Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9–81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3–59·0) in the standard of care group (HR 0·65 [0·55–0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83–1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial). Interpretation: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas

Metal Mobilization As An Effect of Anthropogenic Contamination in Groundwater Aquifers in Tutuila, American Samoa

Groundwater is the primary drinking water source on most oceanic islands, including Tutuila, American Samoa. Drinking water quality on Tutuila is impacted by anthropogenic pollution sources such as on-site sewage disposal systems, piggeries, and agricultural leachate, particularly across the densely populated Tafuna–Leone Plain. The remineralization of anthropogenically sourced organic matter produces nitrate and dissolved inorganic carbon, which, according to previously published studies, have the potential to mobilize naturally occurring metals. This study provides further evidence that nutrients and dissolved inorganic carbon, along with naturally sourced metal concentrations, become elevated along pollution gradients and show correlation with each other. Across the Tafuna–Leone Plain, nitrate concentrations have a moderately positive correlation with uranium and vanadium. Dissolved inorganic carbon also positively correlate with nitrate, uranium, and vanadium. Similar studies elsewhere suggest that, in addition to nitrate, organic matter remineralization associated with carbonate create conditions to favor natural metal mobilization. Correlation analysis results imply that, while the surveyed trace metals are likely naturally sourced, some become soluble and more mobile in the presence of anthropogenically sourced nitrate and dissolved inorganic carbon, which alters redox conditions in the aquifer

Nutrient and Trace Element Contributions from Drained Islands in the Sacramento–San Joaquin Delta, California

Inventorying nutrient and trace element sources in the Sacramento-San Joaquin Delta (the Delta) is critical to understanding how changes—including alterations to point source inputs such as upgrades to the Sacramento Regional Wastewater Treatment Plant (SRWTP) and landscape-scale changes related to wetland restoration—may alter the Delta’s water quality. While island drains are a ubiquitous feature of the Delta, limited data exist to evaluate island drainage mass fluxes in this system. To better constrain inputs from island drains, we measured monthly discharge along with nutrient and trace element concentrations in island drainage on three Delta islands and surrounding rivers from June 2017 to September 2018. These data were used to calculate island-level fluxes and then upscaled to estimate Delta-wide contributions from island drains. Based on these results, we present (1) new estimates of gross and net nutrient and trace element fluxes from Delta island drains, and (2) concomitant N stable isotope data to improve our understanding of island N cycling. Over 60% of nearly all island drainage gross nutrient and trace element loads occurred in winter and spring. Upscaled island drainage net annual total nitrogen (TN), total dissolved nitrogen (TDN), and NH4+ loads comprised an estimated 9%, 7%, and 4%, respectively, of annual inputs to this system in 2018, before the SRWTP upgrade. Under a post-upgrade scenario, we estimated net annual island drainage TDN contributions to increase to 11% and NH4+ contributions to 45% of total Delta inputs as the SRWTP NH4+ load diminished to near zero. Our results suggest that island drainage is a measurable N source that has likely become increasingly important now that the SRWTP upgrade is complete. With over 200 potential active outfalls, these inputs may affect aquatic biogeochemical cycling in many regions of the Delta, especially in areas with long residence times