Detecting androgen receptor (AR), AR variant 7 (AR-V7), prostate-specific membrane antigen (PSMA), and prostate-specific antigen (PSA) gene expression in CTCs and plasma exosome-derived cfRNA in patients with metastatic castration-resistant prostate cancer (mCRPC) by integrating the VTX-1 CTC isolation system with the QIAGEN AdnaTest.

BACKGROUND: Therapies for metastatic castration-resistant prostate cancer (mCRPC) include targeting the androgen receptor (AR) with androgen receptor inhibitors (ARIs) and prostate-specific membrane antigen (PSMA). Having the ability to detect AR, AR splice variant 7 (AR-V7), or PSMA in circulating tumor cells (CTCs) or circulating exosomal cell-free RNA (cfRNA) could be helpful to guide selection of the appropriate therapy for each individual patient. The Vortex Biosciences VTX-1 system is a label-free CTC isolation system that enables the detection of the expression of multiple genes in both CTCs and exosomal cfRNA from the same blood sample in patients with mCRPC. Detection of both AR-V7 and PSMA gene expression in both CTCs and cfRNA simultaneously has not yet been reported. METHODS: To characterize the combined VTX-1-AdnaDetect workflow, 22Rv1 cancer cells were spiked into blood from healthy donors and processed with the VTX-1 to mimic patient samples and assess performances (capture efficiency, purity, AR and AR-V7 expression). Then, we collected 19 blood samples from 16 patients with mCRPC and therapeutic resistance to androgen receptor inhibitors (ARIs). Plasma was separated and the plasma-depleted blood was processed further with the VTX-1 to collect CTCs. Both plasma exosomal cfRNA and CTCs were subsequently analyzed for AR, AR-V7, PSMA, and prostate-specific antigen (PSA) mRNA expression using the AdnaTest ProstateCancerPanel AR-V7 assay. RESULTS: AR-V7 expression could be detected in 22Rv1 cells spiked into blood from healthy volunteers as well as in CTCs and plasma-derived exosomal cfRNA from patients with mCRPC by processing blood with the VTX-1 CTC isolation system followed by the AdnaTest ProstateCancerPanel AR-V7 assay. 94.7% of patient blood samples (18/19) had detectable AR expression in either CTCs or exosomal cfRNA (16 in CTCs, 12 in cfRNA). 15.8% of the 19 patient blood samples (3/19) were found to have AR-V7-positive (AR-V7+) CTCs, one of which was also AR-V7+ in the exosomal cfRNA analysis. 42.1% of patient blood samples (8/19) were found to be PSMA positive (PSMA+): 26.3% (5/19) were PSMA+ in the CTC analysis and 31.6% (6/19) were PSMA+ in the exosomal cfRNA analysis. Of those 8 PSMA+ samples, 2 had detectable PSMA only in CTCs, and 3 had detectable PSMA only in exosomal cfRNA. CONCLUSION: VTX-1 enables isolation of CTCs and plasma exosomes from a single blood draw and can be used for detecting AR-V7 and PSMA mRNA in both CTCs and cfRNA in patients with mCRPC and resistance to ARIs. This technology facilitates combining RNA measurements in CTCs and exosomal cfRNA for future studies to develop potentially clinically relevant cancer biomarker detection in blood.

Emerging and traditional 5-α reductase inhibitors and androgen receptor antagonists for male androgenetic alopecia.

INTRODUCTION: Androgenetic alopecia (AGA) is the most prevalent cause of male hair loss, often requiring medical and/or surgical intervention. The US FDA has approved topical minoxidil and oral finasteride for male AGA treatment. However, some AGA patients fail to respond satisfactorily to these FDA-approved treatments and/or may experience side effects, based on their individual profiles. To mitigate the shortcomings of these treatments, researchers are now exploring alternative treatments such as newer 5-α reductase inhibitors (5-ARIs) and androgen receptor antagonists (ARAs). AREAS COVERED: This article reviews the safety and effectiveness of well-known 5-α reductase inhibitors (5-ARIs) like finasteride and dutasteride, as well as the newer 5-ARIs, emerging androgen receptor antagonists (ARAs), and natural products such as saw palmetto and pumpkin seed oil in the treatment of male AGA. EXPERT OPINION: Although several newer 5-ARIs, ARAs, and natural products have exhibited promise in clinical trials, additional research is essential to confirm their safety and efficacy in treating male AGA. Until additional evidence is available for these agents, the preferred treatment choices for male AGA are the FDA-approved treatments, topical minoxidil, and oral finasteride.

Efficacy and safety of androgen receptor inhibitors for treatment of advanced prostate cancer: A systematic review and network meta-analysis.

AIMS: Androgen receptor inhibitors (ARIs) have become an effective treatment for advanced prostate cancer (PC). However, it is unknown which ARI is the most helpful and safe for men with advanced PC. Our aim is to help physicians make clinical decisions and provide medication guidelines for patients with advanced PC to avoid potential risks when using ARIs for treatment. METHODS: We systematically searched the following databases: PubMed, Embase and Cochrane Library, with a literature publication deadline of February 2023. The primary efficacy outcomes were 18-month overall survival (OS), treatment-emergent adverse events (TEAEs), hypertension and fatigue. The network meta-analysis (NMA) was performed by Stata 15.1, and Revman 5.3 was used to assess the included studies' risk of bias. RESULTS: The analysis included 26 trials with 26 263 people. The surface under the cumulative ranking curve (SUCRA) concluded that enzalutamide (86.8%) showed the best effect in prolonging the OS of patients. Flutamide led to the highest risk of TEAEs (29.9%) and AEs leading to discontinuation (12.8%). Apalutamide (13.4%) led to the highest risk of grade ≥3 TEAEs. Enzalutamide had the highest risk of hypertension (0.2%), grade ≥3 hypertension (4.5%) and fatigue (5.2%). CONCLUSIONS: This NMA indicates there is no one ARI to reach both the most effective and safe therapy aims for treating advanced PC and that there is a compromise between the efficacy and safety of ARIs in the treatment of advanced PC. Physicians should weigh the risks to safety against the anticipated benefits when prescribing these drugs to patients with PC.

Systemic therapies for metastatic hormone-sensitive prostate cancer: network meta-analysis.

OBJECTIVES: To perform a systematic review and network meta-analysis to compare the efficacy and safety of currently available treatments for the management of metastatic hormone-sensitive prostate cancer (mHSPC), as there has been a paradigm shift with the use of next-generation androgen receptor inhibitors (ARIs) and docetaxel. METHODS: Multiple databases were searched for articles published before May 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analysis extension statement for network meta-analysis. Studies comparing overall/progression-free survival (OS/PFS) and/or adverse events (AEs) in patients with mHSPC were eligible. RESULTS: Nine studies (N = 9960) were selected, and formal network meta-analyses were conducted. Abiraterone (hazard ratio [HR] 0.83, 95% credible interval [CrI] 0.76-0.90), docetaxel (HR 0.90, 95% CrI 0.82-0.98), and enzalutamide (HR 0.85, 95% CrI 0.73-0.99) were associated with significantly better OS than androgen-deprivation therapy (ADT), and abiraterone emerged as the best option. Abiraterone (HR 0.71, 95% CrI 0.67-0.76), apalutamide (HR 0.73, 95% CrI 0.65-0.81), docetaxel (HR 0.84, 95% CrI 0.78-0.90), and enzalutamide (HR 0.67, 95% CrI 0.63-0.71) were associated with significantly better PFS than ADT, and enzalutamide emerged as the best option. Abiraterone (HR 0.85, 95% CrI 0.78-0.93), apalutamide (HR 0.87, 95% CrI 0.77-0.98), and enzalutamide (HR 0.80, 95% CrI 0.73-0.88) were significantly more effective than docetaxel. Regarding AEs, apalutamide was the likely best option among the three ARIs. In patients with low-volume mHSPC, enzalutamide was the best option in terms of OS and PFS. CONCLUSIONS: All three ARIs are effective therapies for mHSPC; apalutamide was the best tolerated. All three seemed more effective than docetaxel. These findings may facilitate individualised treatment strategies and inform future comparative trials.

WHICH PATIENTS WILL BENEFIT MOST FROM DOCETAXEL ADDITION TO ANDROGEN DEPRIVATION THERAPY (ADT) IN METASTATIC CASTRATE-SENSITIVE PROSTATE CANCER (MCSPC)?

Docetaxel improved the outcome of patients with mCSPC and became standard of care after CHAARTED, STAMPEDE arm C and GETUG-AFU 15 clinical trials and after subsequent meta-analysis. Patients with high-volume (CHAARTED definition) and high-risk (LATITUDE definition) disease, who have good performance status and are fit for chemotherapy, seem to benefit the most from addition of docetaxel to the androgen deprivation therapy. Results from TITAN trial with apalutamide showed the activity in the same setting. However, predictive biomarkers are still lacking. We have direct evidence of overall survival benefit from abiraterone, apalutamide and enzalutamide for patients with high-volume disease who are not fit for chemotherapy, as well as for patients with low-volume disease. Clinical trials will show is there place for triple therapy in clinical practice. Before obtaining the results of new clinical trial results, physicians should base their treatment decision on risks and benefits of each current approach and consider the patient´s other health issues such as access, costs, patient and patient´s preferences.

Bioactive natural products for chemoprevention and treatment of castration-resistant prostate cancer.

Prostate cancer (PCa), a hormonally-driven cancer, ranks first in incidence and second in cancer related mortality in men in most Western industrialized countries. Androgen and androgen receptor (AR) are the dominant modulators of PCa growth. Over the last two decades multiple advancements in screening, treatment, surveillance and palliative care of PCa have significantly increased quality of life and survival following diagnosis. However, over 20% of patients initially diagnosed with PCa still develop an aggressive and treatment-refractory disease. Prevention or treatment for hormone-refractory PCa using bioactive compounds from marine sponges, mushrooms, and edible plants either as single agents or as adjuvants to existing therapy, has not been clinically successful. Major advancements have been made in the identification, testing and modification of the existing molecular structures of natural products. Additionally, conjugation of these compounds to novel matrices has enhanced their bio-availability; a big step towards bringing natural products to clinical trials. Natural products derived from edible plants (nutraceuticals), and common folk-medicines might offer advantages over synthetic compounds due to their broader range of targets, as compared to mostly single target synthetic anticancer compounds; e.g. kinase inhibitors. The use of synthetic inhibitors or antibodies that target a single aberrant molecule in cancer cells might be in part responsible for emergence of treatment refractory cancers. Nutraceuticals that target AR signaling (epigallocatechin gallate [EGCG], curcumin, and 5α-reductase inhibitors), AR synthesis (ericifolin, capsaicin and others) or AR degradation (betulinic acid, di-indolyl diamine, sulphoraphane, silibinin and others) are prime candidates for use as adjuvant or mono-therapies. Nutraceuticals target multiple pathophysiological mechanisms involved during cancer development and progression and thus have potential to simultaneously inhibit both prostate cancer growth and metastatic progression (e.g., inhibition of angiogenesis, epithelial-mesenchymal transition (EMT) and proliferation). Given their multi-targeting properties along with relatively lower systemic toxicity, these compounds offer significant therapeutic advantages for prevention and treatment of PCa. This review emphasizes the potential application of some of the well-researched natural compounds that target AR for prevention and therapy of PCa.

Incidence and Prognostic Significance of Androgen Receptors (AR) in Indian Triple-Negative Breast Cancer (TNBC).

Molecular sub-characterization of triple-negative breast cancer (TNBC) has great therapeutic and possibly prognostic implications. The primary aim of this study was to investigate the incidence of luminal androgen receptor (LAR) subtype of TNBC and secondary aims were sub-categorization and clinico-pathologic correlation of LAR breast cancers. Retrospective study (January 2008 and 31st of December 2018) consisting of 157 TNBC patients. Androgen receptor (AR) expression was measured by immunohistochemical analysis. One percent cutoff was set as a positive expression. Sub-categorization was done on the basis of EGFR (> 15% of tumor cells) and Ki-67 expression (low- < 11%, intermediate- 11-20%, and high- > 21%). AR expression was correlated with various clinico-pathologic features and outcomes of the patients. The incidence of AR expression in TNBC was 24.8%. Considering different thresholds of > 5%, > 10%, and > 20% immunostaining, the incidence of AR positivity was 18.4, 15.2, and 11.5% respectively. The incidence of Ki-67 (p = 0.89) and EGFR (p = 0.643) expression did not differ significantly in AR-positive and -negative TNBC. Based on EGFR expression 19, 67 and 14% patients were categorized as low, intermediate, and high risk respectively. Low-risk (p ≤ 0.001) and low-grade (p = 0.014) tumors were more likely to have > 10% AR expression. Clinico-pathological profile, response to neoadjuvant chemotherapy, disease-free survival (p = 0.458), and overall survival (p = 0.806) did not significantly differ between AR expressing and negative TNBC. On multivariate analysis, only tumor staging was a significant predictor of survival (p = 0.012) and AR expression of > 10% revealed a trend towards improved survival (p = 0.07). When considering only AR-positive TNBC, AR expression of > 10% (p = 0.038), distant metastases (p = 0.003), and EGFR status (p = 0.024) were significantly associated with survival. AR expression does not seem to very strongly correlate with prognosis in TNBC and further studies could focus more on its predictive role in deciding anti-androgen therapy.

Practical implications of androgen receptor inhibitors for prostate cancer treatment.

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.

Physician preferences for nonmetastatic castration-resistant prostate cancer treatment in China.

Introduction: The treatment preferences of Chinese physicians who treat nonmetastatic castration-resistant prostate cancer (nmCRPC) and how they weigh the benefits and risks of nmCRPC treatment are still unknown. This study aimed to evaluate Chinese physicians' benefit-risk treatment preferences for nmCRPC and assist in setting nmCRPC treatment goals. Methods: A paper-based discrete choice experiment (DCE) survey was administered to 80 nmCRPC-treating physicians. DCE responses were analyzed to produce the preference weight and the relative importance score for each attribute level. The marginal rate of substitution (MRS) was used to quantify the amount of overall survival (OS) physicians were willing to trade for a reduction in treatment-related adverse events (AEs). We further conducted the exploratory analysis, stratifying physicians from 5 perspectives into different subgroups and examining the treatment preferences and OS trade-off in each subgroup. Results: In terms of efficacy attributes, physicians placed greater emphasis on OS than time to pain progression. With regard to safety attributes, serious fracture was perceived as the most important AE by physicians, followed by serious fall, cognitive problems, skin rash, and fatigue. In the exploratory analysis, we found generally that physicians with less clinical practice experience and those from more economically developed regions placed more emphasis on AEs and were willing to give up more of their patients' OS to reduce the risk of AEs. Conclusion: Physicians from mainland China value the importance of minimizing treatment-related AEs when considering different treatment options for patients with nmCRPC, and they are willing to trade a substantial amount of OS to avoid AEs.

[Novel hormone treatment for advanced prostate cancer]. / Neuartige Hormontherapien beim fortgeschrittenen Prostatakarzinom.

The systemic treatment of advanced prostate cancer (PCa) has undergone an absolute revolution in the past decade. Numerous new substances have been approved for all stages of advanced disease and treatment has been increasingly intensified. The focus continues to be on substances with an effect on the androgen receptor axis. In this review, approved treatment options for metastatic hormone-sensitive PCa (mHSPC), non-metastatic castration-refractory PCa (nmCRPC) and metastatic castration-refractory PCa (mCRPC) are summarized. A special focus is on novel hormone therapeutic agents. Based on recent trial data, potential triple combinations for mHSPC as well as treatment sequence options and novel targeted agents for mCRPC are also highlighted.

Cost-Utility Analysis of Darolutamide Combined with Androgen Deprivation Therapy for Patients with High-Risk Non-Metastatic Castration-Resistant Prostate Cancer in China.

INTRODUCTION: The increasing incidence of prostate cancer (PC) in China leads to a significant disease burden. Although three novel androgen inhibitors (darolutamide, apalutamide, and enzalutamide) have been approved for patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC), the economic evaluation of these novel treatments in China remains unknown. In this study, we aimed to evaluate the cost-utility of darolutamide combined with androgen deprivation therapy (ADT), comparing with apalutamide + ADT and enzalutamide + ADT, in patients with high-risk nmCRPC from a healthcare system perspective in China. METHODS: A partitioned survival model was developed to capture time spent by patients in three health states: nmCRPC, metastatic CRPC (mCRPC), and death. Clinical outcomes from the ARAMIS, PROSPER, and SPARTAN studies were obtained. In the absence of head-to-head studies, indirect treatment comparisons were conducted to capture the comparative effectiveness between darolutamide + ADT, apalutamide + ADT, and enzalutamide + ADT. The prices of apalutamide and enzalutamide were assumed to be the same as the initial launch price of darolutamide, since post-negotiation prices after national reimbursement drug list (NRDL) inclusion remain confidential. Other health resources costs, baseline characteristics, treatment patterns, and utility were collected through literature or clinical expert interviews. Selected sensitivity analyses were also performed. RESULTS: For a 20-year time horizon, darolutamide + ADT was associated with lower cost per quality-adjusted life years (QALYs) than apalutamide + ADT and enzalutamide + ADT (202,897 Chinese yuan (CNY)/QALY vs. 228,998 CNY/QALY and 221,409 CNY/QALY, respectively) (exchange rate, 1 USD = 6.7871 CNY). Darolutamide + ADT had better health outcomes and lower total costs compared to both apalutamide + ADT (+ 0.22 QALYs and - 72,818 CNY) and enzalutamide + ADT (+ 0.09 QALYs and - 67,451 CNY). Across the modelled sensitivity analyses (including hazard ratios and drug costs), darolutamide + ADT remained dominant or cost-effective. CONCLUSIONS: This economic evaluation suggested that, in comparison with apalutamide + ADT and enzalutamide + ADT, darolutamide + ADT was a dominant or cost-effective treatment option for patients with high-risk nmCRPC in China.

Novel androgen receptor inhibitors for metastatic hormone-sensitive prostate cancer: Current application and future perspectives.

Androgen receptor (AR) signaling is essential in prostate cancer treatment. For many years, androgen deprivation therapy (ADT) has been primarily applied to manage advanced prostate cancer. However, most individuals with metastatic hormone-sensitive prostate cancer (mHSPC) administered ADT alone are at risk of developing metastatic castration-resistant prostate cancer (mCRPC) in less than two years. New approaches employing novel AR inhibitors (ARi) as intensified upfront systemic treatment in mHSPC have recently demonstrated substantial benefits in delaying disease progression and prolonging overall survival. Administration of novel ARi has become the new standard of care in mHSPC. The new landscape simultaneously makes treatment choice more challenging. This review provides comprehensive data on molecular structure, pharmaceutical properties, and efficacy and safety profiles reported by pivotal clinical trials. We also discuss future directions with ongoing Phase III trials of novel ARi in mHSPC. Considering these biological and clinical insights, this review aimed to provide a comprehensive understanding of differences in the development and applications of novel ARi for mHSPC, which may be helpful in designing strategies for first-line treatment choices.

Comparative efficacy of second-generation androgen receptor inhibitors for treating prostate cancer: A systematic review and network meta-analysis.

Introduction: Second-generation androgen receptor inhibitors (SGARIs), namely enzalutamide, apalutamide, and darolutamide, are good for improving survival outcomes in prostate cancer patients, but some researchers have shown that using SGARIs increases side effects, which complicates clinicians' choice of. Therefore, we performed this network meta-analysis to assess the efficacy and toxicity of several SGARIs in the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC), non-metastatic castration-resistant prostate cancer (nmCRPC), and metastatic castration-resistant prostate cancer (mCRPC). Methods: We searched PubMed, EMBASE and Cochrane Library databases from January 2000 to December 2022 to identify randomized controlled studies associated with SGARIs. We use Stata 16.0 and R 4.4.2 for data analysis, hazard ratio (HR) with 95% confidence intervals (CI) were used to assess the results. Results: This meta-analysis included 7 studies with a total of 9488 patients. In mHSPC, enzalutamide and darolutamide had a positive effect on overall survival (OS) (HR, 0.70; 95% CI, 0.59-0.82), but we did not find a difference in their efficacy to improve OS (HR, 1.19; 95% CI, 0.75-1.89). Also in nmCRPC, enzalutamide, apalutamide and darolutamide were beneficial for metastasis-free survival (MFS) (HR, 0.32; 95% CI, 0.25-0.41). Compared to darolutamide, enzalutamide (HR, 0.71; 95% CI, 0.54-0.93) and apalutamide (HR, 0.68; 95% CI, 0.51-0.91) prolonged MFS, but there was no difference in efficacy between enzalutamide and apalutamide (HR, 0.97; 95% CI, 0.73-1.28). Finally in mCRPC, there was no significant difference in indirect effects on OS between pre- and post-chemotherapy enzalutamide (HR, 0.89; 95% CI, 0.70-1.13). However, using enzalutamide before chemotherapy to improve radiographic progression-free survival (rPFS) was a better option (HR, 2.11; 95% CI, 1.62-2.73). Conclusion: The SGARIs used in each trial were beneficial for the primary endpoint in the study. Firstly there was no significant difference in the effect of enzalutamide and darolutamide in improving OS in patients with mHSPC. Secondly improving MFS in patients with nmCRPC was best achieved with enzalutamide and apalutamide. In addition both pre- and post-chemotherapy use of enzalutamide was beneficial for OS in mCRPC patients, but for improving rPFS pre-chemotherapy use of enzalutamide should be preferred.The INPLASY registration number of this systematic review is INPLASY202310084.

Treatment of non-metastatic castration-resistant prostate cancer: facing age-related comorbidities and drug-drug interactions.

INTRODUCTION: Patients with non-metastatic castration-resistant prostate cancer (nmCRPC) are frequently poly-medicated due to age-related and androgen deprivation therapy (ADT)-derived comorbidities. In high-risk patients, androgen receptor inhibitors (ARIs) have shown to delay disease progression; however, drug-drug interactions (DDIs) with preexisting medications may impact the therapeutic effect and safety of these and of the ARIs themselves. AREAS COVERED: We review the potential comorbidity burden of nmCRPC patients on the basis of epidemiologic studies on age-related comorbidities, the impact of ADT and specific studies analyzing this topic. Using the DDIs compendia Lexicomp® and Drugs.com®, we provide a scenario of the potential DDIs between common mediations used to treat these comorbidities and the three currently available ARIs: apalutamide, enzalutamide and darolutamide. EXPERT OPINION: In high-risk nmCRPC patients to be treated with an ARI, careful multidisciplinary evaluation of potential DDIs is a fundamental component in the clinical-decision making. The lower potential for DDIs, the lower need for dose adjustment or change of current comedications and of patient monitoring, and safer introduction of new comedications. To optimize this step, an effort is still needed to determine the clinical relevance of DDIs and to harmonize their definition and classification among the different compendia.

Prostate cancer is one of the most common cancers in men. It is normally diagnosed at age 60 or above, so these men are usually taking medications to treat age-related conditions (e.g. hypertension, diabetes, high cholesterol, etc.).One of the main treatments for prostate cancer is 'androgen deprivation therapy' (ADT), a hormone treatment that reduces androgens level. This is because the growth of prostate cancer cells is dependent on male sex hormones called androgens. Despite ADT helping keep the cancer controlled for a time, it increases the risk for adverse events that may need new medications. Consequently, men with prostate cancer usually take multiple medications.After some years, ADT may not be enough to control the prostate cancer. A type of medication called 'androgen receptor inhibitors' (ARIs), which prevent the androgen entering the cell, are helpful at this stage, especially the second-generation ones: apalutamide, enzalutamide, and darolutamide. The problem is that these ARIs usually interact with other medications already taken by patients, an effect called 'drug­drug interaction.' When this happens, the ARI (the interaction 'perpetrator') may modify the effectiveness of other medications (the 'victims') and/or cause unexpected effects. Consequently, the conditions being treated by these medications may not be properly controlled, which may pose a risk to the patient's health. Thus, when starting treatment with a second-generation ARI, it is crucial to consider all possible interactions with the medications taken. The fewer potential interactions the ARI has, the easier it is to properly control other common conditions in prostate cancer patients.

Genetic Profiling of Glucocorticoid (NR3C1) and Mineralocorticoid (NR3C2) Receptor Polymorphisms before Starting Therapy with Androgen Receptor Inhibitors: A Study of a Patient Who Developed Toxic Myocarditis after Enzalutamide Treatment.

Enzalutamide is a nonsteroidal inhibitor of the androgen receptor (AR) signaling pathway and is used to treat patients with metastatic castration-resistant prostate cancer. However, the risk of cardiovascular-related hospitalization in patients with no contraindications for the use of enzalutamide is about 1-2%. To date, the underlying molecular basis of this has not been established. The androgen receptor, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are nuclear receptors that share structural similarities and have closely related DNA-binding sites and coregulators. In non-epithelial cells, a fine balance of the activities of these receptors is essential to ensure correct cellular function. In this study, we present a molecular characterization of these nuclear receptors in a prostate cancer patient who developed congestive heart failure after enzalutamide treatment. White cell RNAseq revealed a homozygous rs5522 MR polymorphism and both the rs143711342 and rs56149945 GR polymorphisms, carried in different alleles. No different specific splice isoforms were detected. Recent research suggests that AR inhibition by enzalutamide makes available a coregulator that specifically interacts with the rs5522-mutated MR, increasing its activity and producing adverse effects on cardiovascular health. We suggest an evaluation of the MR rs5522 polymorphism before starting therapy with AR inhibitors.

Novel Treatment Strategy Using Second-Generation Androgen Receptor Inhibitors for Non-Metastatic Castration-Resistant Prostate Cancer.

Non-metastatic castration-resistant prostate cancer (nmCRPC) is defined by a progressively rising prostate-specific antigen level, despite a castrate level of testosterone, in the absence of obvious radiologic evidence of metastatic disease on conventional imaging modalities. As a significant proportion of patients with nmCRPC develop metastatic diseases, the therapeutic goals of physicians for these patients are to delay metastasis development, preserve quality of life, and increase overall survival (OS). Since 2018, the treatment of nmCRPC has changed dramatically with the introduction of second-generation androgen receptor inhibitors, such as enzalutamide (ENZA), apalutamide (APA), and darolutamide (DARO). These drugs demonstrated substantial improvements in metastasis-free survival (MFS) and OS in phase III randomized clinical trials. In addition, these drugs have an excellent safety profile, preserve quality of life, and can delay disease-related symptoms. A recently published indirect meta-analysis reported that APA and ENZA showed better findings in MFS and that DARO had relatively fewer adverse effects. However, in the absence of a direct comparison, careful interpretation is required. Thus, APA, ENZA, and DARO should be considered the new standard drugs for treating nmCRPC.

[Systemic treatment of advanced prostate cancer]. / Systemische Therapie des fortgeschrittenen Prostatakarzinoms.

In recent years there have been substantial changes in the therapeutic landscape for systemic treatment of advanced prostate cancer (PCa), which resulted in a multitude of novel treatment options for different stages of the disease. In the current narrative review currently available treatment options for metastatic hormone-sensitive PCa as well as nonmetastatic castration-resistant PCa are presented. In addition, current treatment sequence options and targeted treatment in the stage of metastatic castration-resistant PCa are highlighted.

Darolutamide: An Evidenced-Based Review of Its Efficacy and Safety in the Treatment of Prostate Cancer.

Men treated with androgen deprivation therapy for rising PSA after failed local therapy will often develop castrate resistance, and the appearance of metastases predicts a poor prognosis. Thus, researchers have long sought to prolong the onset of metastasis in patients with nonmetastatic castration-resistant prostate cancer (CRPC). Until 2018, patients in this group had no FDA-approved treatment options. They were typically managed with androgen-deprivation therapy (ADT) to maintain castrate systemic testosterone levels and given approved therapies for metastatic CRPC once metastases appeared. However, third-generation androgen receptor inhibitors (ARIs) have dramatically changed the treatment paradigm, having shown the ability to extend metastasis-free survival (MFS) significantly over ADT alone in Phase 3 trials. The newest of these, darolutamide, prolonged MFS 22 months over placebo while also improving a host of secondary and exploratory endpoints such as overall survival (OS), prostate-specific antigen (PSA) progression and time to pain progression, chemotherapy initiation, and symptomatic skeletal events. Among third-generation ARIs, darolutamide is unique in that it incorporates two pharmacologically active diastereomers and has demonstrated resistance to all known androgen receptor (AR) mutations. Additionally, patients taking darolutamide appear to experience comparatively few central nervous system-related adverse events (AEs) such as fatigue and falls, and no increases in seizures have been reported in the drug's clinical or preclinical development. Various authors attribute the low incidence of CNS-related AEs to darolutamide's minimal penetration of the blood-brain barrier (BBB). Other side effects ranging from hot flashes to hypothyroidism also occurred at rates similar to those of the placebo arm in Phase 3. As ADT in itself raises cardiovascular risk, the cardiovascular safety of third-generation antiandrogens as a category warrants continued scrutiny. In total, however, published data suggest that darolutamide provides a reasonable option for patients with nonmetastatic CRPC. Ongoing research will determine darolutamide's potential role in additional disease states such as localized and castration-sensitive PCa.

Next-generation androgen receptor inhibitors in non-metastatic castration-resistant prostate cancer.

Until recently, continuing androgen deprivation therapy (ADT) and closely monitoring patients until evolution towards metastatic castration-resistant prostate cancer (CRPC) were recommended in men with non-metastatic CRPC (nmCRPC). Because delaying the development of metastases and symptoms in these patients is a major issue, several trials have investigated next-generation androgen receptor (AR) axis inhibitors such as apalutamide, darolutamide, and enzalutamide in this setting. This review summarizes the recent advances in the management of nmCRPC, highlighting the favourable impact of next-generation AR inhibitors on metastases-free survival, overall survival and other clinically meaningful endpoints.

Enzalutamide for the treatment of nonmetastatic castration-resistant prostate cancer.

INTRODUCTION: Enzalutamide is the first characterized second-generation nonsteroidal androgen receptor inhibitor (ARi). Its efficacy has been established in several clinical trials evaluating its role in different settings of prostate cancer. Recently, enzalutamide has been approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC). AREAS COVERED: In this paper, the authors describe the chemical structure and pharmacologic characteristics of enzalutamide, providing a summary of clinical trials evaluating its efficacy and safety in prostate cancer patients. EXPERT OPINION: Enzalutamide adds to the growing arsenal of ARi used in nmCRPC. An improvement in metastasis-free survival was observed with the use of these new treatment options; recently released preliminary data report also an OS benefit. These novel agents are generally well tolerated, but their safety profiles differ slightly. Since head-to-head comparisons between ARi in nmCRPC are lacking, the adverse events profile, as well as drug availability, costs, and considerations on treatment-sequencing, would most likely influence the selection of the individual agent in this setting. Further research is needed to improve treatment selection and clarify many unsolved issues. Abbreviations ARi: nonsteroidal androgen receptor inhibitor; nmCRPC: nonmetastatic castration resistant prostate cancer; ADT: androgen deprivation therapy; OS: overall survival; PSA: prostate specific antigen; FDA: Food and Drug Administration; AR: Androgen Receptor; MFS: metastasis free survival; PSA-DT: PSA doubling time; HR: hazard ratio; CI: confidence interval; AEs: adverse events; mCRPC: metastatic castration resistant prostate cancer; mHSPC: metastatic hormone-sensitive prostate cancer; rPFS: radiographic progression-free survival; OR: odds ratio.