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A randomized trial tested whether the addition of apalutamide, an androgen receptor blocker, to androgen-deprivation therapy might improve radiographic (including MRI-detected) progression–free survival and overall survival. Apalutamide was significantly more effective than placebo for both end points.

Among men with nonmetastatic prostate cancer who had a rapid PSA doubling time and were receiving androgen-deprivation therapy, the median metastasis-free survival was 40.5 months with apalutamide versus 16.2 months with placebo. Rash occurred in 24% of men receiving apalutamide.

Myeloid cells are recruited to damaged tissues where they can resolve infections and tumor growth or stimulate wound healing and tumor progression. Recruitment of these cells is regulated by integrins, a family of adhesion receptors that includes integrin CD11b. Here we report that, unexpectedly, integrin CD11b does not regulate myeloid cell recruitment to tumors but instead controls myeloid cell polarization and tumor growth. CD11b activation promotes pro-inflammatory macrophage polarization by stimulating expression of microRNA Let7a . In contrast, inhibition of CD11b prevents Let7a expression and induces cMyc expression, leading to immune suppressive macrophage polarization, vascular maturation, and accelerated tumor growth. Pharmacological activation of CD11b with a small molecule agonist, Leukadherin 1 (LA1), promotes pro-inflammatory macrophage polarization and suppresses tumor growth in animal models of murine and human cancer. These studies identify CD11b as negative regulator of immune suppression and a target for cancer immune therapy. Recruitment of myeloid cells can be regulated by integrin CD11b. Here the authors show that in the tumor microenvironment, CD11b is not essential for recruitment of myeloid cells but rather induces macrophage anti-tumorigenic polarization via stimulating let7a and NFκB signaling and that pharmacological activation of CD11b enhances survival in mouse models of cancer.

Apalutamide (Erleada TM ) is a next-generation oral androgen receptor (AR) inhibitor that is being developed by Janssen for the treatment of prostate cancer (PC). It binds directly to the ligand-binding domain of the AR and blocks the effects of androgens. In February 2018, apalutamide received its first global approval in the USA for the treatment of non-metastatic castration-resistant PC (nmCRPC). Apalutamide is undergoing phase III investigation in chemotherapy-naive patients with metastatic CRPC (in combination with abiraterone acetate plus prednisone), patients with high-risk localized or locally advanced PC receiving primary radiation therapy, and in patients with metastatic hormone-sensitive PC and biochemically-relapsed PC. This article summarizes the milestones in the development of apalutamide leading to this first approval in nmCRPC.

Novel drugs, drug sequences and combinations have improved the outcome of prostate cancer in recent years. The latest approvals include abiraterone acetate, enzalutamide and apalutamide which target androgen receptor (AR) signaling, radium-223 dichloride for reduction of bone metastases, sipuleucel-T immunotherapy and taxane-based chemotherapy. Adding abiraterone acetate to androgen deprivation therapy (ADT) in order to achieve complete androgen blockade has proven highly beneficial for treatment of locally advanced prostate cancer and metastatic hormone-sensitive prostate cancer (mHSPC). Also, ADT together with docetaxel treatment showed significant benefit in mHSPC. Ongoing clinical trials for different subgroups of prostate cancer patients include the evaluation of the second-generation AR antagonists enzalutamide, apalutamide and darolutamide, of inhibitors of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, of inhibitors of DNA damage response, of targeted alpha therapy and of prostate-specific membrane antigen (PSMA) targeting approaches. Advanced clinical studies with immune checkpoint inhibitors have shown limited benefits in prostate cancer and more trials are needed to demonstrate efficacy. The identification of improved, personalized treatments will be much supported by the major progress recently made in the molecular characterization of early- and late-stage prostate cancer using “omics” technologies. This has already led to novel classifications of prostate tumors based on gene expression profiles and mutation status, and should greatly help in the choice of novel targeted therapies best tailored to the needs of patients.

The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC. ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone–prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone–prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736. 982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone–prednisone; 490 to abiraterone–prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0–28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4–27·4) in the apalutamide plus abiraterone–prednisone group versus 16·6 months (13·9–19·3) in the abiraterone–prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58–0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5–58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7–27·5) versus 16·6 months (13·9–19·3; HR 0·70, 95% CI 0·60–0·83; p<0·0001). The most common grade 3–4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone–prednisone and 49 [10%] of 489 receiving abiraterone–prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone–prednisone and 181 (37%) patients receiving abiraterone–prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone–prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone–prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death). Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone–prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC. Janssen Research & Development.

Diabetes mellitus remains a global health challenge, necessitating the development of novel therapeutic agents. In this study, a series of thiohydantoin derivatives (FP1–FP7) were synthesized and evaluated for their in silico, in vitro, and in vivo antidiabetic potential. Molecular docking studies revealed strong binding affinities of derivatives towards α-glucosidase (PDB: 3wy1) and α-amylase (PDB: 3dhp), with FP4 exhibiting the most favorable interactions (− 7.8 kcal/mol with α-amylase and − 7.0 kcal/mol with α-glucosidase), involving hydrogen bonding and π-π stacking. During in vitro enzyme inhibition assay, FP4 demonstrated potent inhibitory activity against α-glucosidase and α-amylase, with IC₅₀ values of 129.40 and 128.90 µg/mL, respectively. The DPPH scavenging assay also indicated that FP4 had relatively strong antioxidant activity, with an IC₅₀ value of 39.7 µg/mL. In vivo antidiabetic efficacy was evaluated in STZ-induced diabetic rats over a period of 6-week. FP4 treated diabetic rats exhibited significantly reduced fasting blood glucose by 28.9% than in diabetic controls. In addition, HbA1C levels and diabetes-associated weight loss were significantly curtailed in these animals than untreated diabetic group. Further FP4 treated animals exhibited significantly decreased LDL and triglyceride levels and elevated HDL levels, suggesting a broader metabolic benefit. Taken together, our results suggest that thiohydantoin derivatives, particularly FP4, exhibited interesting antidiabetic and antihyperlipidemic activities warranting further pharmacokinetic and mechanistic investigations also potential for clinical translation and long term safety assessment.

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.Survival of patients with metastatic prostate cancer has improved with the approval of second-generation androgen receptor antagonists. This Review discusses common genomic alterations leading to inevitable resistance to this therapy, and potential alternative therapeutic targets for treatment.

Management of non-metastatic castration-resistant prostate cancer (nmCRPC) has undergone a paradigm shift with next-generation androgen receptor inhibitors. However, direct comparative data are not available to inform treatment decisions and/or guideline recommendations. Therefore, we performed network meta-analysis to indirectly compare the efficacy and safety of currently available treatments. Multiple databases were searched for articles published before June 2020. Studies that compared overall and/or metastasis-free and/or prostate-specific antigen (PSA) progression-free survival (OS/MFS/PSA-PFS) and/or adverse events (AEs) in nmCRPC patients were considered eligible. Three studies (n = 4117) met our eligibility criteria. Formal network meta-analyses were conducted. For MFS, apalutamide, darolutamide, and enzalutamide were significantly more effective than placebo, and apalutamide emerged as the best option (P score: 0.8809). Apalutamide [hazard ratio (HR): 0.85, 95% credible interval (CrI): 0.77–0.94] and enzalutamide (HR: 0.86, 95% CrI: 0.78–0.95) were both significantly more effective than darolutamide. For PSA-PFS, all three agents were statistically superior to placebo, and apalutamide emerged as the likely preferred option (P score: 1.000). Apalutamide (HR: 0.71, 95% CrI: 0.69–0.74) and enzalutamide (HR: 0.76, 95% CrI: 0.74–0.79) were both significantly more effective than darolutamide. For AEs (including all AEs, grade 3 or grade 4 AEs, grade 5 AEs, and discontinuation rates), darolutamide was the likely best option. Apalutamide and enzalutamide appear to be more efficacious agents for therapy of nmCRPC, while darolutamide appears to have the most favorable tolerability profile. These findings may facilitate individualized treatment strategies and inform future direct comparative trials.

PurposeApalutamide plus androgen-deprivation therapy (ADT) improved outcomes in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Nevertheless real-world data are limited. The aim of this multicenter study was to generate real-world data from nmCRPC patients treated with ADT plus apalutamide.MethodsIn this observational cohort based investigator initiated trial data of nmCRPC patients receiving apalutamide plus ADT were collected focusing on patient demographic data, prostate-specific antigen (PSA) declines, safety profile including dose modification/discontinuation as well as subsequent therapy and metastasis-free survival (MFS).ResultsData from a total of 31 nmCRPC patients were documented. Compared to the Phase III study Spartan real-world patients are older, showed a higher ECOG-PS and more aggressive tumors. In the cohort PSA decreased about 98.1%, 74% of patients showed a PSA decrease over 90% and 54.8% reached a PSA-level < 0.2ng/ml. Apalutamide was well tolerated in real world patients: adverse events occurred in 67.7% but were in the majority mild (≥ grade 3: 6.5%). Dose reduction was necessary in 38.7% and 32.2% discontinued apalutamide treatment. MFS was 43 months and majority of patients were subsequently treated with abiraterone.ConclusionIn real world more comorbid nmCRPC patients with a higher ECOG-PS and more aggressive tumors are treated with apalutamide plus ADT. Nevertheless efficacy results as well as side effects are similar in real-world compared to Spartan trial showing also a rapid, durable and deep PSA response with a median MFS of 43 months.