The present retrospective, single-centre study investigated the efficacy and toxicity of upfront docetaxel chemotherapy in patients with hormone-sensitive metastatic prostate cancer and evaluated the impact in high and low-volume disease. Data from 167 patients with hormone-sensitive metastatic prostate cancer treated between January 2016 and December 2019 were analysed. The data cut-off was February 2024; the median follow-up time was 37 months and the median age was 66 years. The cohort consisted of varying Gleason scores, with the majority scoring 9 (n=86; 51.1%). Surgical castration was performed in the majority of cases (n=136; 81.4%). Overall, 66 (39.5 %) of the patients had low-volume disease (≤5 sites of metastasis, no visceral metastasis), while 101 (60.5%) patients had high-volume disease. Disease progression occurred in 100 patients (59.9%), with a median progression-free survival (PFS) of 47 months (95% CI, 37.503-56.497). The median overall survival (OS) was 71 months. In the comparison of low-volume vs. high-volume disease groups, the median PFS was 57 vs. 47 months respectively (P=0.276) and the corresponding median OS was not reached vs. 57 months respectively (P=0.192). Among the 100 patients with disease progression, 20 received second-line therapy. The median OS for untreated patients was 9.88 months, while those treated with antiandrogens was 15.14 months and those with re-challenge chemotherapy was 12.46 months (P=0.496; 95% CI, -6.47-11.83). Grade 3-4 treatment-related toxicities were observed in ~37.8% of patients, while one death was associated with chemotherapy-related neutropenic sepsis. The most common toxicities were mucositis (n=53; 31.7%), febrile neutropenia (n=44; 26.3%) and sepsis (n=29; 17.4%). The present study demonstrated that upfront docetaxel chemotherapy may be an effective and tolerable treatment for hormone-sensitive metastatic prostate cancer, particularly in settings where access to novel antiandrogens is limited, thus potentially offering a viable management strategy amidst resource constraints.

Established first- and second-line standard-of-care treatment options (abiraterone, enzalutamide, taxane chemotherapy) are available for patients with metastatic castration-resistant prostate cancer (mCRPC), but almost all patients experience subsequent disease progression. The randomized, double-blind, phase III KEYNOTE-641 study evaluated pembrolizumab plus enzalutamide versus placebo plus enzalutamide in participants with chemotherapy-naive mCRPC.

Eligible participants were males aged ≥18 years with confirmed mCRPC and no prior chemotherapy except docetaxel in the hormone-sensitive setting. Prior abiraterone treatment was permitted. Participants were randomly assigned 1:1 to receive pembrolizumab 200 mg or placebo intravenously once every 3 weeks for ≤35 cycles plus enzalutamide 160 mg orally daily. Dual primary end points were overall survival (OS) and radiographic progression-free survival (rPFS) per PCWG-modified RECIST v1.1 by blinded independent central review. Safety was a secondary end point.

Between August 21, 2019, and June 10, 2022, 1244 participants were randomly assigned to pembrolizumab plus enzalutamide (n=621) or placebo plus enzalutamide (n=623). At the data cutoff date (December 12, 2022), median follow-up was 27.6 months (range, 6.1-39.8 months). Primary end points of OS (median, 24.7 vs 27.3 months; hazard ratio [HR], 1.04 [95% CI, 0.88-1.22]; P=0.66) and rPFS (median, 10.4 vs 9.0 months; HR, 0.98 [0.84-1.14]; P=0.41) with pembrolizumab plus enzalutamide versus placebo plus enzalutamide were not met. The prespecified boundary for futility for OS was crossed, and the study was stopped. Grade ≥3 treatment-related adverse events occurred in 192 of 615 participants (31.2%) with ≥1 dose of pembrolizumab plus enzalutamide and in 67 of 620 participants (10.8%) with ≥1 dose of placebo plus enzalutamide. Seventy-one (11.5%) and 21 (3.4%) participants, respectively, discontinued study treatment due to treatment-related adverse events.

Adding pembrolizumab to enzalutamide did not improve efficacy outcomes for participants with chemotherapy-naive mCRPC. Additional toxicity was observed with the combination regimen.

Despite recent developments in the treatment of advanced prostate cancer (PCa), taxanes, including docetaxel (DOC) and cabazitaxel (CBZ), remain pivotal in management. DOC has shown efficacy for patients with metastatic hormone-sensitive prostate cancer, whereas CBZ plays a key role in the post-DOC setting. However, taxane-based therapies are associated with significant toxicities. We aimed to provide a comprehensive overview of the incidence, risk factors, and management strategies for taxane-related toxicities to optimize outcomes.

Neutropenia and febrile neutropenia are life-threatening complications. Primary prophylactic granulocyte-colony stimulating factor (G-CSF) is recommended for CBZ. In contrast, evidence of its use with DOC is limited but should be considered for high-risk patients. Other common toxicities, such as nausea/vomiting, fatigue, neuropathy, and skin disorder, are generally nonlife-threatening but can significantly impair patients' quality of life (QoL). Tailored patient selection and individualized management strategies are essential for minimizing toxicities and ensuring treatment continuity.

Despite the wide-ranging toxicities of taxanes, they remain a cornerstone in advanced PCa treatment. Preventing and managing severe neutropenia, febrile neutropenia, and QoL-impairing toxicities are essential for maintaining treatment continuity and achieving optimal outcomes.

The standard of care for metastatic castration-resistant prostate cancer (mCRPC) after second-generation androgen receptor pathway inhibitor (ARPI) therapy is still docetaxel. The randomized, double-blind, phase III KEYNOTE-921 trial (Clinicaltrials.gov identifier: NCT03834506) evaluated the efficacy and safety of pembrolizumab or placebo plus docetaxel for previously treated mCRPC.

Adults with mCRPC who progressed after androgen-deprivation therapy and one ARPI were randomly assigned 1:1 to pembrolizumab or placebo plus docetaxel with concomitant prednisone. Dual primary end points were radiographic progression-free survival (rPFS) by blinded independent central review per Prostate Cancer Working Group 3-modified RECIST 1.1 and overall survival (OS). Safety was a secondary end point.

Between May 30, 2019, and June 17, 2021, 515 participants were randomly assigned to pembrolizumab plus docetaxel and 515 to placebo plus docetaxel. Median time from random assignment to data cutoff date (June 20, 2022) at final analysis (FA) was 22.7 months (range, 12.1-36.7). At first interim analysis (data cutoff date: September 27, 2021), median rPFS was 8.6 months (95% CI, 8.3 to 10.2) with pembrolizumab plus docetaxel versus 8.3 months (95% CI, 8.2 to 8.5) with placebo plus docetaxel (hazard ratio [HR], 0.85 [95% CI, 0.71 to 1.01]; P = .03). At FA, median OS was 19.6 months (95% CI, 18.2 to 20.9) versus 19.0 months (95% CI, 17.9 to 20.9), respectively (HR, 0.92 [95% CI, 0.78 to 1.09]; P = .17). Grade ≥3 treatment-related adverse events occurred in 43.2% of participants who received pembrolizumab plus docetaxel and 36.6% of participants who received placebo plus docetaxel. Two and seven participants, respectively, died due to a treatment-related adverse event. Pneumonitis was the most common immune-mediated adverse event (7.0% v 3.1%).

The addition of pembrolizumab to docetaxel did not significantly improve efficacy outcomes for participants with previously treated mCRPC. The current standard of care remains unchanged.

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.

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.

The treatment landscape of prostate cancer is quite complex because of the many therapeutic options available in different disease settings (hormonal treatments, chemotherapy, poly(adenosine diphosphate ribose) polymerase inhibitors, radiopharmaceutical therapy). Since in most cases we do not have comparative studies between these different agents, the best therapeutic sequence in patients with prostate cancer remains unsolved. In this review, we describe the different systemic therapeutic options available in each disease setting from localized disease to metastatic castration-resistant disease. We also indicate when to use each of these therapeutic options in the therapeutic sequence on the basis of the results of the available studies. A special focus of this review is the place of prostate-specific membrane antigen radiopharmaceutical therapy in the treatment algorithms.

Prostate cancer frequently progresses to castration-resistant prostate cancer (CRPC) following androgen deprivation therapy, presenting a significant clinical challenge. Targeting tumor metabolism, particularly mitochondrial pathways, offers a promising strategy for overcoming CRPC. The modification of melatonin (Mel) to a triphenylphosphonium (TPP) cation-targeted mitochondria-melatonin (Mito-Mel) significantly increases its potency by over 1000-fold. Mito-Mel selectively targets mitochondria, enhancing reactive oxygen species (ROS) generation and causing mitochondrial membrane potential disruption. This leads to the inhibition of mitochondrial respiration including the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), which, in turn, suppresses CRPC survival metabolic adaptations, such as glycolysis. In vitro and in vivo experiments reveal for the first time that natural small molecule compound with mitochondrial targeting via TPP exhibits excellent anticancer efficacy by inducing tumor cellular pyroptosis and facilitating the immune response, underlining the encouraging promise of this strategy for the effective treatment of CRPC.

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.

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.

Kinesins are a family of motor proteins essential for intracellular transport and cellular dynamics, with kinesin family member C1 (KIFC1) emerging as a key regulator of cancer progression. Recent studies highlight KIFC1's crucial role in mitotic spindle assembly, chromosome segregation, and cell migration-processes frequently dysregulated in cancer. Its involvement in promoting malignant cell proliferation and metastasis underscores its significance in tumor biology. In various cancer types, aberrant KIFC1 expression correlates with poor prognosis and aggressive phenotypes, suggesting its potential as a biomarker for disease severity. Mechanistically, KIFC1 influences signaling pathways linked to cell cycle regulation and programmed cell death, reinforcing its role in oncogenesis. Given its pivotal function in cancer cell dynamics, KIFC1 represents a promising therapeutic target. Strategies aimed at modulating its activity, including small molecules or RNA interference, could disrupt cancer cell viability and proliferation. The current review article highlights KIFC1's importance in cancer biology, advocating for further investigation into its mechanisms and the development of KIFC1-targeted therapies to enhance treatment efficacy and improve patient outcomes across various malignancies.

Thioredoxin reductase (TrxR) is a pivotal regulator of redox homeostasis. It is frequently overexpressed in various cancer cells, including prostate cancer, making it a promising target for the development of anti-cancer drugs. In this study, we screened a series of newly designed complexes of gold(I) phosphine. Specifically, Compound 5 exhibited the highest cytotoxicity against prostate cancer cells and demonstrated stronger antitumor effects than commonly used drugs, such as cisplatin and auranofin. Importantly, our mechanistic study revealed that Compound 5 effectively inhibits the TrxR system in vitro. Additionally, Compound 5 promoted intracellular accumulation of reactive oxygen species (ROS), leading to mitochondrial dysfunction and irreversible apoptosis in prostate cancer cells. Our in vivo xenograft study further demonstrated that Compound 5 has excellent antitumor activity against prostate cancer cells, but does not cause severe side effects. These findings provide a promising lead Compound for the development of novel antitumor agents targeting prostate cancer and offer a valuable tool for investigating biological pathways involving TrxR and ROS modulation.

Cuproptosis, along with RNA methylation regulators, has recently come to the fore as innovative mechanisms governing cell death, exerting profound impact on the onset and progression of multiple cancers. Nonetheless, the prognostic implications and underlying regulatory mechanisms of them associated with prostate cancer (PCa) remain to be thoroughly investigated.

Genomic and clinical data for PCa from The Cancer Genome Atlas datasets were analyzed to identify a prognostic model through univariate and Least Absolute Shrinkage and Selection Operator Cox regression analyses that were validated utilizing external datasets. We used receiver operating characteristic curves and C-index to evaluate the accuracy of our prognostic model. In conjunction with this, we conducted single-cell RNA sequencing (scRNA-seq) analyses to investigate underlying mechanisms and evaluate the degree of immune infiltration, as well as to assess patients' responses to diverse chemotherapy agents. Especially, qPCR assay was utilized to unveil the expression of signature genes in PCa.

We meticulously selected six Cuproptosis-Associated RNA Methylation Regulators (CARMRs) to establish a risk prognosis model, which was further verified to obtain enhanced predictive capacity in external validation cohorts. Insights from immune infiltration and scRNA-seq analyses have elucidated the immune characteristics of PCa, and highlighted the immunosuppressive role of regulatory T cells on immune response. Additionally, drug susceptibility analysis demonstrated that patients with PCa in the low-risk category derived better benefit from bicalutamide treatment, whereas those in the high-risk group exhibited a favor response to adriamycin and docetaxel treatments. The qPCR and immunohistochemistry (IHC) staining assays also reveal the a dramatically altered expression pattern of TRDMT1 and ALYREF in PCa tissues.

In general, we established a model involving CARMRs that can better predict the risk of recurrence of PCa and have identified the possible mechanisms affecting PCa progression, thereby promoting further research in this field.

Prostate cancer (PCa) is the most common urological malignancy and second only to lung cancer in incidence among men. Its prognosis varies widely due to its heterogeneity. Research indicates that fatty acid metabolism may play a role in tumor development.

The gene expression profiles of PCa cell lines (GSE6919) in GEO database were analyzed to identify differentially expressed genes and their significance in relation to progression-free interval. The R package was employed to assess overall survival significance and clinicopathological features. The study investigated the effects of gene mutations and methylation on PCa and their correlation with immune cell infiltration in the tumor microenvironment, utilizing cBioPortal and UALCAN resources. TIMER was used in the TCGA project to compare the expression of MECR in tumours and in adjacent normal tissue for different tumours or for specific tumour subtypes. Furthermore, we examined the impact of hub genes on PCa progression through RT qPCR, immunohistochemistry, and cellular assays.

The MECR gene, which plays a role in fatty acid metabolism, has been implicated in the development and progression of PCa. Its expression levels are significantly associated with clinical features, survival outcomes, and prognosis in PCa. Comprehensive analyses of MECR mutations and methylation levels further underscore its involvement in the progression of prostate cancer. Additionally, MECR is closely associated with the immune microenvironment and immune cell infiltration in PCa. Furthermore, the in vitro and in vivo data indicated that MECR plays a role in PCa proliferation, migration, and invasion.

MECR has significant potential for research and application in the assessment of PCa prognosis and the regulation of the immune microenvironment.

In the over 80 years since androgens were found to play a pivotal role in prostate cancer (PCa) progression, androgen deprivation therapy (ADT) has been a cornerstone in treating advanced PCa. Castration-resistant PCa persists, however, with some of these tumors evolving to androgen receptor (AR)-independent forms like neuroendocrine PCa. The development of novel diagnostic and therapeutic approaches to PCa is therefore crucial. This review provides an overview of recent basic research in PCa, focusing on two main areas: PCa cells and their tumor microenvironments. The first section describes current knowledge on the intricate mechanisms of AR signaling pathways, emphasizing the roles of coactivators and chromatin state alterations in gene regulation. Genomic analyses have revealed recurrent mutations and copy number alterations critical for precision medicine. Liquid biopsy has become a promising tool for real-time tumor monitoring, identifying genetic alterations in circulating-tumor DNA or extracellular vesicles. The second section describes the tumor microenvironment of PCa, highlighting its immunosuppressive landscape and the potential of combining ADT with immunotherapy. Advanced techniques, including single-cell RNA sequencing and spatial transcriptomics offer insights into cellular heterogeneity and interactions within the tumor microenvironment, paving the way for novel therapeutic strategies. Integration of these diverse research areas will provide a comprehensive understanding of the current state and future directions of PCa research, underscoring the importance of personalized medicine and the dynamic nature of cancer treatment strategies.

There is no cross-sectional comparison on therapeutic and adverse effects for treatments of metastatic castration-resistant prostate cancer (mCRPCa). We aimed to horizontally compare them for all common first-line and second-line therapies.

We conducted a network meta-analysis with a systematic review in four databases (Pubmed, Web of Science, Embase, and Cochrane Library) up to January 5th, 2025. All randomized controlled trials (RCT) related to mCRPCa treatments with a clear description in study design were included. Endpoints included the radiographic progression-free survival (rPFS), overall survival (OS), time to PSA progression (TTPP), PSA progression rate (PSARR), and adverse events. All data was extracted by two researchers and analyzed with Gemtc package in R and Stata15. This NMA protocol was registered online (ID: CRD42025633178).

After screening among 33,694 articles, 24 RCTs involving 13,059 cases were included. For first-line treatments, combination therapies with second-generation androgen receptor inhibitors (ARIs) showed superior efficacies in OS [HR of poly(ADP-ribose) polymerase inhibitors (PARPi) + ARI: 0.63 (0.32,1.25)], TTPP [HR of Lu177 + ARI: 0.07 (0.01,0.87)] and PSARR [RR of Lu177 + ARI: 33.02 (15.56,71.62)] with the highest SUCRA (Surface under the Cumulative Ranking Curve) (72%, 91% and 97% respectively). PARPi + ARI also performed best for rPFS (SUCRA: 85%, with an insignificant HR [0.12 (0.02,2.35)]. For post-docetaxel second-line treatments, ARI also emerged as the preferred option. Efficacies of post-ARI second-line treatments were not evaluated due to the lack of related RCTs. No obvious heterogeneity and publication bias was detected during the therapeutic comparison.

This study provided comparative evidence for first-line and post-chemotherapy second-line mCRPCa treatment options. Second-generation ARIs exhibited good efficacy, particularly when combined with other treatments. However, the safety analysis necessitated balance between benefits and adverse events, especially for combination therapies. Stronger evidence is needed through direct comparisons in future clinical trials.

The study was supported by The National Natural Science Foundation of China (No. 82172568).

Contemporary advances in prostate cancer treatments have markedly improved patient outcomes, yet concerns persist regarding the increased cardiovascular toxicity of prostate cancer treatments, which is multifaceted. Local therapies entail non-negligible cardiovascular risks. The effects of androgen deprivation therapy, which is pivotal in disease management, on cardiovascular health remains contentious, with gonadotropin-releasing hormone agonists and antagonists showing varying cardiovascular outcomes. Despite the ongoing controversy over the cardiovascular risks of gonadotropin-releasing hormone antagonists versus agonists, current evidence does not support favouring one over the other based solely on cardiovascular risk. Combination therapy with androgen receptor pathway inhibitors and androgen deprivation therapy shows additive cardiovascular risks, but robust comparative data are lacking. Chemotherapies such as docetaxel and cabazitaxel, along with emerging targeted therapies and radiopharmaceuticals, are associated with varied cardiovascular risks, necessitating personalized patient assessment. Clinicians should adhere to cardio-oncology guidelines when prescribing therapeutic agents, especially for patients with pre-existing cardiovascular conditions. Optimal monitoring and management strategies are essential to mitigate cardiovascular morbidity and mortality.

Despite the boom in the development of cancer management in the last decade, most patients with metastatic prostate cancer (PCa) eventually progress to metastatic castration-resistant PCa (mCRPC) and often require multiple lines of treatment. The treatment landscape of mCRPC has evolved rapidly in recent years, introducing various types of systemic therapies, including taxane-based chemotherapy, androgen receptor pathway inhibitors, bone-targeted radionuclides (e.g., radium-223), immune checkpoint inhibitors, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, and radioligand therapies (RLTs) [e.g., a prostate-specific membrane antigen (PSMA) ligand labelled with 177Lu].

To help clinicians navigate the increasingly complex treatment landscape of mCRPC, this article reviews the evidence on different therapeutic regimens from pivotal trials. In addition, it reports on the results of a questionnaire developed and distributed by the Hong Kong Society of Uro-Oncology (HKSUO), with the aim of collecting the perspectives of specialists experienced in the treatment of advanced PCa in Hong Kong with regard to the clinical application of RLT, primarily [177Lu]Lu-PSMA-617/analogue therapy.

A total of 43 questionnaire respondents (including clinical oncologists, urologists, nuclear medicine specialists, and medical oncologists) voted on 27 consensus questions divided into eight sections. Consensus or strong consensus (correspondingly ≥75% or ≥90% acceptance for an answer option) was reached for 10 questions. Subsequently, a panel of 13 local and overseas experts coordinated by the HKSUO discussed the voting results and provided further insights into certain questions.

The literature review, the voting results of the questionnaire, and the expert opinions are expected to facilitate better understanding of recent therapeutic advancements and the role of novel RLTs in the treatment of mCRPC among clinicians.

Genitourinary cancers affect over 480,000 patients in the United States annually. While promising therapeutic modalities continue to emerge, notably immune checkpoint inhibitors, molecular targeted therapies, antibody-drug conjugates, and radioligand therapies, these treatments are associated with a spectrum of adverse side-effects, including ophthalmologic toxicities. In this review, we cover the most commonly used antineoplastic agents for the kidneys, bladder, urinary tracts, prostate, testis, and penis, detailing mechanism, indication, and recent trials supporting their use. For each category of antineoplastic therapy, we describe the epidemiology, management, and clinical presentation, of common ophthalmologic toxicities stemming from these agents. This review serves to augment awareness and recognition of possible ophthalmologic manifestations resulting from the use of antineoplastic agents in genitourinary malignancy. Early identification of these side effects can hasten ophthalmology referral and ultimately improve visual outcomes in patients experiencing medication-induced ocular toxicities.

20% of prostate cancer (PC) patients harbor germinal or somatic alterations in homologous recombination repair (HRR) genes, including BRCA1/2. BRCA mutations represent predictive biomarkers for treatment with polyadenosine diphosphate-ribose inhibitors (PARPi). Olaparib has shown efficacy in metastatic castration-resistant PC (mCRPC) and is currently approved in Italy for mCRPC with BRCA1/2 mutations. National and international guidelines strongly recommend BRCA testing in PC. However, genetic testing presents challenges in clinical practice that may limit access to PARPi.

we conducted a survey directed towards members of the Italian Association of Medical Oncology to highlight the level of implementation of national recommendations and issues associated with genetic testing. Through an anonymous questionnaire, the survey collected clinical data of PC patients undergoing BRCA testing and the main difficulties to face in conducting the analysis.

The survey was completed by 108 participants (5% of AIOM members). 52.8% of respondents test BRCA in all metastatic PC patients. If tissue analysis is invalid, only 17% use liquid biopsy, and 15.7% always consider a re-biopsy of a metastatic lesion. A quarter of respondents have to outsource genetic testing to another center and 17.6% have a split process between different institutions. Long timelines, lack of a predefined procedure, and unavailability of liquid biopsy represent the main issues based on respondents' opinions.

BRCA testing in PC still presents several difficulties in clinical practice that can limit access to PARPi treatment. Better implementation of molecular testing to identify BRCA-mutated patients is crucial for tailored treatment in mCRPC.

Docetaxel resistance is a significant obstacle in the treatment of prostate cancer (PCa), resulting in unfavorable patient prognoses. Intratumoral heterogeneity, often associated with epithelial-to-mesenchymal transition (EMT), has previously emerged as a phenomenon that facilitates adaptation to various stimuli, thus promoting cancer cell diversity and eventually resistance to chemotherapy, including docetaxel. Hence, understanding intratumoral heterogeneity is essential for better patient prognosis and the development of personalized treatment strategies.

To address this, we employed a high-throughput single-cell flow cytometry approach to identify a specific surface fingerprint associated with docetaxel-resistance in PCa cells and complemented it with proteomic analysis of extracellular vesicles. We further validated selected antigens using docetaxel-resistant patient-derived xenografts in vivo and probed primary PCa specimens to interrogate of their surface fingerprint.

Our approaches revealed a 6-molecule surface fingerprint linked to docetaxel resistance in primary PCa specimens. We observed consistent overexpression of CD95 (FAS/APO-1), and SSEA-4 surface antigens in both in vitro and in vivo docetaxel-resistant models, which was also observed in a cell subpopulation of primary PCa tumors exhibiting EMT features. Furthermore, CD95, along with the essential enzymes involved in SSEA-4 synthesis, ST3GAL1, and ST3GAL2, displayed a significant increase in patients with PCa undergoing docetaxel-based therapy, correlating with poor survival outcomes.

In summary, we demonstrate that the identified 6-molecule surface fingerprint associated with docetaxel resistance pre-exists in a subpopulation of primary PCa tumors before docetaxel treatment. Thus, this fingerprint warrants further validation as a promising predictive tool for docetaxel resistance in PCa patients prior to therapy initiation.

Metastasis is a leading cause of cancer-related death in castration-resistant prostate cancer (CRPC) patients. Circular RNAs (circRNAs) have emerged as key regulators of the metastasis of various cancers. However, the functional effects and regulatory mechanisms of circRNAs in metastatic CRPC (mCRPC) remain largely unknown.

The expression of circBNC2 in prostate cancer (PCa), CRPC and neuroendocrine prostate cancer (NEPC) tissues was analyzed through bioinformatics analysis. Functional assays, including cell proliferation, migration, invasion and ferroptosis, were conducted in vitro and in vivo. The interactions between circBNC2, miR-4298, and ACSL6 were explored via luciferase reporter assays, RNA immunoprecipitation, and western blotting analysis. In addition, for the first time in PCa, we developed novel nanobowls (NBs) loaded with docetaxel (DTX) and circBNC2 (Dc-NBs) and evaluated the antitumor efficacy of Dc-NBs in a photothermal therapy (PTT) strategy.

We identified a novel tumor-suppressive circRNA, circBNC2, in human PCa, CRPC and NEPC samples via bioinformatic analysis. CircBNC2 expression was significantly downregulated in PCa tissues and PCa cell lines. Functional assays demonstrated that circBNC2 inhibited PCa cell proliferation and migration both in vitro and in vivo. Mechanistically, circBNC2 acted as a sponge for miR-4298, and ACSL6 was identified as a direct target of the circBNC2/miR-4298 axis. Moreover, we demonstrated that ACSL6 is essential for mediating circBNC2-regulated ferroptosis in PCa cells. More importantly, we demonstrated the nanodelivery of Dc-NBs, which exhibited significant antitumor effects in both subcutaneous and metastatic PCa models.

This study revealed the tumor-suppressive role of circBNC2 in mCRPC by driving ferroptosis via the circBNC2/miR-4298/ACSL6 axis. Additionally, we developed an efficient and safe PTT strategy based on a nanodelivery system that codelivers circBNC2 and DTX, highlighting its potential as a novel therapeutic approach for mCRPC.

Cancer, a significant threat to human lives, has been the target of research for several decades. Although conventional therapies have drawbacks, such as side effects, low efficacy, and weak targeting, they have been applied extensively due to a lack of effective alternatives. The emergence of nanotechnology in medicine has opened up new possibilities and offered promising solutions for cancer therapy. In recent years, 2D nanomaterials have attracted enormous attention in nanomedicine due to their large surface-to-volume ratio, photo-responsivity, excellent electrical conductivity, etc. Among them, black phosphorus (BP) is a 2D nanomaterial consisting of multiple layers weakly bonded together through van der Waals forces. Its distinct structure makes BP suitable for biomedical applications, such as drug/gene carriers, PTT/PDT, and imaging agents. BP has demonstrated remarkable potential since its introduction in cancer therapy in 2015, particularly due to its selective anticancer activity even without the aid of near-infrared (NIR) or anticancer drugs. The present review makes efforts to cover and discuss studies published on the anticancer activity of BP. Based on the type of cancer, the subcategories are organized to shed light on the potential of BP nanosheets and BP quantum dots (BPQDs) against breast, brain, skin, prostate, and bone cancers, and a section is devoted to other cancer types. Since extensive attention has been paid to breast cancer cells and in vivo models, various subsections, including mono-, dual, and triple therapeutic approaches are established for this cancer type. Furthermore, the review outlines various synthesis approaches employed to produce BP nanomaterials, providing insights into key synthesis parameters. This review provides an up-to-date platform for the potential reader to understand what has been done about BP cancer therapy based on each disease, and the conclusions and outlook cover the directions in which this approach is going to proceed in the future.

Prostate cancer is one of the most common diseases among men worldwide and continues to pose a serious threat to health. This review shows the history and the new developments in the management of prostate cancer, with an emphasis on a range of therapeutic approaches, such as hormone therapy, radiation therapy, surgery, and innovative targeted therapeutics. The evolution of these treatments is examined in light of clinical outcomes, patient quality of life, and emerging resistance mechanisms, such as the recently shown vitamin D-based strategies. New developments that have the potential to increase survival rates and reduce side effects are also discussed, including PARP inhibitors (PARPis), immunotherapy, and tailored medication. Additionally, the use of biomarkers and sophisticated imaging methods in therapeutic decision-making is explored, with a focus on how these tools might improve patient care. The absolute necessity for a multidisciplinary approach for improving treatment strategies is becoming more and more apparent as our understanding of the biology of prostate cancer deepens. This approach ensures that patients receive customized medicines that fit their unique profiles. Future avenues of investigation will focus on resolving issues dealing with treatment efficacy and resistance to improve treatment results, ultimately leading to disease cure for prostate cancer patients.

Chromosomal instability (CIN), a hallmark of cancer, is commonly linked to poor prognosis in high-grade prostate cancer (PCa). Paradoxically, excessively high levels of CIN may impair cancer cell viability. Consequently, understanding how tumours adapt to CIN is critical for identifying novel therapeutic targets.

Bioinformatic analyses were conducted to identify genes overexpressed in PCa tissues using The Cancer Genome Atlas (TCGA) and GEO datasets. Western blotting and immunohistochemistry assays were applied to determine the expression levels of euchromatic histone lysine methyltransferase 2 (EHMT2), pT232-Aurora B and Cullin 3 (CUL3). The proliferation of cells was measured through CCK-8 tests, clonogenesis and subcutaneous xenografts of human PCa cells in BALB/c nude mice. Live cell imaging, immunofluorescence (IF) and flow cytometry were used to confirm the role of EHMT2 in PCa cell mitosis. Co-immunoprecipitation, Western blotting and IF assays further elucidated the underlying molecular mechanisms.

EHMT2 was highly expressed in metastatic PCa tissues exhibiting elevated CIN and was strongly associated with adverse clinical outcomes in patients with PCa. Silencing EHMT2 impaired cell division, inducing G2/M-phase arrest and mitotic catastrophe in PCa cells. Mechanistically, EHMT2 is indispensable to ensure the full activation of Aurora B through centromeric R-loop-driven ATR-CHK1 pathway, with EHMT2 protein expression peaking during the G2/M-phase. Moreover, CUL3 was identified as a binding partner of EHMT2, mediating its polyubiquitination and destabilising its protein levels.

This study reveals a CUL3-EHMT2-Aurora B regulatory axis that safeguards accurate chromosome segregation in PCa cells, supporting the potential therapeutic application of EHMT2 inhibitors.

Euchromatic histone lysine methyltransferase 2 (EHMT2) is overexpressed in advanced prostate cancer, restraining catastrophic chromosomal instability (CIN) and enhancing cell fitness. EHMT2 functions via the centromeric R-loop-driven ATR-CHK1-Aurora B pathway to promote chromosomal stability. EHMT2 confers enzalutamide resistance via activating Aurora B. Cullin 3 (CUL3) promotes EHMT2 destabilisation via deubiquitination.

Oral targeted therapies are a standard of care for men with advanced prostate cancer. However, these therapies are expensive, which may be a barrier to some, particularly the most economically disadvantaged. Through investment in programs to assist this population, savings generated from the 340B program have the potential to mitigate barriers to initiating treatment with targeted therapies in these men.

We performed a retrospective study using a 20% national sample of fee-for-service Medicare beneficiaries diagnosed with advanced prostate cancer between 2012 and 2019. The outcome was the patient-level use of a targeted therapy for the first time. This study had two exposures. The first was 340B penetration, representing the percentage of all outpatient hospital revenue in a hospital referral region generated by a 340B hospital. The second was the degree of socioeconomic disadvantage, as measured by the social vulnerability index (SVI). Two separate Cox models were fit to measure relationships between each exposure and use of a targeted therapy. A third model was fitted to assess whether differences in utilization by SVI were mitigated by increasing 340B penetration.

The use of a targeted therapy did not vary with 340B penetration (adjusted HR 1.1, 95% CI 0.96-1.2) for high versus low penetration. Conversely, socioeconomically disadvantaged men were less likely to initiate treatment. Those residing in the third SVI tertile (i.e., most vulnerable) were less likely to start on a targeted therapy compared to men in the first tertile (adjusted HR 0.85, 95% CI 0.78-0.92). However, increasing 340B penetration did not attenuate these differences (Wald test for the interaction term p = 0.10).

There was no association between a region's 340B penetration and use of a targeted therapy. Furthermore, although the use of a targeted therapy decreased with increased SVI, the 340B penetration of a region did not reduce this gap.

Metastatic castration-resistant prostate cancer (mCRPC) that progresses on androgen receptor pathway inhibitors (ARPIs) may continue to be driven by AR signaling. BMS-986365 is an orally administered ligand-directed degrader targeting the AR via a first-in-class dual mechanism of AR degradation and antagonism. CC-94676-PCA-001 (NCT04428788) is a phase I multicenter study of BMS-986365 in patients with progressive mCRPC.

Patients who progressed on androgen deprivation therapy, one or more ARPIs, and taxane chemotherapy (unless declined/ineligible) were enrolled. The study included dose escalation (part A) and expansion (part B) of BMS-986365 up to 900 mg twice daily. Primary objectives were safety and tolerability, and to define maximum tolerated dose and/or recommended phase II dose. Key secondary endpoints included decline in prostate-specific antigen ≥50% (PSA50) and radiographic progression-free survival (rPFS).

Parts A and B enrolled 27 and 68 patients, respectively. In part B, the median number of prior therapies was 4 (range 2-11). The most common treatment-related adverse events were asymptomatic prolonged corrected QT interval (47%) and bradycardia (34%). Part A maximum tolerated dose was not reached and recommended phase II dose selection is ongoing. Across part B three highest doses (400-900 mg twice daily, n = 60), PSA50 was 32% (n = 19), including 50% (n = 10/20) at 900 mg; median rPFS (95% confidence interval) was 6.3 months (5.3-12.6 months), including 8.3 months (3.8-16.6 months) at 900 mg; and rPFS was longer in patients without versus with prior chemotherapy: 16.5 months (5.5 months-not evaluable) versus 5.5 months (2.7-8.3 months), respectively. Efficacy was observed in patients with mCRPC with AR ligand binding domain (LBD) WT or with AR LBD mutations.

BMS-986365 was well tolerated, with a manageable safety profile, and demonstrated activity in heavily pretreated patients with mCRPC with potentially higher benefit in chemotherapy-naive patients. These data show the potential of BMS-986365 to overcome resistance to current ARPIs, regardless of AR LBD mutation status.

Localized high-risk (HR) prostate cancer (PCa) is a heterogeneous disease whose likelihood of a biochemical recurrence, metastatic progression and cancer-related mortality after initial treatment is higher when compared with patients with low (LR) or intermediate-risk (IR) disease. In the past, neoadjuvant therapy has shown an improvement in postoperative oncological variables but failed to demonstrate any survival advantages. With the promising results from novel treatments in metastatic and non-metastatic castration resistant PCa settings, new evidence has appeared in the literature in the neoadjuvant setting. Background/Objectives: To describe the current evidence for different neoadjuvant treatments before a radical prostatectomy in high-risk prostate cancer. Methods: We performed a comprehensive English literature search for original and review articles through January-August 2024, using Pubmed, Medline and ClinicalTrials.gov databases, as well as a comprehensive review of different international guidelines, searching the following terms: "neoadjuvant ADT prostate cancer", "neoadjuvant ADT", "prostate cancer surgery" and "neoadjuvant high-risk prostate cancer". We included 61 papers for the final review. Results and Discussion: Neoadjuvant therapy is not recommended in daily practice by any international guideline. The National Comprehensive Cancer Network (NCCN) guidelines strongly discourage the use of ADT as a neoadjuvant therapy outside of clinical trials. ADT + ARTAs show promising data in phase-II trials, including favorable pCR, MRD, PSA relapse and salvage therapy rates. Clinical trials on chemotherapy, 177Lu-PSMA, genomic-targeted therapies and markers of response leave room for further evidence acquisition due to their encouraging results. Conclusions: Currently, no phase III data supports systemic neoadjuvant therapy before RP. Phase II studies show promising data for ADT with second-generation agents, including favorable pCR, MRD, PSA relapse and salvage therapy rates.

Metastatic prostate cancer (PCa) has much lower survival and ultimately develops castration resistance, which expects novel targets and therapeutic approaches. As a result of iron-dependent lipid peroxidation, ferroptosis triggers programmed cell death and has been associated with castration-resistant prostate cancer (CRPC).

To better understand how ferroptosis can be used to treat CRPC, we reviewed the following: First, ferroptosis mechanisms and characteristics. We then pay attention to ferroptosis effects on CRPC, and the relationship between ferroptosis and CRPC treatment. Finally, we'd like to figure out if ferroptosis could predict the prognosis of CRPC thus screening early for populations that may benefit from appropriate therapies.

The review demonstrated that ferroptosis regulators like PI3K/AKT/mTOR, DECR1 et al., have a significant role in the development of CRPC and that several inducers of ferroptosis, such as erastin, BSO, RSL3, and FIN56, have already demonstrated their effects in that area. What's more, ferroptosis is crucial for radiation-induced anticancer effects by inducing lipid peroxidation and regulating p53, AMPK, and others. Additionally, it has been discovered that certain GPX4 and SLC7A11 inhibitors can increase radiosensitivity, which brings new combination strategies. Finally, among the genes associated with ferroptosis, which may be excellent predictors of prostate cancer prognosis, several risk models have been developed and shown promising predictive capabilities.

Ferroptosis can serve as a potential therapeutic target for CRPC, and could be a new strategy for combination therapy. Moreover, ferroptosis-related genes may be great indicators of PCa prognosis. Further research on ferroptosis in CRPC therapy can benefit from the frameworks provided by this review.

Metastatic castration-resistant prostate cancer is the most dangerous stage of prostate cancer, with a high mortality rate. Docetaxel chemotherapy is one of the most effective treatment methods currently, but some patients do not respond to chemotherapy. To avoid unnecessary toxicity in non-responders, this study explores the potential of circulating microRNAs as early biomarkers of docetaxel response in patients with metastatic castration-resistant prostate cancer.

PC3 cells and DU145 cells were divided into the control, NC mimics, and miRNA-136-5p-mimics groups. Cell viability was measured using the CCK-8 assay. Cell apoptosis was determined by flow cytometry. Cell migration and invasion abilities were evaluated using the Transwell assay. Real-time quantitative PCR was used to measure the miRNA levels in cells and peripheral blood of patients. The miRNA-136-5p target genes were predicted by using the PITA, TargetScan, and miRanda databases. The target genes were analyzed with KEGG pathway analysis.

In both PC3 and DU145 cells, the miRNA-136-5p-mimics group exhibited significantly increased cell survival rates, migration and invasion numbers, and significantly decreased apoptosis rates than the control group (p < 0.05). The miRNA-222-3p and miRNA-136-5p levels were significantly increased in docetaxel-resistant PC3 and DU145 cells (p < 0.05). The levels of circulating miRNA-222-3p and miRNA-136-5p were significantly associated with docetaxel treatment (p < 0.05). Higher levels of miRNA-222-3p were observed in non-responsive patients (p < 0.05). The area under the curve for miRNA-222-3p was 0.76 (95%CI: 0.55-0.97), indicating its effectiveness as a predictive factor for non-responsive patients to docetaxel. Patients with high expression of miRNA-34c-5p after docetaxel chemotherapy had shorter overall survival times (P < 0.05). Bioinformatics analysis identified 110 potential target genes of miRNA-136-5p. KEGG revealed that these genes were mainly distributed in three pathways. Among them, the PI3K-AKT pathway was closely related to the metastasis of prostate cancer cells.

Our study demonstrates that miRNA-136-5p promotes the proliferation and invasion of PC3 and DU145 cells while inhibiting apoptosis. Circulating miRNA-222-3p may serve as a biomarker for early therapeutic response to docetaxel, and further clinical investigation is warranted. Additionally, miRNA-136-5p may have anti-cancer effects during docetaxel chemotherapy in metastatic castration-resistant prostate cancer.

Cancer is characterized by uncontrolled cell growth and spreading throughout the body. This study employed computational approaches to investigate 18 naturally derived anticancer piscidinol A derivatives (1-18) as potential therapeutics. By examining their interactions with 15 essential target proteins (HIF-1α, RanGAP, FOXM1, PARP2, HER2, ERα, NGF, FAS, GRP78, PRDX2, SCF complex, EGFR, Bcl-xL, ERG, and HSP70) and comparing them with established drugs such as camptothecin, docetaxel, etoposide, irinotecan, paclitaxel, and teniposide, compound 10 emerged as noteworthy. In molecular dynamics simulations, the protein with the strongest binding to the crucial 1A52 protein exceeded druglikeness criteria and displayed extraordinary stability within the enzyme's pocket over varied temperatures (300-320 K). Additionally, density functional theory was used to calculate dipole moments and molecular orbital characteristics, as well as analyze the thermodynamic stability of the putative anticancer derivatives. This finding reveals a well-defined, potentially therapeutic relationship supported by theoretical analysis, which is in good agreement with subsequent assessments of their potential in vitro cytotoxic effects of piscidinol A derivatives (6-18) against various cancer cell lines. Future in vivo and clinical studies are required to validate these findings further. Compound 10 thus emerges as an intriguing contender in the fight against cancer.

Metastatic castrate-resistant prostate cancer (mCRPC) is a genetically and phenotypically heterogeneous cancer where advancements are needed in biomarker discovery and targeted therapy. A critical and often effective component of treatment includes taxanes. We perform a high-throughput screen across a cohort of 30 diverse patient-derived castrate-resistant prostate cancer (CRPC) organoids to a library of 78 drugs. Combining quantitative response measures with transcriptomic analyses demonstrates that HNF1 homeobox A (HNF1A) drives a transcriptional program of taxane resistance, commonly dependent upon cellular inhibitor of apoptosis protein 2 (cIAP2). Monotherapy with cIAP2 inhibitor LCL161 is sufficient to treat HNF1A+ models of mCRPC previously resistant to docetaxel. These data may be useful in future clinical trial designs.

To compare the efficacy and toxicity of docetaxel treatment regimens in metastatic castration-resistant prostate cancer (mCRPC).

We retrospectively analyzed 162 patients diagnosed with mCRPC who underwent docetaxel chemotherapy between 2009 and 2020. The patients were divided into three groups according to the dosage and interval of docetaxel (DCT) chemotherapy regimen: 30 mL/m2 weekly, 50 mL/m2 biweekly (every 2 weeks), and 75 mL/m2 triweekly (every 3 weeks).

There were no significant differences in the prostate-specific antigen (PSA) response rates (P = 0.709). The median time to progression was 3.0 [interquartile range (IQR 2.0-5.3)] months, 5.0 (IQR 2.0-13.0) months, and 5.0 (IQR 3.0-12.0) months in the weekly, biweekly, and triweekly groups, respectively (P = 0.062). The median overall survival (OS) was 12.5 (IQR 6.0-14.0) months, 18.8 (IQR 5.5-23.5) months, and 22.9 (IQR 11.0-33.0) months in the weekly, biweekly, and triweekly groups, respectively (P < 0.001). There were no differences in all toxicity and Grade 3 or higher toxicity. In Cox multivariate regression analysis, the Eastern Cooperative Oncology Group performance status (ECOG-PS), response to chemotherapy, and chemotherapy cycle also affected the PFS. Age, ECOG-PS, and chemotherapy cycle affected the OS.

The various options for optimal chemotherapy are indicated depending on the patient's conditions during the diagnosis of mCRPC. Treatment with DCT at 2-week or even 1-week intervals appears to be well tolerated in men diagnosed with mCRPC and represents a useful option when the conventional triweekly regimen is not tolerated due to poor patient condition.

The prevalence of cardiovascular risk factors and disease is high in patients with newly diagnosed prostate cancer (PC). Survivorship of PC patients is often determined by cardiovascular disease (CVD). Our review synthesizes the most recent literature exploring the dynamics between PC and CVD across the disease trajectory and treatments. We review key ongoing clinical trials in the field and highlight avenues for future study.

We conducted a comprehensive narrative review of the literature using various search strategies in three databases (PubMed, Web of Science, ClinicalTrials.gov), focusing on literature published between 2000 and 2024.

We discuss the significance of CVD-related mortality in PC, review the risk factors, and highlight potential mechanisms for accelerated CVD in the androgen-deprivation setting. Furthermore, we summarize key literature of CVD and cardiotoxicity for various therapeutic approaches in PC, including orchiectomy, taxane-based chemotherapy, GnRH-axis targets, and next-generation hormonal agents and PARP inhibitors. Lastly, we discuss prevention strategies and the importance of multi-disciplinary care in this setting.

CVD is a major cause of death in men with PC. Various novel therapeutic approaches have been pivotal in improving oncologic outcomes, but emerging data demonstrate a complex interplay between the androgen axis and CVD that is likely affected by modern treatment strategies. Given the prolonged PC survivorship, unraveling non-oncologic related causes of death and investigating prevention strategies are imperative (Fig. 1). Fig. 1 LANDSCAPE OF PROSTATE CANCER.: Spectrum of prostate cancer disease states (red) and interventions (yellow) with the potential role for optimization (green) to improve cardiovascular outcomes in the future (blue).

Androgen deprivation therapy has been the primary treatment strategy for advanced prostate cancer (PCa). But most patients develop castration resistance over time. For FDA-approved second-generation androgen receptor (AR) antagonists, including enzalutamide (ENZ) and abiraterone (AA), patients who initially respond to them eventually develop resistance. The key mechanism for resistance to ENZ/AA involves AR splice variants (AR-Vs) and specifically AR-V7. Current AR antagonists cannot target AR-V7 due to its lack of the C-terminal ligand-binding domain (LBD) but keeping the AR N-terminal domain (NTD) which still can activate androgen-responsive genes. Therefore, targeting the AR NTD and AR-V7 is critically important to overcome ENZ resistance. Unfortunately, AR NTD has been considered an "undruggable" target due to the difficulty in defining its three-dimensional (3D) structure. In this context, siRNA is highly suitable to address this undruggable target. However, siRNA cannot freely diffuse into cells, and a carrier is needed. In this regard, nucleic acid-based aptamers are highly suitable for cell type-specific delivery of siRNA in vivo. In this study, we have developed a serum-stable bivalent prostate-specific membrane antigen (PSMA) aptamer-AR-V7 siRNA chimera (PAP). The results show that PAP can knock down both AR-full length and AR-V7 in PSMA-expressing castration-resistant cells. It can resensitize ENZ in cell lines and PCa xenografts. ENZ combined with PAP can significantly inhibit 22Rv1 xenograft growth in mice without experiencing castration. Owing to the low toxicity, PAP has potential to offer a new antiandrogen treatment for current ENZ-resistant PCa.

The use of androgen biosynthesis and second-generation androgen receptor inhibitors for advanced prostate cancer is increasing. Because these therapies alter the androgen pathway, they have been associated with cardiometabolic and neurocognitive toxicities. Although their safety profiles have been assessed in clinical trials, real-world data are limited.

A 20% sample of national Medicare claims was used to perform a retrospective cohort study of Medicare beneficiaries with advanced prostate cancer treated with androgen biosynthesis (ie, abiraterone) and second-generation androgen receptor inhibitors between 2012 and 2019. Outcomes were assessed after the first fill of either class of drug for the 12-month period after starting therapy. The primary outcome was a hospital admission or emergency department visit for a cardiometabolic event. Secondary outcomes included neurocognitive events and fractures. Multivariable regression was used to assess the association between the class of drug and occurrence of an adverse event.

There were 3488 (60%) men started on an androgen biosynthesis inhibitor and 2361 (40%) started on an androgen receptor inhibitor for the first time. Cardiometabolic adverse events were more common in men managed with androgen biosynthesis inhibitor (9.2% vs 7.5%, P = .027). No difference between androgen biosynthesis and androgen receptor inhibitors was observed for neurocognitive events (3.3% vs 3.4%, respectively; P = .71) or fractures (4.2% vs 3.6%, respectively; P = .26).

Men with advanced prostate cancer initiating an androgen biosynthesis inhibitor for the first time more commonly had cardiometabolic events than those started on androgen receptor inhibitors. Neurocognitive events and fractures did not differ by drug class.