Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial

Gnant, Michael; Pfeiler, Georg; Dubsky, Peter; Hubalek, Michael; Greil, Richard; Jakesz, R.; Wette, Viktor; Balić, Marija; Haslbauer, Ferdinand; Melbinger, Elisabeth; Bjelic‐Radisic, Vesna; Artner-Matuschek, Silvia; Fitzal, Florian; Marth, Christian; Sevelda, P.; Mlineritsch, Brigitte; Steger, G.; Manfreda, D; Exner, Ruth; Egle, Daniel; Bergh, Jonas; Kainberger, Franz; Talbot, Susan; Warner, Douglas; Fesl, Christian; Singer, Christian F.

doi:10.1016/s0140-6736(15)60995-3

Cited by 482 publications

(339 citation statements)

References 30 publications

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“…If vertebral and non-vertebral fractures are summed, then in year 2, 2.8 % of participants had a fracture, and in years 4 and 5, 2.9 % fractured, suggesting stable fracture incidence. This is also the finding of the just published study of Gnant, which demonstrated stable anti-fracture efficacy of denosumab over 6 years in women receiving aromatase inhibitor treatment for early stage breast cancer [12].…”

supporting

confidence: 69%

Denosumab after 8 years

Reid

2015

Osteoporos Int

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It is now more than 20 years since the alendronate phase 3 program produced the first trials demonstrating global antifracture efficacy for an osteoporosis medication [1,2]. This brought the osteoporosis field into the era of evidence-based medicine. The euphoria that followed from knowing that the interventions we were prescribing really were preventing fractures soon passed as durations of therapy reached 3 years, the endpoint of most fracture prevention clinical trials. A series of unanswered questions then arose. How long should treatment be continued? Are there long-term side-effects? Do these drugs continue to prevent fractures and, if so, is their continued use necessary for sustained fracture prevention? For alendronate, some of these questions were answered by the FLEX trial, which suggested that dose reduction with long-term use did not reduce efficacy, and that for patients whose femoral neck bone density was no longer in the osteoporotic range, drug discontinuation did not negatively impact on fracture rate [3,4]. Similar data have now been published from the zoledronate extension studies [5].In the last decade, osteonecrosis of the jaw (ONJ) and transverse stress fractures of the femoral shaft, referred to as an atypical femoral fractures (AFFs), have emerged as significant new safety concerns associated with the long-term use of anti-resorptive drugs. Most information on these problems is from case series or from analyses of medical claims databases.Some such studies have even suggested that the incidence of atypical femoral fractures attributable to bisphosphonate use might exceed the number of hip fractures prevented by these drugs [6], though other analyses do not support this conclusion [7]. In this context, longer-term data from clinical trials become critically important in assessing the ongoing safety and efficacy of medications for osteoporosis. Longer clinical trials are desirable, though maintaining patients at high risk of fracture on placebo raises ethical and practical issues. The next-best option is to continue long-term follow-up of the cohorts of patients involved in the pivotal clinical trials. While not as robust as a longterm randomized controlled trial because a control group is not continued on placebo, this strategy does provide longitudinal data on a well-characterized cohort, allowing fracture rates and adverse events to be related to duration of therapy. It also allows documentation of chronic effects on bone turnover markers and bone density. The loss of a control group for these measures is not such a problem, since current technology usually generates stable measurements, and the evolution of these parameters in placebo-treated women with osteoporosis is already well documented.The recent report by Papapoulos et al. in Osteoporosis International provides important new information regarding the efficacy and safety of the anti-RANKL monoclonal antibody, denosumab [8]. This drug is a potent antiresorptive which reduces median bone formation rate to zero after 2-3 years use ...

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confidence: 69%

Denosumab after 8 years

Reid

2015

Osteoporos Int

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“…64 Subsequently, in an interim analysis, an improvement in DFSa secondary end point of the trial-was reported. 65 However, unlike the bisphosphonates, which have demonstrated an OS benefit when used as adjuvant therapy, no available data show an OS benefit with denosumab.…”

Section: Denosumabmentioning

confidence: 99%

NCCN Guidelines Insights: Breast Cancer, Version 1.2017

Gradishar¹,

Anderson

Balassanian

et al. 2017

J Natl Compr Canc Netw

396

346

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These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor-positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.

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“…Studies show that metastasis is druggable (25)(26)(27)(28)(29), and as new therapeutic targets for late stage disease emerge, clinical trial endpoints need to shift from progression-free survival to more appropriate measurements of efficacy in this patient population.…”

Section: Barriers and Opportunities In Clinical/ Translational Researmentioning

confidence: 99%

Obstacles, Opportunities and Priorities for Advancing Metastatic Breast Cancer Research

et al. 2017

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In January 2016, the Metastatic Breast Cancer Alliance (the Alliance) convened a think tank of stakeholders from academia, government, industry, and patient advocacy to discuss gaps and opportunities in clinical and translational research in metastatic breast cancer. Priorities that emerged from the meeting included the following: the need for innovative preclinical model systems to study metastatic disease; increased sharing of resources and data; collaboration across cancer care teams and scientists; biorepositories for studies to identify biomarkers for treatment response; creation of patient registries to increase access to clinical trials and tissue procurement; and redesign of clinical trials in metastatic breast cancer. Cancer Res; 77(13); 3386-90. Ó2017 AACR.

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Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial

Cited by 482 publications

References 30 publications

Denosumab after 8 years

Denosumab after 8 years

NCCN Guidelines Insights: Breast Cancer, Version 1.2017

Obstacles, Opportunities and Priorities for Advancing Metastatic Breast Cancer Research

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