Second-generation Androgen Receptor Antagonist Research Articles

A phase I/II study of enzalutamide in combination with indomethacin in men with castration-resistant prostate cancer (CRPC).

e17027 Background: Metastatic castration resistant prostate cancer (mCRPC) remains an incurable disease despite recent advances in therapy. In patients (pts) receiving the second-generation androgen receptor antagonist enzalutamide (enza), primary or adaptive resistance can occur due to upregulation of the steroidogenesis pathway, including aldo-keto reductase 1C3 (AKR1C3), which can also upregulate intratumoral androgen synthesis. Indomethacin, a non-steroidal anti-inflammatory drug and selective inhibitor of AKR1C3, demonstrates synergistic activity when combined with enza against enza-resistant CRPC in vitro and in vivo. We thus sought to study this combination in a clinical trial. Methods: This investigator-initiated Phase I/II trial enrolled pts with enza-naive mCRPC on androgen deprivation therapy. Prior abiraterone was allowed. Pts must have adequate organ function and ECOG performance status 0-2. In the phase I lead-in, a 3+3 dose de-escalation design was used to identify the recommended Phase II dose (RP2D) of indomethacin in combination with enza 160 mg oral (PO) once daily, after which a Phase II expansion proceeded. Pts continued treatment until disease progression or unacceptable toxicity. Co-primary endpoints were safety and PSA response, defined as 50% or more reduction from baseline. Secondary endpoints included overall response as determined by Prostate Cancer Working Group 2 criteria (PCWG2). Results: From 2017 - 2022, 26 pts were enrolled, with a median age of 71 (range 50-88), primarily white (n=16, 62%), median baseline PSA 19.45 (range 1.5-210), ECOG 1 (n=12, 46%), and most received prior abiraterone (n=24, 92%). In 6 pts enrolled to the phase I cohort, there were no grade 3 adverse events (AEs); RP2D of indomethacin was 50mg PO twice daily. All 26 pts were evaluable for safety and efficacy. Most common treatment-related AEs (n; %) were nausea (12; 46%), fatigue (11; 42%), diarrhea (8; 31%), hypertension (7; 27%), anorexia (6; 23%). Most common ≥ grade 3 treatment-related AEs were acute kidney injury (3; 12%), hypertension (3; 12%), and anemia (2; 8%). PSA response was observed in 8 pts (31%). By PCWG2, 14 pts (54%) experienced stable disease, while 10 pts (38%) had progressive disease. Conclusions: The combination of enza and indomethacin was safe, clinically feasible, and had clinical activity in pts with abiraterone-pretreated mCRPC. Further correlative studies are needed to identify pts who may benefit from AKR1C3 inhibition. Clinical trial information: NCT02935205 .

Adverse events and costs among non-metastatic castration-resistant prostate cancer patients

Background Limited real-world evidence exists on the economic burden of adverse events (AEs) to the healthcare system among patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with second-generation androgen receptor antagonists (ARAs). Current data is needed to understand real-world clinical event rates among ARAs and the cost of these events. Objectives Describe the incidence of non-central nervous system (CNS)-related AEs and CNS-related AEs among nmCRPC patients treated in the United States with second-generation ARAs (apalutamide and enzalutamide) and evaluate healthcare resource utilization (HCRU) and costs for these patients. Methods and study design This was a retrospective observational cohort study using claims data from Optum Clinformatics Data Mart to identify adult males with prostate cancer, castration, no metastases, and >1 claim for apalutamide or enzalutamide. The study was conducted from January 2017 to March 2020, with a patient index identification period from January 2018 to December 2019. AEs were classified as CNS-related or non-CNS-related. Results Of 605 patients (156 apalutamide and 449 enzalutamide), most were ≥65 years (94%) and had ≥1 non-CNS-related AE (55%). Many had ≥1 CNS-related AE (32%). Pain (12%) and arthralgia (11%) were the most frequently reported non-CNS-related AEs. Fatigue/asthenia (14%) and dizziness (7%) were the most frequently reported CNS-related AEs. Among patients with versus without non-CNS-related AEs, 34% versus 8% had emergency room (ER) events, and 25% versus 2% had inpatient events. Among patients with versus without CNS-related AEs, 41% versus 14% had ER events, and 38% versus 4% had inpatient events. Adjusted per-patient per-year cost (in 2020 USD) differences were significant between patients with and without non-CNS-related AEs ($30,765, p = 0.0018) and between patients with and without CNS-related AEs ($40,689, p = 0.0017). Conclusion There is significant HCRU and cost burden among nmCRPC patients treated with ARAs developing AEs, highlighting the need for treatments with improved tolerability. Additional studies are warranted to include recently approved agents.

A kinome-wide CRISPR screen identifies CK1α as a target to overcome enzalutamide resistance of prostate cancer

Enzalutamide (ENZA), a second-generation androgen receptor antagonist, has significantly increased progression-free and overall survival of patients with metastatic prostate cancer (PCa). However, resistance remains a prominent obstacle in treatment. Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1α (CK1α) as a therapeutic target to overcome ENZA resistance. Depletion or pharmacologic inhibition of CK1α enhanced ENZA efficacy in ENZA-resistant cells and patient-derived xenografts. Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB signaling, and thus increases ENZA-induced cell death and growth arrest. Our study details a therapeutic approach for ENZA-resistant PCa and characterizes a particular perspective for the function of CK1α in the regulation of DNA-damage response.

A partially open conformation of an androgen receptor ligand-binding domain with drug-resistance mutations.

Mutations in the androgen receptor (AR) ligand-binding domain (LBD) can cause resistance to drugs used to treat prostate cancer. Commonly found mutations include L702H, W742C, H875Y, F877L and T878A, while the F877L mutation can convert second-generation antagonists such as enzalutamide and apalutamide into agonists. However, pruxelutamide, another second-generation AR antagonist, has no agonist activity with the F877L and F877L/T878A mutants and instead maintains its inhibitory activity against them. Here, it is shown that the quadruple mutation L702H/H875Y/F877L/T878A increases the soluble expression of AR LBD in complex with pruxelutamide in Escherichia coli. The crystal structure of the quadruple mutant in complex with the agonist dihydrotestosterone (DHT) reveals a partially open conformation of the AR LBD due to conformational changes in the loop connecting helices H11 and H12 (the H11-H12 loop) and Leu881. This partially open conformation creates a larger ligand-binding site for AR. Additional structural studies suggest that both the L702H and F877L mutations are important for conformational changes. This structural variability in the AR LBD could affect ligand binding as well as the resistance to antagonists.

Updates in the Treatment of Non-Metastatic Castrate-Resistant Prostate Cancer: The Benefit of Second-Generation Androgen Receptor Antagonists.

To review pharmacology, efficacy, safety, and considerations for use, of second-generation androgen receptor (AR) antagonists in treatment of nonmetastatic castrate-resistant prostate cancer (M0CRPC). Conducted search in PubMed and Google scholar (January, 1, 2002-December 31, 2022), using relevant terms. Relevant English-language studies, conducted in humans evaluating second-generation AR antagonists for M0CRPC, and additional articles and package inserts were considered. Apalutamide, darolutamide, and enzalutamide are effective in delaying the time to development of metastatic prostate cancer in men with M0CRPC with a rapid prostate-specific antigen (PSA) doubling time (<10 months). No head-to-head, randomized, clinical trials have been conducted. The most common adverse effects include fatigue and hypertension, and quality of life is maintained in most patients. Cost is similar among the agents (~$15,000/month). Drug-drug interactions vary among these agents and should be considered, when selecting therapy as well as likely adherence. Darolutamide is administered twice daily with the others once daily. Second-generation AR antagonists are effective in reducing time to development of metastatic disease and prolonging overall survival in patients with M0CRPC and a PSA doubling time of <10 months. Recent imaging advances may alter how we evaluate outcomes. Second-generation AR antagonists improve disease control and overall survival. Generally, they are well tolerated and QOL is maintained. Selection of the best agent is based on the adverse effect profile, potential for drug- and disease-interactions, administration, cost, and patient preference.

Transdermal square-wave testosterone therapy: A pilot trial in metastatic castration-resistant prostate cancer.

188 Background: Metastatic castration-resistant prostate cancer (mCRPC) becomes resistant to anti-androgen therapies due to a variety of adaptive mechanisms. Intramuscular bipolar androgen therapy (BAT) which alternates between high and low testosterone (T) levels is therapeutically active in mCRPC and confers sensitivity to second-generation androgen receptor antagonists such as enzalutamide (ENZA). We hypothesized that transdermal T with sustained supraphysiologic T levels would lead to high response rates to ENZA in mCRPC. We also hypothesized Square-wave transdermal T therapy would be a safe alternative to BAT due to the ability to quickly withdraw therapy in the setting of symptoms. Methods: This was an open-label, single-site, phase 2 feasibility trial in men with asymptomatic mCRPC who had not previously received ENZA. Transdermal T was administered at a dose of 100 mg/day for a minimum of 12 weeks and until disease progression. Therapy was then switched to ENZA 160 mg/day until next disease progression. Patients who initially responded to T could receive a second course of transdermal T followed by ENZA, remaining on study until progression on both T and ENZA, or for the 12-month study duration, whichever was sooner. ADT was continued throughout. The primary endpoint of the study was feasibility. T dose was adjusted to achieve T levels between 900-1500 ng/dL. Secondary end points included PSA50 response rate (50% decline in PSA) and safety. Results: Fifteen patients were enrolled. Ten (66.7%) had Gleason &gt;8 disease. Thirteen (86.7%) patients had bone metastases. Median baseline PSA was 11.73 ng/mL. Primary endpoint of feasibility based on patient recruitment and retention was met. The median testosterone level on T was 901.3 ng/dL (Range: 645.2 to 1171.1). Median time on therapy was 15.9 weeks on T and 25.9 weeks on ENZA. PSA50 was 13.3% on initial T therapy and 66.7% after switching to ENZA. Three (20%) patients did not initiate ENZA after T progression. Two desired to avoid androgen-related side effects and 1 initiated chemotherapy. No Grade 3 or higher adverse events (AEs) occurred on T and the most common AEs were weight gain, rash, and nipple sensitivity. Conclusions: Square-wave transdermal T alternating with ENZA is feasible and achieves adequate T levels in the treatment of asymptomatic mCRPC. Given the acceptable safety profile and quick reversibility, transdermal T warrants further exploration, and we have expanded enrollment to include higher risk patient populations. Clinical trial information: NCT03734653 .

Rezvilutamide: First Approval

Rezvilutamide (®) is an oral, second-generation androgen receptor antagonist being developed by Jiangsu Hengrui Medicine Co., Ltd for the treatment of prostate cancer. In June 2022, rezvilutamide was approved in China for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC) with high tumour burden. This article summarizes the milestones in the development of rezvilutamide leading to this first approval for patients with prostate cancer.

HC-1119, a deuterated Enzalutamide, inhibits Migration, Invasion and Metastasis of the AR-positive triple-negative breast Cancer cells

Triple-negative breast cancers (TNBCs) are aggressive, and they develop metastasis at earlier stages, relapse more frequently, and exhibits poorer prognosis than other subtypes of breast cancer. Due to the lack of estrogen receptor for endocrine therapy and HER2 for targeted therapy, new targeted therapies for TNBCs are urgently needed. Enzalutamide is a second-generation androgen receptor (AR) inhibitor, and HC-1119 is a new synthetic deuterated enzalutamide. Owing to the isotope effect, HC-1119 has many advantages over enzalutamide, including slow metabolism, high plasma concentration and low brain exposure. However, the efficacy of HC-1119 in inhibition of AR function in triple-negative breast cancer (TNBC) has not been studied. In this study, we found high-level AR expression in both Hs578T and SUM159PT TNBC cell lines. Activation of AR by dihydrotestosterone (DHT) in both cell lines increased AR protein, induced AR-nuclear localization, enhanced cell migration and invasion in culture, and promoted liver metastasis in mice. Importantly, cotreatment with HC-1119 of these cells efficiently abolished all of these effects of DHT on both Hs578T and SUM159PT cells. These results indicate that HC-1119 is a very effective new second-generation AR antagonist that can inhibit the migration, invasion and metastasis of the AR-positive TNBC cells.

Targeting the androgen receptor signaling pathway in advanced prostate cancer.

This article summarizes current androgen receptor (AR)-directed therapies that have received regulatory approval for the treatment of advanced prostate adenocarcinoma (herein referred to as prostate cancer, PC). PC is an androgen-dependent malignancy in which ligands including testosterone and dihydrotestosterone bind to AR, initiating androgen-AR complex translocation to the nucleus followed by AR-mediated transcription of target genes. Androgen deprivation therapy (ADT), including gonadotropin hormone-releasing hormone (GnRH) agonists with or without AR antagonists (antiandrogens), GnRH antagonists, or bilateral orchiectomy, forms the backbone of treatment for patients with metastatic castration-naive PC and/or castration-resistant PC (CRPC). ADT is also an option for high-risk, early-stage PC after prostatectomy and/or radiation. While ADT is often very effective as initial therapy, resistance ultimately develops despite suppression of gonadal and/or adrenal androgens, leading to CRPC, which is characterized by mechanisms such as reactivation of the AR signaling pathway, AR gene overexpression, and mutations in the ligand-binding domain of AR that lead to disease progression, resulting in increased symptom burden and ultimately death. However, disease in patients with CRPC is still dependent on androgen signaling, and these patients continue on ADT to maintain a castrate level of serum testosterone. Novel hormonal therapies including agents that target AR directly (eg, AR antagonists) are often added to ADT in this setting. Targeting the AR signaling pathway led to the development of second-generation AR antagonists, examples of which include enzalutamide, apalutamide, and darolutamide. These agents do not exhibit partial agonism, possess a higher affinity for AR, and are postulated to improve survival outcomes relative to their first-generation counterparts for patients with CRPC. Lastly, the emergence of ADT, including second-generation AR antagonists, has led to the development of supportive care for treatment-related adverse effects. Major advances have been made in targeting the AR signaling pathway in patients with advanced PC. Further studies are warranted to identify the optimal sequencing of therapies to maximize treatment benefit. Mitigation of treatment-related adverse effects presents new opportunities to advance clinical pharmacy practice.

Novel Strategy of Proxalutamide for the Treatment of Prostate Cancer through Coordinated Blockade of Lipogenesis and Androgen Receptor Axis.

Objective: Prostate cancer (PCa) is the most common malignant tumor diagnosed in men in developed countries. In developing countries, the PCa morbidity and mortality rates are also increasing rapidly. Since androgen receptor (AR) is a key driver and plays a critical role in the regulation of PCa development, AR-targeted agents provide a key component of current therapy regimens. However, even new-generation AR antagonists are prone to drug resistance, and there is currently no effective strategy for overcoming advanced PCa aggressiveness, including drug-resistance progression. The aim of this study was to evaluate the potential efficacy and novel therapy strategy of proxalutamide (a newly developed AR antagonist) in PCa. Methods: Four PCa cell lines with various biological heterogeneities were utilized in this study, namely, androgen-sensitive/-insensitive with/without AR expression. Proliferation, migration and apoptosis assays in PCa cells were used to evaluate the effective therapeutic activity of proxalutamide. The changes in lipid droplet accumulation and lipidomic profiles were analyzed to determine the influence of proxalutamide on lipogenesis in PCa cells. The molecular basis of the effects of proxalutamide on lipogenesis and the AR axis was then further investigated. Results: Proxalutamide significantly inhibited the proliferation and migration of PCa cells, and its inhibitory effect was superior to that of enzalutamide (Enz, second-generation AR antagonist). Proxalutamide induced the caspase-dependent apoptosis of PCa cells. Proxalutamide significantly diminished the level of lipid droplets in PCa cells, changed the lipid profile of PCa cells and reduced the content of most lipids (especially triglycerides) in PCa cells. Proxalutamide attenuated de novo lipogenesis by inhibiting the expression of ATP citrate lyase (ACL), acetyl CoA carboxylase (ACC), fatty acid synthase (FASN) and sterol regulatory element-binding protein-1 (SREBP-1). Moreover, proxalutamide also decreased AR expression in PCa cells, and its inhibitory effect on lipogenesis did not depend on its ability to down-regulate AR expression. However, Enz had no effect on AR expression, lipid accumulation or lipid de novo synthesis in PCa cells. Conclusions: By co-targeting the AR axis and endogenous adipogenesis, a novel and promising strategy was established for proxalutamide to combat the progress of PCa. The unique effect of proxalutamide on the metabolic reprogramming of PCa provides a potential solution to overcome the resistance of current AR-targeted therapy, which will help to effectively prolong its clinical service life.

Ilicicolin A Exerts Antitumor Effect in Castration-Resistant Prostate Cancer Via Suppressing EZH2 Signaling Pathway.

The Polycomb protein enhancer of zeste homolog 2 (EZH2) has critical roles in prostate cancer (PCa) progression and drug-resistance, which remains an obstacle for PCa treatment. Enzalutamide (ENZ) is a second-generation androgen receptor antagonist employed for treatment of metastatic castration-resistant prostate cancer A considerable proportion of tumors eventually develop resistance during treatment. Thus, agents that can overcome resistance to PCa are needed urgently. Ilicicolin A (Ili-A), an ascochlorin derivative isolated from the coral-derived fungus Acremonium sclerotigenum GXIMD 02501, shows antiproliferative activity in human PCa cells, but its mechanism of action against Castration-resistant prostate cancer is not known. Herein, RNA-sequencing showed the EZH2 pathway to be involved in PCa proliferation. Ili-A at low doses reduced the protein level of EZH2, leading to transcriptional change. Interestingly, Ili-A suppressed the binding of EZH2 to promoter regions in AR/serine/threonine polo-like kinase-1/aurora kinase A. Moreover, Ili-A could enhance the anticancer activity of enzalutamide in CRPC cancer models. These data suggest that Ili-A could be used in combination with enzalutamide to treat CRPC.

Abstract 276: Lupeol chemosensitize the cancer stem cells for enzalutamide and ameliorate the enzalutamide induced toxicity in prostate cancer

Abstract Introduction: Prostate cancer (CaP) is one of the most frequent malignancies amongst men throughout the world. CaP cells exhibit aberrant signaling pathways. Signaling biomolecules such as β-Catenin, c-FLIPL, and c-MYC play a very important role in CaP. Lupeol, a pentacyclic triterpene found in fruits, vegetables, other dilatory natural agents, was found possesses strong antioxidant, and anticancer properties. Enzalutamide is the second-generation androgen receptor antagonist having the strong binding affinity and has been permitted by the USFDA against CaP. Objectives: We determined (a) the mechanism-based efficacy of Lupeol (Lup-20(29)-en-3b-ol) alone or in combination with enzalutamide as a potent c-MYC, cFLIP and β-Catenin inhibitor in both in silico and in vitro studies and (b) amelioration of Enzalutamide induced toxicity by Lupeol in in vivo condition. Methods: For in silico studies, molecular docking, MD Simulation [RMSD, RMSF, SASA, Rg, number of H-bonds, PCA and Columbic and Lennard-Jones]. For in vitro studies, normal prostate cell (PNT2), 22Rν1, C4-2b and Du145 cells were used. We considered CD133+/CD44+ positive cells are Cancer Stem Cells (CSCs). The cells were treated with either Lupeol (10-50 μM), or enzalutamide (1.0-10 μM), or combination. The treated cells were tested for cell growth, rate of proliferation, Scratch assay, dye exclusion assay, and luciferase-based reporter assay. Animal studies were done on Swiss albino mice. Animals were treated either lupeol/enzalutamide alone or in combination for 48 h. Next, biochemical assays such as GST, GPx, CAT, SOD activities and MDA levels were examined. We also examined the amelioration of genotoxicity by lupeol induced by enzalutamide. Results: Lupeol is found to dock with -7.1, -6.6, and -7.3 as well as enzalutamide was found to dock with -6.8, -6.0, -7.5 against β-Catenin, c-FLIPL, and c-MYC, respectively. Furthermore, there are good number of hydrogen and hydrophobic interactions between the ligands and proteins. MD simulation data shows further information on interactions between ligands and proteins. This in silico study were verify through in vitro assay performed on CaP cells. Lupeol significantly inhibits the growth of CSCs sparing normal cells and chemosensitize the CSCs for enzalutamide. Lupeol alone or in combination with enzalutamide also significantly inhibit the wound healing of CSCs. Finally, lupeol significantly ameliorates the toxicity caused by FDA approved drug enzalutamide as evident from genotoxicity assay (Chromosome aberration assay &amp; MNT) and Biochemical assays. Conclusion: We suggest that lupeol alone or as an adjuvant to current therapies could be developed as an agent to chemosensitize the therapy resistant cells as well as to ameliorate the enzalutamide induced toxicity. Citation Format: Hifzur R. Siddique, Santosh K. Maurya. Lupeol chemosensitize the cancer stem cells for enzalutamide and ameliorate the enzalutamide induced toxicity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 276.

Resistance to second-generation androgen receptor antagonists in prostate cancer.

The introduction of second-generation androgen receptor antagonists (SG-ARAs) has greatly impacted the treatment of metastatic prostate cancer, providing tolerable and efficacious alternatives to chemotherapy. SG-ARAs provide similar therapeutic benefit to abiraterone, a potent CYP17 inhibitor, and do not require the co-administration of prednisone. Despite considerable improvements in clinical outcomes in the settings of both castration sensitivity and castration resistance, the durability of clinical response to the SG-ARAs enzalutamide, apalutamide and darolutamide, similar to abiraterone, is limited by inevitable acquired resistance. Genomic aberrations that confer resistance to SG-ARAs or provide potential alternative treatment modalities have been identified in numerous studies, including alterations of the androgen receptor, DNA repair, cell cycle, PI3K-AKT-mTOR and Wnt-β-catenin pathways. To combat resistance, researchers have explored approaches to optimizing the utility of available treatments, as well as the use of alternative agents with a variety of targets, including AR-V7, AKT, EZH2 and HIF1α. Ongoing research to establish predictive biomarkers for the treatment of tumours with resistance to SG-ARAs led to the approval of the PARP inhibitors olaparib and rucaparib in pre-treated metastatic castration-resistant prostate cancer. The results of ongoing studies will help to shape precision medicine in prostate cancer and further optimize treatment paradigms to maximize clinical outcomes.

English

BACKGROUND Understanding various risk factors associated with breast cancer can help in early identification &amp; prompt treatment of patients with breast cancer. Apart from clinical parameters like age, disease presentation and menopausal status, important prognostic indicators in histopathology are size and extent of tumour, histologic type,histologic grade and lymph node status. Also, there are other factors which are not only predictive of outcome, but also direct therapies against particular molecular targets. These factors are oestrogen receptor (ER) status, progesterone receptor (PR) status, HER2 / neu status, Ki-67 proliferation index &amp; androgen receptor (AR) status. We wanted to analyse various hormone receptors &amp; their correlation with prognostic factors. In addition, androgen receptor expression is also studied in triple negative breast cancer cases. METHODS The study included 50 cases over a period of 18 months from January 2018 to June 2019 received in the Department of Pathology, Gandhi Medical College, Bhopal, India. These cases were subjected to histopathological &amp; immunohistochemistry (IHC) evaluation. RESULTS Among the 50 cases studied, the most common subtype was infiltrating ductal carcinoma (NOS - no special type, 84 %). Majority of patients were ER, PR, HER2 / neu negative (48 %) and among those triple negative cases, 25 % of cases were androgen receptor positive. CONCLUSIONS Expression of the hormone receptor (ER and PR) and HER2 status may provide significant information in directing patient management. Since traditional pathological methods and IHC remain standard for guiding the use of treatment, clinicians may be challenged with equivocal results that directs towards additional testing for definitive diagnosis and, better patient outcome. The most used therapy for advanced breast cancers is based on the use of AR antagonists, such as bicalutamide and enzalutamide, first- and second-generation AR antagonists respectively. Gene signatures, bioinformatics, and other clinical trials are also beneficial for clinician in estimating the benefits expected from adjuvant chemotherapy. KEY WORDS Breast Cancer, Oestrogen Receptor, Androgen Receptor, Triple Negative

Network meta-analysis (NMA) comparing the efficacy of enzalutamide versus apalutamide, darolutamide, and bicalutamide for treatment of nonmetastatic (nm) castration-resistant prostate cancer (CRPC).

101 Background: Enzalutamide is a potent androgen receptor (AR) inhibitor, targeting multiple steps in AR signaling. In recent years, the EMA and FDA approved enzalutamide for the management of adults with CRPC, irrespective of metastatic status, based on the Phase 3 PROSPER clinical trial results. To provide indirect evidence on the relative efficacy of enzalutamide vs bicalutamide or the second-generation AR antagonists apalutamide and darolutamide for the management of nmCRPC, a NMA was performed using published data from their Phase 3 clinical trials. Methods: NMA enables indirect comparison of ≥3 interventions across a network of studies, identified by systematic literature review and based on a common comparator, to estimate relative effects between interventions. This NMA compared data from PROSPER (enzalutamide vs placebo [PBO]), SPARTAN (apalutamide vs PBO), ARAMIS (darolutamide vs PBO), and STRIVE (enzalutamide vs bicalutamide) studies, following NICE technical support document 2. Four key endpoints (metastasis-free survival [MFS], overall survival [OS], time to prostate-specific antigen progression [TTPP], and time to first use of cytotoxic chemotherapy [TTCH]) were assessed. It was assumed that there was no variation between studies that could influence the size of treatment effect. Fixed-effect models were developed and implemented under a Bayesian framework. Results: MFS, OS, and TTCH outcomes of PROSPER, SPARTAN, and ARAMIS were compared between androgen deprivation treatment alone and in combination with enzalutamide/apalutamide/darolutamide. TTPP of PROSPER, SPARTAN, ARAMIS, and STRIVE was compared between enzalutamide, apalutamide, darolutamide, bicalutamide, and PBO. Enzalutamide showed significant benefit vs PBO for all endpoints measured (median hazard ratio [HR] 0.29, 0.73, 0.54, 0.07 for MFS, OS, TTCH, TTPP respectively, Table), vs darolutamide for MFS HR 0.71, and vs darolutamide HR 0.51 and bicalutamide HR 0.18 for TTPP. OS for enzalutamide vs apalutamide was not statistically different HR 0.94. Conclusions: Enzalutamide showed significant therapeutic benefit; MFS, OS, TTCH, and TTPP were better vs PBO and MFS and/or TTPP were longer compared to darolutamide and bicalutamide. No statistically significant differences were observed between enzalutamide and apalutamide. This NMA may facilitate the development and testing of treatment strategies for nmCRPC. [Table: see text]

Hormonal Therapy for Prostate Cancer.

Huggins and Hodges demonstrated the therapeutic effect of gonadal testosterone deprivation in the 1940s and therefore firmly established the concept that prostate cancer is a highly androgen-dependent disease. Since that time, hormonal therapy has undergone iterative advancement, from the types of gonadal testosterone deprivation to modalities that block the generation of adrenal and other extragonadal androgens, to those that directly bind and inhibit the androgen receptor (AR). The clinical states of prostate cancer are the product of a superimposition of these therapies with nonmetastatic advanced prostate cancer, as well as frankly metastatic disease. Today's standard of care for advanced prostate cancer includes gonadotropin-releasing hormone agonists (e.g., leuprolide), second-generation nonsteroidal AR antagonists (enzalutamide, apalutamide, and darolutamide) and the androgen biosynthesis inhibitor abiraterone. The purpose of this review is to provide an assessment of hormonal therapies for the various clinical states of prostate cancer. The advancement of today's standard of care will require an accounting of an individual's androgen physiology that also has recently recognized germline determinants of peripheral androgen metabolism, which include HSD3B1 inheritance.

Modern antiandrogenic therapy of patients with castration-resistant prostate cancer without metastases

The prevalence of prostate cancer continues to increase worldwide. The effectiveness of androgen deprivation therapy for advanced prostate cancer has a time limit, after which castration resistance and disease progression are formed. A part of patients with castrate-resistant prostate cancer has no metastases (according to standard imaging methods). The main goal of treatment of these patients is to prolong the time before metastasis formation. This article presents a review of the current understanding of the molecular mechanisms underlying the inhibition of androgen-receptor signaling with enzalutamide, a second-generation androgen receptor antagonist, and the results of clinical studies of its efficacy and safety in castrate-resistant prostate cancer without metastases. It was determined that enzalutamide stimulates the expression of a new class of genes that are not regulated by dihydrotestosterone. It was found that, in addition to inhibiting androgen receptors, enzalutamide can act as a partial transcriptional agonist. Enzalutamide therapy has been shown to reduce the risk of tumor progression and death in patients with non-metastatic castrate-resistant prostate cancer and is well tolerated. Treatment with this drug increases the time before metastases appear, before the first use of subsequent anti-tumor therapy is necessary, and the period before prostate-specific antigen levels have progressed. Study of mechanisms induced by enzalutamide – inhibition of prostate cancer cells growth and activation of genes contributing to cancer development by enzalutamide-related androgen receptor – can help to clarify possible ways of resistance formation to this drug and possibilities of its overcoming with combined therapy.

Mechanisms of enzalutamide resistance in castration-resistant prostate cancer and therapeutic strategies to overcome it.

Prostate cancer is the second most common malignancy in men and androgen deprivation therapy is the first-line therapy. However, most cases will eventually develop castration-resistant prostate cancer after androgen deprivation therapy treatment. Enzalutamide is a second-generation androgen receptor antagonist approved by the Food and Drug Administration to treat patients with castration-resistant prostate cancer. Unfortunately, patients receiving enzalutamide treatment will ultimately develop resistance via various complicated mechanisms. This review examines the emerging information on these resistance mechanisms, including androgen receptor-related signalling pathways, glucocorticoid receptor-related pathways and metabolic effects. Notably, lineage plasticity and phenotype switching, gene polymorphisms and the relationship between microRNAs and drug resistance are addressed. Furthermore, potential therapeutic strategies for enzalutamide-resistant castration-resistant prostate cancer treatment are suggested, which can help discover more effective and specific regimens to overcome enzalutamide resistance.

Abstract 5679: Androgen receptor degraders overcome common resistance mechanisms developed during prostate cancer treatment

Abstract Background: Androgen receptor (AR) signaling is critical for prostate development and homeostasis as well as for the initiation and progression of prostate cancer (PCa). Indeed, the clinical development of second-generation AR antagonists, including enzalutamide, has confirmed that AR remains a key oncogene in castration-resistant prostate cancer (CRPC). Furthermore, response to enzalutamide is temporary and incremental, and PCa cells that develop resistance to AR-targeted therapy usually maintain AR expression. Therefore, with the hypothesis that AR protein is still active even during castration- and enzalutamide-resistant states, we employed the proteolysis targeting chimera (PROTAC) strategy to build compounds that targeted the AR through proteasomal degradation. We developed an optimized functional molecule, ARD-61, that targets enzalutamide-resistant and AR splice variant (including AR-V7, which lacks the ligand binding domain) overexpressing cells in vitro and in vivo. Methods/Results: To characterize ARD-61, we performed western blotting, qRT-PCR, growth assays, xenograft studies, as well as proteomic and RNA-sequencing analyses. Additionally, to investigate the sensitivity of AR splice variants to ARD-61, we created CRISPR-Cas9 mediated stable AR-V7 overexpression in LNCaP cells. ARD-61 functions to rapidly and specifically degrade AR protein, and thus decreases downstream AR signaling in a wide variety (e.g. enzalutamide sensitive, AR-mutated, enzalutamide resistant) of AR-positive cell lines and tumor xenografts. Enzalutamide-sensitive and -resistant cell lines were similarly sensitive to ARD-61 in vivo and in vitro. CRISPR-induced endogenous overexpression of AR-V7 had no effect on the sensitivity of cells to ARD-61 or enzalutamide. Conclusions: Our data reveal the necessity of full-length AR in all Pca stages. Despite continued AR-antagonization, enzalutamide-resistant cell lines require full-length AR for sustained survival. Further, AR-variant overexpression, previously shown to promote resistance to AR-targeted therapies, still required AR protein with an intact ligand-binding domain to maintain growth in our models. Our data illustrate the importance of continued targeting of AR in advanced Pca, as well as demonstrate the efficacy of ARD-61. Ultimately, through its clinical translation, we anticipate the development of ARD-61 to be a therapeutic advance for patients with the metastatic CRPC. Citation Format: Steven Kregel, Chao Wang, Xin Han, Lanbo Xiao, Ester Fernandez-Salas, Pushpinder Bawa, Brooke L. McCollum, Kari Wilder-Romans, Ingrid J. Apel, Xuhong Cao, Corey Speers, Shaomeng Wang, Arul M. Chinnaiyan. Androgen receptor degraders overcome common resistance mechanisms developed during prostate cancer treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5679.

Development of Androgen-Antagonistic Coumarinamides with a Unique Aromatic Folded Pharmacophore.

First-generation nonsteroidal androgen receptor (AR) antagonists, such as flutamide (2a) and bicalutamide (3), are effective for most prostate cancer patients, but resistance often appears after several years due to the mutation of AR. Second-generation AR antagonists are effective against some of these castration-resistant prostate cancers, but their structural variety is still limited. In this study, we designed and synthesized 4-methyl-7-(N-alkyl-arylcarboxamido)coumarins as AR antagonist candidates and evaluated their growth-inhibitory activity toward androgen-dependent SC-3 cells. Coumarinamides with a secondary amide bond did not show inhibitory activity, but their N-methylated derivatives exhibited AR-antagonistic activity. Especially, 19b and 31b were more potent than the lead compound 7b, which was comparable to hydroxyflutamide (2b). Conformational analysis showed that the inactive coumarinamides with a secondary amide bond have an extended structure with a trans-amide bond, while the active N-methylated coumarinamides have a folded structure with a cis-amide bond, in which the two aromatic rings are placed face-to-face. Docking study suggested that this folded structure is important for binding to AR. Selected coumarinamide derivatives showed AR-antagonistic activity toward LNCaP cells with T877A AR, and they had weak progesterone receptor (PR)-antagonistic activity. The folded coumarinamide structure appears to be a unique pharmacophore, different from those of conventional AR antagonists.