symptomatology in malignancy. Thorough endoscopic evaluation may be necessary in such cases in order to identify potential metastatic malignancy in otherwise relatively unremarkable appearing polyps. [ABSTRACT FROM AUTHOR]

Purpose: The natural history and clinical manifestations of dural metastases (DM) in castrate-resistant prostate cancer (CRPC) will change with advances in new hormonal therapy. Here, we characterised the incidence, clinical presentation, and outcomes of patients with DM in a contemporary patient cohort with CRPC. Methods: We retrospectively reviewed our CRPC database from 2012 to 2020. The primary outcome was the diagnosis of DM, defined as metastasis to the dura mater in the brain or spine. We describe the presenting symptoms, biochemistry, radiologic findings, and therapy sequence for all DM patients. Multivariable logistic regression was performed to identify predictors of DM. Results: Six of the 275 patients (2.2%) with CRPC developed DM. The average age of CRPC diagnosis for patients with DM was 65.6 years. Mean patient survival was 4.5 months after the diagnosis of DM. At the time of CRPC diagnosis, patients who developed DM were significantly younger, had lower baseline haemoglobin, higher lactate dehydrogenase (LDH), and elevated alkaline phosphatase (ALP) compared to those without DM. On multivariable analysis, younger age of CRPC diagnosis was found to be a predictor for DM. Conclusion: The presence of neurological symptoms in the context of younger age, anaemia, and elevated baseline LDH and ALP are associated with DM in CRPC. Level of Evidence: 4 [ABSTRACT FROM AUTHOR]

In heavily pretreated castrate-resistant prostate cancer patients, the use of carboplatin monotherapy is supported by clinicians, despite the lack of recent clinical trial data. This retrospective study of 51 patients showed that a minority of these patients respond, and those responses are rarely durable, although toxicity was mild. Introduction: Many clinicians consider carboplatin monotherapy in advanced castrate-resistant prostate cancer (CRPC) patients who have progressed through all available hormonal and standard chemotherapy treatment options, despite the limited evidence to justify its use. Patients and Methods: This retrospective analysis aimed to evaluate the use of carboplatin monotherapy in patients with refractory prostate cancer in Australia. Efficacy (PSA response, duration, and survival) as well as toxicity was evaluated. Demographic data, PSA response rates, survival data and details of carboplatin treatment protocols, including dose and duration, were collected. Exploratory analyses were conducted on potential prognostic factors. Results: Fifty-one patients received carboplatin: median age 68 (range 55-86 years). Most patients (78.3%) received carboplatin AUC 5 at 3-week intervals. The median number of cycles of carboplatin received was 3 (range 1-17). The median duration of treatment was 63 days (range 1-441). The median overall survival was 6.8 months. Six (11.8%) patients had a PSA response ≥ 50%. The median time to PSA progression on carboplatin, as defined by PCWG, 2 was 67 days (range 15-418). Sixteen patients (31%) required dose delays or reductions and 8 patients (15.6%) ceased carboplatin due to treatment toxicity. Conclusion: Carboplatin is often used in Australia once all available standard treatment options have been exhausted in patients with CRPC. Toxicit y is mild, and a minorit y of patients have responses, but these responses are rarely durable. [ABSTRACT FROM AUTHOR]

Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for prostate cancer, yet dynamic molecular changes from hormone-sensitive to castration-resistant states in patients treated with ADT remain unclear. Methods: In this study, we combined the dynamic network biomarker (DNB) method and the weighted gene co-expression network analysis (WGCNA) to identify key genes associated with the progression to a castration-resistant state in prostate cancer via the integration of single-cell and bulk RNA sequencing data. Based on the gene expression profiles of CRPC in the GEO dataset, the DNB method was used to clarify the condition of epithelial cells and find out the most significant transition signal DNB modules and genes included. Then, we calculated gene modules associated with the clinical phenotype stage based on the WGCNA. IHC was conducted to validate the expression of the key genes in CRPC and primary PCa patients Results:Nomograms, calibration plots, and ROC curves were applied to evaluate the good prognostic accuracy of the risk prediction model. Results: By combining single-cell RNA sequence data and bulk RNA sequence data, we identified a set of DNBs, whose roles involved in androgen-associated activities indicated the signals of a prostate cancer cell transition from an androgen-dependent state to a castration-resistant state. In addition, a risk prediction model including the risk score of four key genes (SCD, NARS2, ALDH1A1, and NFXL1) and other clinical–pathological characteristics was constructed and verified to be able to reasonably predict the prognosis of patients receiving ADT. Conclusions: In summary, four key genes from DNBs were identified as potential diagnostic markers for patients treated with ADT and a risk score-based nomogram will facilitate precise prognosis prediction and individualized therapeutic interventions of CRPC.

Prostate cancer ranks as the second most common malignancy in males. Prostate cancer progressing on androgen deprivation therapy (ADT) is castration-resistant prostate cancer (CRPC). Poly-ADP ribose polymerase (PARP) inhibitors (PARPis) have been at the forefront of the treatment of CRPC. We aim to better characterize the progression-free survival (PFS) and overall survival (OS) in metastatic CRPC patients treated with PARPis. A systemic review search was conducted using National Clinical Trial (NCT), PubMed, Embase, Scopus, and Central Cochrane Registry. The improvement in overall survival was statistically significant, favoring PARPis (hazard ratio (HR) 0.855; 95% confidence interval (CI) 0.752–0.974; p = 0.018). The improvement in progression-free survival was also statistically significant, with results favoring PARPis (HR 0.626; 95%CI 0.566–0.692; p = 0.000). In a subgroup analysis, similar results were observed where the efficacy of PARPis was evaluated in a subgroup of patients without homologous recombination repair (HRR) gene mutation, which showed improvement in PFS favoring PARPis (HR 0.747; 95%CI 0.0.637–0.877; p = 0.000). Our meta-analysis of seven RCTs showed that PARPis significantly increased PFS and OS when used with or without antihormonal agents like abiraterone or enzalutamide.

Prostate cancer ranks as the second most common malignancy in males. Prostate cancer progressing on androgen deprivation therapy (ADT) is castration-resistant prostate cancer (CRPC). Poly-ADP ribose polymerase (PARP) inhibitors (PARPis) have been at the forefront of the treatment of CRPC. We aim to better characterize the progression-free survival (PFS) and overall survival (OS) in metastatic CRPC patients treated with PARPis. A systemic review search was conducted using National Clinical Trial (NCT), PubMed, Embase, Scopus, and Central Cochrane Registry. The improvement in overall survival was statistically significant, favoring PARPis (hazard ratio (HR) 0.855; 95% confidence interval (CI) 0.752–0.974; p = 0.018). The improvement in progression-free survival was also statistically significant, with results favoring PARPis (HR 0.626; 95%CI 0.566–0.692; p = 0.000). In a subgroup analysis, similar results were observed where the efficacy of PARPis was evaluated in a subgroup of patients without homologous recombination repair (HRR) gene mutation, which showed improvement in PFS favoring PARPis (HR 0.747; 95%CI 0.0.637–0.877; p = 0.000). Our meta-analysis of seven RCTs showed that PARPis significantly increased PFS and OS when used with or without antihormonal agents like abiraterone or enzalutamide. [ABSTRACT FROM AUTHOR]

Meningeal metastases (MM) are a rare progression in advanced prostate. Here we aimed to characterize the incidence, clinical presentation, and outcomes of patients with MM, including dural and leptomeningeal metastases, from primary prostate cancer. A systematic search was performed on MEDLINE, EMBASE, Scopus, and Web of Science. Studies that included patients who developed MM from primary prostate cancer were abstracted. Assessed outcomes included time from primary cancer to MM and MM to death, and clinical presentation of MM, among others. Case reports were compared qualitatively, while observational studies were pooled for quantitative synthesis. The systematic review was prospectively registered on PROSPERO (CRD42020205378). Our institutional series, 11 observational studies, and 46 case reports were synthesized, comprising a total of 191 patients. From the observational studies, the mean age at developing MM was 63.0 years (range: 58.4, 70.9). Presenting neurological symptoms were variable and largely depended on location of MM. The mean time from prostate cancer to MM was 54.6 months (range: 21.0, 101.5), and the mean time from MM to death was 9.0 months (range: 2.6, 23.0). Patients requiring resection for MM had shorter survival after disease progression compared to patients receiving radiation or supportive therapy. All articles had at least moderate risk of bias. We describe the largest synthesis of patients with progression to MM from prostate cancer. Current evidence is very low-quality and primarily stems from small observational studies. Neurological symptoms in the setting of advanced prostate cancer, especially in high-risk disease, warrants radiographic imaging for MM. Further prospective research on risk factors and treatment for MM is warranted. [ABSTRACT FROM AUTHOR]

While the androgen receptor (AR) signalling is the mainstay therapeutic target for metastatic prostate cancers, these tumours will inevitably develop therapy resistance to AR pathway inhibitors suggesting that prostate tumour cells possess the capability to develop mechanisms to bypass their dependency on androgens and/or AR to survive and progress. In many studies, protein kinases such as Src are reported to promote prostate tumour progression. Specifically, the pro-oncogene tyrosine Src kinase regulates prostate cancer cell proliferation, adhesion, invasion, and metastasis. Not only can Src be activated under androgen depletion, low androgen, and supraphysiological androgen conditions, but also through crosstalk with other oncogenic pathways. Reciprocal activations between Src and AR proteins had also been reported. These findings rationalize Src inhibitors to be used to treat castrate-resistant prostate tumours. Although several Src inhibitors had advanced to clinical trials, the failure to observe patient benefits from these studies suggests that further evaluation of the roles of Src in prostate tumours is required. Here, we summarize the interplay between Src and AR signalling during castrate-resistant prostate cancer progression to provide insights on possible approaches to treat prostate cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: With the availability of an increasing number of therapeutic options for advanced prostate cancer (APC), optimal sequencing and combination of therapies have emerged to be the areas of challenges. In the Indian context, there is a dearth of consensus recommendations to guide clinicians regarding optimal sequencing of therapy in APC management. A Delphi-based consensus regarding optimal therapy sequencing in APC management was developed by an expert panel of medical oncologists from across India. Methods: An expert scientific committee of 11 medical oncologists and an expert panel of 53 medical oncologists from India constituted the panel for the Delphi consensus. In the first phase, a questionnaire with 41 clinical statements was developed in several critical controversial areas in APC treatment. In the second phase, 29 clinical statements were reworked and sent to eight experts to obtain their opinions on best practices. The consensus ratings were based on a 9-point Likert scale. Based on the overall response, statements with a mean score of ≥ 7 with 1 outlier were considered as "consensus." Results: Degarelix was the preferred androgen deprivation therapy (ADT). While ADT plus docetaxel was the preferred option for metastatic castrate-sensitive/naïve prostate cancer patients with high-volume disease, ADT with abiraterone was the preferred choice for low-volume disease. Docetaxel was the preferred first-line treatment option in men who received ADT alone in the castrate-sensitive/naïve setting. For patients progressing on or after docetaxel for metastatic castrate-resistant prostate cancer (without prior abiraterone or enzalutamide), the experts reached a consensus on the use of enzalutamide as the preferred second-line treatment option. No consensus was reached for the third-line treatment options. Conclusion: This article is intended to serve as a guide to help clinicians discuss with their patients as part of the shared and multidisciplinary decision-making for improved APC management in India. [ABSTRACT FROM AUTHOR]

While the androgen receptor (AR) signalling is the mainstay therapeutic target for metastatic prostate cancers, these tumours will inevitably develop therapy resistance to AR pathway inhibitors suggesting that prostate tumour cells possess the capability to develop mechanisms to bypass their dependency on androgens and/or AR to survive and progress. In many studies, protein kinases such as Src are reported to promote prostate tumour progression. Specifically, the pro-oncogene tyrosine Src kinase regulates prostate cancer cell proliferation, adhesion, invasion, and metastasis. Not only can Src be activated under androgen depletion, low androgen, and supraphysiological androgen conditions, but also through crosstalk with other oncogenic pathways. Reciprocal activations between Src and AR proteins had also been reported. These findings rationalize Src inhibitors to be used to treat castrate-resistant prostate tumours. Although several Src inhibitors had advanced to clinical trials, the failure to observe patient benefits from these studies suggests that further evaluation of the roles of Src in prostate tumours is required. Here, we summarize the interplay between Src and AR signalling during castrate-resistant prostate cancer progression to provide insights on possible approaches to treat prostate cancer patients.

The role of the androgen receptor (AR) in the progression of prostate cancer (PCa) is well established and competitive inhibition of AR ligand binding domain (LBD) has been the mainstay of antiandrogen therapies for advanced and metastatic disease. However, the efficacy of such drugs is often limited by the emergence of resistance, mediated through point mutations and receptor splice variants lacking the AR-LBD. As a result, the prognosis for patients with malignant, castrate-resistant disease remains poor. The amino terminal domain (NTD) of the AR has been shown to be critical for AR function. Its modular activation function (AF-1) is important for both gene regulation and participation in protein–protein interactions. However, due to the intrinsically disordered structure of the domain, its potential as a candidate for therapeutic intervention has been generally overlooked. In this article, we describe the design and development of a functional cell-based assay aimed at identifying small-molecule inhibitors of the AR-NTD. We demonstrate the suitability of the assay for high-throughput screening platforms and validate two initial hits emerging from a small, targeted, library screen in PCa cells. [ABSTRACT FROM AUTHOR]

Castrate-resistant prostate cancer (CRPC) is the lethal form of prostate cancer. Epithelial mesenchymal plasticity (EMP) has been associated with disease progression to CRPC, and prostate cancer therapies targeting the androgen signalling axis, including androgen deprivation therapy (ADT), promote EMP. We explored effects of castration on EMP in the tumours and circulating tumour cells (CTCs) of patient-derived xenograft (PDX)-bearing castrated mice using human-specific RT-qPCR assays and immunocytochemistry. Expression of prostate epithelial cell marker KLK3 was below detection in most tumours from castrated mice (62%, 23/37 mice), consistent with its known up-regulation by androgens. Endpoint tumour size after castration varied significantly in a PDX model-specific pattern; while most tumours were castration-sensitive (BM18, LuCaP70), the majority of LuCaP105 tumours continued to grow following castration. By contrast, LuCaP96 PDX showed a mixed response to castration. CTCs were detected in 33% of LuCaP105, 43% of BM18, 47% of LuCaP70, and 54% of LuCaP96 castrated mice using RPL32 mRNA measurement in plasma. When present, CTC numbers estimated using human RPL32 expression ranged from 1 to 458 CTCs per ml blood, similar to our previous observations in non-castrated mice. In contrast to their non-castrated counterparts, there was no relationship between tumour size and CTC burden in castrated mice. Unsupervised hierarchical clustering of the gene expression profiles of CTCs collected from castrated and non-castrated mice revealed distinct CTC sub-groups within the pooled population that were classified as having mesenchymal, epithelial, or EMP hybrid gene expression profiles. The epithelial signature was only found in CTCs from non-castrated mice. Hybrid and mesenchymal signatures were detected in CTCs from both castrated and non-castrated mice, with an emphasis towards mesenchymal phenotypes in castrated mice. Post-castration serum PSA levels were either below detection or very low for all the CTC positive samples highlighting the potential usefulness of CTCs for disease monitoring after androgen ablation therapy. In summary, our study of castration effects on prostate cancer PDX CTCs showed that CTCs were often detected in the castrate setting, even in mice with no palpable tumours, and demonstrated the superior ability of CTCs to reveal residual disease over the conventional clinical biomarker serum PSA.

Aim: Radium‐223, a targeted alpha therapy, is approved widely for the treatment of patients with metastatic castrate‐resistant prostate cancer, based on a pivotal phase 3 study in predominantly white patients. We investigated the efficacy and safety of radium‐223 in Asian patients with castrate‐resistant prostate cancer and metastatic bone disease. Methods: This multicenter, prospective, single‐arm, open‐label phase 3 trial evaluated the efficacy and safety of the standard radium‐223 regimen (55 kBq/kg every 4 weeks for six cycles) in patients from Asian countries. The primary endpoints were the safety and overall survival. Results: A total of 226 patients were enrolled and received at least one dose of radium‐223. Median overall survival was 14.0 months (95% confidence interval [CI], 11.2–17.4). Median time to total alkaline phosphatase and prostate‐specific antigen progression were 7.5 (95% CI, 6.8–7.7) and 3.6 (95% CI, 3.1–3.7) months, respectively. Median skeletal‐related event‐free survival was 26.0 months (95% CI, 12.6–not reached). Grade ≥3 treatment‐emergent adverse events were reported in 103 (46%) of 226 patients, with anemia being the most common event (34 [15%] patients). Grade ≥3 drug‐related treatment‐emergent adverse events occurred in 39 (17%) of 226 patients. Serious treatment‐emergent adverse events were reported in 65 (29%) of 226 patients. Seven (3%) patients had an adverse event leading to death; none were considered to be related to radium‐223. Conclusion: The results of this study support the use of the standard radium‐223 regimen for the treatment of Asian patients with castrate‐resistant prostate cancer and symptomatic bone metastases. [ABSTRACT FROM AUTHOR]

Kallikrein‐related peptidase 14 (KLK14) is one of the several secreted KLK serine proteases involved in prostate cancer (PCa) pathogenesis. While relatively understudied, recent reports have identified KLK14 as overexpressed during PCa development. However, the modulation of KLK14 expression during PCa progression and the molecular and biological functions of this protease in the prostate tumor microenvironment remain unknown. To determine the modulation of KLK14 expression during PCa progression, we analyzed the expression levels of KLK14 in patient samples using publicly available databases and immunohistochemistry. In order to delineate the molecular mechanisms involving KLK14 in PCa progression, we integrated proteomic, transcriptomic, and in vitro assays with the goal to identify substrates, related‐signaling pathways, and functional roles of this protease. We showed that KLK14 expression is elevated in advanced PCa, and particularly in metastasis. Additionally, KLK14 levels were found to be decreased in PCa tissues from patients responsive to neoadjuvant therapy compared to untreated patients. Furthermore, we also identified that KLK14 expression reoccurred in patients who developed castrate‐resistant PCa. The combination of proteomic and transcriptomic analysis as well as functional assays revealed several new KLK14 substrates (agrin, desmoglein 2, vitronectin, laminins) and KLK14‐regulated genes (Interleukin 32, midkine, SRY‐Box 9), particularly an involvement of the mitogen‐activated protein kinase 1 and interleukin 1 receptor pathways, and an involvement of KLK14 in the regulation of cellular migration, supporting its involvement in aggressive features of PCa progression. In conclusion, our work showed that KLK14 expression is associated with the development of aggressive PCa suggesting that targeting this protease could offer a novel route to limit the progression of prostate tumors. Additional work is necessary to determine the benefits and implications of targeting/cotargeting KLK14 in PCa as well as to determine the potential use of KLK14 expression as a predictor of PCa aggressiveness or response to treatment.

Within the text we describe a 66-year-old male with a history of prostate cancer (PCa), incidentally found to have left-sided hydronephrosis and a left ureteral lesion. Ureteroscopy was employed to visualize the lesion, a biopsy was taken, and a double J stent was placed. The lesion was of prostatic origin and the patient was subsequently started on androgen deprivation therapy (ADT). 6 months following the procedure, the patient's PSA had decreased and his hydronephrosis had resolved. We are the first to report treating a ureteral metastasis from PCa and its associated hydronephrosis solely with ADT and double J stenting, respectively.

Objectives: To assess whether free PSA ratio (FPSAR) at biochemical recurrence (BCR) can predict metastasis, castrate‐resistant prostate cancer (CRPC), and cancer‐specific survival (CSS), following therapy for localised disease. Patients and Methods: A single‐centre retrospective cohort study (NCT03927287) including a discovery cohort composed of patients with an FPSAR after radical prostatectomy (RP) or radiotherapy (RT) between 2000 and 2017. For validation, an independent Biobank cohort of patients with BCR after RP was tested. Using a defined FPSAR cut‐off, the metastasis‐free‐survival (MFS), CRPC‐free survival, and CSS were compared. Multivariable Cox models determined the association between post‐treatment FPSAR, metastases, and CRPC. Results: Overall, 822 patients (305 RP‐ and 363 RT‐treated patients and 154 Biobank patients) were analysed. In the RP cohort, a total of 272/305 (89.1%) and 33/305 (10.9%) had a FPSAR test incidentally and reflexively, respectively. In the RT cohort, 155/363 (42.7%) and 208/263 (57.3%) had a FPSAR test incidentally and reflexively, respectively. However, in the prospective Biobank RP cohort, FPSAR testing was done on all samples of patients diagnosed with BCR. A FPSAR cut‐off of 0.10 was determined using receiver operating characteristic analyses in both the RP and RT cohorts. A FPSAR of <0.10 resulted in longer median MFS (14.8 vs 9.3 years and 14.8 vs 13 years, respectively), and longer median CRPC‐free survival (median not reached vs 9.9 years and 20.7 vs 13.8 years, respectively). Multivariable analyses showed that a FPSAR of ≥0.10 was associated with increased metastasis in the RP cohort (hazard ratio [HR] 1.915, 95% confidence interval [CI] 1.241–2.955) and RT cohort (HR 1.754, 95% CI 1.112–2.769), and increased CRPC in the RP cohort (HR 2.470, 95% CI 1.493–4.088). Findings were validated in the Biobank cohort. Conclusions: A post‐treatment FPSAR of ≥0.10 is associated with more aggressive disease, suggesting a potentially novel role for this biomarker. [ABSTRACT FROM AUTHOR]

We describe the case of a 75-year-old patient who progressed over a 12-year period from localized to symptomatic metastatic prostate cancer (PrCa) with lung as the sole organ of involvement. In this case, the specific sequence of positron emission tomography (PET)-based next-generation imaging with 18F-sodium fluoride-, 18F-fluoro-2-deoxy-D-glucose-, and 18F-DCFPyL PET/computed tomography and biopsies allowed illustration of the pathway of disease progression from nonglycolytic hormone-sensitive PrCa to glycolytic castrate-resistant PrCa without neuroendocrine features. The observations provide a unique insight into the timelines of anatomical and metabolic progression of metastatic PrCa. They highlight the value of close radiographic surveillance of metastatic PrCa with modern imaging to guide early treatment interventions. [ABSTRACT FROM AUTHOR]

Kallikrein‐related peptidase 14 (KLK14) is one of the several secreted KLK serine proteases involved in prostate cancer (PCa) pathogenesis. While relatively understudied, recent reports have identified KLK14 as overexpressed during PCa development. However, the modulation of KLK14 expression during PCa progression and the molecular and biological functions of this protease in the prostate tumor microenvironment remain unknown. To determine the modulation of KLK14 expression during PCa progression, we analyzed the expression levels of KLK14 in patient samples using publicly available databases and immunohistochemistry. In order to delineate the molecular mechanisms involving KLK14 in PCa progression, we integrated proteomic, transcriptomic, and in vitro assays with the goal to identify substrates, related‐signaling pathways, and functional roles of this protease. We showed that KLK14 expression is elevated in advanced PCa, and particularly in metastasis. Additionally, KLK14 levels were found to be decreased in PCa tissues from patients responsive to neoadjuvant therapy compared to untreated patients. Furthermore, we also identified that KLK14 expression reoccurred in patients who developed castrate‐resistant PCa. The combination of proteomic and transcriptomic analysis as well as functional assays revealed several new KLK14 substrates (agrin, desmoglein 2, vitronectin, laminins) and KLK14‐regulated genes (Interleukin 32, midkine, SRY‐Box 9), particularly an involvement of the mitogen‐activated protein kinase 1 and interleukin 1 receptor pathways, and an involvement of KLK14 in the regulation of cellular migration, supporting its involvement in aggressive features of PCa progression. In conclusion, our work showed that KLK14 expression is associated with the development of aggressive PCa suggesting that targeting this protease could offer a novel route to limit the progression of prostate tumors. Additional work is necessary to determine the benefits and implications of targeting/cotargeting KLK14 in PCa as well as to determine the potential use of KLK14 expression as a predictor of PCa aggressiveness or response to treatment. [ABSTRACT FROM AUTHOR]

Since the Nobel Prize-winning work of Huggins, androgen ablation has been a mainstay for treatment of recurrent prostate cancer. While initially effective for most patients, prostate cancers inevitably develop the ability to survive, grow, and metastasize further, despite ongoing androgen suppression. Here, we briefly review key preclinical studies over decades and include illustrative examples from our own laboratories that suggest prostate cancer cells titrate androgen signaling to optimize growth. Such laboratory-based studies argue that adaptations that allow growth in a low-androgen environment render prostate cancer sensitive to restoration of androgens, especially at supraphysiologic doses. Based on preclinical data as well as clinical observations, trials employing high-dose testosterone (HDT) therapy have now been conducted. These trials suggest a clinical benefit in cancer response and quality of life in a subset of castration-resistant prostate cancer patients. Laboratory studies also suggest that HDT may yet be optimized further to improve efficacy or durability of response. However, laboratory observations suggest that the cancer will inevitably adapt to HDT, and, as with prior androgen deprivation, disease progression follows. Nonetheless, the adaptations made to render tumors resistant to hormonal manipulations may reveal vulnerabilities that can be exploited to prolong survival and provide other clinical benefits.

Prostate cancer (PCa) is the most prevalent malignancy of the male genitourinary system, and its etiology suggests that genetics is an essential risk factor for its development and progression, while exogenous factors may have an significant impact on this risk. Initial diagnosis of advanced PCa is relatively frequent, and androgen deprivation therapy (ADT) is the predominant standard of care for PCa and the basis for various novel combination therapy regimens, and is often required throughout the patient's subsequent treatment. Although diagnostic modalities and treatment options are evolving, some patients suffer from complications, including biochemical relapse, metastasis and treatment resistance. Mechanisms of PCa pathogenesis and progression have been the focus of research. N6-methyladenosine (m6A) is an RNA modification involved in cell physiology and tumor metabolism. It has been observed to affect the evolution of diverse cancers through the regulation of gene expression. Genes associated with m6A are prominent in PCa and are involved in multiple aspects of desmoresistant PCa occurrence, progression, PCa bone metastasis (BM), and treatment resistance. Here, we explore the role of m6A modifications in promoting PCa., (© 2023 Wiley-VCH GmbH.)

Objectives: To investigate if full‐length androgen receptor (AR‐FL) is associated with resistance to androgen receptor (AR)‐directed therapy independently and/or combined with AR splice variant 7 (AR‐V7). Patients and Methods: Plasma samples were prospectively collected from 73 patients with castrate‐resistant prostate cancer before first‐ or second‐line AR‐directed therapy. mRNA was isolated from exosomes and AR‐FL and AR‐V7 were analysed by droplet digital PCR. Results: AR‐FL was detected in all patients and 22% of them were AR‐V7‐positive at baseline. AR‐FL expression was significantly higher in AR‐V7‐positive vs AR‐V7‐negative patients (P < 0.0001). After stratifying patients by tertile for AR‐FL expression, progression‐free survival (PFS) was 22 vs 18 vs 4 months for lower vs intermediate vs higher tertile, respectively (P = 0.0003). The median PFS and overall survival were significantly longer in AR‐V7‐negative vs AR‐V7‐positive patients (20 vs 4 months, P < 0.0001; not reached vs 9 months, P < 0.0001, respectively). Conclusions: Resistance to AR‐directed therapy was associated with the presence of AR‐V7; however, AR‐FL expression may help better refine response and survival of patients to AR‐directed therapy. Both biomarkers, if validated in prospective trials, could be used to select the best treatment strategy. [ABSTRACT FROM AUTHOR]

Homeobox A10 (HOXA10) is an important transcription factor that regulates the development of the prostate gland. However, it remains unknown whether it modulates prostate cancer (PCa) progression into castrate-resistant stages. In this study, we have applied RNA in situ hybridization assays to demonstrate that downregulation of HOXA10 expression is associated with castrate-resistant PCa. These findings are supported by public RNA-seq data showing that reduced HOXA10 expression is correlated with poor patient survival. We show that HOXA10 suppresses PCa cell proliferation, anchorage colony formation and xenograft growth independent to androgens. Using AmpliSeq transcriptome sequencing, we have found that gene groups associated with lipid metabolism and androgen receptor (AR) signaling are enriched in the HOXA10 transcriptome. Furthermore, we demonstrate that HOXA10 suppresses the transcription of the fatty acid synthase (FASN) gene by forming a protein com plex with AR and prevents AR recruitment to the FASN gene promoter. These results lead us to conclude that downregulation of HOXA10 gene expression may enhance lipogenesis to promote PCa cell growth and tumor progression to castrate-resistant stage. [ABSTRACT FROM AUTHOR]

Monica Archibald,1 Tara Pritchard,1 Hayley Nehoff,1 Rhonda J Rosengren,1 Khaled Greish,1,2 Sebastien Taurin1 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Aljawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. Keywords: sorafenib, nilotinib, castrate-resistant prostate cancer, tyrosine kinase inhibitors, nanomedicine

The skeletal system is of paramount importance in advanced stage prostate cancer (PCa) as it is the preferred site of metastasis. Complex mechanisms are employed sequentially by PCa cells to home to and colonize the bone. Bone-resident PCa cells then recruit osteoblasts (OBs), osteoclasts (OCs), and macrophages within the niche into entities that promote cancer cell growth and survival. Since PCa is heavily reliant on androgens for growth and survival, androgen-deprivation therapy (ADT) is the standard of care for advanced disease. Although it significantly improves survival rates, ADT detrimentally affects bone health and significantly increases the risk of fractures. Moreover, whereas the majority patients with advanced PCa respond favorably to androgen deprivation, most experience a relapse of the disease to a hormone-refractory form within 1–2 years of ADT. The tumor adapts to surviving under low testosterone conditions by selecting for mutations in the androgen receptor (AR) that constitutively activate it. Thus, AR signaling remains active in PCa cells and aids in its survival under low levels of circulating androgens and additionally allows the cancer cells to manipulate the bone microenvironment to fuel its growth. Hence, AR and its downstream effectors are attractive targets for therapeutic interventions against PCa. Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2), was recently identified as a key downstream target of AR in coordinating PCa cell growth, survival, and migration. Additionally, this multifunctional serine/threonine protein kinase is a critical mediator of bone remodeling and macrophage function, thus emerging as an attractive therapeutic target downstream of AR in controlling metastatic PCa and preventing ADT-induced bone loss. Here, we discuss the role played by AR-CaMKK2 signaling axis in PCa survival, metabolism, cell growth, and migration as well as the cell-intrinsic roles of CaMKK2 in OBs, OCs, and macrophages within the bone microenvironment.

Prostate cancer (PCa) is the most common form of cancer in men in the developed world and the second leading cause of cancer‐related deaths. While advanced PCa is initially controlled with hormonal therapies targeting the androgen receptor (AR) pathway, recurrence occurs because of the emergence of lethal castration‐resistant PCa (CRPC). Despite newer AR pathway inhibitors that prolong survival, resistance still emerges, most often with rising PSA levels indicative of AR‐driven activity, but increasingly as non‐AR‐driven cancer. Treatment resistance mechanisms include AR‐signalling pathway alterations, AR‐signalling bypass mechanisms, and AR‐independent clonal evolution. The latter mechanism can lead to the emergence of neuroendocrine prostate cancer (NEPC), an aggressive lethal subtype of PCa. The incidence of treatment‐induced NEPC is rising because of the widespread use of more potent AR pathway inhibitors. This comprehensive review of major NEPC drivers and facilitators defines three coordinated processes contributing to NEPC progression. Specifically, castration‐resistant adenocarcinoma cells gain lineage plasticity under selective pressures of potent AR suppression to transform into AR‐independent tumour cells. In concert, neuroendocrine (NE)‐specific transdifferentiation factors induce NE lineage of these PCa cells, which, with support of increased proliferation factors, contributes to clonal expansion and tumour repopulation into NEPC. We examine the roles of each of the major NEPC contributors during the disease progression and identify potential therapeutic opportunities for targeted therapies. [ABSTRACT FROM AUTHOR]

Castrate-resistant prostate cancer is an incurable disease. It continues to be an area of intense research to save prostate cancer patients’ lives. We aim from this review to explore the new lines of treatment that aim at extending disease-specific survival. We conducted a PubMed research on available literature pertaining to key words alone and in combination: prostate cancer, castrate-resistant, immunotherapy, hormonal therapy, chemotherapy, radiation therapy, metastasis, survival and quality of life. We also reviewed the following guidelines on castrate-resistant prostate cancer: National Comprehensive Cancer Network (NCCN), American Urological Association (AUA), the National Institute for Health and Care Excellence (NICE) and the European Association of Urology (EAU). There are four new lines of treatment in castrate-resistant prostate cancer. An immunotherapy, sipuleucel T (Provenge); new hormonal therapies – in the form of a new androgen receptor blocker, enzalutamide (Xtandi) and new adrenal androgen synthesis inhibitor, abiraterone acetate (Zytiga); a new chemotherapy, cabazitaxel (Jevtana) and new radioactive agent, radium 223 (Xofigo). There is an agreement between guidelines that patients with M0 castrate-resistant prostate cancer should not be offered any of these treatments. Similarly, patients with castrate-resistant prostate cancer and poor performance status should be offered only palliative care. There are several new lines of treatment that can be used in castrate-resistant prostate cancer, and hopefully in the near future castrate-resistant prostate cancer will be changing from a lethal disease to more of a chronic disease. [ABSTRACT FROM AUTHOR]

The skeletal system is of paramount importance in advanced stage prostate cancer (PCa) as it is the preferred site of metastasis. Complex mechanisms are employed sequentially by PCa cells to home to and colonize the bone. Bone-resident PCa cells then recruit osteoblasts (OBs), osteoclasts (OCs), and macrophages within the niche into entities that promote cancer cell growth and survival. Since PCa is heavily reliant on androgens for growth and survival, androgen-deprivation therapy (ADT) is the standard of care for advanced disease. Although it significantly improves survival rates, ADT detrimentally affects bone health and significantly increases the risk of fractures. Moreover, whereas the majority patients with advanced PCa respond favorably to androgen deprivation, most experience a relapse of the disease to a hormone-refractory form within 1–2 years of ADT. The tumor adapts to surviving under low testosterone conditions by selecting for mutations in the androgen receptor (AR) that constitutively activate it. Thus, AR signaling remains active in PCa cells and aids in its survival under low levels of circulating androgens and additionally allows the cancer cells to manipulate the bone microenvironment to fuel its growth. Hence, AR and its downstream effectors are attractive targets for therapeutic interventions against PCa. Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2), was recently identified as a key downstream target of AR in coordinating PCa cell growth, survival, and migration. Additionally, this multifunctional serine/threonine protein kinase is a critical mediator of bone remodeling and macrophage function, thus emerging as an attractive therapeutic target downstream of AR in controlling metastatic PCa and preventing ADT-induced bone loss. Here, we discuss the role played by AR-CaMKK2 signaling axis in PCa survival, metabolism, cell growth, and migration as well as the cell-intrinsic roles of CaMKK2 in OBs, OCs, and macrophages within the bone microenvironment. [ABSTRACT FROM AUTHOR]

Conjugated oestrogen is one of the more affordable secondary hormonal options available for castrate-resistant prostate cancer (CRPC) in Jamaica. The present study was conducted to examine the disease response in Jamaican men with CRPC treated with conjugated oestrogen. This study retrospectively reviewed the medical notes of patients who attended the urologic clinic of the University Hospital of the West Indies from 1 January 2009 to 31 December 2013 and a private urology clinic from 2 November 2005 to 3 June 2015 to identify patients diagnosed with CRPC treated with conjugated oestrogen (Premarin ®) as secondary therapy. The primary endpoint of favourable response, using the Prostate Cancer Clinical Trials Working Group 2 criteria is a decline of ≥50% in serum prostate-specific antigen (PSA) concentrations from baseline after treatment. The proportion of patients responding by the first 3-month follow-up visit and the maximal PSA declined over the 24 months of follow-up which were recorded. Thirty-two patients diagnosed with CRPC and treated with conjugated oestrogen were identified. All patients were prescribed 5.0 mg (2.5 mg tablets, twice daily) orally, as well as low dose aspirin. Favourable response was observed in 14 (43.8%) patients; however, eight other patients showed a decline in serum PSA concentration of <50%. There were no reported adverse effects. Conjugated oestrogen produced a PSA decline in Jamaican CRPC patients of this study and may therefore be a useful option for secondary therapy of CRPC. Further assessment is needed. [ABSTRACT FROM AUTHOR]

Prostate cancer is the most frequent noncutaneous cancer occurring in men. On average, men with localized prostate cancer have a high 10-year survival rate, and many can be cured. However, men with metastatic castrate-resistant prostate cancer have incurable disease with poor survival despite intensive therapy. This unmet need has led to recent advances in therapy aimed at treating bone metastases resulting from prostate cancer. The bone microenvironment lends itself to metastases in castrate-resistant prostate cancer, as a result of complex interactions between the microenvironment and tumor cells. The development of 223radium dichloride (Ra-223) to treat symptomatic bone metastases has improved survival in men with metastatic castrate-resistant prostate cancer. Moreover, Ra-223 may have effects on the tumor microenvironment that enhance its activity. Ra-223 treatment has been shown to prolong survival, and its effects on the immune system are under investigation. Because prostate cancer affects a sizable portion of the adult male population, understanding how it metastasizes to bone is an important step in advancing therapy. Clinical trials that are underway should yield new information on whether Ra-223 synergizes effectively with immunotherapy agents and whether Ra-223 has enhancing effects on the immune system in patients with prostate cancer. [ABSTRACT FROM AUTHOR]

The aim of the present study was to construct the 125I‑replication‑selective oncolytic adenovirus (RSOAds)‑ human telomerase reverse transcriptase (hTERT)/prostate specific antigen (PSA) nuclide‑oncolytic virus marker by labelling the hTERT/PSA double‑regulation replicative oncolytic adenovirus with 125I nuclide, and investigate the influence of viral markers under various reaction conditions on labelling efficiency. N‑bromosuccinimide (NBS) was used as the oxidizer for 125I labelling, and the best conditions for labelling were identified through the reactions between oncolytic adenovirus at various concentrations and NBS. Dosage of 125I, reaction duration, pH values and reaction volume were respectively evaluated to determine their effects on the labelling efficiency of 125I‑RSOAds‑hTERT/PSA nuclide‑oncolytic adenovirus markers. Purified nuclide‑oncolytic adenovirus markers were isolated by gel‑filtration chromatography; paper chromatography was performed to assay the radiochemical purity of 125I‑RSOAds‑hTERT/PSA markers at various time points. Radiochemical purity of 125I‑RSOAds‑hTERT/PSA was >95%, and could be maintained at 4˚C for 7 days. The best reaction conditions were set as follows: 0.5 μl of 125I (~0.2 m Ci, 7.4 MBq); 25 qg of NBS; 100 μl of 8x109 VP/ml 125I‑RSOAds‑hTERT/PSA virus solution; 30 min of reaction duration; pH 7.5; 120 μl of PBS. Labelling hTERT/PSA double‑regulation replicative oncolytic adenovirus with 125I was identified to be available, and the radiochemical purity of acquired virus markers could be maintained under specific conditions. [ABSTRACT FROM AUTHOR]

Prostate cancer is one of the most actual problems of modern oncourology. Castrate-refractory prostate cancer (CRPC) is extremely he-terogeneous disease and treatment conception should be individualized in every patient. Therapeutic options in CRPC include 2nd line hormonal therapy, chemotherapy, vaccines, target therapy, radiopharmaceuticals, etc. However, clear algorithm of treatment in using of 1st or 2nd line drugs nowadays is absent. In the article modern concept of treatment of patients with CRPC is present, moreover prognostic factors of therapeutic response are analyzed.

MicroRNAs (miRNAs) are small endogenous non-coding molecules that alters gene expression through post-transcriptional regulation of messenger RNA. Compelling evidence suggest the role of miRNA in cancer biology having potential as diagnostic, prognostic and predictive biomarkers. This review summarizes the current knowledge on miRNA deregulated in prostate cancer and their role as oncogene, tumor suppressor and metastasis regulators. The emerging information elucidating the biological function of miRNA is promising and may lead to their potential usefulness as diagnostic/prognostic markers and development as effective therapeutic tools for management of prostate cancer. [ABSTRACT FROM AUTHOR]

Background: The aim of this retrospective study was to evaluate the clinical outcomes of reduced dose, biweekly docetaxel chemotherapy for Korean patients with castrate-resistant prostate cancer (CRPC).Methods: We retrospectively reviewed the medical records of 48 patients with metastatic CRPC who were treated with a biweekly regimen (intravenous docetaxel 40 mg/m2 on day 1 plus prednisolone 5 mg twice daily) between 2012 and 2015 at Samsung Medical Center (Seoul, Korea). Prior to the adoption of a biweekly regimen in Oct 2013, our institutional standard chemotherapy was docetaxel 75 mg/m2 every 3 weeks for patients with CRPC (n = 24). After Oct 2013, all chemotherapy-naïve patients with CRPC received a 40 mg/m2 biweekly regimen (n = 24). The primary end point was a PSA response, defined as a greater than 50% decline in PSA level from baseline.Results: The baseline characteristics of the patients in the two treatment groups were similar. The most common cause of treatment discontinuation was disease progression, which was exhibited by 17 patients (71%) in the 3-weekly group and 20 (75%) in the biweekly group. PSA responses were observed in 12 (50%) and 11 (46%) patients in the 3-weekly and biweekly groups, respectively (p = 0.683). Time to treatment failure (TTTF, 4.5 vs 3.9 months) and time-to-progression (TTP, 5.0 vs 4.2 months) were not significantly different between the 3-weekly and biweekly groups.Conclusions: Within the limitations of a retrospective study, the biweekly reduced dose docetaxel regimen was active and well-tolerated in Korean patients with metastatic CRPC. [ABSTRACT FROM AUTHOR]

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Objectives To assess time to progression to castrate-resistant prostate cancer ( CRPC) and factors influencing longer-term outcomes in patients receiving androgen-deprivation therapy ( ADT) in an extension to the Triptocare study ( NCT01020448). This is pertinent as the Triptocare study did not show that urinary prostate cancer antigen-3 (PCA3) score was a reliable marker of cancer stage in advanced prostate cancer and was not useful for assessing response 6 months after initiation of ADT with triptorelin 22.5 mg. Patients and Methods An international, multicentre, non-interventional, observational, longitudinal, prospective study involving patients from the Triptocare study. CRPC status of patients was collected for up to 3 years from ADT initiation. Patient treatment and assessments were at the investigator's discretion. Co-primary endpoints were rate of CRPC at 3 years after initiating ADT and the median time to CRPC. An exploratory endpoint was the association of Triptocare baseline variables (including TMPRSS2- ERG and PCA3 scores) and PCA3 score at Triptocare last value available with CRPC onset. Results Of the 325 patients in the Triptocare study safety population, 180 patients were enrolled in the Triptocare LT study (102 received continuous and 78 received intermittent ADT). CRPC rates at 3 years were 24/102 (23.5%) and 6/78 (7.7%) patients in the continuous and intermittent ADT groups, respectively. The median time to CRPC was not reached for either group. PCA3 score status at baseline was the only variable associated with a higher risk of progression to CRPC in both the intermittent and continuous ADT groups; compared with a baseline PCA3 score of ≥35, a PCA3 score below the level of quantification had a hazard ratio ( HR) of 20.04 ([95% confidence interval ( CI) 2.71-148.34] and a HR of 9.44 [95% CI 2.39-37.27], respectively). Baseline metastatic disease and testosterone level were additionally associated with progression to CRPC in the continuous ADT population ( HR 5.20, 95% CI 1.68-16.06 and HR 0.995, 95% CI 0.991-0.999, respectively). Conclusion In men with locally advanced or metastatic prostate cancer, a PCA3 score of ≥35 at the time of initiating ADT may predict a lower risk of developing CRPC in the following 3 years. [ABSTRACT FROM AUTHOR]