ASCO: Adjuvant denosumab halves fracture risk for breast cancer patients on AIs

CHICAGO – Adjuvant denosumab is efficacious and safe for reducing fracture risk among women taking aromatase inhibitors (AIs) as part of their treatment for early breast cancer, finds the Austrian Breast & Colorectal Cancer Study Group’s study 18 (ABCSG-18).

Compared with peers randomized to placebo in the phase III trial, women randomized to the antiresorptive monoclonal antibody at the dose typically used to treat osteoporosis were half as likely to experience a first clinical fracture, first author Dr. Michael Gnant reported at the annual meeting of the American Society of Clinical Oncology. The benefit was similar whether women had normal bone mineral density at baseline or already had osteopenia.

Courtesy MeduniWien/Matern

Patients in the denosumab group did not have a significantly higher rate of adverse events, including the much-feared complication of osteonecrosis of the jaw.

“The actual fracture risk of postmenopausal breast cancer patients on AIs is substantial and may have been underestimated until today,” commented Dr. Gnant, professor of surgery at the Medical University of Vienna. “In these patients with only a modest risk of disease recurrence, adjuvant denosumab significantly reduced the bone side effects of AI treatment. We therefore believe that denosumab 60 mg every 6 months should be considered for clinical practice.”

“Today, several clinical practice guidelines advocate the use of bisphosphonates for breast cancer patients receiving AIs, however, only if they are at high risk for fractures,” he further noted. However, “patients with normal baseline bone mineral density showed a similar fracture risk but also similar benefit from denosumab as compared to patients with baseline T scores below –1, indicating that DEXA scans may be an insufficient way to assess the individual patient’s fracture risk. In view of the benefits in this particular patient subgroup, we may have to rediscuss our current clinical practice guidelines.”

Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England, said, “It’s very important to dissect out fractures related to subsequent recurrence from fractures due to poor bone health.” Most of the reduction in fracture risk in ABCSG-18 appeared to be because of prevention of fractures before any recurrence, whereas most of that in the AZURE trial (Adjuvant Zoledronic Acid to Reduce Recurrence) of an adjuvant bisphosphonate, another type of antiresorptive agent, appeared to be because of prevention of fractures from bone metastases. “So I think we are seeing something very different with denosumab to what we’ve seen to date with a bisphosphonate,” he said.

“As oncologists, we are somewhat wedded to measuring bone mineral density as the reason for giving bone-targeted therapy to protect [against] bone loss, but there are much better ways of predicting fracture with online algorithms such as FRAX [Fracture Risk Assessment Tool] and others,” Dr. Coleman further commented. “And bone mineral density is a pretty poor predictor of fracture, so it’s perhaps not surprising that the risk reductions were fairly similar” across bone mineral density subgroups.

During a question and answer period, session attendee Dr. Toru Watanabe, Hamamatsu (Japan) Oncology Center, said, “It is really clear that the osteoporosis-related fracture is prevented by denosumab at the dose usually used for the treatment of osteoporosis. That part is very clear. My question is, the same dose is being tested for modifying overall survival or progression-free survival. Don’t you think it’s necessary to conduct some kind of dose-finding trial?”

Two studies are addressing the impact of denosumab on breast cancer outcomes, according to Dr. Gnant: the investigators’ ABCSG-18 study and the Study of Denosumab as Adjuvant Treatment for Women With High-Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE), which is using a higher initial dose and tapering after 1 year. “So we will have that indirect comparison at least. My personal expectation would be that there is a trade-off potentially between efficacy and tolerability,” he commented.

The 3,425 postmenopausal breast cancer patients in ABCSG-18 were randomized evenly to receive 60 mg of denosumab or placebo every 6 months. Denosumab is approved by the Food and Drug Administration for the prevention and treatment of fractures due to bone metastases (brand name Xgeva) and osteoporosis after menopause (brand name Prolia), as well as other indications. The study used the dose for postmenopausal osteoporosis, which is much lower than that typically used for bone metastases (120 mg every 4 weeks), Dr. Gnant noted.

Main results showed that denosumab was highly efficacious in reducing the risk of first clinical fractures, meaning those that were clinically evident and causing symptoms (hazard ratio, 0.50; P less than .0001), according to data presented at the meeting and simultaneously published (Lancet 2015 May 31).

The estimated 6-year fracture rate was about 10% in the denosumab group and 20% in the placebo group. “Please note that the frequency of clinical fractures reported in this trial that is focusing on bone health is markedly higher than fracture rates reported in previous large AI trials. Obviously, we had a tendency to underreport them in those trials,” Dr. Gnant commented. “The true magnitude of the problem in clinical practice is likely reflected in the placebo group … with approximately one out of five patients experiencing a new clinical fracture within 5-6 years of adjuvant AI treatment.”

Benefit was similar across numerous patient subgroups studied, including the subgroups of women who had a baseline bone mineral density T-score of less than –1 and women who had a baseline bone mineral density T-score of –1 or greater.

Additionally, the denosumab group had improvements from baseline in bone mineral density of the lumbar spine, total hip, and femoral neck, whereas the placebo group had worsening at all sites (P less than .0001 between groups for each site). And at 36 months, the denosumab group had significantly lower risks of both new vertebral fractures and new or worsening vertebral fractures.

“Adjuvant denosumab at this dose and schedule is safe,” Dr. Gnant maintained. The two groups had similar rates of various adverse events, with musculoskeletal disorders and vascular disorders (including hot flashes) predominating. “This means that we are in essence reporting the side effects of the underlying adjuvant AI treatment,” he noted.

There were 31 cases of dental issues, but none met diagnostic criteria for osteonecrosis of the jaw. “We can safely say that at this dose of denosumab, 60 mg twice yearly, ONJ is not an issue,” Dr. Gnant commented. Additionally, none of the women experienced atypical fractures.

Dr. Gnant disclosed employment of an immediate family member with Sandoz; receipt of honoraria from Amgen, AstraZeneca, GlaxoSmithKline, NanoString Technologies, Novartis, and Roche Pharma AG; a consulting or advisory role with Accelsiors, AstraZeneca, and Novartis; and receipt of research funding from GlaxoSmithKline, Novartis, Pfizer, Roche Pharma AG, Sanofi, and Smiths Medical. The trial was sponsored by Amgen.

CHICAGO – Adjuvant denosumab is efficacious and safe for reducing fracture risk among women taking aromatase inhibitors (AIs) as part of their treatment for early breast cancer, finds the Austrian Breast & Colorectal Cancer Study Group’s study 18 (ABCSG-18).

Compared with peers randomized to placebo in the phase III trial, women randomized to the antiresorptive monoclonal antibody at the dose typically used to treat osteoporosis were half as likely to experience a first clinical fracture, first author Dr. Michael Gnant reported at the annual meeting of the American Society of Clinical Oncology. The benefit was similar whether women had normal bone mineral density at baseline or already had osteopenia.

Courtesy MeduniWien/Matern

Patients in the denosumab group did not have a significantly higher rate of adverse events, including the much-feared complication of osteonecrosis of the jaw.

“The actual fracture risk of postmenopausal breast cancer patients on AIs is substantial and may have been underestimated until today,” commented Dr. Gnant, professor of surgery at the Medical University of Vienna. “In these patients with only a modest risk of disease recurrence, adjuvant denosumab significantly reduced the bone side effects of AI treatment. We therefore believe that denosumab 60 mg every 6 months should be considered for clinical practice.”

“Today, several clinical practice guidelines advocate the use of bisphosphonates for breast cancer patients receiving AIs, however, only if they are at high risk for fractures,” he further noted. However, “patients with normal baseline bone mineral density showed a similar fracture risk but also similar benefit from denosumab as compared to patients with baseline T scores below –1, indicating that DEXA scans may be an insufficient way to assess the individual patient’s fracture risk. In view of the benefits in this particular patient subgroup, we may have to rediscuss our current clinical practice guidelines.”

Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England, said, “It’s very important to dissect out fractures related to subsequent recurrence from fractures due to poor bone health.” Most of the reduction in fracture risk in ABCSG-18 appeared to be because of prevention of fractures before any recurrence, whereas most of that in the AZURE trial (Adjuvant Zoledronic Acid to Reduce Recurrence) of an adjuvant bisphosphonate, another type of antiresorptive agent, appeared to be because of prevention of fractures from bone metastases. “So I think we are seeing something very different with denosumab to what we’ve seen to date with a bisphosphonate,” he said.

“As oncologists, we are somewhat wedded to measuring bone mineral density as the reason for giving bone-targeted therapy to protect [against] bone loss, but there are much better ways of predicting fracture with online algorithms such as FRAX [Fracture Risk Assessment Tool] and others,” Dr. Coleman further commented. “And bone mineral density is a pretty poor predictor of fracture, so it’s perhaps not surprising that the risk reductions were fairly similar” across bone mineral density subgroups.

During a question and answer period, session attendee Dr. Toru Watanabe, Hamamatsu (Japan) Oncology Center, said, “It is really clear that the osteoporosis-related fracture is prevented by denosumab at the dose usually used for the treatment of osteoporosis. That part is very clear. My question is, the same dose is being tested for modifying overall survival or progression-free survival. Don’t you think it’s necessary to conduct some kind of dose-finding trial?”

Two studies are addressing the impact of denosumab on breast cancer outcomes, according to Dr. Gnant: the investigators’ ABCSG-18 study and the Study of Denosumab as Adjuvant Treatment for Women With High-Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE), which is using a higher initial dose and tapering after 1 year. “So we will have that indirect comparison at least. My personal expectation would be that there is a trade-off potentially between efficacy and tolerability,” he commented.

The 3,425 postmenopausal breast cancer patients in ABCSG-18 were randomized evenly to receive 60 mg of denosumab or placebo every 6 months. Denosumab is approved by the Food and Drug Administration for the prevention and treatment of fractures due to bone metastases (brand name Xgeva) and osteoporosis after menopause (brand name Prolia), as well as other indications. The study used the dose for postmenopausal osteoporosis, which is much lower than that typically used for bone metastases (120 mg every 4 weeks), Dr. Gnant noted.

Main results showed that denosumab was highly efficacious in reducing the risk of first clinical fractures, meaning those that were clinically evident and causing symptoms (hazard ratio, 0.50; P less than .0001), according to data presented at the meeting and simultaneously published (Lancet 2015 May 31).

The estimated 6-year fracture rate was about 10% in the denosumab group and 20% in the placebo group. “Please note that the frequency of clinical fractures reported in this trial that is focusing on bone health is markedly higher than fracture rates reported in previous large AI trials. Obviously, we had a tendency to underreport them in those trials,” Dr. Gnant commented. “The true magnitude of the problem in clinical practice is likely reflected in the placebo group … with approximately one out of five patients experiencing a new clinical fracture within 5-6 years of adjuvant AI treatment.”

Benefit was similar across numerous patient subgroups studied, including the subgroups of women who had a baseline bone mineral density T-score of less than –1 and women who had a baseline bone mineral density T-score of –1 or greater.

Additionally, the denosumab group had improvements from baseline in bone mineral density of the lumbar spine, total hip, and femoral neck, whereas the placebo group had worsening at all sites (P less than .0001 between groups for each site). And at 36 months, the denosumab group had significantly lower risks of both new vertebral fractures and new or worsening vertebral fractures.

“Adjuvant denosumab at this dose and schedule is safe,” Dr. Gnant maintained. The two groups had similar rates of various adverse events, with musculoskeletal disorders and vascular disorders (including hot flashes) predominating. “This means that we are in essence reporting the side effects of the underlying adjuvant AI treatment,” he noted.

There were 31 cases of dental issues, but none met diagnostic criteria for osteonecrosis of the jaw. “We can safely say that at this dose of denosumab, 60 mg twice yearly, ONJ is not an issue,” Dr. Gnant commented. Additionally, none of the women experienced atypical fractures.

Dr. Gnant disclosed employment of an immediate family member with Sandoz; receipt of honoraria from Amgen, AstraZeneca, GlaxoSmithKline, NanoString Technologies, Novartis, and Roche Pharma AG; a consulting or advisory role with Accelsiors, AstraZeneca, and Novartis; and receipt of research funding from GlaxoSmithKline, Novartis, Pfizer, Roche Pharma AG, Sanofi, and Smiths Medical. The trial was sponsored by Amgen.

CHICAGO – Adjuvant denosumab is efficacious and safe for reducing fracture risk among women taking aromatase inhibitors (AIs) as part of their treatment for early breast cancer, finds the Austrian Breast & Colorectal Cancer Study Group’s study 18 (ABCSG-18).

Compared with peers randomized to placebo in the phase III trial, women randomized to the antiresorptive monoclonal antibody at the dose typically used to treat osteoporosis were half as likely to experience a first clinical fracture, first author Dr. Michael Gnant reported at the annual meeting of the American Society of Clinical Oncology. The benefit was similar whether women had normal bone mineral density at baseline or already had osteopenia.

Courtesy MeduniWien/Matern

Patients in the denosumab group did not have a significantly higher rate of adverse events, including the much-feared complication of osteonecrosis of the jaw.

“The actual fracture risk of postmenopausal breast cancer patients on AIs is substantial and may have been underestimated until today,” commented Dr. Gnant, professor of surgery at the Medical University of Vienna. “In these patients with only a modest risk of disease recurrence, adjuvant denosumab significantly reduced the bone side effects of AI treatment. We therefore believe that denosumab 60 mg every 6 months should be considered for clinical practice.”

“Today, several clinical practice guidelines advocate the use of bisphosphonates for breast cancer patients receiving AIs, however, only if they are at high risk for fractures,” he further noted. However, “patients with normal baseline bone mineral density showed a similar fracture risk but also similar benefit from denosumab as compared to patients with baseline T scores below –1, indicating that DEXA scans may be an insufficient way to assess the individual patient’s fracture risk. In view of the benefits in this particular patient subgroup, we may have to rediscuss our current clinical practice guidelines.”

Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England, said, “It’s very important to dissect out fractures related to subsequent recurrence from fractures due to poor bone health.” Most of the reduction in fracture risk in ABCSG-18 appeared to be because of prevention of fractures before any recurrence, whereas most of that in the AZURE trial (Adjuvant Zoledronic Acid to Reduce Recurrence) of an adjuvant bisphosphonate, another type of antiresorptive agent, appeared to be because of prevention of fractures from bone metastases. “So I think we are seeing something very different with denosumab to what we’ve seen to date with a bisphosphonate,” he said.

“As oncologists, we are somewhat wedded to measuring bone mineral density as the reason for giving bone-targeted therapy to protect [against] bone loss, but there are much better ways of predicting fracture with online algorithms such as FRAX [Fracture Risk Assessment Tool] and others,” Dr. Coleman further commented. “And bone mineral density is a pretty poor predictor of fracture, so it’s perhaps not surprising that the risk reductions were fairly similar” across bone mineral density subgroups.

During a question and answer period, session attendee Dr. Toru Watanabe, Hamamatsu (Japan) Oncology Center, said, “It is really clear that the osteoporosis-related fracture is prevented by denosumab at the dose usually used for the treatment of osteoporosis. That part is very clear. My question is, the same dose is being tested for modifying overall survival or progression-free survival. Don’t you think it’s necessary to conduct some kind of dose-finding trial?”

Two studies are addressing the impact of denosumab on breast cancer outcomes, according to Dr. Gnant: the investigators’ ABCSG-18 study and the Study of Denosumab as Adjuvant Treatment for Women With High-Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE), which is using a higher initial dose and tapering after 1 year. “So we will have that indirect comparison at least. My personal expectation would be that there is a trade-off potentially between efficacy and tolerability,” he commented.

The 3,425 postmenopausal breast cancer patients in ABCSG-18 were randomized evenly to receive 60 mg of denosumab or placebo every 6 months. Denosumab is approved by the Food and Drug Administration for the prevention and treatment of fractures due to bone metastases (brand name Xgeva) and osteoporosis after menopause (brand name Prolia), as well as other indications. The study used the dose for postmenopausal osteoporosis, which is much lower than that typically used for bone metastases (120 mg every 4 weeks), Dr. Gnant noted.

Main results showed that denosumab was highly efficacious in reducing the risk of first clinical fractures, meaning those that were clinically evident and causing symptoms (hazard ratio, 0.50; P less than .0001), according to data presented at the meeting and simultaneously published (Lancet 2015 May 31).

The estimated 6-year fracture rate was about 10% in the denosumab group and 20% in the placebo group. “Please note that the frequency of clinical fractures reported in this trial that is focusing on bone health is markedly higher than fracture rates reported in previous large AI trials. Obviously, we had a tendency to underreport them in those trials,” Dr. Gnant commented. “The true magnitude of the problem in clinical practice is likely reflected in the placebo group … with approximately one out of five patients experiencing a new clinical fracture within 5-6 years of adjuvant AI treatment.”

Benefit was similar across numerous patient subgroups studied, including the subgroups of women who had a baseline bone mineral density T-score of less than –1 and women who had a baseline bone mineral density T-score of –1 or greater.

Additionally, the denosumab group had improvements from baseline in bone mineral density of the lumbar spine, total hip, and femoral neck, whereas the placebo group had worsening at all sites (P less than .0001 between groups for each site). And at 36 months, the denosumab group had significantly lower risks of both new vertebral fractures and new or worsening vertebral fractures.

“Adjuvant denosumab at this dose and schedule is safe,” Dr. Gnant maintained. The two groups had similar rates of various adverse events, with musculoskeletal disorders and vascular disorders (including hot flashes) predominating. “This means that we are in essence reporting the side effects of the underlying adjuvant AI treatment,” he noted.

There were 31 cases of dental issues, but none met diagnostic criteria for osteonecrosis of the jaw. “We can safely say that at this dose of denosumab, 60 mg twice yearly, ONJ is not an issue,” Dr. Gnant commented. Additionally, none of the women experienced atypical fractures.

Dr. Gnant disclosed employment of an immediate family member with Sandoz; receipt of honoraria from Amgen, AstraZeneca, GlaxoSmithKline, NanoString Technologies, Novartis, and Roche Pharma AG; a consulting or advisory role with Accelsiors, AstraZeneca, and Novartis; and receipt of research funding from GlaxoSmithKline, Novartis, Pfizer, Roche Pharma AG, Sanofi, and Smiths Medical. The trial was sponsored by Amgen.