JP2019059726A - Methods of treating metastatic stage prostate cancer - Google Patents

Abstract

To provide compositions for treating metastatic stage prostate cancer.SOLUTION: The present invention provides compositions for treating metastatic stage prostate cancer of a subject, containing degarelix.SELECTED DRAWING: Figure 1

Description

Prostate cancer is the leading cause of morbidity and mortality in men in industrialized countries, accounting for approximately 9% of cancer-related deaths in men. Prostate cancer is the second leading cause of cancer death in American men following lung cancer. The American Cancer Society estimates that 27,050 US men died of prostate cancer in 2007. In Europe, prostate cancer is the third most common cause of cancer death in men in Europe, with an estimated 87,400 deaths in 2006 (Ferlay et al. (2007)
Ann. Oncol. 18: 581-92; Lukka et al. (2
006) Curr. Oncol. 13: 81-93).

  More than 9 out of 10 prostate cancers are found in localized and locally advanced stages. Compared to men of the same age and race without cancer (relative survival), the five-year relative survival rate of men diagnosed with localized and locally advanced cancer is nearly 100%. However, the 5-year relative survival rate for men with metastatic prostate cancer that has already spread to the distal part of the body at the time of diagnosis is only about 32% (Cancer Trends Progress Report (http: // progress report. Cancer. Gov; SEER Program and National Center for Health Statistics (see http://seer.cancer.gov/) In this last phase of the transition, the surge in survival is pain (eg, bone pain), weight loss, and Thus, treatments that lead to a reduction or postponement of bone metastatic tumor cell growth may not only provide an increase in life expectancy, which may be up to about 3 years or more, as well as these symptoms. Is improved Brought in, also provides for the improvement of quality of life (QoL).

As the majority of prostate cancer grows in a testosterone-dependent manner, current medical management of advanced prostate cancer can be achieved by bilateral orchiectomy or by administration of gonadotropin releasing hormone (GnRH) receptor agonists, androgen blockade etc. With a hormone based treatment. Testicular extraction (castration) has for many years been the standard method of preventing androgen secretion as a means to reduce prostate cancer growth. Recently, androgen secretion has been impaired by chemical means by interfering with the production of luteinizing hormone (LH), which regulates androgen synthesis. Evidence from randomized studies strongly suggests that early endocrine therapy in non-metastatic locally advanced disease is associated with a survival benefit, with or without lymph node metastasis (Granfors et al. (1998) J. Urol. 159: 2030-34; Messing et al. (1999) N
. Eng. J. Med. 341: 1781-88; and (1997) B
r. J. Urol. 79: 235-46).

Gonadotropin releasing hormone (GnRH) is a natural hormone produced by the hypothalamus that interacts with receptors in the pituitary to promote the production of luteinizing hormone (LH). Agonists of GnRH receptor (GnRH-R), such as leuprolide and goserelin, have been developed to reduce LH production. GnRH-R agonists first act to promote LH release, and only after long-term treatment, to sensitize GnRH-R such that LH is no longer produced. The initial stimulation of LH production by the agonist is such that the initial response to agonist therapy is exacerbated for the production of androgen, such that the patient's symptoms may be ameliorated rather than ameliorated (eg, tumor growth may be increased). It leads to a sharp increase. This reduction, known as "testosterone surge" or "flaming response", can last as long as 2 to 4 weeks. In addition, each successive administration of the agonist can cause an additional small LH surge (known as an "acute exacerbation" phenomenon) that can further aggravate the condition. A testosterone spike can stimulate prostate cancer and lead to aggravation of current symptoms or the appearance of new symptoms such as spinal cord compression, bone pain, and urethral obstruction (Thompson et al. (1990) J. Mol.
Urol. 140: 1479-80; Boccon-Gibod et al. (1986) Eur. Urol. 12: 400-402). The relative potency and safety (including side effects) of leuprolide for GnRH agonist therapy (also Leuplin or LUPRON DEPOT) is known in the art (eg, Persad
(2002) Int. J. Clin. Pract. 56: 389-96;
Wilson et al. (2007) Expert Opin. Invest. Drugs 16: 1851-63; and Berges et al. (200
6) Curr. Med. Res. Opin. 22: 649-55). One approach taken to avoid testosterone spikes (redness) is to combine the administration of a GnRH-R agonist with an antiandrogen such as flutamide, known as complete androgen ablation therapy (AAT) It is. Hormonal therapy with GnRH-R agonists, in combination with antiandrogens, has been used as a pretreatment prior to radical prostatectomy known as adjuvant therapy. However, the use of antiandrogens is associated with severe liver and gastrointestinal side effects.

A disadvantage associated with antiandrogens is that the gonadotropin releasing hormone receptor (GnRH-) is such that it overcomes the "testosterone surge" or "flaming response" associated with GnRH agonists.
R) has led to the development of antagonists. GnRH antagonists competitively bind to GnRH receptor, block it and cause rapid reduction of LH and follicle stimulating hormone (FSH) secretion, thereby producing testosterone without initial stimulation / surgery Reduce However, GnRH antagonist peptides are often associated with histamine release activity. This histamine releasing activity represents a serious obstacle to the clinical use of such antagonists, as histamine release results in side effects such as edema and pruritus.

  The search for improved GnRH antagonists has resulted in the production of Antide, Cetrorelix, and Antarelix (US Pat. No. 5,516,887). GnRH antagonists with such markedly modified or unnatural amino acids at position 5 and 6 show good biological effects and those built on Aph generally have particular efficacy Is considered. Particularly useful is Azaline B. Patent 5,506,207 also discloses biologically effective GnRH antagonists, with the acylated amino-substituted phenylalanine side chain of residues at positions 5 and 6. One such decapeptide is Acyline.

Despite the attractive nature of this group of GnRH antagonists, side effects have been observed. The relative potency and safety (including side effects) of the GnRH antagonist abarelix (PLENAXIS) has been reported (eg, Mongiat-Artus et al. (2
004) Expert Opin. Pharmacother. 5: 2171-9
And Debruyne et al. (2006) Future Oncol.
2: 677-96). As such, still further improved GnRH
The search continues for antagonists, especially those that combine a long duration of biological action, and an improved safety profile.

These desirable features are addressed in several issued patents and patent applications directed to GnRH antagonist degarelix for the treatment of prostate cancer (e.g., the contents of which are incorporated herein by reference in its entirety). European Patent No. EP 1 0037 74, U.S. Patent No. 5,925,730, U.S. Patent No. 6,214,798, European Patent No. EP 02749000.2, and U.S. Patent Nos. U.S.S. N. 12/155, 897 and European Patent EP 08250703.9). In addition, U.S. Pat. S. S. N. 61 / 027,742 discloses the results of a long-term evaluation in a multicenter randomized clinical study demonstrating that degarelix exhibits good tolerance without systemic allergic reactions. Degarelix treatment also resulted in rapid and significant sustained suppression of testosterone, as well as good efficacy and safety findings, without testosterone (T) spikes.

  However, while ongoing research has enabled advances in the general prevention and treatment of prostate and other cancers, there is little or no focus on addressing patients suffering from late-stage cancer metastasis. It was not applied.

The present invention relates, in part, to the administration of the GnRH antagonist degarelix to patients with metastatic stage prostate cancer and / or patients with PSA levels of 50 ng / mL or more, with marked salinity of serum alkaline phosphatase (S-ALP). Based on the surprising finding of providing a long-term reduction.
This reduction indicates better control of (e.g., backbone) transition (Example 1, Figure 1-4, Table 2).
See). These results further indicate that degarelix administration may delay or prevent progression from localized and locally advanced prostate cancer to metastatic phase. Furthermore, these results indicate that the administration of degarelix to these patients is associated with slowing the progression to the hormone resistant phase. Above all, this S-AL
A significant long-term decrease in P is not shown after administration of the GnRH agonist leuprolide.

  In one aspect, the invention provides a method of treating a metastatic stage prostate cancer in a subject. The method comprises the initial steps of identifying a suitable subject with metastatic stage prostate cancer and then administering to the subject an initial dose of 160-320 mg of degarelix. The subject is then administered a maintenance dose of 60-160 mg of degarelix once every 20 to 36 days. Thereby, the method treats metastatic prostate cancer in the subject. In a particular aspect, the present invention comprises the initial steps of identifying a suitable subject with metastatic stage prostate cancer, and then administering to the subject an initial dose of about 240 mg of degarelix to the subject. Provides a method of treating cancer. The subject is then administered a maintenance dose of 60-160 mg of degarelix once every 20 to 36 days. Thereby, the method treats metastatic prostate cancer in the subject.

In one embodiment of the method of the present invention, the candidate serum alkaline phosphatase (S-AL)
P) Check the value and then check its S-ALP baseline (baseline S-ALP le
If vel) is 150 IU / L or more, for example, 160 IU / L or more, a subject is identified by selecting as a subject of treatment. In a further embodiment, the candidate subject's serum alkaline phosphatase (S-ALP) value is examined, and then, if the S-ALP standard value is 200 IU / L or more, a therapeutic subject is identified by selecting as a therapeutic subject. Do. In a still further embodiment, the subject is tested for serum alkaline phosphatase (S-ALP) levels, and then, if the S-ALP baseline is greater than or equal to 300 IU / L, then the subject is treated by selecting as a subject for treatment. Identify

In a further embodiment of the method of the present invention, the hemoglobin (Hb) value of the candidate subject is examined, and then, if its Hb value is 130 g / L or less, the treatment subject is identified by selecting it as a treatment subject. In still further embodiments, a prostate candidate antigen (PSA) value of a subject candidate is examined, and then, if the PSA value is 50 ng / mL or more, the subject is identified by selecting as a subject. In certain embodiments, the subject's S-ALP is reduced by at least 60 IU / L from baseline between 112 and 364 days of treatment.

In a further embodiment of the method of the invention, the serum alkaline phosphatase to be treated (S-
ALP) is reduced from baseline by at least 50 IU / L between day 60 and day 364 of treatment. In another embodiment, the subject's S-ALP is reduced by at least 50 IU / L from the baseline value between day 364 and day 450 of treatment. In a further embodiment, the S-ALP to be treated has at least 90 from the reference value between day 112 and day 364 of treatment.
IU / L is reduced. In still further embodiments, the S-ALP to be treated is reduced by at least 160 IU / L from baseline between day 112 and day 364 of treatment.

  In a further embodiment of the method of the invention, the subject to be treated has at least a 95% chance of maintaining a therapeutically low serum testosterone level of 0.5 ng / ml or less by day 28 of treatment. In certain embodiments, the subject has at least a 95% chance of maintaining a therapeutically low serum testosterone level of 0.5 ng / ml or less from day 28 to day 365 of treatment.

  In still further embodiments of the methods of the present invention, the subject has at least a 60% decrease in the value of prostate specific antigen (PSA) by day 14 of treatment. In certain embodiments, the treatment subject has at least a 75% decrease in the value of PSA by day 28 of treatment. In a further embodiment, the subject has at least a 80% chance of maintaining a prostate specific antigen (PSA) level of less than 5 ng / ml during treatment.

  In a further aspect, the present invention first tests potential subject's prostate specific antigen (PSA) and then, if its PSA value is 50 ng / mL or more, by selecting it as a treatment subject Provided is a method of treating prostate cancer. The method further comprises administering an initial dose of 60-320 mg of degarelix to the subject thus identified, and then treating the subject's prostate cancer, once every 20 to 36 days thereafter. Administering a maintenance dose of 60-160 mg of degarelix.

In one embodiment of the method of the present invention, the candidate serum alkaline phosphatase (S-AL)
P) Check the value and then its reference S-ALP value is 150 IU / L or more, eg 160
If it is IU / L or more, a treatment object is identified by selecting as a treatment object. In certain embodiments, the S-ALP to be treated is reduced by at least 60 IU / L from baseline between day 112 and day 364 of treatment. In a further embodiment, the candidate candidate's hemoglobin (Hb) value is examined, and then, if the Hb value is 130 g / L or less, the subject to be treated is identified by selecting as a treatment subject.

  In another aspect, the invention provides methods of using degarelix for the treatment of metastatic stage prostate cancer in a subject. This method of using degarelix involves the first step of identifying a suitable subject with metastatic prostate cancer. The thus identified subjects are then administered an initial dose of 160-320 mg of degarelix, followed by a maintenance dose of 60-160 mg of degarelix, once every 20-36 days, Use degarelix for the treatment of metastatic stage prostate cancer.

In one embodiment of the method of using degarelix, by examining the serum alkaline phosphatase (S-ALP) value of the subject candidate, then, if its standard S-ALP value is 160 IU / L or more, by selecting it as a subject for treatment. Identify subjects with metastatic prostate cancer. In a further embodiment, the candidate subject's serum alkaline phosphatase (S-ALP) level is examined, and then, if its standard S-ALP level is 200 IU / L or more, then it is selected for treatment with metastatic prostate cancer. To identify the subject. In still further embodiments, the candidate subject's serum alkaline phosphatase (S-ALP) value is examined, and then, if the S-ALP standard value is 300 IU / L or more, then by selecting it as a subject, it is possible to metastasize prostate. Identify subjects with cancer. In one embodiment, the candidate candidate's hemoglobin (Hb) value is examined, and then, if the Hb value is 130 g / L or less, then a subject with metastatic prostate cancer is identified by selecting it as a treatment subject. In another embodiment, a subject with metastatic prostate cancer is examined by examining the prostate specific antigen (PSA) level of the subject candidate, and then selecting it as a treatment subject if the PSA level is 50 ng / mL or more. Identify

  In another aspect, the invention provides methods of using degarelix to prevent the progression of locally advanced prostate cancer to metastatic stage prostate cancer in a subject. Methods of using degarelix to prevent the development of locally advanced prostate cancer include the first step of identifying a suitable subject for which there is locally advanced prostate cancer. The thus identified subjects are then administered an initial dose of 160-320 mg of degarelix, followed by a maintenance dose of 60-160 mg of degarelix, once every 20-36 days. Thereby, this method of using degarelix prevents the progression of locally advanced prostate cancer in a subject to metastatic stage prostate cancer.

In one embodiment of the method of using degarelix to prevent metastatic stage prostate cancer, the prostate specific antigen (PSA) level of a candidate for prophylactic treatment is examined and then, if the PSA is 10 to 50 ng / mL, Identify subjects with locally advanced prostate cancer by selecting as targets for prophylactic treatment. In a further embodiment, there is locally advanced prostate cancer by examining the prostate specific antigen (PSA) level of the subject candidate and then selecting if it is 20 to 50 ng / mL as a prophylactic treatment subject Identify the subject. In still further embodiments, the subject candidate is tested for serum alkaline phosphatase (S-ALP) levels, and then the S-ALP baseline value is less than about 160 IU / L, eg, between 44 and 147 IU / L and / or If it is between 50 and 160 IU / L, then a subject with locally advanced prostate cancer is identified by selecting for prophylactic treatment.

  According to the present invention in one aspect, there is provided a composition (eg, a pharmaceutical composition, a drug) comprising degarelix for treating metastatic stage prostate cancer in a subject. According to the present invention in one aspect, there is provided a composition (eg, a pharmaceutical composition, a drug) comprising degarelix for the treatment of prostate cancer in a subject having a PSA level of 50 ng / mL or more.

  The term metastasis, as used herein, means that the cancer is from the site of development to more distant or distal parts of the body, such as lymph nodes, bone, and / or other organs such as brain or liver. Refers to the secondary metastatic growth of malignancy, which forms when spread. Thus, the terms "metastatic" or "metastatic prostate cancer" refer to cancer that has spread from the tumor primary site, eg, the prostate, to distal organs.

  As used herein, “treatment of metastatic prostate cancer” and related methods of “treating metastatic prostate cancer” include, for example, metastatic lesions such as metastatic lesions in bone, brain, lung, and / or lymph nodes. Included are treatments and related methods that reduce the amount of cancerous tissue by reducing the number and / or size of (tumor). As used herein, "treatment of metastatic prostate cancer" and related methods of "treating metastatic prostate cancer" are identified in the skeleton by skeletal metastasis (eg, bone scan or other imaging techniques) Treatment and related methods to reduce the

  As used herein, “treatment of metastatic prostate cancer” and related methods of “treating metastatic prostate cancer” further include treatment and related treatments that reduce and / or ameliorate one or more symptoms associated with metastatic prostate cancer. Methods, eg, treatments that ameliorate and / or reduce symptoms of urinary disorders (eg, obstruction, weak or intermittent urination, frequent urination, dysuria, pain during urination, hematuria) (eg, lumbar back, lumbar region, or Treatments that reduce and / or ameliorate bone pain in the thigh, and / or treatments that reduce and / or improve weight loss, fatigue.

  In another aspect of the invention, the metastasis is reduced to reduce the number and / or size of metastatic lesions and / or to reduce and / or ameliorate one or more symptoms associated with metastatic stage prostate cancer. A composition comprising degarelix for the treatment of advanced prostate cancer is provided.

The terms "preventing metastatic prostate cancer" and "related methods of preventing metastatic prostate cancer" further prevent the onset of metastatic activity in subjects undergoing treatment for prostate cancer, who are in a locally advanced stage, Or maintain the level of metastatic activity (eg, at a known level at the start of dosing, ie at baseline), or (eg, S-ALP
And therapeutic and related methods that reduce and / or delay the return of metastatic activity (as measured by The expression "level of metastatic activity" in this context refers to the size and / or number of metastatic tumors in a subject but not to the rate of metastasis of the subject.

  Thus, the present invention includes therapies and related methods that delay or prevent the progression of the disease and / or result in or promote regression or remission of the disease. For example, the terms “preventing metastatic prostate cancer” and “related methods of“ preventing metastatic prostate cancer ”may extend the life of the patient and / or increase the quality of life (QoL) with treatments and associated methods. Including.

  As used herein, the terms "treatment of metastatic (stage) prostate cancer" and "related methods of treating metastatic (stage) prostate cancer" or "treatment of prostate cancer" and "related methods of treating prostate cancer" The term may also include therapeutic and related methods that delay or prevent the expression of hormone-refractory disease stages.

  Thus, according to the invention in yet another aspect, a composition comprising degarelix for the treatment of prostate cancer in a subject, reducing the prospect of recovery of metastatic tumor activity and / or delaying recovery, and And / or delay or prevent disease progression and / or cause or increase regression or remission of disease, and / or prolong the patient's life and / or increase quality of life (QoL), Related therapeutic methods are provided that delay or prevent the onset of and / or hormone refractory disease stages.

  The terms "treatment of prostate cancer" and "related methods of treating prostate cancer" also include treatments and related methods for curing prostate cancer.

Here, applicants say that administration of the GnRH antagonist degarelix to patients with metastatic stage prostate cancer and / or patients with PSA levels of 50 ng / mL or more is marked and prolonged of serum alkaline phosphatase (S-ALP) To provide a dynamic reduction (see FIGS. 1 and 4, Table 2). Not only is the reduction in S-ALP levels marked, but more importantly, the stably maintained low values of S-ALP levels over time (see FIG. 3) are better than those of metastases (eg of bone) It also indicates good control. This marked long-term reduction of S-ALP is not shown after administration of the GnRH agonist leuprolide.

Marked long-term reduction of S-ALP after administration of the GnRH antagonist degarelix to patients with metastatic stage prostate cancer and / or patients with PSA levels of 50 ng / mL or higher is administration of degarelix to these patients Indicates that it may delay the progression of the cancer to the hormone resistant phase.

Subjects should have a serum alkaline phosphatase (S-ALP) reference level of
In other words, before treatment, ie S-ALP value before administration of the first dose of testosterone), eg, serum alkaline phosphatase (S-ALP) reference value of about 160 IU / L or more, eg, serum alkali of about 200 IU / L or more Phosphatase (S-ALP) reference value, eg,
It may have a serum alkaline phosphatase (S-ALP) reference value of about 300 IU / L or more (see Table 2).

The degarelix composition has a serum alkaline phosphatase value (S-ALP) of at least about 50 IU above baseline over a period of about 60-364 days after administration of the first dose of degarelix.
/ L reduction (or, in other words, a negative change from the reference value), and / or after administration of the first dose of degarelix, for a period of about 112 to 364 days, at least about It may be reduced by 90 IU / L (see Table 2, FIGS. 1 to 3). In certain embodiments, the reduction in serum alkaline phosphatase levels (S-ALP) by at least about 50 IU / L may be extended over a period of more than 364 days (depending on the treatment continuation / maintenance dose, see below) ).

The subject to be treated may have a hemoglobin (Hb) value of about 130 g / L or less. S-ALP baseline values were particularly elevated in subgroups of patients with metastatic disease and Hb <130 g /. For example, 300 IU / L or more of serum alkaline phosphatase (SA
LP) Baseline values were found in patient populations with Hb <130 g / L (see Table 2). Subjects with reduced Hb above also have a reduction of at least 160 IU / L serum alkaline phosphatase (S-ALP) below baseline over a period of about 112 to 364 days after administration of the first dose of degarelix (Or, negative change from the reference value) may be shown (see FIG. 2). Bone metastases affect the bone marrow, and patients with bone metastases may become anemic, therefore Hb below normal for patients with bone metastases has a greater degree of metastasis (more severe Index of disease). As described in further detail herein, the present invention provides a surprising long-term and effective suppression of S-ALP by degarelix in a subpopulation of patients with Hb values below this normal. there's a possibility that.

  According to the invention in a further aspect, there is provided a composition comprising degarelix for the treatment of prostate cancer in a subject having a PSA level of 50 ng / mL or more (see FIG. 4). The prostate cancer may be metastatic prostate cancer.

  The composition is for administration of degarelix at an initial dose of 160-320 mg and thereafter administration at a maintenance dose of 60-160 mg once every 20-36 days, eg, at an initial dose of about 240 mg of degarelix It may be for administration, and thereafter for administration at a maintenance dose of about 80 mg of degarelix, once about every 28 days of treatment.

  A composition comprising degarelix, wherein the subject maintains a therapeutically low serum testosterone level of 0.5 ng / ml or less by day 28 of treatment with at least 95% chance, eg, the subject has at least 95 % May be for the treatment of maintaining therapeutically low serum testosterone levels of 0.5 ng / ml or less from day 28 to day 364 of treatment (eg, FIG. 7) See -8).

  The composition comprising degarelix may be for the treatment of metastatic prostate cancer and may provide at least a 60% reduction of PSA by day 14 of treatment. A composition (or agent) comprising degarelix may provide at least a 60% reduction, eg, at least a 75% reduction, in prostate specific antigen (PSA) by day 28 of treatment (see, eg, FIG. 9) ).

  The composition may be for treatment with the possibility of at least 80%, eg 95%, maintaining a prostate specific antigen (PSA) value of less than 5 ng / ml throughout the treatment.

  According to another aspect of the invention, administering an initial dose of 160-320 mg of degarelix to the subject and then administering a maintenance dose of 60-160 mg of degarelix to the subject once every 20 to 36 days Metastases of the subject, including the steps of administering to the subject an initial dose of about 240 mg of degarelix to the subject, and then administering a maintenance dose of about 80 mg of degarelix to the subject about once every about 28 days Methods are provided for treating prostate cancer.

According to the invention in a further aspect, degarelix for delaying or preventing the progression of localized or locally advanced prostate cancer to metastatic prostate cancer in a subject (eg, a subject having localized or locally advanced prostate cancer). Provided is a composition comprising The subject may have a PSA value of 10 to 50 ng / mL, for example, a PSA value of 20 to 50 ng / mL. The subject may have a serum alkaline phosphatase (S-ALP) value of between 44 and 147 IU / L. The subject may have a serum alkaline phosphatase (S-ALP) value of less than 160 IU / L, such as between 50 and 160 IU / L. The composition is for a first dose administration of 160-320 mg degarelix, and thereafter a maintenance dose administration of 60-160 mg degarelix once every 20 to 36 days, for example, a first dose administration of about 240 mg degarelix, and thereafter , For maintenance doses of about 80 mg degarelix, about once every about 28 days.

  For delaying or preventing the progression of locally advanced prostate cancer, for example, the prostate specific antigen (PSA) level of a candidate for prophylactic treatment is examined, and then the PSA is 10 to 50 ng / mL, for example, 20 to 50 ng / mL. If so, it may include the first step of identifying a suitable subject with locally advanced prostate cancer by selecting for prophylactic treatment. The serum alkaline phosphatase (S-ALP) value of the candidate for prophylactic treatment is examined, and then, if the S-ALP standard value is less than 160 IU / L, for example, 44 to 147 IU / L, then it is selected as the prophylactic treatment object By doing so, subjects with locally advanced prostate cancer may be identified.

Compare mean change over time of S-ALP baseline values with degarelix (240/80 mg) and leuprolide (7.5 mg) treatment for the local (localized), locally progressive, and metastatic populations Is a graphical display. Graph showing mean change over time of S-ALP baseline values with degarelix (240/80 mg), degarelix (240/160 mg), and leuprolide (7.5 mg) treatment for metastatic (+ Hb <130 g / L) subpopulations It is a display. Figure 3 is a graphical representation showing the mean change over time of S-ALP baseline values, with degarelix (240/80 mg) treatment reduced compared to leuprolide (7.5 mg) treatment that was "switched to degarelix" after 364 days It shows the difference in time for the S-ALP reference value to return to the reference value. S-ALP criteria in subjects with <10 ng / mL, 10-20 ng / mL, 20-50 ng / mL, and> 50 ng / mL PSA levels with degarelix (240/80 mg) and leuprolide (7.5 mg) treatment Figure 3 is a graphical representation comparing mean change over time of value. Graphical representation showing the incidence of PSA failure in patients with baseline localized, locally advanced, and metastatic prostate cancer with degarelix (240/80 mg) and leuprolide (7.5 mg) treatment is there. PSA recurrence in subjects with <10 ng / mL, 10-20 ng / mL, 20-50 ng / mL, and> 50 ng / mL PSA baseline with degarelix (240/80 mg) and leuprolide (7.5 mg) treatment It is a graph display which shows the incidence rate. FIG. 10 is a graphical representation showing the median decrease in testosterone levels from day 0 to day 364 by degarelix (240/80 mg) and leuprolide (7.5 mg) treatment. FIG. 16 is a graphical representation showing median change in testosterone levels from day 0 to day 28 with degarelix (240/80 mg) and leuprolide (7.5 mg) treatment. FIG. 10 is a graphical representation showing the median percent change in PSA value from day 0 to day 56 with degarelix (240/80 mg) and leuprolide (7.5 mg) treatment. FIG. 16 is a graphical representation showing median LH values from day 0 to day 364 with degarelix (240/160 mg), degarelix (240/80 mg), and leuprolide (7.5 mg) treatment. FIG. 16 is a graphical representation showing median FSH values from day 0 to day 364 with degarelix (240/160 mg), degarelix (240/80 mg), and leuprolide (7.5 mg) treatment.

Terms and Definitions Certain aspects of the invention are described in more detail below. The nomenclature as used herein as made clear in the present specification is intended to represent the applicants' intention in the present disclosure. The patent and scientific literature referred to herein are incorporated herein in their entirety.

  The singular forms "a", "an" and "the" also include the plural reference unless the context clearly dictates otherwise.

The terms "approximately" and "about" mean approximately the same as the number or value mentioned. As used herein, the terms "about" and "about" should generally be understood to encompass up to ± 10% of the specified amount, frequency or value. The term "CI" refers to a statistical confidence interval. For example, with respect to specific values of serum alkaline phosphatase (S-ALP), prostate specific antigen (PSA), hemoglobin (Hb), testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH), the target population (eg, The specific values described herein for the subject of the clinical study CS21 described in (1), for example, represent the mean (ie the mean value) unless otherwise stated as median. Thus, aspects of the invention requiring specific values of S-ALP, PSA, and / or Hb values of a subject are substantially herein referred to as population data (where relevant numerical data represent the population of interest). (Supported by meaningful limitations).

In general, the present invention provides the use of a composition comprising Degarelix GnRH antagonist for treating metastatic prostate cancer in a subject and related methods of treatment. The disclosure of the present invention is exemplified by data obtained from clinical studies, in particular the CS21 study for degarelix (European Patent Application No. 08250703.9 and US Provisional Application No. 61 / 027,741) There is. Basic methods are available to conduct and analyze the types of comparative clinical studies described herein, including the analysis of safety, efficacy, and selective benefits for certain patient subpopulations (Spilker 1991) Guide to Clinical Trials Raven Press, New York; and Spilker (1996) Quality of Life and Pharmacoeconomics in Clinical Trials Lippincott-Raven Pu
see blishers New York).

  The term "prostate cancer" refers to prostate cancer in which cells of the prostate mutate and begin to grow out of control. The degree to which prostate cancer has progressed in a patient is assessed taking into account clinical and histopathological information. The stage of the cancer is classified based on tumor size (T), whether there is lymph node metastasis (N), presence of metastasis (M), and tumor grading (G). Tumors classified as T1 are limited to the prostate and are too small to be palpated by digital rectal examination. T1 further includes T1a (less than 5% cancer cells in tissue samples) and T1b (5% or more) subdivisions. T1c indicates that the patient has elevated prostate specific antigen (PSA, see definition below). If the tumor is so large that it can be palpated during a digital rectal exam, it is classified as T2. T2a means that only one side (left or right) of the prostate is involved, and T2b means that there are tumors on both sides. T2 is generally referred to as "localized cancer". If the cancer is T3, it has spread to connective tissue (T3a) or seminal vesicles (T3b) near the prostate. T4 indicates that the cancer has spread to tissues next to the prostate, such as the bladder sphincter, rectum, or pelvic wall. Prostate cancer may also spread into the regional lymph nodes of the pelvis, which are evaluated as the N1 stage of prostate cancer. These T3, T4 and N1 phases are collectively referred to as "locally advanced" or regional cancer. If the cancer has spread to distant sites such as bone, it is said to be "metastasized" or in the M1 phase. While prostate cancer that has spread to the distal lymph nodes is classified as M1a, what has spread to the bone is M1b, and spread to organs such as the liver or brain is rated as M1c. When left untreated, prostate cancer metastasizes to bone almost without exception.

  Terms such as "bone metastasis", "skeletal metastasis", "bone lesions", "metastatic lesions" and the like as used herein refer to the metastatic stage and may be used interchangeably. Pain (eg, bone pain), weight loss, and fatigue often accompany the M1 phase. Survival rates are also significantly reduced for subjects with metastatic prostate cancer. The treatment that leads to the reduction of bone metastasis not only improves the quality of life (QoL) such as pain reduction, but also decreases bone mass, and more importantly, the increase in life expectancy by up to about 3 years or more Suggest. However, at some point, metastatic patients may not be able to respond to hormone based therapy, which is known as a "hormone resistant" stage. The term "treatment of metastatic prostate cancer" according to this nomenclature and as employed in the present application includes the treatment of subjects classified as M1a, M1b or M1c, and / or N1.

In general, androgen blockade induces remission in 80 to 90 percent of men with advanced prostate cancer, resulting in median progression-free survival of 12 to 33 months. At that time, an androgen independent phenotype usually appears. Hormone-resistant prostate cancer (sometimes called hormone-resistant prostate cancer or hormone-independent prostate cancer) may have castrate levels of testosterone (T less than 20 ng / dL), which are caused by hormone blocking therapy. It is broadly defined herein as prostate cancer in which the patient's blood PSA is elevated. [Murphy D. (1993) Cancer 72: 3888-3895; Hellerstedt BA and Pienta
KJ (2002) CA Cancer J. Clin. 52: 154-17
9. ]

Alkaline phosphatase (ALP) is a hydrolase enzyme involved in removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. In humans, ALP is present in all tissues throughout the body, but is particularly concentrated in the liver, bile ducts, kidneys, bones, and placenta. The concentration value may be used as a diagnostic tool and abnormally elevated values (hyperphosphataemia) may indicate some disease. These include skeletal involvement of other primary diseases such as liver disease, bone disease, malignancy, osteomalacia, kidney disease (secondary hypothyroidism), and primary hypothyroidism. On the other hand, abnormally low values of ALP (hypophosphataemia) may indicate other conditions such as severe anemia in men or chondroplasia, cretinism, or severe enteritis in children. In general, the value of ALP (S-ALP value) present in the subject's serum is used in conjunction with the treatment methods and compositions described herein.

S-ALP testing is well known in the art (Chernecky CC, Berge
r BJ (2008), Laboratory Tests and Diagnostic Procedures, 5th ed. , WB Saunders & Company, Philadelphia). It is generally used as a test of liver function, but is known as an indicator of metastatic lesions of bones of various malignancies (breast, prostate and colon). In metastatic prostate cancer, S-ALP baseline values (or "ALP values") are consistently higher than focal or locally advanced disease, reflecting bone lesions. As disclosed in the present invention, the subject has a serum alkaline phosphatase (S-ALP) baseline value of about 150 IU / L or more, eg, 160 IU / L or more (ie, prior to treatment, ie, prior to administration of the first dose of testosterone) S-ALP value), for example, it may have a serum alkaline phosphatase (S-ALP) reference value of 200 IU / L or more. Thus, a decrease in S-ALP baseline levels in the treatment of patients with metastatic prostate cancer is, under certain circumstances, indicative of a positive response to treatment.

  One of the most important techniques for diagnosis of prostate cancer is a blood test, in particular the measurement of prostate specific antigen (PSA) levels in the blood. The term "prostate-specific antigen" or "PSA" refers to proteins produced by cells of the prostate, present in minor amounts in the serum of healthy men, but often elevated in the presence of prostate cancer and other prostate diseases. ing. Blood tests to measure PSA are the most effective tests currently available for early detection of prostate cancer. Higher than normal PSA values are associated with both localized and metastatic prostate cancer. According to the invention, a subject with localized or metastatic prostate cancer may have a PSA level of 50 ng / mL or higher.

Degarelix and Related Pharmaceutical Formulations Degarelix incorporates p-ureido-phenylalanine at positions 5 and 6 and is analogous to the GnRH decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH ₂ ) Body, a potent GnRH antagonist (Jiang et al.
al. (2001) J.J. Med. Chem. 44: 453-67). It is indicated for the treatment of patients with prostate cancer (including patients with elevated PSA levels already after prostatectomy or radiation therapy) where androgen blockade is warranted.

Degarelix is a selective GnRH receptor antagonist (blocker) that competitively and reversibly binds to the pituitary GnRH receptor, thereby rapidly reducing the release of gonadotropins and consequently testosterone (T) is there. Prostate cancer is sensitive to testosterone blockade, which is a central principle in the treatment of hormone sensitive prostate cancer. Unlike GnRH agonists, G
nRH receptor blockers do not induce luteinizing hormone (LH) spikes with subsequent testosterone spikes / tumor stimulation and potentially symptomatic flares after initiation of treatment.

The active ingredient degarelix is a synthetic linear decapeptide amide containing seven unnatural amino acids, five of which are D-amino acids. The drug substance is acetate, but the active part of the substance is degarelix as the free base. Degarelix's acetate is obtained after lyophilization as a low density white to off-white amorphous powder. The chemical name is D-alanine amide, N-acetyl-3- (2-naphthalenyl) -D-alanyl-4-chloro-D-phenylalanyl-3- (3-pyridinyl) -D-alanyl-L-seryl -4-[[[(4S) -hexahydro-2,6-dioxo-4-pyrimidinyl] carbonyl] amino] -L phenylalanyl-4-[(aminoarbonyl) amino] -D-phenylalanyl-L Leucyl-N6- (1-methylethyl) -L-lysyl-L-prolyl. It has an empirical formula of C ₈₂ H ₁₀₃ N ₁₈ O ₁₆ Cl and a molecular weight of 1,632.3 Da. The chemical structure of degarelix has been previously shown (European Patent EP 1 0037 74, U.S. Patent 5,925,730, U.S. 6,214,798), according to the formula It may be represented.
Ac-D-Nal-D-Cpa-D-Pal-Ser-Aph (Hor) -D-Aph (Cbm)-
Leu-Lys (iPr) -Pro-D-Ala-NH ₂

Administration and Dosing Degarelix may generally be formulated for subcutaneous administration (as opposed to intravenous) in the abdomen, as described in more detail below. As with the other agents administered by subcutaneous injection, the injection site may be periodically changed to adapt the treatment to injection site discomfort. In general, the injection should be at a site where the patient is not exposed to pressure, such as a site that is not close to the waistband or belt and close to the ribs.

  Since administration of degarelix by subcutaneous or intramuscular injection is effective, but daily injections are generally not acceptable, depot preparations of degarelix have been described in WO 03/006049 and US Publication Nos. 20050245455 and 20040038903. It may be used as described in further detail. Briefly, subcutaneous administration of degarelix may use a depot technique in which the peptide is released from the biodegradable polymer matrix over a period of (typically) 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogues. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, which can serve as a depot from which the peptide is released over a period of weeks or even months.

  A key variable for the formation of an effective degarelix depot is the concentration of the solution combined with the amount of substance to be administered. The concentration should be within the range that indicates function. If the formulation is too dilute, regardless of the amount of drug substance given, no depot will be formed and the persistence of action will be lost. If the formulation is too thick, gel formation will occur before the drug can be administered. An effective depot-forming formulation of degarelix generally has a concentration of 5 mg / mL or more of degarelix, for example, a concentration of 5-40 mg / mL of degarelix.

Thus, degarelix may be provided as a powder for reconstitution (with a solvent) as a solution for injection (eg forming a depot as described above, eg subcutaneous injection). This powder may be provided as a lyophilizate containing degarelix (eg as acetate) and mannitol. The preferred solvent is water (eg, water for injection or WFI). For example, degarelix can be provided in a vial containing 120 mg of degarelix (acetate) for reconstitution with 3 mL of WFI such that 1 mL of solution contains about 40 mg of degarelix. In another example, degarelix can be provided in a vial containing 80 mg of degarelix (acetate salt). When reconstituted with about 4 mL WFI, eg, 4.2 mL WFI, each 1 mL solution contains about 20 mg degarelix.

  According to the present invention, administering an initial dose of 160-320 mg of degarelix to the subject and then administering a maintenance dose of 60-160 mg of degarelix to the subject once every 20 to 36 days, eg, Treating the subject with metastatic prostate cancer, comprising administering to the subject an initial dose of about 240 mg of degarelix, and subsequently administering to the subject a maintenance dose of about 80 mg of degarelix, about once every about 28 days A method is provided for

  The composition may be for administering a first dose of 160-320 mg of degarelix and thereafter, once every 20-36 days, a maintenance dose of 60-160 mg of degarelix.

  The preferred dosing regimen for treating adult men with prostate cancer is to administer a single starting dose of 240 mg of degarelix as two 120 mg subcutaneous injections, followed by monthly degarelix maintenance doses from about 28 days or one month later 80 mg given as a single subcutaneous injection.

  For example, in the degarelix dosing regimen, an initial starting dose of 240 mg is divided into two doses and injected with approximately 3 mg of each approximately 40 mg / mL degarelix formulation, followed by a 80 mg maintenance dose, approximately 4 mg of approximately 20 mg / mL degarelix formulation Can be administered by a single subcutaneous injection once a month. Alternatively, for example, a monthly maintenance dose of 160 mg may be utilized by administering 4 mL of about 40 mg / mL degarelix once a month.

  The reconstituted solution should be a clear liquid, free of undissolved material. A single dose of 240 mg of degarelix followed by a monthly maintenance dose of 80 mg rapidly causes luteinizing hormone (LH), follicle stimulating hormone (FSH), followed by a decrease in the concentration of testosterone. Plasma concentrations of dihydrotestosterone (DHT) also decrease, similar to testosterone.

  Degarelix is effective in achieving and maintaining testosterone suppression well below the medical castration level of 0.5 ng / mL. As described in further detail below, administration of the 80 mg monthly maintenance dose provided sustained testosterone suppression for at least 1 year in 97% of patients. In particular, the median testosterone one year after such treatment was 0.087 ng / mL.

The pharmacokinetic parameters associated with degarelix evaluated in prostate cancer patients are summarized in Table 1 below.

  The median degarelix trough concentration in the 80 mg maintenance phase at a concentration of 20 mg / mL was 10.9 ng / mL.

  After subcutaneous administration of 240 mg degarelix (6 mL at a concentration of 40 mg / mL) to prostate cancer patients, degarelix is biphasically excluded with a median terminal half-life of about 43 days.

  The long half life after subcutaneous administration is the result of a very slow release of degarelix from the depot formed at the injection site.

  The pharmacokinetic behavior of this drug is strongly influenced by the drug concentration in the injection suspension.

  The distribution volume of healthy elderly men is about 1 L / kg. Plasma protein binding is estimated to be about 90%.

  Degarelix is subject to general peptide degradation during passage of the hepatobiliary system and is excreted mainly as a peptide fragment in feces. No significant metabolites were detected in plasma samples after subcutaneous administration. In vitro studies have shown that degarelix is not a substrate for the human CYP450 (cytochrome P450) system. Thus, clinically significant pharmacokinetic interactions with other agents are unlikely to occur.

  In healthy men, approximately 20% of the administered degarelix is excreted in the kidney, which in humans suggests that approximately 80% is excreted via the hepatobiliary system. The clearance in healthy elderly men is 35-50 mL / hr / kg.

Adverse events (side effects)
Degarelix has generally been found to exhibit good tolerability in clinical trials. The most commonly observed adverse reactions during treatment are due to the expected physiological effects of testosterone suppression, mainly flushing and weight gain, and adverse events related to the injection site (side effects related to the injection site ), Mainly pain at the injection site and erythema at the injection site.

Example 1: S-AL of prostate cancer patients treated with degarelix in contrast to leuprolide
P value Example 1 gives the results of serum alkaline phosphatase (S-ALP) analysis of patients treated for prostate cancer treated with degarelix (240/80 mg) or leuprolide (7.5 mg).

Method:
Patients with histologically confirmed prostate cancer (all stages) for which androgen blockade therapy was indicated were employed. 610 patients (mean age 72 years, median PSA 19.0 ng / mL) were randomly assigned to one of the following three dosing regimens: 1 month degarelix s. c. 240 mg (starting dose) followed by 160 mg (n = 202) or 80 mg (n = 207) of degarelix s. c. Monthly maintenance dose or monthly intramuscular injection of leuprolide depot 7.5 mg (n = 201). Patients receiving leuprolide could also be given bicalutamide for clinical flare prevention.
S-ALP analysis:
Blood samples were taken for S-ALP analysis and S-ALP values at various time points were measured in each patient. S-ALP values were measured using a standardised colorimetric assay based on the p-nitrophenyl phosphate AMP buffer method. The normal range for S-ALP is 44-147 IU / L. S-ALP values in patients without metastasis serve as controls. Factor in treatment and days (facto
r) ANOVA analysis with covariate as baseline was used to determine treatment differences at day 364. Repeated measures analysis (incorporating all time points from day 112), with treatment and number of days as factors and reference values as covariates, was used to determine treatment differences from day 112 to day 364.
result:
The results of analysis of the degarelix 240/80 and leuprolide 7.5 mg groups in patients with advanced prostate cancer are presented in Table 2 and FIG. The reference characteristics were balanced among the groups. About half of patients have locally advanced (29.2%) or metastatic (20.5%) disease at baseline, overall mean age is 72 years, median testosterone is 39.3 ng / mL, The median PSA was 19.0 ng / mL.
For localized disease, S-ALP levels showed a slight but gradual increase within the normal range over the study period, regardless of treatment group (leuprolide or degarelix). Similarly, for locally advanced disease, a slight increase was observed by the end of the study in both treatment groups. Table 2 shows that the S-ALP baseline is higher in metastatic patients and even higher in patients with Hb <130 g / L with either treatment. However, after the initial peak in both groups, S-ALP values were suppressed below baseline values for both degarelix 80 mg and leuprolide, as described above for hormonal treatment, but more significantly for degarelix. The initial increase (peak) of S-ALP is associated with increased activity in bone, and metastatic patients experience a surge in S-ALP at the start of all therapies that affect skeletal metastasis. This is a well described phenomenon and completely unrelated to testosterone spikes.

FIG. 1 compares the mean change from S-ALP baseline to time with degarelix (240/80 mg) and leuprolide (7.5 mg) treatments for localized, locally progressive, and metastatic populations. These results clearly illustrate the long-term inhibition of S-ALP using degarelix. Decreased S-ALP baseline levels in treated subjects suffering from prostate cancer indicate a positive response to treatment, for example by reducing skeletal metastatic activity. Conversely, an increase in S-ALP indicates increased metastatic activity. Figure 1 shows that degarelix treatment significantly reduces S-ALP (after initial and expected spikes), and then, during the course of this study
Indicates to maintain the reduction. Most notably, S-ALP is elevated by leuprolide later in the study, indicating restoration of metastatic activity. Such recovery was not observed with degarelix until very late (Figure 3). Thus, FIG. 1 shows that degarelix can reduce (or at least maintain the same level with no increase) the level of skeletal metastasis over an extended period of time. In contrast, leuprolide was less effective in the short term and less effective in the long term compared to degarelix. Similar results were obtained for the 240/160 mg dose of degarelix.

This effect is further enhanced in patients with metastatic disease and hemoglobin (Hb) content of Hb <130 g / L when compared to the overall metastatic disease (see Table 2 and FIG. 2). Bone metastases affect the bone marrow and patients with bone metastases can become anemic. Lower than normal Hb in patients with bone metastases is an indicator of greater degree of metastasis (in other words, an indicator of more serious disease). Table 2 and FIG. 2 show that long-term suppression of S-ALP by degarelix was more effective in this subset with more severe disease.

In the patient group with PSA baseline ≦ 50 ng / mL, a general trend towards a slight increase in S-ALP levels was observed in both treatment groups over time. However, a different trend is seen in patients with PSA baseline 異 な る 50 ng / mL. Table 2 (Part 2) shows baseline PSA (<10 ng / mL), (10-20 ng / mL), (20-50 ng / mL) treated with degarelix (240/80 mg) and leuprolide (7.5 mg) And (-> 50 ng / mL) compare S-ALP values (IU / L) of the population. The same pattern of S-ALP responses described in FIG. 1 was seen in patients with baseline PSA ≧ 50 ng / mL (see FIG. 4 and the second section of Table 2). The initial reduction is not maintained with leuprolide and is above baseline until the end of the study (eg at day 364), reflecting bone lesions in these patients. In contrast, the initial reduction in ALP values was maintained throughout the study using degarelix (240/80 mg treatment regimen). These results indicate that degarelix may be particularly effective in treating subjects (patients) with prostate cancer at baseline PSA 50 50 ng / mL.

Category (a) in Table 2 is degarelix (240/80 mg) and leuprolide (7.5).
mg) S-ALP values (IU / L) of localized, locally progressive, metastatic population, and metastatic (Hb <30 g / L) subpopulations treated.

  Section (b) of Table 2 is baseline PSA (<10 ng / mL), (10-20 ng / mL), (20-50 ng / mL) treated with degarelix (240/80 mg) and leuprolide (7.5 mg) , S-ALP values (IU / L) of the population (> 50 ng / mL) are shown.

Conclusion:
Patients with metastatic disease and / or patients with PSA values 50 50 ng / mL at baseline experienced a greater reduction in S-ALP levels with degarelix than leuprolide. More importantly, an increase in S-ALP (or return to baseline) by leuprolide later in the study, which indicates recovery of metastatic activity, is observed with degarelix (240/80 mg) until much later than that. It was not. This finding is better understood from the observation that patients in the degarelix group did not show any signs of treatment failure, as indicated by the significantly lower ALP value at day 364. Finally, compared to the overall metastatic disease, this effect is further enhanced in patients with metastatic disease and exhibiting a hemoglobin content of Hb <130 g / L. Thus, these results indicate that degarelix may be able to reduce and / or maintain the level of skeletal transfer better than leuprolide.

Example 2: PSA recurrence in prostate cancer patients treated with degarelix versus leuprolide This example is a phase 3 clinical trial examining the efficacy and safety of degarelix over leuprolide over 12 months of prostate cancer treatment Provides additional PSA value analysis from test CS21 (described herein). Specifically, analysis of secondary endpoints referred to as PSA recurrence revealed a surprising beneficial effect of degarelix treatment, especially for patients with metastatic prostate cancer, as compared to leuprolide treatment.

Prostate specific antigen (PSA) is a commonly used marker in the diagnosis of prostate cancer and in recent years has also been used to monitor response to treatment and recurrence and progression of the disease (Fleming et al. (2006) Nat. Clin.
Pract. Oncol. 3: 658-67; Lilja, et al.
(2008) Nat. Rev. Cancer 8: 268-78). In general, P
Higher values of SA are associated with more severe forms of prostate cancer, and metastatic prostate cancer is associated with the highest value of PSA (eg,> 50 ng / mL). Thus, elevated PSA levels in patients undergoing prostate cancer treatment are associated with incomplete or unsuccessful effects of treatment.

  For this analysis, PSA relapse (secondary endpoint) was defined as two consecutive 50% increases and 55 ng / mL compared to nadir. The time to PSA relapse was measured from the first dose to two consecutive occasions separated by at least 2 weeks, from the nadir to when> 50% and> 5 ng / mL increase in serum PSA was observed Defined as the number of days. The second opportunity was when the criteria were met. PSA recurrence rates were also analyzed at stage and PSA baseline. These analyzes focused on the comparison of degarelix 240/80 mg versus leuprolide 7.5 mg, as this dose is a degarelix dose currently approved by the FDA for the treatment of advanced prostate cancer. is there.

The incidence of PSA recurrence was lower in the degarelix 240/80 mg group compared to the other two treatment groups. The probability of completing the study without experiencing PSA recurrence by day 364 was highest for the degarelix 240/80 mg group (91.1%; 95% CI: 85.9-94.5). The observed 364 day probability of leuprolide 7.5 mg is 85.9%
(95% CI: 79.9 to 90.2).

PSA Relapse-By Stage PSA Recurrence is more frequent in patients with progressive disease across all treatment groups, with the majority of PSA relapse occurring in patients with metastatic disease at baseline (Figure 5). In this subgroup of patients, a lower percentage of PSA recurrence was observed during degarelix 240/80 mg treatment as compared to leuprolide (21.6% vs 36.2%; p = 0.1559). These results indicate that degarelix provides an effective treatment of metastatic prostate cancer as assessed by a reduced incidence of PSA recurrence.

PSA recurrence-by PSA baseline PSA recurrence occurred more frequently in patients with higher PSA baseline values across all treatment groups, with the majority of PSA recurrences occurring in patients with baseline PSA> 50 ng / mL (Figure 6). In this subgroup of patients, a lower percentage of PSA recurrence compared to leuprolide was observed during degarelix 240/80 mg treatment (29.2% vs. 40.0%; p = 0.10). Similarly, patients with baseline PSA 20-50 ng / mL had less PSA recurrence during degarelix treatment. Thus, these results are as effective as degarelix is assessed by reducing the incidence of PSA recurrence in subjects with advanced-stage prostate cancer (as reflected by PSA baselines of> 50 ng / mL) It is illustrative of providing a treatment.

Example 3 Clinical Study of Degarelix for the Treatment of Prostate Cancer In this example, an open-label, multicenter, randomized, parallel-group study was conducted to investigate the efficacy and safety of a one-month regimen of degarelix. The Patients in the two degarelix treatment groups are given an initial dose of 240 mg of degarelix at a concentration of about 40 mg / mL, followed by a monthly administration of 160 mg (about 40 mg / mL) and 80 mg (about 20 mg / mL) One of the two different dosing regimens of the monthly dosing was received. These degarelix dosing regimens were compared to 7.5 mg leuprolide in prostate cancer patients requiring androgen ablation therapy.

  Also, in this study, is degarelix safe and effective with respect to achieving and maintaining testosterone suppression to castration values (as a percentage of patients with testosterone suppression 0.5 ng / mL or less with 12 months of treatment)? Whether investigated or not, serum levels of testosterone and prostate specific antigen (PSA) for the first 28 days of treatment with a degarelix dosing regimen were evaluated relative to treatment with leuprolide 7.5 mg. The study further compared the safety and tolerability with the degarelix dosing regimen to that with treatment with leuprolide 7.5 mg, and further, testosterone, luteinizing hormone (LH), follicle stimulating hormone (LH) with the degarelix dosing regimen FSH) and PSA responses were compared to leuprolide 7.5 mg. The study further compared the patient report results (quality of life factors and flushing) with treatment with the degarelix dosing regimen and treatment with leuprolide 7.5 mg. This study also evaluated the pharmacokinetics of the degarelix dosing regimen. Finally, this study examined the effects of degarelix treatment on patients suffering from different stages of cancer.

Study Design A total of 620 patients were randomized 1: 1: 1 to one of three treatment groups. Of these, 610 patients (mean age 72 years, mean PSA 19.0 ng / mL) received degarelix. Ten randomized patients withdrew from the study prior to dosing.

Patients in the two treatment groups are 240 mg at a concentration of 40 mg / mL (240 @ 40) on day 0
The starting degarelix dose was administered as two equal subcutaneous (sc) injections of 120 mg each. Then, every 28 days, patients receive either 80 mg (80 @ 20: degarelix 240/80 mg group) at a concentration of 20 mg / mL or 160 mg (160 @ 40: degarelix 240/160 mg group) at a concentration of 40 mg / mL. One additional single degarelix dose (sc) was received 12 times. In the third treatment group, patients received active treatment with leuprolide 7.5 mg as a single intramuscular (im) injection every day 0 and 28 days. Bicalutamide could be given as clinical flare prevention to the patients treated with leuprolide 7.5 mg at the investigator's discretion.

  Patients were stratified according to geographical area (Central and Eastern Europe, Western Europe and North America) and body weight (<90 kg and 9090 kg).

Degarelix 240/160 mg group This group received an initial dose of 240 mg (240 @ 40) at a concentration of 40 mg / mL on day zero. This starting dose was administered as two equal 120 mg subcutaneous (sc) injections. This group then received 12 maintenance doses, but every 28 days a single sc of degarelix. c. As a dose, 160 mg (160 @ 40) was administered at a concentration of 40 mg / mL.

Degarelix 240/80 mg group This group also received an initial dose of 240 mg (240 @ 40) at a concentration of 40 mg / mL on day zero. This starting dose is two equal doses of 120 mg each. c. It was administered as an injection. This group then received 12 maintenance doses, but every 28 days a single s.c. c. As a dose, 80 mg (80 @ 20) was given at a concentration of 20 mg / mL.

Leuprolide 7.5 mg group This group received 7.5 mg of reference therapy leuprolide. The treatment was administered as a single intramuscular (im) injection once every 28 days starting on day 0. These treatment plans are summarized in Table 3 below.

  The patients were monitored continuously and visited the clinic monthly for up to one year. Patients were observed clinically for at least one hour after each dose of study drug. Patients who completed the study and met appropriate criteria were offered the opportunity to receive long-term treatment and support in an extension study.

  A total of 807 patients were screened and 620 patients were randomized 1: 1: 1 into three treatment groups: degarelix 240/160 mg, degarelix 240/80 mg, and leuprolide 7.5 mg. Of the 620 patients randomized, 610 patients, including Degarelix 240/160 mg, Degarelix 240/80 mg, and 202, 207 and 201 patients in the leuprolide 7.5 mg treatment group, respectively However, he actually received the study drug. A total of 504 patients completed the study.

Diagnostic and Inclusion Criteria Participation in men over 18 years of age who are eligible for androgen deprivation therapy (except for neoadjuvant hormone therapy) and have histopathologically confirmed prostate cancer (all stages) (with Gleason grade) Qualification target. Signed informed consent was obtained prior to commencing research related activities. Patients had baseline testosterone levels> 1.5 ng / mL and PSA levels> 2 ng / mL at screening. Patients with elevated PSA could be included in this study after undergoing prostatectomy or radiation therapy for curative purposes. Patients were required to have an ECOG score of ≦ 2 and a life expectancy of at least 12 months. Previously or currently, hormone management of prostate cancer (surgical castration or other hormonal manipulations such as GnRH agonists, GnRH antagonists, antiandrogens or estrogens) was excluded from the study. However, in patients who have had prostatectomy or radiation therapy for curative purposes, if neoadjuvant hormone therapy has been discontinued at least six months prior to screening, up to 6 months of neoadjuvant hormone therapy Even if it has been received, it is recognized as a research subject. Combination treatment with 5-alpha-reductase inhibitors was also excluded from the study. Patients who were candidates for radical treatment (ie prostatectomy or radiation therapy) were excluded. Patients who have a history of severe hypersensitivity reactions or clinically significant impairment (other than prostate cancer) who are judged by the researcher to influence the outcome of the study are eligible to enter the study. There was not. Patients with significant baseline prolongation of QT / QTcF interval (> 450 ms), or patients who used combination medications that may extend QT / QTcF interval, or additional risk of torsade de pointes ventricular arrhythmias Patients who had a history of factors were excluded. Patients with serum ALT or bilirubin levels above the upper limit of the normal range at screening visits, or patients with known or suspected liver-symptomatic biliary disease were also excluded. Patients were also excluded if they had known hypersensitivity to any component of the study drug. In addition, patients with any form of cancer within the past five years were excluded from the study, except for prostate cancer and basal or squamous cell carcinoma of the surgically removed skin. Patients who were mentally incompetent or language barriers that made it impossible to fully understand or cooperate were not eligible to participate in the study. Within the 28 days preceding screening, no other medication under study was given.

Duration of treatment For patients in the degarelix treatment group, the starting dose is 240 @ 40 on day 0, and every 28 days 160 @ 40 (degarelix 240/160 mg group) or 80 @ 20 (degarelix 240/80 mg group) 12 maintenance doses each. Administration of degarelix was given on day 0 and thereafter every 28 days (± 7 days) until the end of the study practice, ie day 364 (± 7 days). Patients who completed the study and met appropriate criteria were offered the opportunity to receive long-term treatment and support in an extension study.

Patients in the reference therapy group were treated with leuprolide 7.5 mg on day 0 and then treated with 12 maintenance doses every 28 days. Patients who completed the study received a total of 13 doses. Patients who completed the study and met the appropriate criteria were offered a switch to degarelix treatment in a follow-up study. These patients were randomized to degarelix treatment 240/80 mg or 240/160 mg. On day 0 of the study, 240 mg (40 mg / mL) for patients previously treated with leuprolide 7.5 mg in study CS21
A starting dose of degarelix was given followed by a monthly maintenance dose of either 80 mg (20 mg / mL) or 160 mg (40 mg / mL).

  Patients in the comparison group were treated with an intramuscular (im) injection of leuprolide 7.5 mg pre-filled in a dual chamber syringe. Patients were given a single i.v. on day 0 and once every 28 days thereafter. m. 7.5 mg of leuprolide was administered as an injection. At the discretion of the investigator, bicalutamide could be given as a clinical flare prevention.

Criteria for Evaluation of Efficacy In one aspect of the invention, the composition (or agent) may be for treatment, and the subject to be treated has at least 95% chance of day 28 of treatment Maintain a therapeutically low serum testosterone level of 0.5 ng / ml or less, for example, the treatment subject has a possibility of at least 95%, from day 28 to day 364 of treatment, 0.5 ng / day Maintain therapeutically low serum testosterone levels below ml.

  The composition (or agent) may be for treatment, wherein the subject to be treated has at least a 60% reduction (eg, at least a 75% reduction) in prostate specific antigen (PSA) by day 28 of treatment Do. The composition (or agent) may be for treatment to maintain a prostate specific antigen (PSA) level of less than 5 ng / ml during treatment with a possibility of at least 80%.

  The primary efficacy endpoint was the possibility of testosterone levels remaining at ≦ 0.5 ng / mL from day 28 to day 364.

  Secondary efficacy endpoint: proportion of patients with testosterone surge in the first two weeks of treatment; proportion of patients with testosterone value ≦ 0.5 ng / mL on day 3; baseline of PSA up to day 28 Rate of change of testosterone ≦ 0.5 ng / mL from day 56 to day 364; serum testosterone, LH, FSH, and PSA values over time throughout the study; 2 compared to nadir Times of 50 consecutive elevations and time to PSA failure (PSA failure) defined as at least 5 ng / mL; degarelix concentration over the first month and trough values at day 308 and day 336; testosterone at day 252 Frequency and magnitude of testosterone increase at day 255 and / or day 259 compared to values; The quality of life at the end of the 28th, the 84th, the 168th, and the end of the study practice; the frequency and intensity of the flushing that you experienced (scored daily from the start of the study to the end of the study practice) . In addition, the probability of sufficient testosterone response from day 28 to day 364 (patients have testosterone levels> 1.0 ng / mL once on day 28 or> 0.5 ng / mL) The patient was considered to have an inadequate testosterone response if he had shown twice in a row, and two additional secondary endpoints, such as the rate of change from baseline in PSA up to day 14 added.

Evaluation criteria for safety Frequency and severity of adverse events (AE), presence of clinically significant changes in laboratory parameters (clinical chemistry, hematology and urinalysis), changes in electrocardiogram (ECG) and vital signs, body The safety variables of this study were evaluated for changes detected by testing and for weight.

Body weight was measured at screening and at the end of the study. Height (in barefoot) was measured at screening. Body mass index (BMI) is defined as the weight of an individual divided by the height squared. The widely used formula in medicine yields a unit of measurement of kg / m ² . Body mass index may be accurately calculated using any of the formulas known in the art.

Statistical Methods All statistical analyzes were performed using statistical analysis software SASTM version 9 or higher to calculate summary statistics. The populations for analysis were as follows.

  The comprehensive analysis (ITT) analysis set included all randomized patients who received at least one dose of degarelix.

  The per protocol (PP analysis set) included all ITT analysis sets that did not have major protocol violations.

  The safety population is identical to the ITT analysis set, so all safety analyzes were performed on the ITT analysis set.

  Primary efficacy endpoints were analyzed for both the ITT and PP analysis sets, and the ITT analysis set was considered primary. Primary efficacy endpoints were analyzed using the Kaplan-Meier method. Testosterone response rates with 95% confidence intervals (CI) were calculated by log-log transformation of the survivor function for each of the three treatment groups. The difference between the degarelix treatment group and leuprolide 7.5 mg was evaluated using 97.5% CI calculated by normal approximation using pooled standard error.

  Two hypotheses were tested to assess the efficacy of degarelix.

  (1) The Food & Drug Administration (FDA) standard states that the lower limit of the 95% confidence interval (CI) is 90% for the cumulative probability of testosterone ≦ 0.5 ng / mL from day 28 to day 364 It was to determine if it was within.

  (2) The European Medicines Agency (EMEA) criteria determine whether degarelix is comparable to leuprolide 7.5 mg for the cumulative probability of testosterone ≦ 0.5 ng / mL from day 28 to day 364 It was to do. The non-inferiority limit for the difference between treatments (degarelix vs leuprolide 7.5 mg) was -10 percent.

  Unless otherwise stated, all secondary efficacy endpoints were analyzed for both the ITT and PP analysis sets. The proportion of patients with testosterone spikes in the first two weeks of treatment was analyzed using Fisher's exact test. Fisher's exact test was also used to analyze the proportion of patients who showed testosterone values <0.5 ng / mL on day 3. Percent change from baseline of PSA to day 28 endpoint was analyzed by Wilcoxon test. Separate data are presented for treatment group, geographical area, weight group (<90 kg,> 90 kg), and leuprolide 7.5 mg sub-group for both Fisher's exact test and Wilcoxon test.

  Secondary endpoints, probability of testosterone ≦ 0.5 ng / mL from day 56 to day 364, time to PSA relapse, and probability of sufficient testosterone response from day 28 to day 364 And analyzed by the Kaplan-Meier method.

Efficacy Results The primary objective of this study was degarelix in achieving and maintaining testosterone suppression castration values, assessed as the proportion of patients who showed testosterone suppression ≦ 0.5 ng / mL during the 12 months of treatment. To demonstrate the effectiveness of

  The results show that degarelix supplied on a 240/80 mg regimen produced rapid and effective suppression of testosterone levels, which remained low throughout the 364 days of treatment (Figure 7).

  Kaplan-Meier estimates of the probability that testosterone ≦ 0.5 ng / mL from day 28 to 364 are 98.3 for degarelix 240/160 mg, degarelix 240/80 mg, and leuprolide 7.5 mg groups, respectively. %, 97.2%, and 96.4%. For all three treatment groups, the lower 95% CI was above the prespecified 90% threshold. Regarding the probability of testosterone ≦ 0.5 ng / mL from day 28 to day 364, treatment with degarelix proved comparable to leuprolide 7.5 mg therapy. For both degarelix treatment groups, the total 97.5% CI for the difference in probability compared to the leuprolide 7.5 mg group was greater than the non-inferior limit of -10 percent. Thus, this study met the FDA and EMEA criteria for efficacy.

  The robustness of the primary efficacy endpoint results was supported by the observed case analysis. This analysis yields similar estimates for the overall proportion of patients who show testosterone ≦ 0.5 ng / mL from day 28 to day 364, which are: degarelix 240/160 mg group, degarelix 240 / It was 98.2%, 97.0% and 96.0% for the 80 mg group and leuprolide 7.5 mg group respectively. The findings of the primary analysis were further supported by a second-order efficacy analysis with a probability of testosterone ≦ 0.5 ng / mL from day 56 to day 364.

  As expected, the first two weeks of treatment with a testosterone surge (increase from baseline 15 15%) compared to leuprolide 7 compared to the pooled degarelix group (0.2%: 1 patient) It occurred at a significantly higher rate (80.1%) in patients in the 5 mg group (p <0.0001, Fisher's exact test). Patients treated with Degarelix should have low testosterone levels at the baseline (0.0065 ng / mL), and therefore, these patients should be considered as artefacts, as spikes from such lower baselines will not be noticeable Can. Conversely, on day 3, 96% of the patients receiving degarelix showed testosterone suppression, compared to patients in the leuprolide 7.5 mg group who did not show testosterone suppression (p <0.0001 , Fisher's exact test). As shown in FIGS. 7 and 8, the degarelix 240/80 mg regimen rapidly and efficiently suppressed testosterone levels, while leuprolide 7.5 mg worked far more slowly, only after the first testosterone surge. .

  As shown in FIG. 9, the degarelix 240/80 mg regimen also resulted in a more rapid and efficient reduction of PSA levels than treatment with leuprolide 7.5 mg. A rapid decrease in PSA levels was observed for patients treated with degarelix. In contrast, PSA levels in the leuprolide 7.5 mg group plateaued in the first week of treatment and then decreased exponentially to suppression levels. For degarelix patients, a significantly greater reduction from baseline in median PSA values was observed (p <0.0001, Wilcoxon test), compared to leuprolide 7.5 mg patients (Days 14 and 28). The The probability that PSA from the combined degarelix group was less than 1 was slightly higher on day 14 (0.82) than on day 28 (0.70) from the leuprolide 7.5 mg group. The probability of completing the study without experiencing PSA recurrence was highest in the degarelix 240/80 group (91.2%) and slightly lower for both degarelix 240/160 mg and leuprolide 7.5 mg groups (almost 85.8%), this difference was not statistically significant.

  Protocol-based antiandrogen therapy was given at the start of treatment to 22 patients in the leuprolide 7.5 mg group for the prevention of flares. The PSA data for these patients were baselined on day 14 (61.7% reduction) and on day 28 (89.1%) compared to patients in the leuprolide 7.5 mg group who did not receive antiandrogen therapy The median rate of change from value was greater. In this case, the reduction rates for patients in the leuprolide 7.5 mg group who did not receive antiandrogen therapy were 15.3% and 61.7% on days 14 and 28, respectively. The median rate of change of PSA levels in patients with leuprolide plus antiandrogen is similar to patients treated with degarelix, thus, this allows degarelix to be controlled conventionally with respect to suppression of PSA at the start of treatment. It should be noted that it was confirmed to be more effective than GnRH agonist therapy. Degarelix does not require an additional concomitant drug to prevent flares, and an initial dose of 240 mg has the same effect on PSA levels as a combination of GnRH agonist and antiandrogen.

  The profile of serum LH levels over time was similar to that observed for testosterone. After administration of degarelix, the median LTH value of the ITT assay set decreased rapidly, <0.7 IU / L on day 1, which was about a 88% decrease from baseline. For both degarelix treatment groups, median LH values remained suppressed until day 364 at the end of the study. In contrast, for patients in the leuprolide 7.5 mg group, a sharp increase in median LH levels was observed, peaking at 31.0 IU / L on day 1 (> 400% increase from baseline), It decreased exponentially to 0.035 IU / L by day 56 and remained at this value until day 364 (see Figure 10).

  A rapid decrease in FSH levels was also observed in patients treated with degarelix. Administration of degarelix resulted in a reduction of the mean FSH value to ≦ 1.5 IU / L by day 7, which was> 80% reduction from baseline. For both degarelix treatment groups, median FSH values remained suppressed until the end of study 364 days. For patients in the leuprolide 7.5 mg group, there is an initial spike in FSH levels similar to that observed for LH levels, peaking at 22.5 IU / L on day 1 (146% increase over baseline), It decreased exponentially to 2.0 IU / L by 14 days, followed by the median FSH value increasing to a plateau of about 4.40 IU / L at the 56th day, staying there until the 364th day (See FIG. 11).

  The pharmacodynamic profile of degarelix is characteristic of GnRH antagonists and serum levels of testosterone, LH and FSH were rapidly suppressed. In contrast, for patients in the leuprolide 7.5 mg group, serum levels of testosterone, LH, and FSH increased rapidly within the first week of treatment and then dropped to suppression (Fig. 7, 8) , 10 and 11).

Safety Results Safety and tolerability are assessed by AEs that occurred during the observation and reported treatment, which include injection site reactions, hematology, clinical chemistry, and laboratory parameters of urinalysis, signs of survival / clinical Observations were included, as well as weight measurement and physical examination, ECG and concomitant medications.

  Safety parameters were evaluated for all patients included in the ITT analysis set, which included at least all 610 randomized patients who received at least one dose of study medication.

Claims (32)

A composition comprising degarelix for treating metastatic stage prostate cancer in a subject. Baseline value of serum alkaline phosphatase (S-ALP) of the subject
The composition according to claim 1, wherein evel) (before treatment) is about 150 IU / L or more, for example about 160 IU / L or more. The composition according to claim 1 or 2, wherein the reference value of serum alkaline phosphatase of the subject is 200 IU / L or more. 4. The serum alkaline phosphatase value of said subject is reduced by at least 50 IU / L or more above said reference value (S-ALP) for a period of approximately 60 days to 364 days of treatment. The composition as described in. 5. The method according to any one of claims 1 to 4, wherein the subject's serum alkaline phosphatase value is reduced by at least about 50 IU / L or more than the reference value (S-ALP) for a period of between 364 and 450 days of treatment. Composition as described. The method according to any one of claims 1 to 5, wherein the subject's serum alkaline phosphatase value is reduced by about 90 IU / L or more from the reference value (S-ALP) in a period between 112 days to 364 days of treatment. Composition as described. The composition according to any one of claims 1 to 6, wherein the hemoglobin (Hb) value of the subject is 130 g / L or less. The composition according to any one of claims 1 to 7, wherein the reference value of serum alkaline phosphatase (S-ALP) of the subject is 300 IU / L or more. 8. The method according to claim 6, wherein the serum alkaline phosphatase value of said subject is reduced by at least about 160 IU / L above said reference value (S-ALP) for a period between 112 and 364 days of treatment.
The composition according to any one of the above. The composition according to any one of claims 1 to 9, wherein the subject has a PSA value of 50 ng / mL or more. 11. The method according to claim 10, wherein the serum alkaline phosphatase value of said subject is reduced by about 60 IU / L or more from said reference value (S-ALP) in a period between 112 days and 364 days of treatment.
The composition as described in. 12. A composition according to any of the preceding claims, wherein degarelix is administered at an initial dose of 160-320 mg and subsequently at a maintenance dose of 60-160 mg once every 20 to 36 days. 13. A composition according to any of claims 1 to 12 for administering degarelix at an initial dose of about 240 mg and thereafter at a maintenance dose of about 80 mg once every about 28 days. 14. A composition according to any of the preceding claims, wherein said subject maintains a therapeutically low serum testosterone level of less than 0.5 ng / ml by day 28 of treatment with a possibility of at least 95%. . 15. A method according to any of the preceding claims, wherein the subject maintains a therapeutically low serum testosterone level of less than or equal to 0.5 ng / ml from day 28 to 365 of treatment with at least 95% chance. Composition of 16. The composition according to any of the preceding claims, wherein the subject's PSA is reduced by at least 60% by day 14 of treatment, for example by at least 75% by day 28 of treatment. 17. A composition according to any of claims 1 to 16 for treatment to maintain PSA levels below 5 ng / ml during treatment with a possibility of at least 80%. A composition comprising degarelix for treating prostate cancer in a subject having a PSA level of 50 ng / mL or more. 19. The composition according to claim 18, wherein the reference value of the subject's serum alkaline phosphatase (S-ALP) is about 150 IU / L or more, for example about 160 IU / L or more. The subject's serum alkaline phosphatase (S-) for a period between 112 and 364 days
20. The composition according to claim 18 or 19, wherein the ALP) reference value changes negatively by about 60 IU / L or more. 21. The composition of any of claims 18-20, wherein the subject has a hemoglobin (Hb) value of 130 g / L or less. A composition comprising degarelix for delaying or preventing progression of localized or locally advanced prostate cancer in a subject to metastatic stage prostate cancer. 23. The composition of claim 22, wherein the subject has a PSA value of 10 to 50 ng / mL. 24. The composition of claim 22 or 23, wherein the subject has a PSA value of 20 to 50 ng / mL. 25. The composition of any of claims 22-24, wherein the subject has a serum alkaline phosphatase (S-ALP) value between 44 and 147 IU / L. 25. The composition of any of claims 22-24, wherein the subject has a serum alkaline phosphatase (S-ALP) level of less than 160 IU / L. 27. The composition of claim 26, wherein the subject has a serum alkaline phosphatase (S-ALP) level of 50-160 IU / L. 28. A composition according to any of claims 18 to 27 for a first dose administration of Degarelix 160-320 mg and a subsequent maintenance dose of Degarelix 60-160 mg once every 20 to 36 days. Use of degarelix in the manufacture of a medicament for the treatment of metastatic prostate cancer in a subject, wherein the treatment comprises administering degarelix at a first dose of 160-320 mg, and then once every 20-36 days. Administration at a maintenance dose of 60-160 mg. Use of degarelix in the manufacture of a medicament for delaying or preventing progression of localized or locally advanced prostate cancer to metastatic stage prostate cancer in a subject, wherein the treatment comprises an initial dose of 160-320 mg of degarelix And administration thereafter at a maintenance dose of 60 to 160 mg once every 20 to 36 days. 31. The use according to any of claims 29 to 30, wherein said treatment comprises administration at a first dose of about 240 mg of degarelix and subsequently administration of about 80 mg of degarelix once at about every 28 days. . A method of treating metastatic stage prostate cancer in a subject comprising administering an initial dose of about 240 mg of degarelix to said subject, and thereafter maintaining a maintenance dose of about 80 mg of degarelix once about every 28 days. Administering an initial dose of 160-320 mg of degarelix to the subject, such as administering to the subject, and then administering a maintenance dose of 60-160 mg of degarelix to the subject once every 20 to 36 days A method that includes steps.

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