This study aims to comprehensively evaluate and control the impurity profile of enzalutamide, an androgen receptor signaling inhibitor used to treat metastatic castration-resistant prostate cancer. Using liquid chromatography-mass spectrometry (LC-MS), twenty impurities were identified based on their mass-to-charge ratios (m/z) during synthetic method development and stress testing studies. Classification of these compounds according to ICH M7 guidelines revealed two potentially genotoxic impurities: Enzal-2 (4-isothiocyanato-2-(trifluoromethyl)benzonitrile), classified as a Class 3 impurity due to its isothiocyanate group, and Enzal-2A (4-amino-2-(trifluoromethyl)benzonitrile), classified as a Class 2 impurity due to a positive Ames test result. Based on the threshold of toxicological concern (TTC) of 1.5 µg/day and the maximum daily dose of enzalutamide of 160 mg, a control limit of 9.4 ppm was established for Enzal-2 and Enzal-2A to mitigate safety risks. Both Enzal-2 and Enzal-2A were identified as process-related impurities, with Enzal-2A also recognized as a hydrolysis degradation product. Specific ultra-high-performance liquid chromatography (UHPLC) methods were developed and validated for the precise, accurate, and robust quantification of enzalutamide, Enzal-2, Enzal-2A, and related impurities. These methods were applied to enzalutamide samples subjected to various stress conditions, including elevated temperature, daylight, UV radiation, and exposure to oxidative, neutral, alkaline, and acidic environments, as well as under accelerated and long-term stability testing. The findings underscore the importance of comprehensive impurity profiling and validated analytical methods to ensure the safe and effective manufacture, quality control, and use of enzalutamide.

Metastatic castration-resistant prostate cancer (mCRPC) presents a challenge for clinicians in determining the optimal treatment sequence because of the lack of direct head-to-head comparisons, which is further complicated by the now-widespread use of androgen receptor pathway inhibitors (ARPIs) in metastatic hormone-sensitive prostate cancer (mHSPC).

This study is a Bayesian network meta-analysis (NMA) intended to provide a comprehensive evaluation and comparison of the efficacy of mCRPC treatments across different treatment lines.

We performed a systematic search of ClinicalTrials.gov, extracted information, assessed the risk of bias, and reconstructed missing outcomes. We performed an NMA to evaluate treatment efficacy for overall survival (OS) and progression-free survival (PFS) in first and subsequent lines. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) NMA guidelines and was registered with PROSPERO (CRD42024499607).

The NMA included 43 trials with 33,494 patients. ARPI-based therapies, particularly in combination with poly(ADP-ribose) polymerase inhibitors, demonstrated the most significant benefits for OS and PFS in first-line mCRPC treatment, followed by chemotherapy regimens. However, ARPI re-treatment showed limited effectiveness in subsequent lines, leading to weaker OS and PFS benefits.

This NMA highlights the superiority of ARPI-based therapies and chemotherapies as first-line options for mCRPC while emphasizing the need for treatment class switching after ARPI failure. To refine treatment sequencing and enable precision care, future research should integrate individual participant data to better address patient-level heterogeneity and identify biomarkers for personalized therapy.

CALGB 90401 (Alliance) was a phase III trial of 1050 patients with metastatic castration-resistant prostate cancer (mCRPC) comparing docetaxel, prednisone, bevacizumab (DP+B) versus DP alone. While this trial did not show an improvement in overall survival (OS), there were improved intermediate outcomes suggesting that subsets of men may derive benefit from this combination. The purpose of this analysis was to identify prognostic and predictive biomarkers associated with OS and progression-free survival (PFS) benefit from DP+B.

Baseline EDTA plasma samples from 650 consenting patients were analyzed for 24 biomarkers. The proportional hazards model was utilized to test for the prognostic and predictive importance of the biomarkers for OS. The statistically significant biomarkers of OS were further investigated for prognostic and predictive importance for other secondary outcomes.

15 markers [ICAM-1, VEGF-R3, TIMP-1, TSP-2, Ang-2, Her-3, Osteopontin (OPN), PlGF, VCAM-1, HGF, VEGF, Chromogranin A, IL-6, VEGF-R1, BMP-9] were prognostic of OS, while 9 markers (ICAM-1, VEGF-R3, Her-3, TIMP-1, Ang-2, OPN, PlGF, HGF, and VEGF) were also prognostic of PFS. All markers were statistically significant in univariate analyses after adjustment for multiplicity (FDR < 0.1). In multivariable analyses of OS adjusting for risk score, seven markers had FDR < 0.1, including ICAM-1, VEGF-R3, TIMP-1, Ang-2, VEGF, TSP-2 and HGF. In unadjusted analysis, OPN was predictive of PFS improvement with DP+B, in both univariate and multivariable analysis. However, none of the biomarkers tested were predictive of clinical outcomes after adjusting for multiple comparisons.

Multiple biomarkers were identified in CALGB 90401 as prognostic of clinical outcomes but not predictive of OS. While OPN may have promise as a potential biomarker for anti-angiogenic therapies, further mechanistic and clinical studies are needed to determine the underlying biology and potential clinical application.

Anti-androgen or castration therapies are the mainstay treatment for metastatic prostate cancers (PCa). Although effective at first, androgen-dependent PCa (ADPC) universally develops therapy resistance, thereby evolving into an incurable disease called castration-resistant PCa (CRPC). Currently, mechanisms underlying the emergence of CRPC from ADPC are largely unclear.

We used single-cell RNA-sequencing (scRNA-Seq) to determine the transcription heterogeneity of a therapy-naïve ADPC cell line-LNCaP and how it responded to the anti-androgen drug, enzalutamide. Based on the results, we used single-cell/colony-based cloning to isolate a pre-enzalutamide cell subset, displaying low and/or no expression of androgen receptor (ARlow/-).

We found that most LNCaP cells expressed enzalutamide-target androgen receptor (AR+), while a small subpopulation (~10%) expressed low or no AR (ARlow/-). Gene set enrichment analysis (GSEA) revealed that AR+ and ARlow/- cells were enriched with significantly different gene expressions and signaling pathways. Unexpectedly, ARlow/- cells displayed robust transcriptional response, including upregulations of genes and pathways involved in clinical CRPC. Next, we isolated ARlow/- and AR+ cells from enzalutamide-naïve LNCaP cells and functionally confirmed the enzalutamide-resistant phenotype of ARlow/- cells in vitro and in xenograft models in vivo. Through xenograft-based single-nucleus RNA-Seq, we further found that the ARlow/- cells were selected, while the AR+ cells were de-selected in vivo by enzalutamide. Also, we found that the selection and expansion of ARlow/- clone were recapitulated in another enzalutamide-resistant cell model.

In summary, our single-cell-based sequencing and functional tests suggest a clonal selection and expansion model of enzalutamide resistance, in which the pretreatment AR-low subpopulation is selected and expanded to confer treatment resistance.

The reduction of lean body mass (LBM) and the increase of fat body mass (FBM) caused by androgen deprivation therapy (ADT) administered to prostate cancer patients are well known to lead to an increased risk of sarcopenia. The effects of the addition of androgen receptor pathway inhibitors (ARPIs) to ADT on body composition have not been studied thoroughly.

BONENZA (NCT03336983) is a prospective phase 2 trial in which metastatic hormone-sensitive prostate cancer patients were randomized to receive ADT plus enzalutamide with (EZ arm) or without (E arm) the addition of zoledronic acid. Total and regional body composition parameters were evaluated by dual-energy x-ray absorptiometry (DXA) scans at baseline and after 18 mo of therapy.

Eighty-nine patients (46 from the EZ arm and 43 from the E arm) had paired DXA evaluation at both time points. After 18 mo of therapy, FBM increased by +22.8% (p < 0.001), LBM reduced by -6.7% (p < 0.001), and appendicular lean mass index (ALMI) decreased by -9.2% (p < 0.001). The increase in FBM varied considerably according to body districts: from +36.1% in the right arms (p < 0.001) to +3.7% in the head (p < 0.01). Similarly, the decrease in LBM ranged from -9.4% (p < 0.001) in the right arm to -6.4% (p < 0.001) in the trunk. None of the patients met the criteria for sarcopenic obesity; however, after 18 mo of treatment, 11.76% of patients had FBM >40.8%, 3.5% of patients had an ALMI of <5.5, and the ALMI/FBM ratio decreased by -23.9% (p < 0.001). Age and baseline LBM influenced these body composition changes significantly, with younger patients (<70 yr) and those with higher baseline LBM experiencing more marked changes.

Body composition undergoes a significant change with the addition of ARPIs to ADT, with an increase in FBM and a reduction in LBM, which are twice as high as those expected with ADT alone. DXA has been proved to be a reliable tool for monitoring body composition, and an assessment of district variations can aid in implementing individual-supervised physical exercise to prevent the risk of sarcopenic obesity.

In the phase 3 IPATential150 trial, ipatasertib addition to abiraterone significantly reduced the risk of disease progression in men with metastatic castration-resistant prostate cancer (mCRPC) with PTEN loss on immunohistochemistry (IHC), but not in the intention-to-treat (ITT) population. Here we report the final overall survival (OS) analysis and present results for prespecified and exploratory biomarker analyses.

Patients were randomized to receive ipatasertib (400 mg once daily) or placebo. All patients received abiraterone (1000 mg once daily) and prednisone (5 mg twice daily). OS was assessed in patients with PTEN loss on IHC and the ITT population. Exploratory biomarker analyses included PTEN status via next-generation sequencing (NGS) and other key genomic alterations.

At final analysis (median follow-up 33.9 mo), ipatasertib addition did not improve OS for patients with PTEN loss in IHC (n = 521; stratified hazard ratio [sHR] 0.94, 95% confidence interval [CI] 0.76-1.17; p = 0.57) or the ITT population (n = 1101; sHR 0.91, 95% CI 0.79-1.07; not formally tested). Exploratory NGS assessments identified subgroups with genomic PTEN loss (n = 208) or PIK3CA/AKT1/PTEN alterations (n = 250), with potentially better outcomes from ipatasertib (HR 0.76, 95% CI 0.54-1.07; and HR 0.70, 95% CI 0.51-0.96, respectively). Limitations include the exploratory nature of the analysis, incomplete availability of NGS data, and potential intrapatient heterogeneity.

Ipatasertib addition to abiraterone did not improve OS for men with mCRPC, regardless of PTEN status on IHC. Exploratory biomarker analyses identified additional genomic alterations of potential clinical relevance for AKT blockade in mCRPC that require further validation in prospective studies.

For patients with castration-sensitive prostate cancer (mCSPC), treatment intensification with androgen deprivation therapy (ADT) plus new androgen receptor pathway inhibitors (ARPIs) has opened a scenario where no guidance exists to indicate the best treatment after progression to metastatic castration-resistant prostate cancer (mCRPC). Clinical decision-making has become even more complex, with the proven benefit for selected patients of triplet therapy with abiraterone or darolutamide added to the double combination therapy of ADT plus docetaxel. The profile of patients for whom triple therapy would be more beneficial is being defined beyond metastatic disease presentation and volume (eg, poor prognosis features). In October 2023 and October 2024, a panel of eight Spanish medical oncologists with expertise in the management of prostate cancer met to discuss the challenges in treating mCRPC. The scientific evidence was reviewed during this meeting, knowledge and experience were shared, and controversies were discussed until a consensus was reached. This information was collected and turned into a manuscript aimed at helping clinicians determine the optimal treatment sequence after disease progression based on scientific evidence and experts' opinions and consensus. To this end, the profile of mCSPC patients who may have received double or triplet therapy is analyzed, current treatment options are reviewed, and treatment algorithms are proposed. New and expected advancements in this field are also presented.

Globally, the incidence and death rates associated with cancer persist in rising, despite considerable advancements in cancer therapy. Although some malignancies are manageable by a mix of chemotherapy, surgery, radiation, and targeted therapy, most malignant tumors either exhibit poor responsiveness to early identification or endure post-treatment survival. The prognosis for prostate cancer (PCa) is unfavorable since it is a perilous and lethal malignancy. The capacity of phytochemical and nutraceutical chemicals to repress oncogenic lncRNAs and activate tumor suppressor lncRNAs has garnered significant attention as a possible strategy to diminish the development, proliferation, metastasis, and invasion of cancer cells. A potential technique to treat cancer and enhance the sensitivity of cancer cells to existing conventional therapies is the use of phytochemicals with anticancer characteristics. Functional studies indicate that lncRNAs modulate drug resistance, stemness, invasion, metastasis, angiogenesis, and proliferation via interactions with tumor suppressors and oncoproteins. Among them, numerous lncRNAs, such as HOTAIR, PlncRNA1, GAS5, MEG3, LincRNA-21, and POTEF-AS1, support the development of PCa through many molecular mechanisms, including modulation of tumor suppressors and regulation of various signal pathways like PI3K/Akt, Bax/Caspase 3, P53, MAPK cascade, and TGF-β1. Other lncRNAs, in particular, MALAT-1, CCAT2, DANCR, LncRNA-ATB, PlncRNA1, LincRNA-21, POTEF-AS1, ZEB1-AS1, SChLAP1, and H19, are key players in regulating the aforementioned processes. Natural substances have shown promising anticancer benefits against PCa by altering essential signaling pathways. The overexpression of some lncRNAs is associated with advanced TNM stage, metastasis, chemoresistance, and reduced survival. LncRNAs possess crucial clinical and transitional implications in PCa, as diagnostic and prognostic biomarkers, as well as medicinal targets. To impede the progression of PCa, it is beneficial to target aberrant long non-coding RNAs using antisense oligonucleotides or small interfering RNAs (siRNAs). This prevents them from transmitting harmful messages. In summary, several precision medicine approaches may be used to rectify dysfunctional lncRNA regulatory circuits, so improving early PCa detection and eventually facilitating the conquest of this lethal disease. Due to their presence in biological fluids and tissues, they may serve as novel biomarkers. Enhancing PCa treatments mitigates resistance to chemotherapy and radiation.

Currently, several therapies are available for metastatic castration-resistant prostate cancer (mCRPC) but no specific clinical factors to personalize treatment. We first sought the prognostic value of duration on androgen-deprivation therapy (ADT) for hormone-sensitive prostate cancer (HSPC) in patients receiving androgen-receptor-signaling inhibitors (ARSI) for mCRPC.

A multicenter cohort of mCRPC patients who started ARSI between July 2011 and October 2021 was identified. Based on their initial disease burden and duration on ADT for HSPC, primary progressive (PP) men were classified into four groups: low/intermediate-risk localized disease (LOC) and high-risk localized/locally advanced disease (LAD) and short-term (ST) < 24 vs. long-term (LT) ADT ≥ 24 months, whereas de novo (DN) mHSPC were subdivided into short-time vs. long-time to CRPC.

We included 919 mCRPC patients with a median age of 77 years [interquartile range (IQR) = 71-82)]. Median ADT duration in HSPC was 24 months (IQR = 14-40). Median follow-up was 91 months (IQR = 62-138), median OS and PFS from ARSI start were 20 (IQR 10-32) and 10 months (IQR = 5-19), respectively. In PP developing metastatic disease (n = 655, 71.3%), LOC and LAD with ST ADT had a greater than almost double-risk of death compared to LT ADT (LOC/ST: hazard ratio [HR] = 2.01; 95% CI 1.54-2.64; LAD/ST: HR = 1.73; 95% CI 1.34-2.24; p < 0.001). In the multivariate analysis including age, prognostic cohort, Gleason, ECOG, radical radiotherapy and prostatectomy, groups with ST ADT were associated with worse OS compared to LT ADT (LOC/ST: HR = 1.84; 95% CI 1.38-2.45; p < 0.001; LAD/ST: HR = 1.59; 95% CI 1.21-2.10; p < 0.001), along with ECOG > 2 (HR = 1.55; 95% CI 1.06-2.26; p = 0.03). There were also similar results of PFS. Moreover, long-time to CRPC in patients with history of DN mHSPC (n = 264, 28.7%) resulted in a better OS/PFS (HR = 0.76, 95% CI 0.56-1.02, p = 0.064 and HR = 0.74, 95% CI 0.55-0.99, p = 0.042, respectively).

Our study showed that duration on ADT for mHSPC was significantly associated with survival in mCRPC undergoing ARSI. These findings suggest a possible connection between initial management of prostate tumour and a better prognostication in mCRPC. Prospective trials are warranted.

There is an increasing incidence of cancer in younger patients, including prostate cancer. Cancers developing in younger patients are reported to have a more aggressive phenotype. There is a need to examine younger patients with metastatic castration-resistant prostate cancer (mCRPC).

Analysis of the prospectively collected, multisite, electronic Prostate Cancer Australian Database (ePAD) was conducted to identify all mCRPC patients enrolled between June 2016 and March 2024. We defined patients diagnosed aged < 55 years as younger patients (YP) and compared their characteristics, treatment patterns and outcomes to the other patients aged ≥ 55 years (OP).

Of 915 patients with mCRPC, 59 (6%) were YP. De-novo metastatic presentation, Gleason score, presence of liver metastasis and PSA doubling time at mCRPC were similar between YP and OP. In the mCRPC setting, first line treatment with docetaxel (19% YP vs. 21% OP; P = .72) and ARPI (68% YP vs. 74% OP; P = .31) was also similar. YP were more likely to receive ≥ 3 lines of therapy for mCRPC (37% YP vs. 23% OP; P = .016). There was no significant difference in overall survival from start of first line therapy (median 41.9 m YP vs. 35.1 m OP; HR 0.73; 95% CI, 0.47-1.15; P = .17) or time-to-treatment discontinuation for ARPI (median 15.8 m YP vs. 14.9 m OP; HR 0.93; 95% CI, 0.61-1.42; P = .75). Age < 55 was not independently associated with survival on multivariable analysis (HR 0.82; 95% CI, 0.52-1.29; P = .38).

Young patients with prostate cancer who go on to develop mCRPC do not appear to have distinct clinical outcomes to other patients.

The treatment of metastatic castration-resistant prostate cancer (mCRPC) has been rapidly evolving over the last two decades. The advent of new androgen receptor pathway inhibitors (ARPIs) such as abiraterone acetate or enzalutamide marks a great advance for treating mCRPC patientd in the pre- and post-docetaxel settings. The subsequent approval of ARPIs in early stages-i.e., metastatic hormone-sensitive (mHSPC) or nonmetastatic CRPC-led to a realignment of subsequent treatment choices upon progression to mCRPC, given the possibility of cross-resistance between ARPIs. Therapies with mechanisms of action different from those of ARPIs are now the focus of new treatment developments. Also, this anomalous situation brings the focus back to well-known treatments currently used later in the treatment sequence. This is the case of radium-223 which, when administered with enzalutamide, has recently been shown to prolong radiographic progression-free survival vs. enzalutamide alone in the first line in asymptomatic or mildly symptomatic patients with no known visceral metastases. In this narrative review, we summarize the treatment landscape for mCRPC, both from a historical and practical point of view, to understand the new potential of radium-223 as a treatment option in this setting.

Induction of apoptosis is an important strategy for the treatment of prostate cancer. DR5 is a member of the death receptor superfamily and targeting DR5 is an effective way to induce apoptosis. Pyripyropene O is a natural compound isolated from the marine fungus Aspergillus fumigatus SCSIO 41220. We found it has anti-prostate cancer potential by inducing apoptosis; Methods: The effects of pyripyropene O on the viability, proliferation, cell cycle, apoptosis and migration of prostate cancer cells were investigated by MTT assay, plate clone formation assay, 3D cell sphere assay, flow cytometry and real-time cell analysis. Transmission electron microscopy was used to observe the changes in the internal structure of prostate cancer cells after treatment with pyripyropene O. After determining the mode of cell death, the mechanism of action of pyripyropene O on prostate cancer was further investigated using apoptotic protein microarray, western blot, qPCR, molecular docking, cellular immunofluorescence staining and cellular thermal shift assay. After explaining the mechanism of action of pyriproxyfen O, the in vivo absorption, distribution, metabolism, excretion and potential toxicity of pyriproxyfen O were investigated using ADMETLab 2.0 software. Finally, a zebrafish xenograft tumour model was developed to evaluate the anti-prostate cancer effects of pyriproxyfen O in vivo; Results: The experimental results at the cellular level showed that pyripyropene O inhibited the survival, proliferation and migration of prostate cancer cells, and also showed that pyripyropene O blocked the prostate cancer cell cycle at the G2/M phase and induced apoptosis. At the molecular level, pyripyropene O binds to the transcription factor YY1, promotes YY1 nuclear translocation, regulates the transcription level of DR5, a target gene of YY1, and upregulates the expression of DR5 mRNA and protein. The in vivo results showed that pyripyropene O effectively inhibited the development of prostate cancer in zebrafish; Conclusions: Pyripyropene O has a clear anti-prostate cancer effect at both cellular and animal levels, inhibiting the survival and proliferation of prostate cancer cells by binding to the transcription factor YY1 to activate the expression of DR5 to promote apoptosis, thus exerting an inhibitory effect on prostate cancer.

This study investigated clinical benefits of androgen receptor signaling inhibitor (ARSI) in patients with synchronous metastatic hormone-sensitive prostate cancer (mHSPC) based on real-world data from multiple centers.

Clinical records of 1107 mHSPC patients who commenced vintage (bicalutamide) (n = 801) or ARSI (n = 306) treatment in addition to androgen deprivation therapy between 1999 and 2024 were reviewed. Progression-free and overall survival (OS) were examined, and prognostic factors were analyzed using multivariate cox proportional hazard modeling. Propensity score matching (PSM) analysis was performed to balance background characteristics.

Median age and initial prostate-specific antigen level were 73 years and 229 ng/ml, respectively. Kaplan-Meier analysis revealed that upfront ARSI treatment was associated with longer progression-free survival (P < 0.0001, hazard ratio [HR] = 0.37) and OS (P = 0.0088, HR = 0.58) than combined androgen blockade after PSM analysis. In particular, an OS benefit of upfront ARSI was observed in high-volume patients (P = 0.0052, HR = 0.56). ARSI use after castration-resistant prostate cancer (CRPC) development correlated with improved OS as compared to patients without ARSI use (P < 0.0001, HR = 0.52). Multivariate analysis identified ARSI therapy as an independent prognostic factor for OS both when used upfront (P = 0.0141, HR = 0.61) and after CRPC development (P < 0.0001, HR = 0.55). In addition, categorizing all patients into groups receiving no ARSI, ARSI after CRPC, or ARSI as upfront therapy revealed 5-year OS rates of 55.65%, 59.85%, and 65.01%, respectively.

Early use of ARSI in Japanese patients with mHSPC appears clinically beneficial. Our findings suggest the prognostic importance for optimal treatment intensification.

Objective: To review the efficacy and safety of reduced dose compared to standard dose Enzalutamide treatment for patients with castration-resistant prostate cancer (CRPC). Methods: PubMed, Scopus, Web of Science, and Cochrane databases were searched for randomized controlled trials and cohort studies reporting the use of Enzalutamide in reduced and standard doses in patients with castration-resistant prostate cancer. Searches were limited to articles published in the English language. Outcome assessments included progression-free survival (PFS), overall survival (OS), adverse events, and serum prostate-specific antigen (PSA) response. Results: Ten studies met the inclusion criteria, including 2481 patients treated with Enzalutamide. Seven studies were retrospective cohorts, two were prospective trials, and one was a prospective cohort. No consistent relationship was identified between OS and PFS and the Enzalutamide dosage. Reduced doses of Enzalutamide decreased the incidence of adverse events, particularly among elderly patients. Conclusions: This systematic review suggests that reduced doses of Enzalutamide in CRPC may maintain therapeutic efficacy in selected patients while improving tolerability. However, inconsistent findings and methodological limitations highlight the need for prospective randomized trials to define optimal and individualized dosing strategies.

Prostate cancer remains a significant health concern, particularly among older men. This article provides an in-depth examination of prostate cancer, focusing on the critical role of nurses in managing this condition. It covers the pathophysiology, diagnosis and treatment options for prostate cancer, emphasising the importance of patient education, psychosocial support and holistic care. Through a detailed exploration of evidence-based practices, this article aims to enhance nurses' understanding of the subject and their ability to deliver comprehensive care to patients with prostate cancer, ultimately improving patient outcomes and quality of life.

RNA epigenetics is gaining increased attention for its role in the initiation, metastasis, and drug resistance of tumors. These studies have primarily focused on m6A modification. However, despite being the second most abundant modification found in RNA, the role of m5C modification in prostate cancer remains largely unexplored. Here, we predict an RNA m5C methyltransferase, NSUN2, as a potential therapeutic target for prostate cancer using various bioinformatics approaches, and verify the potential of NSUN2 as a target through multiple preclinical models. Mechanistically, NSUN2 enhances the stability of TRIM28 mRNA by adding m5C modification, promoting the expression of TRIM28. Concurrently, FOXA1, a prostate cancer lineage-specific transcription factor, transcriptionally activates the expression of NSUN2. Our study confirms the clinical potential of targeting RNA epigenetics for the treatment of prostate cancer and elucidates, mechanistically, how RNA epigenetics participates in the complex biological activities within tumors via the FOXA1-NSUN2-TRIM28 axis.

To provide evidence-based recommendations for patients with metastatic castration-resistant prostate cancer (mCRPC).

An Expert Panel including patient representation completed a systematic review of the evidence and made recommendations.

Depending upon prior treatment received, androgen receptor pathway inhibitors (ARPIs: enzalutamide, abiraterone with prednisone), poly(ADP-ribose) polymerase inhibitors (PARPi), chemotherapeutic agents (docetaxel, cabazitaxel), radiopharmaceuticals (radium 223, 177Lu-prostate-specific membrane antigen [PSMA]-617), and sipuleucel-T have demonstrated an overall survival (OS) benefit for patients with mCRPC. For patients with BRCA1/2 alterations who did not receive prior ARPI, the combination of PARPi and ARPI (talazoparib + enzalutamide, olaparib and/or niraparib + abiraterone) has shown clinical benefit. For patients with BRCA1/2 alterations who received prior ARPI or ARPI followed by docetaxel, olaparib showed OS benefit. In select patients with microsatellite instability-high/mismatch repair-deficient, pembrolizumab showed clinical efficacy.

Prior systemic therapy for castration-sensitive prostate cancer will determine subsequent therapy used for mCRPC. Continue androgen-deprivation therapy for patients with mCRPC indefinitely. Early adoption of somatic genetic testing and palliative care is recommended. Patients with mCRPC and bony metastases should receive a bone-protective agent. The panel recommends the combination of ARPI with PARPi in patients with BRCA1/2 alterations who did not receive prior ARPI. For patients who received prior ARPI, the panel recommends docetaxel chemotherapy. The panel recommends 177Lu-PSMA-617 or cabazitaxel chemotherapy for patients who receive prior ARPI and docetaxel chemotherapy. For patients with BRCA1/2 alterations who received prior ARPI, the panel recommends PARPi monotherapy. Radium 223 is recommended for patients with symptomatic bone-only disease. Evidence for optimal sequencing for mCRPC regimens is lacking.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.

Prostate cancer represents a significant oncological challenge, with its natural history predominantly driven by androgen receptor (AR) signaling. The pivotal role of this pathway underscores the rationale for targeting AR activity in therapeutic strategies. However, the development of resistance mechanisms has highlighted the need for advanced therapies to address the complexity of the castration-resistant status.

We analyzed the evolving role of second-generation androgen receptor signaling inhibitors (ARSIs) in the management of non-metastatic and metastatic castration-resistant prostate cancer, we critically examine emerging combination strategies involving ARSIs, novel agents targeting resistance pathways, and the mechanisms underlying treatment resistance. The review also provides insights into future directions for enhancing outcomes. PubMed literature research using keywords related to castration-resistant prostate cancer and its treatments was performed, including the most relevant trials and reviews.

ARSIs have revolutionized the management of prostate cancer, providing substantial clinical benefits and representing the cornerstone of current treatment paradigms. However, key challenges remain, including determining optimal treatment sequencing, overcoming resistance mechanisms, and tailoring therapies to specific molecular subtypes. Biomarker-driven approaches are critical for refining patient selection and improving therapeutic outcomes. Ongoing trials investigating novel hormonal-axis-directed agents and innovative combination therapies aim to expand the arsenal of effective treatment.

Corticosteroids are active in castration-resistant prostate cancer (CRPC) by suppression of adrenal androgen production. Triamcinolone is an intramuscular steroid injection which has putative advantages over commonly used steroids, such as dexamethasone and prednisolone.

This was a multicentre, phase II study of intramuscular triamcinolone administered monthly in patients with chemotherapy-naïve CRPC. 55 patients were recruited from 2012 to 2016. Imaging was performed every 3 months. The primary end point was radiological and symptomatic progression-free survival (PFS). Secondary end points included PSA progression, weight changes, and toxicity. We also conducted an exploratory analysis on steroid androgenic precursors, collected before and 1 month after triamcinolone, to measure correlation to PFS.

At a median follow-up time of 18.7 months, the median radiological PFS was 9.4 months (95% confidence interval [CI]: 7.4-20.3 months), and the 6-month radiological PFS rate was 69.1% (95% CI: 55.1%-79.5%). The 50% PSA response rate was 63.6% (95% CI: 49.6-76.2). There were no treatment-related deaths. The most common grade 3 toxicity was hypertension (44%), but only five patients (9%) required concomitant medication. Proximal myopathy was observed in 22 patients (40%). There was no evidence of weight gain (mean weight 83.5 kg pre-study and 79.8 kg post-study). Urinary total androgen metabolites and dehydroepiandrosterone did not predict response to triamcinolone.

Intramuscular triamcinolone is an effective hormonal agent in CRPC. Its side-effect profile is different from other steroids and has the advantage of supervised administration.

Neuroendocrine prostate cancer (NEPC) is rare at the time of initial diagnosis but much more common in patients treated with the combination of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPI) such as abiraterone and enzalutamide. NEPC is typically characterized by the loss of prostate-specific membrane antigen (PSMA) expression while exhibiting variable neuroendocrine markers. Recent advancements in nuclear medicine have provided a promising avenue for the development of molecular imaging techniques and targeted therapies tailored to NEPC. This review examines the current and future role of theranostics in the diagnosis and management of NEPC and explores potential future directions in this rapidly evolving field.

This study investigates the association between thromboembolic events (TE) and castration-resistant prostate cancer (CRPC) patients receiving oral androgen receptor pathway inhibitors (ARPi) compared to those undergoing chemotherapy, both with and without a pre-existing history of cardiovascular disease (CVD).

A total of 2779 men diagnosed with CRPC were identified using the Surveillance, Epidemiology, and End Results (SEER) Medicare Linked Database from 2012 to 2016. Patients were stratified based on their CVD history. Within each CVD stratum (pre-existing CVD vs. no pre-existing CVD), patients were further categorized into two treatment groups: those receiving oral ARPi and those undergoing chemotherapy. Unadjusted and inverse probability treatment weight (IPTW)-adjusted proportional hazards models, using Fine and Gray's method, were applied to evaluate the potential association between ARPi treatment and TE.

Patients with pre-existing CVD treated with ARPi exhibited a significantly lower crude hazard ratio (HR) for TE compared to chemotherapy (HR 0.39, 95% CI 0.27-0.58, p < 0.001). However, after adjustment using IPTW, this association was no longer significant (adjusted hazard ratio [AHR] 1.00, 95% CI 0.75-1.32, p = 0.99). For patients without CVD, ARPi use was also associated with a reduced risk of TE in the crude analysis (HR 0.53, 95% CI 0.32-0.87, p = 0.01), but this effect was not statistically significant after IPTW adjustment (HR 0.99, 95% CI 0.69-1.41, p = 0.94).

ARPi demonstrated no significant effect on TE risk compared to chemotherapy, regardless of pre-existing CVD status. Similarly, when excluding patients with a prior history of TE, ARPi use remained non-significantly associated with new TE in the IPTW-adjusted competing risk analysis, highlighting the need for further investigation.

Androgen receptor stimulation by testosterone and dihydrotestosterone is crucial for prostate cancer progression. Despite the initial effectiveness of androgen deprivation therapy (ADT), castration-resistant prostate cancer eventually develops in most men. A common germline missense-encoding polymorphism in HSD3B1 increases extra-gonadal androgen biosynthesis from adrenal precursors owing to increased availability of the encoded enzyme 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) - hence, it is called the adrenal-permissive enzyme. This mechanism explains the more rapid progression to castration-resistant prostate cancer in men who inherit this allele than in men without it via sustained androgen receptor activation despite ADT. Multiple clinical studies, including data derived from prospective phase III studies, have linked adrenal-permissive allele inheritance to inferior clinical responses to ADT and increased mortality, but reversal is possible with upfront adrenal androgen blockade. The adrenal-permissive allele exhibits divergent frequencies across various groups worldwide, which could contribute to differences in clinical outcomes among these populations. Large-scale data from the Million Veteran Program have shown homozygous HSD3B1 adrenal-permissive allele inheritance to be an independent biomarker of prostate cancer-specific mortality. Together, these observations support the integration of HSD3B1 into germline testing and clinical trials as it might help to identify groups at increased likelihood of benefiting from early, intensified, AR-targeting interventions. Lastly, 3βHSD1 is a promising target for pharmacological inhibition, which enables new strategies for systemic prostate cancer therapy.

Androgen receptor signaling inhibitors (ARSI) demonstrated to be efficacious as first-line therapy for mCRPC. The present real-world study aimed to identify the characteristics of the long-term responders (LTR) patients to first-line ARSI.

We retrospectively reviewed a consecutive series of 622 mCRPC patients treated with one ARSI as first line. Patients received standard doses of abiraterone (1000 mg daily plus prednisone 10 mg daily) or enzalutamide (160 mg daily) until progression. Patients with an ARSI exposure ≥ 36 months were considered as LTR.

We identified 99 LTR patients who were compared to 523 no-LTR patients. At the multivariable analysis, LTR patients showed younger age (p < 0.0001), longer time to mCRPC (p < 0.0001), higher baseline levels of hemoglobin (p = 0.007), lower baseline PSA levels (p = 0.03), longer PSA doubling time (p = 0.03), low number of bone metastases (p = 0.01), and receivedenzalutamide (p = 0.01). The median overall survival (OS) of LTR was 78.2 months (95% CI 72.3-84.1 months) vs 27.7 months of no-LTR (95% CI 25.9-29.6 months).

Several clinical and biological factors allow to identify those patients with higher probability of becoming LTR to ARSI in first-line mCRPC setting.

Prostate cancer is the most common nonskin cancer in men in the US, with an estimated 299 010 new cases and 35 250 deaths in 2024. Prostate cancer is the second most common cancer in men worldwide, with 1 466 680 new cases and 396 792 deaths in 2022.

The most common type of prostate cancer is adenocarcinoma (≥99%), and the median age at diagnosis is 67 years. More than 50% of prostate cancer risk is attributable to genetic factors; older age and Black race (annual incidence rate, 173.0 cases per 100 000 Black men vs 97.1 cases per 100 000 White men) are also strong risk factors. Recent guidelines encourage shared decision-making for prostate-specific antigen (PSA) screening. At diagnosis, approximately 75% of patients have cancer localized to the prostate, which is associated with a 5-year survival rate of nearly 100%. Based on risk stratification that incorporates life expectancy, tumor grade (Gleason score), tumor size, and PSA level, one-third of patients with localized prostate cancer are appropriate for active surveillance with serial PSA measurements, prostate biopsies, or magnetic resonance imaging, and initiation of treatment if the Gleason score or tumor stage increases. For patients with higher-risk disease, radiation therapy or radical prostatectomy are reasonable options; treatment decision-making should include consideration of adverse events and comorbidities. Despite definitive therapy, 2% to 56% of men with localized disease develop distant metastases, depending on tumor risk factors. At presentation, approximately 14% of patients have metastases to regional lymph nodes. An additional 10% of men have distant metastases that are associated with a 5-year survival rate of 37%. Treatment of metastatic prostate cancer primarily relies on androgen deprivation therapy, most commonly through medical castration with gonadotropin-releasing hormone agonists. For patients with newly diagnosed metastatic prostate cancer, the addition of androgen receptor pathway inhibitors (eg, darolutamide, abiraterone) improves survival. Use of abiraterone improved the median overall survival from 36.5 months to 53.3 months (hazard ratio, 0.66 [95% CI, 0.56-0.78]) compared with medical castration alone. Chemotherapy (docetaxel) may be considered, especially for patients with more extensive disease.

Approximately 1.5 million new cases of prostate cancer are diagnosed annually worldwide. Approximately 75% of patients present with cancer localized to the prostate, which is associated with a 5-year survival rate of nearly 100%. Management includes active surveillance, prostatectomy, or radiation therapy, depending on risk of progression. Approximately 10% of patients present with metastatic prostate cancer, which has a 5-year survival rate of 37%. First-line therapies for metastatic prostate cancer include androgen deprivation and novel androgen receptor pathway inhibitors, and chemotherapy for appropriate patients.

To compare demographics, clinical characteristics, health care resource utilization (HCRU), treatment duration, and overall survival (OS) with enzalutamide (ENZA) or abiraterone acetate (AA) in patients with metastatic castration-resistant prostate cancer (mCRPC) in England.

This retrospective study analyzed data from the Cancer Analysis System database on patients receiving ENZA or AA (January 2014-March 2020) for chemotherapy-naïve mCRPC (mCRPC was the only funded indication for ENZA/AA during study period). Baseline characteristics were assessed using standardized mean difference (SMD) (<0.1: balanced); differences were adjusted for using propensity score weighting (PSW). Cox proportional hazard models were used for OS and treatment duration. Number needed to treat was calculated from HCRU incidence rate ratios (IRRs).

Overall, 8,485 patients were included (ENZA, 5,330; AA, 3,155). Diabetes mellitus was more prevalent in the ENZA group (SMD, 0.12) at treatment initiation. HCRU was comparable between groups before treatment initiation (SMD < 0.1), but HCRU IRR after treatment initiation favored ENZA. Compared with AA, ENZA was associated with significantly fewer inpatient stays, outpatient or accident and emergency (A&E) visits, and hospitalization days (P < .01), and significantly lower likelihood of treatment discontinuation (adjusted hazard ratio [aHR], 0.90 [95% CI, 0.86 to 0.96]; P < .01) and mortality risk (aHR, 0.92 [95% CI, 0.87 to 0.98]; P = .010). Assuming 8 months' treatment and comparable groups through PSW, 1.9 inpatient admissions, 17.3 outpatient visits, 1.4 A&E visits, and 19.5 hospitalization days could be avoided per 10 patients on ENZA versus AA.

Patients with mCRPC on ENZA or AA had generally similar baseline characteristics apart from diabetes prevalence. ENZA was associated with longer OS and treatment duration, and lower HCRU after treatment initiation than AA.

Next-generation hormonal-targeted therapies for advanced prostate cancer are widely used. We aimed to evaluate the effectiveness and health resource utilization (HRU) of novel hormonal agents (NHAs) compared to chemotherapy in a real-world context. After propensity score matching, survival analysis revealed no significant difference in overall survival between the individuals treated with NHAs and those treated with docetaxel (hazard ratio [HR]: 1.00, 95% confidence interval [CI]: 0.89-1.11) in the cohort of 1,056 patients. Similar results were observed for prostate-specific antigen (PSA) progression-free survival (HR: 1.02, 95% CI: 0.91-1.14) and PSA response rate (72% [95% CI: 68-76%] for NHAs vs. 76% [95% CI: 72-80%] for docetaxel, p > 0.05). Additionally, patients treated with NHAs had a significantly lower annual HRU during follow up. These findings indicate comparable effectiveness between NHAs and chemotherapy, with a more favorable HRU profile for NHA-treated patients, suggesting potential cost-effectiveness of NHAs.

Optimal treatment selection for metastatic castration resistant prostate cancer (mCRPC) remains challenging due to evolving standards of care in castration sensitive setting.

To synthesize and appraise evidence on systemic therapy for mCRPC patients stratified by prior therapy and HRR alterations informing a clinical practice guideline.

MEDLINE and EMBASE (inception to 5 March 2025) using living search.

Randomized clinical trials assessing systemic therapy in mCRPC.

Primary outcomes assessed were progression free survival (PFS) and overall survival (OS).

This report of the living systematic review (LSR) includes 143 trials with 17,523 patients (59 phase III/IV trials, 8,941 patients; 84 phase II, 8,582 patients). In the setting of prior androgen deprivation therapy (ADT) alone or ADT+docetaxel, treatment benefit was observed with poly (ADP-ribose) polymerase inhibitors (PARPi) in combination with androgen receptor pathway inhibitors (ARPI) for BRCA+ subgroup. In the setting of prior ADT+ARPI or ADT+ARPI+docetaxel, treatment benefit was observed with PARPi monotherapy for BRCA+ subgroup. Treatment benefit with PARPi may be observed for select non-BRCA homologous recombination repair (HRR) alterations (CDK12, PALB2). Treatment benefit was observed with abiraterone, enzalutamide, cabazitaxel, docetaxel (if no prior docetaxel), and Lu177 (if PSMA+) for patients without HRR alterations.

Study-level data and indirectness in evidence.

Findings from the current LSR suggest that optimal treatment for mCRPC should be individualized based on prior therapy and HRR alterations. Current evidence favors PARPi alone (ARPI exposed) or in combination with ARPI (ARPI naïve) for patients with BRCA alterations, while ARPI alone, chemotherapy, and Lu177 remain potential options for patients without HRR alterations.

The optimal treatment sequence of approved therapies for castration-resistant prostate cancer (PC) is unclear. This study assessed real-world patient characteristics, treatment patterns, and effectiveness in patients with castration-resistant PC in Japan.

Using data from the Japan Study Group of Prostate Cancer registry (2016-2018), this retrospective study included patients with ≥1 record of: primary androgen-deprivation therapy for hormone-sensitive PC and clinical progression to castration-resistant PC during primary androgen-deprivation therapy. The primary outcomes were patient characteristics, treatment patterns, and treatment duration. Other outcomes were overall survival (OS), cancer-specific survival (CSS), time to disease progression, and time to second disease progression.

A total of 600 patients were included. The mean age was 75.3 (SD: 7.9) years at PC diagnosis. The median prostate-specific antigen level was 135.5 (IQR: 37.3-542.2) ng/mL. The most common first-line castration-resistant PC treatments were enzalutamide (30%), docetaxel (20%), abiraterone (18%), flutamide (12%), and bicalutamide (8.7%). The most common second-line treatments were enzalutamide (28.5%), abiraterone (21.9%), and docetaxel (16.6%). The median treatment duration for enzalutamide, docetaxel, abiraterone, and flutamide was 254.0, 176.0, 197.0, and 111.5 days, respectively. Across all treatments, the median OS, CSS, time to disease progression, and second disease progression was 1028.0, 1239.0, 616.0, and 887.0 days, respectively.

Androgen receptor signaling inhibitors and docetaxel were the most common first- and second-line castration-resistant PC treatments. Enzalutamide was the preferred androgen receptor signaling inhibitor with the longest treatment duration.

Purine metabolism is a promising therapeutic target in cancer; however how cancer cells respond to purine shortage,particularly their adaptation and vulnerabilities, remains unclear. Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated these responses in prostate, lung and glioma cancer models. We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multi-protein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. While this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the microtubule-stabilizing chemotherapeutic drug Docetaxel. Furthermore, we show that although cancer cells primarily rely on de novo purine biosynthesis, they also exploit Methylthioadenosine Phosphorylase (MTAP)-mediated purine salvage as a crucial alternative source of purine supply, especially under purine shortage stress. In support of this finding, combining DRP-104 with an MTAP inhibitor significantly enhances tumor suppression in prostate cancer (PCa) models in vivo. Finally, despite the resilience of the purine supply machinery, purine shortage-stressed tumor cells exhibit increased DNA damage and activation of the cGAS-STING pathway, which may contribute to impaired immunoevasion and provide a molecular basis of the previously observed DRP-104-induced anti-tumor immunity. Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.

Metastatic hormone-sensitive prostate cancer (mHSPCa) presents de novo or represents significant disease progression and requires systemic treatment. However, progression to castration resistance is inevitable. The treatment landscape has evolved with the introduction of intensified systemic therapy, including androgen deprivation therapy (ADT) combined with either androgen receptor signaling inhibitors (ARSIs) or cytotoxic chemotherapy (doublet therapy) or combined therapy with both agents (triplet therapy). Landmark trials such as CHAARTED, STAMPEDE, LATITUDE, ENZAMET, and TITAN have established combination therapies as the standard of care, demonstrating significant overall survival benefits. More recently, triplet therapy-integrating ADT, docetaxel, and an ARSI-has emerged as an effective approach, particularly in high-volume metastatic disease, as supported by ARASENS and PEACE-1. Advances in imaging, such as PSMA PET-CT, have improved disease detection, allowing earlier detection of metastasis and appropriate therapy. Similarly, genomic profiling has enabled biomarker-driven, personalized treatment strategies. The role of treatment of the primary tumor, by either radiation therapy or cytoreductive prostatectomy, in low-volume disease continues to be explored. As novel therapies, targeted agents, and immunotherapies undergo investigation, optimizing treatment selection based on disease burden, molecular characteristics, and patient factors will be essential. The future of mHSPCa management lies in multidisciplinary, precision-based approaches to improve patient outcomes while balancing treatment efficacy and tolerability.

Prostate cancer (PCa) remains a significant health concern for males, and serum/glucocorticoid-regulated kinase-1 (SGK1) plays a crucial role in its pathogenesis. This provides a promising target for the development of novel therapies against PCa. Herein, we reported the structural optimization of the hit compound H1, which was discovered in our previous work as an SGK1 inhibitor. Based on docking research for the active binding conformation of compound H1, a series of novel 4-trifluoromethyl quinoline derivatives were developed by replacing the 6-methoxy group in the quinoline skeleton of compound H1 with a larger aryl ring to occupy the hinge region of SGK1. Among them, compound 12f showed the strongest SGK1 inhibitory potency, with an IC50 value of 0.39 μM, representing a 7.8-fold improvement over compound H1. Molecular docking studies revealed that the 6-methoxyphenylamine moiety of compound 12f effectively extends into the hinge region of SGK1, establishing a crucial hydrogen bonding interaction with Glu183 that enhances its biological potency. In vivo, compound 12f effectively suppressed tumor growth in the PC3 xenograft model in BALB/c nude mice without inducing any observable toxicity. Moreover, mechanistic studies showed that compound 12f hindered PC3 cell migration and invasion, improved the thermal stability of SGK1 protein in PC3 cells, decreased SGK1 protein levels in tumor tissues, and effectively inhibited the phosphorylation of SGK1 and its substrates in PC3 cells in a dose- and time-dependent manner. In summary, the results of this study highlight the potential of 12f as a lead compound for further optimization in the development of new therapies against PCa targeting SGK1.