Castration-resistant Prostate Cancer Patients Research Articles

The value of real world evidence and pragmatic trials in advanced prostate cancer- insights from the electronic Prostate Cancer Australian and Asian Database

Prostate cancer is a common malignancy with an increasing incidence in ageing populations. However, older patients with prostate cancer are often underrepresented in traditional clinical trials. The electronic Prostate Cancer Australian and Asian Database (ePAD) is a multi-centre, multi-national prospective clinical registry, that records real world data from a broader population. An analysis of the first 753 metastatic castration-resistant prostate cancer (mCRPC) patients within ePAD demonstrated that 43% were aged 75 years and older. Older patients were more likely to have comorbidities including ischemic heart disease, diabetes and previous stroke. Treatment outcomes were similar in all age groups. However, older patients receiving chemotherapy were more likely to stop treatment due to toxicity. Furthermore, in a smaller ePAD analysis involving additional chart reviews within 3 high volume centres, at least one relative or absolute contraindication to abiraterone was seen in 72% of our cohort and with enzalutamide in 14%. In total, 47% had potential clinically significant drug interactions with abiraterone and 67% with enzalutamide. Registry-based randomised controlled trials (RRCTs) are a novel trial methodology aiming to bridge the gap between retrospective registry analyses and traditional randomised controlled trials. We conducted the REAL-Pro study in advanced prostate cancer, comparing cognition, depression and falls risk between CRPC patients receiving abiraterone or enzalutamide. The study closed early due to slow recruitment and a changing treatment landscape, highlighting the need for further research to understand clinician and patient perspectives towards pragmatic trials such as RRCTs and subsequently develop strategies to optimise future trial design and recruitment.

Comparative analysis of gut microbiota in hormone-sensitive and castration-resistant prostate cancer in Japanese men.

Gut microbiota plays a crucial role in the development and progression of prostate cancer, with previous studies indicating that certain bacterial taxa are more abundant in castration-resistant prostate cancer (CRPC) compared to hormone-sensitive prostate cancer (HSPC). Notably, the composition of gut microbiota can vary significantly by geographic region, and Japanese individuals have a distinct microbial profile. However, research exploring these differences within Japanese populations remains limited. This study investigated the gut microbiota differences between Japanese men with HSPC and CRPC and further validated these findings using a transgenic mouse model. Rectal swab samples were collected from 140 Japanese men diagnosed with HSPC (n = 84) or CRPC (n = 56) between September 2020 and July 2022. Gut microbiota composition was analyzed using 16S rRNA gene sequencing. Additionally, Pten-KO mice, which model the progression from HSPC to CRPC, underwent similar microbiota analysis. Results revealed significant differences in gut microbiota composition between HSPC and CRPC patients. Specifically, the CRPC group showed a higher abundance of Firmicutes, including Gemella and Lactobacillus, compared to the HSPC group. These differences were mirrored in the mouse model, where CRPC mice also showed an increase in these bacteria. This study identifies distinct microbial differences between HSPC and CRPC in Japanese men, suggesting that Gemella and Lactobacillus may be associated with the progression to castration resistance in prostate cancer. These findings suggest that gut microbiota differences may be associated with prostate cancer progression. Further research is needed to explore the potential of targeting the microbiota as a therapeutic strategy.

Targeting Androgen Receptor Variants in Castration-Resistant Prostate Cancer (CRPC)

Castration-resistant prostate cancer (CRPC) remains a lethal stage of prostate cancer, characterized by resistance to androgen deprivation therapy (ADT) and poor clinical prognosis. One of the key drivers in CRPC progression is the androgen receptor (AR), specifically the emergence of androgen receptor variants (AR-Vs) that sustain AR signaling even in the absence of androgens. AR-Vs, such as AR-V7, promote androgen-independent activation of oncogenic pathways, leading to uncontrolled cell proliferation and therapeutic resistance. Targeting AR-Vs offers a promising therapeutic strategy to manage CRPC effectively. This review explores the molecular mechanisms underpinning AR-V expression, examines the roles of major AR variants in CRPC progression, and evaluates current and emerging therapies targeting AR-Vs. By summarizing recent advancements and the limitations of current approaches, we highlight potential future directions to improve therapeutic outcomes for CRPC patients. Keywords: Androgen receptor variants, Castration-resistant prostate cancer, AR-V7, Androgen deprivation therapy, Targeted therapy, Oncogenic pathways

Administration and cancer-control outcomes of bone-modifying agents in real-world metastatic castration resistant prostate cancer patients

Abstract Hormonal agents administered for metastatic castration-resistant prostate cancer may lead to osteoporosis, skeletal events, reduced quality of life and even reduced overall survival. Bone-modifying agents may prevent from those events but their effect on cancer-control outcomes remain uncertain. Relying on our institutional tertiary-care database to explore the effect of bone-modifying agents (bisphosphonates such as zoledronic acid and denosumab) on OS and progression-free survival in metastatic castration-resistant prostate cancer patients with at least one bone metastasis in Kaplan-Meyer estimates and Cox regression models. Of 420 metastatic castration-resistant prostate cancer patients, 60% received bone-modifying agents, which were younger (68 vs. 69 years) with more systemic treatment lines for mCRPC (3 vs. 2) and higher proportion of initial DeNovo metastatic disease (72% vs. 62%, all P≤.04) than patients without bone-modifying agents. In progression-free survival analyses, no significant differences were observed between both groups. In overall survival analyses, significant median overall survival differences were observed in favor of patients with bone-modifying agents (58 vs. 45 months, hazard ratio [HR]: 0.66), even after multivariable adjustment (HR: 0.37, both P≤.01). In bone-modifying agent-stratified analyses, 57% received denosumab vs. 43% bisphosphonates, with a significant higher rate of Eastern Cooperative Oncology Group status ≥2 patients in the bisphosphonates group. In progression-free and overall survival analyses, no significant differences were observed between bisphosphonates vs. denosumab patients, with numeric better results in progression-free survival analysis for denosumab after adjusting for covariates. Cumulative rate of osteonecrosis of the jaw at any treatment time was 12% in both groups and significantly decreased over time. Real-world data suggest a relatively low administration rate of bone-modifying agents in osseous metastatic castration-resistant prostate cancer patients. However, real-world also suggest an overall survival benefit, when bone-modifying agents are used, even after controlling for possible confounding patient and tumor characteristics.

GDF15 propeptide promotes bone metastasis of castration-resistant prostate cancer by augmenting the bone microenvironment

BackgroundBone metastasis (BM) is a common and fatal condition in patients with castration-resistant prostate cancer (CRPC). However, there are no useful blood biomarkers for CRPC with BM, and the mechanism underlying BM is unclear. In this study, we investigated precise blood biomarkers for evaluating BM that can improve the prognosis of patients with CRPC.MethodsWe comprehensively examined culture supernatants from four prostate cancer (PCa) cell lines using Orbitrap mass spectrometry to identify specific proteins secreted abundantly by PCa cells. The effects of this protein to PCa cells, osteoblasts, osteoclasts were examined, and BM mouse model. In addition, we measured the plasma concentration of this protein in CRPC patients for whom bone scan index (BSI) by bone scintigraphy was performed.ResultsA total of 2,787 proteins were identified by secretome analysis. We focused on GDF15 propeptide (GDPP), which is secreted by osteoblasts, osteoclasts, and PCa cells. GDPP promoted the proliferation, invasion, and migration of PC3 and DU145 CRPC cells, and GDPP aggravated BM in a mouse model. Importantly, GDPP accelerated bone formation and absorption in the bone microenvironment by enhancing the proliferation of osteoblasts and osteoclasts by upregulating individual transcription factors such as RUNX2, OSX, ATF4, NFATc1, and DC-STAMP. In clinical settings, including a total of 416 patients, GDPP was more diagnostic of BM than prostate-specific antigen (PSA) (AUC = 0.92 and 0.78) and the seven other blood biomarkers (alkaline phosphatase, lactate dehydrogenase, bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b, osteocalcin, procollagen I N-terminal propeptide and mature GDF15) in patients with CRPC. The changes in BSI over time with systemic treatment were correlated with that of GDPP (r = 0.63) but not with that of PSA (r = -0.16).ConclusionsGDPP augments the tumor microenvironment of BM and is a novel blood biomarker of BM in CRPC, which could lead to early treatment interventions in patients with CRPC.

Abstract B019: Androgen receptor-regulated lncRNA PRCAT71 promotes AR signaling through the interaction with RBPs in prostate cancer

Abstract Prostate cancer (PCa) is the second leading cause of cancer death in American men. PCa patients usually receive androgen deprivation therapy but eventually, they will relapse and tumors become castration-resistant PCa (CRPC) without effective treatments, highlighting the urgent need to develop better therapeutics to target advanced PCa. The main mechanism identified leading to castration resistance is aberrant androgen receptor (AR) reactivation, including AR overexpression. Approximately 80% of CRPC patients have a marked increase in AR mRNA and protein expression. Emerging evidence suggests genomic and transcriptomic changes insufficiently predict biology and mRNA and protein expression levels frequently do not correlate. Posttranscriptional regulation of AR mRNA can lead to AR overexpression. RNA binding proteins (RBPs) and non-coding RNAs (ncRNAs), such as microRNAs, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), can control gene expression via direct binding to mRNAs and regulating mRNA processing, modification, and translation. Here in this study, we identified a novel PCa-specific lncRNA, PRCAT71, which is higher expressed in prostate tumor tissues than in benign tissues. Silencing PRCAT71 suppressed the cancerous properties of PCa cells, and reduced AR mRNA and protein expression levels, leading to inhibited AR signaling. We further uncovered that PRCAT71 formed an RNA-RNA duplex with AR mRNA, which enhanced the stability of AR mRNA. RNA pulldown assay identified PRCAT71- interacted RBPs. Silencing PRCAT71 reduced the interaction between key RBPs and AR mRNA, which is related to PRCAT71 regulating AR mRNA stability. Interestingly, PRCAT71 is transcriptionally regulated by AR-driven enhancers, thus forming a positive regulatory loop between AR and PRCAT71 in PCa. The high expression of PRCAT71 and key RBPs in PCa tumors are positively correlated with PSA level, AR activity and indicate worse patient overall survival and metastasis-free survival. Our study revealed a novel regulatory mechanism by which lncRNA PRCAT71 enhances the interaction of key RBPs with AR mRNA, stabilizes AR mRNA and promotes AR expression and PCa progression. Targeting PRCAT71-RBPs is a promising approach to treating CRPC. Citation Format: Yongyong Yang, Ting-You Wang, Qianru Li, Adam B Weiner, Jiawen Lu, Yanan Ren, Qingxiang Guo, Chaehyun Yum, Qi Liu, Rui Wang, Zhe Ji, Tamara L Lotan, Edward M Schaeffer, Rendong Yang, Qi Cao. Androgen receptor-regulated lncRNA PRCAT71 promotes AR signaling through the interaction with RBPs in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B019.

Fuzheng-Buyi formula for treating castration-resistant prostate cancer: A systematic review and meta-analysis.

The study was designed to systematically evaluate the efficacy and safety of Fuzheng-Buyi formula in treating castration-resistant prostate cancer (CRPC). A computer-based search were conducted in the databases, including CNKI, WanFang Data, VIP, CBM, PubMed, EMbase, and the Cochrane database to identify all randomized controlled trials. The studies investigating the efficacy and safety of Fuzheng-Buyi formula combined with Western medicine for the treatment of CRPC were included from January 1st, 2010 to December 31st, 2023. The quality of the included studies was evaluated according to the Cochrane Handbook manual, and meta-analysis was performed using Review Manager 5.3 and R Studio 4.2.3 software. In this study, a total of 18 trials were included, encompassing a population of 1093 patients diagnosed with CRPC. The results of the meta-analysis showed that the combination of Fuzheng-Buyi formula and Western drugs was more effective in increasing the overall efficacy rate (risk ratio = 1.31, 95% confidence interval [CI] [1.17, 1.46], P < .00001), decreasing Traditional Chinese Medicine syndrome score (mean difference [MD] = -4.40, 95% CI [-6.10, -2.70], P < .00001), and quality of life scale (physiological condition MD = -2.31, 95% CI [-3.13, -1.48], P < .00001; social well-being MD = 1.26, 95% CI [0. 59, 1.94], P = .0002; emotional well-being MD = -2.04, 95% CI [-2.96, -1.12], P < .00001; functional well-being MD = -3.18, 95% CI [2.11, 4.26], P < .00001; others should be paid to MD = -3.15, 95% CI [-4.93, -1.37], P = .0005) compared with the Western medicine alone. And the incidence of adverse events was significantly lower in the combination treatment group compared with Western medicine group (risk ratio = 0.58, 95% CI [0.46, 0.73], P < .00001). The combination of Fuzheng-Buyi formula and Western medicine was more effective in improving the clinical efficacy and quality of life of CRPC patients, with lower incidence of adverse events compared with Western medicine alone.

Influence of metastatic sites and burden on oncological outcomes in patients progressing to metastatic castration resistant prostate cancer

PurposeMetastatic castration-resistant prostate cancer (mCRPC) patients harbor reduced life expectancy after first-line treatment progression. Currently, no information is available regarding the influence of metastatic sites and osseous burden on progression-free (PFS) and overall survival (OS) of mCRPC patients.MethodsWe relied on the Frankfurt Metastatic Cancer Database of the Prostate (FRAMCAP) database to select patients progressing to mCRPC and stratified them according to lymph node vs. osseous vs. visceral metastatic sites. Moreover, we stratified osseous mCRPC patients regarding the number of metastatic lesions. Endpoints were PFS and OS in uni- and multivariable Cox regression models.ResultsOf 363 patients, 9.4% harbored M1a vs. 78% M1b vs. 12% M1c mCRPC with significantly higher PSA in M1b (9 vs. 22 vs. 8ng/ml). Rates of DeNovo (15% vs. 60% vs. 56%) were significantly lower in the M1a mCRPC group, compared to M1b and M1c (p < 0.001). In PFS analyses, a median of 12.7 vs. 10.1 vs. 15.9 months for M1a vs. M1b vs. M1c mCRPC was observed (p > 0.05). In multivariable Cox regression models, M1c mCRPC was independently at higher risk for progression (hazard ratio [HR]: 5.93, p = 0.048), relative to M1a. Regarding OS, significant differences were observed (p = 0.002), with median OS of 58 vs. 42 vs. 25 months for M1a vs. M1b vs. M1c mCRPC and corresponding HRs of 1.54 (p = 0.11) and 2.76 (p < 0.01). In multivariable models M1c mCRPC was associated with higher risk of death (HR: 3.56, p = 0.049), relative to M1a. No differences were observed after stratification according to number of bone lesions (all p ≥ 0.05).ConclusionM1c mCRPC patients are independently at higher risk for progression and death, while M1a patients harbor best cancer-control outcomes.

Nodularin-R Synergistically Enhances Abiraterone Against Castrate- Resistant Prostate Cancer via PPP1CA Inhibition.

Clinically, most prostate cancer (PCa) patients inevitably progress to castration-resistant prostate cancer (CRPC) with poor prognosis after androgen deprivation therapy (ADT), including abiraterone, the drug of choice for ADT. Therefore, it is necessary to explore the resistance mechanism of abiraterone in depth. Genome-wide CRISPR/Cas9 knockout technology was used to screen CRPC cell line 22Rv1 for abiraterone-resistant genes. Combined with bioinformatics, a key gene with high expression and poor prognosis in CRPC patients was screened. Then, the effects of target gene on abiraterone-resistant 22Rv1 cell function were explored by silencing and overexpression. Further, a natural product with potential targeting effect was identified and validated by molecular docking and protein expression. Molecular dynamics simulations revealed potential mechanism for the natural product affecting target protein expression. Finally, the combined anti-CRPC effects of the natural product and abiraterone were validated by cellular and invivo experiments. Five common resistance genes (KCNJ3, COL2A1, PPP1CA, MDH2 and EXOSC5) were identified successfully, among which high PPP1CA expression had the worst prognosis for disease-free survival. Moreover, PPP1CA was highly expressed in abiraterone-resistant 22Rv1 cells. Silencing PPP1CA increased cell sensitivity to abiraterone while promoting apoptosis and inhibiting clone formation. Overexpressing PPP1CA exerted the opposite effects. Molecular docking revealed the binding mode of the natural product nodularin-R to PPP1CA with a dose-dependent manner for inhibition. Mechanistically, nodularin-R attenuates the interaction between PPP1CA and USP11 (deubiquitinating enzyme), potentially promoting PPP1CA degradation. Additionally, combination of 2.72 μM nodularin-R and 54.5 μM abiraterone synergistically inhibited the resistant 22Rv1 cell function. Invivo experiments also revealed that combination therapy significantly inhibited tumour growth and reduced inducible expression of PPP1CA. PPP1CA is a key driver for abiraterone resistance, and nodularin-R enhances the anti-CRPC effects of abiraterone by inhibiting PPP1CA.

The Prognostic Value of Elimination Rate Constant K Score of Prostate-Specific Antigen in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Docetaxel

BackgroundTo evaluate the prognostic value of the elimination rate constant K (KELIM), a marker of chemosensitivity, in mCRPC patients treated with docetaxel. MethodsThe study included patients who had received first-line docetaxel for mCRPC. The KELIM score was calculated using PSA measurements obtained within the first 100 days of chemotherapy. The patients were divided into two groups based on the KELIM levels: KELIM PSA <1 and KELIM PSA ≥ 1. The relationship between overall survival (OS) and the KELIM groups was evaluated. ResultsA total of 164 patients were included in this study. The median age was 68.1 years (interquartile range (IQR) 62.2-71.1). There were 76 and 88 patients in the KELIM PSA <1 and KELIM PSA ≥1 groups, respectively. The median OS in the KELIM PSA ≥1 group (46.2 months, 95% confidence interval (CI): 38.8–53.6) was found to be longer than in the KELIM PSA <1 group (32.0 months, 95% CI: 23.1–40.9) (P = 0.032). In multivariate analysis, the risk of death was independently higher in the KELIM PSA <1 group than in the KELIM PSA ≥1 group (Hazard Ratio (HR): 1.58, 95% CI: 1.02-2.43, P=0.037). ConclusionHigher KELIM scores are positively correlated with improved overall survival in mCRPC patients treated with docetaxel.

Insufficient Effective Time of Suberanilohydroxamic Acid, a Deacetylase Inhibitor, Treatment Promotes PC3 Cell Growth.

Castration-resistant prostate cancer (CRPC) contributes mostly to prostate cancer-specific mortality, and conventional castration therapy is almost ineffective, new therapies are needed. As a new potential anti-cancer drug, histone deacetylases (HDACs) inhibitors were demonstrated to be effective in inhibiting drug-resistance cancers in preclinical studies, but the results from clinical trials on CRPC patients were disappointing, and the reasons are unknown. In this study, we investigated the effect of suberanilohydroxamic acid (SAHA), a broad-spectrum pan-HDAC inhibitor, on proliferation, apoptosis, cell cycle progression in PC3 cells, and found that, unlike significant inhibiting effects at high-dose, low-dose SAHA significantly promoted PC3 cell growth. Further colony formation assay showed that the inhibitory effect of SAHA is also dependent on the treatment time, high-dose SAHA also exhibited promoting effect on PC3 cells when the treatment time was insufficient. However, this effect was not observed in another CRPC cell line, DU145, or another HDAC inhibitor, Trichostatin A (TSA). Our results indicate that, instead of inhibitory effect, SAHA would promote PC3 cell growth if the dose is low or the treatment time is insufficient, but this effect has not been observed in other CRPC cell line or HDAC inhibitors.

The role of Cabazitaxel in Patients With Castration-Resistant and Osseous Metastases Prostate Cancer. A Hellenic Cooperative Oncology Group Phase II Study: Cabazitaxel in mCRPC patients with osseous metastases

BackgroundCabazitaxel is an effective treatment in metastatic castration-resistant prostate cancer (mCRPC) patients previously exposed to docetaxel and novel hormonal treatments. Understanding the molecular biology of mCRPC disease and taking into account the several approved treatment options, biomarkers are needed to guide decision making including cabazitaxel treatment. MethodsCababone was a phase II translational study that attempted to identify predictors of cabazitaxel efficacy. mCRPC with documented bone metastases were enrolled prospectively and treated with cabazitaxel 25mg/m2 every 3 weeks. Prostate cancer biopsies, bone marrow aspirates and blood samples were collected for translational research. ResultsSixty patients were enrolled and 59 received treatment according to protocol. Six-month progression free survival (PFS) rate was 47% (95% CI: 33% - 59%) and 12-month Overall Survival (OS) rate was 70% (95% CI: 56% - 80%). Patients with reactive hematopoiesis had improved PFS and OS with cabazitaxel treatment. Mutations in HRR genes were detected in 7 patients. ConclusionsNo differences in cabazitaxel efficacy were noted according to mutational status of HRR genes analyzed. No new safety issues were detected. In conclusion, CabaBone confirmed efficacy of cabazitaxel in mCRPC patients including the subgroup of patients with HRR mutations. Reactive hematopoiesis in bone marrow biopsies was related to improved survival warranting further investigation of bone biomarkers as predictors of cabazitaxel efficacy.

Assessment of the therapeutic efficacy of [177Lu]Lu-PSMA-X compared to taxane chemotherapy in taxane-chemo-naïve patients with metastatic castration-resistant prostate cancer: A systematic review and meta-analysis.

Radioligand therapy (RLT) with 177Lu-labelled prostate specific membrane antigen ([177Lu]Lu-PSMA-X, referring with "PSMA-X" to a generic PSMA chemical compound) inhibitors has emerged as a viable treatment option in metastatic castration resistant prostate cancer patients having previously progressed on taxane and androgen receptor inhibitors. The aim of this study was to perform a systematic review and meta-analysis to assess the therapeutic efficacy of [177Lu]Lu-PSMA-X compared to taxane chemotherapy in taxane-chemo-naïve patients with metastatic castration-resistant prostate cancer. Searches in several bibliographic databases were made using relevant key words, and articles published up to March 2024 were included. The endpoints included prostate specific antigen (PSA) response rate (RR), progression-free survival, and overall survival. Individual patient data were pooled when feasible. PSA50 was defined as the median proportion of patients achieving at least a 50% decline in serum PSA from baseline. A meta-analysis of the PSA50 response rate (proportion meta-analysis) was performed, generating pooled estimates and 95% confidence intervals (95% CI). From the initially selected 8,414 studies published between 2019 and 2023, 24 were included in the [177Lu]Lu-PSMA-X treated group and 17 in the taxane treated group. Our findings show that [177Lu]Lu-PSMA-X RLT yielded comparable PSA50 responses in taxane-naïve patients versus those receiving taxane chemotherapy, despite considerable study heterogeneity. Notably, the taxane-naïve group had more extensive pretreatment. This meta-analysis combines the largest cohorts of taxane-naïve mCRPC patients treated with [177Lu]Lu-PSMA-X RLT and taxane-treated mCRPC. It underscores similar PSA50 response rates in both groups, suggesting a potential role for [177Lu]Lu-PSMA-X RLT in taxane-naïve patients who cannot or choose not to undergo chemotherapy.

IL-17RA/CTSK axis mediates H. pylori-induced castration-resistant prostate cancer growth.

In this investigation, we explored the molecular dynamics guiding the progression of castration-resistant prostate cancer (CRPC) influenced by Helicobacter pylori (H. pylori)-mediated M2 polarization of macrophages through the IL-17RA/CTSK/EMT axis. An 830-patient clinical trial categorized subjects into hormone-sensitive prostate cancer (HSPC) and CRPC groups. H. pylori infection, evaluated by ELISA, exhibited a higher incidence in CRPC patients, impacting overall survival (OS) and progression-free survival. In-depth in vitro and in vivo experiments, including 16S rDNA sequencing, immunohistochemical tests, and transcriptome analysis, unveiled that H. pylori promotes CRPC growth and metastasis by upregulating IL-17RA and CTSK, leading to enhanced EMT. Notably, M2 macrophages emerged as pivotal immune cells influencing CRPC progression. This study uncovers a novel pathway wherein H. pylori enrichment exacerbates CRPC by inducing macrophage M2 polarization, IL-17RA/CTSK expression, and EMT activation, shedding light on a previously unrecognized mechanism contributing to the growth and metastasis of CRPC.

Comparison of abiraterone, enzalutamide, and apalutamide for metastatic hormone-sensitive prostate cancer: A multicenter study.

We aimed to assess the differential efficacy and safety of androgen receptor pathway inhibitors (ARPI), such as abiraterone, enzalutamide, and apalutamide, in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in a real-world practice setting. We retrospectively reviewed the records of consequent 668 patients with mHSPC treated with ARPI plus androgen deprivation therapy between September 2015 and December 2023. Based on the LATITUDE criteria, the comparison among abiraterone, enzalutamide, and apalutamide was exclusively conducted in high-risk patients. Prostate-specific antigen (PSA) responses such as the achievement of 95% and 99% PSA decline, overall survival (OS), cancer-specific survival (CSS), time to castration-resistant prostate cancer (CRPC), and the incidence of adverse events (AEs) were compared. All two-group comparisons relied on propensity score matching (PSM) to minimize the effect on possible confounders. In total, 297 patients with high-risk mHSPC treated with abiraterone, 127 with enzalutamide, and 142 with apalutamide were compared. There were no differences in time to CRPC (p = 0.13), OS (p = 0.7), and CSS (p = 0.5) among the three ARPIs. No differences were observed in the achievement rates for 95% PSA decline at 3 months among the three ARPIs, while abiraterone was significantly better in 99% PSA decline achievement compared to apalutamide (72% vs. 57%, p = 0.003). The aforementioned oncologic outcomes were sustained even when performing PSM analyzes. Although skin rash for APA (34%) was the highest incidence of AEs, there were no differences in the rates of severe AEs across the three ARPIs. Enzalutamide resulted in the lowest treatment discontinuation rates (10%) other than disease progression compared to the other regimens. Abiraterone, enzalutamide, and apalutamide have comparable oncologic outcomes in terms of OS, CSS, and time to CRPC in patients with high-risk mHSPC. Our data on differential treatment discontinuation rates, PSA response, and AE profiles can help guide clinical decision-making.

Navigating therapeutic sequencing in the metastatic castration-resistant prostate cancer patient journey.

Novel therapies for metastatic castration-resistant prostate cancer (mCRPC) have improved patient outcomes. However, there is uncertainty on the optimal selection of therapeutic agents for subsequent lines of therapy. We conducted a comprehensive review of published evidence from pivotal clinical trials and recent guidelines for the treatment of mCRPC. We further identify gaps in knowledge and areas for future research. Key considerations to help guide treatment selection for patients with mCRPC include personal treatment history, individual clinical characteristics, symptoms, prognosis, availability of clinical trials, and other patient-specific factors. Genetic testing and prostate-specific membrane antigen-targeted imaging are important tools to evaluate candidacy for newer therapeutic options such as poly (ADP-ribose) polymerase inhibitors, alone or in combination with androgen receptor pathway inhibitors, and [177Lu]Lu-PSMA-617. This article provides an overview of the evolving treatment landscape of mCRPC, discussing guideline-recommended treatment options and data from key clinical trials, while highlighting ongoing trials that may impact the future treatment landscape. Recommendations for optimal treatment sequencing based on individual patient factors are provided.

Prognostic Role of PSMA-Targeted Imaging in Metastatic Castration-Resistant Prostate Cancer: An Overview.

Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has gained a primary role in prostate cancer (PCa) imaging, overcoming conventional imaging and prostate-specific antigen (PSA) serum levels, and has recently emerged as a promising technique for monitoring therapy response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with novel hormonal therapy, taxanes, and radioligand therapy (RLT). In this review, we aim to provide an overview of the most relevant aspects under study and future prospects related to the prognostic role of PSMA PET/CT in mCRPC. A systematic literature search was performed in the following databases: MEDLINE, PubMed, and EMBASE databases. The study focused exclusively on English-language studies, excluding papers not pertinent to the topic. PSMA PET imaging offers a higher sensitivity and specificity than conventional imaging and provides accurate staging and efficient diagnosis of distant metastases. The data presented herein highlight the usefulness of PET in risk stratification, with a prognostic potential that can have a significant impact on clinical practice. Several prospective trials are ongoing and will shortly provide more evidence supporting the prognostic potential of PET PSMA data in this clinical scenario. Current evidence proves the prognostic role of PSMA PET/CT in different settings, with raising relevance also in the context of mCRPC.

Evaluation of glucocorticoid-related genes reveals GPD1 as a therapeutic target and regulator of sphingosine 1-phosphate metabolism in CRPC

Prostate cancer (PCa) is an androgen-dependent disease, with castration-resistant prostate cancer (CRPC) being an advanced stage that no longer responds to androgen deprivation therapy (ADT). Mounting evidence suggests that glucocorticoid receptors (GR) confer resistance to ADT in CRPC patients by bypassing androgen receptor (AR) blockade. GR, as a novel therapeutic target in CRPC, has attracted substantial attention worldwide. This study utilized bioinformatic analysis of publicly available CRPC single-cell data to develop a consensus glucocorticoid-related signature (Glu-sig) that can serve as an independent predictor for relapse-free survival. Our results revealed that the signature demonstrated consistent and robust performance across seven publicly accessible datasets and an internal cohort. Furthermore, our findings demonstrated that glycerol-3-phosphate dehydrogenase 1 (GPD1) in Glu-sig can significantly promote CRPC progression by mediating the cell cycle pathway. Additionally, GPD1 was shown to be regulated by GR, with the GR antagonist mifepristone enhancing the anti-tumorigenic effects of GPD1 in CRPC cells. Mechanistically, targeting GPD1 induced the production of sphingosine 1-phosphate (S1P) and enhanced histone acetylation, thereby inducing the transcription of p21 that involved in cell cycle regulation. In conclusion, Glu-sig could serve as a robust and promising tool to improve the clinical outcomes of PCa patients, and modulating the GR/GPD1 axis that promotes tumor growth may be a promising approach for delaying CRPC progression.

Prognostic Outcomes and Predictive Factors in Non-Metastatic Castration-Resistant Prostate Cancer Patients Not Treated with Second-Generation Antiandrogens.

Background/Objectives: Patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and high-risk features frequently have progression to life-threatening metastasis without second-generation antiandrogens. This study investigated nmCRPC patients for the survival and prognostic factors from a cohort before the approved use of second-generation antiandrogens. Methods: From March 2016 to January 2021, 326 patients treated with second-generation antiandrogens for metastatic castration-resistant prostate cancer (mCRPC) or metastatic castration-sensitive prostate cancer were retrieved. Forty-four patients experiencing nmCRPC with no use of second-generation antiandrogens were reviewed. The prognostic factors, at initial diagnosis or at nmCRPC, associated with metastasis-free survival (MFS) and overall survival (OS) were analyzed. Results: The median follow-up time after nmCRPC was 46 months. The median PSA level at nmCRPC was 2.7 ng/mL. Thirty-eight of forty-four patients with nmCRPC had a PSA doubling time (PSADT) of 10 months or shorter, and the median PSADT was 4 months. The median OS from nmCRPC was 53 months, and the median interval for nmCRPC patients progressing to mCRPC was 20 months. Upon univariate analysis, PSADT < 10 months (p = 0.049) and the very-high-risk group at the initial diagnosis (p = 0.043) were associated with significantly shorter post-nmCRPC MFS. The very-high-risk group (p = 0.031) was associated with significantly worse post-nmCRPC OS. In terms of survivals from the initial diagnosis of prostate cancer, Gleason grade ≥ 8 was the only independent factor with MFS and OS. Conclusions: Without second-generation antiandrogens, nmCRPC patients with PSADT <10 months and in the initial very-high-risk group developed subsequent mCRPC in a significantly faster fashion. Patients of the very-high-risk group had shorter survival rates after nmCRPC.

NFYA-mediated promotion of castration-resistant prostate cancer progression through EGR4 regulation

This research investigates the intricate involvement of nuclear Transcription Factor Y Subunit Alpha (NFYA) in the advancement of castration-resistant prostate cancer (CRPC) and its consequential impact on early Growth Response 4 (EGR4) expression. NFYA demonstrates a significant elevation in CRPC tissues and cell lines, displaying robust upregulation in metastatic prostate cancer (mPCa) samples, closely associated with the Gleason score. Immunohistochemistry validates heightened nuclear staining of NFYA in CRPC patients, highlighting its crucial role in the progression of advanced prostate cancer. Silencing NFYA through siRNA in androgen-independent cell lines markedly impedes cell growth and migration, emphasizing NFYA’s pivotal role in promoting CRPC behavior. RNA-seq analysis identifies EGR4 as a downstream target of NFYA, with both genes consistently upregulated in CRPC. Validating this finding, heightened expression of EGR4 is observed in CRPC samples. In vivo studies utilizing a mouse model demonstrate that NFYA silencing substantially inhibits LNCaP-AI/22RV1shNFYA xenograft tumor growth, accompanied by reduced expression of EGR4 and Ki67. This comprehensive study reveals the multifaceted role of NFYA in CRPC progression, elucidates its downstream impact on EGR4, and underscores the therapeutic potential of targeting NFYA to inhibit CRPC growth in vivo. These findings contribute valuable insights into potential therapeutic strategies for managing CRPC.