DEGARELIX, powder for subcutaneous injection (modified release), 80 mg and 120 mg, (as acetate) with solvent, syringe and needles, Firmagon®
Page last updated: 29 October 2010
Public Summary Document
Product: DEGARELIX, powder for subcutaneous
injection (modified release), 80 mg and 120 mg, (as acetate) with
solvent, syringe and needles, Firmagon®
Sponsor: Ferring Pharmaceuticals Pty Ltd
Date of PBAC Consideration: July 2010
1. Purpose of Application
To seek an Authority Required listing for the treatment of locally
advanced (equivalent to stage C) or metastatic (equivalent to stage
D) carcinoma of the prostate.
2. Background
This drug had not been previously considered by the PBAC.
3. Registration Status
Degarelix was TGA registered on 16 February 2010 for treatment of
patients with prostate cancer in whom androgen deprivation is
warranted.
4. Listing Requested and PBAC’s View
Authority Required
Locally advanced (equivalent to stage C) or metastatic (equivalent
to stage D) carcinoma of the prostate.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Prostate cancer, localised within the prostate gland, can be
treated successfully with surgery or radical radiotherapy. However,
30% of patients will develop metastatic disease. The current
endocrine therapy, including the blockade of androgen receptors
(anti-androgen therapy) and indirect inhibition of the biosynthesis
of androgen (gonadotropin releasing hormone (GnRH) agonist
therapy), is the first and primary means of treatment for patients
with metastatic prostate cancer.
Degarelix is a GnRH receptor antagonist and unlike the GnRH
agonists does not induce a luteinising hormone (LH) surge with
subsequent testosterone surge/tumour stimulation and symptomatic
flare after the initiation of treatment. It will provide an
alternative treatment option for the treatment of prostate
cancer.
6. Comparator
The submission nominated leuprorelin acetate, 7.5 mg, powder for
I.M injection as the main comparator. This was considered
reasonable by the PBAC.
7. Clinical Trials
The submission presented one randomised trial, Trial CS21 comparing
subcutaneous injections of degarelix 240 mg initially, then 80 mg
every 28 days (referred to as 240/80mg) with intramuscular
injections of leuprorelin 7.5 mg given every 28 days in patients
with Stage C or D prostate cancer for 12 months.
This trial had been published at the time of submission as
follows:
| Trial ID/First author | Protocol title | Publication citation |
| CS21 | ||
| Klotz et al (2008). | The efficacy and safety of degarelix: a 12-motnh, comparative, randomised, open-label, parallel-group phase III study in patients with prostate cancer. | British Journal of Urology International 2008; 102(11): 1531-8. |
8. Results of Trials
The primary outcome of Trial CS21 was the difference between
degarelix and leuprorelin of the cumulative probabilities of
maintaining testosterone ≤0.5 ng/mL from Day 28 to Day 364.
Results were summarised for both the treated patient population, of
all patients who received at least one dose of the medication, and
the per protocol (PP) patient population.
Cumulative probability of testosterone ≤0.5 ng/mL from
Day 28 to Day 364 – Kaplan-Meier estimates of individual
response rates
| Trial CS21 | Degarelix 240/80 mg n (%) [95% CI] | Leuprorelin 7.5 mg n (%) [95% CI] | Difference to Leuprorelin (%) [97.5% CI] |
| Treated population Response rate | N=207 202 (97.2%) [93.5;98.8%] | N=201 194 (96.4%) [92.5;98.2%] | (0.9%) [-3.2;5.0%] |
| PP population Response rate | N=200 195 (97.2%) [93.3;98.8%] | N=195 188 (96.3%) [92.4;98.2%] | 0.9% [-3.3;5.1%] |
Abbreviations: treated population = patients who received at least
one dose of the medication; PP=per protocol population.
The cumulative probability of testosterone ≤0.5 ng/mL from Day
28 to Day 364 was high in both the degarelix and leuprorelin
treatment groups, the lower bound 95% CI for both the treated and
the PP patient populations were above 90%. The submission claimed
that according to the U.S Food and Drug Administration (FDA)
efficacy criteria, this demonstrates that both degarelix and
leuprorelin were effective in achieving and maintaining
testosterone at castrate levels (≤0.5 ng/mL) from Day 28 through
Day 364.
Comparing patients treated with degarelix and leuprorelin, the
difference in cumulative probability of testosterone ≤0.5 ng/mL
between the two groups was 0.9% (95% CI: -3.2, 5.0%) and 0.9%
(95%CI: -3.3, 5.1%) in the treated and PP populations respectively.
The submission claimed that Trial CS21 demonstrated that treatment
with degarelix 240/80 mg was non-inferior to leuprorelin 7.5 mg
therapy in achieving and maintaining testosterone ≤ 0.5 ng/mL
from Day 28 through Day 364 for both the treated and PP analysis
sets.
The submission presented the results of secondary outcomes of the
proportions of patients with testosterone level ≤ 0.5 ng/mL at
Day 3 and the proportions of patients who demonstrated a
testosterone surge during the first two weeks of the trial, and
median percent change in prostate specific antigen (PSA) levels
from Day 0 to Day 14 and Day 28 of Trial CS21.
The results illustrated that more rapid suppression of PSA and
testosterone levels occurred in patients treated with degarelix
compared to patients treated with leuprorelin. The submission
provided no evidence to demonstrate whether the prevention of a
testosterone surge and/or the more expediant reduction in PSA
levels in the first month of possible long-term treatment with
degarelix would have significant effects on patient relevant
outcomes such as disease progression or overall survival compared
with leuprorelin.
For PBAC’s view, see Recommendation and
Reasons.
The incidence of adverse events was similar for patients treated
with degarelix 240/80 mg (79%) and leuprorelin 7.5 mg (78%) RR
(95%CI): 1.01 (0.92, 1.12), p value=0.78. There were no significant
differences between degarelix 240/80 mg and leuprorelin 7.5 mg arms
in the incidence of serious AEs (10% vs. 14%, p value=0.24), deaths
(2% vs. 4%, p value = 0.26) and adverse events leading to
discontinuations (7% vs. 6%, p value = 0.60). However,
significantly more patients treated with degarelix 240/80 mg (57%)
reported adverse drug reactions (ADRs) compared with patients
treated with leuprorelin (42%), RR (95% CI): 1.36 (1.12, 1.67), p
value = 0.003. The majority of treatment-emergent ADRs were general
disorders and administration site conditions including
injection-site reactions which occurred in 73 (35%) patients in the
degarelix 240/80 mg group compared with 1 patient (0.5%) in the
leuprorelin arm (RR(95%CI): 70.88 (9.95, 505.13); p value <
0.0001).
9. Clinical Claim
The submission described degarelix as non-inferior in terms of comparative safety and non-inferior in terms of comparative effectiveness:
- Over leuprorelin 7.5 mg for Days 28 to 364 for the maintenance dose of degarelix 80 mg and
- Over leuprorelin 7.5 mg in combination with an anti-androgen for Days 0 to 28 for initiation dose of degarelix 240 mg.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated for maintenance therapy (Days
28 onwards): degarelix 80 mg monthly vs. leuprorelin 7.5 mg
monthly; and for initiation therapy (Days 0 to 28): degarelix 240mg
vs. leuprorelin 7.5 mg in combination with a bicalutamide (50
mg).
The submission did not consider potential costs associated with any
co-administered pain relief with degarelix to account for injection
site reactions in the cost minimisation analysis.
The PBAC did not accept that bicalutamide would be used in all
patients commenced on leuprorelin. See Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The drug cost/patient/year was estimated by the submission based on
one starter pack of 2x120 mg injections and 11 monthly injections
of 80mg.
The likely number of packs dispensed per year was estimated by the
submission to be between 10,000 and 50,000 in Year 5. The
submission’s estimate may be uncertain due to assumptions
about the degarelix market share and/or market growth.
The net financial cost to the PBS, based on the submission’s
assumptions, was estimated to be zero.
For PBAC’s view, see Recommendation and
Reasons.
12. Recommendation and Reasons
The PBAC recommended listing of degarelix on the PBS as an
Authority Required (STREAMLINED) listing for locally advanced
(equivalent to stage C) or metastatic (equivalent to stage D)
carcinoma of the prostate on a cost-minimisation basis compared
with leuprorelin acetate 7.5 mg powder for I.M. injection. The
equi-effective doses are for maintenance therapy (Days 28 onwards)
degarelix 80 mg monthly and leuprorelin 7.5mg monthly, and for
initiation therapy (Days 0 to 28) degarelix 240 mg and leuprorelin
7.5 mg, in combination with bicalutamide (50 mg) daily for 11%
patients.
The PBAC noted that the current restrictions for anti-androgens
permit combination use with GnRH agonists only. The PBAC considered
that there was no reason to preclude degarelix (an GnRH antagonist)
from use in combination with the currently PBS listed
anti-androgens as there was a clinical need in certain patients for
total androgen blockade and requested the Secretariat to write to
those sponsors informing them of the proposed change.
The PBAC noted that the submission assumed that all patients
started on leuprorelin would receive an anti-androgen. However,
only 11% of the patients in Trial CS21 were co-administered
anti-androgens with leuprorelin and the PBAC considered this to be
a reasonable reflection of current clinical practice. The PBAC
noted that testosterone surge may not be a relevant consideration
for patients switching to degarelix therapy after established
androgen deprivation therapy and guidelines indicate that
anti-androgens are only indicated with GnRH agonists in patients
with features such as impending spinal cord compression or urinary
obstruction (Loblaw et al 2004). The PBAC considered the DUSC
estimate of 19.2 % to be overestimated as it captured people with a
script for a peripheral anti-androgen blockade 2 months prior to
and 12 months post leuprorelin. However, for flare prevention the
anti-androgen should have preceded or at least been given
concurrently with goserelin.
The PBAC accepted that use of testosterone levels as a surrogate
outcome was reasonable and that degarelix was non-inferior in terms
of efficacy compared with leuprorelin. However, the PBAC noted that
there are more injection site reactions compared with leuprorelin
and therefore degarelix may not be non-inferior with regards to
safety.
The PBAC noted that there was potential for increased costs to the
Government if degarelix, given monthly, was substituted for GnRH
agonists, given 3 monthly, requiring extra visits to the doctor or
nurse practitioner. The PBAC noted that currently most patients
receive an injection of a GnRH agonist at intervals of 3 months or
more. Therefore, the PBAC considered that any additional costs
associated with the administration of degarelix should be included
in the cost-minimisation of degarelix versus leuprorelin.
Recommendation: DEGARELIX, powder for
subcutaneous injection (modified release), 80 mg and 120 mg, (as
acetate) with solvent, syringe and needles
Restriction:
Authority Required (STREAMLINED)
Locally advanced (equivalent to stage C) or metastatic (equivalent to stage D) carcinoma of the prostate.
NOTE: No applications for increased maximum quantity and/or repeats will be authorised for the 120 mg powder for injection.
Maximum quantity:
‡1 (120 mg, 2 vials)
1 (80 mg)
Repeats:
Nil (120 mg)
5 (80 mg)
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
Ferring welcomes the PBAC decision to recommend listing of
Degarelix (FIRMAGON) for patients with locally advanced (equivalent
to stage C) or metastatic (equivalent to stage D) carcinoma of the
prostate.
