Denosumab, solution for subcutaneous injection, 120 mg in 1.7 mL, Xgeva® - July 2011
Page last updated: 23 November 2011
Public Summary Document
Product: Denosumab, solution for subcutaneous
injection, 120 mg in 1.7 mL, Xgeva®
Sponsor: Amgen Australia Pty Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The submission sought an Authority required (STREAMLINED) listing
for the treatment of bone metastases from breast and
hormone-resistant prostate cancer.
2. Background
This drug had not previously been considered by the PBAC for this
indication.
3. Registration Status
Denosumab (Xgeva®) was TGA registered on 8 September
2011 for the prevention of skeletal related events in patients with
bone metastases from solid tumours.
4. Listing Requested and PBAC’s View
Authority Required (STREAMLINED)
Bone metastases from breast cancer.
Bone metastases from hormone-resistant prostate cancer, with
demonstration of biochemical progression despite maximal therapy
with hormone treatments.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Among patients with advanced breast or prostate cancer, 65 to 75%
develop bone metastases. Complications of bone metastases include
severe pain, pathologic fractures and spinal cord compression which
all have the potential to significantly impact a patient’s
quality of life and functional independence.
The submission proposed that the place in therapy of denosumab is
as an alternative therapy for the treatment of bone metastases.
Denosumab is not renally cleared and therefore it is able to be
used in patients with severe renal insufficiency or by those
patients receiving dialysis.
6. Comparator
The submission nominated intravenous (IV) zoledronic acid as the
main comparator. This was accepted by the PBAC.
7. Clinical Trials
The basis of the submission was two head-to-head trials of
denosumab compared to zoledronic acid for the prevention of
skeletal related events (SREs) associated with bone metastases from
breast cancer (Study 136) or hormone-resistant prostate cancer
(Study 103). Both pivotal studies presented in the submission
excluded patient with renal insufficiency (defined as creatinine
clearance < 30 mL/min).
Publication details of the trials and associated reports presented
in the submission are in the table below.
Randomised trials presented in the submission
| Trial ID | Protocol title/ Publication title | Publication citation |
| Breast cancer | ||
| Study 136 Stopeck A, et al | Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomised double-blind study | Journal of Clinical Oncology 2010; 28(35): 5132-5139 |
| Hormone-resistant prostate cancer | ||
| Study 103 Fizazi K, et al | Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised double-blind study | Lancet 2011; 377 (9768): 813-822 |
8. Results of Trials
The main outcome measures of both trials were associated with the
prevention of SREs.
SREs were defined as radiation therapy (for debilitating pain and
the treatment or prevention of pathologic fractures/spinal cord
compression); pathologic fractures; surgery to bone and spinal cord
compressions. Events could be asymptomatic or symptomatic.
The SRE outcomes reported in Study 136 are presented in the table
below.
SRE outcomes reported in Study 136 (breast cancer)
| Outcome | Denosumab (N = 1026) | Zoledronic acid (N = 1020) |
| Time to first on-study SRE (both asymptomatic and symptomatic) | ||
| Number of patients with an SRE (%) | 315 (30.7) | 372 (36.5) |
| Median time to event, days (95% CI) Median time to event, months | NE NE | 806 (666, NE) 26.5 |
| Hazard ratio (95% CI) | 0.82 (0.71, 0.95) | |
| p-value (unadjusted) | Non-inferiority <0.0001; Superiority 0.0101 | |
| First on-study SRE by subtype | ||
| Pathological fracture (%) | 212 (20.7) | 238 (23.3) |
| Radiation to the bone (%) | 82 (8.0) | 119 (11.7) |
| Surgery to the bone (%) | 12 (1.2) | 8 (0.8) |
| Spinal cord compression (%) | 9 (0.9) | 7 (0.7) |
| Time to first-and-subsequent on-study SRE | ||
| Number of events | 474 | 608 |
| Mean number of events per subject | 0.46 | 0.60 |
| Rate Ratio (95% CI) | 0.77 (0.66, 0.89) | |
| p-value (unadjusted) | 0.0006 | |
| Time to first symptomatic SRE | ||
| Number patients with a symptomatic SRE (%) | 156 (15.2) | 198 (19.4) |
| Median time to event, days (95% CI) | NE | NE |
| Hazard ratio (95% CI) | 0.76 (0.61, 0.93) | |
| p-value | 0.0092 | |
Abbreviations: CI, confidence interval; NE, not estimable; SRE,
skeletal related event
The results of Study 136 indicate that denosumab treatment was
associated with a statistically significant reduction in the risk
of developing a first on-study SRE compared to zoledronic acid in
breast cancer patients (Hazard ratio 0.82 [95% CI: 0.71, 0.95]).
Denosumab significantly reduced the risk of developing
first-and-subsequent SREs by 23 % compared with zoledronic acid
(Rate ratio 0.77 [95% CI: 0.66, 0.89]).
The SRE outcomes reported in Study 103 are presented in the table
below.
SRE outcomes reported in Study 103 (prostate cancer)
| Outcome | Denosumab (N = 950) | Zoledronic acid (N = 951) |
| Time to first on-study SRE (both asymptomatic and symptomatic) | ||
| Number of patients with an SRE (%) | 341 (35.9) | 386 (40.6) |
| Median time to event, days (95% CI) Median time to event, months | 629 (573, 757) 20.7 | 521 (456, 592) 17.1 |
| Hazard ratio (95% CI) | 0.82 (0.71, 0.95) | |
| p-value (unadjusted) | Non-inferiority 0.0002; Superiority 0.0085 | |
| First on-study SRE by subtype | ||
| Pathological fracture (%) | 137 (14.4) | 143 (15.0) |
| Radiation to the bone (%) | 177 (18.6) | 203 (21.3) |
| Surgery to the bone (%) | 1 (0.1) | 4 (0.4) |
| Spinal cord compression (%) | 26 (2.7) | 36 (3.8) |
| Time to first-and-subsequent on-study SRE | ||
| Number of events | 494 | 584 |
| Mean number of events per subject | 0.52 | 0.61 |
| Rate Ratio (95% CI) | 0.82 (0.71, 0.94) | |
| p-value (unadjusted) | 0.0044 | |
| Time to first symptomatic SRE | ||
| Number patients with a symptomatic SRE (%) | 241 (25.4) | 289 (30.4) |
| Median time to event, days (95% CI) | NE | 736 (630, 918) |
| Hazard ratio (95% CI) | 0.78 (0.66, 0.93) | |
| p-value | 0.0051 | |
Abbreviations: CI, confidence interval; NE, not estimable; SRE,
skeletal related event
The results of Study 103 indicate that the risk of developing a
first on-study SRE was statistically significantly reduced with
denosumab treatment compared to zoledronic acid in prostate cancer
patients (Hazard ratio 0.82 [95% CI: 0.71, 0.95]). Denosumab
significantly reduced the risk of developing first-and-subsequent
SREs by 18% compared with zoledronic acid (Rate ratio 0.82 [95% CI
0.71, 0.94]).
Outcomes reported in Study 136 showed that quality of life outcomes
favoured denosumab, however, the difference between treatments was
small and did not reach statistical significance. Pain outcomes
also favoured denosumab but only reached statistical significance
for time to moderate to severe pain (Hazard ratio 0.87 [95% CI:
0.79, 0.97]).
In both trials, overall survival and progression-free survival were
similar between denosumab and zoledronic acid.
Similar proportions of patients in the denosumab and zoledronic
acid treatment arms experienced adverse events during the trials,
however the adverse event profiles of the two products differed.
Zoledronic acid was more commonly associated with renal adverse
events (including renal failure) and acute phase reactions
(flu-like syndrome including pyrexia, chills, flushing, pain,
arthralgia and myalgia) while denosumab was more commonly
associated with hypocalcaemia, hypersensitivity reactions (a causal
relationship to drug exposure has not been established) and
osteonecrosis of the jaw (ONJ). However, the incidence of ONJ was
low and not statistically different between treatment groups.
For PBAC’s comments on these results, see Recommendation
and Reasons.
9. Clinical Claim
The submission described denosumab as superior to zoledronic acid
in terms of comparative efficacy. This was accepted by the
PBAC.
The submission made no specific claim in terms of comparative
safety but stated that the benefit-risk profile of denosumab
compared with zoledronic acid is positive.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented two separate economic analyses, one for
the breast cancer population and one for the hormone-resistant
prostate cancer population. Both analyses were based on single
cohort Markov models with three health states (alive without an SRE
whilst receiving treatment, alive with an SRE whilst receiving
treatment and dead). The cohort transits through the Markov model
in monthly cycles (28 days) until death. The models used a 10-year
time horizon.
The results of the economic analyses showed denosumab treatment to
be dominant (i.e., more effective and less costly).
During the evaluation, a series of sensitivity analyses were
conducted to evaluate the impact of lowering IV zoledronic acid
administration costs.
Denosumab treatment remained dominant at 50% of base case IV
administration costs, however as the assumed administration costs
were lowered the incremental cost-effectiveness ratio (ICER)
increased. Using the lowest cost tested in sensitivity analysis,
the ICER for denosumab was between $100,000 and $200,000 per
quality adjusted life year (QALY) for both breast cancer and
prostate cancer treatment.
The results of the multivariate sensitivity analyses conducted
during the evaluation indicated that in addition to IV drug
administration costs the model was also sensitive to time horizon,
the disutility associated with SREs, the risk of first and
subsequent SREs and the cost of managing SREs.
11. Estimated PBS Usage and Financial Implications
The likely number of packs dispensed per year was estimated in the
submission to be between 50,000 and 100,000 in Year 5, at a net
cost to the PBS/RPBS of between $10-30 million in Year 5. The net
cost to Government health budgets (taking into account infusion
cost-offsets) was estimated in the submission to be less than $10
million in Year 5.
12. Recommendation and Reasons
The PBAC recommended the listing of denosumab on the PBS as an Authority Required
benefit for treatment of bone metastases from breast cancer and hormone-resistant
prostate cancer on the basis of acceptable cost-effectiveness compared with zoledronic
acid 4 mg in 5 mL injection concentrate for I.V. infusion.
The PBAC recommended removal of the wording “with demonstration of biochemical progression
despite maximal therapy with hormone treatments” as this was the definition of hormone-resistance
and was consistent with the recommendation from the Restrictions Working Group (RWG).
The PBAC noted that denosumab treatment was associated with a statistically significant
reduction in the risk of developing a first on-study skeletal related event (SRE),
both asymptomatic and symptomatic, compared to zoledronic acid in breast cancer patients
(HR 0.82; 95% CI 0.71, 0.95) and in prostate cancer patients (HR 0.82; 95% CI 0.71,
0.95). Denosumab treatment also significantly reduced the risk of developing first-and-subsequent
SREs) in both breast and prostate cancer patients. The PBAC noted that denosumab treatment
was not associated with any improvement in survival or disease progression compared
to zoledronic acid and although pain and quality of life outcomes generally favoured
denosumab the differences between treatments was small and did not reach statistical
significance for most outcomes.
The PBAC accepted that the appropriate comparator was zoledronic acid and the submission’s
claim that denosumab is superior to zoledronic acid in terms of comparative efficacy.
The PBAC noted that the submission did not make a specific claim regarding comparative
safety. However, the overall incidence of adverse events is similar between denosumab
and zoledronic acid. Denosumab was more commonly associated with hypocalcaemia, hypersensitivity
reactions and osteonecrosis of the jaw while zoledronic acid was more commonly associated
with renal adverse events (including renal failure) and acute phase reactions.
The PBAC was concerned that the results presented in the economic model showing dominance
of denosumab treatment were primarily driven by the high drug administration cost
estimate attributed to infusion of zoledronic acid. The Committee considered that
there was considerable uncertainty around this estimate as there is a large disparity
in drug administration costs for zoledronic acid infusions between treatment settings
and between the States and Territories.
Even with the uncertainty surrounding the drug administration cost of zoledronic acid
infusions, the PBAC considered that the revised base case ICERs, presented in the
Pre-PBAC Response calculated with a revised price offer and with various scenarios
of infusion costs for zoledronic acid were acceptable.
The PBAC recommended denosumab is suitable for inclusion in the PBS medicines for
prescribing by nurse practitioners within collaborative arrangements as continuing
therapy only.
Recommendation:
DENOSUMAB, injection, 120 mg in 1.7 mL
Restriction:
Authority Required
Bone metastases from breast cancer.
Bone metastases from hormone-resistant prostate cancer.
Note
Continuing Therapy Only:
For prescribing by nurse practitioner as continuing therapy only, where the treatment of, and prescribing of medicine for, a patient has been initiated by a medical practitioner. Further information can be found in the Explanatory Notes for Nurse Practitioners.
Maximum Quantity 1
No. of Repeats 5
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Amgen is pleased that denosumab (Xgeva®) has been
recommended for PBS listing for Australian patients with bone
metastases from breast cancer and hormone-resistant prostate
cancer.
