Meeting News CoveragePerspective

Adjuvant denosumab may prolong DFS among postmenopausal women with breast cancer

SAN ANTONIO — Adjuvant denosumab appeared to reduce the risk for disease recurrence or death among postmenopausal women with breast cancer, according to study results presented at the San Antonio Breast Cancer Symposium.

Adjuvant endocrine therapy is known to negatively impact bone health among pre- and postmenopausal women with breast cancer, according to study background.

The primary analysis of the ABCSG-18 trial — presented at the 2015 ASCO Annual Meeting — showed 60 mg adjuvant denosumab (Prolia, Amgen) twice yearly significantly reduced the risk for clinical fractures (HR = 0.5; P ˂ .001) and improved bone health without measurable toxicity among postmenopausal women with breast cancer.

Michael Gnant, MD

Michael Gnant

“The question remaining is, are we also impacting outcomes of DFS and OS in these patients?” Michael Gnant, MD, professor of surgery at the Medical University of Vienna, said during a press conference. “Following the primary endpoint results, the independent data monitoring committee recommended we offer patients the option of unblinding. … In 2016, we are going to offer all trial patients the option of being unblinded. If they were on placebo, they will be offered the antibody for 3 years.

“However, since this will somewhat compromise the integrity of the blinded outcome data, the recommendation was to do a DFS analysis now based on a time–treatment analysis,” Gnant added.

Researchers defined DFS as time to any evidence of local or distant metastasis, contralateral metastasis, secondary cancer or deaths from any cancer.

The analysis included 3,425 postmenopausal patients (median age, 64 years; range, 38-91) with non-metastatic breast cancer. Seventy-two percent of women had tumors smaller than 2 cm and 71% had node-negative disease. Twenty-five percent of women received neoadjuvant or adjuvant chemotherapy, and all women received an aromatase inhibitor.

After a median follow-up of 4 years, 203 DFS events occurred in the placebo group vs. 167 in the denosumab group. These data equated to a borderline statistically significant difference in the intent-to-treat analysis (HR = 0.81; 95% CI, 0.66-1).

The absolute benefit was 1.2% at 3 years, 2.1% after 5 years and 3.1% at 7 years of follow-up.

Gnant and colleagues then conducted exploratory subgroup analyses. Starting denosumab early, ductal histology (HR=0.79; P = .048) and having both ER- and PR-positive tumors (HR=0.75; P = .013) appeared to drive the denosumab benefit. Further, a significantly greater proportion of women with tumors larger than 2 cm (n = 946) achieved 7-year DFS when they received denosumab vs. placebo (80.3% vs. 69.8%; HR = 0.66; 95% CI, 0.47-0.93).

Researchers also conducted an indirect comparison with these data and bisphosphonate meta-analysis data. Data from the Early Breast Cancer Trialists’ Group showed a 3% gain in recurrence benefit at 10 years with bisphosphonates.

“I believe it’s fair to say that adjuvant denosumab does at least as much as adjuvant bisphosphates do,” Gnant said. “I believe that we should offer this treatment to postmenopausal breast cancer patients on aromatase inhibitors.” – by Alexandra Todak

References:

Disclosure: The study was funded by Amgen. Gnant reports research grants unrelated to this study from GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi and Smith Medical.

SAN ANTONIO — Adjuvant denosumab appeared to reduce the risk for disease recurrence or death among postmenopausal women with breast cancer, according to study results presented at the San Antonio Breast Cancer Symposium.

Adjuvant endocrine therapy is known to negatively impact bone health among pre- and postmenopausal women with breast cancer, according to study background.

The primary analysis of the ABCSG-18 trial — presented at the 2015 ASCO Annual Meeting — showed 60 mg adjuvant denosumab (Prolia, Amgen) twice yearly significantly reduced the risk for clinical fractures (HR = 0.5; P ˂ .001) and improved bone health without measurable toxicity among postmenopausal women with breast cancer.

Michael Gnant, MD

Michael Gnant

“The question remaining is, are we also impacting outcomes of DFS and OS in these patients?” Michael Gnant, MD, professor of surgery at the Medical University of Vienna, said during a press conference. “Following the primary endpoint results, the independent data monitoring committee recommended we offer patients the option of unblinding. … In 2016, we are going to offer all trial patients the option of being unblinded. If they were on placebo, they will be offered the antibody for 3 years.

“However, since this will somewhat compromise the integrity of the blinded outcome data, the recommendation was to do a DFS analysis now based on a time–treatment analysis,” Gnant added.

Researchers defined DFS as time to any evidence of local or distant metastasis, contralateral metastasis, secondary cancer or deaths from any cancer.

The analysis included 3,425 postmenopausal patients (median age, 64 years; range, 38-91) with non-metastatic breast cancer. Seventy-two percent of women had tumors smaller than 2 cm and 71% had node-negative disease. Twenty-five percent of women received neoadjuvant or adjuvant chemotherapy, and all women received an aromatase inhibitor.

After a median follow-up of 4 years, 203 DFS events occurred in the placebo group vs. 167 in the denosumab group. These data equated to a borderline statistically significant difference in the intent-to-treat analysis (HR = 0.81; 95% CI, 0.66-1).

The absolute benefit was 1.2% at 3 years, 2.1% after 5 years and 3.1% at 7 years of follow-up.

Gnant and colleagues then conducted exploratory subgroup analyses. Starting denosumab early, ductal histology (HR=0.79; P = .048) and having both ER- and PR-positive tumors (HR=0.75; P = .013) appeared to drive the denosumab benefit. Further, a significantly greater proportion of women with tumors larger than 2 cm (n = 946) achieved 7-year DFS when they received denosumab vs. placebo (80.3% vs. 69.8%; HR = 0.66; 95% CI, 0.47-0.93).

Researchers also conducted an indirect comparison with these data and bisphosphonate meta-analysis data. Data from the Early Breast Cancer Trialists’ Group showed a 3% gain in recurrence benefit at 10 years with bisphosphonates.

“I believe it’s fair to say that adjuvant denosumab does at least as much as adjuvant bisphosphates do,” Gnant said. “I believe that we should offer this treatment to postmenopausal breast cancer patients on aromatase inhibitors.” – by Alexandra Todak

References:

Disclosure: The study was funded by Amgen. Gnant reports research grants unrelated to this study from GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi and Smith Medical.

    Perspective
    Virginia Kaklamani

    Virginia Kaklamani

    This was a randomized, clinical trial on 3,400 postmenopausal women with ER-positive breast cancer who received 3 years of adjuvant denosumab. The study showed that not only does denosumab treatment decrease fracture risk, but it also improves DFS.

    We have several studies on bisphosphonates, and it’s pretty clear, either from a subset patient population or from the whole study, that in postmenopausal women, bisphosphonate treatment improves DFS and OS. Now we have the denosumab data. At the same time, we don’t in clinic use those for our patients. What are we missing? What could we do to give these treatments to our patients to improve their outcomes?

    • Virginia Kaklamani, MD
    • UT Health Science Center San Antonio

    Disclosures: Kaklamani reports no relevant financial disclosures.

    Perspective
    Lajos Pusztai

    Lajos Pusztai

    This is a very important study because it adds to a series of studies that each show with a greater or lesser statistical significance that using a bone-modifying agent as adjuvant therapy improves outcome.

    Several studies showed a significant improvement, whereas some showed a marginal improvement. But all of them showed trends outcomes are betting using a bisphosphonate, or in this instance, denosumab (Prolia, Amgen). Probably at one point — and maybe this is the point when this actually reaches the sticking point — people will adopt these therapies as a way to improve outcomes for ER-positive patients.

    What really makes this even more appealing is that endocrine therapy used in that setting often times increases the risk for osteoporosis. Including a drug that minimizes the risk for osteoporosis and having a chance of improving your outcome is really a no-brainer. More and more patients will receive some form of a bone-modifying agent like the bisphosphonate and denosumab in routine practice.

    The only issue was the cost. Denosumab is much more expensive than the bisphosphonates.

    • Lajos Pusztai, MD, DPhil
    • Yale Cancer Center

    Disclosures: Pusztai reports no relevant financial disclosures.

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