Prospective assessment of AR splice variant and multi-biomarker expression on circulating tumor cells of mCRPC patients undergoing androgen receptor targeted agents: interim analysis of PRIMERA trial (NCT04188275).

Circulating tumor cells detection and ARV7 expression are associated with worse clinical outcomes in metastatic Castration-Resistant Prostate Cancer (mCRPC) undergoing Androgen Receptor Targeted Agents. ARFL, PSMA and PSA may help to refine prognostic models. In our institution, a prospective observational trial testing CTC detection in mCPRC undergoing I line ARTA therapy terminated the planned enrollment in 2020. Here, we present a pre-planned interim analysis with 18 months of median follow-up. RT-qPCR was used to determine the CTC expression of PSA, PSMA, AR and ARV7 before starting ARTA. PSA-drop, Progression-Free and Overall Survival (PFS and OS) and their correlation with CTC detection were reported. Forty-four patients were included. CTC were detected in 43.2% of patients, of whom 8.94% expressed PSA, 15.78% showed ARV7, 63.15% and 73.68% displayed ARFL and PSMA, respectively. Biochemical response was significantly improved in CTC + vs CTC- patients, with median PSA-drop of 18.5 vs 2.5 ng/ml (p = 0.03). After a median follow-up of 18 months, 50% of patients progressed. PFS was significantly longer in CTC- patients (NR vs 16 months). Eight (18.2%) patients died, a non-significant trend in terms of OS was detected in favor of CTC- patients (NR vs 29 months, p = 0.05). AR, PSA and PSMA expression in CTC + had no significant impact on PSA-drop, PFS or OS. PRIMERA-trial confirmed the CTC detection predictive importance in mCRPC patients.

Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer.

PURPOSE: Therapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR-targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance in CSPC remains understudied. EXPERIMENTAL DESIGN: We assessed different approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines, patient-derived xenograft (PDX) models, publicly available cohorts, and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein and its association with clinical outcome. RESULTS: In CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increased sensitivity and specificity for AR-V7 protein detection by immunohistochemistry (IHC) in CRPC cohorts but rarely identified AR-V7 protein reactivity in CSPC cohorts, when compared with the EPR15656 AR-V7 antibody. Using multiple CRPC PDX models, we demonstrated that AR-V7 expression was exquisitely sensitive to hormonal manipulation. In CSPC institutional cohorts, AR-V7 protein quantification by either assay was associated neither with time to development of castration resistance nor with overall survival, and intense neoadjuvant androgen-deprivation therapy did not lead to significant AR-V7 mRNA or staining following treatment. Neither pre- nor posttreatment AR-V7 levels were associated with volumes of residual disease after therapy. CONCLUSIONS: This study demonstrates that further analytical validation and clinical qualification are required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker.

In silico and in vitro assessment of androgen receptor antagonists.

There is a growing concern for male reproductive health as studies suggest that there is a sharp increase in prostate cancer and other fertility related problems. Apart from lifestyle, pollutants are also known to negatively affect the reproductive system. In addition to many other compounds that have been shown to alter androgen signaling, several environmental pollutants are known to disrupt androgen signaling via binding to androgen receptor (AR) or indirectly affecting the androgen synthesis. We analyzed here the molecular mechanism of the interaction between the human AR Ligand Binding Domain (hAR-LBD) and two environmental pollutants, linuron (a herbicide) and procymidone (a pesticide), and compared with the steroid agonist dihydrotestosterone (DHT) and well-known hAR antagonists bicalutamide and enzalutamide. Using molecular docking and dynamics simulations, we showed that the co-activator interaction site of the hAR-LBD is disrupted in different ways by different ligands. Binding free energies of the ligands were also ordered in increasing order as follows: linuron, procymidone, DHT, bicalutamide, and enzalutamide. These data were confirmed by in vitro assays. Reporter assay with MDA-kb2 cells showed that linuron, procymidone, bicalutamide and enzalutamide can inhibit androgen mediated activation of luciferase activity. Gene expression analysis further showed that these compounds can inhibit the expression of prostate specific antigen (PSA) and microseminoprotein beta (MSMB) in prostate cell line LNCaP. Comparative analysis showed that procymidone is more potent than linuron in inhibiting AR activity. Furthermore, procymidone at 10 µM dose showed equivalent and higher activity to AR inhibitor enzalutamide and bicalutamide respectively.

Next generation risk assessment of human exposure to anti-androgens using newly defined comparator compound values.

Next Generation Risk Assessment (NGRA) can use the so-called Dietary Comparator Ratio (DCR) to evaluate the safety of a defined exposure to a compound of interest. The DCR compares the Exposure Activity Ratio (EAR) for the compound of interest, to the EAR of an established safe level of human exposure to a comparator compound with the same putative mode of action. A DCR ≤ 1 indicates the exposure evaluated is safe. The present study aimed at defining adequate and safe comparator compound exposures for evaluation of anti-androgenic effects, using 3,3-diindolylmethane (DIM), from cruciferous vegetables, and the anti-androgenic drug bicalutamide (BIC). EAR values for these comparator compounds were defined using the AR-CALUX assay. The adequacy of the new comparator EAR values was evaluated using PBK modelling and by comparing the generated DCRs of a series of test compound exposures to actual knowledge on their safety regarding in vivo anti-androgenicity. Results obtained supported the use of AR-CALUX-based comparator EARs for DCR-based NGRA for putative anti-androgenic compounds. This further validates the DCR approach as an animal free in silico/in vitro 3R compliant method in NGRA.

Cyclic depsipeptide mycotoxin exposure may cause human endocrine disruption: Evidence from OECD in vitro stably transfected transcriptional activation assays.

The presence of cyclic depsipeptide mycotoxins in foods and feedstuffs could potentially cause endocrine disrupting effects on humans and wildlife by their inhibition of active steroidogenesis. Therefore, we attempted to assess the human estrogen receptor (ER) and androgen receptor (AR) agonistic/antagonistic effects of representative cyclic depsipeptide mycotoxins, enniatin A1 (ENN A1), and enniatin B1 (ENN B1), by OECD Performand Based Test Guideline (PBTG) No.455, VM7Luc ER transcriptional activation (TA) assay and OECD TG No. 458, 22Rv1/MMTV_GR-KO AR TA assay. No tested cyclic depsipeptide mycotoxins were found to be ER and AR agonists in VM7Luc ER TA and 22Rv1/MMTV_GR-KO AR TA assays. On the other hand, ENN A1, and ENN B1 exhibited the ER and AR antagonistic effects with IC30 and IC50 values in both TA assays. These two cyclic depsipeptide mycotoxins, which were determined as ER and AR antagonists by two in vitro assays, bound to ERα, and AR. Then ENN A1, and ENN B1 inhibited the dimerization of ERα, and AR. These results, for the first time indicated that ENN A1, and ENN B1 could have potential endocrine disrupting effects mediated by interaction of ERα and AR using international standard testing methods to determine the potential endocrine disrupting chemical.

Urological implications of SARS CoV-19.

INTRODUCTION: The novel coronavirus disease 2019 (COVID-19), pandemic has afflicted > 3.3 million people around the world since December 2019. Though, more than 1000 publications have appeared in scientific journals addressing a plethora of questions, there is a considerable hiatus in understanding of the behavior and natural history of the virus and its impact on urology. Also, a modified approach is the need of hour in taking care of patients as urologists should safeguard their teams, families, and patients. MATERIAL AND METHODS: The authors have used guidelines from USA, Canada, UK, Europe and India for making recommendations to help urologist define their own policies that may have to be fine-tuned on the basis of continued and evolving challenges they would encounter and the local resources at their disposal. RESULTS: COVID-19 do effect genitourinary system from kidney to testis. The authors provide scientific basis to urologists to help identify patients by remote consultation who are likely to be harmed by coming to the hospital, and not to miss those who need hospitalization for diagnostic or therapeutic interventions. There is uncompromised need of specific precautions during surgery to safe guard the surgeon and his team along with the patient. CONCLUSIONS: Urological operations during COVID-19 pandemic should be limited to emergency cases during the acute phase with an exit strategy planned in a staggered manner, based on the scientific risk stratification. Telemedicine (e-clinics or virtual clinics) would help achieve the goal of risk stratification.

An interim internal Threshold of Toxicologic Concern (iTTC) for chemicals in consumer products, with support from an automated assessment of ToxCast™ dose response data.

Additional non-animal methods are urgently needed to meet regulatory and animal welfare goals. TTC is a broadly used risk assessment tool. TTC based on external dose has limited utility for multi-route exposure and some types of structure activity relationship assessments. An internal TTC (iTTC), where thresholds are based on blood concentration, would extend the applicability of TTC. While work is on-going to develop robust iTTC thresholds, we propose an interim conservative iTTC. Specifically, an interim iTTC of 1 µM, supported by the published experience of the pharmaceutical industry, a literature review of non-drug chemical/receptor interactions, and analysis of ToxCast™ data. ToxCast™ data were used to explore activity versus the 1 µM interim iTTC and recommendations for the analysis and interpretation of HTS data. Test concentration-based points of departure were classified to identify quality of fit to the Hill Model. We identified, for exclusion from the approach, estrogen receptor and androgen receptor targets as potent chemical/receptor interactions potentially associated with low dose exposure to non-pharmaceutical active ingredients in addition to the original TTC exclusions. With these exclusions, we conclude that a 1 µM plasma concentration is unlikely to be associated with significant biological effects from chemicals not intentionally designed for biological activity.

Use of in vitro bioassays to facilitate read-across assessment of nitrogen substituted heterocycle analogues of polycyclic aromatic hydrocarbons.

Nitrogen-containing polycyclic aromatic hydrocarbons (PANHs or azaarenes) are compounds structurally similar to PAHs (carbon substituted by a nitrogen) reported to occur at low levels in food. Although limited, literature may suggest possible higher toxicity than for PAHs. Using a battery of in vitro assays, the toxicological properties of uncharacterized PANHs of increasing ring number were compared to those of characterized structural PAH analogues. The parameters measured covered key events relevant to the AOP developed for Benzo(a)pyrene: AhR activation, mutagenicity and DNA-damage with and without metabolic activation and endocrine receptors activation/inhibition. There was a strong correlation between the chemical structure and the biological activities of the compounds. AhR activation was the most sensitive parameter with a direct correlation between potency and ring number. The most potent genotoxic chemicals were found amongst the ones with the highest number of ring, and under metabolic activation. Such an approach allowed designing sub-groups based on biological properties in addition to structural similarities. Within a sub-group, toxicological data of tested chemicals may be used to characterize hazard of biologically similar but toxicologically uncharacterized substances. This indicates that in addition to structural properties, in vitro biological data may be useful to conduct read-across.

Comparative assessment of prognostic outcomes between first-generation antiandrogens and novel androgen-receptor-axis-targeted agents in patients with non-metastatic castration-resistant prostate cancer.

BACKGROUND: To compare the prognostic outcomes between first-generation antiandrogen (FGA) and novel androgen-receptor-axis-targeted agent (ARATA) as first-line therapy in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). METHODS: This study retrospectively included a total of 103 consecutive nmCRPC patients consisting of 47 (45.6%) and 56 (54.4%) who received FGA (bicalutamide or flutamide) and ARATA (abiraterone acetate or enzalutamide), respectively, as the first-line agent after the failure of primary androgen deprivation therapy (ADT). RESULTS: There were no significant differences in the major clinicopathological parameters and previous therapeutic histories between the FGA and ARATA groups. During the observation period, 31 (66.0%) and 29 (51.8%) discontinued first-line therapy in the FGA and ARATA groups, respectively, and of these, 27 (87.1%) and 23 (79.3%) in the FGA and ARATA groups, respectively, were subsequently treated with approved agents as second-line therapy. The prostate-specific antigen (PSA) response rate in the FGA group was significantly lower than that in the ARATA group. Although no significant difference in overall survival was noted between the FGA and ARATA groups, there were significant differences in the PSA progression-free survival on first-line therapy and metastasis-free survival between the two groups, favoring the ARATA group compared with FGA group. CONCLUSIONS: Collectively, these findings suggest that among nmCRPC patients who progressed following treatment with the primary ADT, the introduction of ARATA may result in the delay of disease progression compared with FGA.

Assessment of agonistic and antagonistic properties of widely used oral care antimicrobial substances toward steroid estrogenic and androgenic receptors.

Personal care product consumption has increased in the last decades. A typical representative ingredient, i.e., triclosan, was identified in the scientific literature as an endocrine disruptor, and its use is restricted in several applications. Oral hygiene formulations contain various compounds, including synthetic phenol derivatives, quaternary ammonium compounds (QACs), various amides and amines, or natural essential oils containing terpenes. The aim of this paper was to explore possible endocrine-disrupting effects of these most-used compounds. For this purpose, two different assays based on recombinant yeast (BMAEREluc/ERα; BMAEREluc/AR) and human cell lines (T47D; AIZ-AR) were employed to investigate the agonistic and antagonistic properties of these compounds on human estrogen and androgen receptors. The results showed that none of the compounds were indicated as agonists of the steroid receptors. However, octenidine (OCT, QAC-like) and hexadecylpyridinium (HDP, QAC) were able to completely inhibit both androgenic (IC50 OCT = 0.84 µM; IC50 HDP = 1.66 µM) and estrogenic (IC50 OCT = 0.50 µM; IC50 HDP = 1.64 µM) signaling pathways in a dose-dependent manner. Additionally, chlorhexidine was found to inhibit the 17ß-estradiol response, with a similar IC50 (2.9 µM). In contrast, the natural terpenes thymol and menthol were found to be competitive antagonists of the receptors; however, their IC50 values were higher (by orders of magnitude). We tried to estimate the risk associated with the presence of these compounds in environmental matrices by calculating hazard quotients (HQs), and the calculated HQs were found to be close to or greater than 1 only when predicted environmental concentrations were used for surface waters.

Assessment of morphological changes and steroid receptors in the uteri of postmenopausal women.

INTRODUCTION: The morphology of the endometrium constantly changes in the reproductive period, depending on the levels of ovarian steroid hormones, and undergoes atrophic changes during menopause as a result of their insufficiency. The purpose of this study was to analyze morphological and morphometric changes in the mucous and muscle layers of the uterine wall in postmenopausal women, and to assess localization and number of cells showing the expression of steroid hormone receptors, namely estrogen receptor α (ER-α), progesterone receptor (PR), and androgen receptor (AR) in glandular epithelial cells and smooth muscle cells in particular groups of women. MATERIAL AND METHODS: The study material consisted of uterine specimens sectioned across the full thickness of the uterine wall, and embedded in 164 paraffin blocks. The specimens came from women without menopausal hormone therapy (MHT) operated due to reproductive organ prolapse or uterine myomas. The material was divided into four groups depending on the time interval from menopause to surgery: group I - from 1 to 5 years after menopause, group II - from 6 to 10 years after menopause, group III - more than 11 years after menopause, and group IV - women over 70 years of age. The sections were stained by standard HE, Masson's trichrome, and immunohistochemical methods (ERα, PR, AR). Quantitative assessment of the results was based on computer image analysis. RESULTS: Analysis of morphological changes in the endometrium and myometrium revealed the presence of increasing regressive changes, such as various types of atrophy, fibrosis, and calcification, augmented over time from the last menstruation. Furthermore, endometrial polyps, foci of endometriosis, and leiomyomas were observed. Based on the results of morphometric measurements, a constant decrease in the endometrial and myometrial thickness was noticed in the studied groups (I-IV). Significant differences between the groups were observed in the number of ER-α positive cells in the myometrium, but not in the endometrial glandular epithelium. Statistically significant differences in the number of AR positive cells were detected in the endometrial epithelium and in the uterine muscle. The analysis the number of PR positive cells demonstrated differences between the groups in the endometrial stroma and the myometrium. CONCLUSION: The uterus of postmenopausal woman undergo major morphological changes (mainly atrophic lesions in the endometrium and myometrium), leading to a decline in their morphometric parameters over time from the last menstruation. Localization and number of cells showing the expression of steroid receptors: ER-α, PR, and AR in the uterus of postmenopausal women, depending on the time interval from the last menstruation.

In vitro-to-in vivo extrapolation (IVIVE) by PBTK modeling for animal-free risk assessment approaches of potential endocrine-disrupting compounds.

While in vitro testing is used to identify hazards of chemicals, nominal in vitro assay concentrations may misrepresent potential in vivo effects and do not provide dose-response data which can be used for a risk assessment. We used reverse dosimetry to compare in vitro effect concentrations-to-in vivo doses causing toxic effects related to endocrine disruption. Ten compounds (acetaminophen, bisphenol A, caffeine, 17α-ethinylestradiol, fenarimol, flutamide, genistein, ketoconazole, methyltestosterone, and trenbolone) have been tested in the yeast estrogen screening (YES) or yeast androgen-screening (YAS) assays for estrogen and androgen receptor binding, as well as the H295R assay (OECD test guideline no. 456) for potential interaction with steroidogenesis. With the assumption of comparable concentration-response ratios of these effects in the applied in vitro systems and the in vivo environment, the lowest observed effect concentrations from these assays were extrapolated to oral doses (LOELs) by reverse dosimetry. For extrapolation, an eight-compartment Physiologically Based Toxicokinetic (PBTK) rat model based on in vitro and in silico input data was used. The predicted LOEL was then compared to the LOEL actually observed in corresponding in vivo studies (YES/YAS assay versus uterotrophic or Hershberger assay and steroidogenesis assay versus pubertal assay or generation studies). This evaluation resulted in 6 out of 10 compounds for which the predicted LOELs were in the same order of magnitude as the actual in vivo LOELs. For four compounds, the predicted LOELs differed by more than tenfold from the actual in vivo LOELs. In conclusion, these data demonstrate the applicability of reverse dosimetry using a simple PBTK model to serve in vitro-in silico-based risk assessment, but also identified cases and test substance were the applied methods are insufficient.

Assessment of endocrine disruption potential of essential oils of culinary herbs and spices involving glucocorticoid, androgen and vitamin D receptors.

Essential oils (EOs) of culinary herbs and spices are consumed on a daily basis. They are multicomponent mixtures of compounds with already demonstrated biological activities. Taking into account regular dietary intake and the chemical composition of EOs, they may be considered as candidates for endocrine-disrupting entities. Therefore, we examined the effects of 31 EOs of culinary herbs and spices on transcriptional activities of glucocorticoid receptor (GR), androgen receptor (AR) and vitamin D receptor (VDR). Using reporter gene assays in stably transfected cell lines, weak anti-androgen and anti-glucocorticoid activity was observed for EO of vanilla and nutmeg, respectively. Moderate augmentation of calcitriol-dependent VDR activity was caused by EOs of ginger, thyme, coriander and lemongrass. Mixed anti-glucocorticoid and VDR-stimulatory activities were displayed by EOs of turmeric, oregano, dill, caraway, verveine and spearmint. The remaining 19 EOs were inactive against all receptors under investigation. Analyses of GR, AR and VDR target genes by means of RT-PCR confirmed the VDR-stimulatory effects, but could not confirm the anti-glucocorticoid and anti-androgen effects of EOs. In conclusion, although we observed minor effects of several EOs on transcriptional activities of GR, AR and VDR, the toxicological significance of these effects is very low. Hence, 31 EOs of culinary herbs and spices may be considered safe, in terms of endocrine disruption involving receptors GR, AR and VDR.

Assessment of the analgesic dipyrone as a possible (anti)androgenic endocrine disruptor.

Mild analgesics have been associated with antiandrogenic effects, but there are no such studies on dipyrone, despite its high prevalence of use in many countries. We examined the production of steroid hormones in human H295R cells after exposure to dipyrone and two metabolites, 4-Methylaminoantipyrine (MAA) and 4-Aminoantipyrine (AA), as well as fetal testicular testosterone production in rats following maternal dipyrone exposure. Androgen agonistic/antagonistic effects were examined in vitro for dipyrone and its metabolites in the Yeast Androgen Screen (YAS) assay and in vivo for dipyrone through the Hershberger assay. In vitro we tested dipyrone, MAA, and AA (0.1-1000 µM) while in vivo we used dipyrone (50, 100, 200 mg/kg/day). In the H295R assay, dipyrone, MAA and AA reduced the production of androgens and corticosteroids. Testosterone was reduced at concentrations 4-13 times higher than the maximum plasma concentrations reported in humans for MAA and AA. No effects were observed in the fetal testosterone production assay. In the YAS and Hershberger assays, no androgen agonistic/antagonistic activities were observed. These results indicate that dipyrone and its metabolites do not interact with the androgen receptor, but have the potential to inhibit steroidogenesis, however only at concentrations that are not relevant under normal medical use.

Impact of prior androgen receptor-axis-targeted agents on the clinical activity of subsequent docetaxel in patients with metastatic castration-resistant prostate cancer: comparative assessment between abiraterone acetate and enzalutamide.

The objective of this study was to investigate the impact of prior treatment with androgen receptor-axis-targeted (ARAT) agents, abiraterone acetate (AA) and enzalutamide (Enz), on the activity of subsequently introduced docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). This study included a total of 114 mCRPC patients consisting of 54 and 60 who progressed following treatment with AA and Enz, respectively, prior to the introduction of docetaxel, and compared oncological outcomes with docetaxel between these two groups. There were no significant differences in the major clinicopathological characteristics before treatment with docetaxel between the AA and Enz groups. The prostate-specific antigen (PSA) response rates to docetaxel in the AA and Enz groups were 40.7 and 43.3%, respectively, with no significant differences in the rates between these two groups. Following the introduction of docetaxel, the median PSA progression-free survival (PFS) and overall survival (OS) in the 114 patients were 7.2 and 17.5 months, respectively. There was no significant difference in the PSA PFS or OS between the AA and Enz groups. Despite the lack of a significant impact of the type of ARAT agent on PSA PFS or OS by univariate analysis, multivariate analyses identified the following independent prognostic predictors: performance status (PS) for PSA PFS and PS and visceral metastasis for OS. Collectively, these findings suggest that the type of ARAT agent may not have a significant impact on disease control by subsequent docetaxel therapy in mCRPC patients.

Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease.

Sex differences between women and men are often overlooked and underappreciated when studying the cardiovascular system. It has been long assumed that men and women are physiologically similar, and this notion has resulted in women being clinically evaluated and treated for cardiovascular pathophysiological complications as men. Currently, there is increased recognition of fundamental sex differences in cardiovascular function, anatomy, cell signaling, and pathophysiology. The National Institutes of Health have enacted guidelines expressly to gain knowledge about ways the sexes differ in both normal function and diseases at the various research levels (molecular, cellular, tissue, and organ system). Greater understanding of these sex differences will be used to steer future directions in the biomedical sciences and translational and clinical research. This review describes sex-based differences in the physiology and pathophysiology of the vasculature, with a special emphasis on sex steroid receptor (estrogen and androgen receptor) signaling and their potential impact on vascular function in health and diseases (e.g., atherosclerosis, hypertension, peripheral artery disease, abdominal aortic aneurysms, cerebral aneurysms, and stroke).

Comparative Assessment of Efficacies Between 2 Alternative Therapeutic Sequences With Novel Androgen Receptor-Axis-Targeted Agents in Patients With Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: The objective of this study was to compare the efficacies of sequential therapies with novel androgen receptor-axis-targeted (ARAT) agents in patients with docetaxel-naïve metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This study included 108 consecutive patients with mCRPC who sequentially received abiraterone acetate (AA) and enzalutamide (Enz), in either order, without prior treatment with docetaxel. The combined prostate-specific antigen (PSA) progression-free survival (PFS) was defined as the sum of PFS1 and PFS2, representing PSA PFSs on the first and second ARAT agents, respectively. RESULTS: Of these patients, 49 and 59 received ARAT therapy with the AA-to-Enz sequence (AA-to-Enz group) and with the reverse sequence (Enz-to-AA group), respectively. No significant differences in the baseline characteristics were noted between the 2 groups. In the overall patient population, the PSA response rate to the second-line ARAT agent (21.3%) was significantly lower than that of the first-line ARAT agent (58.3%). The combined PSA PFS in the AA-to-Enz group (median, 18.4 months) was significantly superior to that of the Enz-to-AA group (median, 12.8 months). Furthermore, multivariate analysis identified the treatment sequence (ie, AA-to-Enz vs. Enz-to-AA group) in addition to performance status as an independent predictor of combined PSA PFS in these patients. However, there was no significant difference in overall survival (OS) between the 2 groups. CONCLUSIONS: Although cross-resistance between ARAT agents is a common phenomenon in docetaxel-naïve patients with mCRPC, different efficacies were observed favoring the AA-to-Enz rather than Enz-to-AA sequence in this series with respect to combined PSA PFS but not OS.

Molecular basis for prostate cancer racial disparities.

Prostate cancer (PCa) remains the most common cancer in American men. African-American (AA) men continue to have higher PCa prevalence and mortality rates compared to men in other populations. In addition to socioeconomic factors and lifestyle differences, molecular alterations contribute to this discrepancy. We summarize molecular genetics research results interrelated with the biology of PCa racial disparity. Androgen and androgen receptor (AR) pathways have long been associated with prostate growth. Racial differences have also been found among variants of genes of the enzymes involved in androgen biosynthesis and metabolism. Growth factors and their receptors are a potential cause of the disparity in PCa. Recent molecular and biotechnological approaches in the field of proteomics and genomics will greatly aid the advancement of translational research on racial disparity in PCa, which may help, in finding new prognostic markers and novel therapeutic approaches for the treatment of PCa in AA.

Precision medicine for advanced prostate cancer.

PURPOSE OF REVIEW: Precision cancer medicine, the use of genomic profiling of patient tumors at the point-of-care to inform treatment decisions, is rapidly changing treatment strategies across cancer types. Precision medicine for advanced prostate cancer may identify new treatment strategies and change clinical practice. In this review, we discuss the potential and challenges of precision medicine in advanced prostate cancer. RECENT FINDINGS: Although primary prostate cancers do not harbor highly recurrent targetable genomic alterations, recent reports on the genomics of metastatic castration-resistant prostate cancer has shown multiple targetable alterations in castration-resistant prostate cancer metastatic biopsies. Therapeutic implications include targeting prevalent DNA repair pathway alterations with PARP-1 inhibition in genomically defined subsets of patients, among other genomically stratified targets. In addition, multiple recent efforts have demonstrated the promise of liquid tumor profiling (e.g., profiling circulating tumor cells or cell-free tumor DNA) and highlighted the necessary steps to scale these approaches in prostate cancer. SUMMARY: Although still in the initial phase of precision medicine for prostate cancer, there is extraordinary potential for clinical impact. Efforts to overcome current scientific and clinical barriers will enable widespread use of precision medicine approaches for advanced prostate cancer patients.