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Hormone-Refractory Prostate Cancer or Castrate-Resistant Prostate Cancer
Understanding
Treating Maintaining Quality of Life
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Some possible utility as
a 2nd line hormone therapy Author:
Howard Hansen Date:
14 July 2010 Introduction Degaralix (manufactured by Ferring Pharmaceutical) and
now named Firmagon(R). It is a new injectable gonadotropin-releasing
hormone (GnRH) receptor antagonist approved by the U.S. Food and Drug
Administration (FDA) for the treatment of hormone sensitive advanced
prostate cancer. Degarelix provides fast, long-term suppression of
testosterone. Clinical trials
demonstrated that degarelix is effective in quickly reducing and
sustaining castrate levels of testosterone. Degarelix works
differently than a luteinizing hormone-releasing hormone (LHRH) agonist
(e.g., Lupron, Zoladex and others)
by binding immediately and reversibly to GnRH receptors in the pituitary
gland, quickly reducing the release of gonadotropins and consequently
testosterone. Phase III - Leuprolide vs degarelix This was a 12 month, randomized, open-label,
parallel-group study to evaluate the efficacy and safety of degarelix
compared to leuprolide. The drugs were administered monthly over one
year of PCa treatment. Degarelix (207 patients) was a subcutaneous
injection of 240mg for one month followed by monthly maintenance doses
of 80mg. Leuprolide (201 patients) was injected intramuscularly on a
monthly schedule at a dose of 7.5mg. One Leuprolide brand name is Lupron
for example. Castrate was defined as ≤ 50 ng/dl. (why not 32ng/dl? -
see www.hrpca.org/FAQ) Note: No PSA surge with degarelix. Degarelix group: 90 percent decrease in median testosterone levels at Day 3 of
treatment. Leuprolide group: 65 percent increase in median
testosterone levels at Day 3 of treatment. Day 3 Degarelix: 96 percent reached castrate levels of testosterone Day 3 Leuprolide: zero percent were castrate. Day 28 to Day 364: Degarelix - 97.2% maintained medical
castrate levels and leuprolide patients had 96.4% maintained at medical
castrate levels. PSA levels
were lowered by 64 percent two weeks after administration of degarelix,
85 percent after one month, 95 percent after three months, and remained
suppressed throughout the one year of treatment. Adverse Events from Phase III: The most commonly observed adverse reactions during degarelix therapy
included injection site reactions (e.g. pain, erythema, swelling or
induration), hot flashes, increased weight, fatigue, and increases in
serum levels of transaminases and gamma-glutamyltransferase (GGT).
Ninety-nine percent of these observed adverse reactions were Grade 1 or
2 (mild to moderate). Specifically relating to the injection site
adverse reactions, most were transient, of mild to moderate intensity,
occurred primarily with the starting dose and led to few
discontinuations (<1%). Grade 3 (severe) injection site reactions
occurred in two percent or less of patients receiving degarelix. Using Degarelix as a 2nd Line Hormonal Therapy There are at least two ways of
using degarelix that might be useful for HRPC (as well as hormone
sensitive patients) patients. One is to use it
instead of leuprolide (e.g., Lupron). There is a chance your PSA will drop when you make this change (7). The author
experienced this when switching from Zoladex to Lupron. The 2nd use would be as a
second-line hormonal therapy treatment as outlined below (8). Reference (8) reported that
degarelix could stabilize or reverse disease progression in patients
after failure of GnRH agonist treatment. This was the 3-month results of
an exploratory, multicenter study exploring the potential use of
degarelix as a non-cytotoxic 2nd line therapy for prostate cancer with
signs of hormone resistance. This study included 25 patients with prostate cancer who had experienced PSA progression despite at least 1
year of treatment (mean duration, 4.1 years) with a GnRH agonist. PSA
progression was defined as 2 consecutive 50% rises in PSA above nadir at
least 2 weeks apart and at least 1 PSA value of >=2.5 ng/mL in the last
6 months of treatment. Most patients had locally advanced (44%) or
metastatic (28%) disease and a Gleason score of 7 to 10 (76%). Patients
received an initial dose of degarelix 240 mg followed by monthly
maintenance doses of 80 mg, all given by subcutaneous injection. They
reported that degarelix: Maintained PSA suppression Lowered luteinising hormone (LH).
This became undetectable in 88% (22 patients). Lowered follicle-stimulating
hormone (FSH). Levels fell in 84% of patients. Lowered testosterone levels PSA doubling time was prolonged in
64% (14 patients). LH was
undetectable in 88% (n=22) of patients after the switch to degarelix.
FSH levels fell in 84% of patients, and testosterone levels decreased in
40% of patients (n = 10). Some patients appeared to have a late response
(>3 mo) to degarelix. A total of 60 adverse events were reported by 18
patients (72%); most were mild (n = 14; 56%) or moderate (n = 8; 32%),
and 1 patient discontinued due to treatment. Stabilized PSA. This was
defined as a relative change from baseline not exceeding 10% after 3
month on degarelix. At 1 month, there were 8 responders, 4 patients
(16) achieved the primary endpoint; 1 patient had castrate
testosterone at screening, but a borderline tesosterone value and a
high LH at study entry. A second responder had castrate testosterone
but measurable LH at entry, while the
remaining 2 responders had castrate testosterone and undetectable LH.
In reference
(7), switching from leuprolide to degarelix or having continuous
degarelix, was discussed. Among other
things, they found that up to 1 year, musculoskeletal and connective
tissue AEs
occurred in 17% (degarelix) vs 26% (leuprolide; p<0.05) of patients.
Beyond 1 year, these AEs were similar in the two groups (16% vs 18%
[p=0.75]). The authors concluded that: "Conclusions: These data suggest that patients with hormone-sensitive PCa
receiving leuprolide experience improved PSA control after switching to
degarelix. Patients receiving continuous degarelix have fewer
musculoskeletal AEs. Further studies are required to confirm these
findings" Other studies
with degarelix Reference (9)
examined PSA failures during the phase III trial. Their conclusion was "PSA failures in this 1-year
trial occurred mainly in patients with advanced disease. Patients
with metastatic PCa or those with PSA levels >20 ng/mL at baseline
experienced numerically fewer PSA failures with degarelix 240/80 mg
compared with degarelix 240/160 mg or leuprolide 7.5 mg." See the
abstract for more details. In reference (10) J. W. Moul,
et al discussed PSA failure and serum alkaline phosphatase (S-ALP) control
in patients with prostate cancer receiving degarelix or leuprolide
in the CS21 trial for the 240mg/80mg approved dose vs leuprolide at
7.5mg. Serum alkaline phosphatase levels may be associated with
progression of bone metastases. Their results are "PSA failure occurred in 8.9% vs
14.1% of patients receiving degarelix and leuprolide.
PSA progression-free survival was significantly
different between arms (p < 0.05, log-rank). Failures
occurred most frequently in patients with advanced PCa
and higher baseline PSA. Mean S-ALP in
metastatic patients was suppressed below baseline with degarelix but not leuprolide and the late rise in S- ALP
seen with leuprolide was not observed with degarelix (p
= 0.014). Musculoskeletal adverse events were reported
in 17% (degarelix) vs 26% (leuprolide; p = 0.001) of
patients." Furthermore, they concluded that "These data indicate the
potential for significantly longer disease control
(fewer PSA failures and lower S-ALP) with degarelix
240/80 mg compared with leuprolide. Comments Just how useful
degarelix will be in HRPC patients remains to be seen. We have here only
a small trial, but given a choice of being on degarelix
or leuprolide it seems clear that making a switch from leuprolide to
degarelix might serve as a 2nd line hormonal treatment. Note that this
had been tried before with Plenaxis,
but that was not successsful as far as the author knows. The one
downside right now is the need for monthly subcutaneous injections, but
in time longer formulations likely will become available. A 6 month
injection is being tested already. (1) Degarelix. Parsippany, NJ: Ferring
Pharmaceuticals Inc; FDA approved Degarelix on 24 December 2008. For
prescribing information, see
www.firmagon.com or call 1-888-FERRING
(1-888-337-7464) or visit www.FerringUSA.com. (2) Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of
degarelix: a 12-month comparative, randomized, open-label,
parallel-group phase III study in patients with prostate cancer. BJU
Int. 2008;102(11):1531-1538. (6) American Cancer Society. Cancer Reference Information, Overview:
Prostate Cancer. http://www.cancer.org/docroot/CRI/CRI_2_1x.asp?dt=36;
Last accessed 11/12/08.
(7) N. D. Shore, J. W. Moul, E. Crawford, T. Olesen, B. Persson;
Long-term prostate-specific antigen (PSA) control in prostate cancer (PCa)
patients switched from leuprolide to degarelix or receiving continuous
degarelix treatment,
2010 ASCO Annual Meeting, J Clin Oncol 28:15s, 2010 (suppl; abstract 4673).
(8) Kurt Miller, MD, Press release
title: Degarelix Shows Promise as
Second-Line Hormonal Therapy for Patients With Prostate Cancer:
Presented at EAU;
By Jenny Powers BARCELONA, Spain -- April 20, 2010 -- Note that this is
a press release. 25th Annual European Association of Urology (EAU)
Congress. Funding for this study was provided by Ferring Pharmaceuticals. [[Presentation title: Open-Label,
Exploratory Study of Degarelix as Second-Line Hormonal Therapy in
Patients With Prostate Cancer (CS27). Abstract 144].
(9) M. Gittelman,
N. Shore, J. Jensen, B. Persson, T. Olesen; Degarelix versus leuprolide treatment in patients
with advanced prostate cancer (Pca): PSA failures during a
randomized, phase III trial (CS21).
2009 Genitourinary Cancers Symposium,
abstract no. 209.
(10) J. W. Moul, E. Crawford, N. Shore, T. Olesen, J. Jensen,
B. Persson; PSA and serum alkaline phosphatase (S-ALP) control
in patients with prostate cancer (PCa) receiving
degarelix or leuprolide,
2010 Genitourinary Cancers
Symposium, abstract no. 111.
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