Abiraterone, tablet, 250 mg (as acetate), Zytiga® - November 2011
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Public Summary Document
Product: Abiraterone, tablet, 250 mg (as acetate),
Zytiga®
Sponsor: Janssen-Cilag Pty Ltd
Date of PBAC Consideration: November 2011
1. Purpose of Application
The submission requested an Authority Required PBS listing for
initial and continuing treatment of a patient with metastatic
advanced prostate cancer (castration resistant prostate cancer) in
patients whose disease progression has occurred following treatment
with docetaxel, in combination with prednisone or prednisolone. The
submission also requested that the PBAC consider whether the rule
of rescue is applicable.
2. Background
This drug had not previously been considered by the PBAC.
The Rule of Rescue:
There are four factors, which when applied concurrently in
exceptional circumstances, are called the ‘rule of
rescue’ as follows.
- No alternative exists in Australia to treat patients with the specific circumstances of the medical condition meeting the criteria of the restriction. This means that there are no nonpharmacological or pharmacological interventions for these patients.
- The medical condition defined by the requested restriction is severe, progressive and expected to lead to premature death. The more severe the condition, or the younger the age at which a person with the condition might die, or the closer a person with the condition is to death, the more influential the rule of rescue might be in the consideration by PBAC.
- The medical condition defined by the requested restriction applies to only a very small number of patients. Again, the fewer the patients, the more influential the rule of rescue might be in the consideration by PBAC. However, PBAC is also mindful that the PBS is a community-based scheme and cannot cater for individual circumstances.
- The proposed drug provides a worthwhile clinical improvement sufficient to qualify as a rescue from the medical condition. The greater the rescue, the more influential the rule of rescue might be in the consideration by PBAC.
3. Registration Status
On 1 March 2012, abiraterone was registered by the TGA for the following indication:
Abiraterone is indicated with prednisone or prednisolone for the treatment of metastatic advanced prostate cancer (castration resistant prostate cancer) in patients who have received prior chemotherapy containing a taxane.
4. Listing Requested and PBAC’s View
Authority Required
Initial treatment, in combination with prednisone/prednisolone, of
a patient with metastatic advanced prostate cancer (castration
resistant prostate cancer) in whom disease progression has occurred
following treatment with docetaxel.
Continuing treatment, in combination with prednisone/prednisolone,
of a patient with metastatic advanced prostate cancer (castration
resistant prostate cancer) who has previously received treatment
with PBS subsidised abiraterone acetate and who does not have
progressive disease.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Prostate cancer is the most common cancer in Australian men and the
second leading cause of male deaths due to cancer. The initial
treatment choice is hormone therapy. However, the disease often
develops into metastatic castrate resistant prostate cancer (mCRPC)
as the tumour no longer responds to hormonal therapies. Docetaxel
is currently used first-line in the treatment of patients with
mCRPC. Due to the nature of the disease, disease progression after
initial chemotherapy treatment occurs frequently.
Treatment options for mCRPC include secondary hormonal
manipulations, palliative radiotherapy, chemotherapy and best
supportive care. Currently, mitozantrone may be given to patients
who are fit for chemotherapy in the second-line setting.
The submission proposed that the place in therapy of abiraterone
was as a second-line therapy for patients with metastatic prostate
cancer in whom disease progression has occurred following treatment
with docetaxel.
6. Comparator
The submission nominated placebo (prednisone/prednisolone plus
other care) and mitozantrone (mitozantrone plus
prednisone/prednisolone plus other care) as the main comparators,
which the PBAC considered appropriate.
The submission nominated cabazitaxel as an additional comparator,
which the PBAC also considered appropriate. However, the PBAC noted
that although cabazitaxel is likely to replace mitozantrone as
second line therapy in the treatment of mCRPC for patients who are
candidates for cytotoxic chemotherapy, it is not clear whether
abiraterone would replace cabazitaxel.
7. Clinical Trials
The submission presented one direct randomised trial comparing
abiraterone with best supportive care (placebo; Trial 301), three
trials comparing mitozantrone and best supportive care (placebo;
Berry, Tannock, Kantoff) and one trial comparing cabazitaxel with
mitozantrone (TROPIC).
The submission also presented indirect comparisons of abiraterone
versus mitozantrone and cabazitaxel, using placebo as the common
comparator in the former and assuming placebo and mitozantrone are
equivalent in the latter.
The following trials had been published at the time of
submission:
| Trial ID / First author | Protocol title/ Publication title | Publication citation |
|---|---|---|
| Abiraterone | ||
| Mitozantrone | ||
| Cabazitaxel | ||
| COU-AA-301 | ||
| de Bono JS et al | Abiraterone and increased survival in metastatic prostate cancer. | The New England Journal of Medicine 2011; 364(21):1995-2005 |
| Tannock et al | Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative endpoints. | Journal of Clinical Oncology 1996; 14(6):1756-1764. |
| Dowling AJ et al | A retrospective analysis of the relationship between changes in serum PSA, palliative response and survival following systemic treatment in a Canadian randomized trial for symptomatic hormone-refractory prostate cancer. | Annals of Oncology 2001; 12(6): 773-778. |
| Osoba D et al | Health related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. | Journal of Clinical Oncology 1999; 17 (6):1654-1663. |
| Bloomfield DJ et al | Economic evaluation of chemotherapy with mitoxantrone plus prednisone for symptomatic hormone-resistant prostate cancer: Based on a Canadian randomized trial with palliative endpoints. | Journal of Clinical Oncology 1998; 16(6): 2272-2279. |
| Bloomfield DJ et al | Economic evaluation of chemotherapy with mitoxantrone plus prednisone for symptomatic hormone resistant prostate cancer based on a Canadian randomized trial with palliative endpoints [Abstract 1130]. | Proceedings of the American Society of Clinical Oncology 1997; 16:317 |
| Tannock I et al | Chemotherapy with mitoxantrone (M) and prednisone (P) palliates patients with hormone resistant prostate cancer (HRPC): results of a randomized Canadian trial. | Proceedings of the Annual Meeting of the American Society for Clinical Oncology 1995; 14: 653 |
| Berry et al | Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. | Journal of Urology 2002; 168: 2439-2443. |
| Gregurich M et al | Phase III study of mitoxantrone/low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone-refractory carcinoma of the prostate [Abstract 1321]. | Proceedings of the American Society of Clinical Oncology 2000; 19:336 |
| Kantoff et al | Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B9182 study. | Journal of Clinical Oncology 1999; 17(8):2506-2513 |
| TROPIC de Bono JS et al | Prednisone plus cabazitaxel or mitoxantrone for metastatic castration resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. | The Lancet 2010; 376: 1147-1154. |
| Cabazitaxel plus prednisone/prednisolone significantly increases overall survival compared to mitoxantrone plus prednisone/prednisolone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: Final results with updated overall survival of a multinational Phase III trial (TROPIC). | Poster presented at 35th ESMO, Milan, Italy, October 8-12, 2010. | |
8. Results of Trials
In the pivotal Trial 301, patients were randomly assigned in a 2:1
ratio, stratified by baseline ECOG (0 - 1 versus 2), presence or
absence of pain, prior chemotherapies (1 versus 2) and documented
type of prostate cancer (PSA progression only versus radiographic
progression in bone or soft tissue with or without PSA progression)
to receive either abiraterone or best supportive care (placebo).
Trial 301 was powered to detect a difference between abiraterone
and placebo and one interim analysis was planned (after 534 deaths
were observed; 67% of the 797 total events). Median survival was
statistically significantly longer for patients treated with
abiraterone (14.8 months) than for those treated with placebo (10.9
months); resulting in an incremental overall survival of 3.9 months
(p<0.0001). The hazard ratio was 0.646 (95% CI: 0.543, 0.768) in
favour of abiraterone, corresponding to a 35.4% reduction in risk
of death.
The indirect comparison of abiraterone and mitozantrone
demonstrated a HR of 0.66 (95% CI: 0.51, 0.86 median overall
survival) and the indirect comparisons of cabazitaxel and
mitozantrone (TROPIC) showed a median overall survival for
cabazitaxel of 15.1 months versus 12.7 months for mitozantrone, an
incremental survival of 2.4 months (HR of 0.70 (95% CI: 0.59,
0.83). The indirect comparison of abiraterone and cabazitaxel
demonstrated a HR of 0.93 (95% CI: 0.73, 1.19).
For PBAC’s comments on these results, see Recommendation
and Reasons.
Statistically significant differences in functional assessment of
cancer therapy – prostate (FACT-P) scores between the
abiraterone and placebo arms of Trial 301 were demonstrated.
However, the magnitude of changes in the FACT-P Total Scores
between the trial arms were small and changes in the subscale
FACT-P scores were similar in both groups.
The overall safety of abiraterone was comparable with that of
placebo.
9. Clinical Claim
The submission claimed:
- abiraterone plus prednisone/prednisolone is superior in terms of comparative effectiveness and equivalent in terms of comparative safety over best supportive care (prednisone/prednisolone alone);
- abiraterone plus prednisone/prednisolone is superior in terms of comparative effectiveness and superior in terms of comparative safety over mitozantrone plus prednisone/prednisolone alone;
- abiraterone plus prednisone/prednisolone is non-inferior in terms of comparative effectiveness and superior in terms of comparative safety over cabazitaxel plus prednisone/prednisolone alone.
Whilst the PBAC considered that there are uncertainties inherent
from indirect comparisons, it accepted the clinical claims in the
submission, see Recommendation and Reasons.
10. Economic Analysis
A stepped economic evaluation was presented. A decision analytic
Markov model was used to estimate the incremental
cost-effectiveness of abiraterone for mCRPC after disease
progression with first-line docetaxel compared with best supportive
care (mitozantrone plus prednisolone and prednisolone
monotherapy).
The incremental cost/extra QALY (base case) gained (over 5 years)
was estimated to be between $105,000 - $200,000.
Sensitivity analyses conducted during the evaluation, assuming all
patients remained on abiraterone therapy until death, indicated
that the model was most sensitive to the treatment effect
associated with abiraterone, the price requested and the assumption
that all patients discontinue abiraterone at disease progression
rather than continuing treatment beyond disease progression until
death.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The net financial cost to the PBS was estimated by the submission
to be between $30 – $60 million in Year 5 of listing. The
estimate was considered uncertain because of the potential of
extended use beyond disease progression given the safety profile
and ease of administration of abiraterone.
12. Recommendation and Reasons
The PBAC noted that neither the TGA Clinical Evaluator’s
Report nor the Delegate’s Summary had been received and that
this would be helpful in determining the future place in therapy of
abiraterone. The PBAC agreed that placebo (prednisone/prednisolone
plus other care) and mitozantrone (mitozantrone plus
prednisone/prednisolone plus other care) are the appropriate
comparators. The PBAC also agreed that cabazitaxel is an
appropriate additional comparator. However, the PBAC noted that
although cabazitaxel is likely to replace mitozantrone as second
line therapy in the treatment of mCRPC for patients who are
candidates for cytotoxic chemotherapy, it is not clear whether
abiraterone would replace cabazitaxel. The PBAC noted that the
requested restriction does not preclude concomitant use of
cabazitaxel and abiraterone nor does it preclude the use of
abiraterone after cabazitaxel treatment. The PBAC considered there
is also a risk that abiraterone could be used instead of docetaxel
for patients who are not candidates for chemotherapy i.e. as
first-line therapy. Therefore, the PBAC considered that there is
considerable uncertainty regarding the clinical place in therapy of
abiraterone.
The submission presented one direct randomised trial comparing
abiraterone with best supportive care (placebo; Trial 301), three
trials comparing mitozantrone and best supportive care (placebo;
Berry, Tannock, Kantoff) and one trial comparing cabazitaxel with
mitozantrone (TROPIC). There are also indirect comparisons of
abiraterone versus mitozantrone and cabazitaxel, using placebo as
the common comparator in the former and assuming placebo and
mitozantrone are equivalent in the latter.
The PBAC noted that median survival was statistically significantly
longer for patients treated with abiraterone (14.8 months) than for
those treated with placebo (10.9 months); resulting in an
incremental overall survival of 3.9 months (p<0.0001). The
hazard ratio was 0.65 (95% CI: 0.54, 0.77) in favour of
abiraterone, corresponding to a 35.4% reduction in risk of death.
The PBAC agreed that it was reasonable to assume that there is no
overall survival benefit for mitozantrone and that placebo and
mitozantrone are equivalent. The indirect comparison of abiraterone
and mitozantrone demonstrated a HR of 0.66 (95% CI: 0.51, 0.86)
median overall survival) and the indirect comparisons of
cabazitaxel and mitozantrone (TROPIC) showed a median overall
survival for cabazitaxel of 15.1 months versus 12.7 months for
mitozantrone, an incremental survival of 2.4 months (HR of 0.70
(95% CI: 0.59, 0.83). The indirect comparison of abiraterone and
cabazitaxel demonstrated a HR of 0.93 (95% CI: 0.73, 1.19).
Whilst the PBAC considered that there are uncertainties inherent
from indirect comparisons, it accepted the submission’s
clinical claims: 1) abiraterone plus prednisone/prednisolone is
superior in terms of comparative effectiveness and equivalent in
terms of comparative safety over best supportive care
(prednisone/prednisolone alone); 2) abiraterone plus
prednisone/prednisolone is superior in terms of comparative
effectiveness and superior in terms of comparative safety over
mitozantrone plus prednisone/prednisolone alone; 3) abiraterone
plus prednisone/prednisolone is non-inferior in terms of
comparative effectiveness and superior in terms of comparative
safety over cabazitaxel plus prednisone/prednisolone alone.
The PBAC noted that the economic model assumes that treatment with
abiraterone and mitozantrone ceases upon disease progression and is
highly sensitive to discontinuation of treatment. The PBAC
considered that as abiraterone is given orally and has a relatively
good safety profile, there is the potential that abiraterone may
continue to be used well beyond disease progression and until
death. The PBAC noted that sensitivity analyses were conducted
during the evaluation, assuming all patients remained on
abiraterone therapy until death. The results indicate that the
model is most sensitive to treatment effect associated with
abiraterone, the price requested for abiraterone and the assumption
that all patients discontinue abiraterone at disease progression
rather than continuing treatment beyond disease progression until
death. The PBAC noted that the incremental cost/extra QALY (base
case) gained (over 5 years) was estimated to be between $105,000 -
$200,000, which was considered to be unacceptably high.
Regarding the rule of rescue, the PBAC agreed that the criteria are
not intended to allow for the acceptance of extremely high
incremental cost effectiveness for last line treatments of
end-stage cancers. Therefore, the clinical place of abiraterone, as
an additional treatment in a sequence of treatment options that do
not considerably transform a patient’s quality of life or
extend survival substantially, does not qualify it as a drug for
consideration under rule of rescue. Furthermore, there are
alternative therapies available for the management of mCRPC, such
as docetaxel retreatment, cyclophosphamide and carboplatin .
The PBAC therefore rejected the submission on the basis of an
unacceptably high incremental cost-effectiveness ratio and due to
uncertainty regarding the clinical place in therapy.
Recommendation:
Reject
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 has no comment.
