Darolutamide in combination with BRAF and MEK inhibitors for melanoma treatment

Abstract

The present invention relates to combinations of an AR inhibitor and one or more MAPK signalling inhibitor(s) like BRAF inhibitor and / or MEK inhibitors and the use of said combinations for the treatment or prophylaxis of diseases, in particular of skin melanoma, as a sole combination or in combination with other active ingredients.

Description

The present invention relates to triple pharmaceutical combinations of component A (androgen receptor (AR) inhibitor or AR degrader), component B (inhibitor of Serine / threonine-protein kinase B-RAF (BRAF)) and component C (mitogen-activated protein kinase kinase (MEK) inhibitor) and its use in treating cancer, particularly melanoma. More specifically the invention relates to: • combinations of: o a component A: which is an androgen receptor (AR) inhibitor, such as darolutamide, or enzalutamide or apalutamide or proxalutamide or bicalutamide, or an AR degrader such as bavdegalutamide (ARV-110) or luxdegalutamide (AR-766); o a component B: which is an inhibitor of serine / threonine-protein kinase B-RAF (BRAF), such as dabrafenib or vemurafenib or encorafenib; and / or, o a component C: which is a mitogen-activated protein kinase kinase (MEK) inhibitor, such as trametinib, or selumetinib or cobimetinib or binimetinib; o and optionally one or more pharmaceutical agents D; in which optionally either or both or three of said components A, B and C are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially; • use of such combinations: o in the treatment of a cancer, particularly melanoma, or o for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly melanoma; • methods of treatment or prophylaxisof a cancer, particularly melanoma, in a subject, comprising administering to said subject a therapeutically effective amount of such a combination; • compositions containing such a combination, together with pharmaceutically acceptable ingredients; and • kits comprising such a combination. Component A may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. Component B may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. Component C may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. Component D may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. BACKGROUND TO THE INVENTION Melanoma is a prevalent cause of cancer worldwide with 97,610 estimated new cases in the United States in 2023, where it is the fifth most frequent tumor type (R.L. Siegel et al., CA Cancer J Clin, 2023, 73:17-48). Substantial progress has been made in identifying environmental and hereditary causes of melanoma. Also, new targeted therapies have been developed in recent years and the current 5-year relative survival rate is 94%. There is nonetheless a high need for additional therapeutic modalities which significantly prolong progression-free and overall survival in patients. Following confirmation of the disease with the help of a skin and lymph node biopsy, melanoma can be removed by surgery. Chemotherapy drugs are used for treatment of metastatic disease but their impact is limited. Targeted therapies have more recently been developed to address oncogenic mutations in melanoma, mainly those found in BRAF, NRAS and C-KIT (G Ponti et al, Anticancer Res, 2017, 37:7043; EJ Davis, Cancer, 2018, 124:3490-3499; MA Gouda and V Subbiah, ESMO Open, 2023, 8:100788). BRAF mutations, mainly V600E, are observed in about 70% of cases and several specific inhibitors including dabrafenib, vemurafenib, and encorafenib are now approved (KT Flaherty, Pigment Cell Melanoma Res, 2023, 36:563-575; MA Gouda and V Subbiah, ESMO Open, 2023, 8:100788). BRAF is part of the mitogen-activated protein kinase (MAPK) pathway, an essential signalling pathway activated by several growth factors and involved in cell growth, proliferation and survival (R Ullah et al, Semin Cancer Biol, 2022,85:123-154). Beside melanoma, BRAF is also frequently mutated in thyroid cancer, with the hotspot V600E mutation being found in 60% of papillary cancer forms and in 45% of anaplastic cancer forms (L Schubert et al, Cancers, 2023, 15:710). Other important kinases of the MAPK pathway are the mitogen-activated protein kinase kinase MEK1 and MEK2, which are immediately downstream of BRAF, and thereafter collectively named MEK (R Ullah et al, Semin Cancer Biol, 2022,85:123-154). Combining a BRAF inhibitor with a MEK inhibitor such as dabrafenib shows superior efficacy (M Wahid et al, Crit Rev Oncol Haematol, 2018, 125:84-88). NRAS mutations are found in about 19 % of melanoma patients but they are difficult to address directly so that other approaches such as MEK inhibitors including trametinib, cobimetinib, selumetinib, and binimetinib have been evaluated (MF Fernandez, Cancers, 2023, 15:3224). C-KIT mutations are found in about 11% of melanoma patients and first clinical studies with imatinib, a drug that targets C-KIT and Abi look promising (L Si and J Guo, Curr Opin Oncol, 2013, 25:160-165). Checkpoint inhibitors have also proven efficient in treating melanoma patients. Approved and clinically evaluated monoclonal antibodies include ipilimumab and tremelimumab against CTLA-4, nivolumab, pembrolizumab, cemiplimab and spartalizumab against PD-1, and durvalumab, avelumab and atezolizumab against PD-L1 (AM Gorabi, Int Immunopharmacol, 2022, 113:109300). An important characteristic of melanoma is that its incidence, mortality rate and response to treatment varies between men and women. Several studies show that melanoma susceptibility and mortality are higher in men than in women (A Nosrati and ML Wei, Arch Biochem Biophys, 2014, 563:42-50; MR Schwartz et al., Curr Epidemiol Rep, 2019, 6:112-118). Yearly increase trends have altogether stabilized since 2015. However, whereas melanoma rates declined by about 1% per year in men, they were stable in women younger than 50 years but increased by about 1% per year in older women (R.L. Siegel et al., CA Cancer J Clin, 2023, 73:17-48). Other studies report that response to targeted treatments differs between men and women. Several clinical trials show that men with metastatic melanoma who are treated with BRAF / MEK inhibitors have a significantly worst survival probability than women (RN Amaria, Lancet Oncol, 2018, 19:181-193; C Robert et al, N Engl J Med, 2019, 381:626-636; CP Vellano et al, Nature, 2022, 606:797-803; L Pala, Semin Oncol, 2023, 50:34-39). On the other hand, men with advanced melanoma have a better response to immunotherapy than women (K Kudura, Cancers, 2022, 14:5145). Altogether, these data show sex-specific differences in the incidence of melanoma and the response to targeted therapies, which suggests that steroid receptor signalling may be involved. Beside melanoma, MAPK pathway inhibitors, more specifically BRAF inhibitors combined with MEK inhibitors, are approved for non-small cell lung cancer (NSCLC) and anaplastic thyroid cancer (JJ Adashek, Mol Cancer Ther, 2022, 21:871-878). Several other cancer indications show clinical response to MAPK inhibition, that is to BRAF inhibitors as monotherapy or in combination with MEK inhibitors, including biliary tract cancer, colorectal cancer, hairy cell leukemia, high-grade glioma, low-grade glioma, (MA Gouda and V Subbiah, ESMO Open, 2023, 8:100788). MAPK inhibition by combining the BRAF inhibitor dabrafenib and the the MEK inhibitor is now approved for tissue-agnostic therapy of cancer patients harboring the BRAF V600E mutation (MA Gouda and V Subbiah, ESMO Open, 2023, 8:100788). Several new reports show that AR function plays an essential role in melanoma growth and in the resistance to approved therapies. Preclinical studies reveal that sustained AR expression is essential for melanoma growth whereas loss or inhibition of activity is followed by reduced proliferation and increased infiltration of immune cells (M Ma et al, J Exp Med, 2021, 218:e20201137). AR inhibition improves the response to BRAF / MEK inhibitors in male and female mice harboring a melanoma model whereas stimulation of AR activity has the opposite effect (CP Vellano, Nature, 2022, 606:797-803). Melanoma cells turning resistant to BRAF inhibition have elevated AR expression and enrichment of the WO 2025 / 146444                                   PCT / EP2025 / 050017 downstream signalling pathway (A Samarkina, Nat Common, 2023:14:6498). Also, AR activity reduces the impact of immune checkpoint inhibitors by preserving the stem cell state and promoting the exhaustion of CD8+ T cells (X Guan et al, Nature, 2022, 606:791-796; H Kwon et al, Sci Immunol, 2022, 7:eabq2630; C Yang et al, Immunity, 2022, 55:1268-1283). All these new studies strongly suggest that the AR pathway plays an essential role in the sex differences observed in melanoma incidence and in the response to approved treatments, including MARK inhibitors. It is therefore desirable to demonstrate that adding an AR inhibitor to drugs targeting the MARK pathway leads to superior efficacy in controlling melanoma cell proliferation. AR inhibitors such as darolutamide are approved for prostate cancer and MARK pathway inhibitors are approved for melanoma. However, the state of the art does not disclose the combinations of the AR inhibitor darolutamide with specific MARK pathway inhibitors for melanoma treatment. SUMMARY OF THE INVENTION Surprisingly, it was observed that by administering darolutamide together with MARK pathway inhibitors, more specifically the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, a superior anti-proliferative effect could be achieved in vivo in a melanoma model implanted on male or female mice. Hence, in accordance with a first aspect, the present invention relates to: • combinations of: o a component A: which is an AR inhibitor, such as darolutamide, or a salt thereof, in particular a physiologically acceptable salt; o a component B: which is an BRAF inhibitor, such as dabrafenib, or a salt thereof, in particular a physiologically acceptable salt for example; and, optionally, o a component C: which is a MEK inhibitor, such as trametinib, or a salt thereof, in particular a physiologically acceptable salt for example; and, optionally o one or more pharmaceutical agents D; in which optionally either or both or all three of said components A, B and C are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. In accordance with a second aspect, the present invention relates to • use of such combinations according to the first aspect of the present invention: o in the treatment or prophylaxis of a cancer, particularly melanoma, or o for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly melanoma. In accordance with a third aspect, the present invention relates to: • methods of treatment or prophylaxisof a cancer, particularly melanoma, in a subject, comprising administering to said subject a therapeutically effective amount of such combinations according to the first aspect of the present invention. In accordance with a fourth aspect, the present invention relates to: • compositions containing such a combination, together with pharmaceutically acceptable ingredients. In accordance with a fifth aspect, the present invention relates to: • kits comprising such combinations according to the first aspect of the present invention. WO 2025 / 146444                                   PCT / EP2025 / 050017 In the second and third aspects, component A may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route, component B may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route, and component C may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. A further aspect of the invention is component A, component B and component C for the use in a method of treatment or prophylaxis of a cancer, particularly melanoma, characterized by the BRAF V600 mutation in a subject. In particular, the invention refers to the use of component A, component B and component C for the treatment and / or prophylaxis of a cancer, particularly melanoma, characterized by the BRAF V600 mutation. Furthermore, the invention refers to a pharmaceutical combination comprising component A, component B and component C for use in a method of treating and / or prophylaxis of a cancer, particularly melanoma, characterized by the BRAF V600 mutation in a subject. In particular, said pharmaceutical formulation comprising component A, component B and component C is further in combination with an inert, nontoxic, and / or pharmaceutically suitable adjuvant for use in a method of treating and / or prophylaxis of a cancer, particularly melanoma, characterized by the BRAF V600 mutation. A further aspect of the invention refers to component A, component B and component C for the use in a method of treating a subject diagnosed with a cancer, particularly melanoma, characterized by BRAF V600 mutation said method comprising the steps: 1. assaying a sample, preferably a tumor cell's sample or blood's sample, from the subject by an immunohistochemical method and 2. determining if BRAF V600 mutation and 3. administering a therapeutically effective amount of Component A, component B and component C if BRAF V600 mutation is determined positively. The invention further refers to the use of Component A, component B and component C in the manufacture of a medicament for treating a cancer, particularly melanoma, wherein the subject has been determined to be identified by a method as described above. The invention also refers to the use of Component A, component B and component C in the manufacture of a medicament for a method of treatment of a cancer, particularly melanoma, in a subject said method comprising the steps a) assaying a sample, preferably a tumor cell's sample or blood's sample, from the subject by an immunohistochemical method and b) determining if BRAF V600 mutation and c) administering a therapeutically effective amount of "compound" if BRAF V600 mutation is determined positively. A method of treating a cancer, particularly melanoma characterized by the BRAF V600 mutation in a subject comprising administering a therapeutically effective amount of Component A, component B and component C to the subject is also part of the present invention. More particularly the invention also refers to a method of treating a cancer, particularly melanoma in a subject comprising: a) determining or having determined that said cancer of said subject is characterized by the BRAF V600 mutation; and b) administering a therapeutically effective amount of the Component A, component B and component C to said subject. More in detail said method is comprising: WO 2025 / 146444                                   PCT / EP2025 / 050017 a) obtaining or having obtained a sample, preferably a tumor cell's sample or blood's sample, from said subject; b) performing or having performed an immunohistochemical method on said sample; c) selecting or having selected a subject having a cancer, particularly melanoma characterized by the BRAF V600 mutation; and d) administering a therapeutically effective amount of the Component A, component B and component C to said subject having a cancer, particularly melanoma, characterized by the BRAF V600 mutation. According to the invention the BRAF V600 mutation is determined preferably by an immunohistochemical method on sample, preferably a tumor cell's sample or blood's sample. In accordance with to all different aspect of the invention as identified above the relates to a combination comprising a further component D as mentioned herein According to all different aspect of the invention as identified above the components are administered independently of one another through the same or through different administration routes, particularly by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. Furthermore, according to all different aspect of the invention as identified above, the components or their pharmaceutical formulation are administered independently with the same or a different administration regime, independently once or more times daily. Furthermore, the components or their pharmaceutical formulation are administered simultaneously, concurrently, separately or sequentially. According to all different aspect of the invention as identified above, in the above mentioned aspect Component A is darolutamide, enzalutamide, apalutamide, proxalutamide or bicalutamide, compound B is dabrafenib, vemurafenib or encorafenib and compound C is trametinib, selumetinib, cobimetinib, or binimetinib. According to all different aspect of the invention as identified above, preferably component A is darolutamide, compound B is dabrafenib and compound C is trametinib. According to all different aspect of the invention as identified above the BRAF mutation is particularly a BRAF V600E mutation. DETAILED DESCRIPTION OF THE INVENTION Component A Component A concists of one or more pharmaceutical agents that block androgen function. Such pharmaceutical agents block androgen receptor function by binding in its androgen-binding pocket or in its DNA-binding region or in the N-terminal domain or prevent AR expression or destabilize AR protein. Common examples of component A are for instance darolutamide, enzalutamide, apalutamide, proxalutamide or bicalutamide. Further examples are bavdegalutamide (ARV-110) or luxdegalutamide (AR-766). Component A is for example the AR inhibitor darolutamide. Darolutamide (ODM-201) is a high-affinity AR inhibitor with low nanomolar binding affinity for the AR and high inhibition of transactivation function (AM Moilanen et al, Sci Rep, 2015, 5:12007). Darolutamide (ODM-201) was obtained from Orion Pharma, Turku, Finland. Component A can also be selected from inhibitors of AR specifically or generically disclosed e.g. in the following publications: enzalutamide (MDV3100; C Tran et al, Science, 2009, 324:787-790), apalutamide (ARN-509; NJ Clegg et al, Cancer Res, 2012, 72:1494-1503), proxalutamide (F Qu et al, Invest New Drugs, 2020, 38:1292-1302), bicalutamide (ICI 176,334; BJ Furr et al, J Endocrinol, 1987, 113:R7-R9). ). Component A can also be selected from other AR competitive inhibitors including flutamide, bicalutamide, nilutamide, rezvilutamide (QD Xia et al, Biomed Pharmacother, 2023,168:115806). Component A can also be selected from AR degraders specifically or generically disclosed e.g. in the following publications: bavdegalutamide (ARV-110), luxdegalutamide (ARV-766) (ND Shore et al, J Clin Oncol, 2022, 40:16 suppl TPS5106; DP Petrylak et al, J Clin Oncol, 2023, 41:6 suppl TPS290); CC-94676 or AC-0176; HP-518; (X Jia and X Han, Biomed Pharmacother, 2023, 158:114112); RO7656594 / GDC-2992 (Clinical trial NCT05800665); ONCT-534 / UT-34 (S Ponnusamy et al, Clin Cancer Res, 2019, 25:6764-6780). Component A can also be selected from agents-targeting AR splice variants including UT-143 (T Thiyagarajan et al, Proc Natl Acad Sci, 2023,120:e2211832120), VPC-220010 (F Ban et al, Cancers, 2021, 13:3488) MTX-23 (GT Lee et al, Mol Cancer Ther, 2021, 20:490-499), ralatinen (CA Banuelos et al, Cancers, 2020, 12:1991) or EPI-7170 (Y Hirayama et al, Mol Oncol, 2020, 14:2455-2470). Component A can also be selected from agents targeting the AR DNA-binding domain including VPC-17160 and VPC-17281 (M Radaeva et al, Int J Mol Sci, 2021, 22:2493), Cpd39 (JP Pang et al, Acta Pharmacol Sin, 2022, 43:229-239). Component A can also be selected from agents targeting AR dimerization including DIM20 compounds (C Helsen et al, Mol Cancer Ther, 2022, 21:1823-1834) and VPC-17005 (K Dalal et al, Cancer Lett, 2018, 437:35-43). Component B Component B consists of one or more pharmaceutical agents that inhibit serine / threonine-protein kinase B-RAF (BRAF). It can be an ATP-competitive or an allosteric inhibitor of B-RAF (BRAF). Common examples of component B are for instance dabrafenib, vemurafenib or encorafenib. Component B blocks the MAPK signalling pathway and is a BRAF inhibitor, such as dabrafenib for example. Dabrafenib is an ATP-competitive and reversable inhibitor of BRAF V600E and V600K (GSK2118436; DS Hong et al, Clin Cancer Res, 2012, 18:2326-2335; AM Menzies et al, Drug Des Devel Ther, 2012, 6:391405). Component B can be selected from BRAF inhibitors specifically or generically disclosed e.g. in the following publications: vemurafenib (PLX4032; E Sala, Mol Cancer Res, 2008, 6:751-759), encorafenib (LGX818, Z Li, Cancer Lett, 2016, 370:332-344). ). Component B can also be selected from other BRAF inhibitors including sorafenib, BI-882370, XL-281, MLN-2480, LY-3009120, CEP-32496, BAL-3833, BGB-283, PLX-8394, and RAF-265 (AK Singh et al, ACS Omega, 2023, 8:27819-27844). Component C Component C concists of one or more pharmaceutical agents that inhibit mitogen-activated protein kinase kinase (MEK) inhibitor, especially MEK1. It can be an ATP-competitive or an allosteric inhibitor of MEK or MEK1. Common examples of component C are for instance trametinib, selumetinib, cobimetinib or binimetinib. Component C blocks the MAPK signalling pathway and is a MEK inhibitor, such as trametinib for example. Trametinib (GSK1120212) is an allosteric inhibitor of MEK1 and MEK2 which prevents phosphorylation of MEK1 S217 and enhances p-ERKl / 2 inhibition (AG Gilmartin, Clin Cancer Res, 2011, 17:989-1000). Component C can be selected from MEK inhibitors specifically or generically disclosed e.g. in the following publications: selumetinib (AZD6244; TC Yeh et al, 2007, 13:1576-1583), cobimetinib (GDC-0973; KD Rice, ACS Med Chern Lett, 20212, 3:416-421), binimetinib (MEK162, J Thumar, Mol Cancer, 2014,13:45). Component C can also be selected from other MEK inhibitors including tunlametinib (Y Liu, Front Pharmacol, 2023,14:1271268), CI-1040 / PD184352, mirdametinib, AZD-8330, TAK-733, GDC-0623, refametinib, pimasertib, RO4987655, RO5126766, EBI-1051, DPS-2, KZ-001, KZ-02, BI-847325, and URML-3881 (T Ram et al, RSC Med Chern, 2023, 14:1837-1857). In accordance with an embodiment, the present invention relates to a combination of any component A mentioned herein with any component B mentioned herein with any component C mentioned herein, and optionally with any component D mentioned herein. Component D consists of one or more pharmaceutical agents approved for human treatment, particularly those pharmaceutical agents approved for cancer treatment. In one embodiment WO 2025 / 146444                                   PCT / EP2025 / 050017 component A of the combination is the AR inhibitor used in the experimental section, component B is a BRAF inhibitor, such as dabrafenib for example being used in the experimental section, component C is a MEK inhibitor, such as trametinib for example being used in the experimental section. In a particular embodiment, the present invention relates to a combination of a component A with a component B, optionally with a component C, optionally with a component D, as mentioned in the Examples Section herein. Further, the present invention relates to a kit containing: • a combination of: o a component A : which is an AR inhibitor, such as darolutamide ; o a component B : which is a BRAF inhibitor, such as dabrafenib for example ; and, optionally o a component C: which is a MEK inhibitor, such as trametinib for example ; and, optionally, o one or more pharmaceutical agents D ; in which optionally either or both of said components A, B and C are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The term "component D" being at least one pharmaceutical agent includes the effective compound itself as well as its pharmaceutically acceptable salts, solvates, hydrates or stereoisomers as well as any composition or pharmaceutical formulation comprising such effective compound or its pharmaceutically acceptable salts, solvates, hydrates or stereoisomers. A list of such readily available agents is being provided further below. The components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. Component A is administered intravenously, intraperitoneally, preferably it is administered orally. Component B is administered intravenously, intraperitoneally, preferably it is administered orally. Component C is administered intravenously, intraperitoneally, preferably it is administered orally. Component D being administered as the case may be. The term "pharmaceutically acceptable" is used synonymously to the term "physiologically acceptable". The term "pharmaceutically or physiologically acceptable salt" of component A refers to a relatively nontoxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see SM Berge et al, J Pharm Sc, 1977, 66:1-19. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods. Representative salts of a component A, B, C or d of this invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, or butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl sulfate, or diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. A solvate for the purpose of this invention is a complex of a solvent and a compound of the invention in the solid state. Exemplary solvates would include, but are not limited to, complexes of a compound of the invention with ethanol or methanol. Hydrates are a specific form of solvate wherein the solvent is water. Compositions (formulations) of the present invention Components of this invention can be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both. Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present. Components of this invention can also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soybean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin. WO 2025 / 146444                                   PCT / EP2025 / 050017 Syrups and elixirs can be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents. Components of this invention can also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-l,l-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants. Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures. The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a nonionic surfactant having a hydrophile-lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB. Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The pharmaceutical compositions can be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this WO 2025 / 146444                                   PCT / EP2025 / 050017 purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables. Components of the invention can also be administered in the form of suppositories for rectal administration of the drug. These components can be prepared by mixing the drug with a suitable nonirritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol. Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 11, 1991, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art. It can be desirable or necessary to introduce a component of the present invention to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,011,472, issued April 30, 1991. The compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: MF Powell et al, PDA J Pharm Sci Technol, 1998, 52:238-311; RG Strickley, PDA J Pharm Sci Technol, 1999, Part I, 53:324-349; and S Nema et al, PDA J Pharm Sci Technol, 1997, 51:166-171. Commonly used pharmaceutical ingredients that can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CCI2F2, F2CIC-CCIF2 and CCIF3) air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); WO 2025 / 146444                                   PCT / EP2025 / 050017 binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene-butadiene copolymers); buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate) carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection) chelating agents (examples include but are not limited to edetate disodium and edetic acid) colorants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas) plasticizers (examples include but are not limited to diethyl phthalate and glycerol); solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)); surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate); suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples include but are not limited to magnesium stearate and talc); WO 2025 / 146444                                   PCT / EP2025 / 050017 tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch); tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc); tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet / capsule opaquants (examples include but are not limited to titanium dioxide); tablet polishing agents (examples include but are not limited to carnuba wax and white wax); thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin); tonicity agents (examples include but are not limited to dextrose and sodium chloride); viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate). Pharmaceutical compositions according to the present invention can be illustrated as follows: Sterile IV Solution: A 5 mg / mL solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg / mL with sterile 5% dextrose and is administered as an IV infusion over about 60 minutes. Lyophilized powder for IV administration: A sterile preparation can be prepared with (i) 100 -1000 mg of the desired compound of this invention as a lyophilized powder, (ii) 32- 327 mg / mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg / mL, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg / mL, and is administered either IV bolus or by IV infusion over 15 - 60 minutes. Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection: 50 mg / mL of the desired, water-insoluble compound of this invention 5 mg / mL sodium carboxymethylcellulose 4 mg / mLTWEEN 80 9 mg / mL sodium chloride 9 mg / mL benzyl alcohol Hard Shell Capsules: A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate. Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix. Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and nonaqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption. Immediate Release Tablets / Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid-state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water. Commercial utility of the present invention Component A Darolutamide and other AR inhibitors are referred to above as components A. The compounds according to the combination have valuable pharmaceutical properties, which make them commercially utilizable. In particular, they inhibit AR function and the downstream pathway, and exhibit cellular activity. They are expected to be commercially applicable in the therapy of diseases (e.g. diseases dependent on AR signalling). The AR pathway is an essential step towards the initiation and maintenance of prostate cancer and other AR-dependent tumors, and thus its inhibition, for example with AR inhibitors, is understood to be a valid approach for treatment of human prostate cancer and other AR-dependent tumors. For a recent review see SJ Baumgart et al, Int J Mol Sci, 2019, 20:2883. Components B and C are inhibitors of the MARK signalling pathway. Component B Dabrafenib and other BRAF inhibitors are referred to above as components B. Due to the mechanism as discussed in the introductory section component B is especially suitable to have effects on tumor diseases, especially those developing resistance mechanism via antiapoptotic pathways or cell cycle activation. The compounds according to the combination have valuable pharmaceutical properties, which make them commercially utilizable. In particular, they inhibit BRAF function and the downstream pathway, and exhibit cellular activity. They are expected to be commercially applicable in the therapy of diseases (e.g. diseases dependent on BRAF signalling). The BRAF pathway is an essential step towards the initiation and maintenance of human tumors and thus its inhibition, for example with BRAF inhibitors, is understood to be a valid approach for treatment of human tumors. For recent reviews see I Proietti et al, Cancers, 2020, 12:1823 and AK Singh et al, ACS Omega, 2023, 8:27819-27844. Component C Trametinib and other MEK inhibitors are referred to above as components C. Due to the mechanism as discussed in the introductory section component C is especially suitable to have effects on tumor diseases, especially those developing resistance mechanism via antiapoptotic pathways or cell cycle activation. The compounds according to the combination have valuable pharmaceutical properties, which make them commercially utilizable. In particular, they inhibit MEK function and the downstream pathway, and exhibit cellular activity. They are expected to be commercially applicable in the therapy of diseases (e.g. diseases dependent on MEK signalling). The MEK pathway is an essential step towards the initiation and maintenance of human tumors and thus its inhibition, for example with MEK inhibitors, WO 2025 / 146444                                   PCT / EP2025 / 050017 is understood to be a valid approach for treatment of human tumors. For a recent review see T Ram et al, RSC Med Chern, 2023, 14:1837-1857. Component D Due to the mechanism as discussed in the introductory section component D is especially suitable to have effects on tumor diseases, especially those developing resistance mechanism via antiapoptotic pathways or cell cycle activation. Combination The combinations of the present invention thus can be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, such as, for example, haematological tumors and / or metastases thereof, solid tumors, and / or metastases thereof, e.g. leukaemias, multiple myeloma thereof and myelodysplastic syndrome, malignant lymphomas, breast tumors including and bone metastases thereof, tumors of the thorax including non-small cell and small cell lung tumors and bone metastases thereof, gastrointestinal tumors, endocrine tumors, mammary and other gynaecological tumors and bone metastases thereof, urological tumors including renal, bladder and prostate tumors, skin tumors, and sarcomas, and / or metastases thereof. One embodiment relates to the use of a combination as defined herein for the preparation of a medicament for the treatment or prophylaxis of a cancer, in particular melanoma. One embodiment relates to the use of a combination as defined herein in the treatment or prophylaxis of a cancer, in particular melanoma. In one embodiment the invention relates to combinations comprising component A or a pharmaceutically acceptable salt thereof and component B being intravenously, intraperitoneally, preferably it is administered orally and component C being intravenously, intraperitoneally, preferably it is administered orally and component D being intravenously, intraperitoneally, preferably it is administered orally. The term "inappropriate" within the context of the present invention, in particular in the context of "inappropriate cellular immune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as preferably meaning a response which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases. Combinations of the present invention might be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and / or cell division, and / or produce apoptosis. This invention includes a method comprising administering to a mammal in need thereof, including a human, an amount of a component A and an amount of component B of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc. and an amount of component C of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc., and an amount of component D of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc., which is effective to treat the disorder. Hyper-proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), as well as malignant neoplasia. Examples of malignant neoplasia treatable with the compounds according to the present invention include solid and hematological tumors. Solid tumors can be exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, anum, endocrine glands (e.g. thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva. Malignant neoplasias include inherited cancers exemplified by Retinoblastoma and Wilms tumor. In addition, malignant neoplasias include primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases"). Hematological tumors can be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown primary site as well as AIDS related malignancies. Examples of malignant melanoma include, but are not limited to superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, mucosal melanoma, desmoplatic melanoma, melanoma with small cell nevus-like cells, melanoma with features of a Spitz nevus, uveal melanoma, vaginal melanoma, polypoid melanoma. Additional examples of skin cancers include, but are not limited to basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer and non-melanoma skin cancer. Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ, particularly with bone metastases. Examples of cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma. Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor. Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus. Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers. Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers. Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma. Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma. Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system. Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention. The term "treating" or "treatment" as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma. WO 2025 / 146444                                   PCT / EP2025 / 050017 Combinations of the present invention might also be used for treating disorders and diseases associated with excessive and / or abnormal angiogenesis. Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity (LP Aiello et al, New Engl J Med, 1994, 331, 1480-1487; J Peer et al, Lab Invest, 1995, 72:638-645), age-related macular degeneration (AMD; see PF Lopez et al, Invest Opththalmol Vis Sci, 1996, 37:855-868), neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumor enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, combinations of the present invention can be utilized to treat and / or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and / or reducing blood vessel formation ; by inhibiting, blocking, reducing, decreasing, endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types. Dose and administration of the present invention Component A, component B, component C and component D Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredients to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular component and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated. The total amount of the active ingredients to be administered will generally range from about 0.001 mg / kg to about 200 mg / kg body weight per day, and preferably from about 0.01 mg / kg to about 20 mg / kg body weight per day. Clinically useful dosing schedules of a compound will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg / kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg / kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg / kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg / kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg / kg of total body weight. Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compounds employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests. WO 2025 / 146444                                   PCT / EP2025 / 050017 Combinations of the present invention The combinations of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumor growth and metastases, including solid and haematological tumors of all indications and stages with or without pre-treatment of the tumor growth. Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art. The combinations of component A, component B, component C and optionally component D of this invention can be administered as the sole pharmaceutical agent or in combination with one or more further pharmaceutical agents D where the resulting combination of components A, B, C, and D causes no unacceptable adverse effects. For example, the combinations of components A, B and C of this invention can be combined with component D, i.e. one or more further pharmaceutical agents, such as known anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agents, and the like, as well as with admixtures and combinations thereof. Component D, can be one or more pharmaceutical agents such as 1311-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan,  mepitiostane,  mercaptopurine, mesna,  methadone, methotrexate,  methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin,   mitobronitol,   mitoguazone,   mitolactol, mitomycin, mitotane,   mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant / palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymethoIone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEGepoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib, rucaparib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin, or combinations thereof. Alternatively, said component D can be one or more further pharmaceutical agents selected from gemcitabine, paclitaxel, cisplatin, carboplatin, sodium butyrate, 5-FU, doxirubicin, tamoxifen, etoposide, trastumazab, gefitinib, intron A, rapamycin, 17-AAG, U0126, insulin, an insulin derivative, a PPAR ligand, a sulfonylurea drug, an a-glucosidase inhibitor, a biguanide, a PTP-1B inhibitor, a DPP-IV inhibitor, a 11-beta-HSD inhibitor, GLP-1, a GLP-1 derivative, GIP, a GIP derivative, PACAP, a PACAP derivative, secretin or a secretin derivative. Optional anti-hyper-proliferative agents which can be added as component D to the combination of components A, B and C of the present invention include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine. Other anti-hyper-proliferative agents suitable for use as component D with the combination of components A, B and C of the present invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel (when component B is not itself paclitaxel), pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine. Other anti-hyper-proliferative agents suitable for use as component D with the combination of components A, B and C of the present invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan. WO 2025 / 146444                                   PCT / EP2025 / 050017 Generally, the use of cytotoxic and / or cytostatic agents as component D in combination with a combination of components A, B and C of the present invention will serve to: (1) yield better efficacy in reducing the growth of a tumor and / or metastasis or even eliminate the tumor and / or metastasis as compared to administration of either agent alone, (2)     provide for the administration of lesser amounts of the administered chemotherapeutic agents, (3)     provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, (4) provide for treating a broader spectrum of different cancer types in mammals, especially humans, (5)     provide for a higher response rate among treated patients, (6)     provide for a longer survival time among treated patients compared to standard chemotherapy treatments, (8) provide a longer time for tumor progression, and / or (9) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects. FIGURES Figure 1: AR expression in melanoma models and patient biopsies Comparison of AR gene expression profiles in human melanoma cell lines models (A), mouse melanoma tumor models (B) and clinical paired melanoma biopsies (values from the same patient are linked with a line) (C) between the vehicle or baseline groups and the respective on-treatment conditions. Data are from GSE185284 (Fig. 1 Al) Human melanoma cell line models - SKMEL5 BRAF V600E mutant cell line treated with vehicle or 100 nM o rlpM binimetinib for 72 hours; F Grigore et al, Neoplasia, 2020, 22:376-389 (Fig. 1 A2) M14 BRAF V600E mutant cell line untreated or treated with 2 pm vemurafenib for 20 days; JE Long et al, Cell Death Diff, 2019, 26:2416-2429 (Fig. 1 Bl) Tumors from genetically engineered Braf V600E mutant mice untreated or treated with vermurafenib, 50 mg / kg, twice daily, orally; C Song et al, Cancer Discov, 2017, 7:1248-1265 (Fig. 1 B2 - YUMM1.7 Braf V600E mutant syngeneic melanoma from mice treated with vemurafenib, 100 mg / kg, daily orally and Fig. 1 C- Paired biopsies from melanoma patients taken before and during treatment with single or combined BRAF inhibitor and MEK inhibitor). Figure 2: Body weight changes from start of treatment (Male mice). Body weight of male mice treated as indicated. Figure 3: Results of the in vivo efficacy study following treatment of male mice harboring the YU MM 1.7 melanoma model with the indicated treatments. YUMM1.7 tumor growth from start of treatment (Male mice - All treatment arms) Figure 4: Results for the combination groups. YUMM1.7 tumor growth from start of treatment (Male mice -Combination arms) WO 2025 / 146444                                   PCT / EP2025 / 050017 Figure 5: Mean tumor sizes at day 14 (Fig. 5A- YUMM1.7 tumor size on day 14, Male mice, dose groups) and day 16 (Fig. 5B - YUMM1.7 tumor size on day 16, Male mice, dose groups) for the combination treatments with dabrafenib and trametinib; dabrafenib, trametinib and darolutamide; dabrafenib, trametinib and castration. Figure 6: Body weight changes from start of treatment (Female mice). Body weight of female mice treated as indicated. Figure 7 Results of the in vivo efficacy study following treatment of female mice harboring the YUMM1.7 melanoma model. YUMM1.7 tumor growth from start of treatment (Female mice - All treatment arms) Figure 8 Mean tumor sizes at day 17 (Fig. 8A- YUMM1.7 tumor size on day 17, Female mice dose groups) and day 20 (Fig. 8B- YUMM1.7 tumor size on day 20, Female mice dose groups) for the combination treatments with dabrafenib and trametinib (high or low dose); dabrafenib and trametinib (high or low dose) with additional darolutamide. Figure 9 Tumor growth observed in individual female mice following 30-day treatment with high or low dose of dabrafenib and trametinib, and darolutamide. Treatment was stopped for all mice at day 30. YUMM1.7 tumor growth from start of treatment (Female mice) - Fig. 9A Dabrafenib + trametinib (high) + darolutamide; Fig. 9B Dabrafenib + trametinib (low) + darolutamide. Figure 10. Barplot showing Normalized Enrichment Score of the top enriched genesets in comparative gene expression analysis of triple vs. double combination treatment. EXPERIMENTAL SECTION Examples demonstrating the enhanced anti-tumor effect of the combinations of components A, B and C of the present invention 1. Compounds used: • Component A: In this Experimental section and in the Figures, the term "compound A" is : • Darolutamide (ODM-201), which is N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)-lH-pyrazol-l-yl]propan-2-yl}-5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide, of structure : Darolutamide or a solvate, hydrate or stereoisomer thereof. The synthesis of compound A is described in WO2011 / 051540. Darolutamide is an AR inhibitor with nanomolar inhibitory activity in AR transactivation assays (AM Moilanen et al, Sci Rep, 2015, 5:12007). Human androgen receptor, also known as NR3C4 has the gene ID 367, the transcript variant 1 mRNA RefSeq NM_000044.6 and the isoform 1 protein RefSeq NP_000035. or • Component B: In this Experimental Section and in the Figures, the term "compound B" refers to : • Dabrafenib (PLX4032 / GSK2118436), which is N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(2-methyl-2-propanyl)-l,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, of structure : Dabrafenib or a solvate, hydrate or stereoisomer thereof. • Dabrafenib (PLX4032 / GSK2118436) is a high-affinity BRAF inhibitor (EW Joseph et al, Proc Natl Acad Sci USA, 2010, 107:14903-14908); DS Hong et al, Clin Cancer Res, 2012, 18:2326-2335; AM Menzies et al, Drug Des Devel Ther, 2012, 6:391-405). • Dabrafenib is exemplified together with its synthesis in WO2007002433A1. • Human BRAF, also known as B-RAF1 has the gene ID 673, the transcript variant 1 mRNA RefSeq NM_004333.6 and the isoform 1 protein RefSeq NP_004324.2. • Component C: In this Experimental Section and in the Figures, the term "compound C" refers to : • Trametinib (JTP-74057 / GSK1120212), which is acetamide, N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-l(2H)-yl]phenyl], of structure : or a solvate, hydrate or stereoisomer thereof. • Trametinib (JTP-74057 / GSK1120212) is a high-affinity MEK inhibitor (T Yamaguchi et al, Int J Oncol, 39:23-31; AG Gilmartin, Clin Cancer Res, 2011, 17:989-1000). • Trametinib is exemplified together with its synthesis in WO2005121142A1 • Human MEK1, also known as MAP2K1 has the gene ID 5604, the transcript variant mRNA RefSeq NM_002755 and the protein RefSeq NP_002746. • Human MEK2, also known as MAP2K2 has the gene ID 5605, the transcript variant mRNA RefSeq NM_030662 and the protein RefSeq NP_109587. WO 2025 / 146444                                   PCT / EP2025 / 050017 2. Generated data: 2.1 Gene Expression Analysis: A set of datasets with gene expression from human melanoma cell line models, mouse melanoma models and melanoma biopsies from patients was collected to determine AR gene expression levels before and after treatment with a BRAF inhibitor or a MEK inhibitor. Gene expression and sample annotations were downloaded from NCBI Gene Expression Omnibus (E Clough et al, Nucleic Acids Res, 2023, gkad965). Normalized expression data was used as provided. Analysis was done in R statistical software, plotting boxplots and comparing expression levels of AR in vehicle group or at baseline to on-treatment conditions. Wilcoxon test (paired for the human biopsies comparison and unpaired otherwise) was used to calculate p-values. 2.2 Experimental Analysis Efficacy studies were performed with a melanoma tumor model derived from male mouse skin was used (Table 1). This model was obtained from LGC Standards GmbH / ATCC (CRL-3362™) and has the genotype Braf V600E / wt, Pten - / -, Cdkn2- / -. It is described in K Meeth et al, Pigment Cell Melanoma Res, 2016, 29:590-597 Table 1: Cell line Provider Origin YUMM.1.7 ATCC CRL-3362™ Skin of adult male mouse with melanoma 2.2.1 Compounds: Dabrafenib was obtained from Cell Signalling Technology (#91942) and dissolved in 0.5% Hydroxypropylmethylcellulose (HPMC), 0.2% Tween80 in Water For Injection (WFI) with pH 8.8 at a final concentration of 3 mg / mL; Trametinib was obtained from Biozol (1187431-43-1) and dissolved in 0.5% HPMC+0.2% Tween80 in WFI with pH 8.8 at a final concentration of 0.1 mg / mL; Darolutamide was obtained from Orion Corporation and dissolved in PEG400 / propylene glycol / 5%glucose (5 / 3 / 2) at a final concentration of 10 mg / mL. 2.2.2 Cell culture conditions : For the expansion of cells needed for mouse implantation, the YUMM1.7 melanoma cells were seeded in Dulbecco's Modified Eagle's Medium / HAM's F12 medium supplemented with 10% fetal calf serum, 1% Non-Essential Amino Acid. The cells were grown to 95% confluency and split every 3-4 days 1:3 to 1:8. 2.2.3 In vivo studies : Immunocompetent C57BI / 6J male and female mouse were purchased from Janvier Labs at an age of 78 weeks and used for studies after one week of isolation. They were housed in individual ventilated cages (1 per cage after randomization) at a temperature of 20-26 gC, humidity of 30-70%, photoperiod of 12 hours light and 12 hours dark. The mice had free access to irradiation-sterilized dry granule food during the entire study period and free access to sterile drinking water. All procedures were performed according to guidelines approved by the Institutional Animal Care and Use Committee (IACUC) following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). For the tolerability study, 6 to 8-week-old C57BI / 6 male mice were treated orally with a combination of dabrafenib (30 mg / kg, daily) and trametinib (1 mg / kg, daily). Darolutamide was first given at 50 mg / kg daily, then at 100 mg / kg, daily and finally at 100 mg / kg, twice daily. Four animals were used per dose group. Body weight was measured on a daily basis and no tolerability issues occurred (data not shown). For the efficacy study, 2 x 10e5 (male mice) or 1 x 10e5 (female mice) YUMM1.7 cells in 100 pl FBS-free medium were inoculated into the right flank of each mouse. Male animals were randomized on day 14 after inoculation when tumors reached a mean size of 50 mm2 into 6 groups of 10 animals per group. Female animals were randomized on day 12 after inoculation when tumors reached a mean size of 45 mm2 into 6 groups of 10 animals per group. Male mice were dosed orally with a combination of dabrafenib (30 mg / kg, daily) and trametinib (1 mg / kg, daily) and additionally combined with darolutamide (100 mg / kg, twice daily) or castrated. Female mice were dosed orally with a combination of dabrafenib (30 mg / kg, daily, for the high dose; 15 mg / kg, daily, for the low dose) and trametinib (1 mg / kg, daily, for the high dose; 0.5 mg / kg, daily, for the low dose) and additionally combined with darolutamide (100 mg / kg, twice daily). T / C was taken as endpoints to determine when the tumor growth can be delayed or mice can be cured. Tumor size was measured thrice weekly in two dimensions using a caliper, and the volume is expressed in mm2 and mm3. The tumor size is then used for calculation of T / C values. Relative tumor volume could not be calculated as the control group was stopped on day 14 due to attainment of the maximal allowed tumor size. Body weight was measured daily. Statistical analysis: For comparison among three or more groups, a one-way ANOVA and a Kruskal-Wallis test was performed followed by multiple comparison procedures. All data were analyzed using GraphPad Prism 9.1.2. P<0.05 is considered to be statistically significant. 2.3 Differential Gene Expression Analysis: C57BL / 6J male and female mice were inoculated with 0.1 Mio YUMM1.7 cells. Animals were treated for 3 days when tumors reached ~80mm2. Treatment was done in two arms: o BRAF / MEKi (trametinib 1 mg / kg / dabrafenib 30 mg / kg, daily) o BRAF / MEKi (trametinib 1 mg / kg / dabrafenib 30 mg / kg, daily) + Darolutamide (100 mg / kg twice daily) Table 1. Treatment groups and the number of animals per group analyzed: Treatment groups Number of mice Female Male Trametinib+dabrafenib 5 5 Trametinib+dabrafenib+darolutamide 5 6 3 Hours after the last dose animals were sacrificed, tumors isolated, RNA was extracted and sequenced as described previously (Baumgart Mol Oncol. 2020; 14: 2022-2039). Sequencing reads were aligned to the mouse genome GRCm39 with STAR and counts in genes were calculated with RSEM based on Gencode vM34 annotation. Differential expression analysis for protein-coding genes was done using DESeq2 accounting for gender differences (by adding gender as a co-factor in the design formula). We focused the differential gene expression analysis on the differences between triple (Trametinib+dabrafenib+darolutamode) and double (Trametinib+dabrafenib) combination treatment. We found a large (N = 286) number of genes that are differentially expressed between triple and double combination treatments with absolute fold change of 1.5 and FDR < 0.1. This indicates a difference in molecular response in tumors treated with triple vs. double combination, which might potentially explain difference in tumor growth response. Gene Set Enrichment Analysis (GSEA) showed genesets corresponding to cell cycle and proliferation down-regulated in triple combination treatment. On the other hand, genes that are normally downregulated by KRAS are up-regulated by triple combination indicating stronger repression of KRAS signalling in triple combination compared to double (Fig. 10.) Based on the GSEA analysis we selected the list of most affected genes related to cell cycle and KRAS (Tables 2 and 3 respectively) WO 2025 / 146444                                   PCT / EP2025 / 050017 Table 2. Cell cycle genes significantly down-regulated in triple vs. double combination treatment. Gene Symbol Description Hmgalb high mobility group AT-hook IB Cdc20 cell division cycle 20 Pbk PDZ binding kinase Plkl Polo like kinase 1 Cdkn3 Cyclin dependent kinase inhibitor 3 Hmmr Hyaluronan mediated motility receptor Kif4 Kinesin family member 4 Ccna2 cyclin A2 Kif2c Kinesin family member 2C Nek2 NIMA (never in mitosis gene a)-related expressed kinase 2 Ccnb2 Cyclin B2 Prcl Protein regulator of cytokinesis 1 Ube2c Ubiquitin-conjugating enzyme E2C Tpx2 TPX2, microtubule-associated Racgapl Rac GTPase-activating protein 1 Cenpe Centromere protein E Diaph3 Diaphanous related formin 3 Cenpm Centromere protein M Mxd3 Max dimerization protein 3 Melk Maternal embryonic leucine zipper kinase Dlgap5 DLG associated protein 5 Depdcla DEP domain containing la Anin Anillin, actin binding protein Ect2 Ect2 oncogene WO 2025 / 146444                                   PCT / EP2025 / 050017 Table 3. Genes from KRAS downregulated geneset, which are up-regulated in triple combination compared to double combination. Gene Symbol Description Itgblbp2 Integrin beta 1 binding protein 2 Cacngl Calcium channel, voltage-dependent, gamma subunit 1 Nosl Nitric oxide synthase 1, neuronal Smpx Small muscle protein, X-linked Myot Myotilin Ryrl Ryanodine receptor 1, skeletal muscle Efhdl EF hand domain containing 1 2.4 Results : Figure 1 shows normalized AR expression data in melanoma cell lines (A), mouse melanoma models (B), and in paired melanoma biopsies from patients (C). Comparisons were made between the vehicle or baseline groups and the respective on-treatment conditions. The results show significant upregulation of AR expression following treatment with a BRAF inhibitor or a MEK inhibitor. They also show significant upregulation of AR expression in a mouse melanoma syngeneic model that escapes BRAF inhibitor treatment (Fig. 1 B2, right-hand panel). Figure 2 shows the body weight of male mice during the treatment period, as indicated. No significant body weight loss was observed in all treatment groups, the group which lost most body weight was the castrated group, possibly due to the operation. Figure 3 shows the results of the in vivo efficacy study following treatment of male mice harboring the YUMMl.? melanoma model with the indicated treatments: vehicle group; castration; darolutamide; combination of dabrafenib and trametinib; combination of dabrafenib, trametinib and darolutamide; combination of dabrafenib, trametinib and castration. Treatment with darolutamide and surgical castration did not result in tumor growth inhibition compared to the vehicle group. Treatment with different compound combinations resulted in tumor growth inhibition and stasis for 9 to 11 days under continuous dosing. The vehicle, castration and darolutamide groups had to be stopped at day 7 due to tumor size. Figure 4 shows the same results as in figure 3, but only for the combination groups. They were dosed up to day 16 as they showed strong inhibition and even tumor stasis. The double combination dabrafenib and trametinib plus castration group lost tumor stasis at around day 4 and tumors started to regrow. The double combination showed the same tumor growth inhibition, there was no difference observed when castrating the mice or not. The triple combination with darolutamide, dabrafenib and trametinib showed the best tumor growth inhibition from day 11 of treatment. A slow release of inhibition did set on and tumors were growing. Statistical analysis using the Kruskal-Wallis test indicates that the mean tumor size following triple combination with dabrafenib, trametinib and darolutamide significantly differs from the mean tumor size determined in the two other groups at days 11 (p = 0.0026), 14 (p = 0.0118) and 16 (p = 0.0226). Figure 5 shows the mean tumor sizes at day 14 (Fig. 5A) and day 16 (Fig. 5B) for the combination treatments with dabrafenib and trametinib; dabrafenib, trametinib and darolutamide; dabrafenib, trametinib and castration. Statistical analysis using the Kruskal-Wallis test indicates that the mean tumor WO 2025 / 146444                                   PCT / EP2025 / 050017 size following triple combination with dabrafenib, trametinib and darolutamide significantly differs from the mean tumor size determined in the two other groups at day 14 (p = 0.0118) and day 16 (p = 0.0226). Figure 6 shows the body weight of female mice during the treatment period, as indicated. No overall significant body weight loss was observed in all treatment groups. Figure 7 shows the results of the in vivo efficacy study following treatment of female mice harboring the YUMMl.7 melanoma model with the indicated treatments: AR inhibitor darolutamide, the BRAF inhibitor dabrafenib, the MEK inhibitor trametinib, and the indicated combinations. Treatment with darolutamide did not result in tumor growth inhibition compared to the vehicle group. The double combinations of dabrafenib and trametinib resulted in dose-dependent tumor growth inhibition and stasis up to day 10 for the low dose and up to day 13 for the high dose group under continuous dosing. Adding darolutamide to the low or high dose dabrafenib and trametinib dual treatment showed superior efficacy. Tumor stasis and regression were observed. Figure 8 shows the mean tumor sizes at day 17 (Fig. 8A) and day 20 (Fig. 8B) for the combination treatments of female mice with dabrafenib and trametinib (low or high dose); dabrafenib and trametinib (low or high dose) and darolutamide. Statistical analysis using the Kruskal-Wallis test indicates that the mean tumor size following triple combination with dabrafenib and trametinib (low or high dose) and darolutamide is significantly smaller compared to the mean tumor size determined in the double combination dabrafenib and trametinib at day 17 (double vs. triple combination, low dose: p = 0.0016; double vs. triple combination, high dose: p = 0.0067) and day 20 (double vs. triple combination, low dose: p = 0.0066; double vs. triple combination, high dose: p = 0.0085). Figure 9 shows the tumor growth observed in individual female mice following 30-day treatment with high (Fig. 9A) or low dose (Fig. 9B) of dabrafenib and trametinib, and darolutamide. Treatment was stopped for all mice at day 30. The results indicate that in the low-dose triple combination group, five tumors started to regrow between day 15 and day 31. In the high dose triple combination group, five tumors started to regrow between day 20 and day 34. There was a delay of regrowing tumors in a dosedependent manner. Figure 10 is Barplot showing Normalized Enrichment Score of the top enriched gene sets in comparative gene expression analysis of triple vs. double combination treatment. In summary, our bioinformatic data indicate that AR expression is upregulated in human melanoma cell line models, in melanoma mouse tumor models and in melanoma patients treated with a BRAF inhibitor or a MEK inhibitor, in comparison to the respective control groups. Experimental studies in male and female mice carrying the YUMMl.7 melanoma model reveal superior in vivo anti-tumor efficacy of the triple combination with the AR inhibitor darolutamide, the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib and warrant further clinical evaluation of this promising combination therapy for the treatment of cancer, in particular melanoma. European Medicines Agency (EMA) product recommendation related to taking dabrafenib (tafinlar) and trametinib (mekinist) for melanoma treatment advises over the determination of BRAF V600 mutation. Determination of BRAF mutation status Before taking dabrafenib or combination with trametinib, patients must have BRAF V600 mutation positive tumour status confirmed by a validated test. In the Phase II and III clinical trials, screening for eligibility required central testing for BRAF V600 mutation using a BRAF mutation assay conducted on the most recent tumour sample available. Primary tumour or tumour from a metastatic site was tested with an investigational use only assay (IUO). The IUO is an allele-specific polymerase chain reaction (PCR) assay performed on DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue. The assay was specifically designed to differentiate between the V600E and V600K mutations. Only subjects with BRAF V600E or V600K mutation positive tumours were eligible for study participation. Subsequently, all patient samples were re-tested using the bioMerieux (bMx) THxID BRAF validated assay, which has CE marking. The bMx THxID BRAF assay is an allele-specific PCR performed on DNA extracted from FFPE tumour tissue. The assay was designed to detect the BRAF V600E and V600K mutations with high sensitivity (down to 5% V600E and V600K sequence in a background of wild-type sequence using DNA extracted from FFPE tissue). Non-clinical and clinical studies with retrospective bidirectional Sanger sequencing analyses have shown that the test also detects the less common BRAF V600D mutation and V600E / K601E mutation with lower sensitivity. Of the specimens from the non-clinical and clinical studies (n=876) that were mutation positive by the THxID BRAF assay and 5 subsequently were sequenced using the reference method, the specificity of the assay was 94%. Concordance in BRAF V600E status over time in malignant melanoma and corresponding metastases was also reported in the literature (Nielsen L B, et al. (2018) Histopathology 72, 814-825. https: / / doi.org / 10.llll / his.13431). Immunohistochemical (IHC) can be safely used as a BRAF pretreatment screening tool, and no additional test is needed when staining is positive. However, if 10 stains are negative, additional tests are essential for detection of other BRAF mutations. It is suggest that using primary melanoma tissues is just as safe as using metastatic tissue for detection of BRAF V600E, as BRAF intertumour heterogeneity is extremely rare. The determination of BRAF mutation in melanoma patients, it can be determined either on tumor tissue or in blood on circulating DNA, as reviewed by L. Cheng et al in Mod Pathol, 2017, 31:24-38. 15    .

Claims

1. Pharmaceutical combination comprising of component A, component B and component C.

2. Pharmaceutical combination according to claim 1 further comprising a component D.

3. Pharmaceutical combination according to claim 1 or 2 for simultaneous, concurrent, separate or sequential administration.

4. Pharmaceutical combination according to claim 1 or 2 wherein component A is an AR inhibitor.

5. Pharmaceutical combination according to claim 1 or 2 wherein component A is an AR degrader.

6. Pharmaceutical combination according to claim 1 or 2 wherein component A is selected fromthe group consisting of darolutamide, or enzalutamide or apalutamide or proxalutamide orbicalutamide, or an AR degrader such as bavdegalutamide (ARV-110) or luxdegalutamide.

7. Pharmaceutical combination according to claim 1 or 2 wherein component A is darolutamide.

8. Pharmaceutical combination according to claim 1 or 2 wherein component B is an ATP-competitive inhibitor of B-RAF.

9. Pharmaceutical combination according to claim 1 or 2 wherein component B is an allosteric inhibitor of B-RAF.

10. Pharmaceutical combination according to claim 1 or 2 wherein component B is dabrafenib.

11. Pharmaceutical combination according to claim 1 or 2 wherein component B is vemurafenib.

12. Pharmaceutical combination according to claim 1 or 2 wherein component B is encorafenib.

13. Pharmaceutical combination according to claim 1 or 2 wherein component C is an ATP-competitive inhibitor of MEK.

14. Pharmaceutical combination according to claim 1 or 2 wherein component C is an ATP-competitive inhibitor of MEK1.

15. Pharmaceutical combination according to claim 1 or 2 wherein component C is an allosteric inhibitor of MEK.

16. Pharmaceutical combination according to claim 1 or 2 wherein component C is an allosteric inhibitor of MEK1.

17. Pharmaceutical combination according to claim 1 or 2 wherein component C is trametinib.

18. Pharmaceutical combination according to claim 1 or 2 wherein component C is selumetinib.

19. Pharmaceutical combination according to claim 1 or 2 wherein component C is cobimetinib.

20. Pharmaceutical combination according to claim 1 or 2 wherein component C is binimetinib.

21. Use of a pharmaceutical combination according to claim 1 to 19 to treat or prevent human diseases.

22. Use according to claim 20 wherein the human disease is a MAPK pathway-positive cancer.

23. Use according to claim 21 wherein the MAPK pathway-positive cancer is Melanoma.

24. Use according to claim 4 wherein the targeted BRAF is mutated at position V600, more specifically where the mutation is V600E.

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