Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer.

BACKGROUND: Darolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. Whether a combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival among patients with metastatic, hormone-sensitive prostate cancer is unknown. METHODS: In this international, phase 3 trial, we randomly assigned patients with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to receive darolutamide (at a dose of 600 mg [two 300-mg tablets] twice daily) or matching placebo, both in combination with androgen-deprivation therapy and docetaxel. The primary end point was overall survival. RESULTS: The primary analysis involved 1306 patients (651 in the darolutamide group and 655 in the placebo group); 86.1% of the patients had disease that was metastatic at the time of the initial diagnosis. At the data cutoff date for the primary analysis (October 25, 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.001). Darolutamide was also associated with consistent benefits with respect to the secondary end points and prespecified subgroups. Adverse events were similar in the two groups, and the incidences of the most common adverse events (occurring in ≥10% of the patients) were highest during the overlapping docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group; neutropenia was the most common grade 3 or 4 adverse event (in 33.7% and 34.2%, respectively). CONCLUSIONS: In this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups. (Funded by Bayer and Orion Pharma; ARASENS ClinicalTrials.gov number, NCT02799602.).

Phase 1 Dose Escalation Study of the Allosteric AKT Inhibitor BAY 1125976 in Advanced Solid Cancer-Lack of Association between Activating AKT Mutation and AKT Inhibition-Derived Efficacy.

This open-label, phase I first-in-human study (NCT01915576) of BAY 1125976, a highly specific and potent allosteric inhibitor of AKT1/2, aimed to evaluate the safety, pharmacokinetics, and maximum tolerated dose of BAY 1125976 in patients with advanced solid tumors. Oral dose escalation was investigated with a continuous once daily (QD) treatment (21 days/cycle) and a twice daily (BID) schedule. A dose expansion in 28 patients with hormone receptor-positive metastatic breast cancer, including nine patients harboring the AKT1E17K mutation, was performed at the recommended phase 2 dose (R2D) of 60 mg BID. Dose-limiting toxicities (Grades 3-4) were increased in transaminases, γ-glutamyltransferase (γ-GT), and alkaline phosphatase in four patients in both schedules and stomach pain in one patient. Of the 78 patients enrolled, one patient had a partial response, 30 had stable disease, and 38 had progressive disease. The clinical benefit rate was 27.9% among 43 patients treated at the R2D. AKT1E17K mutation status was not associated with tumor response. Genetic analyses revealed additional mutations that could promote tumor cell growth despite the inhibition of AKT1/2. BAY 1125976 was well tolerated and inhibited AKT1/2 signaling but did not lead to radiologic or clinical tumor responses. Thus, the refinement of a selection of biomarkers for AKT inhibitors is needed to improve their monotherapy activity.

What are the potential preventive population-health effects of a tax on processed meat? A quantitative health impact assessment for Germany.

The International Agency for Research on Cancer considers processed meat to be carcinogenic. Further, processed meat is associated with diabetes, ischemic heart disease (IHD) and all-cause mortality. We aimed to assess health gains of four processed meat taxation scenarios in comparison to the reference and a minimum-risk-exposure-scenario. To estimate the shift in processed meat intake following respective taxes, we calculated price elasticities for processed meat. DYNAMO-HIA was used to dynamically project policy-attributable differences in the prevalence of diseases and deaths. In projection year 10, an extra 9300 males and 4500 females would be alive under the lowest tax scenario (4% tax), compared to the reference scenario. Prevalent IHD, diabetes and colorectal cancer cases in males would be 8400, 9500 and 500 lower, respectively, and there would be 4600, 7800 and 300 less cases in females. Of the respective death and disease reduction that would be achieved under the minimum-risk-exposure-scenario, the lowest tax reaches 2.84% (colorectal cancer in males) to 6.02% (diabetes in females). Under the highest tax scenario (33.3% tax), an extra 76,700 males and 37,100 females would be alive, compared to the reference scenario. Prevalent IHD, diabetes and colorectal cancer cases would be 70,800, 77,900 and 4900 lower in males and 29,900, 48,900 and 2300 lower in females, which represents 27.84% (colorectal cancer in males) to 37.76% (diabetes in females) of the maximal preventable death and disease burden. Further research needs to examine to what extent these health benefits are outweighed by a simultaneous tax-induced decrease in fish intake.

Dietary patterns of adolescents in Germany--associations with nutrient intake and other health related lifestyle characteristics.

BACKGROUND: The aim of this study was to identify dietary patterns among a representative sample of German adolescents and their associations with energy and nutrient intake, socioeconomic and lifestyle characteristics, and overweight status. METHODS: In the analysis, data from the German Health Interview and Examination Survey for Children and Adolescents were used. The survey included a comprehensive dietary history interview conducted among 1272 adolescents aged 12 to 17 years. Dietary patterns were determined with principal component analysis (PCA) based on 48 food groups, for boys and girls separately. RESULTS: Three dietary patterns among boys and two among girls were identified. Among boys, high adherence to the 'western' pattern was associated with higher age, lower socioeconomic status (SES), and lower physical activity level (PA). High adherence to the 'healthy' pattern among boys, but not among girls, was associated with higher SES, and higher PA. Among boys, high adherence to the 'traditional' pattern was associated with higher age. Among girls, high adherence to the 'traditional and western' pattern was associated with lower age, lower SES and more hours watching TV per day. The nutrient density of several vitamins and minerals, particularly of B-vitamins and calcium, increased with increasing scores of the 'healthy' pattern among both sexes. Conversely, with increasing scores of the 'western' pattern among boys, most nutrient densities decreased, particularly of fibre, beta-carotene, vitamin D, biotin and calcium. Among girls with higher scores of the 'traditional and western' pattern, nutrient densities of vitamin A, C, E, K and folate decreased. Among boys, high adherence to the 'traditional' pattern was correlated with higher densities of vitamin B12 and vitamin D and lower densities of fibre, magnesium and iron. No significant associations between dietary patterns and overweight were found. CONCLUSIONS: Higher scores for dietary patterns characterized by higher consumption of take away food, meat, confectionary and soft drinks ('western' and 'traditional and western') were found particularly among 16- to 17-years old boys and among adolescents with lower SES. These patterns were also associated with higher energy density, higher percent of energy from unsaturated fatty acids and lower percent of energy from carbohydrates as well as lower nutrient densities of several vitamins and minerals. Therefore, nutritional interventions should try to focus more on adolescents with lower SES and boys in general.