Treatment intensification with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPi) have led to improved survival in advanced prostate cancer. However, ADT is linked to significant cardiovascular toxicity, and ARPi also negatively impacts cardiovascular health. Together with a higher prevalence of baseline cardiovascular risk factors reported among prostate cancer survivors at diagnosis, there is a pressing need to prioritise and optimise cardiovascular health in this population. Firstly, While no dedicated cardiovascular toxicity risk calculators are available, other tools such as SCORE2 can be used for baseline cardiovascular risk assessment. Next, selected patients on combination therapy may benefit from de-escalation of ADT to minimise its toxicities while maintaining cancer control. These patients can be characterised by an exceptional PSA response to hormonal treatment, favourable disease characteristics and competing comorbidities that warrant a less aggressive treatment regime. In addition, emerging molecular and genomic biomarkers hold the potential to identify patients who are suited for a de-escalated treatment approach either with ADT or with ARPi. One such biomarker is AR-V7 splice variant that predicts resistance to ARPi. Lastly, optimization of modifiable cardiovascular risk factors for patients through a coherent framework (ABCDE) and exercise therapy is equally important. This article aims to comprehensively review the cardiovascular impact of hormonal manipulation in metastatic hormone-sensitive prostate cancer, propose overarching strategies to mitigate cardiovascular toxicity associated with hormonal treatment, and, most importantly, raise awareness about the detrimental cardiovascular effects inherent in our current management strategies involving hormonal agents.

BACKGROUND: This qualitative research study was conducted to develop a novel, comprehensive, patient-reported outcome measure (PRO), the \"Symptoms and Impacts of Androgen Deprivation Therapy (ADT) for Prostate Cancer\" (SIADT-PC), assessing hormonal therapy-related symptoms and their impacts on men with advanced prostate cancer.
METHODS: Concept elicitation (CE) interviews were conducted among adult men with prostate cancer to evaluate their experiences with ADT. Based on key symptom and impact concepts mentioned, an initial PRO measure was developed. The draft measure was further assessed in cognitive debriefing (CD) interviews with men with prostate cancer, in which participants reviewed items, response options, and recall periods. Initial item-based psychometric analyses were conducted using interview data. The draft questionnaire was revised on the basis of participant feedback, quantitative psychometric results, and consultation with clinical experts.
RESULTS: A total of 21 participants were interviewed (CE concept elicitation, n = 12; CD cognitive debriefing, n = 17; n = 8 completed both). Mean participant age (SD) was 59.7 (8.7) years and 76.2% were white. The de novo SIADT-PC measure consists of 27 items: 11 symptoms (e.g., fatigue, hot flashes, and erectile dysfunction), 2 long-term symptoms (e.g., weight gain), 10 impacts (e.g., impacts on physical activities and relationships), and 4 related to mode of administration (i.e., injection-site reactions). Items were assessed with a 5-point verbal rating scale, with answer choices that capture frequency or severity.
CONCLUSIONS: Once fully validated, this de novo measure may be used in clinical studies and clinical practice to assess hormone therapy-related symptoms and impacts, enabling physicians to identify timely and appropriate interventions.

There is controversy regarding the most effective primary treatment of choice for prostate cancer (PCa) in terms of patient outcomes, such as surgery or radiotherapy (RT). This study evaluated the comparative efficacy and long-term outcomes of radical prostatectomy (RP) and RT for PCa treatment. A thorough literature review of relevant databases was conducted, focusing on academic and clinical studies published from 2019 onwards. The inclusion criteria included randomized controlled trials (RCTs) and other observational studies comparing survival outcomes in patients treated with surgery and RT. We followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines to provide an overview of the data. We selected 19 studies based on the inclusion criteria. Of the total 19 studies, 12 advocated RP as the preferred treatment to improve survival outcomes in patients with PCa. The results of our synthesis showed that prostate cancer-specific mortality (PCSM) was lower in patients treated with RT. The total effect size for the analysis was calculated as Z=1.19 (p-value=0.23). The heterogeneity in the studies was as follows: Tau2=0.09, Chi2=20.25, df=4, I2=80%. Moreover, overall survival (OS) was shown to be higher in patients who underwent prostatectomy. The combined effect for the analysis was found to be: HR=0.97 (0.93, 1.01). The total effect was calculated as Z=1.33 (p-value= 0.18). The heterogeneity was found to be Tau2=0.00, Chi2=1.33, df=2, and I2=0%. However, overall mortality (OM) was shown to be independent of the treatment modality. RT is the preferred strategy for PCa treatment, as it balances efficacy and long-term outcomes. Clinical decision-making should consider individual patient characteristics and future research should delve into specific subpopulations and long-term outcomes to further refine the treatment guidelines.

BACKGROUND: Early diagnosis of prostate cancer is key to achieving a cure and its proper management leads to a good prognosis. In Ghana a large percentage of patients present with advanced disease and unusual presentations in these patients result in greater delay in the diagnosis thus worsening the outcomes.
METHODS: We present three African males with advanced prostate cancer who had delayed diagnosis. The first patient, a 64 year old male presented with ascites of 2 years duration with weight loss and no lower urinary tract symptoms, the second, a 69 year old man with end stage renal failure of 6 months duration and was receiving dialysis, the third case, an 87 year old man was managed for pulmonary tuberculosis after he presented with chronic cough and lower urinary tract symptoms. All patients eventually had a prostate specific antigen done which were elevated. Further investigations including prostate biopsies, abdominopelvic CT scans for case 1, abdominopelvic ultrasound, prostate biopsies and blood urea and electrolytes for case 2, prostate biopsies, chest and lumbosacral showed a diagnosis of metastatic prostate carcinoma, and all patients were managed with androgen deprivation. The second patient received additional radiotherapy.
CONCLUSIONS: A lack of knowledge of prostate cancer symptoms including unusual symptoms, can result in delayed diagnosis especially in regions of the world where a large number of patients present with advanced disease.

The metastasis-associated protein 1/protein kinase B (MTA1/AKT) signaling pathway has been shown to cooperate in promoting prostate tumor growth. Targeted interception strategies by plant-based polyphenols, specifically stilbenes, have shown great promise against MTA1-mediated prostate cancer progression. In this study, we employed a prostate-specific transgenic mouse model with MTA1 overexpression on the background of phosphatase and tensin homolog (Pten) null (R26MTA1; Ptenf/f) and PC3M prostate cancer cells which recapitulate altered molecular pathways in advanced prostate cancer. Mechanistically, the MTA1 knockdown or pharmacological inhibition of MTA1 by gnetin C (dimer resveratrol) in cultured PC3M cells resulted in the marked inactivation of mammalian target of rapamycin (mTOR) signaling. In vivo, mice tolerated a daily intraperitoneal treatment of gnetin C (7 mg/kg bw) for 12 weeks without any sign of toxicity. Treatment with gnetin C markedly reduced cell proliferation and angiogenesis and promoted apoptosis in mice with advanced prostate cancer. Further, in addition to decreasing MTA1 levels in prostate epithelial cells, gnetin C significantly reduced mTOR signaling activity in prostate tissues, including the activity of mTOR-target proteins: p70 ribosomal protein S6 kinase (S6K) and eukaryotic translational initiation factor 4E (elF4E)-binding protein 1 (4EBP1). Collectively, these findings established gnetin C as a new natural compound with anticancer properties against MTA1/AKT/mTOR-activated prostate cancer, with potential as monotherapy and as a possible adjunct to clinically approved mTOR pathway inhibitors in the future.

OBJECTIVE: The study aimed at investigating prostate cancer patients\' choice of androgen deprivation treatment (ADT) and possible factors that would affect their preferences of ADT.
METHODS: This was a single-centre cross-sectional study investigating the usage and preferences of ADT. Consecutives prostate cancer patients who were receiving injectable luteinizing hormone-releasing hormone (LHRH) agonist or antagonist were recruited from the prostate cancer clinic in a tertiary academic hospital. Patients who received bilateral orchidectomy or those who could not consent to the study were excluded. Disease characteristics, treatment information and patient background were documented. The survey collected information related to their change in ADT regimen, preferences on drug usage (routes and frequency of administration) and their reasons. A hypothetical set of three drug formularies was designed. Questions regarding patient preference and the contributing reasons raised in the format of questionnaire.
RESULTS: 100 patients completed the survey. Most patients started with more frequent injections (3-monthly, 54%; 1-monthly, 38%) and switched to 6-monthly injections (89%) at the time of the survey. Primary reasons for the change were healthcare opinion (72%) and less frequent treatment (51%). Three options of ADT (oral daily, 1-monthly and 6-monthly injection) with the same efficacies and side effect profile were offered: 61% preferred 6-monthly injection, 1% preferred 1-monthly injection and 38% preferred oral regimen. When patients were informed of lower cardiovascular side effects in 1-monthly injection or daily oral drug, patients\' preference was 56% (6-monthly), 6% (1-monthly), and 39% (oral). Patients with polypharmacy (more than 5 regular medications) were more inclined to choose injections (p = 0.025). Patient age, educational background, employment status, marriage status and disease status were not found to be statistically significant contributing factors to patient preference.
CONCLUSIONS: 6-monthly ADT injection was the preferred ADT despite greater cardiovascular risks. Among 1-monthly or daily oral LHRH antagonist, more patients prefer oral option. Convenience factor was highly valued.

UNASSIGNED: The objective of the study is to evaluate whether low nadir testosterone during treatment with triptorelin pamoate, a luteinising hormone-releasing hormone (LHRH) agonist, is associated with improved clinical outcomes in patients with advanced prostate cancer using a retrospective analysis of clinical trial data.
UNASSIGNED: Data were pooled from three prospective, 9-12-month Phase III studies of triptorelin monotherapy in patients with advanced prostate cancer (including NCT00751790). The serum testosterone concentration suppression targets evaluated were <0.35 nmol/L (<10 ng/dl), <0.7 nmol/L (<20 ng/dl), <1.7 nmol/L (<50 ng/dl) and ≥1.7 nmol/L. Overall survival (OS) and disease-specific survival (DSS) by testosterone suppression group were assessed by Kaplan-Meier analysis, with log-rank test. The time frame for the primary analysis was Days 1-518 (median OS follow-up 254 days [range, 29-518 days]) and for the sensitivity analyses was Days 1-262. Supplementary analyses combined the ≥0.7- to <1.7-nmol/L and ≥1.7-nmol/L groups.
UNASSIGNED: The sample size comprised 592 patients (most received triptorelin monotherapy; four reported concomitant androgen receptor-axis-targeted therapy). Nadir testosterones of <0.35, ≥0.35 to <0.7, ≥0.7 to <1.7 and ≥1.7 nmol/L were achieved by 96%, 3.2%, 0.34% and 0.17% of patients, respectively. Better OS with decreasing level of nadir testosterone was observed (p < 0.001) and this persisted after sensitivity/supplemental analyses (all p < 0.001). Differences in DSS with decreasing levels of nadir testosterone were not statistically significant in the primary analysis. Sensitivity/supplemental analysis showed better DSS with decreasing level of nadir testosterone (Days 1-262, p = 0.01; combined groups Days 1-518, p = 0.03; combined groups Days 1-262, p = 0.005).
UNASSIGNED: Low nadir testosterone achieved during treatment with the LHRH agonist triptorelin was associated with improved OS and DSS in patients with advanced prostate cancer.

BACKGROUND: Advanced prostate cancer (PC) is characterized by insensitivity to androgen deprivation therapy and chemotherapy, resulting in poor outcome for most patients. Thus, advanced PC urgently needs novel therapeutic strategies. Mounting evidence points to splicing dysregulation as a hallmark of advanced PC. Moreover, pharmacologic inhibition of the splicing process is emerging as a promising option for this disease.
METHODS: By using a representative androgen-insensitive PC cell line (22Rv1), we have investigated the genome-wide transcriptomic effects underlying the cytotoxic effects exerted by three splicing-targeting drugs: Pladienolide B, indisulam and THZ531. Bioinformatic analyses were performed to uncover the gene structural features underlying sensitivity to transcriptional and splicing regulation by these treatments. Biological pathways altered by these treatments were annotated by gene ontology analyses and validated by functional experiments in cell models.
RESULTS: Although eliciting similar cytotoxic effects on advanced PC cells, Pladienolide B, indisulam and THZ531 modulate specific transcriptional and splicing signatures. Drug sensitivity is associated with distinct gene structural features, expression levels and cis-acting sequence elements in the regulated exons and introns. Importantly, we identified PC-relevant genes (i.e. EZH2, MDM4) whose drug-induced splicing alteration exerts an impact on cell survival. Moreover, computational analyses uncovered a widespread impact of splicing-targeting drugs on intron retention, with enrichment in genes implicated in pre-mRNA 3\'-end processing (i.e. CSTF3, PCF11). Coherently, advanced PC cells displayed high sensitivity to a specific inhibitor of the cleavage and polyadenylation complex, which enhances the effects of chemotherapeutic drugs that are already in use for this cancer.
CONCLUSIONS: Our study uncovers intron retention as an actionable vulnerability for advanced PC, which may be exploited to improve therapeutic management of this currently incurable disease.

UNASSIGNED: Prostate cancer (PC) has a serious public health impact, and its incidence is rising due to the aging population. There is limited evidence and consensus to guide the management of PC in Southeast Asia (SEA). We present real-world data on clinical practice patterns in SEA for advanced PC care.
UNASSIGNED: A paper-based survey was used to identify clinical practice patterns and obtain consensus among the panelists. The survey included the demographics of the panelists, the use of clinical guidelines, and clinical practice patterns in the management of advanced PC in SEA.
UNASSIGNED: Most panelists (81%) voted prostate-specific antigen (PSA) as the most effective test for early PC diagnosis and risk stratification. Nearly 44% of panelists agreed that prostate-specific membrane antigen positron emission tomography-computed tomography imaging for PC diagnostic and staging information aids local and systemic therapy decisions. The majority of the panel preferred abiraterone acetate (67%) or docetaxel (44%) as first-line therapy for symptomatic mCRPC patients. Abiraterone acetate (50%) is preferred over docetaxel as a first-line treatment in metastatic castration-sensitive prostate cancer patients with high-volume disease. However, the panel did not support the use of abiraterone acetate in non-metastatic castration-resistant prostate cancer (nmCRPC) patients. Apalutamide (75%) is the preferred treatment option for patients with nmCRPC. The cost and availability of modern treatments and technologies are important factors influencing therapeutic decisions. All panelists supported the use of generic versions of approved therapies.
UNASSIGNED: The survey results reflect real-world management of advanced PC in a SEA country. These findings could be used to guide local clinical practices and highlight the financial challenges of modern healthcare.

UNASSIGNED: Prostate cancer screening with prostate-specific antigen (PSA) can result in unnecessary biopsies and overdiagnosis. Alternately, PSA density (PSAD) calculation may help support biopsy decisions; however, evidence of its usefulness is not concrete.
UNASSIGNED: To evaluate the predictive value of PSAD for clinically significant prostate cancer detection by systematic and MRI-targeted biopsies.
UNASSIGNED: This prospective study was conducted at two tertiary hospitals in Riyadh, Saudi Arabia, between December 2018 and November 2021. Patients suspected of prostate cancer were subjected to multi-parametric MRI, and for those with positive findings, systematic and targeted biopsies were performed. Clinically non-significant and significant prostate cancer cases were classified based on histopathology-defined ISUP grade or Gleason score. The PSAD was measured using the prostate volume determined by the MRI and categorized into ≤0.15, 0.16-0.20, and >0.20 ng/ml2 subgroups.
UNASSIGNED: Systematic and targeted biopsies were carried out for 284 patients. The discriminant ability of PSAD is higher in MRI-targeted biopsy compared with systematic biopsy (AUC: 0.77 vs. 0.73). The highest sensitivity (97%) and specificity (87%) were detected at 0.07 ng/ml2 in targeted biopsy. More than half of the clinically significant cases were detected in the >0.2 ng/ml2 PSAD category (systematic: 52.4%; targeted: 51.1%). The CHAID methodology found that the probability of having clinically significant cancer (CSC) in patients with PSAD >0.15 ng/ml2 was more than threefold than that in patients with PSAD ≤0.15 ng/ml2 (64% vs. 20.2%). When considered by age, in PSAD ≤0.15 ng/ml2 subgroup, the percentage of CSC detection rate increased from 20.2% to 24.6% in patients aged ≥60 years.
UNASSIGNED: PSAD has good discriminant power for predicting clinically significant prostate cancer. A cutoff of 0.07 ng/ml2 should be adopted, but should be interpreted with caution and by considering other parameters such as age.