Anastrozole, tablets, 1 mg, Arimidex® , July 2005
Public Summary Document for Anastrozole, tablets, 1 mg, Arimidex®, July 2005.
Page last updated: 24 October 2005
Public Summary Document
Product: Anastrozole, tablets, 1 mg, Arimidex®
Sponsor: AstraZeneca Pty Ltd
Date of PBAC Consideration:July 2005
1. Purpose of Application
This application sought to extend the current restricted benefit listing for anastrozole
to allow for Pharmaceutical Benefit Scheme (PBS) subsidised treatment of hormone-dependent
early breast cancer in all post-menopausal women.
2. Background
Anastrozole was first recommended for authority listing at the March 1997 PBAC meeting
for the treatment of advanced breast cancer in postmenopausal women with disease progression
following tamoxifen therapy. The restricted benefit listing was recommended at the
June 1998 PBAC meeting. At the December 2002 meeting, the current advanced breast
cancer listing was recommended on a cost-minimisation basis compared with letrozole,
on the basis that 1 mg anastrozole is equivalent to 2.5 mg letrozole.
At the June 2003 meeting, the PBAC considered a submission to amend the restricted
benefit listing from: "treatment of hormone-dependent advanced breast cancer in post-menopausal
women" to "hormone-dependent breast cancer in post-menopausal women". The PBAC rejected
the submission because of uncertainty in the extent of clinical benefit and resulting
uncertain cost-effectiveness.
In July 2004, the PBAC recommended an extension to the restricted benefit listing
to allow subsidised use in early breast cancer for patients in whom tamoxifen is contra-indicated
or for whom tamoxifen is not tolerated.
3. Registration Status
Anastrozole has Therapeutic Goods Administration marketing approval for:
Early breast cancer:
Adjuvant treatment of early breast cancer in postmenopausal women with oestrogen/
progesterone-receptor-positive disease.
Advanced breast cancer:
First line treatment of advanced breast cancer in postmenopausal women with oestrogen/
progesterone-receptor-positive disease; and
Treatment of advanced breast cancer in postmenopausal women with disease progression
following tamoxifen therapy. Patients with oestrogen-receptor-negative disease and
patients who have not responded to previous tamoxifen therapy rarely respond to Arimidex.
This application for PBS listing was for the treatment of hormone-dependent early
breast cancer in all postmenopausal women.
Anastrozole is currently available on the PBS for the treatment of hormone-dependent
advanced breast cancer in all postmenopausal women and for the treatment of hormone-dependent
early breast cancer in postmenopausal women who are intolerant of tamoxifen or in
whom tamoxifen therapy is contraindicated.
4. Listing Requested and PBAC’s View
The submission requested the following listing:
Restricted benefit
Treatment of hormone-dependant breast cancer in postmenopausal women.
NOTE:
This drug is not PBS-subsidised for primary prevention of breast cancer.
The PBAC had no comments on the wording of the restriction.
5. Clinical Place for the Proposed Therapy
Anastrozole can be used for adjuvant treatment of post-menopausal women with
hormone-dependent early breast cancer as an alternative to the current standard adjuvant
endocrine treatment, tamoxifen. It is also used in the treatment of hormone-dependent
advanced breast cancer in post-menopausal women.
6. Comparator
The submission nominated tamoxifen as the main comparator.
This was accepted as appropriate by the Committee.
7. Clinical Trials
The submission presented the final (68-month follow-up) results of the ATAC (Arimidex,
Tamoxifen, Alone or in Combination) trial, which has been published as follows:
|
Trial/first author |
Protocol title |
Publication citation |
|---|---|---|
| ATAC Trialists’ Group. | Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. | Lancet 2005;365:60-2. |
8. Results of Trials
The key results of the ATAC trial are summarised in the table below (Intent To Treat
(ITT) analysis).
|
Outcome (in ITT population) |
AnastrozoleN(ITT)=3125N (%) |
TamoxifenN(ITT)=3116n (%) |
Hazard ratio |
|
|---|---|---|---|---|
| Disease-free survival ‡ |
575 (18.4%) |
651 (20.9%) |
0.87 (0.78 to 0.97) |
0.013 |
| Time to Recurrence † |
402 (12.9%) |
498 (16.0%) |
0.79 (0.70 to 0.90) |
<0.001 |
| Time to distant recurrence † |
324 (10.4%) |
375 (12.0%) |
0.86 (0.74 to 0.99) |
0.043 |
| Overall survival |
2714 (86.8%) |
2696 (86.5%) |
0.97 (0.85 to 1.12) |
NS |
| Time to death following recurrence |
Not provided |
Not provided |
0.88 (0.74 to 1.05) |
0.168 |
| Contralateral breast cancer |
35 (1.1%) |
59 (1.9%) |
0.59 (0.39 to 0.89)* |
0.013 ‡ |
Endpoint includes non-cancer death, † endpoint excludes non-cancer death, * odds ratio
Bolded: primary outcome
There was a statistically significant difference favouring anastrozole on the following
key outcomes (in the ITT population and in the relevant group of patients with hormone-
receptor positive tumours).
· Disease-free survival (DFS, primary analysis) and time to recurrence (secondary
outcome similar to the primary, but with deaths without recurrence censored). The
annual rates of DFS and time to recurrence were increasing over the 5 years of follow
up.
· Time to distant recurrence (deaths without recurrence are censored).
· Incidence of new primary (contralateral) breast cancer.
Overall survival was not significantly different at 5 years of follow up, although
the number of deaths in the tamoxifen group was higher than in the anastrozole group
(420 vs 411).
The key toxicity results are summarised in the following table:
|
Event |
AnastrozoleN=3092, n (%) |
TamoxifenN=3094, n (%) |
p-value |
|---|---|---|---|
| All adverse events | 2904 (93.9) | 2928 (94.6) | NS |
| Drug-related adverse events | 1884 (60.9) | 2117 (68.4) | <0.0001 |
| All serious adverse events | 1170 (37.8) | 1269 (41.0) | 0.011 |
| Drug-related serious adverse events | 146 (4.7) | 277(9.0) | <0.0001 |
| Adverse events leading to withdrawal | 344 (11.1) | 442 (14.3) | 0.0002 |
| Drug-related adverse events leading to withdrawal | 200 (6.5) | 274 (8.9) | 0.0004 |
|
Pre-specified adverse events |
|||
| Hot flushes | 1104 (35.7) | 1264 (40.9) | <0.0001 |
| Joint pain/stiffness | 1100 (35.6) | 911 (29.4) | <0.0001 |
| Mood disturbances | 597 (19.3) | 554 (17.9) | NS |
| Fatigue/asthenia | 575 (18.6) | 544 (17.6) | NS |
| Nausea and vomiting | 393 (12.7) | 384 (12.4) | NS |
| Fractures | 315 (10.2) | 209 (6.8) | <0.0001 |
| Cataracts | 182 (5.9) | 213 (6.9) | NS |
| Vaginal bleeding | 167 (5.4) | 317 (10.2) | <0.0001 |
| Ischaemic cardiovascular disease | 127 (4.1) | 104 (3.4) | NS |
| Vaginal discharge | 109 (3.5) | 408 (13.2) | <0.0001 |
| Venous thromboembolic events | 87 (2.8) | 140 (4.5) | 0.0004 |
| Deep venous thromboembolic events | 48 (1.6) | 74 (2.4) | 0.0185 |
| Ischaemic cerebrovascular events | 62 (2.0) | 88 (2.8) | 0.0328 |
| Endometrial cancer | 4 (0.2) | 13 (0.6) | 0.0394 |
| Hysterectomy | 1.2% | 4.7% | <0.0001 |
Anastrozole was generally associated with fewer side effects than tamoxifen and the
incidence of discontinuations due to adverse events, serious adverse events and drug-related
adverse events were significantly lower. In pre-specified categories of adverse events,
endometrial cancer, ischaemic cerebrovascular events, venous thromboembolic events
including deep venous thromboembolic events, vaginal bleeding, vaginal discharge and
hot flushes were significantly less frequent in patients receiving anastrozole, while
fractures and arthralgia were more frequent. However, (i) the incidence of hip fractures
was similar, and (ii) the difference in fracture rates for the total fractures remained
generally constant throughout the study (did not increase with time) and returned
to pre-treatment levels on treatment completion.
The PBAC agreed that these results support the submission’s claim that anastrozole
has a superior safety profile to tamoxifen with the exception of an increased incidence
of fractures.
9. Clinical Claim
The submission claimed that anastrozole has significant clinical advantages over tamoxifen
and is significantly more effective and has less toxicity.
The PBAC accepted that, while the ATAC trial showed no overall survival gain, in the
long-term sufficiently large incremental survival benefits could be expected, in part
due to the prevention of contralateral breast cancer.
10. Economic Analysis
An updated preliminary economic evaluation was presented. Types of resources included
the adjuvant drugs, the management of adverse events and bisphosphonates.
The trial-based incremental discounted cost/extra discounted year free of disease
after 68 months follow-up was in the range $105,000 to $200,000.
An updated modelled economic evaluation was presented using a cost utility analysis.
The clinical benefit gains (effectiveness and toxicity) were based on the final results
of the trial, while the incremental cost effectiveness ratios (ICER) were extrapolated
over 5-25 years.
The base case modelled incremental discounted cost per extra discounted quality adjusted
life year (QALY) gained was calculated to be in the range $15,000 - $45,000. The incremental
discounted cost per extra discounted life-year gained was in the range $15,000 - $45,000
extrapolated over 20 years.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients/year to be in the range 10,000
– 50,000 in Year 4, at a net financial cost/year to the PBS in the range $10 - $30
M.
The PBAC recognised that it is likely that a substantial proportion of women who are
currently taking tamoxifen would switch to anastrozole following implementation of
this recommendation. The utilisation estimates provided by the sponsor did take this
into consideration, but it is difficult to accurately estimate the extent of switch
that will occur.
12. Recommendation and Reasons
The PBAC recommended the listing for anastrozole be extended to include all post-menopausal
women with hormone-dependent early breast cancer on the basis of acceptable cost-effectiveness
compared with tamoxifen. While the ATAC trial showed no overall survival gain, the
PBAC accepted that in the long-term, sufficiently large incremental survival benefits
could be expected, in part due to the prevention of contralateral breast cancer, to
justify the incremental costs.
The PBAC noted the mature ATAC trial results were presented and the new modelled economic
evaluation presented an acceptable incremental cost per extra discounted quality-adjusted
life-year gained in the range $15,000 - $45,000. Knowing that the follow-up of the
ATAC trial remains on-going, the PBAC requested that it receive regular updates, including
a schedule of when these will occur, from the ATAC trial over the coming years until
all follow-up from the trial is ceased to determine if a statistically significant
gain in overall survival is realised as expected.
The PBAC noted that the incremental cost-effectiveness ratio based on quality-adjusted
life-years gained is numerically more favourable than the corresponding ratio based
on life-years gained and that this is consistent with the claim that an important
aspect of the incremental clinical benefit of anastrozole over tamoxifen is the significant
delay to breast cancer recurrence on average.
Recommendation:
Amend listing as follows:
| Restriction: | Restricted benefit Treatment of hormone-dependent breast cancer in postmenopausal women. NOTE: This drug is not PBS-subsidised for primary prevention of breast cancer. |
| Maximum Quantity: Repeats: |
30 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
The sponsor agrees with the PBAC’s assessment and is pleased that anastrozole will
be available as a subsidised treatment option for all postmenopausal women with hormone-dependent
early breast cancer.
