Bcl-2 inhibitors and aurora kinase inhibitors for treating cancer

Abstract

The present invention relates to a combination therapy of an inhibitor of the Bcl-2 protein family selected from navitoclax, venetoclax, A-1331852, AZD5991, or A-1155463 with an Aurora kinase inhibitor for use in a method of treating a cancer selected from breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer in a patient.

Description

[Technical field]

[0001] The present invention relates to combination therapies for the treatment of cancer. [Background technology]

[0002] Despite advances in treatment, cancer continues to have a significant impact on societies, families, and individuals worldwide. It is one of the leading causes of death worldwide. According to statistics provided by the National Cancer Institute, there were 18.1 million new cases and 9.5 million cancer-related deaths worldwide in 2018. By 2040, the number of new annual cancer cases is projected to rise to 29.5 million, and the number of cancer-related deaths to 16.4 million. Summary of the Invention [Problem to be solved by the invention]

[0003] Cancer treatment has improved with the use of single-agent targeted therapy in patients with molecularly defined tumors. Nevertheless, many patients still lack effective treatments, and existing or acquired resistance limits the clinical benefit of even our most advanced medicines. Combination therapy using an increasing number of targeted anticancer drugs has the potential to overcome resistance to existing drugs, enhance response, reduce dose-limiting toxicity of single agents, and expand the scope of treatment for patients. [Means for solving the problem]

[0004] The present invention is directed to the use of therapeutic combinations of active ingredients for the treatment of cancer in patients, in particular the combination of an inhibitor of the Bcl-2 protein family with an Aurora kinase inhibitor.As described herein, the inventors have observed synergistic effects for the combination of an inhibitor of the Bcl-2 protein family, such as navitoclax, with an Aurora kinase inhibitor in cancer cell lines.

[0005] In a first aspect, the present invention may provide a combination of an inhibitor of the Bcl-2 protein family selected from navitoclax, venetoclax, A-1331852, AZD5991, or A-1155463 and an Aurora kinase inhibitor for use in a method of treating a cancer selected from breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer in a patient.

[0006] In some cases, the present invention may provide an inhibitor of the Bcl-2 protein family selected from navitoclax, venetoclax, A-1331852, AZD5991, or A-1155463 for use in a method of treating a cancer selected from breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer in a patient, where the inhibitor of the Bcl-2 protein family is administered to the patient in combination with an Aurora kinase inhibitor.

[0007] In some cases, the present invention may provide an Aurora kinase inhibitor for use in a method of treating a cancer selected from breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer in a patient, wherein the Aurora kinase inhibitor is administered to the patient in combination with an inhibitor of the Bcl-2 protein family selected from navitoclax, venetoclax, A-1331852, AZD5991, or A-1155463.

[0008] In some embodiments, navitoclax is used. In some embodiments, venetoclax is used. In some embodiments, A-1331852 is used. In some embodiments, AZD5991 is used. In some embodiments, A-1155463 is used.

[0009] In some embodiments, the cancer is a non-HER2 rich breast cancer. The inventors have observed significant synergy in non-HER2 breast cancer cell lines. In some embodiments, the cancer is determined to be HER2-.

[0010] In some embodiments, the cancer is basal-like breast cancer. In some embodiments, the cancer is triple-negative breast cancer.

[0011] In some embodiments, the cancer is luminal A breast cancer.

[0012] In some embodiments, the cancer is luminal B breast cancer.

[0013] In some embodiments, the Aurora kinase inhibitor is an Aurora A kinase inhibitor. In some embodiments, the Aurora kinase inhibitor is selected from alisertib, tozasertib, ZM447439, AZD2811 (also known as barasertib-hQPA), AZD1152 (barasertib, a prodrug of barasertib-hQPA), LY3295668, MK-5108, GSK1070916, and MLN8054. In some embodiments, the Aurora kinase inhibitor is selected from alisertib, tozasertib, ZM447439, AZD2811, and AZD1152. In some embodiments, the Aurora kinase inhibitor is selected from alisertib, tozasertib, and ZM447439. In some embodiments, the Aurora kinase inhibitor is alisertib.

[0014] It is understood that the Bcl-2 protein family inhibitor selected from navitoclax, venetoclax, A-1331852, AZD5991, or A-1155463 and the Aurora kinase inhibitor can be administered together (concurrently) or separately, and can be administered at the same time or at different times. For example, the compounds can be administered on different days as part of a treatment cycle or treatment regimen. Preferably, but not necessarily, the Bcl-2 protein family inhibitor and the Aurora kinase inhibitor described herein are formulated separately. In a preferred method, both compounds are formulated for oral administration.

[0015] The claimed combination therapy can be used for both curative and symptomatic (palliative) purposes. It may lead to better patient outcomes and / or experiences when compared to other treatment regimens and may additionally or alternatively expand the treatment options available to patients.

[0016] Suitably, the patient may be a human patient.

[0017] The present invention also relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of an inhibitor of the Bcl-2 protein family selected from navitoclax, venetoclax, A-1331852, AZD5991, or A-1155463 in combination with an effective amount of an Aurora kinase inhibitor, wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

[0018] The present invention also relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a Bcl-2 protein family inhibitor selected from navitoclax, venetoclax, A-1331852, AZD5991, or A-1155463 in combination with an effective amount of an Aurora kinase inhibitor, wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

[0019] The present invention also relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of an Aurora kinase inhibitor in combination with an effective amount of an inhibitor of the Bcl-2 protein family selected from navitoclax, venetoclax, A-1331852, AZD5991, or A-1155463, wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

[0020] The present invention also relates to the use of a combination of an inhibitor of the Bcl-2 protein family selected from navitoclax, venetoclax, A-1331852, AZD5991, or A-1155463 and an Aurora kinase inhibitor in the manufacture of a medicament for the treatment of cancer in a patient, wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

[0021] The present invention also relates to the use of an inhibitor of the Bcl-2 protein family selected from navitoclax, venetoclax, A-1331852, AZD5991, or A-1155463 in combination with an Aurora kinase inhibitor in the manufacture of a medicament for the treatment of cancer in a patient, wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

[0022] The present invention also relates to the use of an Aurora kinase inhibitor in combination with an inhibitor of the Bcl-2 protein family selected from navitoclax, venetoclax, A-1331852, AZD5991, or A-1155463, in the manufacture of a medicament for the treatment of cancer in a patient, wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

[0023] The present invention includes combinations of the described embodiments and preferred features except where such combinations are clearly unacceptable or explicitly avoided.

[0024] BRIEF DESCRIPTION OF THE DRAWINGS Embodiments and experiments illustrating the principles of the present invention will now be discussed with reference to the accompanying drawings. [Brief description of the drawings]

[0025] [Figure 1]Figure 1 shows the activity of the combination therapy of the present invention in 51 breast cancer cell lines stratified by PAM50 subtype as described in Example 1. The combination of navitoclax and AURK inhibitors is frequently synergistic in breast cancer cell lines, except Her2 cells. Binary synergy of navitoclax (anchor) paired with three AURK inhibitors in cell lines from the PAM50 subtype. [Diagram 2] Graph showing sensitivity of breast cancer cell lines to navitoclax + Aurora kinase inhibitor combinations. Breast cancer cell lines were selected to cover the range of PAM50 subtypes: Basal, Luminal A (LumA), Luminal B (LumB) or Her2. Cells were treated with navitoclax plus Aurora kinase inhibitor as indicated in each point plot (A-G). Synergy metrics, BLISS windows and I-windows were generated as described. Each point is a single replicate, with 5-8 replicates per cell line. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Aspects and embodiments of the present invention will now be discussed with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0027] Inhibitors of the Bcl-2 protein family The Bcl-2 protein family consists of a number of evolutionarily conserved proteins that share a Bcl-2 homology (BH) domain. The Bcl-2 family is most notable for its regulation of apoptosis, a form of mitochondrial programmed cell death. The Bcl-2 protein family consists of members that either promote or inhibit apoptosis, and manages apoptosis by controlling mitochondrial outer membrane permeabilization (MOMP), a key step in the intrinsic apoptotic pathway.

[0028] The Bcl-2 protein family includes several family members, including Bcl-2 (B cell lymphoma 2), Bcl-xL (B cell large lymphoma), Bcl-w (Bcl-2-like protein 2 or BCL2L2), Mcl-1 (myeloid leukemia cell differentiation-inducing protein), and A1 (Bcl-2-related protein A1 or BCL2A1).

[0029] The combination therapy described herein includes an inhibitor of the Bcl-2 protein family. The inhibitor of the Bcl-2 protein family can be an inhibitor of one or more of the Bcl-2 protein family, such as Bcl-2, Bcl-xL, Bcl-w, Mcl-1 and A1, and combinations thereof. For example, the inhibitor of the Bcl-2 protein family can be an inhibitor of Bcl-2 and Bcl-xL.

[0030] In some embodiments, the combinations for use in the treatment methods described herein include an inhibitor of Bcl-2, i.e., the combinations for use in the treatment methods described herein include a Bcl-2 inhibitor.

[0031] In some embodiments, the combinations for use in the treatment methods described herein include an inhibitor of Bcl-xL, i.e., the combinations for use in the treatment methods described herein include a Bcl-xL inhibitor.

[0032] In some embodiments, the combinations for use in the treatment methods described herein include an inhibitor of Bcl-w, i.e., the combinations for use in the treatment methods described herein include a Bcl-w inhibitor.

[0033] In some embodiments, the combination for use in the treatment methods described herein comprises an inhibitor of Mcl-1. That is, the combination for use in the treatment methods described herein comprises an Mcl-1 inhibitor.

[0034] In some embodiments, the combinations for use in the treatment methods described herein include an inhibitor of A1, i.e., the combinations for use in the treatment methods described herein include an A1 inhibitor.

[0035] Various Bcl-2, Bcl-xL, Bcl-w, Mcl-1 and A1 inhibitors are known in the art and include navitoclax, venetoclax, A-1331852, AZD5991 and A-1155463. In some embodiments, the combination for use in the treatment methods described herein comprises navitoclax. In some embodiments, the combination for use in the treatment methods described herein comprises venetoclax. In some embodiments, the combination for use in the treatment methods described herein comprises A-1331852. In some embodiments, the combination for use in the treatment methods described herein comprises AZD5991. In some embodiments, the combination for use in the treatment methods described herein comprises A-1155463.

[0036] Preferably, the combination for use in the treatment methods described herein comprises a Bcl-xL inhibitor, such as navitoclax, A-1331852 and A-1155463. In some embodiments, the combination for use in the treatment methods described herein comprises navitoclax. In some embodiments, the combination for use in the treatment methods described herein comprises A-1331852. In some embodiments, the combination for use in the treatment methods described herein comprises A-1155463.

[0037] Navitoclax Navitoclax, also known as ABT-263 or ABT263, is a Bcl-2 inhibitor (K i Navitoclax also exhibited a K iIt is also a potent inhibitor of Bcl-xL and Bcl-w with affinity for .ltoreq.0.5 nM and .ltoreq.1 nM, but binds less strongly to Mcl-1 and A1. Its structure is

[0038] [ka] It is.

[0039] In IUPAC nomenclature, navitoclax can be referred to as 4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-(trifluoromethanesulfonyl)benzene-1-sulfonyl)benzamide.

[0040] Navitoclax is disclosed in EP1888550, which is incorporated herein by reference in its entirety, together with representative general synthetic methods. The compound is commercially available. Navitoclax is in Phase III clinical trials studying the treatment of myelofibroma.

[0041] Venetoclax Venetoclax is also known as ABT-199 and GDC-0199. Venetoclax is a selective inhibitor of Bcl-2 and inhibits K i It has a potent agonist activity of <0.01 nM and is >4800-fold selective for Bcl-xL and Bcl-w, with no activity against Mcl-1. Venetoclax is approved for the treatment of certain blood cancers. Its structure is:

[0042] [ka] It is.

[0043] In IUPAC nomenclature, venetoclax can be referred to as 4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide. Its synthesis is known in the art and the compound is commercially available.

[0044] A-1331852 A-1331852 is a potent and selective Bcl-xL inhibitor, i The values ​​are less than 0.01 nM for Bcl-xL, 6 nM, 4 nM, and 142 nM for Bcl-2, Bcl-w, and Mcl-1, respectively. A-1331852 may be useful in the treatment of cancer, immune disorders, and autoimmune diseases. Its structure is:

[0045] [ka] It is.

[0046] In IUPAC nomenclature, A-1331852 can be referred to as 3-[1-(1-adamantylmethyl)-5-methyl-pyrazol-4-yl]-6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]pyridine-2-carboxylic acid, the synthesis of which is known in the art and the compound is commercially available.

[0047] AZD5991 AZD5991 (or AZD-5991) is a macrocyclic Mcl-1 inhibitor with subnanomolar affinity for Mcl-1 (K i =0.13 nM). The binding affinity of AZD5991 is approximately 25-fold lower for mouse Mcl-1 compared to human Mcl-1, but only 4-fold lower for rat Mcl-1. Its structure is:

[0048] [ka] It is.

[0049] In the IUPAC nomenclature, AZD5991 is 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentazaheptacyclo[27.7.1.1 4,7 .0 11,15 .0 16,21 .0 20,24 .0 30,35 ]Octatriaconta-1(36),4(38),6,11,14,16,18,20,23,29(37),30(35),31,33-tridecane-23-carboxylic acid, the synthesis of which is known in the art and the compound is commercially available.

[0050] AZD5991 exists in two rotamer forms, or atropisomers (R) and (S) (conformational isomers that differ by rotation around a single bond).

[0051] [ka] It is.

[0052] When referring to AZD5991 herein, we refer to both rotamers (or the racemate) unless specifically specified.

[0053] A-1155463 A-1155463 is a highly potent and selective inhibitor of Bcl-xL. It exhibits picomolar binding affinity for Bcl-xL but not Bcl-2, as well as the related protein Bcl-w (K i = 19 nM) and Mcl-1 (K i >440 nM), it has a weaker binding affinity of 1000 times less than that of

[0054] [ka] It is.

[0055] In IUPAC nomenclature, A-1155463 can be referred to as 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-(dimethylamino)prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, the synthesis of which is known in the art and the compound is commercially available.

[0056] Aurora kinase inhibitors Aurora kinase inhibitors are also referred to herein and in the art as AURK inhibitors or AURKi.

[0057] Aurora kinases (AURKs) are phosphotransferase enzymes that are understood to be important in the cell division process. Modulation of the Aurora kinase pathway is of interest for the treatment of cancer, particularly in the prevention and treatment of tumorigenesis.

[0058] Three classes of AURKs have been identified in humans: Aurora A, Aurora B and Aurora C. Aurora A is also known as Aurora 2 and Aurora B is also known as Aurora 1.

[0059] In some embodiments, the AURK inhibitors of the present invention inhibit Aurora A kinase.

[0060] Various AURK inhibitors are known in the art, including alisertib, tozasertib, ZM447439, AZD2811 (active barasertib-hQPA), AZD1152 (barasertib, a prodrug of barasertib-hQPA), LY3295668, MK-5108, GSK1070916, and MLN8054. In some embodiments, the Aurora kinase inhibitor is selected from alisertib, tozasertib, ZM447439, AZD2811, and AZD1152. In some embodiments, the Aurora kinase inhibitor is selected from alisertib, tozasertib, and ZM447439. In some embodiments, the AURKi is alisertib. In some embodiments, the AURKi is tozasertib. In some embodiments, the AURKi is ZM447439.

[0061] Alisertib Alisertib, also known as MLN8237, is an orally available selective Aurora A kinase inhibitor. Its structure is:

[0062] [ka] It is.

[0063] In IUPAC nomenclature, Alisertib can be referred to as 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid, the synthesis of which is known in the art and the compound is commercially available.

[0064] Tozasertib Tozasertib, also known as VX-680 and MK-0457, is a pan-Aurora kinase inhibitor. Tozasertib is significantly more potent against Aurora A kinase than B / C. Its structure is:

[0065] [ka] It is.

[0066] In IUPAC nomenclature, tozasertib can be referred to as N-[4-({4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide. Its synthesis is known in the art and the compound is commercially available.

[0067] ZM447439 ZM447439 is a selective, ATP-competitive inhibitor of Aurora A and Aurora B kinases. Its structure is:

[0068] [ka] It is.

[0069] In IUPAC nomenclature, ZM447439 can be referred to as N-[4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinazolin-4-yl}amino)phenyl]benzamide. Its synthesis is known in the art and the compound is commercially available.

[0070] AZD2811 AZD2811 is a selective Aurora B kinase inhibitor with IC 50 is 0.37 nM. AZD2811, also known as balasertib-hQPA (-hydroxyquinazoline-pyrazole-aniline) or AZD1152-hQPA, is the active metabolite of AZD1152, described below. AZD2811 induces growth arrest and apoptosis in cancer cells. Its structure is:

[0071] [ka] It is.

[0072] In IUPAC nomenclature, AZD2811 can be referred to as 2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]quinazolin-4-yl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide. Its synthesis is known in the art and the compound is commercially available. AZD2811 can be provided as the Accurin™ formulation (BIND Therapeutics, Inc.).

[0073] AZD1152 AZD1152 is also known as barasertib. AZD1152 is a prodrug of barasertib-hQPA (AZD2811) and has an IC 50 It is a highly selective Aurora B kinase inhibitor with a CdA of 0.37 nM. Its structure is:

[0074] [ka] It is.

[0075] In IUPAC nomenclature, AZD1152 can be referred to as 2-[ethyl-[3-[4-[[5-[2-(3-fluoroanilino)-2-oxoethyl]-1H-pyrazol-3-yl]amino]quinazolin-7-yl]oxopropyl]amino]ethyl dihydrogen phosphate. Its synthesis is known in the art and the compound is commercially available.

[0076] LY3295668 LY3295668 is also known as AK-01. LY3295668 is a potent, orally active, specific Aurora A kinase inhibitor, and has been shown to inhibit AURKA and AURKB kinase. i are 0.8 nM and 1038 nM, respectively. The structures are:

[0077] [ka] It is.

[0078] In IUPAC nomenclature, LY3295668 can be referred to as (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid. Its synthesis is known in the art and the compound is commercially available.

[0079] LY3295668 can also exist in other isomeric forms: (2R,4S), (2S,4R) and (2S,4S). Thus, LY3295668 may also exist as (2R,4S)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid, (2S,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid, and (2S,4S)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid.

[0080] When referring to LY3295668 herein, we refer to all isomeric forms unless specifically specified.

[0081] MK-5108 MK-5108 is also known as VX-689. MK-5108 is a highly selective Aurora A kinase inhibitor with an IC 50 is 0.064 nM. MK-5108 is 220-fold and 190-fold more selective for Aurora A kinase over Aurora B / C, while MK-5108 inhibits Tropomyosin Receptor Kinase A (TrkA) with over 100-fold less selectivity. MK-5108 is known to induce autophagy. MK-5108 has the following structure:

[0082] [ka]

[0083] In IUPAC nomenclature, MK-5108 can be referred to as (4-(3-chloro-2-fluoro-phenoxy)-1-[[6-(thiazol-2-ylamino)-2-pyridyl]methyl]cyclohexanecarboxylic acid. Its synthesis is known in the art and the compound is commercially available.

[0084] GSK1070916 GSK1070916 is a reversible, ATP-competitive Aurora B / C kinase inhibitor with IC 50 is 3.5nM / 6.5nM. GSK1070916 shows >100-fold selectivity for the closely related Aurora A-TPX2 complex. GSK1070916 has the following structure:

[0085] [ka]

[0086] In IUPAC nomenclature, GSK10709016 can be referred to as 3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-pyrazol-3-yl]phenyl]-1,1-dimethyl-urea, the synthesis of which is known in the art and the compound is commercially available.

[0087] MLN8054 MLN8054 is a potent and selective inhibitor of Aurora A kinase, with IC 50 is 4 nM in insect cells Sf9. MLN8054 is more than 40-fold selective for Aurora A kinase over Aurora B kinase. MLN8054 has the following structure:

[0088] [ka]

[0089] In IUPAC nomenclature, MLN8054 can be referred to as 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid, the synthesis of which is known in the art, and the compound is commercially available.

[0090] Specific inhibitor combinations In some cases, the combination of an inhibitor of the Bcl-2 protein family, e.g., a Bcl-2, Bcl-xL, Bcl-w, Mcl-1 and A1 inhibitor with an Aurora kinase inhibitor for use in the treatment methods described herein may be a combination of specific inhibitors.

[0091] In some cases, the combinations can be selected from navitoclax and alisertib, navitoclax and barasertib, navitoclax and GSK1070916, navitoclax and LY3295668, navitoclax and MLN8054, navitoclax and tozasertib, navitoclax and ZM447439, A-1331852 and alisertib, A-1331852 and LY3295668, A-1331852 and MK-5108, A-1155463 and alisertib, A-1155463 and LY3295668, and A-1155463 and MK-5108.

[0092] In some cases, the combinations can be selected from navitoclax and alisertib, navitoclax and barasertib, navitoclax and GSK1070916, navitoclax and LY3295668, navitoclax and MLN8054, navitoclax and tozasertib, navitoclax and ZM447439, and A-1331852 and alisertib.

[0093] In some cases, the combination for use in the treatment methods described herein may be a combination of navitoclax and alisertib. In some cases, the combination for use in the treatment methods described herein may be a combination of navitoclax and barasertib. In some cases, the combination for use in the treatment methods described herein may be a combination of navitoclax and GSK1070916. In some cases, the combination for use in the treatment methods described herein may be a combination of navitoclax and LY3295668. In some cases, the combination for use in the treatment methods described herein may be a combination of navitoclax and MLN8054. In some cases, the combination for use in the treatment methods described herein may be a combination of navitoclax and tozasertib. In some cases, the combination for use in the treatment methods described herein may be a combination of navitoclax and ZM447439. In some cases, the combination for use in the treatment methods described herein can be a combination of A-1331852 and alisertib.

[0094] Pharmaceutically acceptable salts As described herein, any compound may be provided as a pharmaceutically acceptable salt, hydrate or solvate (solvate). Suitable pharmaceutically acceptable salts are known in the art and are described, for example, in Berge et al., J Pharm Sci, 1977 66(1) p. 1.

[0095] Administration of the active ingredient The compound used in the method of the present invention can be administered by any suitable route, including oral and intravenous routes.It is understood that oral administration may be preferred.The compound can be provided in a pharmaceutical composition that includes the compound and one or more pharma-ceutically acceptable excipients.The formulation for oral administration can be in the form of a tablet or a capsule that contains powder or liquid.

[0096] Administration is preferably in a "therapeutically effective amount" or "effective amount" (used interchangeably) sufficient to show benefit to an individual. The actual amount administered, as well as the rate and time-course of administration, will depend on the nature and severity of the disease being treated. Prescription of treatment, such as determining dosage, is within the responsibility of general practitioners and other physicians, and typically takes into account the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration, and other factors known to physicians. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins.

[0097] Any art-known dosage regimen for the active ingredients described herein can be used in the present invention.

[0098] For example, navitoclax has been administered as a single agent at an oral dose of 325 mg on a continuous 21 / 21 dosing schedule (Wilson et al., Lancet Oncol., December 2010, 11(12):1149-1159). 2Navitoclax was also administered at 325 mg in Cleary et al. (Invest New Drugs, October 2014, 32(5):937-945) when combined with gemcitabine. Navitoclax has also been administered intermittently over a 21-day cycle, with patients receiving navitoclax on day -3 in the intermittent dosing regimen followed by days 1-14 of a 21-day cycle. Patients in the continuous dosing regimen received a one-week lead-in at a 150 mg dose followed by continued daily dosing in the same study (Gandhi et al., J Clin Oncol, March 1, 2011, 29(7):909-916). It is therefore desirable that a suitable dose regimen for navitoclax can be prescribed by a physician. Suitable dosing regimens for venetoclax, A-1331852, AZD5991 and A-1155463 are also described in the art.

[0099] Dosage regimens of AURKi, such as alisertib, tozasertib, ZM447439, AZD2811, AZD1152 and LY3295668, are also known in the art. For example, alisertib has been tested in a Phase I clinical trial in East Asian patients with advanced solid tumors or lymphomas. Patients received alisertib twice daily (BID) for 7 days in a 21-day cycle, with dose escalation from 30 mg BID to 40 mg BID, which was well tolerated (Venkatakrishnan et al., Invest New Drugs, August 2015, 33(4):942-953). This was slightly lower than the dose of 50 mg alisertib twice daily received by patients in Europe and the United States (Beltran et al., Clin. Cancer Res., 1 Jan 2019; 25(1):43-51; Kelly et al., Invest New Drugs, 32(3):489-499; June 2014).

[0100] Tozasertib (also known as MK-0457 or VX-680) was also studied in a Phase I dose-escalation study in adult patients with advanced solid tumors. Patients received tozasertib as a 24-hour continuous intravenous (CIV) infusion escalated every 21 days, with a maximum tolerated dose (MTD) of 64 mg / m 2 / hr. Patients also received 100 mg of tozasertib orally (Traynor et al., Cancer Chemother Pharmacol. 2011 Feb. 67(2): 305-314). In a Phase II trial, patients received 40 mg / m2 every 14 days. 2 / h, 32 mg / m 2 / h or 24 mg / m 2 Tozasertib was administered at 100 mg / h for 5 days as a continuous infusion (Seymour et al., Blood Cancer Journal, 2014, 4, e238). Suitable dosing regimens for ZM447439, AZD2811, AZD1152 and LY3295668 are also described in the art.

[0101] Thus, the active ingredients described herein can be administered in a dosage of about 1 mg to about 1000 mg, for example, about 5 mg to about 500 mg, for example, about 10 mg to about 400 mg.

[0102] In some embodiments, navitoclax can be administered at a dosage of about 1 mg to about 1000 mg, such as about 5 mg to about 500 mg, for example, about 10 mg to about 400 mg, for example, about 150 mg to about 325 mg, for example, about 150 mg or about 325 mg. In some embodiments, venetoclax can be administered at a dosage of about 1 mg to about 1000 mg, for example, about 5 mg to about 500 mg, for example, about 10 mg to about 400 mg, for example, about 150 mg to about 325 mg, for example, about 150 mg or about 325 mg. In some embodiments, A-1331852 can be administered at a dosage of about 1 mg to about 1000 mg, for example, about 5 mg to about 500 mg, for example, about 10 mg to about 400 mg, for example, about 150 mg to about 325 mg, for example, about 150 mg or about 325 mg. In some embodiments, AZD5991 can be administered at a dosage of about 1 mg to about 1000 mg, such as about 5 mg to about 500 mg, for example, about 10 mg to about 400 mg, for example, about 150 mg to about 325 mg, for example, about 150 mg or about 325 mg. In some embodiments, A-1155463 can be administered at a dosage of about 1 mg to about 1000 mg, for example, about 5 mg to about 500 mg, for example, about 10 mg to about 400 mg, for example, about 150 mg to about 325 mg, for example, about 150 mg or about 325 mg.

[0103] In some embodiments, an AUR Ki, such as alisertib, tozasertib, ZM447439, AZD2811, AZD1152 and LY3295668, can be administered at a dosage of about 1 mg to about 1000 mg, such as about 5 mg to about 500 mg, for example, about 10 mg to about 300 mg, for example, about 20 mg to about 100 mg, for example, about 30 mg to about 50 mg, for example, about 30 mg or about 40 mg or about 50 mg.

[0104] The active ingredients described herein can be administered simultaneously or sequentially, or at different times within a prescribed administration cycle.The active ingredients described herein can be administered daily, for example, once a day (QD), twice a day (BID), three times a day (TID), or four times a day (QID), or can be administered on a less frequent or intermittent schedule.

[0105] Suitably, the patient may be a human patient.

[0106] Cancer type The present invention relates to methods for the treatment of cancer in a patient, in particular basal-like, TNBC (triple negative breast cancer), and / or HRD (homologous recombination repair deficient) cancer.

[0107] Diagnosis of HRD deficiency is art-recognized and can be based on criteria including the following: 1. Genetic testing for somatic or germline loss-of-function mutations in the BRCA1 or BRACA2 genes is used clinically to determine HRD. See, e.g., Gonzalez-Martin et al., N Engl J Med 2019, 381(25):2391-2402 (PMID 51362799). Available testing platforms include Myriad Genetics, Inc.'s myChoice® CDx (https: / / myriad.com / products-services / precision-medicine / mychoice-cdx / ), which is FDA-approved as a companion diagnostic to Lynparza™ (olaparib) (https: / / myriad.com / investors / news-release / news-release-detail / ?newsItemId=21171) for advanced ovarian cancer, and Foundation Medicine, Inc.'s FoundationOneLiquid® CDx (https: / / www.foundationmedicine.com / test / foundationone-liquid-cdx), which is FDA-approved (https: / / www.fda.gov / drugs / resources-information-approved-drugs / fda-grants-marketing-approval-foundationone-cdx-in-vitro-diagnostic). Information about the FoundationOne® CDx platform can be found, for example, at https: / / assets.ctfassets.net / w98cd481qyp0 / 41rJj28gFwtxCwHQxopaEb / fba378cd309082f09570f32fc16b5d01 / FoundationOne_CDx_Label_Technical_Info.pdf. 2. Mutational signature analysis from whole genome sequencing data is proposed. These assays look for "genetic scars" as a result of HRD; some look for changes in copy number profiles in genes, others for patterns of nucleotide substitutions. A weighted model, HRDetect, is developed that predicts germline or somatic mutations in BRCA1 or BRCA2, and functional BRCA1 or BRCA2 loss where no mutations are detected, based on the mutational signature (Davies et al., Nat Med. 2017 Apr;23(4):517-525). 3. Alterations in other DNA repair pathway genes can also confer HRD (e.g., ATM, ATR, PALB2, RAD51C, RAD51D, BRIP1, BARD1, RPA, PTEN, CHEK1, CHEK2, MRE11, RADa50, MLH1, MSH2, MSH6, PMS2, etc. [this list is not comprehensive]). 4. Functional assays, e.g. RAD51 foci formation in cells or sensitivity to platinum-based drugs (Ngoi and Tan, ESMO Open, June 2021, 6(3):100144).

[0108] In some embodiments, the cancer is determined to be HRD deficient by one or more of the above criteria or tests.

[0109] The defining feature of TNBC is the increased frequency of BRCA1 / 2 mutations, the diagnosis of which is art-recognized.

[0110] In some cases, the treatment is for a cancer selected from breast cancer, ovarian cancer, pancreatic cancer and prostate cancer.Breast cancer, ovarian cancer, pancreatic cancer and prostate cancer are cancer types with a certain percentage of tumors that are HRD, and therefore the inventors reason that treatments that are effective in HER2-negative / TNBC may also be effective in ovarian cancer, pancreatic cancer and prostate cancer.For example, PARP inhibitors are used clinically to treat breast cancer, ovarian cancer, prostate cancer and pancreatic cancer patients with BRCA1 / 2 mutation tumors.

[0111] The patient may have breast cancer. Breast cancer is a disease of heterogeneous origin and is typically classified into five subtypes: Luminal A (LumA), Luminal B (LumB), HER2-rich (HER2 or HER2-E), Basal-like (Basal) and normal breast-like (Normal). These subtypes can be differentiated based on the expression levels of four recognized biomarkers by immunohistochemistry: Estrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal Growth Factor Receptor 2 (HER2) and Ki-67. For example, the National Cancer Institute provides Breast Cancer Treatment (Adult) Information (PDQ®) - Professional Version, which can be accessed at https: / / www.cancer.gov / types / breast / hp / breast-treatment-pdq#_18. Although other advice and resources are available to physicians and those skilled in the art, it is recognized that typing breast cancer is routine and well understood in the art.

[0112] Preferably, the breast cancer is a non-HER2-rich (non-HER2-E) breast cancer. That is, the breast cancer can be classified as luminal A (LumA), luminal B (LumB), or basal-like (basal). Diagnostically, HER2 status is typically defined by IHC / FISH subtype classification. IHC refers to immunohistochemistry test, and FISH refers to fluorescence in situ hybridization test. IHC for HER2 is classified as 0, +1, +2, or +3, with a result of +3 indicating HER2-rich cancer, and a result of 0 or 1+ indicating non-HER2-rich cancer. A result of +2 is considered equivocal, and in this case, FISH is usually also used.

[0113] Thus, the present invention may be relevant to the treatment of non-HER2-rich breast cancer, as determined by IHC and / or FISH subtyping, in patients.

[0114] Alternatively, the present invention may relate to the treatment of non-HER2-rich breast cancer as determined by gene expression-based molecular subtyping in a patient, such as PAM50 subtyping in a patient. Gene expression-based molecular subtyping in a patient, such as PAM50 subtyping, can be determined using diagnostic tests such as gene expression analysis, e.g., Oncotype DX®.

[0115] In some embodiments, the breast cancer is basal-like.

[0116] In some embodiments, the breast cancer is triple-negative breast cancer (TNBC). TNBC may have basal-like gene expression or non-basal-like gene expression. Its diagnosis is recognized in the art and described, for example, in information provided by the National Cancer Institute (Breast Cancer Treatment (Adult) (PDQ®)-Medical Professional Edition), which can be accessed at https: / / www.cancer.gov / types / breast / hp / breast-treatment-pdq#_18.

[0117] In some embodiments, the breast cancer is Luminal A.

[0118] In some embodiments, the breast cancer is luminal B.

[0119] PAM50 Subtype Classification The patients described herein can be classified using the PAM50 subtype classification. PAM50 is a 50-gene test designed to identify intrinsic subtypes of breast cancer (basal, Her2, LumA, LumB and normal) and generate a risk of recurrence (ROR) score, and was developed to be performed in accredited routine hospital pathology laboratories. PAM50 is described in Gnant et al., Ann. Oncol., 2014 25(2) 339-45 and Nielson et al., Clin Cancer Res, 2010 16(21) 5255-32.

[0120] The features disclosed in the preceding description, or the following claims, or the accompanying drawings, are expressed in their specific form, or in terms of means for performing a disclosed function, or methods or processes for obtaining a disclosed result, and can be utilized, as appropriate, separately or in any combination of such features to realize the invention in various of its forms.

[0121] Although the present invention has been described in conjunction with the example embodiments set forth above, numerous equivalent modifications and variations will be apparent to those skilled in the art given this disclosure. Accordingly, the example embodiments of the present invention set forth above are considered to be illustrative and not limiting. Various modifications can be made to the described embodiments without departing from the spirit and scope of the present invention.

[0122] For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purpose of improving the understanding of the reader, and the inventors do not wish to be bound by any of these theoretical explanations.

[0123] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0124] Throughout this specification, including the appended claims, unless the context requires otherwise, the words "comprise" and "include", as well as variations such as "comprises", "comprising" and "including", are understood to imply the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps.

[0125] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. As used herein, ranges may be expressed as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, it is understood that the particular value forms another embodiment by use of the antecedent "about." The term "about" in connection with numerical values ​​is optional and may mean, for example, + / - 10%. EXAMPLES

[0126] [Example] [Example 1] Navitoclax was screened in combination with three AURK inhibitors (alisertib, ZM447439, and tozasertib) in 51 breast cancer cell lines. Viability was read 72 h after drug treatment using CellTiter-Glo and drug responses to single agents and combination responses were fitted.

[0127] Synergy is the improvement in efficacy of the combination (ΔE max ) or intensity (ΔIC 50 ) was determined based on a significant shift in [calculated by Bliss (Annals of Applied Biology, 1939, 26(3), pp. 585-615), ΔE max ≥20% survival or ΔIC 50 Synergy was defined as a concentration shift of ≥ 3 (= 8-fold shift in concentration). Activity was determined based on a significant shift in viability reduction of the combination compared to single agent activity (e.g., efficacy was determined if the combination showed 20% more viability reduction than the expected combination effect based on single agent activity).

[0128] Using RNASeq data, breast cancer cell lines were annotated for PAM50 subtypes, see Figure 1.

[0129] Navitoclax in combination with any of the three Aurora kinase (AURK) inhibitors, alisertib, tozasertib or ZM447439, had particularly high synergy rates in the cell lines (61%, 60% and 53% of cell lines, respectively).

[0130] Navitoclax with alisertib and ZM447439 were included in independent viability screens performed using the same format and assay, and synergy was reproducible (94% and 88% overlap of cell line synergy determinations between screens, respectively).

[0131] Synergy was frequently observed for at least two of the three navitoclax and AURKi combinations in cell lines from all PAM50 subtypes (63% in basal-like (12 / 19 cell lines), 73% in LumA (8 / 11) and 75% in LumB (3 / 4)), with the exception of Her2 cell lines where synergy was much less frequent (17% or 1 / 6 cell lines). See Table 1 and Figure 1.

[0132] [Table 1]

[0133] [Example 2] Other Navitoclax + Aurora Kinase Inhibitor Combinations in Cancer Cell Lines method: Screens were performed in 10 breast cancer cell lines (JIMT-1, HCC38, BT-20, CAL-51, CAMA-1, HCC1428, BT-483, MDA-MB-415, EFM-192A, HCC1419) using a 7x7 matrix approach generating 49 wells of data per cell line / drug combination. For each combination, one Aurora kinase inhibitor was combined with one Navitoclax across a discrete dose range of 1,000 fractions (7 points). Viability was measured using CellTiter-Glo reagent 72 h after drug treatment. Single agent and combination viability measurements were fitted for each cell line to derive multiple parameters, including ranges of single agent values ​​and synergy scores.

[0134] For all 49 concentration combination measurements, Bliss excess was calculated by comparing the observed cellular response to the combination with the Bliss-independent predicted response based on monotherapy activity. The "Bliss window" was reported as the largest mean Bliss excess value measured in 25 possible 3x3 submatrices, or "windows," of the 7x7 dose matrix.

[0135] In addition, I (highest single drug) excess was calculated for all 49 concentration combination measurements by comparing the observed cellular response to the combination with the highest best single drug response to either drug A or drug B. The "I window" was reported as the largest mean I excess value measured in 25 possible 3 x 3 sub-matrices, or "windows," within the 7 x 7 dose matrix.

[0136] result: The screen included navitoclax in combination with each of the following Aurora kinase inhibitors: alisertib, MLN8054, barasertib, tozasertib, GSK1070916, ZM447439, LY3295668. The cell lines used covered a range of PAM50 subtypes, including two annotated as Her2 (Figure 2A-G). The results show poor synergy in Her2 cell lines for all combinations, as judged by the presence of this PAM50 subtype in the bottom left of the plots in Figure 2A-G. In contrast, the majority of basal, luminal A and luminal B cell lines show greater synergy in response to all combinations, as seen by higher Bliss window and I window scores.

[0137] [Example 3] Other BH3 family and Aurora kinase inhibitor combinations in cancer cell lines method: Compounds were tested in the Her2-positive breast cancer cell line, JIMT-1, using a 7x7 matrix approach generating 49 wells of data per cell line / drug combination. Alisertib was combined with a single BH3 mimetic for each combination across a dose range of 1,000 discrete fractions (7 points). Viability was measured using CellTiter-Glo reagent 72 h after drug treatment. Single agent and combination viability measurements were fitted for each cell line to derive multiple parameters, including ranges of single agent values ​​and synergy scores.

[0138] The viability measurements of the single agents and combinations were fitted for each combination to derive several parameters, including: 1) the effect of the single agents on viability; 2) the maximum concentration used (E max ) the effect on survival at 100 mg / kg / day, and 3) the estimated drug concentration resulting in a 50% reduction in survival (IC 50 We compared the observed cellular responses to the combinations with the Bliss Independence predicted responses based on monotherapy activity and measured the intensity (ΔIC 50 , i.e., increased sensitivity) or efficacy (ΔE maxDrug combinations were classified based on a shift in the potency of the β-dependent agonist (i.e., decreased cell viability) beyond Bliss independence (Bliss, Annals of Applied Biology, 1939, 26(3), 585-615).

[0139] result: Inhibitors of two different Bcl-2 family proteins were tested in combination with the Aurora kinase inhibitor alisertib in JIMT-1 cells, a Her2-positive breast cancer cell line. The Bcl-2 family can be divided into pro-apoptotic proteins (including BAX and BAK) and anti-apoptotic proteins (including Bcl-2, Bcl-xL, and Mcl-1). All anti-apoptotic Bcl-2 family proteins share the BH3 domain, a structural feature that has been exploited in the treatment of cancer for the development of a class of drugs known as BH3 mimetics. These agents mimic the activity of pro-apoptotic proteins and inhibit other pro-survival family members (Diepstraten et al., Nat Rev Cancer. 2022 Jan;22(1):45-64; Kelekar and Thompson Trends Cell Biol. 1998 Aug;8(8):324-30; Townsend et al., J Exp Clin Cancer Res. 2021 Nov;9;9;40(1):355). Navitoclax is a potent inhibitor of Bcl-2, Bcl-xL and Bcl-w but binds more weakly to Mcl1 and A1, while A-1331852 is a selective inhibitor of Bcl-xL, exhibiting ≧400-fold selectivity for Bcl-xL compared to Bcl-2, Bcl-w and Mcl-1. Table 2 below shows the ΔIC values ​​obtained for each combination from two independent replicates. 50 and ΔE max The maximum values ​​of navitoclax and A-1331852 are shown in Table 1. The results show that both navitoclax and A-1331852 are synergistic with alisertib in this cell line.

[0140] [Table 2]

[0141] References In order to more fully describe and disclose the present invention and the state of the art to which it pertains, a number of publications are cited above. Full citations for these references are set forth below. Each of these references is incorporated herein in its entirety. Beltran et al., Clin. Cancer Res., 2019 Jan 1;25(1):43-51 Berge et al., J Pharm Sci, 1977 66(1) p 1 Bliss, Annals of Applied Biology, 1939, 26(3), 585-615 Cleary et al., Invest New Drugs, 2014 Oct;32(5):937-945 Davies et al., Nat Med. 2017 Apr; 23(4): 517-525 Diepstraten et al., Nat Rev Cancer. 2022 Jan;22(1):45-64 EP1888550 Gandhi et al., J Clin Oncol, 2011 Mar 1;29(7):909-916 Gnant et al. Ann. Oncol.;2014 25(2) pp. 339-45 Gonzalez-Martin et al. N Engl J Med 2019; 381(25):2391-2402 (PMID 51362799) Kelekar and Thompson Trends Cell Biol. 1998 Aug;8(8):324-30 Kelly et al., Invest New Drugs, 2014 Jun;32(3):489-499 Ngoi and Tan, ESMO Open, 2021 Jun;6(3):100144 Nielson et al. Clin Cancer Res; 2010 16(21) pp. 5255-32 Seymour et al., Blood Cancer Journal, 2014, 4, e238 Townsend et al., J Exp Clin Cancer Res. 2021 Nov 9;40(1):355 Traynor et al., Cancer Chemother Pharmacol. 2011 February; 67(2): 305-314 Wilson et al., Lancet Oncol.; 2010 Dec;11(12):1149-1159 Venkatakrishnan et al., Invest New Drugs, 2015 Aug;33(4):942-953 https: / / assets.ctfassets.net / w98cd481qyp0 / 41rJj28gFwtxCwHQxopaEb / fba378cd309082f09570f32fc16b5d01 / FoundationOne_CDx_Label_Technical_Info.pdf https: / / www.cancer.gov / types / breast / hp / breast-treatment-pdq#_18 https: / / myriad.com / products-services / precision-medicine / mychoice-cdx /

[0142] For standard molecular biology techniques, see Sambrook, J., Russell, DW Molecular Cloning, A Laboratory Manual. 3rd ed. 2001, Cold Spring Harbor, New York, Cold Spring Harbor Laboratory Press.

[0143] Prevailing Terms 1. A combination of navitoclax or venetoclax with an Aurora kinase inhibitor for use in a method for treating a cancer selected from breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer in a patient. 2. A combination for use according to clause 1, wherein the combination is navitoclax and an aurora kinase inhibitor. 3. A combination for use according to clause 1, wherein the combination is venetoclax and an aurora kinase inhibitor. 4. The combination for use according to any one of clauses 1 to 3, wherein the cancer is non-HER2 rich breast cancer. 5. The combination for use according to any one of clauses 1 to 4, wherein the cancer is determined to be HER2-. 6. The combination for use according to any one of clauses 1 to 5, wherein the cancer is basal-like breast cancer. 7. The combination for use according to any one of clauses 1 to 6, wherein the cancer is triple-negative breast cancer. 8. The combination for use according to any one of clauses 1 to 5, wherein the cancer is luminal B breast cancer. 9. The combination for use according to any one of clauses 1 to 5, wherein the cancer is luminal A breast cancer. 10. The combination for use according to any one of clauses 1 to 9, wherein the Aurora kinase inhibitor is an Aurora A kinase inhibitor. 11. The combination for use according to any one of clauses 1 to 10, wherein the Aurora kinase inhibitor is selected from alisertib, tozasertib, ZM447439, AZD2811 and AZD1152. 12. The combination for use according to any one of clauses 1 to 11, wherein the Aurora kinase inhibitor is selected from alisertib, tozasertib and ZM447439. 13. The combination for use according to any one of clauses 1 to 12, wherein navitoclax or venetoclax and the Aurora kinase inhibitor are administered separately.

Claims

1. A combination of an inhibitor of the Bcl-2 protein family selected from navitoclax, venetoclax, A-1331852, AZD5991, or A-1155463 and an Aurora kinase inhibitor for use in a method for treating cancer selected from breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer in a patient.

2. An inhibitor of the Bcl-2 protein family selected from navitoclax, venetoclax, A-1331852, AZD5991, or A-1155463 for use in a method for treating cancer selected from breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer in a patient, wherein the inhibitor of the Bcl-2 protein family is administered to the patient in combination with an Aurora kinase inhibitor.

3. 1. An Aurora kinase inhibitor for use in a method for treating a cancer selected from breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer in a patient, wherein the Aurora kinase inhibitor is administered to the patient in combination with an inhibitor of the Bcl-2 protein family selected from navitoclax, venetoclax, A-1331852, AZD5991, or A-1155463.

4. 10. The combination for use according to claim 1, the inhibitor of the Bcl-2 protein family for use according to claim 2, or the Aurora kinase inhibitor for use according to claim 3, wherein the inhibitor of the Bcl-2 protein family is navitoclax.

5. 10. The combination for use according to claim 1, the inhibitor of the Bcl-2 protein family for use according to claim 2, or the Aurora kinase inhibitor for use according to claim 3, wherein the inhibitor of the Bcl-2 protein family is A-1331852.

6. 10. The combination for use according to claim 1, the inhibitor of the Bcl-2 protein family for use according to claim 2, or the Aurora kinase inhibitor for use according to claim 3, wherein the inhibitor of the Bcl-2 protein family is A-1155463.

7. 10. The combination for use according to claim 1, the inhibitor of the Bcl-2 protein family for use according to claim 2, or the Aurora kinase inhibitor for use according to claim 3, wherein the inhibitor of the Bcl-2 protein family is venetoclax.

8. 10. The combination for use according to claim 1, the inhibitor of the Bcl-2 protein family for use according to claim 2, or the Aurora kinase inhibitor for use according to claim 3, wherein the inhibitor of the Bcl-2 protein family is AZD5991.

9. The cancer is breast cancer, 10. The combination for use according to claim 1, the inhibitor of the Bcl-2 protein family for use according to claim 2, or the Aurora kinase inhibitor for use according to claim 3, optionally wherein the cancer is non-HER2-rich breast cancer, basal-like breast cancer, triple-negative breast cancer, luminal B breast cancer, or luminal A breast cancer.

10. 10. The combination for use according to claim 1, the inhibitor of the Bcl-2 protein family for use according to claim 2, or the Aurora kinase inhibitor for use according to claim 3, wherein the cancer is determined to be HER2-.

11. 2. A combination for use according to claim 1, an inhibitor of the Bcl-2 protein family for use according to claim 2, or an Aurora kinase inhibitor for use according to claim 3, wherein the Aurora kinase inhibitor is an Aurora A kinase inhibitor.

12. the Aurora kinase inhibitor is selected from alisertib, tozasertib, ZM447439, AZD2811, AZD1152, LY3295668, MK-5108, GSK1070916 and MLN8054; optionally, the Aurora kinase inhibitor is selected from alisertib, tozasertib, ZM447439, AZD2811, and AZD1152; optionally, the Aurora kinase inhibitor is selected from alisertib, tozasertib, and ZM447439; Optionally, the combination for use according to claim 1, the inhibitor of the Bcl-2 protein family for use according to claim 2, or the Aurora kinase inhibitor for use according to claim 3, wherein the Aurora kinase inhibitor is alisertib.

13. 10. The combination for use according to claim 1, the inhibitor of the Bcl-2 protein family for use according to claim 2, or the Aurora kinase inhibitor for use according to claim 3, wherein the inhibitor of the Bcl-2 protein family and the Aurora kinase inhibitor are administered separately.

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