ELIGARD: LEUPROLIDE ACETATE IN A NOVEL

SUSTAINED-RELEASE DELIVERY SYSTEM

OLIVER SARTOR

ABSTRACT
Androgen deprivation as a treatment for prostate cancer has evolved since the pioneering studies of Huggins
and Hodges 60 years ago using surgical castration or estrogen treatments. The most common hormonal
treatments today use injections of luteinizing hormone–releasing hormone (LHRH) agonists. The US Food
and Drug Administration (FDA) has approved 5 LHRH agonist formulations for treatment of prostate cancer
in the United States. Of these approved products, 3 involve different delivery systems for the LHRH
superagonist leuprolide acetate. Sustained-release formulations of 2 distinct LHRH agonists, goserelin
acetate and triptorelin pamoate, are also commercially available. This review focuses on new data on a novel
formulation of leuprolide acetate (Eligard; Atrix Laboratories Inc., Fort Collins, CO) that incorporates a
unique mixture of selected polymers and solvents to achieve sustained drug delivery after subcutaneous
injection. The FDA has approved 1-month and 3-month formulations of Eligard, and 4-month and 6-month
products are in development. In clinical trials, Eligard achieves reliable and sustained suppression of serum
testosterone to castration levels (ⱕ50 ng/dL). Of the patients treated with the 1-month and 3-month
formulations, 98% (115 of 117) and 94% (104 of 111), respectively, reached testosterone levels of ⱕ20
ng/dL. Breakthroughs, defined as testosterone levels ⬎50 ng/dL after achievement of castration levels,
occurred rarely at 0% (0 of 117) for the 1-month and at 0.9% (1 of 111) for the 3-month formulations in
patients receiving Eligard. The degree of disease control and the adverse-events profile are commensurate
with the effectiveness of the testosterone suppression; the incidence of severe hot flashes is actually lower
than anticipated. Additional studies with these novel formulations are warranted. UROLOGY 61 (Suppl 2A):
25–31, 2003. © 2003, Elsevier Science Inc.

R ecognition of the sensitivity of prostate cancer

to androgenic stimuli dates back ⬎6 decades
to the landmark studies published by Huggins and
Hodges1 in 1941. These studies established andro-
gen deprivation, accomplished via orchiectomy or
estrogen treatment, as the primary treatment for
advanced prostate cancer. For his work on hor-
monal treatment of prostate cancer, Dr. Huggins
was awarded the Nobel Prize for Physiology or
Medicine in 1966. Research into the regulatory
pathways controlling testosterone production sub-
sequently centered on the critical role of the hypo-
From the Stanley S. Scott Cancer Center, Louisiana State Univer-
sity School of Medicine, New Orleans, Louisiana, USA
This supplement was funded by Sanofi-Synthelabo. Dr. Sartor
is a member of the scientific advisory board for Atrix Laborato-
ries, and is a paid consultant to Sanofi-Synthelabo.
Reprint requests: Oliver Sartor, MD, Stanley S. Scott Cancer
Center, Suite 620, 2025 Gravier Street, Louisiana State Univer-
sity Health Sciences Center, New Orleans, Louisiana 70112. E-
mail: osarto@Isumc.edu
thalamic-pituitary axis. In 1971, Andrew Schally et
al.2 isolated luteinizing hormone–releasing hor-
mone (LHRH) from porcine hypothalamic extracts
and demonstrated that this decapeptide was both
necessary and sufficient for release of luteinizing
hormone (LH) from the pituitary. In 1977, Dr.
Schally shared the Nobel Prize for discoveries on
peptide production in the brain (reviewed in
Schally et al.2).
These basic physiologic findings provided the in-
tellectual foundation for the next advance in hor-
monal therapy for prostate cancer. Shortly after the
isolation of LHRH, experimental substitution of
amino acids in the basic LHRH structure resulted
in analogs with potent agonist activity. Although
the initial studies of LHRH agonists were aimed at
developing treatments for infertility, these com-
pounds, when administered in either a continuous
or daily manner, resulted in a paradoxical de-
crease, rather than increase, in both LH and testos-

© 2003, ELSEVIER SCIENCE INC. 0090-4295/03/$30.00

ALL RIGHTS RESERVED PII S0090-4295(02)02396-8 25
terone levels. The decrease was a consequence of
downregulated LHRH receptors at the pituitary
level.2 In 1980, LHRH agonists were first used to
treat patients with prostate cancer.3 The US Food
and Drug Administration (FDA) approval of LHRH
analogs for treatment of prostate cancer was
granted in 1985, after pivotal randomized studies
demonstrated that the time to cancer progression
was equivalent in patients treated with daily 3-mg
doses of diethylstilbestrol (DES) and daily 1-mg
subcutaneous LHRH injections.4 Toxicity varied
between the 2 treatment groups, favoring the
LHRH-treated subjects: fluid retention, nausea, gy-
necomastia, and breast tenderness were more com-
monly reported in the patients treated with DES.
Hot flashes were more commonly reported in pa-
tients treated with the LHRH analog. Given these
findings, and the strong preference patients have
expressed for injections as opposed to orchiec-
tomy, LHRH agonists have virtually replaced both
estrogens and orchiectomy as the initial hormonal
treatment of choice for patients with prostate can-
cer in the United States.
TESTOSTERONE SUPPRESSION AND
CANCER RESPONSIVENESS
The studies of Huggins and Hodges1 clear-
ly established that androgen deprivation re-
sulted in improved outcomes for patients with
advanced prostate cancer. Although the broad
relation between androgen suppression and re-
sponsiveness of tumors in patients with prostate
cancer has now been well documented, the exact
relation between testosterone levels (after thera-
peutic intervention) and length of survival or
time to cancer progression has yet to be defined.
In their most recently issued guidelines, the
National Comprehensive Cancer Network (NCCN)
has recommended that orchiectomy or addition of
an oral antiandrogen be considered if a patient’s
serum testosterone levels remain ⬎20 ng/dL dur-
ing monotherapy with an LHRH agonist.5 This
threshold is not based on published clinical evi-
dence. The FDA has established serum testoster-
one levels of ⱕ50 ng/dL as being consistent with
levels obtained after surgical castration. This level
of testosterone has been used as the standard for
approval of new hormonal therapies in the United
States since the advent of LHRH agonists. Current
studies demonstrate that only about 5% of patients
being treated with LHRH agonist therapy fail to
achieve testosterone suppression ⬍50 ng/dL.6 The
consequences of this relative lack of suppression
are unknown.7
26
CURRENTLY APPROVED LUTEINIZING
HORMONE–RELEASING HORMONE
AGONISTS
The FDA has approved 5 LHRH agonist formu-
lations for the treatment of prostate cancer: 3 de-
livery systems that administer leuprolide acetate in
a sustained manner, a goserelin acetate implant
(Zoladex; AstraZeneca Pharmaceuticals, Maccles-
field, London, UK), and a sustained-release form of
triptorelin pamoate (Trelstar; Pharmacia, Peapack,
NJ). Of the 3 sustained-release delivery systems for
leuprolide acetate, 2 are injectable forms: Lupron
Depot (TAP Pharmaceuticals, Lake Forest, IL) and
Eligard (Atrix Laboratories, Inc., Fort Collins,
CO), and the third is a subcutaneously implanted
minipump approved for 1-year dosing (Viadur;
Alza Corporation, Mountain View, CA). Each of
these agents has been shown to maintain mean tes-
tosterone levels ⬍50 ng/dL. Limited data are avail-
able about which products meet the more stringent
testosterone suppression guidelines established by
the NCCN.
The remainder of this article describes a compre-
hensive series of data from clinical trials of the
Eligard formulation of leuprolide acetate for sub-
cutaneous injection. The leuprolide acetate is ad-
ministered via an implanted depot delivery system,
which releases the drug in a controlled manner
over defined intervals—1, 3, 4, or 6 months. The
FDA has approved the 1-month and 3-month for-
mulations for the palliative treatment of advanced
prostate cancer. The 4-month formulation has
completed clinical trials and is awaiting FDA ap-
proval; clinical trials of the 6-month formulation
are currently under way.
ELIGARD DELIVERY SYSTEM
The implant system used in the Eligard product
consists of leuprolide acetate admixed with a
combination of biodegradable polymers in a liquid
carrier. The polymeric delivery system (Atrix
Laboratories, Inc.) is composed of a biodegrad-
able poly (DL-lactide-co-glycolide) polymer for-
mulation dissolved in a biocompatible solvent,
N-methyl-2-pyrrolidone.8 Leuprolide acetate is
physically mixed with the polymer/solvent combi-
nation immediately before injection. The drug/
polymer combination is then injected via a 20-
gauge needle into the subcutaneous tissue, where
it forms a solid drug-delivery implant, slowly re-
leasing the leuprolide acetate at a controlled
rate as the polymer is degraded by normal biologic
processes. Variations in the molecular weight of
the polymer and solvent concentrations allow
sustained release of the drug for the specified du-
ration.
UROLOGY 61 (Supplement 2A), February 2003
FIGURE 1. Testosterone suppression in dogs (N ⫽ 6) with Eligard (Atrix Laboratories, Inc., Fort Collins, CO) and
Lupron Depot (TAP Pharmaceuticals, Lake Forest, IL) 3-month products. T ⫽ testosterone. (Data on file, Atrix
Laboratories, Inc.9).

FIGURE 2. Testosterone levels in dogs with Eligard (45 mg) 6-month depot. LA ⫽ leuprolide acetate; NMP ⫽
N-methyl-2-pyrrolidone; PLG ⫽ poly (DL-lactide-co-glycolide). (Data on file, Atrix Laboratories, Inc.9)

ELIGARD PRECLINICAL STUDIES
Preclinical studies conducted with various for-
mulations of Eligard in dogs established proof of
principle. With the 3-month formulation, testos-
terone levels increased within the first week after
administration but then decreased to well below
canine castration levels within 14 days after admin-
istration (Figure 1).9 The 6-month formulations of
Eligard have been shown to effectively suppress
testosterone levels in dogs over the 6-month period
(Figure 2). These data clearly demonstrate utility
of the leuprolide acetate delivery system to reduce
testosterone levels in a preclinical model.
ELIGARD CLINICAL TRIALS
THE 1-MONTH FORMULATION
The 1-month depot formulation of Eligard (7.5
mg leuprolide acetate) has been evaluated clini-
cally in an open-label, multicenter study of 120
patients with prostate cancer.10 Of these patients,

UROLOGY 61 (Supplement 2A), February 2003 27

FIGURE 3. Testosterone levels in humans after subcutaneous injection of Eligard (Atrix Laboratories, Inc., Fort
Collins, CO) 7.5 mg 1-month depot. (Adapted with permission from Clin Ther.10)
TABLE I. Testosterone values with Eligard (7.5 mg) 1-month
depot11
Testosterone
Mean value
Baseline (N ⫽ 120)
Month 6 (N ⫽ 117)
Median time to suppression (range)
ⱕ50 ng/dL
ⱕ20 ng/dL
Proportion with suppression at month 6
ⱕ50 ng/dL
ⱕ20 ng/dL
* Lower limits of detection.
89 had Jewett stage C disease and 31 had stage D
disease. (TNM staging was not done.) A total of
117 patients completed 6 months of treatment,
consisting of 6 subcutaneous injections (1 subcu-
taneous injection every 28 days in the upper abdo-
men). The 3 patients who withdrew cited nonmed-
ical reasons for not completing the study. Over a
6-month period, the following were evaluated: (1)
safety and efficacy, measured in terms of testoster-
one levels; (2) levels of prostate-specific antigen
(PSA); and clinical adverse events. Secondary effi-
cacy endpoints included performance status, bone
pain, urinary symptoms, and urinary pain.
As would be expected at the initiation of ther-
apy with an LHRH agonist, the mean testosterone
concentration increased from 361.2 ng/dL at
baseline to 574.6 ng/dL at day 3 after the initial
subcutaneous injection (Figure 3).11 Mean test-
osterone concentration then decreased to below
baseline by day 10, reaching a mean level of 21.8
28
Value
361.2 ng/dL
6.1 ng/dL (3.0*–27.0)
21 d (10–42 d)
28 d (14–49 d)
117 patients (100%)
115 patients (98%)
ng/dL on day 28. Median time to suppression to
ⱕ50 ng/dL was 21 days; median time to suppres-
sion to ⱕ20 ng/dL was 28 days. At the conclusion
of the study (month 6), the mean testosterone con-
centration was 6.1 ng/dL (Table I). By day 28
(week 4), 112 of 119 patients (94.1%) had
achieved castration levels of testosterone, defined
as serum testosterone levels ⱕ50 ng/dL. By day 42,
100% of the patients had achieved testosterone lev-
els ⱕ50 ng/dL. Once serum testosterone levels
were ⱕ50 ng/dL, no patient demonstrated a break-
through response (concentration ⬎50 ng/dL) at
any time in the study. All 117 patients providing
evaluable data had testosterone concentrations
ⱕ50 ng/dL at month 6. In addition, at 6 months,
98% (115 of 117) of the patients treated with Eli-
gard had testosterone levels at or below the more
stringent NCCN threshold of ⱕ20 ng/dL. The
baseline mean serum PSA level for the 117
patients enrolled in the study was 31.0 ng/mL
UROLOGY 61 (Supplement 2A), February 2003
FIGURE 4. Testosterone levels in humans after subcutaneous injection of Eligard (Atrix Laboratories, Inc., Fort
Collins, CO) 22.5 mg 3-month depot. (Adapted with permission from J Urol.11)
TABLE II. Testosterone values with Eligard (22.5 mg) 3-month
depot11
Testosterone
Mean value ⫾ SD (range)
Baseline (N ⫽ 117)
Month 6 (N ⫽ 111)
Median time to suppression (range)
ⱕ50 ng/dL
ⱕ20 ng/dL
Proportion with suppression at month 6
ⱕ50 ng/dL
ⱕ20 ng/dL
* Lower limit of detection.
(range, 0.1 to 639.0 ng/mL). At month 6, the mean
PSA value was 1.9 ng/nL (range, 0.1 to 93.9 ng/
mL), representing a 94% mean reduction from
baseline. As expected with an effective hormonal
therapy, serum PSA levels decreased in all patients
whose baseline values were elevated above the
normal limit.
A total of 716 injections of Eligard 7.5 mg were
administered in the 120 patients enrolled in the
study. Overall, adverse events were consistent with
androgen deprivation. The most common adverse
events reported by patients were hot flashes. Side
effects related to sexual function were not volun-
tarily reported by the patients in the trial. Hot
flashes were reported in 68 of the 120 patients
(56.7%). Of the reported hot flashes, 83% were
mild, 16% moderate, and 1% severe. Injection site
adverse events were reported either as mild in 60
patients (50%) or moderate in 14 patients (11.7%).
There were no trends toward increased severity,
UROLOGY 61 (Supplement 2A), February 2003
Value
367 ng/dL ⫾ 13.2 ng/dL (140–839 ng/dL)
10.1 ⫾ 0.7 ng/dL (3.0*–50.0 ng/dL)
21 d (14–35 d)
28 d (14–84 d)
115 patients (98%)
104 patients (94%)
duration, or recurrence of adverse events with sub-
sequent injections. No treatment-related serious
adverse events occurred, and no deaths were re-
ported during the study. No patients discontinued
the study because of a treatment-related adverse
event.
THE 3-MONTH FORMULATION
A multicenter, open-label study investigated a
3-month subcutaneous depot formulation of leu-
prolide acetate in patients with prostate cancer
(Jewett stage A, B, C, and D). Of the 117 patients
enrolled, 111 patients completed 6 months of
treatment consisting of 2 subcutaneous injections
of 22.5 mg, with 1 injection administered to the
upper abdomen every 3 months. Safety and efficacy,
as assessed by testosterone and PSA levels, were
evaluated. After an initial increase in testosterone
levels, mean testosterone concentrations de-
creased to ⱕ50 ng/dL by day 21 and to ⱕ20 ng/dL
29
 TABLE III. Adverse events with Eligard (22.5 mg) 3-month depot
(6-month study, N ⴝ 117)11
Adverse Event
Hot flashes/flushes
Nausea
Fatigue
Arthralgia
Urinary frequency
Pruritus (not otherwise specified)
TABLE IV. Summary of Eligard products10,11
Final Mean
Patients Testosterone
Product (Completed) (ng/mL)
1-Month Depot 117 6.1
3-Month Depot 111 10.1
by day 28 (Figure 4; Table II). The mean testoster-
one values remained ⬍20 ng/dL for the rest of the
evaluation period (168 days). There was 1 patient
who had a transient increase in testosterone to 112
ng/dL on day 49 after achieving castration levels,
but he regained suppression (27.0 ng/dL) on day
98, 14 days after the second injection. No studies
were performed to establish a mechanism for the
breakthrough. Baseline PSA values decreased from
a mean baseline value of 86.4 ng/mL to a mean
value at 6 months of 1.7 ng/mL, representing a
mean reduction of ⬎98%. At the end of the evalu-
ation period, 103 of 111 patients (93%) had
achieved a PSA level ⱕ4 ng/mL.11
As with the 1-month formulation, hot flashes
were the most frequent adverse events in patients
treated with the Eligard 22.5-mg, 3-month depot
formulation, occurring in 56.4% of patients (Table
III). The incidence of severe hot flashes/sweats was
low. Although hot flashes/sweats were not pro-
spectively evaluated during the trial, of the 84 hot
flashes/sweats reported by 66 of the 117 patients,
87% were considered mild, 13% moderate, and 0%
severe. Other reported adverse events occurred in
⬍5% of patients, with the exception of fatigue,
which occurred in 6%. Injection site reactions
overall were mild and brief in duration.
DISCUSSION
There have been 2 clinical trials that have now
been published for Eligard evaluating the 1-month
30
Incidence of Possibly or
Probably
Treatment-Related Systemic
Adverse Events
Reported by >2% of Patients
Patients (N) Percent
66 56.4
4 3.4
7 6.0
4 3.4
3 2.6
3 2.6
Testosterone Volume of
Breakthrough Injection
(Patients) [mL]
0/117 0.25
1/111 0.375
and 3-month formulations, respectively (Table
IV).10,11 Each formulation has been shown to be
highly effective in reducing mean testosterone lev-
els to below castration levels established by the
FDA (ⱕ50 ng/dL) as well as below the values rec-
ommended by the NCCN for LHRH agonist mono-
therapy (ⱕ20 ng/dL). Breakthrough increases in
testosterone levels (concentrations ⱖ50 ng/dL)
were infrequent and transient. Among the patients
being treated with the 1-month formulation, none
experienced breakthrough testosterone increases;
with the other formulations, transient break-
through occurred at 1 time point in 1 patient
treated with the 3-month formulation and in 3 pa-
tients treated with the 4-month formulation. As
expected, PSA levels normalized in most patients
treated with the Eligard products. Although time
to normalization of PSA values is tumor dependent
and varies from patient to patient, 25% to 33% of
patients treated in the 3 trials began the trial with
baseline values of ⬍4 ng/mL, and by the end of
each trial, 92% to 95% of patients achieved normal-
ization. No data are available for time to progres-
sion or time to death, because these trials were not
designed to assess these endpoints. In all 3 clinical
trials, the frequency of severe hot flashes with Eli-
gard treatment was low. Prospective trials designed
to carefully monitor hot flashes are needed to es-
tablish the comparative incidence of hot flashes
with Eligard and other available medical therapies
used to induce androgen ablation. Additional stud-
ies are needed to clarify the relation between the
UROLOGY 61 (Supplement 2A), February 2003
extent of testosterone suppression, time to cancer
progression, and cancer-specific survival.
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31