National PBM Monograph Template Rev20091005



Degarelix (Firmagon()

National Drug Monograph

October 2010

VA Pharmacy Benefits Management Services,

Medical Advisory Panel, and VISN Pharmacist Executives

The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current.

Executive Summary:

Clinical Efficacy

• Degarelix is a new gonadotropin releasing-hormone (GnRH) antagonist indicated for use in the treatment of patients with advanced prostate cancer.

• Unlike previous GnRH antagonists, degarelix does not cause systemic allergic reactions due to histamine release.

• Dosing: Initial dose of 240mg subcutaneously (2 X 120mg) followed by a maintenance dose of 80mg subcutaneously monthly.

• In a phase III, open-label trial comparing 2 different maintenance doses of degarelix with monthly leuprolide injections, degarelix produced a quick suppression of testosterone levels to castrate level (50 ng/dL at least once|5 (2.4) |3 (1.5) |7 (3.5) |

|between days 28-364), n(%) | | | |

|Insufficient response (one testosterone >100 ng/dL or 2 |4 (1.9) |2 (1.0) |6 (3.0) |

|consecutive values >50 ng/dL), n(%) | | | |

|Testosterone suppression by day 3 (median day 3 value ≤50|96.1 |95.5 |Levels increased by |

|ng/dL) % |(median 24 ng/dL) |(median 26 ng/dL) |65% from baseline |

|%PSA decline days 14-28 |64-85 |65-83 |18-68 |

| | | |(+ bicalutamide % |

| | | |decline similar to |

| | | |degarelix) |

|Incidence of PSA Failure % |8.9 |14.2 |14.1 |

Suppression of testosterone levels by day 3 reflects the inherent differences in the mechanisms of action of GnRH agonists and antagonists. Initial increases in testosterone levels produced by GnRH agonists prior to a negative feedback to the pituitary gland, may expose patients to temporary growth of prostate cancer cells and disease symptoms.

In the leuprolide group, 11% received concomitant bicalutamide to prevent a flare reaction. Of the patients who did not receive bicalutamide, 81% had a surge in testosterone levels to greater than or equal to 15% from baseline on any 2 days during the first 2 weeks.

PSA response is biochemical evidence of a clinical response. Degarelix produced a more rapid decline in PSA levels during the first 28 days of therapy compared to leuprolide, reflecting a difference in the mechanism of action. The clinical significance of a rapid PSA response is not known.

Microsurges of testosterone due to agonist stimulation (acute on chronic) were assessed on days 255 and 259, 3 and 7 days after the ninth leuprolide doses and the largest value on day 255 or 259 was compared to the testosterone levels on day 252. There was a statistically significant increase of 4.5 ng/dL in the leuprolide group (P25 ng/dL and 2% to >50 ng/dL.

As expected, after administration of degarelix, there was a rapid decrease in median LH and FSH levels, while there was an increase in median levels at the start of the study in the leuprolide group and the FSH never fell to the same extent as in the degarelix group.

Phase II supporting trials

Table #5 Phase II trials

|Citation |Eligibility |Interventions |Patient |Efficacy Results |Safety Results |

|Design |Criteria | |Population | | |

|Analysis type | | |Profile | | |

|Setting | | | | | |

|Gittelman, et |Inclusion criteria|Degarelix |Age:76 |NR = 127 |No reports of |

|al.[iii] |Adeno-carcinoma |Starting Dose |Sex: M |23 protocol violations excluded from per |systemic allergic |

|1-yr, |prostate |200mg |Race:84% white |protocol analysis |reactions |

|open-label, |Requires endocrine|Maintenance |Local 43% |Withdrawals: |Most rated mild or |

|randomized, |treatment (not |Dose: |Advanced: 11% |16 inadequate T suppression |moderate |

|parallel group |neoadjuvant) |60 or 80mg for |Metastatic: 19%|6 due to AE’s |13% rated severe |

|Phase II in US |Baseline T >2.2 |1 year |Unclassified:28|18 due to other reasons |Withdrawal: |

|and Canada The |ng/mL | |% | |6 for: injections |

|Degarelix Study|ECOP ≤2 | | | |site urticaria, |

|Group |PSA≥2 ng/mL | | |60mg |Pelvic DVT, MI, |

| |Exclusion criteria| | |80mg |asthenia, acute MI |

| |Previous hormonal | | |Total |3 died: ages 82-85 |

| |tx for prostate | | | |with pre-existing |

| |cancer (except | | | |heart disease had MIs|

| |neoadjuvant) | | |N = |not considered |

| |No anti-androgens | | | 42 |related to degarelix.|

| | | | |N = | |

| | | | |45  | |

| | | | |N =  | |

| | | | |87 | |

| | | | | | |

| | | | |T ≤50 on D3 | |

| | | | |90% | |

| | | | |95%CI | |

| | | | |79-96 | |

| | | | |89% | |

| | | | |95%CI | |

| | | | |78-95 | |

| | | | |89% | |

| | | | |95%CI | |

| | | | |83-94 | |

| | | | | | |

| | | | |T ≤50 on D30 | |

| | | | |93% | |

| | | | |95%CI | |

| | | | |84-98 | |

| | | | |83% | |

| | | | |95%CI | |

| | | | |71-91 | |

| | | | |88% | |

| | | | |95%CI | |

| | | | |81-93 | |

| | | | | | |

| | | | |T≤ | |

| | | | |50 D30-364 | |

| | | | |93% | |

| | | | |95%CI | |

| | | | |82-99 | |

| | | | |98% | |

| | | | |95%CI | |

| | | | |87-100 | |

| | | | |NSS | |

| | | | |P=0.669 | |

| | | | |NA | |

| | | | | | |

|Van Poppel, et |Inclusion |Degarelix |Age:72 |NR- 189 |No cases of systemic |

|al.[iv] |criteria: |Starting dose |Sex: M |3 not randomized |allergic reactions |

|1-yr, |Adeno-carcinoma of|200 or 240mg |Race:96% white |4with major protocol violations |Most AE’s mild or |

|open-label, |the prostate |Maintenance |Local22% |Withdrawals: |moderate. |

|randomized, |Requires endocrine|doses: |Advanced 32% |16 inadequate T suppression |Most common: hot |

|parallel-group,|treatment (not |80,120,160mg |Metastatic 19% |13 due to AE’s |flushes, |

|dosage finding |neoadjuvant) | |Unclassified |13 due to other reasons |injection-site pain, |

|phase II trial |Baseline T >2.2 | |27% |Completed N=147 |increased weight, |

|in Europe The |ng/mL | | |Initial |back pain, fatigue, |

|Degarelix Study|ECOG ≤2 | | |200mg |increased ALT |

|Group |PSA≥2 ng/mL | | |240mg |11% had at least one |

| |Bone scan | | | |severe AE |

| | | | |T ≤50 on D3 |14% had serious |

| |Exclusion | | |88% |treatment-emergent |

| |criteria: | | |92% |AE’s:13 withdrew (3 |

| |Prior hormone | | | |with progressive |

| |therapy for | | |T≤50 after 1 month |disease, 3 with CV |

| |prostate cancer | | |OR |events, 2 with CVA, 2|

| |(except | | |95%CI |with cachexia, 1 with|

| |neoadjuvant or | | |P |bronchospasm, 1 with |

| |adjuvant) | | |86% |laryngeal cancer) |

| |No anti-androgens | | |95% |11 patients died; no |

| | | | | |temporal correlation |

| | | | | |with degarelix |

| | | | |2.57 |administration |

| | | | |1.01-6.651 | |

| | | | |0.048 | |

| | | | | | |

| | | | | | |

| | | | |% with T ≤50 monthly months 1-12 | |

| | | | |Initial Dose | |

| | | | |80mg | |

| | | | |120mg | |

| | | | |160mg | |

| | | | | | |

| | | | |200 | |

| | | | |61 | |

| | | | |84 | |

| | | | |96 | |

| | | | | | |

| | | | |240 | |

| | | | |90 | |

| | | | |90 | |

| | | | |92 | |

| | | | | | |

| | | | |All | |

| | | | |92 | |

| | | | |96 | |

| | | | |100 | |

| | | | | | |

T=testosterone; ALT=alanine aminotransferase

Adverse Events (Safety Data)

Table #6 Adverse Events in >5% of Patients

| |Degarelix 240mg/160 mg |Degarelix 240mg/80mg |Leuprolide 7.5mg |

| |(N=202) |(N=207) |(N=201) |

|% of patients with adverse |83% |79% |78% |

|events | | | |

|Injection site AE |44 |35 | ................
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