Pembrolizumab with or without enzalutamide in selected populations of men with previously untreated metastatic castration-resistant prostate cancer harbouring programmed cell death ligand-1 staining: a retrospective study.

BACKGROUND: The purpose of this retrospective study was to evaluate the survival outcomes of pembrolizumab (PEM) plus enzalutamide (ENZ) versus PEM alone in selected populations of men with previously untreated metastatic castration-resistant prostate cancer (mCRPC) harbouring programmed cell death ligand-1 (PD-L1) staining. METHODS: Consecutive men with previously untreated mCRPC harbouring PD-L1 staining who underwent treatment with PEM plus ENZ (PE) or PEM alone (PA) at our medical centre from January 1, 2017, to January 31, 2021, were retrospectively identified. Follow-up was conducted monthly during the first year and then every 1 month thereafter. The primary outcomes of the study were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were the frequency of key adverse events (AEs). RESULTS: In total, 302 men were retrospectively reviewed, 96 of whom were deemed to be ineligible per the exclusion criteria, leaving 206 men (PE: n = 100, median age 64 years [range, 43-85] and PA: n = 106, 65 years [range, 45-82]) who were eligible for the study. The median follow-up for both groups was 34 months (range, 2-42). At the final follow-up, the median OS was 25.1 months (95% confidence interval [CI], 22.3-27.6) in the PE group versus 18.3 months (95% CI, 16.5-20.9) in the PA group (hazard ratio [HR] 0.56; 95% CI, 0.39-0.80; p = 0.001). A marked distinction was also observed in the median PFS (6.1 months [95% CI, 4.7-7.8] for PE vs. 4.9 months for PA (95% CI, 3.2-6.4) for PA; HR 0.55, 95% CI, 0.41-0.75; p = 0.001). There were noteworthy differences in the rate of the key AEs between the two groups (72.0% for PE vs. 45.3% for PA, p < 0.001). Noteworthy differences were also detected for fatigue events (7.0% in the PE group vs. 0.9% in the PA group, p = 0.025) and musculoskeletal events (9.0% for PE vs. 0.9% for PA, p = 0.007), but these events tended to be manageable. CONCLUSIONS: Among selected populations of men with previously untreated mCRPC harbouring PD-L1 staining, PEM added to ENZ treatment may significantly increase the survival benefits compared with PEM treatment alone regardless of tumor mutation status. The safety profile for PE plus ENZ tends to be manageable.

COVIDENZA - A prospective, multicenter, randomized PHASE II clinical trial of enzalutamide treatment to decrease the morbidity in patients with Corona virus disease 2019 (COVID-19): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The main goal of the COVIDENZA trial is to evaluate if inhibition of testosterone signalling by enzalutamide can improve the outcome of patients hospitalised for COVID-19. The hypothesis is based on the observation that the majority of patients in need of intensive care are male, and the connection between androgen receptor signalling and expression of TMPRSS2, an enzyme important for SARS-CoV-2 host cell internalization. TRIAL DESIGN: Hospitalised COVID-19 patients will be randomised (2:1) to enzalutamide plus standard of care vs. standard of care designed to identify superiority. PARTICIPANTS: Included participants, men or women above 50 years of age, must be hospitalised for PCR confirmed COVID-19 symptoms and not in need of immediate mechanical ventilation. Major exclusion criteria are breast-feeding or pregnant women, hormonal treatment for prostate or breast cancer, treatment with immunosuppressive drugs, current symptomatic unstable cardiovascular disease (see Additional file 1 for further details). The trial is registered at Umeå University Hospital, Region Västerbotten, Sweden and 8 hospitals are approved for inclusion in Sweden. INTERVENTION AND COMPARATOR: Patients randomised to the treatment arm will be treated orally with 160 mg (4x40 mg) enzalutamide (Xtandi®) daily, for five consecutive days. The study is not placebo controlled. The comparator is standard of care treatment for patients hospitalised with COVID-19. MAIN OUTCOMES: The primary endpoints of the study are (time to) need of mechanical ventilation or discharge from hospital as assessed by a clinical 7-point ordinal scale (up to 30 days after inclusion). RANDOMISATION: Randomisation was stratified by center and sex. Each strata was randomized separately with block size six with a 2:1 allocation ratio (enzalutamide + "standard of care": "standard of care"). The randomisation list, with consecutive subject numbers, was generated by an independent statistician using the PROC PLAN procedure of SAS version 9.4 software (SAS Institute, Inc, Cary, North Carolina) BLINDING (MASKING): This is an open-label trial. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The trial is designed to have three phases. The first, an exploration phase of 45 participants (30 treatment and 15 control) will focus on safety and includes a more extensive laboratory assessment as well as more frequent safety evaluation. The second prolongation phase, includes the first 100 participants followed by an interim analysis to define the power of the study. The third phase is the continuation of the study up to maximum 600 participants included in total. TRIAL STATUS: The current protocol version is COVIDENZA v2.0 as of September 10, 2020. Recruitment started July 29, 2020 and is presently in safety pause after the first exploration phase. Recruitment is anticipated to be complete by 31 December 2021. TRIAL REGISTRATION: Eudract number 2020-002027-10 ClinicalTrials.gov Identifier: NCT04475601 , registered June 8, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

A noncanonical AR addiction drives enzalutamide resistance in prostate cancer.

Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.

Upregulation of glucocorticoid receptor-mediated glucose transporter 4 in enzalutamide-resistant prostate cancer.

Enzalutamide (Enz) is a second-generation androgen receptor (AR) antagonist for castration-resistant prostate cancer (CRPC) therapy, and it prolongs survival time in these patients. However, during Enz treatment, CRPC patients usually acquire resistance to Enz and often show cross-resistance to other AR signaling inhibitors. Although glucocorticoid receptor (GR) is involved in this resistance, the role of GR has not yet been clarified. Here, we report that chronic Enz treatment induced GR-mediated glucose transporter 4 (GLUT4) upregulation, and that upregulation was associated with resistance to Enz and other AR signaling inhibitors. Additionally, inhibition of GLUT4 suppressed cell proliferation in Enz-resistant prostate cancer cells, which recovered from Enz resistance and cross-resistance without changes in GR expression. Thus, a combination of Enz and a GLUT4 inhibitor could be useful in Enz-resistant CRPC patients.

Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and Ad-ACE2-transduced mice. Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids. Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 regulatory locus in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.

Clinical Efficacy of Enzalutamide vs Bicalutamide Combined With Androgen Deprivation Therapy in Men With Metastatic Hormone-Sensitive Prostate Cancer: A Randomized Clinical Trial.

Importance: Black patients have been underrepresented in prospective clinical trials of advanced prostate cancer. This study evaluated the efficacy of enzalutamide compared with bicalutamide, with planned subset analysis of Black patients with metastatic hormone-sensitive prostate cancer (mHSPC), which is a disease state responsive to androgen deprivation therapy (ADT). Objective: To compare the efficacy of enzalutamide vs bicalutamide in combination with ADT in men with mHSPC, with a subset analysis of Black patients. Design, Setting, and Participants: In this randomized clinical trial, a phase 2 screening design enabled a nondefinitive comparison of the primary outcome by treatment. Patients were stratified by race (Black or other) and bone pain (present or absent). Accrual of at least 30% Black patients was required. This multicenter trial was conducted at 4 centers in the US. Men with mHSPC with no history of seizures and adequate marrow, renal, and liver function were eligible. Data analysis was performed from February 2019 to March 2020. Interventions: Participants were randomized 1:1 to receive oral enzalutamide (160 mg daily) or bicalutamide (50 mg daily) in addition to ADT. Main Outcomes and Measures: The primary end point was the 7-month prostate-specific antigen (PSA) response (SMPR) rate, a previously accepted surrogate for overall survival (OS) outcome. Secondary end points included adverse reactions, time to PSA progression, and OS. Results: A total of 71 men (median [range] age, 65 [51-86] years) were enrolled; 29 (41%) were Black, 41 (58%) were White, and 1 (1%) was Asian. Thirty-six patients were randomized to receive enzalutamide, and 35 were randomized to receive bicalutamide. Twenty-six patients (37%) had bone pain and 37 patients (52%) had extensive disease. SMPR was achieved in 30 of 32 patients (94%; 95% CI, 80%-98%) taking enzalutamide and 17 of 26 patients (65%; 95% CI, 46%-81%) taking bicalutamide (P = .008) (difference, 29%; 95% CI, 5%-50%). Among Black patients, the SMPR was 93% (95% CI, 69%-99%) among those taking enzalutamide and 42% (95% CI, 19%-68%) among those taking bicalutamide (P = .009); among non-Black patients, the SMPR was 94% (95% CI, 74%-99%) among those taking enzalutamide and 86% (95% CI, 60%-96%) among those taking bicalutamide. The 12-month PSA response rates were 84% with enzalutamide and 34% with bicalutamide. Conclusions and Relevance: The findings of this randomized clinical trial comparing enzalutamide with bicalutamide suggest that enzalutamide is associated with improved outcomes compared with bicalutamide, in terms of the rate and duration of PSA response, in Black patients with mHSPC. Trial Registration: ClinicalTrials.gov Identifier: NCT02058706.

Optimal treatment sequencing of abiraterone acetate plus prednisone and enzalutamide in patients with castration-resistant metastatic prostate cancer: A systematic review and meta-analysis.

PURPOSE: To evaluate the impact of the hormonal treatment sequencing including abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) in mCRPC, and determine which sequence provides more benefits for patients. METHODS: Studies published in English between 1 January 2013 and 30 September 2017 were identified in PubMed and EMBASE electronic databases. Studies assessing the efficacy of treatment sequences, based on AAP and ENZ, in mCRPC patients, were eligible for analysis. RESULTS: Seventeen studies met the inclusion criteria. Two assessed both treatment sequences AAP â†’ ENZ and ENZ â†’ AAP; it was found that sequence of AAP â†’ ENZ showed a statistically significantly longer PSA-PFS than the observed in ENZ â†’ AAP (pooled HR: 0,54; 95% CI; 0,36-0,82; p < 0,05). The nine studies analysing Doc â†’ AAP â†’ ENZ sequence, revealed favourable results in terms of PFS. The 5 studies which analysed AAP â†’ ENZ sequence, show a decrease in PSA levels ≥ 50% in 11-41% of patients treated with enzalutamide after previous treatment with AAP. In the two studies that analysed the Doc â†’ ENZ â†’ AAP sequence, PSA response rates were much lower than those reported with Doc â†’ AAP â†’ ENZ, with decreases in PSA ≥ 30 of 3-18% and PSA ≥ 50 of 8-11%. CONCLUSION: Significant clinical efficacy of AAP administered as the first-line treatment in mCRPC patients followed by enzalutamide, delaying disease progression, compared with the ENZ â†’ AAP sequence. However, more studies and randomized trials are needed, to validate the best treatment sequencing.

Inhibition of Androgen Receptor Signaling Promotes Prostate Cancer Cell Migration via Upregulation of Annexin A1 Expression.

BACKGROUND: Recent studies indicate that androgen deprivation therapy (ADT), the main therapeutic approach for metastatic prostate cancer (PCa), accelerates PCa invasion and metastasis. Annexin A1 (ANXA1) is a Ca2+-regulated phospholipid-binding protein that can promote PCa migration and invasion. AIM OF THE STUDY: The aim of this study is to determine whether ANXA1 is regulated by ADT and participates in PCa progression after ADT, and to explore the possible mechanism of ANXA1-mediated PCa migration. METHODS: Expression of ANXA1 and androgen receptor (AR) in PCa cell lines and tissues was detected, and the association between these two proteins were analyzed. Expression of ANXA1 was evaluated after AR knockdown or AR inhibition in PCa cell lines. Cell migration of PCa cell liness after ANXA1 knockdown or overexpression was determined by in vitro migration assay. Transcriptome analysis was used to explore the possible mechanism of ANXA1-mediated PCa migration. RESULTS: ANXA1 expression in PCa cell lines and tissues was reversely associated with AR. In vitro studies revealed an increase in ANXA1 expression after AR knockdown or treatment with AR antagonist. Moreover, functional assays indicated that ANXA1 knockdown in PCa cells significantly inhibited cell migration, while ANXA1 overexpression in PCa cells significantly accelerated cell migration. Transcriptome analysis showed that ANXA1 regulated multiple genes involved in cell junction organization, such as CADM1, LIMCH1 and PPM1F. CONCLUSIONS: Our results indicate that ADT might accelerate PCa metastasis via ANXA1 expression and PCa cell migration.

Comprehensive analysis of serum chromogranin A and neuron-specific enolase levels in localized and castration-resistant prostate cancer.

OBJECTIVES: To assess chromogranin A (CGA) and neuron-specific enolase (NSE) levels and changes in these at different stages of prostatic adenocarcinoma (PCA). METHODS: Overall, 1095 serum samples from 395 patients, divided into three treatment groups, were analysed; the radical prostatectomy (RP) cohort (n = 157) included patients with clinically localized PCA, while the docetaxel (DOC) and the abiraterone (ABI)/enzalutamide (ENZA) cohorts included 95 and 143 patients, respectively, with metastatic castration-resistant prostate cancer. CGA, NSE and total PSA levels were measured using the KRYPTOR method. RESULTS: Baseline CGA and NSE levels were higher in castration-resistant (DOC and ABI/ENZA cohorts) than in hormone-naïve, clinically localized PCA (P < 0.001). High baseline CGA levels were independently associated with poor overall survival in both the DOC and the ABI/ENZA cohorts, with a stronger association in the ABI/ENZA cohort. In the ABI/ENZA cohort, a > 50% CGA increase at 3 months was associated with poor survival, especially in patients with high baseline CGA levels. CONCLUSIONS: The two- to threefold higher neuroendocrine marker levels in castration-resistant compared to hormone-naïve PCA support the presence of neuroendocrine transdifferentiation under androgen deprivation therapy. Our results showed patients with high baseline CGA levels who experienced a further CGA increase during ABI and ENZA treatment had the poorest prognosis. Serum CGA levels could help in tailoring and monitoring therapy in advanced PCA.

Androgen receptor signaling-targeted therapy and taxane chemotherapy induce visceral metastasis in castration-resistant prostate cancer.

BACKGROUND: Visceral metastasis (VM), an important poor prognostic factor of prostate cancer (PC), is not commonly observed in castration sensitive status but is often observed after castration-resistant progression. However, the site, timing of emergence, and incidence of VM in castration-resistant patients have not yet been fully elucidated. METHODS: Demographic, surgical, pathological, and follow-up data of PC patients treated at Kanazawa University Hospital between January 2000 and December 2016 were retrospectively analyzed using their medical charts. From this data, risk factors of VM and survival of patients with VM were elucidated. RESULTS: Of 1364 patients, 21 (1.5%) had VM at diagnosis. Of 179 (13.1%) castration-resistant patients, 55 experienced emergence of new VM during treatment course. Incidence of new VM, especially nonlung, such as liver and adrenal metastases, increased significantly in proportion with the number of prescribed treatments. Multivariate analysis revealed that T stage, M stage, age, and treatment history with androgen receptor (AR) signaling-targeted agents and/or taxanes significantly increased the risk of VM. Compared with the group with VM at diagnosis, survival after diagnosis of VM following treatment was significantly shorter. CONCLUSION: Although sequential use of new AR signaling-targeted agents and taxanes for castration-resistant PC (CRPC) is a standard treatment strategy, it often results in development of VM. Elucidating the mechanisms of VM are essential to improve survival in patients with CRPC.

Overall Survival Among Chemotherapy-Naive Patients With Castration-Resistant Prostate Cancer Under Abiraterone Versus Enzalutamide: A Direct Comparison Based on a 2014-2018 French Population Study (the SPEAR Cohort).

Abiraterone acetate (ABI) and enzalutamide (ENZ) are considered to be clinically relevant comparators among chemotherapy-naive patients with castration-resistant prostate cancer. No clinical trials comparing overall survival with ABI versus ENZ in a head-to-head approach have been published so far. A few observational studies with low power suggested a potential benefit of ENZ. We used the French National Health Data System to compare overall survival of new users of ABI and ENZ among chemotherapy-naive patients with castration-resistant prostate cancer in 2014-2017, followed through 2018 (the SPEAR cohort, a 2014-2018 cohort study). With an intent-to-treat approach, a survival analysis was performed, estimating hazard ratios for overall survival with the inverse probability weighted Cox model method. Among 10,308 new users, 64% were treated with ABI and 36% with ENZ. The crude mortality rate was 25.2 per 100 person-years (95% confidence interval (CI): 24.4, 26.0) for ABI and 23.7 per 100 person-years (95% CI: 22.6, 24.9) for ENZ. In the weighted analysis, ENZ was associated with better overall survival compared with ABI (hazard ratio = 0.90 (95% CI: 0.85, 0.96) with a median overall survival of 31.7 months for ABI and 34.2 months for ENZ). When restricting to 2015-2017 new users, the effect estimate shifted up to a hazard ratio of 0.93 (95% CI: 0.86, 1.01).

Comparing the clinical efficacy and safety of abiraterone and enzalutamide in metastatic castration-resistant prostate cancer: A systematic review and meta-analysis.

BACKGROUND: Two new drugs, abiraterone and enzalutamide, had recently shown beneficial effects on survival in patients with metastatic castration-resistant prostate cancer. We systematically reviewed the efficacy and safety of abiraterone and enzalutamide in metastatic castration-resistant prostate cancer in real-world practice. METHODS: A search from PubMed, Web of Science, Cochrane, Embase was conducted up to 6 March 2019. Available articles from conferences were searched. The endpoint was prostate-specific antigen response, overall survival, progression-free survival, number of patients with any adverse event. RESULTS: Fourteen cohort studies involving 3469 participants were included. Pooled result showed that prostate-specific antigen response was higher for patients receiving enzalutamide than abiraterone (790 patients, odds ratio (OR) 0.47, 95% confidence interval (CI) 0.29-0.77, P = 0.003, I2=59%). Enzalutamide was significantly associated with increased adverse events rate in comparison with abiraterone (730 patients, OR 0.35, 95%CI 0.13-0.92, P = 0.03, I2=65%). There was no statistical difference between abiraterone and enzalutamide with respect to perceived cognitive impairments (1856 patients, OR 0.90, 95%CI 0.29-2.76, P = 0.85, I2=5%). Enzalutamide was significantly associated with increased fatigue risk in comparison with abiraterone (2477 patients, OR 0.46, 95%CI 0.34-0.63, P＜0.00001, I2=0%). CONCLUSIONS: Our results demonstrated that enzalutamide was more efficacious than abiraterone for patients with metastatic castration-resistant prostate cancer, but was associated with a significantly elevated risk of side effects, particularly fatigue.

PROACTA: a survey on the actual attitude of the Italian radiation oncologists in the management and prescription of hormonal therapy in prostate cancer patients.

AIM: To investigate the actual attitude of Radiation Oncologists in the prescription of hormonal therapy in prostate cancer (PC) with or without Radiation Therapy (RT). MATERIALS AND METHODS: In 2019, a survey named Prescription of Radiation Oncologists ACtual Attitude including 18 items was sent to all Italian Radiation Oncologists of the Italian Association of Radiotherapy and Clinical Oncology. The first 4 items were about the Radiation Oncology Centers characteristics and years of practice of the respondents. The remaining 14 items concerned the setting in which hormone therapy was prescribed in PC patients (radical, postprostatectomy/oligometastatic state), the kind of drug, the choice modality (Multidisciplinary Group/autonomy decision) and other factors. RESULTS: A total of 127 questionnaires were returned, mainly by Northern Italy Radiation Oncology Centres (44.9%), and by experienced Radiation Oncologists (78%), who declared to prescribe independently hormone therapy in 85.8% of cases. The Androgen deprivation therapy (ADT) prescription in castration naive PC was made independently by 56.7% of respondents and associated with radical RT, postoperative or salvage RT according to various risk factors. In castration-sensitive oligorecurrent PC, the majority (51.2%) administered ADT only if local ablative treatment was not feasible, while in metastatic castration resistant disease novel hormone therapy use was established in almost half of cases within multidisciplinary board. Radiation Oncologists could prescribe these drugs independently in 64% of cases. CONCLUSION: Our survey established the prescription attitude of ADT and new hormonal agents (abiraterone, enzalutamide, apalutamide) by Italian Radiation Oncologists and highlighted the importance of expertise in global PC management.

Functional characterization of androgen receptor in two patient-derived xenograft models of triple negative breast cancer.

Extensive efforts, through cell line-based models, have been made to characterize the androgen receptor (AR) signaling pathway in triple-negative breast cancer (TNBC). However, these efforts have not yet reached a consensus with regards to the mechanism of AR in TNBC. Considering that patient-derived xenografts (PDXs) are more appropriate than cell line-based models for recapitulating the structural and molecular features of a patient's tumor, we have identified and molecularly characterized two new AR-positive TNBC PDX models and assessed the impacts of AR agonist [dihydrotestosterone (DHT)] and antagonist (enzalutamide) on tumor growth and gene expression profiles by utilizing immunohistochemistry, western blots, and RNA-Seq analyses. Two PDX models, termed TN1 and TN2, were derived from two grade-3 TNBC tumors, each harboring 1∼5% of AR nuclear positive cancer cells. DHT activated AR in both PDX tumors by increasing nuclear localization and AR protein levels. However, the endpoint tumor volume of DHT-treated TN1 was 3-folds smaller than that of non-treated TN1 tumors. Conversely, the endpoint tumor volume of DHT-treated TN2 was 2-folds larger than that of non-treated TN2. Moreover, enzalutamide failed to antagonize DHT-induced tumor growth in TN2. The RNA-Seq analyses revealed that DHT mainly suppressed gene expression in TN1 (961 down-regulated genes versus 149 up-regulated genes), while DHT promoted gene expression in TN2 (673 up-regulated genes versus 192 down-regulated genes). RNA-Seq data predicted distinct TNBC molecular subtypes for TN1 and TN2. TN1 correlated to a basal-like 1 (BL1) subtype, and TN2 correlated to a basal-like 2 (BL2) subtype. These analyses suggest that TN1 and TN2, which both express functional AR, are two molecularly distinct PDX models. The molecular characterization of these PDX models expands our current knowledge on AR-positive TNBC. Our results do not support that AR is a suitable therapeutic target in TNBC. To our best knowledge, the molecular mechanisms of AR in TNBC are equivocal and should be evaluated using clinically relevant models, considering both the heterogeneous expression of AR in TNBC and the general complexities of AR signaling.

An up-to-date evaluation of darolutamide for the treatment of prostate cancer.

Introduction: Currently, in prostate cancer, an increasing number of novel drugs are being used to delay its advancement to metastatic castration-resistant prostate cancer (mCRPC). Apalutamide, enzalutamide, and most recently, darolutamide (novel androgen receptor antagonists) have been approved for nonmetastatic castration-resistant prostate cancer (nmCRPC).Areas covered: The authors have evaluated darolutamide, covering all aspects of the clinical development, competence, and safety profile of the drug.Expert opinion: The unique structure of darolutamide is characterized by a high affinity for androgen receptors and detainment of antagonist activity in mutant isoforms of androgen receptors. In clinical practice, this is the main reason that makes darolutamide exceptional in terms of safety and efficacy compared to other drugs in this category. Darolutamide is considered to have the lowest probability for adverse events (AEs) compared to apalutamide and enzalutamide. Future studies, along with real-world clinical data are warranted to improve personalized treatment strategies as well as sequencing treatment between approved novel drugs.

Enzalutamide response in a panel of prostate cancer cell lines reveals a role for glucocorticoid receptor in enzalutamide resistant disease.

Representative in vitro model systems that accurately model response to therapy and allow the identification of new targets are important for improving our treatment of prostate cancer. Here we describe molecular characterization and drug testing in a panel of 20 prostate cancer cell lines. The cell lines cluster into distinct subsets based on RNA expression, which is largely driven by functional Androgen Receptor (AR) expression. KLK3, the AR-responsive gene that encodes prostate specific antigen, shows the greatest variability in expression across the cell line panel. Other common prostate cancer associated genes such as TMPRSS2 and ERG show similar expression patterns. Copy number analysis demonstrates that many of the most commonly gained (including regions containing TERC and MYC) and lost regions (including regions containing TP53 and PTEN) that were identified in patient samples by the TCGA are mirrored in the prostate cancer cell lines. Assessment of response to the anti-androgen enzalutamide shows a distinct separation of responders and non-responders, predominantly related to status of wild-type AR. Surprisingly, several AR-null lines responded to enzalutamide. These AR-null, enzalutamide-responsive cells were characterized by high levels of expression of glucocorticoid receptor (GR) encoded by NR3C1. Treatment of these cells with the anti-GR agent mifepristone showed that they were more sensitive to this drug than enzalutamide, as were several of the enzalutamide non-responsive lines. This is consistent with several recent reports that suggest that GR expression is an alternative signaling mechanism that can bypass AR blockade. This study reinforces the utility of large cell line panels for the study of cancer and identifies several cell lines that represent ideal models to study AR-null cells that have upregulated GR to sustain growth.

Observational study on time on treatment with abiraterone and enzalutamide.

INTRODUCTION: The aim of this study was to assess time on treatment with abiraterone and enzalutamide, two androgen receptor targeted (ART) drugs, the impact on time on treatment of time interval without drug supply between prescription fillings, and adherence to treatment. MATERIAL AND METHODS: By use of data from The National Prostate Cancer Register, The Prescribed Drug Registry and the Patient Registry, time on treatment with the abiraterone and enzalutamide was analyzed in all men with castration resistant prostate cancer (CRPC) in Sweden 2015-2019. Three time intervals between consecutive fillings, i.e. time without drug supply, were assessed. Adherence to the treatment was evaluated by use of the Medication Possession Ratio. Kaplan Meier analysis and multivariable Cox regression model were used to assess factors affecting time on treatment. RESULTS: Between January 2015 and October 2019, 1803 men filled a prescription for abiraterone and 4 534 men filled a prescription for enzalutamide. With a time interval of 30 days or less between two fillings, median time on treatment was 4.9 months (IQR 2.6-11.7) for abiraterone and 8.0 months (IQR 3.6-16.4) for enzalutamide. In sensitivity analyses, allowing for no more than 14 days without drug supply between fillings, median time on treatment was 3.9 months (IQR 2.1-9.0) for abiraterone and 5.9 months (IQR 2.8-12.1) for enzalutamide. Allowing for any time period without drug between fillings, median time on treatment was 5.7 months (IQR 2.7-14.0) for abiraterone and 9.8 months (IQR 4.4-21.0) for enzalutamide. Adherence to treatment was above 90% for both drugs. CONCLUSION: Time on treatment with abiraterone and enzalutamide was shorter in clinical practice than in randomized controlled trials and varied almost two-fold with time interval without drug. Adherence to treatment was high. The main limitation of our study was the lack of data on use of chemotherapy.

Chronic IL-1 exposure drives LNCaP cells to evolve androgen and AR independence.

Chronic inflammation promotes prostate cancer (PCa) initiation and progression. We previously reported that acute intereluekin-1 (IL-1) exposure represses androgen receptor (AR) accumulation and activity, providing a possible mechanism for IL-1-mediated development of androgen- and AR-independent PCa. Given that acute inflammation is quickly resolved, and chronic inflammation is, instead, co-opted by cancer cells to promote tumorigenicity, we set out to determine if chronic IL-1 exposure leads to similar repression of AR and AR activity observed for acute IL-1 exposure and to determine if chronic IL-1 exposure selects for androgen- and AR-independent PCa cells. We generated isogenic sublines from LNCaP cells chronically exposed to IL-1α or IL-1ß. Cells were treated with IL-1α, IL-1ß, TNFα or HS-5 bone marrow stromal cells conditioned medium to assess cell viability in the presence of cytotoxic inflammatory cytokines. Cell viability was also assessed following serum starvation, AR siRNA silencing and enzalutamide treatment. Finally, RNA sequencing was performed for the IL-1 sublines. MTT, RT-qPCR and western blot analysis show that the sublines evolved resistance to inflammation-induced cytotoxicity and intracellular signaling and evolved reduced sensitivity to siRNA-mediated loss of AR, serum deprivation and enzalutamide. Differential gene expression reveals that canonical AR signaling is aberrant in the IL-1 sublines, where the cells show constitutive PSA repression and basally high KLK2 and NKX3.1 mRNA levels and bioinformatics analysis predicts that pro-survival and pro-tumorigenic pathways are activated in the sublines. Our data provide evidence that chronic IL-1 exposure promotes PCa cell androgen and AR independence and, thus, supports CRPCa development.