Final Survival Research Articles

Overall survival results from the NETTER-1 trial in neuroendocrine tumours: an important milestone.

Jonathan Strosberg and colleagues1 report the final overall survival and long-term safety results of the phase 3 NETTER-1 study in patients with midgut neuroendocrine tumours (NETs). These data are the first long-term prospective results with the radiopharmaceutical 177Lu-Dotatate in patients with locally advanced or progressive, well differentiated, somatostatin receptor-positive midgut NETs with a Ki67 index of 20% or less. The primary objective of the NETTER-1 trial was met in 2017, showing a significantly longer progression-free survival in patients with these tumours following treatment with 177Lu-Dotatate in combination with long-acting octreotide (20–30 mg) versus high-dose (60 mg) long-acting octreotide alone (p=0·0001).

Valorization Use of Amphipod Meal, Gammarus pulex, as a Fishmeal Substitute on Growth Performance, Feed Utilization, Histological and Histometric Indices of the Gut, and Economic Revenue of Grey Mullet

The future of aquaculture development is directed toward high intensification to overcome the decline in natural fishing and to provide enough protein for the increasing world population. The spread of aquaculture production and intensification requires the search for high-quality, new efficient feed ingredients with low cost and sustainable importance. Therefore, the current study aimed to detect the effects of partial or total replacement of fishmeal with amphipod meal, Gammarus pulex, on growth performance, survival percent, feed utilization, histological alteration of intestine and liver, and economic yield of grey mullet, Mugil cephalus, fry. Five diets were formulated to contain 100% fishmeal (FM), or FM replaced with 25%, 50%, 75%, or 100% amphipod meal (APM) (D0, D25, D50, D75, and D100, respectively). A total of 300 grey mullet fry (0.097 ± 0.001 g), were divided into five groups (three replicates each) at an initial stocking density of 20 fry per aquaria (100 L). The aquarium’s water is renewed at a rate of 30% daily. During a 60-day experimental period, the feeding rate was 20% of body weight, which was introduced as five meals per day. Fish fed D50 achieved the highest significant values of final weight (1.80 g), weight gain (1.70 g), survival (86.67%), final length (4.47 cm), and length gain (2.06 cm). In addition, the feed utilization of diets containing increasing substitution levels of FM showed that the highest protein intake (0.82 g ish−1), protein efficiency ratio (0.83), protein productive value (30.65%), and the lowest significant feed conversion ratio (1.21) were recorded with D50. The dose-response study revealed that the best substitution levels could range between 50% and 75%. Histological observations confirmed that the highest number of goblet cells and intestinal villi were recorded in the group fed D50. No pathological effect was observed in the liver at all substitution levels. In terms of economic efficiency, the best economic conversion ratio was recorded in the group fed D50. This study confirmed that 50% partial substitution of FM with APM is the ideal replacement level for grey mullet fry. In addition, the use of a new renewable alternative, such as APM to substitute FM, could relieve the pressure on the capture of wild fish and reduce the environmental impact of inland aquaculture.

Comparison between horizontal and vertical substrate in shrimp super-intensive culture in bioflocs system.

Shrimp culture in biofloc technology system (BFT) is supported by many tools that allow the stocking densities to reach a super-intensive status. The artificial substrate is a well-known tool that allows increasing the relative area and consequently the stocking density of cultured shrimp. In order to evaluate the efficiency of this tool, the present study determinated three experimental treatments, each of them performed in a triplicate: i. culture without artificial substrate (WS); ii. Culture with vertical substrate (VS), and iii. Culture with horizontal substrate (HS). Each substrate aimed to increase 100% of the total tank inner surface walls area. Densities of 500 shrimp.m−2 with an initial weight of 0.35 g were cultured during 84 days on a BFT system. The water quality did not present significant differences (p > 0.05), the growth parameters however presented significant differences in final weight, survival, final biomass, yields and FCR. Shrimp cultured in VS treatment presented the higher survival (82.70 ± 5.08%) and yield (3.73 ± 0.04 kg.m−2). The present study suggests that the increase in the relative area can improve shrimp growth and survival, in this sense vertical substrate presented more benefits than horizontal substrate. In addition, that is important to consider shrimp behavior when developing new tools. Moreover, those artificial substrates are feasible for improving culture density and survival.

Uncovering the Novel QTLs and Candidate Genes of Salt Tolerance in Rice with Linkage Mapping, RTM-GWAS, and RNA-seq

Salinity is a major abiotic stress that limits plant growth and crop productivity. Indica rice and japonica rice show significant differences in tolerance to abiotic stress, and it is considered a feasible method to breed progeny with stronger tolerance to abiotic stress by crossing indica and japonica rice. We herein developed a high-generation recombinant inbred lines (RILs) from Luohui 9 (indica) X RPY geng (japonica). Based on the high-density bin map of this RILs population, salt tolerance QTLs controlling final survival rates were analyzed by linkage mapping and RTM-GWAS methods. A total of seven QTLs were identified on chromosome 3, 4, 5, 6, and 8. qST-3.1, qST-5.1, qST-6.1, and qST-6.2 were novel salt tolerance QTLs in this study and their function were functionally verified by comparative analysis of parental genotype RILs. The gene aggregation result of these four new QTLs emphasized that the combination of the four QTL synergistic genotypes can significantly improve the salt stress tolerance of rice. By comparing the transcriptomes of the root tissues of the parents’ seedlings, at 3 days and 7 days after salt treatment, we then achieved fine mapping of QTLs based on differentially expressed genes (DEGs) identification and DEGs annotations, namely, LOC_Os06g01250 in qST-6.1, LOC_Os06g37300 in qST-6.2, LOC_Os05g14880 in qST-5.1. The homologous genes of these candidate genes were involved in abiotic stress tolerance in different plants. These results indicated that LOC_Os05g14880, LOC_Os06g01250, and LOC_Os06g37300 were the candidate genes of qST-5.1, qST-6.1, and qST-6.2. Our finding provided novel salt tolerance-related QTLs, candidate genes, and several RILs with better tolerance, which will facilitate breeding for improved salt tolerance of rice varieties and promote the exploration tolerance mechanisms of rice salt stress.

CTIM-20. FINAL RESULTS OF CONTROLLED IL-12 MONOTHERAPY AND IN COMBINATION WITH PD-1 INHIBITOR IN ADULT SUBJECTS WITH RECURRENT GLIOBLASTOMA

Abstract Ad-RTS-hIL-12(Ad) is a gene therapy candidate conditionally expressing IL-12 under the transcriptional control of veledimex(V) acting via the RheoSwitch Therapeutic System® gene switch. Veledimex plasma and tumor PK demonstrated a dose-response relationship and crossing the BBB. PD-1+ T-cells were increased in tumor biopsy samples after treatment with Controlled-IL-12 in a phase-l study. This finding was the rationale for conducting 2 trials of Controlled-IL-12 in combination with PD-1-inhibitor to enhance T-cell-mediated anti-tumor effects. Data from two completed phase-I studies (presented in SNO2020), and an ongoing phase-II study of Controlled-IL-12 with cemiplimab study for the treatment of recurrent glioblastoma (rGBM) will be discussed. Ziopharm has conducted 3 phase-I (NCT02026271/NCT03679754 (monotherapy), NCT03636477 (combination with nivolumab)) and one phase-ll (NCT04006119) multicenter, open-label, single-arm trial in subjects with rGBM is evaluating Ad (single intratumoral injection, 2 x 1011-viral-particles, Day0) with oral V dosing (20mg, Days 0-14) with cemiplimab infusions (350 mg IV) on Days -7, 15, then Q3W. Systemic biomarkers (serum cytokines, and immune-activation-markers), local effects (tumor cytokines, T-cell immunobiology, pathology), neoepitope, and imaging will be assessed. Subject characteristics (Controlled IL-12 monotherapy (n=75); combination (Controlled IL-12 with anti-PD-1s) (n=61) were consistent across all 3 studies. Safety profiles were comparable between monotherapy and in combination with anti-PD-1s. Adverse reactions (ARs) after nivolumab or cemiplimab were consistent with labeling of anti-PD-1s. ARs related to Controlled IL-12 were all manageable and reversible with no synergistic toxicities in combination with anti-PD-1s. Increases in serum cytokine levels and pathology findings consistent with immune-mediated anti-tumor effect were observed in subjects who received Controlled-IL-12 monotherapy and in combination with anti-PD-1s. Final survival data and results from neoepitope analysis will be presented. Further investigation is warranted to understand the impact of monotherapy vs. combination, concurrent steroids use and unifocal vs. multifocal disease on overall survival in subjects with rGBM receiving Controlled-IL-12.

Venetoclax in Combination with Gilteritinib Demonstrates Molecular Clearance of FLT3 mutation in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

Venetoclax in Combination with Gilteritinib Demonstrates Molecular Clearance of FLT3 mutation in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

Final Overall Survival Results from BELLINI, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma

Final Overall Survival Results from BELLINI, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma

Cyanobacteria reduction in the integrated culture of Pacific white shrimp and West India pointed venus in a biofloc system

This study aimed to evaluate the integrated culture of the Pacific white shrimp (Litopenaeus vannamei) and the West Indian pointed venus (Anomalocardia flexuosa) reared in a biofloc system. The performance of both species and the phytoplankton community were evaluated. Shrimp monoculture and three stocking densities of West Indian pointed venus (2.5, 5.0 and 7.5 Kg m-3) were evaluated in 0.05 m3 tanks. First of all, the addition of A. brasiliana did not affect the water quality parameters of the culture. Regarding the phytoplankton community, 13 taxa were found: 5 cyanobacteria, 4 dinoflagellates, 3 diatoms and 1 green algae. Although diatoms were dominant at the beginning of cultivation, in the middle and at the end a cyanobacterial dominance was observed (proven by ANOSIM and nMDS). The taxa that most contributed to the abundance of cyanobacteria were Aphanocapsa sp. and Pseudanabaena sp. Regarding the performance of the shrimp, all integrated treatments present the higher growth performances (final weight, yield and survival) when compared to shrimp monoculture. Moreover, gradual mortalities of A. brasiliana were observed, probably due to the high concentration of cyanobacteria. Thus, it can be observed that the integration of molluscs in shrimp culture can reduce the concentration of harmful algae and improve the zootechnical performance of the shrimp.

Predictive factors associated with induction-related death in acute myeloid leukemia in a resource-constrained setting.

Despite advances in supportive measures, acute myeloid leukemia (AML) remission induction still has a high mortality rate in real-world studies as compared to prospective reports. We analyzed data from 206 AML adult patients treated with conventional chemotherapy. The primary endpoint was the 60-day mortality rate, aiming to find risk factors and to examine the role of anti-infection prophylaxis. The 60-day mortality rate was 26%, raising to 41% among those older than 60years. Complete response was documented at the end of induction in 49%. The final survival model showed that age > 60years (HR 3.2), Gram-negative colonization (HR 3), monocytic AML (HR 1.8), C-reactive protein (CRP) > 15mg/dL (HR 10), and an adverse risk in the genetic stratification (HR 3) were associated with induction death. Multidrug-resistant bacteria colonization, thrombosis, and AKI were documented in 71%, 12%, and 66% of the cohort, respectively. Antibacterial and antifungal prophylaxis did not improve outcomes in this study. Our report corroborated the higher mortality during AML induction compared to real-world data from the USA and Europe. In line with other publications, age and cytogenetic stratification influenced early death in this cohort. Noticeably, Gram-negative colonization, monocytic AML, and CRP were also significant to early mortality.

Echocardiographic recovery changes in patients supported with veno-arterial extracorporeal membrane oxygenator and weaning success

Abstract Introduction The weaning from veno-arterial extracorporeal membrane oxygenation (VA-ECMO) decision involves a meticulous evaluation of different factors, among which echocardiography is a decisive factor. Purpose Evaluate echocardiographic changes from the beginning of the support to the weaning test. Methods Analysis of VA-ECMO cases in a referral hospital which completed a weaning test. We evaluated the changes of echocardiographic parameters during the VA-ECMO support (initial and during weaning test) and successful weaning (survival >24h after explant and no mortality from cardiogenic shock/heart failure or cardiac arrest during admission). Results 85 out of 134 VA-ECMO patients were included from 2013 to Oct-2020 (table 1.1). Successful weaning was achieved in 61.2% and final survival at discharge 49.4%. We observed a significant increase in left ventricular ejection fraction (LVEF), left ventricular outflow tract time–velocity integral (LVOT VTI), tricuspid annular plane systolic excursion (TAPSE) and the percentage of patients with normal qualitative right ventricular function and 1:1 aortic valve opening from the initial to the weaning echocardiography (table 1.2), without significant changes in ventricular diameters. Among these changes, the increase in LVOT VTI was the only parameter that was related to weaning success (p=0.037, table 1.2). A higher LVEF increase from the initial value showed a trend to greater successful VA-ECMO disconnection (p=0.053 table 1.2). Conclusion Left and right ventricular function parameters improved significantly from baseline to weaning test echocardiography in VA-ECMO supported patients. Of these changes, the increase in LVOT VTI was related to successful disconnection from VA-ECMO and the LVEF improvement showed a trend to weaning success. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Instituto de Salud Carlos III in Spain (Co-funded by European Social Fund “Investing in your future”). Characteristics ECMO-VA patients

ES11.02 Advances in Thoracic Radiation in SCLC

ES11.02 Advances in Thoracic Radiation in SCLC

Optimizing Harvest Time Through Absolute and Relative Growth of the Black Clam, Chionista fluctifraga, Cultivated in the Intertidal Along the Southeastern Coast of the Gulf of California

The shell height-body weight relationship of the black clam Chionista fluctifraga cultivated in the intertidal of the southeastern Gulf of California, was evaluated for the first time, to improve the knowledge in determining its harvesting time. Clam seeds (n=900,000; 6.1±1.9 mm) were produced in the laboratory. The culture was divided into pre-fattening in racks on the bottom (2 months) and fattening directly in the bottom (16 months) from May 2018 to October 2019. Each month, 60 (n=1080) clams were randomly selected to stablish the morphometric relationship between shell height (SH) and body weight (BW). The growth rate (mm/d and g/d) was recorded. The SH-BW Interaction in both cultivation phases showed positive allometry. SH in prefattening and fattening registered a growth rate of 0.072 and 0.058 mm/d, respectively. In fattening, the interaction BW-SH displayed a high coefficient of determination (R2=0.99). A final survival rate of 90% was obtained. The results yielded the equations that describe the relative growth of C. fluctifraga for the fattening stage. A harvesting time after 10 months of fattening in the intertidal zone is stablished to reach the commercial size (35 mm, SH).

Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation

Isocitrate dehydrogenase 1 (IDH1) variations occur in up to approximately 20% of patients with intrahepatic cholangiocarcinoma. In the ClarIDHy trial, progression-free survival as determined by central review was significantly improved with ivosidenib vs placebo. To report the final overall survival (OS) results from the ClarIDHy trial, which aimed to demonstrate the efficacy of ivosidenib (AG-120)-a first-in-class, oral, small-molecule inhibitor of mutant IDH1-vs placebo for patients with unresectable or metastatic cholangiocarcinoma with IDH1 mutation. This multicenter, randomized, double-blind, placebo-controlled, clinical phase 3 trial was conducted from February 20, 2017, to May 31, 2020, at 49 hospitals across 6 countries among patients aged 18 years or older with cholangiocarcinoma with IDH1 mutation whose disease progressed with prior therapy. Patients were randomized 2:1 to receive ivosidenib, 500 mg, once daily or matched placebo. Crossover from placebo to ivosidenib was permitted if patients had disease progression as determined by radiographic findings. The primary end point was progression-free survival as determined by blinded independent radiology center (reported previously). Overall survival was a key secondary end point. The primary analysis of OS followed the intent-to-treat principle. Other secondary end points included objective response rate, safety and tolerability, and quality of life. Overall, 187 patients (median age, 62 years [range, 33-83 years]) were randomly assigned to receive ivosidenib (n = 126; 82 women [65%]; median age, 61 years [range, 33-80 years]) or placebo (n = 61; 37 women [61%]; median age, 63 years [range, 40-83 years]); 43 patients crossed over from placebo to ivosidenib. The primary end point of progression-free survival was reported elsewhere. Median OS was 10.3 months (95% CI, 7.8-12.4 months) with ivosidenib vs 7.5 months (95% CI, 4.8-11.1 months) with placebo (hazard ratio, 0.79 [95% CI, 0.56-1.12]; 1-sided P = .09). When adjusted for crossover, median OS with placebo was 5.1 months (95% CI, 3.8-7.6 months; hazard ratio, 0.49 [95% CI, 0.34-0.70]; 1-sided P < .001). The most common grade 3 or higher treatment-emergent adverse event (≥5%) reported in both groups was ascites (11 patients [9%] receiving ivosidenib and 4 patients [7%] receiving placebo). Serious treatment-emergent adverse events considered ivosidenib related were reported in 3 patients (2%). There were no treatment-related deaths. Patients receiving ivosidenib reported no apparent decline in quality of life compared with placebo. This randomized clinical trial found that ivosidenib was well tolerated and resulted in a favorable OS benefit vs placebo, despite a high rate of crossover. These data, coupled with supportive quality of life data and a tolerable safety profile, demonstrate the clinical benefit of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation. ClinicalTrials.gov Identifier: NCT02989857.

Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer

Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59–1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.

Determination of suitable stocking density for good aquaculture practice-based carp fattening in ponds under drought-prone areas of Bangladesh

Stocking larger sized fish in fattening along with good aquaculture practices (GAP) are considered potentials for achieving sustainable and safe fish production under the climatically challenged drought-prone areas where the maintenance of optimal water level throughout the culture period is a real obstacle. To be sustainable, fattening requires optimal stocking density, as lower stocking density can bring up economic loss and at higher stocking density fish are severely challenged by stressors. The present study was designed to explore suitable stocking density for fattening of carp using overwintered fish and maintaining the aspects of good aquaculture practices. The present study was conducted for a period of 6 months from July to December 2019 in ponds of Rajshahi district, Bangladesh with three different treatments of carp stocking densities such as T1: 2470 fishes/ha; T2: 3705 fishes/ha and T3: 4940 fishes/ha. Individual stocking weight of all the fishes was kept significantly higher at T1, medium at T2 and lower at T3. However, stocking biomass was maintained significantly indifferent in all the treatments. Fishes were fed with pelleted feed (containing 25% crude protein, 10% moisture, 4–5% crude fat and 8% crude fiber) twice a day and water quality parameters were monitored monthly. Significant variation was observed only in dissolved oxygen, NH3-N, plankton cell density and total heterotrophic bacterial count. However, two opportunistic bacterial counts (Pseudomonas spp. and Aeromonas spp.) were higher at treatment T3, and the presence of non-indigenous pathogenic bacteria (Salmonella spp., Shigella spp. and Escherichia coli) was not evident in all the treatments. Significantly higher final weight and survival of fishes were obtained with treatment T1, while combined production of fishes was significantly higher at treatment T3 followed by T2 and T1. Furthermore, the higher market price of larger fishes at T1 resulted in significantly higher total return and benefit-cost ratio (BCR), in which the average selling price of fishes at T1, T2 and T3 were 250, 218 and 195 BDT/kg, respectively. The data obtained from this study has the potency to be used as baseline information on the sustainability of GAP based carp fattening in water deprived drought-prone areas in Bangladesh and other comparable geographical areas in the tropics.

Atrial Fibrillation and Clinical Outcomes in a Cohort of Hospitalized Patients with Sars-Cov-2 Infection and Chronic Kidney Disease.

The aim of the study was to investigate the role of chronic kidney disease (CKD) on in-hospital mortality and on incident atrial fibrillation (AF) in patients infected with SARS-CoV-2. The incidence of acute kidney injury (AKI) was also investigated. Multivariable regression models were used to assess the association between renal function groups (estimated Glomerular Filtration Rate, eGFR, >60 mL/min, 30–59 mL/min, <30 mL/min) and in-hospital all-cause mortality and incident AF and AKI. A cohort of 2816 patients admitted in one year for COVID-19 disease in two large hospitals was analyzed. The independent predictors of mortality were severe CKD [HR 1.732 (95%CI 1.264–2.373)], older age [HR 1.054 (95%CI 1.044–1.065)], cerebrovascular disease [HR 1.335 (95%CI (1.016–1.754)], lower platelet count [HR 0.997 (95%CI 0.996–0.999)], higher C-reactive protein [HR 1.047 (95%CI 1.035–1.058)], and higher plasma potassium value 1.374 (95%CI 1.139–1.658). When incident AKI was added to the final survival model, it was associated with higher mortality [HR 2.202 (1.728–2.807)]. Incident AF was more frequent in patients with CKD, but in the multivariable model only older age was significantly related with a higher incidence of AF [OR 1.036 (95%CI 1.022–1.050)]. Incident AF was strongly associated with the onset of AKI [HR 2.619 (95%CI 1.711–4.009)]. In this large population of COVID-19 patients, the presence of severe CKD was an independent predictor of in-hospital mortality. In addition, patients who underwent AKI during hospitalization had a doubled risk of death. Incident AF became more frequent as eGFR decreased and it was significantly associated with the onset of AKI.

LBA48 DUBLIN-3 (BPI-2358-103): A global phase (Ph) III trial with the plinabulin/docetaxel (Plin/Doc) combination vs. Doc in 2nd/3rd Line NSCLC patients (pts) with EGFR-wild type (wt) progressing on a prior platinum-based regimen

PD1-i therapy is standard of care in 1st line, and Doc-based regimens in 2nd/3rd line EGFR-wt NSCLC pts. Doc improves survival, however, may negatively impact safety and quality of life (QoL). Plin, a novel immune-enhancing small molecule enhances dendritic cell maturation and T-Cell proliferation. Final survival, safety and QoL data of DUBLIN-3 are reported.

LBA25 Final overall survival (OS) analysis from ARCHES: A phase III, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) + androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC)

In ARCHES (NCT02677896), ENZA + ADT reduced risk of radiographic progression and improved secondary outcomes in men with mHSPC over PBO + ADT. Here we report the final OS (after 356 events), a key secondary endpoint in ARCHES and a critical benchmark of clinical efficacy, which was immature at the time of primary analysis. Men with de novo or relapsed mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel use. At the time of data cut-off and unblinding, 180 (31.3%) patients treated with PBO + ADT crossed over to open-label ENZA + ADT. A stratified log-rank test was performed at a two-sided significance level of 0.04 for OS based on an O’Brien-Fleming boundary. Kaplan-Meier estimates of OS and time to subsequent antineoplastic therapy (TTNAnti) were reported and hazard ratios (HRs) were estimated from a stratified Cox proportional hazards model. Safety was assessed via treatment-emergent adverse events. Baseline characteristics were similar between treatment arms. As of the data cut-off of May 28, 2021, 397 (34.5%) patients remained on treatment, with a median follow-up of 44.6 months). Median treatment duration was 40.2 months on ENZA + ADT, 13.8 months on PBO + ADT, and 23.9 months for crossover patients. ENZA + ADT extended survival vs PBO + ADT (HR 0.66; 95% confidence interval 0.53, 0.81; p<0.0001) [Table] with similar results in most prespecified subgroups. ENZA + ADT continued to prolong TTNAnti vs PBO + ADT. The safety profile of ENZA + ADT vs PBO + ADT was consistent with findings from the primary analysis. This final analysis demonstrates that ENZA + ADT significantly prolongs survival in men with mHSPC and, together with the acceptable safety profile, supports the clinical benefit of ENZA + ADT in men with mHSPC.Table: LBA25Time to event efficacy endpointsEndpointENZA + ADT(n=574)PBO + ADT(n=576)p valueOSEvents, n (%)154 (26.83)202 (35.07)Median, months (95% CI)NR (NR, NR)NR (49.74, NR)HR (95% CI)0.66 (0.53, 0.81)<0.00012-year OS rate, %86.1982.353-year OS rate, %77.8868.954-year OS rate, %70.6157.01Median TTNAnti, months (95% CI)NR (NR, NR)40.5 (26.25, NR)HR (95% CI)0.38 (0.31, 0.48)CI, confidence interval; NR, not reached.Analyses include all randomized patients. OS was defined as time from randomization to death from any cause. For patients still alive at the date of the analysis cut-off point, OS was censored on the last date the patient is known to be alive. Open table in a new tab

Exploring the Impact of Treatment Switching on Overall Survival from the PROfound Study in Homologous Recombination Repair (HRR)-Mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC).

BackgroundIn oncology trials, treatment switching from the comparator to the experimental regimen is often allowed but may lead to underestimating overall survival (OS) of an experimental therapy.ObjectiveThis study evaluates the impact of treatment switching from control to olaparib on OS using the final survival data from the PROfound study and compares validated adjustment methods to estimate the magnitude of OS benefit with olaparib.Patients and methodsThe primary population from PROfound (Cohort A) was included, alongside two populations approved for treatment with olaparib by the European Medicines Agency and US Food and Drug Administration: BRCAm and Cohort A+B (excluding the PPP2R2A gene). Five methods were explored to adjust for switching: excluding or censoring patients in the control arm who receive subsequent olaparib, Rank Preserving Structural Failure Time Model (RPSFTM), Inverse Probability of Censoring Weights, and Two-Stage Estimation.ResultsThe RPSFTM was considered the most appropriate approach for PROfound as the results were robust to sensitivity analysis testing of the common treatment effect assumption. For Cohort A, the final OS hazard ratio reduced from 0.69 (95% CI 0.5–0.97) to between 0.42 (0.18–0.90) and 0.52 (0.31–1.00) for olaparib versus control, depending on the RPSFTM selected. Median OS reduced from 14.7 months to between 11.73 and 12.63 months for control.ConclusionsThe magnitude of the statistically significant (P < 0.05) survival benefit of olaparib versus control observed in Cohort A of PROfound is likely to be underestimated if adjustment for treatment switching from control to olaparib is not conducted. The RPSFTM was considered the most plausible method, although further development and validation of robust methods to estimate the magnitude of impact of treatment switching is needed.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-021-00837-y.

Assessment of microalgae concentrate as diet for hard clam, Mercenaria mercenaria , larvae

The on-site culture of live microalgae represents a major challenge for bivalve hatchery operations due to high cost and labour demands. This study evaluated the efficacy of commercially available microalgae concentrates as a partial or complete replacement diet for live microalgae for culture of the hard clam, Mercenaria mercenaria, larvae. Larvae were fed from D-larval stage to post-set, 2–14 days post fertilization (DPF). Larvae fed the complete replacement diets were significantly smaller than those fed partially replaced or live microalgae diets. Foot development was significantly delayed in larvae fed complete replacement diets compared to partially replaced or live microalgae diets. Although early survival (at 5 DPF) was similar among the treatments, final survival (at 14 DPF) varied significantly among treatments. The average final survival was 69%–77% for larvae fed live microalgae, 60%–61% for larvae fed partially replaced diets and 14%–16% for larvae fed complete replacement diets. These results suggest that a live microalgae diet could be partially replaced by a concentrate to feed hard clam larvae. However, complete replacement diet may be used only for a short duration (up to 3 days) without affecting survival.