'Bad News': Adjuvant Denosumab Disappoints in Early Breast Cancer

Pam Harrison

December 27, 2019

For women with high-risk, early-stage breast cancer, adjuvant use of the bone agent denosumab (Prolia/Xgeva, Amgen) did not delay bone metastasis or disease recurrence compared with placebo in the international phase 3 D-CARE trial.

"Bone is the most frequent site of distant relapse, occurring in approximately 40% of all first distant recurrences," note the investigators, led by Robert Coleman, MD, University of Sheffield, the United Kingdom.

Denosumab is a RANKL inhibitor that prevents the development of osteoclasts and thus bone resorption. Preclinical evidence suggested that RANKL inhibition might delay the development of bone metastasis or disease recurrence in patients with early-stage breast cancer, the investigators explain.

However, they continue, "this study did not meet either its primary or key secondary endpoints.

"The exploratory endpoints assessing denosumab, as compared with placebo, on bone-related endpoints, including time to bone metastasis as site of first recurrence and first on-study fracture, did not support the expected bone health aspects of denosumab," Coleman and colleagues write.

"The absence of beneficial effects on either disease-free survival, breast cancer recurrence, or overall survival suggests that denosumab at the intensive dosing schedule selected for this study has no role in the management of early breast cancer," they conclude.

The study was published online December 2 in the Lancet Oncology.

Negative Results Are "Bad News"

The negative results from the D-CARE trial are "bad news" for several reasons, say Francesco Perrone, MD, PhD, and Adriano Gravina, MD, Istituto Nazionale per lo Studio e la Cura dei Tumori IRCCS Fondazione G Pascale, Naples, Italy, in an accompanying editorial.

"First, the findings provide strong evidence against the hypothesis that inhibition of RANKL, an innovative mechanism of action among bone-modifying agents, might have a direct and substantial anticancer effect," they write.

Furthermore, they predict that the negative results observed in the D-CARE trial will lessen physician confidence in findings from a secondary analysis of the ABCSG18 trial, which indicated that a less intensive schedule of denosumab might improve disease-free survival for postmenopausal women treated with adjuvant aromatase inhibitors.

Indeed, on the basis of findings from the ABCSG18 trial, denosumab was approved in Europe for the treatment of postmenopausal women who are at increased risk for fractures and for the treatment of osteoporosis in men.

At the same time, a meta-analysis involving more than 18,000 women showed that the addition of bisphosphonates to the treatment of postmenopausal women with early breast cancer led to a 25% to 30% reduction in the risk for recurrence, distant recurrence, bone recurrence, and even mortality from breast cancer, the editorialists point out.

The European Society of Medical Oncology recommends the prophylactic use of bisphosphonates for women with breast cancer to prolong disease-free survival and reduce skeletal complications. However, bone-modifying agents are not approved by the European Medicines Agency for prophylactic use in early breast cancer.

This is another reason why the negative results of D-CARE are bad news, the editorialists suggest. Had the results been positive, the trial would have helped close the gap between what the European Society of Medical Oncology currently recommends and what the European Medicines Agency has thus far approved for the prophylactic treatment of early breast cancer.

"Academic groups have an important role in identifying treatment strategies that ultimately improve prognosis of patients," Perrone and Gravina suggest.

"Solving discrepancies between scientific recommendations and regulatory approval (eg, in the case of bisphosphonates in early breast cancer) should be a mission of academic researchers who contributed to developing scientific evidence," they conclude.

D-CARE Study Design

The D-CARE study was conducted in 4509 patients with stage II or III breast cancer or locally advanced disease. Patients were randomly assigned to receive denosumab 120 mg or placebo given every 4 weeks concomitantly with adjuvant or neoadjuvant systemic therapy for about 6 months.

"This initial treatment phase was followed by denosumab or placebo every 3 months...for a total duration of treatment of 5 years and a maximum of 26 treatments," the investigators report.

Radiologic assessments of disease were carried out at study enrollment, after 1 year of treatment, and every year thereafter, they add.

"The primary endpoint was the composite endpoint of bone metastasis–free survival," the study authors note. A series of secondary endpoints was also prespecified and reported.

When the primary analysis was done, 69% of patients were still enrolled in the study; 30% of participants discontinued the protocol before the analysis was completed.

A median of 25 doses of denosumab or placebo were administered during the 5 years of follow-up.

No Significantly Differences

"The primary endpoint of bone metastasis–free survival was not significantly different between the groups," Coleman and colleagues report.

Moreover, no survival benefit in favor of denosumab was seen in any patient subgroup, and menopausal status did not affect bone metastasis–free survival either, they add.

This findings contrasts with what has been seen with the bisphosphonates in early breast cancer. Adjuvant bisphosphonates have been shown to reduce the risk for recurrence in bone, as well as to reduce breast cancer–specific survival, although only for women who were postmenopausal at the time treatment was initiated.

There were also no differences in disease-free survival between the two treatment groups: 20% of disease-free survival events occurred by study endpoint in the denosumab group, vs 19% with placebo control patients.

In addition, the investigators observed no significant effect on disease-free survival within any patient subgroup, nor was this endpoint affected by menopausal status.

The median distant recurrence–free survival rates were not estimable in either group by study endpoint.

However, overall survival rates were similar between the two study groups.

Adverse Events With Denosumab

Of the treatment-emergent adverse effects of interest, 5% of patients who received the RANKL inhibitor developed osteonecrosis of the jaw (ONJ), compared with fewer than 1% of patients who received placebo.

However, the majority of patients who did develop ONJ had recent predisposing factors for ONJ, including a prior extraction, the need for a dental appliance, or periodontal disease, the study authors point out.

A few (<1%) patients in the denosumab group also developed atypical femur fracture; none of the patients who received placebo did so.

Rates of discontinuation because of treatment-emergent adverse events were similar between the two groups, at 4% for denosumab patients vs 3% for patients who received, the authors report.

The D-CARE study was funded by Amgen (manufacturer of denosumab). Coleman has received steering committee fees and travel support from Amgen; funding for IME lectures from Eisai, Amgen, and Genomic Health; consulting fees from Astellas and Scancell; and has a patent pending for biomarker testing (Inbiomotion). Perrone reports personal fees from Bayer, Janssen Cilag, Pierre Fabre, AstraZeneca,Celgene, Incyte, Sandoz, Bristol-Myers Squibb, Ipsen, and Eli Lilly. Gravina has disclosed no relevant financial relationships.

Lancet Oncol. Published online December 2, 2019. Abstract, Editorial

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