Search

Androgens like testosterone and dihydrotestosterone are essential for the growth and development of the prostate gland. Androgenic receptors are overexpressed, which promotes the progression of prostate cancer; therefore, androgenic receptors are a key target in the therapy of prostate cancer. Enzalutamide is used to treat prostate cancer; however, it also causes toxicities such as cardiovascular toxicity, acute myocarditis, hypertension, and seizures. The objective of this research was to create novel and safer analogues of enzalutamide, followed by the prediction of the pharmacokinetic and toxicity characteristics of these enzalutamide analogues. Molecular docking studies of analogues were also done to guess how ligands will work biologically in treating prostate cancer. A total of 195 analogues were generated, and among them, 23 bioisosteres were selected for further pharmacokinetic, toxicological screening and docking studies. The predicted physical-chemical, medicinal, and ADMET characteristics of the designed bioisosteres were optimal to good compared to enzalutamide. Additionally, the drug likeness and drug score of analogues were superior to enzalutamide. According to docking studies of analogues, EZ12, EZ8, and EZ10 formed hydrogen bonds of SER778 with replaceable amide groups in enzalutamide molecules. SER778 residue may be responsible for antagonistic activity towards androgen receptors. Based on the results of the ADMET, drug likeness, drug score, and docking study of designed enzalutamide analogues, the ligands EZ12, EZ8, and EZ10 could be used to find more possible antiandrogen drugs that could be used to treat prostate cancer. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy (ADT) is a mainstay treatment for metastatic prostate cancer, improving progression-free survival. ADT suppresses the production of testosterone and reduces circulating levels of the hormone. Luteinizing hormone-releasing hormone (LH-RH) agonists are the most commonly used ADT modality. They can be given alone or in combination with androgen synthesis inhibitors or androgen receptor antagonists. An estimated 40% of prostate cancer patients will receive ADT as part of their therapy during their lifetime. However, ADT has numerous adverse effects, including an increased cardiovascular risk that impacts quality of life. Relugolix is an alternative form of ADT. It is the only oral gonadotropin-releasing hormone antagonist, circumventing injection site reactions, making it easier for patients to take, and thus increasing compliance. Testosterone suppression with relugolix is excellent and testosterone recovery after discontinuation is rapid. This paper reviews the ADT and anti-androgen treatment options for men with prostate cancer and the cardiovascular effects of these therapies. There is accumulating evidence that cardiovascular risk with relugolix is lower than with other ADT medications and also lower than with androgen synthesis inhibitors and androgen receptor antagonists. This paper provides insight into the use of different ADT regimens based on the cardiovascular status and circumstances. It explores strategies to mitigate negative cardiovascular consequences and highlights the need for further study. [ABSTRACT FROM AUTHOR]

Simple Summary: The current real-world study suggests that important differences exist in patients progressing to mCRPC. Specifically, we found that a proportion of over 20% of patients progress without a PSA level rise, emphasizing the importance of regular staging intervals. Moreover, we found that patients with worse PSA responses are at higher risk for biochemical progression, emphasizing the need for regular PSA check-ups and kinetic measurements. However, no differences in PFS and OS outcomes between these patients were observed. Finally, staging with PSMA-PET/CT might provide better PFS and OS, relative to conventionally staged mCRPC patients. However, this observation may be substantially influenced by the detection of earlier disease progression and the possibility of treatment in patients with a lower metastatic burden, as well as more contemporary patients with better treatment options. Background/Objectives: Progression to metastatic castration-resistant prostate cancer (mCRPC) is defined either biochemically, radiographically or both. Moreover, staging for mCRPC can be performed either conventionally or with molecular imaging such as prostate-specific membrane antigen computer tomography (PSMA-PET/CT). Methods: We relied on the Frankfurt Metastatic Cancer Database of the Prostate (FRAMCAP) database to compare progression-free (PFS) and overall survival (OS) outcomes regarding the cause of castration resistance and the staging modality used. Results: Overall, 35% progressed to mCRPC biochemically vs. 23% radiographically vs. 42% biochemically + radiographically. The PSA nadir in mHSPC (1.4 vs. 0.4 vs. 0.8 ng/mL) and PSA level at mCRPC progression (15 vs. 2 vs. 21 ng/mL, both p ≤ 0.01) were significantly higher for biochemical vs. radiographic vs. both progressed patients. In PFS and OS analyses, no significant differences were observed among all three compared groups. In the comparison of the staging used for progression to mCRPC, 67% received conventional vs. 33% PSMA-PET/CT, with higher metastatic burden in mHSPC and osseous lesions in mCRPC for conventionally staged patients (both p < 0.01). In PFS (15.3 vs. 10.1 months, hazard ratio [HR]: 0.75) and OS analyses (52.6 vs. 34.3 months, HR: 0.61, both p < 0.05), PSMA-PET/CT harbored better prognosis; however, this did not hold after multivariable adjustment. Similar results were observed for further analyses in second- and third-line mCRPC or patients with a PSA level of ≥2 ng/mL. Conclusions: The cause of progression to mCRPC seems not to influence cancer-control outcomes, despite important baseline tumor characteristic differences. The PSMA-PET/CT staging modality might be associated with better PFS and OS outcomes, possibly due to its more sensitive detection of progression or new metastatic lesions. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is most commonly diagnosed in males after the age of 55 years. These patients are also at risk for cardiovascular disease and venous thromboembolism requiring antithrombotic therapy. Prostate cancer treatments, such as androgen receptor axis-targeted therapies (ARATs, i.e., abiraterone acetate, apalutamide, darolutamide, and enzalutamide), may interact with common antithrombotic medications like warfarin, clopidogrel, and the direct oral anticoagulants. However, the data detailing the clinical outcomes of patients treated with these combinations are limited. We undertook a comprehensive review of the literature and modified Delphi process to enable development of an evidence-based consensus document for the co-prescribing of ARATs with antithrombotic medications. Our assessments relied heavily on pharmacokinetic data and extrapolation from drug interaction studies of similarly metabolized drugs, highlighting the need for more research into the clinical impact of drug interactions in prostate cancer patients. Nonetheless, we provide a practical framework to support clinicians in day-to-day therapeutic decision making. Background/Objectives: Abiraterone acetate, apalutamide, darolutamide, and enzalutamide, which make up the androgen receptor axis-targeted therapies (ARATs) drug class, are commonly used in the management of prostate cancer. Many patients on ARATs also receive oral antithrombotic therapy (i.e., anticoagulants or antiplatelets). The concomitant use of ARATs and antithrombotic therapies creates the potential for clinically relevant drug–drug interactions, but the literature regarding the actual consequences of these interactions, and guidance for co-prescribing, is limited. We assembled a multidisciplinary panel of experts and provided them with clinical information derived from a comprehensive literature review regarding the drug–drug interactions between ARATs and antithrombotic therapies. Methods: A three-stage modified electronic Delphi process was used to gather and consolidate opinions from the panel. Each stage consisted of up to three rounds of voting to achieve consensus on which ARAT/antithrombotic therapy drug pairs warrant attention, the possible clinical consequences of drug–drug interactions, and suggested actions for management. Results: The panel achieved consensus to avoid 11 ARAT/antithrombotic therapy drug pairs and modify therapy for eight pairs. Assessments relied heavily on pharmacokinetic data and extrapolation from drug–drug interaction studies of similarly metabolized drugs. Conclusions: This e-Delphi process highlights the need for further research into the clinical impact of ARAT/antithrombotic drug interactions. Nonetheless, the suggested actions aim to provide clinicians with a practical framework for therapeutic decision making. [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), as a novel endocrine therapy, has been investigated in patients with metastatic castration-resistant prostate cancer (mCRPC) in recent years. Multiple large-scale clinical trials have consistently demonstrated that various PARP inhibitors, including olaparib, rucaparib, niraparib, and talazoparib, confer longer radiographic progression-free survival (rPFS) compared to new hormonal agents (NHA) in mCRPC patients with homologous recombination deficiency (HRD). Moreover, the incidence of grade 3 and above adverse events did not significantly increase. Additionally, when combined with androgen receptor signaling inhibitors (ARSI), olaparib, niraparib, and talazoparib have shown significant extension of rPFS but also an increased occurrence of serious adverse events in HRD-positive patients. Only PROpel yielded positive results among the homologous recombination repair (HRR) mutation negative population. Therefore, it remains uncertain whether ARSI-PARPi combination therapy should be considered as first-line treatment for mCRPC patients without HRR mutations. In this review article, we aim to elucidate the necessity and feasibility of combination therapy versus monotherapy specifically within the HRR mutant population while exploring its potential applicability to other non-HRR mutant subtypes. Furthermore, we conducted a comprehensive search on registered clinical trials at present to summarize the research progress of PARP inhibitors in prostate cancer patients at different disease stages. [ABSTRACT FROM AUTHOR]

BACKGROUND. Metastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3β-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes. METHODS. Our prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes. RESULTS. Patients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide. CONCLUSION. These data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible. FUNDING. National Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council. [ABSTRACT FROM AUTHOR]

Simple Summary: Upfront novel androgen receptor signaling inhibitors (ARSIs) are the first-line treatment for metastatic castration-sensitive prostate cancer (mCSPC). However, there are a certain number of cases in which androgen deprivation therapy (ADT) is more effective in patients of Asian descent. If we can identify patients who show a marked response to ADT within 12 weeks after ADT, which is the inclusion criterion for upfront ARSI clinical trials, it would be valuable from an economic standpoint. A total of 218 patients who received ADT treatment at Kanazawa University Hospital between 2000 and 2020 were included in this study. Multivariate analysis revealed that a decrease in PSA levels of <95% at 12 weeks after ADT initiation was a predictor of short time to castration resistance (TTCR) in low-risk patients. We propose a new treatment strategy, in which patients with low-risk mCSPC are treated with ADT and switched to ARSIs, based on the rate of PSA reduction at 12 weeks. Background: The treatment strategy for metastatic castration-sensitive prostate cancer (mCSPC) has changed significantly in recent years. Based on various guidelines, an upfront androgen receptor signaling inhibitor (ARSI) is the first choice, but in patients of Asian descent, including Japanese patients, there are a certain number of cases in which androgen deprivation therapy (ADT) and CAB are more effective. If patients can be identified who show a marked response to ADT within 12 weeks after the initiation of ADT, which is the inclusion criterion for ARSI clinical trials targeting mCSPC, it would be valuable from an economic standpoint. Methods: A total of 218 patients with pure prostate adenocarcinoma and treated with ADT at the Kanazawa University Hospital between January 2000 and December 2020 were included in this study. As a risk classification for mCSPC, in addition to the LATITUDE and CHAARTED criteria, we used the castration-sensitive prostate cancer classification proposed by Kanazawa University (Canazawa), developed by the Department of Urology of Kanazawa University. The Canazawa classification was based on three factors: Gleason pattern 5, bone scan index (BSI) ≥ 1.5, and lactate dehydrogenase (LDH) ≥ 300 IU/L. It defined patients with one factor or less as low-risk and patients with two or three factors as high-risk. The overall survival (OS) and time to castration resistance (TTCR) were estimated retrospectively using the Kaplan–Meier method, and factors associated with TTCR were identified using univariate and multivariate analyses. Results: The median follow-up period was 40.4 months, the median OS period was 85.2 months, and the median TTCR period was 16.4 months. The Canazawa risk classification provided the clearest distinction between the OS and TTCR in mCSPC patients. Multivariate analysis revealed a decrease in PSA levels of <95% at 12 weeks after ADT initiation and was a predictor of short TTCR in low-risk, low-volume patients across all risk classifications. Conclusion: The Canazawa classification differentiated the prognosis of mCSPC patients more clearly. A PSA reduction rate of <95% at 12 w after starting ADT in low-risk, low-volume patients of all risk classifications was significantly shorter than the TTCR. We propose a new treatment strategy, in which patients with low-risk mCSPC are treated with ADT and switched to ARSIs based on the rate of PSA reduction at 12 w. [ABSTRACT FROM AUTHOR]

This study was conducted to provide evidence, using in vitro and in silico testing methods, regarding the adverse effects of iprodione, a representative dichlorophenyl dicarboxamide fungicide, on the endocrine system. In the present study, we used the HeLa9903 stably transfected transactivation assay (OECD TG 455), 22Rv1/MMTV_GR‒KO androgen receptor transcriptional activation assay (OECD TG 458), and toxicity prediction using VEGA QSAR. Our results showed that iprodione had no estrogen receptor antagonistic or androgen receptor agonistic effects; however, iprodione was determined to be an estrogen receptor agonist (log PC10 value is less than − 9) and androgen receptor antagonist (log IC30 value is − 4.58) without intrinsic toxicity against the human cell lines used in this study. VEGA QSAR was used to evaluate five substances with structures similar to that of iprodione. Among them, four chemicals were found to have positive androgen receptor and aromatase activities and have been observed to be developmental toxicants. These results suggest that iprodione regulates steroid hormone receptor interactions and is a potential reproductive toxicant. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is the second most common cancer among males and is a significant cause of morbidity and mortality. The chemokine C-C motif ligand 2 (CCL2) and its receptor C-C motif chemokine receptor 2 (CCR2) are expressed in prostate cancer but their prognostic value is unclear. This study investigated CCL2 and CCR2 as prognostic biomarkers in locally advanced prostate cancer using the large TROG 03.04 RADAR clinical trial cohort. The results demonstrate that despite being expressed in prostate tumours, CCR2 and CCL2 have no prognostic value in the disease. This study investigated the prognostic value of the chemokine C-C motif ligand 2 (CCL2) and its receptor C-C motif chemokine receptor 2 (CCR2) expression in locally advanced prostate cancer treated with radiotherapy and androgen deprivation using the 10-year outcome data from the TROG 03.04 RADAR clinical trial. CCL2 and CCR2 protein expression in prostate cancer biopsies at the time of diagnosis were quantified by immunohistochemistry and digital quantification. CCR2 protein expression was detected in prostate cancer cells and was associated with prostate-specific antigen serum concentration (p = 0.045). However, neither CCL2 nor CCR2 tissue expression could predict prostate cancer progression, or other clinicopathological parameters including perineural invasion and patient outcome. In serum samples, CCL2 concentration at the time of diagnosis, as assayed by enzyme-linked immunosorbent assay, was significantly higher in patients with prostate cancer compared with benign prostatic hyperplasia (median difference 0.22 ng/mL, 95% CI, 0.17–0.30) (p < 0.0001) and normal controls (median difference 0.13 ng/mL, 95% CI, 0.13–0.17) (p < 0.0001). However, circulating CCL2 was not statistically significant as a predictor of disease progression and patient outcome. In conclusion, this study shows that although CCL2 and CCR2 are expressed in prostate cancer, with an increased level of CCL2 in the serum, neither CCL2 nor CCR2 expression has a clinical prognostic value in locally advanced prostate cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Castration-resistant prostate cancer (CRPC) resists standard therapies, partly due to the androgen receptor variant AR-V7. Conventional treatments like chemotherapy and radiation have limited success and significant side effects. Natural compounds from herbal medicine offer promise as complementary therapies. This review examines how these natural compounds can improve treatment outcomes and reduce side effects, presenting a safer and more effective approach to managing CRPC and overcoming resistance to conventional therapies. Castration-resistant prostate cancer (CRPC) remains a significant therapeutic challenge due to its resistance to standard androgen deprivation therapy (ADT). The emergence of androgen receptor splice variant 7 (AR-V7) has been implicated in CRPC progression, contributing to treatment resistance. Current treatments, including first-generation chemotherapy, androgen receptor blockers, radiation therapy, immune therapy, and PARP inhibitors, often come with substantial side effects and limited efficacy. Natural compounds, particularly those derived from herbal medicine, have garnered increasing interest as adjunctive therapeutic agents against CRPC. This review explores the role of AR-V7 in CRPC and highlights the promising benefits of natural compounds as complementary treatments to conventional drugs in reducing CRPC and overcoming therapeutic resistance. We delve into the mechanisms of action underlying the anti-CRPC effects of natural compounds, showcasing their potential to enhance therapeutic outcomes while mitigating the side effects associated with conventional therapies. The exploration of natural compounds offers promising avenues for developing novel treatment strategies that enhance therapeutic outcomes and reduce the adverse effects of conventional CRPC therapies. These compounds provide a safer, more effective approach to managing CRPC, representing a significant advancement in improving patient care. [ABSTRACT FROM AUTHOR]

Simple Summary: Men with prostate cancer undergoing Androgen Deprivation Therapy (ADT) have an increased risk of fractures. Despite this risk, fracture risk assessment is often not systematically applied. To address this issue, a care pathway for preventing fractures in these patients was developed. A multidisciplinary working group designed this pathway based on Dutch guidelines for prostate cancer, osteoporosis and fracture prevention and a thorough literature review. The care pathway includes five steps: case finding, fracture risk assessment, bone mineral density testing, vertebral fracture assessment, differential diagnosis, treatment, and annual follow-up. This pathway focuses on a patient-centered approach and early preventive measures. The ongoing implementation and evaluation aim to enhance fracture preventive care for men with prostate cancer starting ADT. Fracture risk is increased in men with prostate cancer (PCa) receiving Androgen Deprivation Therapy (ADT). However, routine assessment of fracture risk is often not systematically applied. We aimed to establish a comprehensive care pathway for fracture prevention in men with PCa starting ADT. Therefore, a multidisciplinary working group designed and implemented a care pathway using the 'Knowledge to Action' framework, based on current Dutch guidelines for PCa, osteoporosis and fracture prevention, and an extensive literature review of other guidelines. The pathway was developed according to a five-step clinical approach including case finding, fracture risk assessment based on risk factors, bone mineral density test, vertebral fracture assessment, differential diagnosis, treatment, and annual follow-up. Our fracture prevention care pathway for patients with PCa at the time of ADT initiation was designed to promote a patient-centered, multidisciplinary approach to facilitate the implementation of early fracture prevention measures. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastatic prostate cancer (mPCa) is a leading cause of death primarily due to its resistance to treatments like enzalutamide. This study investigates how the protein HMGA2 contributes to this resistance. We found that cancer cells with high levels of HMGA2 became less sensitive to enzalutamide but not to another drug, alisertib. Interestingly, although these cells resisted enzalutamide, they did not show changes in a key prostate cancer protein called AR. Furthermore, a knockdown of HMGA2 sensitized the cells to both drugs. Clinically, 3% of patients showed changes in HMGA2, which were more common in cancers that had metastasized to bones, lymph nodes, and the liver. Our research suggests that HMGA2 could be used as a marker to predict enzalutamide resistance in mPCa cells. Additionally, alisertib may be an effective treatment for patients with high HMGA2 levels, offering a new potential therapeutic strategy for managing metastatic prostate cancer. Metastatic prostate cancer (mPCa) is a leading cause of mortality, partly due to its resistance to anti-androgens like enzalutamide. Snail can promote this resistance by increasing full-length AR and AR-V7. High Mobility Group AT-hook 2 (HMGA2), a DNA-binding protein upstream of Snail, is crucial in proliferation and epithelial–mesenchymal transition (EMT). This study examines HMGA2's role in enzalutamide resistance. LNCaP and 22Rv1 cells overexpressing wild-type HMGA2, but not truncated HMGA2, showed EMT. Both variants led to a decreased sensitivity to enzalutamide but not alisertib compared to Neo control cells. The overexpression of HMGA2 did not alter AR expression. Enzalutamide-resistant C4-2B cells (C4-2B MDVR) had higher HMGA2 and AR/AR variant expression than enzalutamide-sensitive C4-2B cells but remained sensitive to alisertib. The HMGA2 knockdown in C4-2B MDVR cells increased sensitivity to both enzalutamide and alisertib without changing AR expression. A clinical analysis via cBioPortal revealed HMGA2 alterations in 3% and AR alterations in 59% of patients. The HMGA2 changes were linked to treatments like enzalutamide, abiraterone, or alisertib, with amplifications more prevalent in bone, lymph node, and liver metastases. Conclusively, HMGA2 is a potential biomarker for enzalutamide resistance in mPCa, independent of Snail and AR signaling, and alisertib may be an effective treatment for mPCa that expresses HMGA2. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome is a common and frequently undiagnosed female endocrine disorder that is associated with diverse symptoms and features, and an increased risk of long-term chronic diseases such as type 2 diabetes and cardiovascular disease. Pharmacotherapy for polycystic ovary syndrome should be directed at the key concerns of the individual patient. The combined oral contraceptive pill or metformin may be prescribed for irregular periods. The combined oral contraceptive pill is preferred over antiandrogens for treatment of hirsutism and acne. Metformin is of benefit for reducing excess body weight and improving hormonal and metabolic outcomes in those with high metabolic risk (e.g. body mass index greater than 25 kg/m²). Inositol appears to have limited benefits for metabolic outcomes, although it is associated with fewer adverse effects than metformin. Modification of lifestyle factors is important as part of a holistic approach to managing polycystic ovary syndrome. Anti-obesity drugs may be considered for weight management in addition to lifestyle interventions. [ABSTRACT FROM AUTHOR]

Prostate cancer is one of the most prevalent malignancies in men. In the United States, 1 in 8 men will be diagnosed with prostate cancer in their lifetime. Specifically, studies have delved into male subgroups that present a heightened risk for prostate cancer. Despite such high prevalence, prostate cancer can be heterogeneous and carry complexities that manifest differently between individuals. Metastatic hormone-sensitive prostate cancer (mHSPC) often has an abbreviated, aggressive disease course, and can have varying presentations with different molecular profiles that determine response/resistance to the approved treatments targeting the androgen-receptor pathway (eg, enzalutamide, apalutamide, darolutamide, and abiraterone acetate). We present a case of mHSPC quickly progressing to mCRPC, found to have microsatellite instability in mCRPC and excellent response to pembrolizumab, which raises the critical issues of early molecular testing and treatments personalized for the individual patient. [ABSTRACT FROM AUTHOR]

Background: Several randomized controlled trials (RCTs) demonstrated a significant survival benefit of novel treatment regimens compared with androgen deprivation therapy (ADT) for metastatic hormone-sensitive prostate cancer (mHSPC), especially in high-volume disease (HVD, CHAARTED defined). As an influence on poor prognosis, the treatment for patients with HVD, especially visceral metastasis (VM) needed to be distinguished from mHSPC. This study was conducted to rank the treatment options for patients with HVD and VM, respectively, according to the latest data. Methods: We synthesized current evidence based on well-designed RCTs. Only phase III trials were included. A Bayesian network meta-analysis was conducted by using R-4.2.3, and the pooled hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS) with a 95% credible interval (CI) were calculated. Note that the definitions of PFS were various. The ranking plots were generated. OR of adverse events was also calculated and presented. This study was registered in the International Prospective Register of Systematic Reviews (CRD42023416334). Results: Eleven RCTs were included through Pubmed, Embase and Cochrane. In HVD patients, all combination therapies can improve OS and PFS. Among them, The HR for Darolutamide (Daro) + Docetaxel (Doc) + androgen deprivation therapy (ADT) was most significant over ADT in both OS and PFS (hazard ratio [HR]: 0.50, 95% confidence interval [CI]: 0.39–0.63; HR: 0.25; 95% CI: 0.19–0.31). In patients with visceral metastasis, adding novel hormonal agents (NHAs) to ADT showed better survival outcome. But in analysis of treatment ranking, not alike the outcome of high-volume disease, Doc + ADT seems ranked higher than other NHA + ADT. Almost all combination therapies lead to more grade ≥ 3 adverse events. Conclusion: Triplet therapy achieved the best effect on both HVD and visceral metastasis with a tolerable adverse effect. In HVD, our findings demonstrated that any NHA, Docetaxel or triplet combination therapy was superior to ADT alone. Ranking of combination therapy differs between patients with HVD and visceral metastases. In patients with visceral metastasis, chemotherapy has a higher priority than novel hormonal agents. Abiraterone's efficacy ranked better compared to other NHAs but still worse than docetaxel. The sensitivity treatments of bicalutamide versus placebo lead to diversity of results. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the role of non-coding RNAs in resistance to the antiandrogen drug darolutamide in prostate cancer. RNA sequencing identified LOC730101 as a significantly elevated lncRNA in darolutamide-resistant cancer cells. Silencing LOC730101 reduced cancer cell proliferation, in support of its role in drug-resistant cancer growth. Elevated LOC730101 levels were observed in metastatic castration-resistant prostate cancer (CRPC) tumors compared to primary prostate tumors. LOC730101 modulates the expression of cell cycle genes by suppressing microRNA miR-1-3p. Hi-C sequencing revealed that the LOC730101 gene is situated within a dynamic topologically associating domain (TAD) that is activated in resistant cells. This study indicates that LOC730101 is crucial for darolutamide resistance and a potential target to overcome antiandrogen resistance in CRPC. Antiandrogen is part of the standard-of-care treatment option for metastatic prostate cancer. However, prostate cancers frequently relapse, and the underlying resistance mechanism remains incompletely understood. This study seeks to investigate whether long non-coding RNAs (lncRNAs) contribute to the resistance against the latest antiandrogen drug, darolutamide. Our RNA sequencing analysis revealed significant overexpression of LOC730101 in darolutamide-resistant cancer cells compared to the parental cells. Elevated LOC730101 levels were also observed in clinical samples of metastatic castration-resistant prostate cancer (CRPC) compared to primary prostate cancer samples. Silencing LOC730101 with siRNA significantly impaired the growth of darolutamide-resistant cells. Additional RNA sequencing analysis identified a set of genes regulated by LOC730101, including key players in the cell cycle regulatory pathway. We further demonstrated that LOC730101 promotes darolutamide resistance by competitively inhibiting microRNA miR-1-3p. Moreover, by Hi-C sequencing, we found that LOC730101 is located in a topologically associating domain (TAD) that undergoes specific gene induction in darolutamide-resistant cells. Collectively, our study demonstrates the crucial role of the lncRNA LOC730101 in darolutamide resistance and its potential as a target for overcoming antiandrogen resistance in CRPC. [ABSTRACT FROM AUTHOR]

Simple Summary: In 2021, the randomized controlled trial VISION showed that prostate-specific membrane antigen (PSMA)-based third-line radioligand therapy as monotherapy for patients with metastatic castration-resistant prostate cancer with positive lesions on PSMA PET/CT increases overall survival relative to the comparator treatment. The good results have inspired new trials. Our review provides a comprehensive update on post-VISION trials on RLT. The results are promising and may expand the role of PSMA-based RLT in patients with prostate cancer. In 2021, two randomized controlled trials (RCTs), TheraP and VISION, demonstrated that 177Lu-PSMA-617 as monotherapy was more effective for the decline of PSA than the comparator third-line treatments. Methods: Our review summarizes new RCTs that add to the use of radioligand therapy (RLT) for patients with high-risk prostate cancer (PCa). Results: Four past and present RCTs included 1081 patients. An RCT, ENZA-p, studied first-line treatment of patients with metastatic castration-resistant PCa (mCRPC). A combination of enzalutamide (ENZA) and 177Lu-PSMA-617 gave longer progression-free survival than ENZA as monotherapy. Other RCTs of patients with mCRPC, including the PSMAfore, and SPLASH trials, showed 177Lu-PSMA-617 as second-line treatment gave better progression-free survival than androgen receptor pathway inhibitors (combined p value < 6.9 × 10−6). Conclusions: Patients with PCa gain if they are given PSMA-RLT early in the treatment of PCa and as part of combination therapies. [ABSTRACT FROM AUTHOR]

A new class of pyrazolylmethylene-2-thioxoimidazolidin-4-one derivatives 3a–p were rationally designed and synthesized with the aim of exploring their potential as treatments for prostate cancer. The synthesized compounds 3a–p were biologically analyzed for their anticancer effects against AR+LNCaP, AR-PC-3, and Wi38 cell lines. The observed IC50 values against AR+LNCaP ranged between 10.27 ± 0.14 and 109.72 ± 2.06 µM after 24 h of incubation. Compounds 3i–k, 3m, and 3o–p recorded IC50 values of 05.22 ± 0.12 to 11.75 ± 0.07 µM after 48 h incubation in the presence of 1 nM DHT, with higher selectivity towards AR+LNCaP. Moreover, compounds 3i and 3k significantly induced Caspase 3 accumulation, reduced DNA content at the various stages of the cell cycle, and ultimately caused AR+LNCaP cell growth arrest, as confirmed by cell apoptosis assays. These findings suggest that these analogues of androgen receptor blockers have promising potential for further investigation as effective treatments for prostate cancer. [ABSTRACT FROM AUTHOR]

Introduction: Combination of abiraterone with androgen deprivation therapy (ADT) has better survival outcomes than ADT alone in metastatic Hormone-sensitive prostate cancer (mHSPC) in the Western population. In this prospective (Clinical Trials Registry-India [CTRI] registered) observational study, we present the comparative oncological outcomes of ADT alone and ADT + abiraterone in Indian patients, which is not available currently. Methods: This study (CTRI-number-CTRI/2020/07/026545) included newly diagnosed mHSPC patients from January 2020 to June 2023 in a tertiary care hospital, urology department. Patients fulfilling inclusion criteria were advised ADT with abiraterone (A + ADT), and those not affording received ADT monotherapy (ADT). The primary endpoint was overall survival (OS). Secondary outcomes included prostate-specific antigen (PSA) decline >90%, radiographic progression-free survival (rPFS), and PSA progression-free survival (pPFS). Results: Out of278 patients with mHSPC, 163 patients were excluded and 115 were analyzed (ADT = 40 vs. A + ADT = 75). After a median follow-up of 20.3 months, 11 of 40 (27.5%) in ADT-only arm and 15 of 75 (20%) in ADT + abiraterone arm had died (Hazard-ratio of death 0.72; 95% confidence interval 0.68-0.88; P < 0.001). A PSA decline of >90% was seen in 85% in the ADT alone group and 93.3% in the ADT + abiraterone group. Significantly better outcomes of the ADT + abiraterone were seen in the secondary endpoints of rPFS (P < 0.001) and pPFS (P < 0.001). The OS benefit was 28% reduction in risk of death in our study versus 37% and 38% in STAMPEDE and LATITUDE, respectively. pPFS and rPFS were also poorer in Indian subsets. Conclusions: Abiraterone with ADT improves OS, PSA response, rPFS, and pPFS in the Indian population akin to the Western data but with poorer OS, rPFS, and PSA progression-free survival on comparison. [ABSTRACT FROM AUTHOR]

Antiandrogens have been used for the treatment of prostate cancer as a single agent or in combination with hormone deprivation therapy. New generation antiandrogens act like androgen receptor inhibitors (ARIs). Their binding complex blocks the pathways of cellular proliferation and differentiation of the prostate. Enzalutamide, apalutamide and darolutamide are the new ARIs that demonstrated acceptable tolerability and toxicity, both active in hormone-sensitive and castration-resistant prostate cancer (CRPC). There is no evidence of superiority of one drug over the other, therefore the therapeutic choice depends on the safety profile in relation to the individual patient, their comorbidities and clinical condition. ARIs have also shown promising results in association with new drugs that are active on patients with metastatic CRPC carrying the mutated breast cancer gene (BRCA). Before undergoing new antiandrogenic therapies, patients should be evaluated for cardiological and metabolic risk and possible drug interactions.

The most common type of alopecia in women is female androgenetic alopecia (FAGA), characterized by progressive hair loss in a patterned distribution. Many oral therapies, including spironolactone (an aldosterone antagonist), androgen receptor blockers (e.g., flutamide/bicalutamide), 5-alpha-reductase inhibitors (e.g., finasteride/dutasteride), and oral contraceptives, target the mechanism of androgen conversion and binding to its respective receptor and therefore could be administered for the treatment of FAGA. Despite significant advances in the oral treatment of FAGA, its management in patients with a history of gynecological malignancies, the most common cancers in women worldwide, may still be a concern. In this review, we focus on the safety of antiandrogens for the treatment of FAGA patients. For this purpose, a targeted literature review was conducted on PubMed, utilizing the relevant search terms. To sum up, spironolactone seems to be safe for the systemic treatment of FAGA, even in high-risk populations. However, a general uncertainty remains regarding the safety of other medications in patients with a history of gynecologic malignancies, and further studies are needed to evaluate their long-term safety in patients with FAGA and risk factors to establish an optimal risk assessment and treatment selection protocol. [ABSTRACT FROM AUTHOR]

The article focuses on the screening and management practices of specialists treating prostate cancer patients undergoing androgen deprivation therapy (ADT) regarding cardiac, bone, and metabolic health issues. The study reveals that specialized physicians generally feel unlikely to screen and manage metabolic and cardiac health but are more comfortable addressing bone health, suggesting a need for comprehensive management strategies to enhance patient care.

Simple Summary: This reassessment of the findings from our phase I/II study seeks to evaluate the effectiveness of SBRT for treating local intermediate–high-risk prostate cancer in the absence of androgen deprivation therapy due to patient refusal, with a median follow-up of 6.5 years. Our primary focus is on analyzing the treated areas compared to recurrence patterns in the seven patients who experienced local relapse. Additionally, we provide updated data on late toxicities of grade ≥ 2, both genitourinary and gastrointestinal. Objectives: We investigated spatial patterns between primary and recurrent tumor sites and assessed long-term toxicity after dose escalation stereotactic body radiation therapy (SBRT) to the dominant intra-prostatic nodule (DIN). Materials and methods: In 33 patients with intermediate–high-risk prostate cancer (PCa), doses up to 50 Gy were administered to the DIN. Recurrence sites were determined and compared to the original tumor development sites through multiparametric MRI and 68Ga-labeled prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (68Ga-PSMA-PET/CT) images. Overlap rates, categorized as 75% or higher for full overlap, and 25–74% for partial overlap, were assessed. Long-term toxicity is reported. Results: All patients completed treatment, with only one receiving concomitant androgen deprivation therapy (ADT). Recurrences were diagnosed after a median of 33 months (range: 17–76 months), affecting 13 out of 33 patients (39.4%). Intra-prostatic recurrences occurred in 7 patients (21%), with ≥75% overlap in two, a partial overlap in another two, and no overlap in the remaining three patients. Notably, five patients with intra-prostatic recurrences had synchronous bone and/or lymph node metastases, while six patients had isolated bone or lymph node metastasis without intra-prostatic recurrences. Extended follow-up revealed late grade ≥ 2 GU and GI toxicity in 18% (n = 6) and 6% (n = 2) of the patients. Conclusions: Among patients with intermediate–high-risk PCa undergoing focal dose-escalated SBRT without ADT, DIN recurrences were infrequent. When present, these recurrences were typically located at the original site or adjacent to the initial tumor. Conversely, relapses beyond the DIN and in extra-prostatic (metastatic) sites were prevalent, underscoring the significance of systemic ADT in managing this patient population. Advances in knowledge: Focal dose-escalated prostate SBRT prevented recurrences in the dominant nodule; however, extra-prostatic recurrence sites were frequent. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is the most common cancer in American men, aside from skin cancer, and it is the second deadliest. For patients with advanced or metastatic disease, systemic therapies are warranted. The backbone of these systemic therapies is androgen deprivation therapy (ADT). While providing effective tumor control, ADT can have significant side effects, especially problematic for the many overweight or obese men who are at higher risk for aggressive cancer. Our review investigates how lifestyle changes, particularly a low- carbohydrate diet, might reduce the unwanted metabolic effects of ADT. We specifically discuss two clinical trials, Carbohydrate and Prostate Study 1 (CAPS1) and Carbohydrate and Prostate Study 2 (CAPS2), examining this diet's impact on metabolic issues and cancer progression. Additionally, we explore how ADT might influence metabolism, aiming to improve patient outcomes by balancing treatment efficacy with quality of life. Prostate cancer (PC) stands as the most frequently diagnosed non-skin cancer and ranks as the second highest cause of cancer-related deaths among men in the United States. For those facing non-metastatic PC necessitating intervention, solely local treatments may not suffice, leading to a possible transition toward systemic therapies, including androgen deprivation therapy (ADT), chemotherapy, and therapies targeting androgen. Yet, these systemic treatments often bring about considerable adverse effects. Additionally, it is observed that overweight men are at a higher risk of developing aggressive forms of PC, advancing to metastatic stages, and succumbing to the disease. Consequently, there is a pressing demand for new treatment options that carry fewer side effects and enhance the current standard treatments, particularly for the majority of American men who are overweight or obese. In this article, we will review the metabolic response to ADT and how lifestyle modulation can mitigate these ADT-associated metabolic responses with a particular focus on the two clinical trials, Carbohydrate and Prostate Study 1 (CAPS1) and Carbohydrate and Prostate Study 2 (CAPS2), which tested the effects of low-carbohydrate diets on the metabolic side effects of ADT and PC progression, respectively. Furthermore, we will summarize the findings of serum metabolomic studies to elucidate the potential mechanisms by which ADT and low-carbohydrate diets can affect the metabolic response to mitigate the metabolic side effects while maximizing therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Adult acne is a chronic inflammatory disease of the pilosebaceous unit characterized by the excessive production of abnormal sebum favoring an imbalance of the skin microbiota and the hyperproliferation of Cutibacterium acnes and other virulent microbial strains, leading to an inflammatory environment, innate immunity overactivation, and keratinocyte hyperproliferation in hair follicles pores. Degraded keratinocytes plug the pores, consequently forming microcomedons, which can later evolve to papules, nodules, pustules and scars. Distinct from juvenile acne, in adult female acne (AFA) the symptomatology occurs or persists in postadolescence (after age 25). Although hyperandrogenism or the excessive sensitivity of androgen receptors are the main causes, AFA can be triggered by multiple factors, either including or not including androgen disturbances. The prevalence in adult women is 15–20%. Hyperandrogenism is present in 50% of cases; 70% of hyperandrogenism cases feature polycystic ovary syndrome (PCOS), a complex endocrine and metabolic condition. Genetic susceptibility occurs in 80% of acne cases, often with familial inheritance. Beyond classical stepwise therapeutic protocols (topical agents, isotretinoin, antibiotics, hormonal therapy with estrogens, progestins, spironolactone), novel approaches include the highly effective topical antiandrogen clascoterone, the management of insulin resistance by diet, exercise, stress avoidance, and adjuvant therapies such as berberine. Vaccines against the pathogenic proinflammatory C. acnes hyaluronidase A are in development. [ABSTRACT FROM AUTHOR]

Simple Summary: To date, effective treatment for metastatic prostate cancer (PCa) remains a clinical challenge. Our previous study demonstrated that tumor suppressive miR-99b-5p negatively regulates the expression of androgen receptor (AR) and mTOR, potentially serving as a therapeutic agent for aggressive PCa. In this study, we show for the first time that combination of miR-99b-5p mimic and second-generation AR antagonist (such as enzalutamide or abiraterone) simultaneously targets AR and mTOR signaling, consequently inhibiting epithelial-mesenchymal transition (EMT) in PCa. This novel combination therapy may provide a unique opportunity for effectively suppressing EMT-mediated metastasis in aggressive PC, especially African American PCa and castration-resistant prostate cancer (CRPC). Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer deaths among American men. Androgen deprivation therapy (ADT) has been systemically applied as a first-line therapy for PCa patients. Despite the initial responses, the majority of patients under ADT eventually experienced tumor progression to castration-resistant prostate cancer (CRPC), further leading to tumor metastasis to distant organs. Therefore, identifying the key molecular mechanisms underlying PCa progression remains crucial for the development of novel therapies for metastatic PCa. Previously, we identified that tumor-suppressive miR-99b-5p is frequently downregulated in aggressive African American (AA) PCa and European American (EA) CRPC, leading to upregulation of mTOR, androgen receptor (AR), and HIF-1α signaling. Given the fact that mTOR and HIF-1α signaling are critical upstream pathways that trigger the activation of epithelial–mesenchymal transition (EMT), we hypothesized that miR-99b-5p may play a critical functional role in regulating EMT-mediated PCa metastasis. To test this hypothesis, a series of cell biology, biochemical, and in vitro functional assays (wound healing, transwell migration, cell/ECM adhesion, and capillary-like tube formation assays) were performed to examine the effects of miR-99b-5p mimic on regulating EMT-mediated PCa metastasis processes. Our results have demonstrated that miR-99b-5p simultaneously targets MTOR and AR signaling, leading to upregulation of E-cadherin, downregulation of Snail/N-cadherin/Vimentin, and suppression of EMT-mediated PCa metastasis. MiR-99b-5p alone and in combination with enzalutamide or abiraterone significantly inhibits the EMT-mediated metastasis of AA PCa and EA CRPC. [ABSTRACT FROM AUTHOR]

Simple Summary: In this paper, we look at the role of artificial intelligence (AI) advancements in prostate cancer diagnosis and management. Specifically, we focus on magnetic resonance prostate reconstruction, prostate cancer detection/stratification/reconstruction, positron emission tomography/computed tomography, androgen deprivation therapy, and prostate biopsy. A total of 64 studies were included. Our results showed that deep learning AI models in prostate cancer diagnosis show promise but are not yet ready for clinical use due to variability in methods, labels, and evaluation criteria. Conducting additional research while acknowledging the limitations is crucial for reinforcing the utility and effectiveness of AI-based models in clinical settings. Background: The aim was to analyze the current state of deep learning (DL)-based prostate cancer (PCa) diagnosis with a focus on magnetic resonance (MR) prostate reconstruction; PCa detection/stratification/reconstruction; positron emission tomography/computed tomography (PET/CT); androgen deprivation therapy (ADT); prostate biopsy; associated challenges and their clinical implications. Methods: A search of the PubMed database was conducted based on the inclusion and exclusion criteria for the use of DL methods within the abovementioned areas. Results: A total of 784 articles were found, of which, 64 were included. Reconstruction of the prostate, the detection and stratification of prostate cancer, the reconstruction of prostate cancer, and diagnosis on PET/CT, ADT, and biopsy were analyzed in 21, 22, 6, 7, 2, and 6 studies, respectively. Among studies describing DL use for MR-based purposes, datasets with magnetic field power of 3 T, 1.5 T, and 3/1.5 T were used in 18/19/5, 0/1/0, and 3/2/1 studies, respectively, of 6/7 studies analyzing DL for PET/CT diagnosis which used data from a single institution. Among the radiotracers, [68Ga]Ga-PSMA-11, [18F]DCFPyl, and [18F]PSMA-1007 were used in 5, 1, and 1 study, respectively. Only two studies that analyzed DL in the context of DT met the inclusion criteria. Both were performed with a single-institution dataset with only manual labeling of training data. Three studies, each analyzing DL for prostate biopsy, were performed with single- and multi-institutional datasets. TeUS, TRUS, and MRI were used as input modalities in two, three, and one study, respectively. Conclusion: DL models in prostate cancer diagnosis show promise but are not yet ready for clinical use due to variability in methods, labels, and evaluation criteria. Conducting additional research while acknowledging all the limitations outlined is crucial for reinforcing the utility and effectiveness of DL-based models in clinical settings. [ABSTRACT FROM AUTHOR]

Background: Polymorphic ventricular tachycardia (PMVT) is an unstable and often fatal cardiac tachyarrhythmia. While there are many causes of this rhythm, including electrolyte imbalances, ischemia, and genetic disorders, iatrogenic etiologies are important to recognize. Abiraterone is an androgen synthesis antagonist effective in treating prostate cancer, but here we describe a case of severe hypokalemia secondary to abiraterone resulting in polymorphic ventricular tachycardia and cardiac arrest. While this is a potential adverse effect of the medication, severe hypokalemia causing polymorphic ventricular tachycardia and cardiac arrest, as seen in our patient's case, has not been described. Case presentation: A 78-year-old African-American man with history of prostate cancer presents with polymorphic ventricular tachycardia and cardiac arrest. After resuscitation, he was found to be severely hypokalemic and refractory to large doses of repletion. Evaluation of secondary causes of hypokalemia identified the likely culprit to be adverse effects from prostate cancer treatment. Conclusion: A broad differential diagnosis for polymorphic ventricular tachycardia is essential in identifying and treating patients presenting in this rhythm. Here we present a case of iatrogenic polymorphic ventricular tachycardia secondary to oncologic treatment. [ABSTRACT FROM AUTHOR]

Extensive exploration of the molecular subtypes of triple-negative breast cancer (TNBC) is critical for advancing precision medicine. Notably, the luminal androgen receptor (LAR) subtype has attracted attention for targeted treatment combining androgen receptor antagonists and CDK4/6 inhibitors. Unfortunately, this strategy has proven to be of limited efficacy, highlighting the need for further optimization. Using our center's comprehensive multiomics dataset (n = 465), we identified novel therapeutic targets and evaluated their efficacy through multiple models, including in vitro LAR cell lines, in vivo cell-derived allograft models and ex vivo patient-derived organoids. Moreover, we conducted flow cytometry and RNA-seq analysis to unveil potential mechanisms underlying the regulation of tumor progression by these therapeutic strategies. LAR breast cancer cells exhibited sensitivity to chidamide and enzalutamide individually, with a drug combination assay revealing their synergistic effect. Crucially, this synergistic effect was verified through in vivo allograft models and patient-derived organoids. Furthermore, transcriptomic analysis demonstrated that the combination therapeutic strategy could inhibit tumor progression by regulating metabolism and autophagy. This study confirmed that the combination of histone deacetylase (HDAC) inhibitors and androgen receptor (AR) antagonists possessed greater therapeutic efficacy than monotherapy in LAR TNBC. This finding significantly bolsters the theoretical basis for the clinical translation of this combination therapy and provides an innovative strategy for the targeted treatment of LAR TNBC. [ABSTRACT FROM AUTHOR]

Women around the world are most frequently afflicted with breast cancer, and it is one of the most frequent causes of cancer death in females. Breast cancer is usually classified according to biomarker status, triple‐negative breast cancer (TNBC) represents a distinct subtype characterized by immunohistochemical findings that denote negativity for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (Her-2) on cancer tissue. It is more common in younger women than in other subtypes. As an invasive breast cancer subtype with a unique drug-resistant phenotype and metastatic burden, it has limited treatment options, and patients have a poor prognosis with high rates of local, distant recurrence and mortality, and there is still a lack of standardized treatment protocols for TNBC. In this review, we delve into the current treatment strategies for TNBC and explore the potential for new approaches and targets in the future. This trial is registered with NCT03997123. [ABSTRACT FROM AUTHOR]

Antiandrogens were originally developed as therapeutic agents for prostate cancer but are also expected to be effective for breast cancer. However, the role of androgen signaling in breast cancer has long been controversial due to the limited number of experimental models. Our study aimed to comprehensively investigate the efficacy of antiandrogens on breast cancer. In the present study, a total of 18 breast cancer cell lines were treated with the agonist or antagonists of the androgen receptor (AR). Among the 18 cell lines tested, only T‐47D cells proliferated in an androgen‐dependent manner, while the other cell lines were almost irresponsive to AR stimulation. On the other hand, treatment with AR antagonists at relatively high doses suppressed the proliferation of not only T‐47D cells but also some other cell lines including AR‐low/negative cells. In addition, expression of the full‐length AR and constitutively active AR splice variants, AR‐V7 and ARV567es, was not correlated with sensitivity to AR antagonists. These data suggest that the antiproliferative effect of AR antagonists is AR‐independent in some cases. Consistently, proliferation of AR‐knockout BT‐549 cells was inhibited by AR antagonists. Identification of biomarkers would be necessary to determine which breast cancer patients will benefit from these drugs. [ABSTRACT FROM AUTHOR]

Recently, with discriminatory legislation efforts and changing participation policies in organized sports, media attention surrounding transgender and gender-diverse (TGD) individuals has increased. These changes and the historical lack of competence and education regarding the transgender patient population have resulted in subpar patient care and a misunderstanding of the athletic trainer's (AT's) role within the health care and compliance systems. This literature review is the second part of a 2-paper series, and our objective was to educate ATs on the processes relevant to medical affirmation, including compliance considerations regarding medical eligibility, and to establish the AT's role. The gender affirmation framework includes social and legal components, which are discussed in part 1 of this literature, and the medical component is thoroughly discussed in part 2. All health care providers involved in the care of TGD individuals should work collaboratively on an interprofessional care team and have a general knowledge of the gender-affirmation process, including gender-affirming hormone therapy, surgical options, known risks and complications, and the general health needs of TGD patients. With this knowledge, ATs, as point-of-care providers and members of the interprofessional care team, are uniquely positioned to help reduce health and health care disparities. Furthermore, ATs can use their knowledge to facilitate medical compliance and eligibility in the evolving policies of sporting organizations. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) displays diverse intra-tumoral traits, impacting its progression and treatment outcomes. This study aimed to refine PCa cell culture conditions for dynamic monitoring of androgen receptor (AR) activity at the single-cell level. We introduced an extracellular matrix-Matrigel (ECM-M) culture model, enhancing cellular tracking during bioluminescence single-cell imaging while improving cell viability. ECM-M notably tripled the traceability of poorly adherent PCa cells, facilitating robust single-cell tracking, without impeding substrate permeability or AR response. This model effectively monitored AR modulation by antiandrogens across various PCa cell lines. Single-cell imaging unveiled heterogeneous antiandrogen responses within populations, correlating non-responsive cell proportions with drug IC50 values. Integrating ECM-M culture with the PSEBC-TSTA biosensor enabled precise characterization of ARi responsiveness within diverse cell populations. Our ECM-M model stands as a promising tool to assess heterogeneous single-cell treatment responses in cancer, offering insights to link drug responses to intracellular signaling dynamics. This approach enhances our comprehension of the nuanced and dynamic nature of PCa treatment responses. [ABSTRACT FROM AUTHOR]

Simple Summary: Salivary duct carcinomas (SDC) can present with distinct immunologic profiles similar to breast cancer, such as androgen receptor (AR) and HER-2/Neu-positivity, raising the hypothesis that these tumors may respond to hormonal signaling. No consensus exists on how to best manage this entity. The data evaluating the use of targeted therapies, such as androgen deprivation therapy and HER-2 receptor inhibitors, in the front-line setting when treating curatively is limited. We studied patients with AR+ SDC, demonstrating high rates of control and survival using an aggressive approach to treatment. Immunoprofiles were highly variable, highlighting the potential for future treatment individualization. We hope that this may allow for personalization of treatment in the future, using molecular profiling to determine whether the addition of biological agents in the definitive setting against specific targets, such as AR and HER-2/Neu, will further improve outcomes for these patients. Background: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland neoplasm. They can present with distinct immunoprofiles, such as androgen receptor (AR) and HER-2/Neu-positivity. To date, no consensus exists on how to best manage this entity. Methods: All patients diagnosed with nonmetastatic AR+ SDC of the parotid from 2013 to 2019 treated with curative intent were included. Immunologic tumor profiling was conducted using 24 distinct markers. Kaplan–Meier analyses were used to estimate locoregional recurrence (LRR), distant control, and overall survival (OS). Results: Fifteen patients were included. Nine (60%) patients presented with T4 disease and eight (53%) had positive ipsilateral cervical lymphadenopathy. Ten (67%) patients underwent trimodality therapy, including surgery followed by adjuvant radiation and concurrent systemic therapy. The median follow-up was 5.5 years (interquartile range, 4.8–6.1). The estimated 5-year rates of LRR, distant progression, and OS were 6%, 13%, and 87%, respectively. Conclusion: Despite only including AR+ SDC of the parotid, immunoprofiles, such as expression of HER-2, were highly variable, highlighting the potential to tailor systemic regimens based on individual histologic profiles in the future. Studies with larger patient numbers using tumor-specific molecular profiling and tumor heterogeneity analyses are justified to better understand the biology of these tumors. Molecularly informed treatment approaches, including the potential use of AR- and HER-2/Neu-directed therapies upfront in the definitive setting, may hold future promise to further improve outcomes for these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The efficacy of immunotherapies in salivary gland cancer (SGC) remains controversial. To optimize immunotherapy, understanding the tumor microenvironment (TME) of SGC is necessary. In this review, we demonstrate that high-grade mucoepidermoid carcinoma and salivary duct carcinoma exhibit immune-hot TME. In contrast, adenoid cystic carcinomas exhibit an immune-cold TME. While the reported efficacy of immune checkpoint inhibitors (ICIs) for SGCs is generally poor, several studies have shown promising clinical efficacy of ICIs indicating that ICIs might be beneficial for a specific population of SGC. Molecule-targeted therapies have shown promising clinical efficacy against SGC. Recent evidence indicates that these molecules could be targets for antigen-specific immunotherapies. This review discusses the current understanding and future directions of immunotherapies for SGCs. Salivary gland cancer (SGC) is rare and comprises over 20 histological subtypes. Recently, clinical experience regarding immunotherapies for SGCs has been accumulating, yet their efficacy remains controversial. Understanding the tumor microenvironment (TME), including the expression of immune checkpoint molecules in SGC, is crucial to optimizing immunotherapy. In this review, we demonstrate that high-grade mucoepidermoid carcinoma and salivary duct carcinoma generally exhibit immune-hot TME with high immune cell infiltration, frequent genetic mutations, and robust immune checkpoint molecule expression. In contrast, adenoid cystic carcinomas exhibit an immune-cold TME. While the reported efficacy of immune checkpoint inhibitors (ICIs) for SGCs is generally poor, several studies showed promising clinical efficacy of ICIs, with an objective response rate ranging from 20.0–33.3%, indicating that ICIs might be beneficial for a specific population of SGC. Molecule-targeted therapies including anti-human epidermal growth factor receptor 2 and anti-androgen receptor therapies have shown promising clinical efficacy against SGC. Recent evidence indicates that these molecules could be targets for antigen-specific immunotherapies including chimeric antigen receptor-T therapy and cancer vaccines. This review discusses the current understanding and future directions of immunotherapies for SGCs, including ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Background In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; P  < .0001) compared with placebo plus ADT with docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We present efficacy and safety of darolutamide versus placebo in Black patients from ARASENS. Patients and Methods Patients with mHSPC were randomized 1:1 to darolutamide 600 mg or placebo twice daily in combination with ADT and docetaxel. The primary endpoint was overall survival. Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety. Results In ARASENS, 54 Black patients received darolutamide (n  = 26) or placebo (n  = 28) plus ADT and docetaxel. In Black patients, overall survival favored darolutamide versus placebo (median, not reached vs. 38.7 months; stratified HR, 0.41; 95% CI, 0.17-1.02), with 4-year survival rates of 62% versus 41%. The darolutamide group also had longer time to CRPC compared with the placebo group (median, not reached vs.12.6 months; HR, 0.09; 95% CI, 0.02-0.30). The safety profile of darolutamide in Black patients was consistent with that observed for the overall ARASENS population (grade 3/4 treatment-emergent adverse events, TEAEs: 61.5% vs. 66.1%; serious TEAEs: 42.3% vs. 44.8%). Conclusion In this small population of Black patients with mHSPC from the ARASENS trial, darolutamide was associated with an improvement in survival and time to CRPC and was well tolerated. Efficacy and safety findings in Black patients were consistent with the overall ARASENS population. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common cause of chronic liver disease in children and adolescents, but its etiology remains largely unknown. Adrenarche is a critical phase for hormonal changes, and any disturbance during this period has been linked to metabolic disorders, including obesity and dyslipidemia. However, whether there is a causal linkage between adrenarche disturbance and the increasing prevalence of NAFLD in children remains unclear. Results: Using the young female rat as a model, we found that the liver undergoes a transient slowdown period of growth along with the rise of adrenal-derived sex steroid precursors during adrenarche. Specifically blocking androgen actions across adrenarche phase using androgen receptor antagonist flutamide largely increased liver weight by 47.97% and caused marked fat deposition in liver, thus leading to severe NAFLD in young female rats. Conversely, further administrating nonaromatic dihydrotestosterone (DHT) into young female rats across adrenarche phase could effectively reduce liver fat deposition. But, administration of the aromatase inhibitor, formestane across adrenarche had minimal effects on hepatic de novo fatty acid synthesis and liver fat deposition, suggesting adrenal-derived sex steroid precursors exert their anti-NAFLD effects in young females by converting into active androgens rather than into active estrogens. Mechanistically, transcriptomic profiling and integrated data analysis revealed that active androgens converted from the adrenal sex steroid precursors prevent NAFLD in young females primarily by inactivating hepatic sterol regulatory element-binding transcription factor 1 (Srebf1) signaling. Conclusions: We firstly evidenced that adrenarche-accompanied rise of sex steroid precursors plays a predominant role in preventing the incidence of NAFLD in young females by converting into active androgens and inactivating hepatic Srebf1 signaling. Our novel finding provides new insights into the etiology of NAFLD and is crucial in developing effective prevention and management strategies for NAFLD in children. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of biomarkers that can predict the effectiveness of treatments for metastatic castration-resistant prostate cancer (mCRPC) has been a recent challenge. We focused on the efficacy of circulating tumor cell (CTC) status as a prognostic biomarker after enzalutamide administration. A retrospective subgroup analysis and prognostic survey were conducted on 43 patients with mCRPC and bone metastases. The results showed that patients with no detected CTCs at baseline showed significantly longer overall survival (OS) than those with CTCs at baseline. Furthermore, patients who exhibited a negative reversion of CTC status during enzalutamide treatment had significantly longer OS compared to patients with persistent CTC positivity. Achieving CTC-negative reversion during treatment for mCRPC with bone metastases was associated with improved long-term OS. Chronological measurement of CTC status might be clinically useful in the treatment of mCRPC. Enzalutamide is a second-generation androgen receptor inhibitor that increases overall survival (OS) rates in patients with metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the efficacy of circulating tumor cell (CTC) status as a prognostic biomarker following enzalutamide administration. A retrospective subgroup analysis and prognostic survey were conducted on 43 patients with mCRPC and bone metastases treated in Juntendo University-affiliated hospitals from 2015 to 2022. Patients were treated with 160 mg enzalutamide daily. CTC analyses on blood samples were performed regularly before and every three months after treatment. The relationship between the patients' clinical factors and the OS rate was analyzed using the log-rank test; the median OS was 37 months. Patients with no detected CTCs at baseline showed significantly longer OS than those with detectable CTCs at baseline. Furthermore, patients demonstrating negative reversion of CTCs during enzalutamide treatment had significantly longer OS than patients with CTC-positivity. Two biomarkers—higher hemoglobin at baseline and achieving negative reversion of CTCs—were significantly associated with prolonged OS. This study suggests that patients achieving CTC-negative reversion during treatment for mCRPC with bone metastases exhibit improved long-term OS. Chronological measurement of CTC status might be clinically useful in the treatment of mCRPC. [ABSTRACT FROM AUTHOR]

Simple Summary: The risk of early progression to metastatic disease in the event of biochemical recurrence (BCR) after primary treatment for prostate cancer (PC) is extremely variable. PSA-doubling time (DT) is the best parameter currently available to define patients who are at a higher risk of progression, but a single temporal parameter is not sufficient to describe the heterogeneity of this condition. A real precision medicine approach is strongly suggested to offer tailored management to patients with biochemical relapse. At present, patients with low-risk BCR should be offered active observation, while patients with high-risk BCR are likely to benefit from early systemic therapy. Results from the EMBARK study are likely to impact how physicians choose to manage high-risk BCR. The introduction of the concept of anticipation and intensification of treatment through the use of androgen receptor signaling inhibitors (ARSIs) and ADT combination therapy in this indolent but crucial phase is the main innovation of the study. The aim of this review is to provide a comprehensive understanding of the definition, classification, diagnosis, and treatment modalities of BCR, with a focus on the latest innovations and ongoing trials in the management of high-risk BCR. Biochemical recurrence (BCR) after primary treatments for prostate cancer (PC) is an extremely heterogeneous phase and at least a stratification into low- and high-risk cases for early progression in metastatic disease is necessary. At present, PSA-DT represents the best parameter to define low- and high-risk BCR PC, but real precision medicine is strongly suggested to define tailored management for patients with BCR. Before defining management, it is necessary to exclude the presence of low-volume metastasis associated with PSA progression using new-generation imaging, preferably with PSMA PET/CT. Low-risk BCR cases should be actively observed without early systemic therapies. Early treatment of low-risk BCR with continuous androgen deprivation therapy (ADT) can produce disadvantages such as the development of castration resistance before the appearance of metastases (non-metastatic castration-resistant PC). Patients with high-risk BCR benefit from early systemic therapy. Even with overall survival (OS) as the primary treatment endpoint, metastasis-free survival (MFS) should be used as a surrogate endpoint in clinical trials, especially in long survival stages of the disease. The EMBARK study has greatly influenced the management of high-risk BCR, by introducing the concept of anticipation and intensification through the use of androgen receptor signaling inhibitors (ARSIs) and ADT combination therapy. In high-risk (PSA-DT ≤ 9 months) BCR cases, the combination of enzalutamide with leuprolide significantly improves MFS when compared to leuprolide alone, maintaining an unchanged quality of life in the asymptomatic phase of the disease. The possibility of using ARSIs alone in this early disease setting is suggested by the EMBARK study (arm with enzalutamide alone) with less evidence than with the intensification of the combination therapy. Continued use versus discontinuation of enzalutamide plus leuprolide intensified therapy upon reaching undetectable PSA levels needs to be better defined with further analysis. Real-world analysis must verify the significant results obtained in the context of a phase 3 study. [ABSTRACT FROM AUTHOR]

Simple Summary: Androgen receptor signaling is an important target to investigate in urothelial carcinoma of the bladder because basic and clinical evidence strongly suggests that the androgen receptor is involved in bladder carcinogenesis. Moreover, androgen receptor signaling may suppress anti-tumor immunity. These factors may also be important contributors to the strong male sex bias in urothelial carcinoma of the bladder. Preclinical and clinical data suggest that androgen receptor signaling strongly contributes to bladder cancer development. The roles of the androgen receptor in bladder carcinogenesis have obvious implications for understanding the strong male sex bias in this disease and for potential therapeutic strategies as well. In this review, we summarize what is known about androgen receptor signaling in urothelial carcinoma as well as in tumor-infiltrating immune cells, reviewing preclinical and clinical data. We also highlight clinical trial efforts in this area. [ABSTRACT FROM AUTHOR]

Simple Summary: The efficacy of abiraterone plus prednisolone (ABI) against nonmetastatic castration-resistant prostate cancer (CRPC) remains unclear. To evaluate enzalutamide and ABI as the first-line treatment for CRPC, we conducted the randomized controlled trial including both metastatic and nonmetastatic CRPC. As a sub-analysis, we focused on nonmetastatic CRPC in this study. ABI and enzalutamide had similar efficacy and safety profiles in patients with nonmetastatic CRPC. Enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) can improve the survival of patients with castration-resistant prostate cancer (CRPC). However, the agent that is more effective against nonmetastatic CRPC remains unclear. To evaluate the agent that can be used as the first-line treatment for CRPC, an investigator-initiated, multicenter, randomized controlled trial (ENABLE Study for PCa) including both metastatic and nonmetastatic CRPC was conducted in Japan. The prostate-specific antigen (PSA) response rate, overall survival, some essential survival endpoints, and safety of patients with nonmetastatic CRPC were also analyzed. In this subanalysis, 15 and 26 patients in the ENZ and ABI arms, respectively, presented with nonmetastatic CRPC. There was no significant difference in terms of the PSA response rate between the ENZ and ABI arms (80% and 64%, respectively; p = 0.3048). The overall survival did not significantly differ between the two arms (HR: 0.68; 95% CI: 0.22–2.14, p = 0.5260). No significant differences were observed in terms of radiographic progression-free survival and cancer-specific survival between the ENZ and ABI arms (HR: 0.81; 95% CI: 0.35–1.84; p = 0.6056 and HR: 0.72; 95% CI: 0.19–2.73; p = 0.6443, respectively). Only four and six patients in the ENZ and ABI arms, respectively, had ≥grade 3 adverse events. ABI and ENZ had similar efficacy and safety profiles in patients with nonmetastatic CRPC. [ABSTRACT FROM AUTHOR]

Rationale: Numerous epidemiological studies have reported a link between low testosterone levels and an increased risk of cerebrovascular disease in men. However, there is ongoing controversy surrounding testosterone replacement therapy due to potential side effects. PBMT has been demonstrated to improve cerebrovascular function and promote testosterone synthesis in peripheral tissues. Despite this, the molecular mechanisms that could connect PBMT with testosterone and vascular function in the brain of photothrombosis (PT)‐induced stroke rats remain largely unknown. Methods: We measured behavioral performance, cerebral blood flow (CBF), vascular permeability, and the expression of vascular‐associated and apoptotic proteins in PT‐induced stroke rats treated with flutamide and seven consecutive days of PBM treatment (350 mW, 808 nM, 2 min/day). To gain further insights into the mechanism of PBM on testosterone synthesis, we used testosterone synthesis inhibitors to study their effects on bEND.3 cells. Results: We showed that PT stroke caused a decrease in cerebrovascular testosterone concentration, which was significantly increased by 7‐day PBMT (808 nm, 350 mW/cm2, 42 J/cm2). Furthermore, PBMT significantly increased cerebral blood flow (CBF) and the expression of vascular‐associated proteins, while inhibiting vascular permeability and reducing endothelial cell apoptosis. This ultimately mitigated behavioral deficits in PT stroke rats. Notably, treatment with the androgen receptor antagonist flutamide reversed the beneficial effects of PBMT. Cellular experiments confirmed that PBMT inhibited cell apoptosis and increased vascular‐associated protein expression in brain endothelial cell line (bEnd.3) subjected to oxygen‐glucose deprivation (OGD). However, these effects were inhibited by flutamide. Moreover, mechanistic studies revealed that PBMT‐induced testosterone synthesis in bEnd.3 cells was partly mediated by 17β‐hydroxysteroid dehydrogenase 5 (17β‐HSD5). Conclusions: Our study provides evidence that PBMT attenuates cerebrovascular injury and behavioral deficits associated with testosterone/AR following ischemic stroke. Our findings suggest that PBMT may be a promising alternative approach for managing cerebrovascular diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic recently represented an unexpected global issue. Due to its rapid spread and severity, the identification of possible therapies emerged as an urgent need. In this sense, the molecular landscape of SARS-CoV-2 infection was thoroughly analyzed to find possible therapeutic vulnerabilities. In such a context, the correlation between SARS-CoV-2 infection and antiandrogens was explored, finding promising but also contradictory results. In our work, we systematically reviewed the current literature to explore this issue. Background: In 2019, the breakthrough of the coronavirus 2 disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represented one of the major issues of our recent history. Different drugs have been tested to rapidly find effective anti-viral treatments and, among these, antiandrogens have been suggested to play a role in mediating SARS-CoV-2 infection. Considering the high heterogeneity of studies on this topic, we decided to review the current literature. Methods: We performed a systematic review according to PRISMA guidelines. A search strategy was conducted on PUBMED and Medline. Only original articles published from March 2020 to 31 August 2023 investigating the possible protective role of antiandrogens were included. In vitro or preclinical studies and reports not in the English language were excluded. The main objective was to investigate how antiandrogens may interfere with COVID-19 outcomes. Results: Among 1755 records, we selected 31 studies, the majority of which consisted of retrospective clinical data collections and of randomized clinical trials during the first and second wave of the COVID-19 pandemic. Conclusions: In conclusion, we can state that antiandrogens do not seem to protect individuals from SARS-CoV-2 infection and COVID-19 severity and, thus, their use should not be encouraged in this field. [ABSTRACT FROM AUTHOR]

Simple Summary: Chemotherapy is the first line of treatment for malignant tumors. However, recent discoveries have shown that a relapse and the formation of metastatic disease could be facilitated by these treatments. In this study, we show how several chemotherapeutic drugs induced prostate cancer cells migration. Additionally we propose that combination therapy with newly synthesized inhibitors could block the chemotherapy-driven metastatic behavior of prostate cancer cells. We have previously shown that heterotrimeric G-protein subunit alphai2 (Gαi2) is essential for cell migration and invasion in prostate, ovarian and breast cancer cells, and novel small molecule inhibitors targeting Gαi2 block its effects on migratory and invasive behavior. In this study, we have identified potent, metabolically stable, second generation Gαi2 inhibitors which inhibit cell migration in prostate cancer cells. Recent studies have shown that chemotherapy can induce the cancer cells to migrate to distant sites to form metastases. In the present study, we determined the effects of taxanes (docetaxel), anti-androgens (enzalutamide and bicalutamide) and histone deacetylase (HDAC) inhibitors (SAHA and SBI-I-19) on cell migration in prostate cancer cells. All treatments induced cell migration, and simultaneous treatments with new Gαi2 inhibitors blocked their effects on cell migration. We concluded that a combination treatment of Gαi2 inhibitors and chemotherapy could blunt the capability of cancer cells to migrate and form metastases. [ABSTRACT FROM AUTHOR]

We evaluated the prognostic value of the hemoglobin albumin lymphocyte and platelet (HALP) score and inflammatory index in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone and enzalutamide. In this retrospective study, 136 patients with mCRPC were treated with enzalutamide and abiraterone between January 2018 and March 2023; all data were collected from the hospital database. The HALP score and neutrophil-to-lymphocyte ratio (NLR) were calculated from baseline blood tests, and their impacts on progression-free survival (PFS) and overall survival (OS) were analyzed. Patients with lower HALP scores (= 23.78) exhibited a significantly reduced OS of 31.2 months compared with those with higher scores (> 23.78, OS: 63.9 months). Similarly, patients with a higher NLR (> 2.15) showed a poorer OS of 38.4 months compared with those with a lower NLR (= 2.15, OS: 70.1 months). The results were significant in terms of PFS. Patients with lower HALP scores had a PFS of 22.9 months, whereas those with higher scores had a longer PFS of 43.2 months. For NLR, patients with a score = 2.15 had a PFS of 43.0 months, whereas those with scores > 2.15 had a PFS of 33.5 months. These findings, supported by ROC curve analysis, Kaplan-Meier estimates, and Cox regression analysis, underscore the significance of the HALP score and NLR as prognostic factors. This study highlights the HALP score and NLR as effective, low-cost prognostic markers for patients with mCRPC undergoing treatment with next-generation anti-androgens. These biomarkers can predict patient outcomes and guiding treatment strategies. [ABSTRACT FROM AUTHOR]

Resistance exercise training is effective to counteract the adverse effects of androgen deprivation therapy (ADT) on body composition, muscle mass and leg strength in prostate cancer patients (PCa). However, it is unknown whether these effects can be autonomously maintained after cessation of the supervised program. Sixty‐eight PCa patients on ADT were included. The exercise intervention group (EX, n = 37) performed 20 weeks of supervised resistance exercise training. Thereafter, patients were advised to autonomously continue exercise training. The control group (CON, n = 31) only received usual care. Outcome measures were compared between baseline and after 1 year. Changes during the intervention (baseline vs. 20 weeks) and follow‐up period (20 weeks vs. 1 year) were descriptively explored. In EX, 83% reported to have continued exercise training themselves. After 1 year, fat mass gains were attenuated in EX compared to CON (1.2 ± 2.6 and 2.8 ± 1.9 kg, respectively; time × treatment effect p = 0.032). The fat percentage increased, and lean mass and quadriceps muscle cross‐sectional area decreased over time, with no differences between groups (overall 1.6 ± 2.1%, −0.7 ± 2.3 kg and −2.2 ± 2.9 cm2, respectively; time effects, all p < 0.05). For muscle strength, an increase of ∼5% in EX was observed, significantly different from the ∼10% decrease in CON (p < 0.001). Subsequent analyses showed that the initial exercise training‐obtained gains in lean mass, muscle mass and strength in EX compared to CON, declined during the follow‐up period. In conclusion, PCa patients on ADT are not capable to autonomously maintain the exercise‐obtained gains of a 20‐week supervised training program over a subsequent 1‐year period. Highlights: ADT for prostate cancer results in many side effects, including muscle mass lossA supervised resistance exercise training program can counteract many side effectsAfter cessation of the supervised program, exercise benefits are not effectively preservedMore focus on sustainability of exercise programs during ADT is required [ABSTRACT FROM AUTHOR]

Simple Summary: Localized prostate cancer has a favorable prognosis and can be effectively treated with radiotherapy, as well as therapies that target hormone production and signaling. However, if the disease progresses past these treatments, treatment options are limited, and the disease often becomes fatal. In this review, we discuss the changes in treatment as prostate cancer develops, as well as the genetic mutations that accompany advanced prostate cancer. We highlight how these mutations can provide clinical opportunities to manipulate the DNA damage response for therapeutic gain using cancer-specific alterations in the genome and new therapeutic agents that are under development or entering clinical trials. Prostate cancers that progress despite androgen deprivation develop into castration-resistant prostate cancer, a fatal disease with few treatment options. In this review, we discuss the current understanding of prostate cancer subtypes and alterations in the DNA damage response (DDR) that can predispose to the development of prostate cancer and affect its progression. We identify barriers to conventional treatments, such as radiotherapy, and discuss the development of new therapies, many of which target the DDR or take advantage of recurring genetic alterations in the DDR. We place this in the context of advances in understanding the genetic variation and immune landscape of CRPC that could help guide their use in future treatment strategies. Finally, we discuss several new and emerging agents that may advance the treatment of lethal disease, highlighting selected clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer therapy suffers from a lack of effective targets because, typically, success with blockade of the androgen receptor gives way to drug resistance and lethal disease relapse. Large scale genome sequencing efforts have demonstrated that lethal recurrent disease most often presents with loss of the PTEN and TP53 tumor suppressors. Unfortunately, the systematic testing of PTEN/ PI 3-Kinase pathway-specific inhibitors has shown only limited results in prostate cancer trials. Thus, there are currently no FDA-approved drugs targeting this axis in prostate cancer patients. Here we propose a new target, the FABP5 lipid carrier. FABP5 amplification and surge in expression are strongly correlated to that of the MYC oncogene, a known driver of advanced PTEN-deficient prostate cancer. Here, we present a new pre-clinical platform to assess the efficacy and biology of inhibiting FABP5 with small molecules. Our platform is based on a PTEN-deficient prostate cancer cell type that is insensitive to standard of care therapies. Resistance to standard of care taxane and androgen deprivation therapy (ADT) causes the vast majority of prostate cancer (PC) deaths worldwide. We have developed RapidCaP, an autochthonous genetically engineered mouse model of PC. It is driven by the loss of PTEN and p53, the most common driver events in PC patients with life-threatening diseases. As in human ADT, surgical castration of RapidCaP animals invariably results in disease relapse and death from the metastatic disease burden. Fatty Acid Binding Proteins (FABPs) are a large family of signaling lipid carriers. They have been suggested as drivers of multiple cancer types. Here we combine analysis of primary cancer cells from RapidCaP (RCaP cells) with large-scale patient datasets to show that among the 10 FABP paralogs, FABP5 is the PC-relevant target. Next, we show that RCaP cells are uniquely insensitive to both ADT and taxane treatment compared to a panel of human PC cell lines. Yet, they share an exquisite sensitivity to the small-molecule FABP5 inhibitor SBFI-103. We show that SBFI-103 is well tolerated and can strongly eliminate RCaP tumor cells in vivo. This provides a pre-clinical platform to fight incurable PC and suggests an important role for FABP5 in PTEN-deficient PC. [ABSTRACT FROM AUTHOR]