medwireNews: Two opposing sets of phase III results regarding the effect of denosumab on the recurrence of hormone receptor (HR)-positive nonmetastatic breast cancer have been presented at the ASCO Annual Meeting 2018 in Chicago, Illinois, USA.
While the ABCSG-18 trial showed that adjuvant treatment with the RANK-L inhibitor significantly improved disease-free survival (DFS) – a secondary endpoint of the trial – relative to placebo, the D-CARE trial found no such positive effect on either its primary endpoint of bone metastasis-free survival (BMFS) or DFS, which was a secondary outcome.
Discussant David Cameron, from the University of Edinburgh and NHS Lothian in the UK, pointed out, however, that the trials used different intensities of the denosumab regimen and enrolled different patient populations, both in terms of menopausal status and recurrence risk.
In the ABCSG-18 trial, the 1711 postmenopausal women with nonmetastatic HR-positive breast adenocarcinoma who were randomly assigned to receive subcutaneous denosumab 60 mg every 6 months were a significant 18% more likely to remain disease-free than their 1709 counterparts who were given placebo.
This improvement appeared to be driven primarily by a decrease in the incidence of unverified distant metastases or new primary malignancies, commented presenting author Michael Gnant, from the Medical University of Vienna in Austria.
Additionally, he highlighted that the rate of adverse and serious adverse events was comparable between the denosumab and placebo groups, with no cases of osteonecrosis of the jaw (ONJ) and just one potential case of an atypical femoral fracture (AFF) over a median follow-up of 72 months.
Gnant summarized that adjuvant denosumab “reduces the risk of cancer recurrence, occurrence, or deaths in postmenopausal breast cancer patients,” and pointed out that “[t]his benefit comes in addition to cutting fractures in half and improving bone health.”
Therefore, he concluded: “Based on these results, adjuvant denosumab should be offered to postmenopausal breast cancer patients on adjuvant aromatase inhibitor therapy.”
The D-CARE trial recruited 4509 pre- or postmenopausal women with stage II or III breast cancer at a high risk for recurrence, as indicated by node positivity, a tumor size larger than 5 cm, and/or locally advanced disease. Participants were randomly assigned to receive either denosumab 120 mg every 3–4 weeks for six doses – after which it was given every 3 months for 54 months – or placebo, in the neoadjuvant (24.2%) or adjuvant (75.8%) setting.
During a median follow-up period of 67 months, neither BMFS, nor DFS were significantly improved with denosumab relative to placebo, with corresponding nonsignificant hazard ratios of 0.97 and 1.04, and no subgroup appeared to benefit preferentially from denosumab, said Robert Coleman (Massachusetts General Hospital, Boston, USA) who presented the findings.
He pointed out that BMFS, which was “chosen by the sponsors and endorsed by the FDA,” is an “unusual” endpoint. Around 40% of the events that contribute to the endpoint are deaths, either without recurrence or after local or non-bone distant recurrence, and as such are effects unlikely to be influenced by a bone-targeted therapy, Coleman explained.
Although no new safety signals were identified in this study, 5.4% of denosumab-treated patients experienced ONJ, with the incidence rising by around 1% annually, and there were nine (0.4%) confirmed cases of AFF in the denosumab arm.
Cameron noted that a previous meta-analysis showed that adjuvant bisphosphonate treatment resulted in “a clear reduction in bone recurrence and improvement in overall survival of the order of around 18%” in postmenopausal breast cancer patients.
And he concluded: “[W]hilst the use of bisphosphonates in early breast cancer to prevent recurrence may be off-label, […] I do not see that those two sets of denosumab data are showing us a greater effect than we would achieve with bisphosphonates.”
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