Novel adjuvant therapy for use in prostate cancer treatment

Abstract

To provide a novel adjuvant therapy in the field of prostate cancer treatment.SOLUTION: The present invention provides a therapy in the field of prostate cancer treatment, and in particular in the field of prostate cancer treatment by Androgen Deprivation Therapy (ADT). The present treatment involves oral administration of an estetrol component in conjunction with ADT.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to the field of prostate cancer treatment, particularly to the field of prostate cancer treatment by androgen deprivation therapy (ADT). This treatment includes oral administration of an estetrol component in combination with ADT.

Background Art

[0002] Prostate cancer is the second leading cause of cancer death in men in the United States. For the past 60 years, hormone therapy has been an important treatment for advanced prostate cancer. One such method is the suppression of endogenous androgen production by diethylstilbestrol (DES). DES is a substance known to exhibit estrogenic activity. However, the use of DES is compromised by significant cardiovascular toxicity. Methods to reduce thromboembolism, such as dose reduction or the use of warfarin sodium, have not been satisfactory (Malkwicz et al., "The role of diethylstilbestrol in the treatment of prostate cancer", Urology 2001 August; 58(2 Suppl 1): 108-13). Furthermore, the use of DES is thought to increase the risk of male breast cancer.

[0003] Currently, the use of DES and other estrogens has been replaced by treatment with gonadotropin-releasing hormone (GnRH) agonists (now the first-choice treatment), antagonists, and recently available antiandrogens (such as enzalutamide sold as Xtandi®).

[0004] When treatment with a GnRH agonist begins, the concentrations of luteinizing hormone (LH) and testosterone (T) increase significantly during the first 2 to 3 weeks, which is a highly undesirable side effect and can cause symptom exacerbation, particularly pain due to bone metastasis. Subsequently, the GnRH receptor is downregulated and LH and T are suppressed.

[0005] (Since male estrogen results from the aromatization of androgens), androgen deprivation therapy (ADT) reduces estrogen levels, which then induces hot flashes and sweating, joint pain, sleep disturbances, cognitive impairment and memory loss, unfavorable lipid changes, mood changes (depression / irritability), fatigue, body composition changes, and, very importantly, bone loss (osteoporosis and osteopenia) and fractures. It has been proposed to supplement patients treated with ADT with estrogen.

[0006] However, oral estrogen administration induces an increased risk of thromboembolic and cardiovascular events due to first-pass liver metabolism. For this reason, this is not considered feasible.

[0007] Some researchers have proposed instead the use of transdermal estrogen (Phillips et al, Oncology and Hematology Review, 2014; 10(1):42-47). This can be delivered in the form of a daily patch or gel. However, this dosing method is a significant daily burden, so patient medication compliance is an issue.

[0008] For example, International Publication No. WO 2004 / 096259 proposes other methods of administering estrogen in the context of treating prostate cancer by androgen deprivation. This application teaches administering a second sustained-release formulation comprising an estrogen composition that reduces the increased bone density loss or hot flashes generally caused by the administration of a GnRH composition, together with a sustained-release formulation of "GnRH, an agonist of GnRH or an antagonist of GnRH".

[0009] However, as stated by the applicant of International Publication No. WO 2004 / 096259, in the second stage of release, it is necessary to limit the release of the estrogen component to about 10 to 100 μg of estradiol equivalent per day, and preferably not to exceed about 50 μg of estradiol equivalent per day. This is because of the increased cardiovascular risk induced by estrogen administration. Therefore, the applicant of International Publication No. WO 2004 / 096259 has to solve the dilemma of administering sufficient estrogen to effectively counteract the side effects of GnRH administration without unnecessarily increasing the risks associated with high concentrations of estrogen (lines 21 on page 10 to line 4 on page 11 of International Publication No. WO 2004 / 096259). They have proposed a sustained-release formulation that results in a serum estradiol equivalent of about 10 pg / mL to about 50 pg / mL. Here, it is worth noting that since estradiol binds to SHBG with a relatively high affinity of about 40% (Hammond GL et al., Climacteric. 2008;11 Suppl 1:41-6), only 60% of the amount delivered by the formulation of International Publication No. WO 2004 / 096259 is biologically available.

[0010] Dutman et al. (Effect of human fetal estrogen estetrol (E4) in healthy men to estimate its potential use in prostate cancer treatment. Eur Urol Suppl (2017), 16(3)) reported on a single-center, double-blind, randomized, placebo-controlled, multiple-dose study conducted in healthy men (40 - 70 years old). 20 mg of estetrol was administered once daily to the first cohort and 40 mg to the second cohort. It was found that the concentrations of total testosterone, free testosterone, FSH, and estradiol decreased, the concentration of LH did not change, and the concentration of SHBG increased. These observed changes suggest a dose-dependency. The body weight and safety parameters did not change. During treatment with estetrol, a decrease in libido was reported in 8 out of 20 men, and breast tenderness was reported in 7 out of 20 men. SUMMARY OF THE INVENTION

[0011] The present invention provides an adjuvant therapy for the treatment of prostate cancer using ADT, which further reduces the total testosterone and free testosterone concentrations, achieves effective estrogen replacement, and reduces the side effects of ADT.

[0012] Most preferably, the present invention relates to the treatment of prostate cancer, which comprises oral administration of at least 4 weeks of an estetrol component at a high dose of at least 20 mg per day simultaneously with ADT, and the estetrol component is selected from estetrol; an ester of estetrol in which a hydrogen atom of at least one hydroxyl group is substituted with an acyl group of a carboxylic acid, sulfonic acid, or sulfamic acid having 1 to 25 carbon atoms; and combinations thereof. The present invention is subject to a rather surprising discovery by the applicant.

[0013] First, co-administration of the estetrol component at a high daily oral dose of at least 20 mg for at least 4 weeks results in a further significant decrease in T concentration, particularly the biologically active free T concentration.

[0014] Second, co-administration of the estetrol component according to the present invention effectively alleviates the low estrogen-like symptoms induced in prostate cancer patients by ADT.

[0015] Third, co-administration of the estetrol component described herein reduces the risk of arterial and cardiovascular diseases. This is further explained in the following section of "Improvement of lipid profile" and is observed in prostate cancer patients treated according to the present invention.

[0016] When a GnRH agonist is used in ADT, the combination of the start of GnRH agonist administration and oral administration of the estetrol component has the advantage that LH synthesis is immediately suppressed, thereby suppressing the initial increase (flare) in LH concentration and T concentration. This flare delays castration and causes deterioration of symptoms. BRIEF DESCRIPTION OF THE DRAWINGS

[0017]

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[0018] A first aspect of the present invention is the treatment of prostate cancer in a patient, the treatment comprising androgen deprivation therapy and co - administration (adjuvant therapy) for at least 4 weeks of an estetrol component of at least 20 mg per day, the estetrol component being selected from estetrol; an ester of estetrol in which a hydrogen atom of at least one hydroxyl group is substituted with an acyl group of a carboxylic acid, a sulfonic acid, or a sulfamic acid having 1 to 25 carbon atoms; and combinations thereof.

[0019] Definition As used herein, the term "estetrol component" refers to a substance selected from the group consisting of estetrol; an ester of estetrol in which a hydrogen atom of at least one hydroxyl group is substituted with an acyl group of a carboxylic acid, a sulfonic acid, or a sulfamic acid having 1 to 25 carbon atoms; and combinations thereof. Even more preferably, the estetrol component is estetrol (including estetrol hydrate). Most preferably, the estetrol component contained in the dosage unit is estetrol monohydrate.

[0020] As used herein, "dosage" or "dose" refers to the dose of the estetrol component equivalent to the specified oral dose of estetrol monohydrate, unless otherwise specified. Thus, for example, a daily oral dose of 40 mg of a particular estetrol component is a dose of the estetrol component equivalent to a daily oral dose of 40 mg of estetrol monohydrate.

[0021] Therapeutic method In this treatment method, the estetrol component is administered to prostate cancer patients receiving ADT at a dose of preferably 80 mg or less per day, more preferably 60 mg or less per day.

[0022] The administration of the estetrol component is preferably carried out simultaneously with ADT as long as ADT is being performed.

[0023] In a preferred embodiment, the estetrol component is administered for 12 weeks, most preferably for at least 50 weeks.

[0024] In a particularly preferred embodiment, the estetrol component is administered once daily, simultaneously, in a convenient once-daily unit dose.

[0025] In this treatment method, the estetrol component is preferably administered in an amount sufficient to achieve a plasma trough concentration of estetrol of at least 600 pg / mL, preferably at least 1000 pg / mL, more preferably at least 1500 pg / mL, and even more preferably at least 2000 pg / mL.

[0026] Generally, the plasma trough concentration of estetrol as a result of administration does not exceed 20000 pg / mL, preferably 18000 pg / mL, more preferably 16000 pg / mL, and even more preferably 14000 pg / mL. As used herein, "trough concentration" means the lowest concentration that the drug reaches before the next dose.

[0027] To enable estrogen replacement that is far more effective than can be achieved using other estrogens, the safety of the estetrol component is an important aspect of this treatment method. Furthermore, due to the significant testosterone-lowering effect achieved by the co-administration of the estetrol component, this treatment method is more effective than ADT itself.

[0028] The androgen deprivation therapy used in this treatment method preferably includes the administration of an androgen inactivating agent selected from GnRH agonists, GnRH antagonists, anti-androgen agents, and combinations thereof. More preferably, the ADT includes the administration of a GnRH agonist.

[0029] As a result of the estetrol component showing a T concentration lowering effect, in certain embodiments, the treatment according to the present invention enables the achievement of a 5%, preferably 10%, more preferably 20% reduction in the dose of GnRH agonist, antagonist or antiandrogen agent while maintaining the same castration level of T. This effect is shown in Figures 1A and 1B and is further described in Example 1.

[0030] The co - administration of the estetrol component according to the present invention provides the advantage of reducing the side effects of ADT, particularly the adverse effects on the lipid profile. In another aspect, the treatment of the present invention has a favorable effect on the patient's lipid profile as described in the section "Improvement of lipid profile" below.

[0031] This treatment method provides the advantage of effectively reducing the total testosterone concentration and / or free testosterone concentration in the patient's plasma compared to ADT without co - administration of the estetrol component.

[0032] This treatment method further provides the advantage that the patient's LDL cholesterol concentration is maintained at a lower level compared to the case without co - administration of the estetrol component and compared to the case without the undesirable increase in TG concentration as commonly seen with estrogen. This effect is referred to herein as "improvement of lipid profile".

[0033] Along with the positive effect on LDL cholesterol, the co - administration of the estetrol component contributes to the maintenance of a higher HDL cholesterol concentration as shown in Example 1 below. These three concurrent effects (decrease in LDL cholesterol, increase in HDL cholesterol and stable TG concentration) are associated with a reduction in the risk of arterial and cardiovascular diseases. As used herein, "arterial and cardiovascular diseases" includes conditions such as atherosclerosis and arterial thrombosis. "Arterial and cardiovascular diseases" includes, but is not limited to, peripheral arterial disease.

[0034] The co - administration of the estetrol component in this treatment method effectively prevents the decrease in bone mass measured by the bone mineral density of the patient in the combination treatment according to the present invention, which is the decrease in bone mass usually observed in patients in the treatment with ADT alone. In other words, while the treatment with ADT alone causes bone mass loss, the combination treatment according to the present invention enables the observation of the prevention of bone mass loss.

[0035] Furthermore, the co - administration of the estetrol component reduces the median daily hot - flash score of patients during the combination treatment according to the present invention by at least 40%, at least 60%, and at least 80% compared to the median daily hot - flash score of patients during the treatment with ADT alone. In this specification, the term "median daily hot - flash score" corresponds to the number obtained by multiplying the average severity per day measured over 7 days for the number of hot - flashes. The details of the measurement of this score are described in the 2010 paper by Irani et al. (Lancet Oncol. 2010, 11, 147 - 54).

[0036] When the flare delays castration, in the aspect where the ADT treatment includes the administration of a GnRH agonist, the co - administration of the estetrol component according to the present invention makes the PSA response of the patient faster compared to the treatment with the GnRH agonist alone.

[0037] Composition Another aspect of the present invention relates to a pharmaceutical dosage unit suitable for oral administration, which contains an estetrol component of 20 - 80 mg selected from estetrol, esters of estetrol in which the hydrogen atom of at least one hydroxyl group is substituted with an acyl group of a carboxylic acid, a sulfonic acid, or a sulfamic acid having 1 - 25 carbon atoms, and combinations thereof as the first active ingredient, and an androgen - inactivating agent selected from GnRH agonists, GnRH antagonists, anti - androgen agents, and combinations thereof as the second active ingredient.

[0038] Preferably, the estetrol component is estetrol (including estetrol hydrate). Most preferably, the estetrol component contained in the dosage unit is estetrol monohydrate.

[0039] The estetrol component of the present invention is preferably contained in the dosage unit in an amount not exceeding 60 mg.

[0040] The oral dosage unit according to the present invention is a solid preparation or semi-solid preparation such as tablets, capsules, cachets, pellets, pills, powders and granules. The term "solid preparation or semi-solid preparation" also includes capsules containing a liquid, e.g. oil, in which the estetrol component of the present invention is dissolved or dispersed. Tablets and equivalent solid and semi-solid preparations can suitably contain materials such as binders (e.g. hydroxypropylmethylcellulose, polyvinylpyrrolidine, other cellulose-based materials and starch), excipients (e.g. lactose and other sugars, starch, dicalcium phosphate, and cellulose-based materials), disintegrants (e.g. starch polymers and cellulose-based materials) and lubricants (e.g. stearates and talc).

[0041] Antiandrogens such as enzalutamide (sold as Xtandi (registered trademark)) can be suitably used according to the present invention.

[0042] GnRH antagonists and agonists can also be used according to the present invention. Since agonist therapy first stimulates the secretion of both LH and FSH and then significantly suppresses it, GnRH antagonists are preferred. The advantage of GnRH antagonists compared to GnRH agonists is that they immediately cause a decrease in gonadotropin concentration without first increasing gonadotropin release (flare). Thus, the undesirable effects of GnRH agonist therapy on LH and FSH secretion are avoided by antagonist therapy.

[0043] Concurrent administration of an estetrol component and a GnRH agonist also suppresses unwanted flares. As described above, when an estetrol component is concurrently administered at the start of treatment with a GnRH agonist, LH synthesis is immediately inhibited, thereby suppressing the flare.

[0044] Many such GnRH antagonists are available, such as cetrorelix, ganirelix, abarelix or degarelix. The approved dosages and routes of administration of the corresponding commercially available agents are as follows: · Cetrorelix: 0.25 mg subcutaneous injection, once daily; · Ganirelix: 0.25 mg subcutaneous injection, once daily; · Abarelix: 100 mg intramuscular injection every 4 weeks; · Degarelix: Initial dose 240 mg subcutaneous injection, followed by maintenance dose 80 mg subcutaneous injection every 4 weeks.

[0045] In embodiments where the treatment involves the use of a GnRH antagonist, dosages of 0.05 - 5 mg per day, preferably 0.1 - 1 mg per day, are used.

[0046] In another embodiment where the treatment involves the use of an injectable long - acting GnRH antagonist, dosages of 10 - 500 mg, preferably 50 - 250 mg, are used weekly, every two weeks, every four weeks, every two months, every three months, or every six months.

[0047] In addition, non - peptidic orally active GnRH antagonists, such as elagolix which is currently in phase III clinical trials, are known in the art. The dosages of elagolix are 150 mg per day (oral) and 200 mg twice a day (oral). Non - peptidic orally active GnRH antagonists under development include relugolix (TAK - 385), KLH - 2109 and ASP - 1707.

[0048] In addition, many GnRH agonists are available, such as buserelin, goserelin, leuprorelin, nafarelin or triptorelin. The approved dosages and administration routes of the corresponding commercially available drugs are as follows: · Buserelin: Initial dose (subcutaneous administration), 500 μg every 8 hours for 7 days. The maintenance dose is 200 μg / day by subcutaneous administration or 400 μg (200 μg in each nostril) 3 times a day by intranasal administration; · Goserelin: Subcutaneous administration of 3.6 mg every 4 weeks; · Leuprorelin: Intramuscular or subcutaneous administration of 7.5 mg every 4 weeks, 22.5 mg every 3 months, 30 mg every 4 months, 45 mg every 6 months; · Nafarelin: Intranasal spray of 200 - 400 μg twice a day; · Triptorelin: Intramuscular administration of 3.75 mg every 4 weeks, 11.25 mg every 3 months, 22.5 mg every 6 months.

[0049] By using an oral GnRH antagonist or anti - androgen, the treatment method of the present invention can be applied using an intentionally developed oral formulation, such as a tablet containing the daily dosage of a GnRH antagonist and an estetrol component.

[0050] In a particularly preferred embodiment of the present invention, the dosage unit is a combined oral formulation containing both a GnRH antagonist or anti - androgen agent and an estetrol component.

[0051] Kit Yet another aspect of the present invention relates to a kit comprising a first pharmaceutical composition comprising an androgen inactivation agent selected from GnRH agonists, GnRH antagonists, antiandrogens and combinations thereof, and a second pharmaceutical composition suitable for oral administration comprising 20-80 mg of an estetrol component selected from estetrol, esters of estetrol in which the hydrogen atom of at least one hydroxyl group is substituted with an acyl group of a carboxylic acid, sulfonic acid, or sulfamic acid having 1-25 carbon atoms, and combinations thereof, together with instructions for use in the prostate cancer treatment described herein.

[0052] The present invention has been described above with reference to several exemplary forms. Modifications and alternative implementations of some parts or elements are possible and are included within the scope of protection by the claims.

Example

[0053] Example 1: Safety, pharmacokinetics and pharmacodynamics of estetrol in healthy men A Phase 1, double-blind, randomized, placebo-controlled, multiple-dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of multiple doses of estetrol in healthy men.

[0054] Male participants aged 40-70 years were assigned to one of the following groups: · Group 1: 20 mg of E4 (estetrol) or placebo; · Group 2: 40 mg of E4 (estetrol) or placebo; · Group 3: 60 mg of E4 (estetrol) or placebo; A total of 15 subjects were assigned to each dose group: 10 randomly selected subjects received active treatment (E4) and 5 randomly selected subjects received placebo treatment. A total of 60 subjects participated in this study. Random assignment to groups was done at Visit 2 after the participants were found to be eligible.

[0055] Administration started with Group 1. The other groups were also administered continuously. Based on adverse events (AE), SHBG concentration, lipids, and hemostasis parameters, the dose increase to the next E4 dose group was advanced. The decision whether to continue with the next higher E4 dose was made by the principal investigator, an independent expert, and the sponsor.

[0056] E4 was provided as tablets and taken orally every morning from 8:00 to 10:00 am for 28 days. The total study period including screening was 84 days for each subject. (Screening was from Day - 28 to Day - 1, and the clinical phase was from Day 1 to Day 56.)

[0057] Evaluation Methods Main parameters There were two primary parameters in this study. The first primary parameter was the safety evaluation of E4. Safety variables included vital signs, regular clinical examinations, physical examinations, ECG measurements, and monitoring of (S)AE.

[0058] The second primary parameter was the hormone related to prostate function. FSH, LH, E2, total testosterone, free testosterone, and sex hormone - binding globulin (SHBG) were measured.

[0059] Secondary parameters Secondary parameters included other pharmacodynamic and pharmacokinetic parameters. The pharmacodynamic parameters evaluated were as follows: · Hemostatic factors: (extrinsic) APC resistance, prothrombin fragment 1 + 2, free tissue factor pathway inhibitor (TFPI), antithrombin activity, protein S activity, D - dimer, angiotensinogen; · Lipids and lipoproteins: total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol, and lipoprotein(a) (Lp(a)); · Carbohydrates: fasting blood glucose; · Bone metabolism markers: osteocalcin, type I collagen telopeptide (CTX-1), and parathyroid hormone (PTH); · Prostate-specific antigen (PSA).

[0060] Pharmacokinetics were evaluated by measuring trough concentrations of E4 on days 2, 7, 14, and 28. Additionally, E4 concentrations were measured at several time points before and after dosing on day 28.

[0061] Results A daily dose of 20 mg, 40 mg, or 60 mg of E4 was well tolerated in healthy men aged 40 - 70 years. No changes in vital signs, ECG, physical examination, or body weight were observed.

[0062] Figures 1 and 2 show the concentrations of markers on day 1 and day 28 for several hormones related to prostate function, and for lipid, hemostasis, and bone parameters, respectively.

[0063] From Figures 1a and 1b, it can be seen that testosterone concentrations (free testosterone and total testosterone) decreased with treatment. Additionally, Figure 1c shows that an increase in SHBG was induced by treatment. The FSH concentration (Figure 1e) decreased, while there was no significant change in LH (Figure 1d). Since the LH concentration decreased for only a few hours after E4 administration, the latter may be due to the sampling time. (This hormone is known to have pulsatile secretion at 2 - hour intervals in men.)

[0064] The various parameters reported in Figure 2 confirm the beneficial estrogenic effect of E4 on bone and the safety of treatment at these doses. Regarding lipids, HDL cholesterol increased slightly, TG did not change, and a significant decrease of about 20% was observed in LDL cholesterol.

[0065] Example 2: Estetrol plasma concentration as a function of dose In each group where 2, 10, 20, 40, or 60 mg of estetrol was administered daily (orally), the plasma content of estetrol in 7 - 10 male patients on the 7th and 14th days was tested. In each group, the mean trough concentration for all patients on both days was calculated.

[0066] As shown in Table 1, the results show good dose linearity.

[0067]

Table 1

[0068] Example 3: Efficacy and tolerance of estetrol in prostate cancer patients undergoing androgen deprivation therapy Male patients with histologically confirmed adenocarcinoma of the prostate and eligible for androgen deprivation therapy (ADT: GnRH agonist) were selected. This trial is a randomized placebo - controlled one.

[0069] Random allocation is carried out after the patient is found to be eligible at the time of visit. The subjects are administered the drug for a total of 24 weeks.

[0070] The subjects are administered the blinded drug (orally) as follows: · Investigational drug: GnRH agonist and 40 mg of estetrol (E4) per day; · Placebo: GnRH agonist and placebo.

[0071] The drug needs to be taken between 8:00 - 10:00 am. All patients are simultaneously administered a prophylactic dose of dabigatran (220 mg once a day) or another anticoagulant.

[0072] A total of 30 patients are dosed as follows: 20 patients in the estetrol group and 10 patients in the reference treatment group (placebo).

[0073] The primary objective is to evaluate the impact of the addition of E4 on total T and free T. The secondary objectives are the evaluation of the impact of E4 on SHBG, PSA response, and lipids and lipoproteins.

[0074] Other secondary objectives include the impact of E4 on the health-related quality of life of prostate cancer patients during ADT (using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EORTC QLQ-C30 (version 3.0) and the Short-Form Expanded Prostate Index (EPIC 26)), and the evaluation of the impact on hot flashes and bone turnover (bone markers and DEXA measurements).

[0075] Daily administration of estetrol at the prescribed dose is shown to be an effective treatment for improving the effectiveness and quality of life of ADT for prostate cancer.

[0076] Example 4: Effects of estetrol on testosterone suppression and quality of life in prostate cancer patients undergoing androgen deprivation therapy Male patients with histologically confirmed adenocarcinoma of the prostate and eligible to receive androgen deprivation therapy (ADT: GnRH agonist) participate in a randomized placebo-controlled trial. Random assignment is done after the patient is found to be eligible at the time of visit. The subjects are administered the drug for a total of 24 weeks.

[0077] The subjects are administered blinded drugs: · Investigational drug: GnRH agonist and 40 mg of estetrol monohydrate (E4) orally per day; · Placebo: GnRH agonist and placebo. The selection of the GnRH agonist is left to the physician treating the individual patient. The drugs are taken between 8:00 and 10:00 in the morning.

[0078] A total of 60 patients are dosed as follows: 40 patients in the estetrol group and 20 patients in the reference treatment group (placebo).

[0079] Evaluate the effects of the drug on total T, free T, SHBG, hot flashes, PSA response, endocrine parameters, adrenal androgens, and lipid profile. Further evaluate the effects on health-related quality of life (by using the Functional Assessment of Cancer Therapy - Prostate (FACT-P) questionnaire and a simple questionnaire regarding the presence or absence of endocrine-related symptoms (Q-man questionnaire)) and bone turnover (bone markers).

[0080] Oral administration of 40 mg of estetrol daily is found to improve the effectiveness of ADT and improve the quality of life of prostate cancer patients.

Claims

1. An estetrol component for use in treating prostate cancer in a patient, the estetrol component being selected from estetrol; esters of estetrol in which at least one hydroxyl hydrogen atom is replaced with an acyl group of a carboxylic acid, sulfonic acid, or sulfamic acid having 1 to 25 carbon atoms; and combinations thereof, the treatment comprising androgen deprivation therapy and simultaneous oral administration of at least 20 mg of the estetrol component per day for at least 4 weeks.

2. 2. The estetrol component for use according to claim 1, wherein the androgen deprivation therapy comprises the administration of an androgen inactivator selected from GnRH agonists, GnRH antagonists, antiandrogens and combinations thereof.

3. The estetrol component for use according to claim 2, wherein the androgen deprivation therapy comprises administration of a GnRH agonist.

4. 3. The estetrol component for use according to claim 2, wherein the androgen deprivation therapy comprises oral administration of a dosage unit comprising a GnRH antagonist or an antiandrogen together with the estetrol component.

5. The estetrol component for use according to any one of claims 1 to 4, wherein the estetrol component is administered simultaneously in a daily dose of 80 mg or less.

6. 6. The estetrol component for use according to claim 5, wherein the estetrol component is administered simultaneously in a daily dose of 60 mg or less.

7. The estetrol components for use according to any one of claims 1 to 6, wherein the estetrol components are administered simultaneously once a day for at least 12 weeks.

8. The estetrol component for use according to any one of claims 1 to 7, wherein the estetrol component is estetrol.

9. 1. A pharmaceutical dosage unit adapted for oral administration, comprising, as a first active ingredient, 20 to 80 mg of an estetrol component selected from estetrol, esters of estetrol in which at least one hydrogen atom of the hydroxyl group is replaced with an acyl group of a carboxylic acid, a sulfonic acid, or a sulfamic acid having 1 to 25 carbon atoms, and combinations thereof; and, as a second active ingredient, an androgen deactivator selected from a GnRH agonist, a GnRH antagonist, an antiandrogen, and combinations thereof.

10. 10. The pharmaceutical dosage unit of claim 9, wherein the estetrol component is estetrol.

11. 11. The pharmaceutical dosage unit of claim 9 or 10, wherein the dosage unit contains 60 mg or less of the estetrol component.

12. A pharmaceutical dosage unit according to any one of claims 9 to 11, wherein the androgen inactivator is a GnRH agonist or an antiandrogen.

13. 1. A kit comprising: a first pharmaceutical composition comprising an androgen inactivator selected from a GnRH agonist, a GnRH antagonist, an antiandrogen, and combinations thereof; and a second pharmaceutical composition suitable for oral administration comprising 20 to 80 mg of an estetrol component selected from estetrol, esters of estetrol in which at least one hydroxyl hydrogen atom is replaced with an acyl group of a carboxylic acid, sulfonic acid, or sulfamic acid having 1 to 25 carbon atoms, and combinations thereof, together with instructions for use in a method for treating prostate cancer.

14. 14. The kit of claim 13, wherein the estetrol component is estetrol.

15. 15. The kit of claim 13 or 14, wherein the second pharmaceutical composition comprises 60 mg or less of the estetrol component.

16. The kit of any one of claims 13 to 15, wherein the androgen inactivator is a GnRH agonist.

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