european urology supplements 5 (2006) 905910

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EligardW 6: A New Form of Treatment for Prostate Cancer

Oliver Sartor *
Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, United States

Article info Keywords: Atrigel Eligard Leuprolide Luteinising hormonereleasing hormone agonist prolonged-release formulation Prostate cancer

Abstract Objectives: Luteinising hormone-releasing hormone (LHRH) agonists have become the mainstay for the treatment of advanced and metastatic prostate cancer (pCA) but are increasingly used in earlier stages of the disease for various indications. Eligard1 is a depot formulation of leuprolide acetate using the novel delivery system Atrigel1. Eligard 6 is the first and only LHRH agonist commercially available that extends treatment for 6 mo. Methods: This literature review evaluates the efcacy and tolerability of Eligard 6 and discusses its potential advantages and therapeutic applications. Results: In a 12-mo open-label multicentre study, Eligard 6 rapidly suppressed testosterone levels to 50 ng/dl in 97% of patients and 20 ng/dl in 83% of patients. This was maintained during the course of the study; only one patient experienced a breakthrough testosterone escape. Eligard 6 had a comparable tolerability to the 1- and 3-mo formulations of Eligard. Hot ashes were the most common adverse event with the majority being of mild intensity. Eligard 6 offers practical advantages to patients and physicians in terms of convenience and patient comfort and has cost benets for the health care system. Its ability to provide 6-mo testosterone suppression may be of particular interest in the (neo)adjuvant setting and/or in patients receiving intermittent therapy for biochemical failure after radical therapy. Conclusions: Eligard 6 is a new LHRH agonist formulation that provides testosterone control for 6 mo and offers physicians the ability to tailor the management of pCA to the lifestyles of their patients.
# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Dana Farber Cancer Institute, Dana 1230, Lank Center for GU Oncology, 44 Binney Street, Boston, MA 02115, United States. Tel. +1 617 632 64 66; Fax: +1 617 632 21 65. E-mail address: oliver_sartor@dfci.harvard.edu.

1.

Introduction

Prostate cancer (pCA) is a leading cancer diagnosis and causes significant morbidity and mortality. Because of the dependence of most pCA on

testosterone, hormone therapy is used throughout various stages of pCA, that is, for metastatic, locally advanced, and recurrent disease [1]. In clinical practice it is also used as a neoadjuvant or adjuvant therapy to radiation [2]. Luteinising
doi:10.1016/j.eursup.2006.08.006

1569-9056/$ see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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hormone-releasing hormone (LHRH) agonists have become the first choice of hormonal therapy for obtaining castration in patients with pCA because patients prefer injections to surgical castration. Initially, LHRH agonists were administered by means of daily subcutaneous injections, but in the last 10 yr, various extended-release depot formulations have been developed that provide treatment for 13 mo [3]. These depot formulations have increased patient compliance and satisfaction with the therapy [4]. However, some patients, for example, those with low compliance or those frequently travelling, may opt for an LHRH agonist with even longer treatment duration. Eligard1 6 is the only commercially available LHRH agonist that extends treatment to once every 6 mo [5]. This article reviews the efficacy and tolerability of Eligard 6 in the treatment of pCA and its potential benefits and therapeutic applications.

Fig. 1 EligardW 6 uses the AtrigelW delivery system. A liquid mixture of leuprolide acetate and a biodegradable polymer is subcutaneously injected after which it forms a solid depot. This dissolves over time to provide a continuous controlled release of leuprolide acetate.

2.

Eligard, a unique LHRH agonist formulation

Eligard is an extended-release formulation of Atrigel1 and leuprolide acetate. Atrigel is a novel delivery system that consists of a biodegradable polymer of D,L-lactide-co-glycolic acid (PLGA) dissolved in the biocompatible solvent, N-methyl-2pyrrolidone [6]. The rate of release of leuprolide acetate is controlled by varying the molecular weight of the polymer and the solvent concentrations. The unique Atrigel formulation gives rise to a range of Eligard depot formulations: 1, 3, and 6 mo. For the 1-mo formulation the PLGA has a 50:50 molar ratio of D,L-lactide to glycolide with carboxyl end groups. The 3-mo formulation of Eligard contains the PLG polymer in this formulation in a molar ratio of 75:25 of D,L-lactide to glycolide with hexanediol. The PLG molar ratio for the 6-mo formulation is 85:15 [6]. The respective dosage strengths of the 1, 3, and 6-mo Eligard formulations are 7.5, 22.5, and 45 mg. The Eligard injection is supplied as a twosyringe system, one of which contains leuprolide acetate powder and the second containing the Atrigel polymer. Prior to administration, the two syringes are coupled and mixed back and forth between the syringes to obtain a uniform suspension. When the polymer solution is injected into the body, the organic solvent dissipates into the surrounding tissue as the water permeates into the implant (Fig. 1) [7]. This process leads to phase separation and subsequent coagulation of the polymer to form an implant in situ. Leuprolide encapsulated within the implant is then released in a controlled manner as the polymer matrix

biodegrades with time (Fig. 1) [6]. Other depot formulations of leuprolide use lyophilised microspheres for drug delivery; the single, relatively large sphere formed by Atrigel presents a smaller surface area protecting the leuprolide acetate from degradation on the surface [8]. Probably because of this attribute the Atrigel can contain a greater amount of leuprolide, and as such, Eligard delivers a double dose of leuprolide acetate compared to the microsphere formulations [3,8]. Thus, because of its unique formulation, Eligard delivers a high and continuous dose of leuprolide acetate over its dosing intervals of every 1, 3, and 6-mo, respectively.

3.

Optimal control of testosterone

It is recognised that during LHRH agonist therapy castrate testosterone levels of 2050 ng/dl should be achieved and maintained during therapy without injection-related testosterone escapes or breakthrough testosterone escapes [9]. Despite being intuitively favourable, no clinical data are available to support the concept that a lower nadir testosterone level is associated with a better clinical outcome. It has been shown that some proportion of men on currently available LHRH agonists do not achieve or maintain castrate levels of testosterone [10]. The role of this in terms of clinical medicine is not clear. Eligard was developed to provide an alternative to other LHRH agonists with hopes that testosterone suppression would be well controlled [10]. In two open-label, multicentre studies, the Eligard 1-mo formulation (Eligard 1) and the Eligard

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3-mo formulation (Eligard 3) suppressed testosterone levels 20 ng/dl in 9498% of patients [11,12]. Castrate testosterone levels were also maintained during the course of therapy because no injectionrelated testosterone escapes occurred and only 1% of patients experienced a breakthrough testosterone escape [11,12]. The adverse event profile of Eligard was comparable to other agents in this class [11,12]. The question arises whether the excellent testosterone suppression and good safety profile are maintained with the Eligard 6-mo formulation.

4.
4.1.

Efficacy and safety of Eligard 6

Efficacy

Fig. 3 Eligard 1, 3, and 6 suppress testosterone levels well below castrate levels [5,11,12].

Eligard 6 was investigated in a 12-mo, multicentre, open-label, fixed-dose study. Eligard 6 was given every 6 mo in a single 45-mg dose with a total of two injections [5]. Patients were required to have a histologic or cytologic diagnosis of pCA (higher than stage T1), a World Health Organization (WHO) performance score of 02, and a life expectancy of at least 1 yr. Serum testosterone levels were measured at baseline and at regular intervals throughout the 12-mo study. A total of 111 men with pCA (4% Jewett stage A, 39% stage B, 17% stage C, and 40% stage D) were included in the study; 103 completed the 12-mo protocol. After injection, serum testosterone levels initially increased. However, Eligard 6 rapidly suppressed testosterone levels (Fig. 2); after 1 mo of treatment 97% of patients had a testosterone level 50 ng/dl and 83% of patients had a testosterone

level 20 ng/dl. Mean time to testosterone suppression to 50 ng/dl was 21.2 d (median, 21 d). At study completion, 99% of patients had a testosterone level 50 ng/dl and 88% 20 ng/dl. Mean testosterone levels after treatment with Eligard 6 (12.3 2.1 ng/dl) were comparable to those achieved by Eligard 1 (6.1 4.3 ng/dl) and Eligard 3 (10.1 0.7 ng/dl), which were well below the castrate level of 20 ng/dl (Fig. 3) [5,11,12]. The castrate testosterone levels achieved with Eligard 6 were well maintained during the course of treatment because no patients experienced an injection-related testosterone escape and only one patient (1%) experienced a breakthrough testosterone escape (i.e., a single serum testosterone value increasing above 50 ng/dl after castrate levels were achieved) [5]. Mean prostate specific antigen (PSA) levels were elevated (>4 ng/ml) in 75.5% of patients at the start of the study. PSA levels then steadily decreased during the study such that at month 12, only 4% of the patients had an increased PSA value. Decreases in PSA levels with Eligard 6 were comparable to those achieved with the 1- and 3-mo formulations; 98%, 93%, and 96% of patients had a PSA level <4.0 ng/ml at end point with Eligard 1, 3, and 6, respectively [5,11,12].
4.2. Safety

Fig. 2 Eligard 6 effectively reduces serum testosterone levels below castrate levels [5]. Reprinted from J Urol, 175, Crawford ED, Sartor O, Chu F, Perez R, Karlin G, Garrett JS. A 12-month clinical study of LA-2585 (45.0 mg): a new 6-month subcutaneous delivery system for leuprolide acetate for the treatment of prostate cancer. Pages 5336, Copyright (2006), with permission from the American Urological Association.

No clinically relevant flare reactions to the initial increase in testosterone levels were reported [5]. A total of 82 patients reported 211 treatment-related adverse events of which 210 were mild to moderate. The 6-mo formulation of Eligard did not increase the rate of adverse events compared to the 1- and 3-mo formulations (Fig. 4) [5,11,12]. Hot flashes were reported by 56%, 59%, and 58% of patients receiving Eligard 1, 3, and 6, respectively and 18%, 6%, and 12%

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Fig. 4 Eligard 6 has a comparable favourable tolerability as Eligard 1 and Eligard 3 [5,11,12].

of patients reported asthenia with Eligard 1, 3, and 6, respectively. Gynaecomastia occurred in 2%, 1%, and 4% of patients taking Eligard 1, 3 and 6, respectively [5,11,12]. It should be noted that no severe hot flashes occurred during Eligard 6 treatment. The majority of hot flashes were of mild (33.3% of patients) or moderate intensity (24.3% of patients; Fig. 5). Patient self-assessment of bone pain, urinary symptoms, and urinary pain did not change during the study [5].

5.

Practical advantages of Eligard 6

The 6-mo formulation of Eligard may offer advantages to patients and physicians compared to LHRH agonists with shorter treatment duration in selected cases. Patients who can benefit from Eligard 6 include those who are currently receiving LHRH agonist therapy but who may require monitoring less frequently, express a desire for fewer injections, travel frequently, or may be away from their treating physician for long periods. Patients with restrictive work schedules and those who live far from the physicians office or have transportation difficulties may also benefit from prolonged treatment with Eligard 6. Moreover, Eligard 6 offers increased comfort as a consequence of a decreased number

of injections. These factors may make Eligard 6 even more patient friendly [8]. A formulation that only has to be administered once every 6 mo also has implications for the health care system. Factors such as nurse time, storage and ordering of medication, paperwork, and administrative time all may be reduced, which in principle should lead to a cost benefit. Thus, Eligard 6 provides a new treatment option that offers physicians the ability to tailor the management of pCA to the lifestyles of their patients. Although it offers greater convenience for patients and physicians, it is still important for patients to see their physicians on a regular basis for overall management of their pCA. Although follow-up intervals for patients with pCA are not well studied, the European Association of Urology (EAU) 2005 guidelines recommend that follow-up after hormone therapy should be tailored according to symptoms, prognostic factors, and treatment given [13]. Most physicians use routine follow-ups of 36 mo with biochemical monitoring more frequently if needed. In this respect, Eligard 6 is advantageous because it removes the need for visits purely to administer injections and allows the patient and physician more liberty in follow-up frequency. This freedom of visit frequency, however, also places some responsibility with the patient. This may lead to less frequent monitoring visits, where a higher frequency may be required. For some patients, the reassurance gained from frequent visits to their physician may decrease disease-related anxiety, and as such, shorter visit intervals than needed purely on the basis of Eligard 6 injections may be scheduled to provide such reassurance.

6.
6.1.

Eligard 6 applied in different stages of pCA

Advanced disease

LHRH agonist therapy has traditionally been reserved for patients with advanced pCA. As discussed, Eligard effectively suppressed testosterone levels below the nadir of 20 ng/dl in the majority of patients. PSA levels also decreased during the course of treatment.
6.2. Neoadjuvant and adjuvant therapy

Fig. 5 The majority of hot flashes reported during Eligard 6 treatment are of mild and moderate intensity [5].

Currently, LHRH agonists are increasingly used in the neoadjuvant and/or adjuvant setting for patients with early or localised disease being treated with radical therapy. Several studies have suggested the improvement of local control and survival in

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patients who have received adjuvant hormonal therapy after radical prostatectomy [2]. Immediate hormone therapy in an adjuvant setting to patients who underwent radical prostatectomy for lymph node-positive disease may improve overall and cause-specific survival [14,15]. The benefits in terms of overall survival, disease-specific survival, and disease-free survival of neoadjuvant and adjuvant hormonal therapy to radiation therapy are supported by evidence from randomised trials such as those performed by the Radiation Therapy Oncology Group (RTOG) and European Organization for Research and Treatment of Cancer (EORTC) groups [2,1622]. The EORTC 22863 study compared radiotherapy alone (n = 208) with the combination of radiotherapy and immediate LHRH agonist therapy (n = 207) in patients with T1T4, N0 pCA [16]. After a median follow-up of 45 mo, 5-yr overall survival, disease-specific survival, and disease-free survival were significantly better after combination therapy compared to radiotherapy alone. A follow-up of 66 mo confirmed these results [18]. Immediate androgen suppression with the LHRH agonist given during radiotherapy and for 3 yr after radiotherapy improved disease-free and overall survival. DAmico et al. performed a prospective, randomised controlled trial in patients with clinically localised pCA (T1T2, PSA !10 ng/ml, or Gleason !7) randomised to radiation therapy alone (n = 104) or radiation therapy plus 6-mo adjuvant hormone therapy (n = 102) with a median follow-up of 4.52 yr [23]. Patients receiving radiotherapy plus 6 mo of hormone therapy had a significantly higher survival rate and a lower pCA-specific mortality rate than patients receiving radiotherapy alone. Although the optimal duration of neoadjuvant or adjuvant therapy to radiotherapy is not yet defined, it is suggested to be between 3 and 6 mo for neoadjuvant therapy and between 6 mo and 3 yr for adjuvant therapy. This depends, of course, on the grade and stage of the disease and additional randomised studies are needed to study optimal duration of therapy [2]. The ability of Eligard 6 to suppress testosterone levels for 6 mo may thus provide a complete treatment course for some of the patients on neoadjuvant or adjuvant therapy.
6.3. Biochemical failure after radical therapy

survival benefit [13]. However, this is controversial and no randomised data are available to support the concept that earlier hormonal therapy in this setting provides patient benefit. Because the main objective in these patients is to delay disease progression with minimal side-effects, the concept of intermittent hormonal therapy was developed. It aims at delaying the onset of androgen-independent pCA cells as well as reducing adverse events and costs. Hormonal therapy is typically administered until a preset PSA nadir is reached and then started again when the PSA starts rising or exceeds a preset threshold. It was anticipated that the patient would experience a better quality of life due to breaks in hormonal therapy [26]. However, because there is lack of mature prospective randomised comparative trials evaluating its benefits on survival, the value of intermittent therapy remains the subject of debate [1]. In view of this limitation it can be argued that one injection of Eligard 6, which provides 6 mo of testosterone suppression, may be an ideal formulation for some patients who desire intermittent hormonal treatment after biochemical failure following radical therapy. It can be concluded that Eligard 6 is indicated for hormone-responsive pCA and in particular for patients with advanced disease. Its ability to provide 6 mo of testosterone suppression may be of interest in the neoadjuvant or adjuvant setting and/or in patients receiving intermittent therapy for biochemical failure after early definitive therapies. Additional clinical data are needed, particularly in the setting of salvage hormonal therapy after local definitive therapies have failed.

7.

Conclusions

About 2540% of patients who undergo radical therapy will have biochemical recurrence after a follow-up of about 10 yr [24,25]. The EAU recommends immediate hormone therapy for patients with a rising PSA level because it may be beneficial in delaying progression and possibly achieve a

Eligard 6 is the first 6-mo injection among the currently available LHRH agonists. It rapidly and effectively suppresses testosterone below castrate levels with a low rate of injection-related sideeffects or breakthrough testosterone escapes. Eligard 6 offers the convenience of 6 mo of continuous testosterone suppression, which has practical advantages for patients and their physicians. Its ability to provide 6 mo of testosterone suppression may be of interest in the neoadjuvant or adjuvant setting to radical therapy and/or in patients receiving intermittent therapy for biochemical failure after radical therapy. Eligard 6 provides a new treatment option that offers physicians the ability to tailor the management of pCA to the needs of their patients.

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