In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in ...patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2).
One thousand two hundred and seven patients with nmCRPC were randomized 2-:-1 to apalutamide (240-mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O’Brien–Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed.
Median follow-up was 41-months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59–0.96; P-=-0.0197), although the P-value did not cross the pre-specified O’Brien–Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45–0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed.
In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.
The monomeric photosystem I-light-harvesting antenna complex I (PSI-LHCI) supercomplex from the extremophilic red alga Cyanidioschyzon merolae represents an intermediate evolutionary link between the ...cyanobacterial PSI reaction center and its green algal/higher plant counterpart. We show that the C. merolae PSI-LHCI supercomplex is characterized by robustness in various extreme conditions. By a combination of biochemical, spectroscopic, mass spectrometry, and electron microscopy/single particle analyses, we dissected three molecular mechanisms underlying the inherent robustness of the C. merolae PSI-LHCI supercomplex: (1) the accumulation of photoprotective zeaxanthin in the LHCI antenna and the PSI reaction center; (2) structural remodeling of the LHCI antenna and adjustment of the effective absorption cross section; and (3) dynamic readjustment of the stoichiometry of the two PSI-LHCI isomers and changes in the oligomeric state of the PSI-LHCI supercomplex, accompanied by dissociation of the PsaK core subunit. We show that the largest low light-treated C. merolae PSI-LHCI supercomplex can bind up to eight Lhcr antenna subunits, which are organized as two rows on the PsaF/PsaJ side of the core complex. Under our experimental conditions, we found no evidence of functional coupling of the phycobilisomes with the PSI-LHCI supercomplex purified from various light conditions, suggesting that the putative association of this antenna with the PSI supercomplex is absent or may be lost during the purification procedure.
Rhabdomyosarcomas (RMS) are the most frequent soft-tissue sarcoma in children and characteristically show features of developing skeletal muscle. The alveolar subtype is frequently associated with a ...PAX3-FOXO1 fusion protein that is known to contribute to the undifferentiated myogenic phenotype of RMS cells. Histone methylation of lysine residues controls developmental processes in both normal and malignant cell contexts. Here we show that JARID2, which encodes a protein known to recruit various complexes with histone-methylating activity to their target genes, is significantly overexpressed in RMS with PAX3-FOXO1 compared with the fusion gene-negative RMS (t-test; P < 0.0001). Multivariate analyses showed that higher JARID2 levels are also associated with metastases at diagnosis, independent of fusion gene status and RMS subtype (n = 120; P = 0.039). JARID2 levels were altered by silencing or overexpressing PAX3-FOXO1 in RMS cell lines with and without the fusion gene, respectively. Consistent with this, we demonstrated that JARID2 is a direct transcriptional target of the PAX3-FOXO1 fusion protein. Silencing JARID2 resulted in reduced cell proliferation coupled with myogenic differentiation, including increased expression of Myogenin (MYOG) and Myosin Light Chain (MYL1) in RMS cell lines representative of both the alveolar and embryonal subtypes. Induced myogenic differentiation was associated with a decrease in JARID2 levels and this phenotype could be rescued by overexpressing JARID2. Furthermore, we that showed JARID2 binds to and alters the methylation status of histone H3 lysine 27 in the promoter regions of MYOG and MYL1 and that the interaction of JARID2 at these promoters is dependent on EED, a core component of the polycomb repressive complex 2 (PRC2). Therefore, JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS. JARID2 and other components of PRC2 may represent novel therapeutic targets for treating RMS patients.
Fluorescence excitation spectroscopy at cryogenic temperatures carried out on hybrid assemblies composed of photosynthetic complexes deposited on a monolayer graphene revealed that the efficiency of ...energy transfer to graphene strongly depended on the excitation wavelength. The efficiency of this energy transfer was greatly enhanced in the blue-green spectral region. We observed clear resonance-like behavior for both a simple light-harvesting antenna containing only two chlorophyll molecules (PCP) and a large photochemically active reaction center associated with the light-harvesting antenna (PSI-LHCI), which pointed towards the general character of this effect.
Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), ...particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2).
Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS) were assessed.
Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 95% confidence interval (CI) 0.39-0.78; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed.
MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.
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•Niraparib + AAP reduced risk of radiographic progression/death by 45% in BRCA1/2-altered mCRPC (median follow-up 24.8 mo).•Niraparib + AAP improved secondary endpoints and patient-reported outcomes in the BRCA1/2 subgroup.•Adverse events of niraparib + AAP were tolerable, manageable, and consistent with previous reports; no new safety signals.•MAGNITUDE second interim analysis continues to support niraparib + AAP for mCRPC and HRR alterations, especially BRCA1/2.•MAGNITUDE supports genomic testing for BRCA1/2 alterations in mCRPC due to poor outcomes and emerging treatment options.
The development of treatment response and surrogate biomarkers for advanced prostate cancer care is an unmet clinical need. Patients with baseline circulating tumour cell (BLCTCs) counts <5/7.5mL ...represent a good prognosis subgroup but are non-evaluable for response assessment (decrease in CTCs). The aim of the study is to determine the value of any increase in CTCs (CTC progression) as an indicator of progression in prostate cancer patients with low pre-treatment CTCs (<5).
We carried out a post hoc analysis of patients with BLCTCs<5 treated in the COU-AA-301 (abiraterone or placebo+prednisone) and IMMC-38 (chemotherapy) trials. The association of CTC progression (increase in CTCs at 4, 8 or 12weeks) with overall survival (OS) was evaluated in multi-variable Cox regression models. Performance of survival models with and without CTC progression was evaluated by calculating ROC curve area under the curves (AUCs) and weighted c-indices.
Overall, 511 patients with CTCs<5 (421 in COU-AA-301 and 90 in IMMC-38) were selected; 212 (41.7%) had CTC progression at 4, 8 or 12weeks after treatment initiation. CTC progression was associated with significantly worse OS 27.1 versus 15.1 m; hazard ratio (HR) 3.4 (95% confidence interval CI 2.5–4.5; P<0.001), independent of baseline CTCs and established clinical variables. Adding CTC progression to the OS model significantly improved ROC AUC (0.77 versus 0.66; P<0.001). Models including CTC progression had superior ROC AUC (0.77 versus 0.69; P<0.001) and weighted c-index 0.750 versus 0.705; delta c-index: 0.045 (95% CI 0.019–0.071) values than those including CTC conversion (increase to CTCs≥5). In COU-AA-301, the impact of CTC progression was independent of treatment arm.
Increasing CTCs during the first 12 weeks of treatment are independently associated with worse OS from advanced prostate cancer in patients with baseline CTCs<5 treated with abiraterone or chemotherapy and improve models with established prognostic variables. These findings must be prospectively validated.
The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced ...prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.
Abiraterone and docetaxel are both approved treatments for men with metastatic castration-resistant prostate cancer (mCRPC). Abiraterone pre-docetaxel is currently undergoing evaluation in a phase ...III study. In vitro studies indicate that taxanes may act by disrupting androgen receptor signalling. We hypothesised that prior abiraterone exposure would adversely impact docetaxel efficacy.
We retrospectively evaluated activity of docetaxel in mCRPC patients previously treated with abiraterone, using Prostate Cancer Working Group and radiological criteria.
Of the 54 patients treated with abiraterone, 35 subsequently received docetaxel. Docetaxel resulted in a prostate-specific antigen (PSA) decline of ≥50% in nine patients 26%, 95% confidence interval (CI) 13% to 43%, with a median time to PSA progression of 4.6 months (95% CI 4.2% to 5.9%). PSA declines ≥30% were achieved by 13 patients (37%, 95% CI 22% to 55%). The median overall survival was 12.5 months (95% CI 10.6–19.4). All patients who failed to achieve a PSA fall on abiraterone and were deemed abiraterone-refractory were also docetaxel-refractory (N = 8). In the 24 patients with radiologically evaluable disease, partial responses were reported in four patients (11%), none of whom were abiraterone-refractory.
The activity of docetaxel post-abiraterone appears lower than anticipated and no responses to docetaxel were observed in abiraterone-refractory patients.
Burnout in health care professionals could have serious negative consequences on quality of patient care, professional satisfaction and personal life. Our aim was to investigate the burnout ...prevalence, work and lifestyle factors potentially affecting burnout amongst European oncologists≤40 (YOs).
A survey was conducted using the validated Maslach Burnout Inventory (MBI) and additional questions exploring work/lifestyle factors. Statistical analyses were carried out to identify factors associated with burnout.
Total of 737 surveys (all ages) were collected from 41 European countries. Countries were divided into six regions. Results from 595 (81%) YOs were included (81% medical oncologists; 52% trainees, 62% women). Seventy-one percent of YOs showed evidence of burnout (burnout subdomains: depersonalization 50%; emotional exhaustion 45; low accomplishment 35%). Twenty-two percent requested support for burnout during training and 74% reported no hospital access to support services. Burnout rates were significantly different across Europe (P<0.0001). Burnout was highest in central European (84%) and lowest in Northern Europe (52%). Depersonalization scores were higher in men compared with women (60% versus 45% P=0.0001) and low accomplishment was highest in the 26–30 age group (P<0.01). In multivariable linear regression analyses, European region, work/life balance, access to support services, living alone and inadequate vacation time remained independent burnout factors (P<0.05).
This is the largest burnout survey in European Young Oncologists. Burnout is common amongst YOs and rates vary across Europe. Achieving a good work/life balance, access to support services and adequate vacation time may reduce burnout levels. Raising awareness, support and interventional research are needed.
Trypanosomiases are neglected tropical diseases caused by Trypanosoma (sub)species. Available treatments are limited and have considerable adverse effects and questionable efficacy in the chronic ...stage of the disease, urgently calling for the identification of new targets and drug candidates.
Recently, we have shown that impairment of glycosomal protein import by the inhibition of the PEX5-PEX14 protein-protein interaction (PPI) is lethal to Trypanosoma. Here, we report the development of a novel dibenzob,f1,4oxazepin-11(10H)-one scaffold for small molecule inhibitors of PEX5-PEX14 PPI. The initial hit was identified by a high throughput screening (HTS) of a library of compounds. A bioisosteric replacement approach allowed to replace the metabolically unstable sulphur atom from the initial dibenzob,f1,4thiazepin-11(10H)-one HTS hit with oxygen. A crystal structure of the hit compound bound to PEX14 surface facilitated the rational design of the compound series accessible by a straightforward chemistry for the initial structure-activity relationship (SAR) analysis. This guided the design of compounds with trypanocidal activity in cell-based assays providing a promising starting point for the development of new drug candidates to tackle trypanosomiases.
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•Trypanosoma parasites cause severe disease and peroxisomal transport (PEX) is a valid drug target.•PEX5-PEX14 interaction inhibitors are delivered and SAR information is provided.•The developed small molecule PEX14 inhibitors kill Trypanosoma parasites in a cell-based assay.•Provided inhibitors offer a starting point for the development of pharmacologically relevant trypanocidal compounds.
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