Flutamide With or Without PROSTVAC in Non-metastatic Castration Resistant (M0) Prostate Cancer.

BACKGROUND: Before 2018, there was no standard of care for non-metastatic (M0) castration resistant prostate cancer nmCRPC. Androgen receptor antagonists (ARAs) were commonly used sequentially nmCRPC. METHODS: This was a multicenter, randomized clinical trial comparing the ARA flutamide+/-PROSTVAC, a pox viral vaccine targeting PSA that includes T-cell co-stimulatory molecules. Eligible men had negative CT and Tc99 bone scans, and rising PSA on ADT. Previous treatment with ARA was a stratification factor. Patients were also evaluated for antigen-specific immune responses using intracellular cytokine staining. RESULTS: Thirty-three patients randomized to flutamide and 31 to flutamide+vaccine. The median age was 71.8 and 69.8 years, respectively. The median time to treatment failure after a median potential follow-up of 46.7 months was, 4.5 months (range 2-70) for flutamide alone vs. 6.9 months (2.5-40; P = .38) with flutamide+vaccine. Seven patients in each arm had a >50% PSA response. Antigen-specific responses were similar in both arms (58% of patients in flutamide alone and 56% in flutamide+vaccine). The treatments were well tolerated. The most common side effect > grade 2 was injection site reaction seen in 29/31 vaccine patients which were self-limiting. CONCLUSION: The combination of flutamide+PROSTVAC did not improve outcomes in men with nmCRPC compared with flutamide alone. (ClinicalTrials.gov Identifier: NCT00450463).

Adjuvant enzalutamide for the treatment of early-stage androgen-receptor positive, triple-negative breast cancer: a feasibility study.

PURPOSE: Chemotherapy with or without immunotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC). A subset of TNBCs express the androgen receptor (AR), representing a potential new therapeutic target. This study assessed the feasibility of adjuvant enzalutamide, an AR antagonist, in early-stage, AR-positive (AR +) TNBC. METHODS: This study was a single-arm, open-label, multicenter trial in which patients with stage I-III, AR ≥ 1% TNBC who had completed standard-of-care therapy were treated with enzalutamide 160 mg/day orally for 1 year. The primary objective of this study was to evaluate the feasibility of 1 year of adjuvant enzalutamide, defined as the treatment discontinuation rate of enzalutamide due to toxicity, withdrawal of consent, or other events related to tolerability. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and genomic features of recurrent tumors. RESULTS: Fifty patients were enrolled in this study. Thirty-five patients completed 1 year of therapy, thereby meeting the prespecified trial endpoint for feasibility. Thirty-two patients elected to continue with an optional second year of treatment. Grade ≥ 3 treatment-related adverse events were uncommon. The 1-year, 2-year, and 3-year DFS were 94%, 92% , and 80%, respectively. Median OS has not been reached. CONCLUSION: This clinical trial demonstrates that adjuvant enzalutamide is a feasible and well-tolerated regimen in patients with an early-stage AR + TNBC. Randomized trials in the metastatic setting may inform patient selection through biomarker development; longer follow-up is needed to determine the effect of anti-androgens on DFS and OS in this patient population.

Androgen Metabolism and Response in Prostate Cancer Anti-Androgen Therapy Resistance.

All aspects of prostate cancer evolution are closely related to androgen levels and the status of the androgen receptor (AR). Almost all treatments target androgen metabolism pathways and AR, from castration-sensitive prostate cancer (CSPC) to castration-resistant prostate cancer (CRPC). Alterations in androgen metabolism and its response are one of the main reasons for prostate cancer drug resistance. In this review, we will introduce androgen metabolism, including how the androgen was synthesized, consumed, and responded to in healthy people and prostate cancer patients, and discuss how these alterations in androgen metabolism contribute to the resistance to anti-androgen therapy.

Non-metastatic castration-resistant prostate cancer: the evolving treatment landscape and role of nurse specialists.

Prostate cancer is the most common type of cancer in men in the UK. Within 2 years of diagnosis, one-third of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) will develop metastatic disease, which is associated with significantly greater morbidity and mortality compared to disease without metastases. The approval of second-generation androgen receptor inhibitors such as darolutamide has transformed the nmCRPC treatment landscape because they lead to prolonged metastasis-free survival and better maintenance of quality of life compared with placebo. Early identification of patients with nmCRPC who are suitable for treatment is imperative because most of these patients are asymptomatic. Clinical nurse specialists (CNSs) play a critical, supportive role in the management of disease and treatment follow-up. This product-focused article discusses the use of darolutamide in nmCRPC and the vital role that CNSs play in the management and care of patients with prostate cancer.

RNA-binding protein Musashi2 stabilizing androgen receptor drives prostate cancer progression.

The androgen receptor (AR) pathway is critical for prostate cancer carcinogenesis and development; however, after 18-24 months of AR blocking therapy, patients invariably progress to castration-resistant prostate cancer (CRPC), which remains an urgent problem to be solved. Therefore, finding key molecules that interact with AR as novel strategies to treat prostate cancer and even CRPC is desperately needed. In the current study, we focused on the regulation of RNA-binding proteins (RBPs) associated with AR and determined that the mRNA and protein levels of AR were highly correlated with Musashi2 (MSI2) levels. MSI2 was upregulated in prostate cancer specimens and significantly correlated with advanced tumor grades. Downregulation of MSI2 in both androgen sensitive and insensitive prostate cancer cells inhibited tumor formation in vivo and decreased cell growth in vitro, which could be reversed by AR overexpression. Mechanistically, MSI2 directly bound to the 3'-untranslated region (UTR) of AR mRNA to increase its stability and, thus, enhanced its transcriptional activity. Our findings illustrate a previously unknown regulatory mechanism in prostate cancer cell proliferation regulated by the MSI2-AR axis and provide novel evidence towards a strategy against prostate cancer.

Phase II open-label study investigating apalutamide in patients with biochemical progression after radical prostatectomy.

Apalutamide, a competent inhibitor of the androgen receptor, has shown promising clinical efficacy results for patients with advanced prostate cancer. Here, we describe the rationale and design for the SAVE trial, a multi-center, Phase II study, wherein 202 men with biochemical progression after radical prostatectomy are randomly assigned 1:1 to apalutamide plus salvage radiotherapy (SRT) or androgen-deprivation therapy with an luteinizing hormone-releasing hormone agonist or antagonist plus SRT. The primary objective is to compare sexual function between the two treatment arms based on the expanded prostate cancer index-26 sexual domain score at nine months after start of hormonal treatment. The key secondary objectives are to assess quality of life, to evaluate the safety profile and the short-term efficacy of apalutamide in combination with SRT. ClinicalTrials.gov identifier: NCT03899077.

Is the suppressive effect of cyproterone acetate on serum anti-Müllerian-hormone levels in women with polycystic ovary syndrome stronger than under oral contraceptive pill?

OBJECTIVE: To compare the suppressive effect of anti-androgen therapy by cyproterone acetate (CPA) and by oral contraceptive pill (OCP) on anti-müllerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS) in order to detect a putative direct anti-androgen effect on AMH excess. METHODS: This is a prospective longitudinal study including 58 women with PCOS between January 2010 and April 2014 at the Lille University Hospital. A total of 47 women with clinical hyperandrogenism were treated by CPA (50 mg/d was administered 20 days out of 28) and 11 women with PCOS but without clinical hyperandrogenism received OCP. RESULT(S): Serum AHM levels at baseline were similar in CPA and OCP groups (median [5-95th percentiles]: 60.4 pmol/l [25.1-200.2] versus 58 pmol/l [27.6-100], respectively, p = 0.39). After 3 months of treatment, serum AMH levels decreased significantly by 28% ± 20% and by 22% ± 27% in CPA and OCP groups, respectively. The decrease under both treatments was similar (p = 0.48). CONCLUSION(S): That any anti-androgen effect could be observed on AMH in our CPA group in addition to the gonadotropin-suppressing effect suggests that either androgens are not involved in AMH regulation or that they act by interfering with gonadotropin effects on granulosa cells.

Prevalence of Hepatocellular Carcinoma in Men and the Contribution of Androgen and its Receptor in Pathogenesis and Therapy.

BACKGROUND: Hepatocellular carcinoma (HCC) is a solid cancer with high predominance in males. Liver tissue of both genders has saturable specific oestrogen receptors. Androgen and its receptor (AR) have been suggested to contribute to the predominance in men. Anti-oestrogens, like tamoxifen may reduce the expression of oestrogen receptors, sustaining cellular in HCC. In vitro and human, studies confirmed that both testosterone and dihydrotestosterone (DHT) enhanced the growth and proliferation of hepatic normal and tumour cells. Although the activity of AR is escalated by the chemical induction of hepatocarcinogenesis; clinical trials with AR-targeted agents alone failed to generate survival benefits. PURPOSE: This review will outline the possible pathophysiological mechanisms by which both androgen and AR contribute to hepatocarcinogenesis and to which extent this pathway can be responsible for the male prevalence and if they could be pharmacological targets in HCC management. CONCLUSION: Influencing factors that seem to be responsible for male prevalence include testosterone, dihydrotestosterone and androgen receptors, as well as, proteomic deficiency of DNA packaging, nuclear proteins and homeostasis-related functional proteins. Understanding the reasons for males, rather than females the HCC prevalence may help in suggesting new approaches by improving the anti-AR therapies through co-targeting of AR and protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway.

Metastatic Prostate Cancer With Reticular Micronodular Opacities of Lung: A Case Report.

Prostate cancer, a common malignancy in males, can metastasize to various sites such as the bone, brain, liver, and less commonly, the lung. Detecting pulmonary metastases presents both diagnostic and therapeutic difficulties. Identifying patients with this condition is crucial for gaining a deeper comprehension of the disease's pathogenesis. In this report, we describe the case of a 64-year-old African American male who exhibited elevated prostate antigen levels and was found to have unique reticular Micronodular opacities in the lungs caused by prostate cancer.

Association between preconception anti-androgen therapy and pregnancy outcomes of patients with PCOS: A prospective cohort study.

Background: Polycystic ovary syndrome (PCOS) not only increases fertility challenges for women of reproductive age, but also leads to increased complications during pregnancy and even affects the birth weight of newborns. Also, hyperandrogenemia is associated with lower pregnancy rates and lower live birth rates and may even play a role in preterm delivery and pre-eclampsia in patients with PCOS. However, it is still controversial whether PCOS patients are treated with androgen-lowering therapy before pregnancy. Objective: To assess the effect of anti-androgen therapy prior to ovulation induction on maternal and infant pregnancy outcomes in patients with PCOS. Methods: Prospective cohort study. Results: A total of 296 patients with PCOS were enrolled in the study. The prevalence of adverse pregnancy outcomes, and neonatal complications was lower in DRSP(with drospirenone ethinyl estradiol tablets (II) pretreatment) group than in NO-DRSP(without drospirenone ethinyl estradiol tablets (II) pretreatment) groups (DRSP vs. NO-DRSP: adverse pregnancy outcomes, 12.16% vs. 27.03%, P=0.001; neonatal complications, 17.16% vs. 36.67%, P<0.001). No significant difference was found in maternal complications. Further subgroup analysis revealed that PCOS with pretreatment decreased the risk of preterm delivery (2.99% vs. 10.00%; Adjusted RR, 3.80; 95% CI, 1.19-12.13), pregnancy loss (9.46% vs. 18.92%; Adjusted RR, 2.07; 95% CI, 1.08-3.96), low birth weight (0.75% vs 7.50%; Adjusted RR, 12.08; 95% CI, 1.50-97.31), fetal malformations(1.49% vs. 8.33%; Adjusted RR, 5.63; 95% CI, 1.20-26.33).There were no significant differences in the incidence of DM and PIH as pregnancy complications between the two groups (P>0.05). Conclusion: Our findings suggest that preconception androgen-lowering therapy in patients with PCOS improves pregnancy outcomes and reduces neonatal complications.

Metastatic Prostate Cancer to the Optic Canal: A Large-Cohort Analysis.

Prostate cancer (PCa) can present with metastases in rare cases, including those to the optic canal. Currently, no guidelines exist for managing PCa metastases in this patient population. This article aims to examine optic canal metastases through a large-cohort analysis. It involves a systematic review of the literature through a pooled analysis of published cases of PCa with optic canal or orbital metastasis, including one case previously reported from our institution. A subgroup analysis was employed to compare cases with optic metastases as their initial PCa presentation, hormone-naive (HN), versus those with optic metastases after PCa diagnosis, hormone-refractory (HR).  A total of 45 patients with ocular metastasis from PCa were included in this study. The mean age at diagnosis overall was 66.8 years (range: 45-85 years). Moreover, 16 cases (50%) had deceased, with a median time-to-death of 22 (range: 2-84) months. Regarding subgroup analysis, the mean age at diagnosis was 69.5 years (53-85 years) in the HN group and 64.5 years (45-83 years) in the HR group. With regard to reported survival, 10 (62.5%) cases belonged to the HN subset with a median follow-up duration of 12 (range: 1.5-36) months. In terms of reported mortality, 10 (62.5%) were from the HR subset with a median time-to-death of 32.5 (range 0.5-84) months. Our study constitutes the largest and most comprehensive examination of patients with optic canal metastases due to PCa so far. While optic canal metastases are a rare manifestation of PCa, they are linked with a poor prognosis. We also observed significant differences between HR and HN cohorts, which may indicate a difference in clinical presentations.

Anti-Androgenic Therapies Targeting the Luminal Androgen Receptor of a Typical Triple-Negative Breast Cancer.

Triple-negative tumors are progressively delineating their existence over the extended spectrum of breast cancers, marked by intricate molecular heterogeneity, a low overall survival rate, and an unexplored therapeutic approach. Although the basal subtype transcends the group and contributes approximately 80% to triple-negative breast cancer (TNBC) cases, the exceptionally appearing mesenchymal and luminal androgen receptor (LAR) subtypes portray an unfathomable clinical course. LAR with a distinct generic profile frequently metastasizes to regional lymph nodes and bones. This subtype is minimally affected by chemotherapy and shows the lowest pathologic complete response. The androgen receptor is the only sex steroid receptor that plays a cardinal role in the progression of breast cancers and is typically overexpressed in LAR. The partial AR antagonist bicalutamide and the next-generation AR inhibitor enzalutamide are being assessed in standard protocols for the mitigation of TNBC. There arises an inevitable need to probe into the strategies that could neutralize these androgen receptors and alleviate the trajectory of concerning cancer. This paper thus focuses on reviewing literature that provides insights into the anti-androgenic elements against LAR typical TNBC that could pave the way for clinical advancements in this dynamic sphere of oncology.

The Combined Efficacy of a Two-Year Period of Cybernic Treatment With a Wearable Cyborg Hybrid-Assistive Limb and Leuprorelin Therapy in a Patient With Spinal and Bulbar Muscular Atrophy: A Case Report.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a rare, slowly progressive, incurable, and hereditary neurodegenerative disease caused by the testosterone-dependent accumulation of pathogenic polyglutamine-expanded androgen receptor protein. After extensive review, two treatments for SBMA have recently been approved in Japan; this decision was based on the results of randomized controlled trials: First, anti-androgen therapy using leuprorelin acetate (leuprorelin), a disease-modifying drug that can inhibit the progression of dysphagia but has not yet been proved to improve gait function; second, cybernic treatment with a wearable cyborg hybrid assistive limb (HAL®) (Cyberdyne Inc. Tsukuba, Japan). The HAL is an innovative walking exercise system that has been shown to significantly improve gait function in eight neuromuscular diseases without reduction in muscle function, including SBMA. It is possible that the combination of these two approaches might yield better outcomes. However, the long-term effects of such a combined approach have yet to be clinically evaluated. Here, we describe the case of a 39-year-old male with SBMA who commenced anti-androgen therapy with leuprorelin 1 year previously; this was followed by cybernic treatment with HAL. The duration of walking exercise with HAL was 20-30 min a day in one session. Over 2 weeks, the patient underwent nine sessions (one course). The efficacy of HAL was evaluated by gait function tests before and after one course of cybernic treatment. Then, leuprorelin treatment was combined with cybernic sessions every 2 months for 2 years (13 courses in total). Walking ability, as evaluated by the 2-min walk test, improved by 20.3% in the first course and peaked 10 months after the commencement of combined therapy (a 59.0% improvement). Walking function was maintained throughout the period. Generally, SBMA is characterized by moderately increased serum levels of creatine kinase (CK), reflecting neuromuscular damage; interestingly, the patient's CK levels decreased dramatically with combined therapy, indicating remarkable functional improvement. Long-term combined therapy improved the patient's gait function with a steady reduction in CK levels. The combination of leuprorelin with cybernic treatment can, therefore, improve and maintain gait function without damaging the motor unit and may also suppress disease progression.

Cardiovascular Effects of Androgen Deprivation Therapy in Prostate Cancer Patients: A Systematic Review.

The purpose of this study was to investigate the relationship between androgen deprivation therapy (ADT) and cardiovascular events in men with prostate cancer. Cardiovascular disease (CVD) is a primary cause of noncancer mortality in men with prostate cancer. Surveillance, Epidemiology, and End Results (SEER) Medicare-linked data revealed that CVD was responsible for about a quarter of deaths among men with prostate cancer, with a focus on the role of ADT as a contributing cause. We performed a literature search in November 2021 utilizing search engines such as PubMed, Scopus, Science Direct, and Google Scholar. Original publications with data published between 2006 and 2020 were used in the investigation of men with prostate cancer undergoing ADT treatment with a CVD outcome. Two reviewers independently examined the content of the studies and extracted data from the final papers after they had been validated for quality using quality assessment tools. A total of 14 observational studies and two randomized controlled trials are included in this systematic review. Sample sizes in the examined publications varied from 79 to 201,797 individuals. ADT was the intervention in all of the investigations. Seven of the included studies did not identify the type of ADT utilized; instead, they compared the outcomes of individuals who got ADT against those who did not. The specific type of ADT used is mentioned in the remaining nine studies included in the systematic review. Patients who got ADT, such as gonadotropin-releasing hormone (GnRH) agonists, combination androgen blockade, surgical castration, and oral anti-androgen, are compared to those who did not receive ADT to discover who had a better prognosis. In conclusion, even though ADT has several negative metabolic side effects that increase the risk of cardiovascular toxicity, published research utilizing a variety of designs has demonstrated inconsistency in the impact of ADT on cardiovascular outcomes. While the risk of CVD should be considered when prescribing ADT, the findings suggest that it should not be considered a contraindication if the expected benefit is substantial.

SWATH-MS Based Proteomic Profiling of Prostate Cancer Cells Reveals Adaptive Molecular Mechanisms in Response to Anti-Androgen Therapy.

Prostate cancer (PCa) is the second most common cancer affecting men worldwide. PCa shows a broad-spectrum heterogeneity in its biological and clinical behavior. Although androgen targeted therapy (ATT) has been the mainstay therapy for advanced PCa, it inevitably leads to treatment resistance and progression to castration resistant PCa (CRPC). Thus, greater understanding of the molecular basis of treatment resistance and CRPC progression is needed to improve treatments for this lethal phenotype. The current study interrogated both proteomics and transcriptomic alterations stimulated in AR antagonist/anti-androgen (Bicalutamide and Enzalutamide) treated androgen-dependent cell model (LNCaP) in comparison with androgen-independent/castration-resistant cell model (C4-2B). The analysis highlighted the activation of MYC and PSF/SFPQ oncogenic upstream regulators in response to the anti-androgen treatment. Moreover, the study revealed anti-androgen induced genes/proteins related to transcription/translation regulation, energy metabolism, cell communication and signaling cascades promoting tumor growth and proliferation. In addition, these molecules were found dysregulated in PCa clinical proteomic and transcriptomic datasets, suggesting their potential involvement in PCa progression. In conclusion, our study provides key molecular signatures and associated pathways that might contribute to CRPC progression despite treatment with anti-androgens. Such molecular signatures could be potential therapeutic targets to improve the efficacy of existing therapies and/or predictive/prognostic value in CRPC for treatment response.

The Use of High-Intensity Focused Ultrasound (HIFU) Plus 150mg Bicalutamide as First Line Salvage Therapy for Local Recurrent Prostate Cancer.

Patients with localized prostate cancer (PCa) are often treated with radical prostatectomy (RP). However, more than 30% of such patients have high risk of recurrence. Salvage radiotherapy (SRT), androgen deprivation therapy (ADT) and combination of radiotherapy and ADT are the standard care for recurrent PCa. Recently, high intensity focused ultrasound (HIFU) has gradually applied in the treatment of recurrent PCa. Here, we proposed a hypothesis that combined HIFU and bicalutamide 150mg as first line salvage therapy to treat patients with local recurrent PCa with visible lesions due to the following advantages: (1) HIFU is effective in reducing local tumor load, and bicalutamide 150mg is a feasible and safety option to combine with HIFU. (2) Compared with radiotherapy, HIFU plus 150mg bicalutamide is minimal invasiveness with fewer adverse effects and better quality of life(QOL); (3) Radiotherapy can be preserved as the second-line salvage method in the cases who are failure to HIFU and 150mg bicalutamide combination. More clinical trials are warranted to confirm this hypothesis in treatment with recurrent PCa.

Proxalutamide Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blinded Placebo-Controlled Trial.

Antiandrogens have demonstrated a protective effect for COVOD-19 patients in observational and interventional studies. The goal of this study was to determine if proxalutamide, an androgen receptor antagonist, could be an effective treatment for men with COVID-19 in an outpatient setting. A randomized, double-blinded, placebo-controlled clinical trial was conducted at two outpatient centers (Brasilia, Brazil). Patients were recruited from October 21 to December 24, 2020 (clinicaltrials.gov number, NCT04446429). Male patients with confirmed COVID-19 but not requiring hospitalization (COVID-19 8-point ordinal scale <3) were administered proxalutamide 200 mg/day or placebo for up to 7 days. The primary endpoint was hospitalization rate at 30 days post-randomization. A total of 268 men were randomized in a 1:1 ratio. 134 patients receiving proxalutamide and 134 receiving placebo were included in the intention-to-treat analysis. The 30-day hospitalization rate was 2.2% in men taking proxalutamide compared to 26% in placebo, P < 0.001. The 30-day hospitalization risk ratio was 0.09; 95% confidence interval (CI) 0.03-0.27. Patients in the proxalutamide arm more frequently reported gastrointestinal adverse events, however, no patient discontinued treatment. In placebo group, 6 patients were lost during follow-up, and 2 patients died from acute respiratory distress syndrome. Here we demonstrate the hospitalization rate in proxalutamide treated men was reduced by 91% compared to usual care.

Proxalutamide Significantly Accelerates Viral Clearance and Reduces Time to Clinical Remission in Patients with Mild to Moderate COVID-19: Results from a Randomized, Double-Blinded, Placebo-Controlled Trial.

Background The entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into type II pneumocytes is dependent on a modification of viral spike proteins by transmembrane protease serine 2 (TMPRSS2) expressed on the surface of human cells. TMPRSS2 is regulated by the androgen receptor, hence, SARS-CoV-2 infectivity is indirectly dependent on androgenic status and phenotype. Previously, we have reported that men affected by androgenetic alopecia (AGA) are overrepresented in severe coronavirus disease 2019 (COVID-19). Additionally, we have reported that men taking antiandrogenic drugs, e.g., 5-alpha-reductase inhibitors (5ARis), are less likely to have severe COVID-19. Here we aimed to test whether the androgen receptor antagonist, Proxalutamide, would be a beneficial treatment for subjects with SARS-CoV-2 infection. Methods Male and female subjects were recruited to a double-blinded, randomized, prospective, investigational study of Proxalutamide for the treatment of COVID-19. Mild to moderate, non-hospitalized subjects, who were confirmed positive for SARS-CoV-2, were treated with either Proxalutamide 200 mg/day or placebo. Endpoints for the study were remission time (days) and the percentage of subjects confirmed negative for SARS-CoV-2 on Day 7 after treatment. A negative SARS-CoV-2 test was defined by concentration-time (Ct)>40 determined by real-time reverse transcription-polymerase chain reaction (rtPCR). Results Two-hundred thirty-six (2360 subjects were included in the study (108 female, 128 male); 171 were randomized to the Proxalutamide arm and 65 were in the placebo group. On Day 7, SARS-CoV-2 became non-detectable with rtPCR (cT>40) in 82% of the subjects in the Proxalutamide group versus 31% in the placebo group (p < 0.001). The average clinical remission time for patients treated with Proxalutamide was 4.2 ±5.4 days versus 21.8 ±13.0 days in the placebo arm (p < 0.001). Conclusion Proxalutamide significantly accelerated viral clearance on Day 7 in mild to moderate COVID-19 patients versus placebo. Further, the time to clinical remission was significantly reduced in patients treated with Proxalutamide versus placebo.

Androgen Receptor Signaling and the Emergence of Lethal Neuroendocrine Prostate Cancer With the Treatment-Induced Suppression of the Androgen Receptor: A Literature Review.

Androgen receptor signaling primarily influences both the normal growth and proliferation of the prostate gland and the development of prostatic carcinoma. While localized prostate cancers are typically managed with definitive therapies like surgery and radiotherapy, many patients have recurrences in the form of metastatic disease. Androgen deprivation therapy, by way of castration via orchiectomy or with drugs like luteinizing hormone-releasing hormone (commonly called gonadotropin-releasing hormone) agonists and luteinizing hormone-releasing hormone antagonists, is the primary mode of therapy for advanced castration-sensitive prostate cancer. Castration resistance invariably develops in these patients. Further treatment has shifted to newer anti-androgen drugs like enzalutamide or abiraterone and taxane-based chemotherapy. Prolonged inhibition of the androgen receptor signaling pathway causes androgen receptor-independent clonal evolution which leads to the development of treatment-emergent neuroendocrine prostate cancer. All prostate cancers at the initial presentation should undergo evaluation for the markers of neuroendocrine differentiation. Detection of serum biomarkers of neuroendocrine differentiation and circulating tumor cells is a prospective non-invasive method of detecting neuroendocrine transdifferentiation in patients undergoing treatment with androgen receptor pathway inhibitors. It is essential to perform a biopsy in the presence of red flags of neuroendocrine differentiation. Alisertib, an Aurora kinase inhibitor, showed promising clinical benefit in a subgroup of patients with certain molecular alterations. A thorough understanding of the molecular and clinical programming of treatment-emergent neuroendocrine prostate cancer can potentially lead to the development of drugs to prevent the development of this lethal variant of prostate cancer.

Acute liver failure and liver transplantation secondary to flutamide treatment in a prostate cancer patient.

Flutamide is a first-generation nonsteroidal antiandrogen, used for treatment of advanced prostate cancer (PCa). We present the clinical case of a patient with localized high-risk PCa who started flutamide before radical prostatectomy and evolved with acute liver failure and liver transplantation. Hepatotoxicity induced by antiandrogen therapy, and current indications for first generation anti-androgen therapy were reviewed. To our knowledge, this is the first report of a man diagnosed with PCa who evolved with acute liver failure secondary to flutamide, and finally required liver transplantation.