Combination therapy for treating cancer

Abstract

The present invention provides a method of treating ovarian, breast, gastrointestinal, lung, brain, or prostate cancer in a subject in need thereof, the method comprising administering to the subject a first amount of a selective PARP1 inhibitor, or a pharmaceutically acceptable salt thereof, and a second amount of an ATR inhibitor, or a pharmaceutically acceptable salt thereof. Also disclosed are compositions and kits comprising a PARP inhibitor and an ATR inhibitor.

Description

[0001] The present disclosure relates to methods of treating ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer, or prostate cancer in a patient in need thereof. Background Art

[0002] Clinical PARP inhibitors (PARPi) mainly work by “trapping” the PARP1-DNA complex, generating DNA damage, thereby blocking DNA replication fork progression, inducing replication stress and activating the ataxia telangiectasia and Rad3-related (ATR)-dependent replication stress response (RSR) pathway to promote DNA repair (Cimprich 2008, Forment 2018).

[0003] ATR is a serine / threonine protein kinase, and multiple small molecule kinase inhibitors of ATR are in clinical development for the treatment of cancer as monotherapy or in combination with targeted agents, chemotherapy / radiotherapy, or immune checkpoint blockade (Foote 2015, Barneih 2021).

[0004] In particular, ATR inhibition is expected to act synergistically in combination with PARP inhibition, resulting in increased DNA damage and enhanced anti-tumor activity. Extensive preclinical studies of ATR inhibitors (e.g., ceralasertib, elimusertib, berzosertib, gartisertib, VE-821, RP-3500) in combination with first generation clinical PARP inhibitors (e.g., olaparib, talazoparib, niraparib, rucaparib) have demonstrated greater anti-tumor activity than can be obtained with either agent alone.

[0005] The clinical use of PARPi in the treatment of epithelial ovarian cancer (EOC) has expanded dramatically. Olaparib, rucaparib, and niraparib were initially approved as monotherapy for the relapsed setting (Kim 2015, Balasubramaniam 2017) without known platinum sensitivity and were subsequently approved as post-chemotherapy maintenance therapy for platinum-sensitive disease (Ison 2018). PARPi are now FDA-approved as first-line maintenance therapy. Olaparib received FDA approval in 2018 as maintenance therapy after a response to first-line platinum-based therapy for patients with germline or somatic BRCA-mutated EOC. In April 2020, niraparib received FDA approval as maintenance therapy after a response to first-line platinum therapy (regardless of HR status), and the combination of olaparib / bevacizumab received FDA approval in May 2020 as maintenance therapy for patients with HRD EOC.

[0006] Combinations of PARP inhibitors and certain ATR inhibitors have been demonstrated in PARPi-naïve or PARPi-resistant BRCA1-mutated EOC models (VE-821, Burgess 2020; AZD6738, Kim 2020), breast cancer models (BAY-1895344, Wengner 2020; AZD6738, Wilson 2022; RP-3500, Roulston 2022), and lung cancer models (bercetinib, Gorecki 2020; AZD6738, Lloyd 2020; M4344, Jo 2021). Furthermore, the combination has demonstrated the ability to overcome innate or acquired PARP inhibitor resistance mechanisms (Prados-Carvajal 2021), such as fork protection pathways through BRCA reversal (Kim 2021), homologous recombination (HR) rearrangement (loss of 53BP1 / Shieldin complex), and partial restoration of HR function (Yazinski 2017) or SLFN11-loss (Murai 2016).

[0007] It is expected that as the use of PARPi increases, more and more patients will be found to have de novo or acquired resistance to PARPi.

[0008] Reports from small clinical trials of olaparib and serasertib in patients with relapsed, platinum-resistant BRCA-mutated EOC (the CAPRI trial, Shah 2021) and in patients with BRCA-mutated PARP inhibitor-resistant HGSOC (the OLAPCO trial, Madhi 2021) have shown signs of clinical activity.

[0009] However, it was recently reported that the combination of olaparib and seracept did not improve outcomes in previously treated metastatic triple-negative breast cancer compared with olaparib alone (Tutt 2022).

[0010] Although great progress has been made in the treatment of ovarian, breast, gastrointestinal, lung, brain or prostate cancer, many patients with these cancers still live with incurable disease. Therefore, it is important to continue to find new treatments for patients with incurable cancers. Summary of the invention

[0011] In some embodiments, a method of treating ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer in a subject in need thereof is disclosed, the method comprising administering to the subject a first amount of a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, and a second amount of an ATR inhibitor or a pharmaceutically acceptable salt thereof. In the method, the first amount and the second amount together constitute a therapeutically effective amount.

[0012] In some embodiments, a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof is disclosed for use in treating ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer in a subject, wherein the treatment comprises separately, sequentially or simultaneously administering to the subject i) the selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, and ii) an ATR inhibitor or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, an ATR inhibitor or a pharmaceutically acceptable salt thereof is disclosed for use in treating ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer in a subject, wherein the treatment comprises administering to the subject separately, sequentially or simultaneously i) the ATR inhibitor or a pharmaceutically acceptable salt thereof, and ii) a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, disclosed is the use of a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer, wherein the treatment comprises administering to the subject separately, sequentially or simultaneously i) the medicament comprising the selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, and ii) an ATR inhibitor or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, a pharmaceutical product is disclosed, comprising i) a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, and ii) an ATR inhibitor or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, a kit is disclosed, comprising: a first pharmaceutical composition comprising a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising an ATR inhibitor or a pharmaceutically acceptable salt thereof; and instructions for using the first pharmaceutical composition and the second pharmaceutical composition in combination.

[0017] The combination of a selective PARP1 inhibitor and an ATR inhibitor may produce fewer side effects or be more effective than current monotherapy or combination treatments. This may be due to the selectivity of PARP1 inhibitors. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Shown is a complete loss of 53BP1 protein expression in the SUM149PT 53BP1 KO cell pool compared to the control SUM149PT 53BP1 WT cell pool (CNTR).

[0019] Figure 2 Shown are the clonal growth of SUM149PT CNTR or 53BP1 KO cell pools after AZD5305 (PARP1Sel=AZD5305) monotherapy.

[0020] Figure 3 Shown is the clonal growth of SUM149PT CNTR or 53BP1 KO cell pools following a single AZD5305 (PARP1Sel = AZD5305) dose in combination with a 5 point concentration response of AZD6738. DETAILED DESCRIPTION

[0021] Selective PARP1 inhibitors

[0022] A selective PARP1 inhibitor is a compound that selectively inhibits PARP1 (relative to other members of the PARP family, including PARP2, PARP3, PARP5a, and PARP6). Advantageously, the selective PARP1 inhibitor has selectivity for PARP1 relative to PARP2. In an embodiment, the selective PARP1 inhibitor is 10 times more selective for PARP1 than for PARP2. In a further embodiment, the selective PARP1 inhibitor is 100 times more selective for PARP1 than for PARP2. In a further embodiment, the selective PARP1 inhibitor is 500 times more selective for PARP1 than for PARP2.

[0023] In some embodiments, the selective PARP1 inhibitor is a compound disclosed in WO 2021 / 013735 A1. These compounds have formula (I):

[0024]

[0025] in:

[0026] X 1 and X 2 are each independently selected from N and C(H),

[0027] X 3 are independently selected from N and C(R 4 ), where R 4 is H or fluorine,

[0028] R 1 It is C 1-4 Alkyl or C 1-4 Fluoroalkyl,

[0029] R 2 are independently selected from H, halo, C 1-4 Alkyl, and C 1-4 fluoroalkyl, and

[0030] R 3 Is H or C 1-4 alkyl,

[0031] or a pharmaceutically acceptable salt thereof

[0032] The conditions are:

[0033] When X 1 When it is N, then X 2 is C(H), and X 3 is C(R 4 ),

[0034] When X 2 When it is N, then X 1 =C(H), and X 3 is C(R 4 ),and

[0035] When X 3 When it is N, then X 1 and X 2 All are C(H).

[0036] Alkyl groups and moieties are straight or branched chain, e.g. C 1-8 Alkyl, C 1-6 Alkyl, C 1-4 Alkyl or C 5-6 Alkyl. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl, such as methyl or n-hexyl.

[0037] A fluoroalkyl group is an alkyl group in which one or more H atoms are replaced by one or more fluorine atoms, for example C 1-8 Fluoroalkyl, C 1-6 Fluoroalkyl, C 1-4 Fluoroalkyl or C 5-6 Fluoroalkyl. Examples include fluoromethyl (—CH2F), difluoromethyl (—CHF2), trifluoromethyl (—CF3), 2,2,2-trifluoroethyl (CF3CH2-), 1,1-difluoroethyl (CH3CHF2-), 2,2-difluoroethyl (CHF2CH2-), and 2-fluoroethyl (CH2FCH2-).

[0038] Halo means fluorine, chlorine, bromine, and iodine. In one embodiment, halo is fluorine or chlorine.

[0039] In some embodiments, the selective PARP1 inhibitor is "AZD5305", which refers to a compound with the chemical name 5-{4-[(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide, and its structure is shown below:

[0040]

[0041] AZD5305 is a potent and selective PARP1 inhibitor and PARP1-DNA trap with excellent in vivo efficacy. AZD5305 is highly selective for PARP1 over other PARP family members, has favorable secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, and has reduced effects on human bone marrow progenitor cells in vitro.

[0042] The synthesis of AZD5305 is described in Johannes 2021 and WO 2021 / 013735, the contents of which are hereby incorporated by reference in their entirety. In some embodiments, the free base AZD5305 is administered to the subject. In some embodiments, a pharmaceutically acceptable salt of AZD5305 is administered to the subject. In some embodiments, crystalline AZD5305 or a pharmaceutically acceptable salt of AZD5305 is administered to the subject.

[0043] In some embodiments, the selective PARP1 inhibitor is a compound disclosed in WO 2021 / 260092 A1. These compounds have formula (II):

[0044]

[0045] in:

[0046] R 1 Independently selected from H, C1-4 Alkyl, C 1-4 Fluoroalkyl, and C 1-4 Alkoxy;

[0047] R 2 are independently selected from H, halo, C 1-4 Alkyl, and C 1-4 fluoroalkyl; and

[0048] R 3 Is H or C 1-4 alkyl;

[0049] R 4 Is halogenated or C 1-4 alkyl,

[0050] or a pharmaceutically acceptable salt thereof.

[0051] Alkoxy is an alkyl group attached to the rest of the molecule via an oxygen atom. Suitable C 1-4 Examples of alkyloxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy.

[0052] In some embodiments, the selective PARP1 inhibitor is "AZD9574", which refers to a compound with the chemical name 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridine-2-carboxamide, and its structure is shown below:

[0053]

[0054] AZD9574 is a blood-brain barrier permeabilizer PARP1 selective inhibitor. The synthesis of AZD9574 is described in WO2021 / 260092A1 (Example 20), the contents of which are hereby incorporated by reference in their entirety. In some embodiments, the free base AZD9574 is administered to the subject. In some embodiments, a pharmaceutically acceptable salt of AZD9574 is administered to the subject. In some embodiments, crystalline AZD9574 or a pharmaceutically acceptable salt of AZD9574 is administered to the subject.

[0055] In some embodiments, the selective PARP1 inhibitor is "AZ14114554", which refers to a compound with the chemical name 7-((4-(1,5-dimethyl-1H-imidazol-2-yl)piperazin-1-yl)methyl)-3-ethylquinolin-2(1H)-one, and its structure is shown below:

[0056]

[0057] The synthesis of AZ14114554 is described in Johannes 2021 (Compound 16), the contents of which are hereby incorporated by reference in their entirety. In some embodiments, the free base AZ14114554 is administered to the subject. In some embodiments, a pharmaceutically acceptable salt of AZ14114554 is administered to the subject. In some embodiments, crystalline AZ14114554 or a pharmaceutically acceptable salt of AZ14114554 is administered to the subject.

[0058] In some embodiments, the selective PARP1 inhibitor is a compound disclosed in any one of WO 2010 / 133647, WO 2011 / 006794, WO 2011 / 006803, WO 2013 / 014038, WO 2013 / 076090 and WO 2014 / 064149, which are incorporated by reference. The core of these selective PARP1 inhibitors is:

[0059]

[0060] and in some embodiments:

[0061]

[0062] Compounds of particular interest are:

[0063]

[0064]

[0065] ATR inhibitors

[0066] Ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in the DNA damage response (DDR) by activating the fundamental signaling pathway for DNA damage repair. There are many known ATR inhibitors, including:

[0067] ·Seraset

[0068] Bezosertinib

[0069] Elimositib

[0070] VE-821

[0071] ·Getiseti

[0072] Camonsertib

[0073] AZ20

[0074] ATRN-119

[0075] ART-0380

[0076] IMP-9064

[0077] SC-0245

[0078] ATG-018

[0079] LR-02

[0080] These and other ATR inhibitors are described in Barnieh 2021. ATR inhibitors may be suitable for use in the present invention if they meet one or more of the following criteria:

[0081] ·IC 50 ≤100nM

[0082] >10-fold, e.g. >100-fold selectivity for PI3K

[0083] ·Selectivity for ATM >10-fold, e.g. >100-fold

[0084] · Selectivity for DNA-PK > 10-fold, e.g. > 100-fold

[0085] "Serasertib" refers to a compound whose chemical name is 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]-pyridine, and its structure is shown below:

[0086]

[0087] Selasertib (formerly known as AZD6738) is an orally available morpholino-pyrimidine-based inhibitor of ataxia telangiectasia and rad3-related (ATR) kinase with potential anti-tumor activity. Following oral administration, selasertib selectively inhibits ATR activity by blocking downstream phosphorylation of the serine / threonine protein kinase CHK1. This prevents ATR-mediated signaling and leads to inhibition of DNA damage checkpoint activation, impairing DNA damage repair and inducing tumor cell apoptosis. In addition, selasertib sensitizes tumor cells to chemotherapy and radiotherapy. ATR is a serine / threonine protein kinase that is upregulated in multiple cancer cell types and plays a key role in DNA repair, cell cycle progression and survival; it is activated by DNA damage caused during DNA replication-related stress.

[0088] The synthesis of celasetinib is described in WO 2011 / 154737 (Example 2.02), WO 2020 / 127208, and Foote 2018, the contents of which are hereby incorporated by reference in their entirety. In some embodiments, the free base celasetinib is administered to the subject. In some embodiments, a pharmaceutically acceptable salt of celasetinib is administered to the subject. In some embodiments, crystalline celasetinib or a pharmaceutically acceptable salt of celasetinib is administered to the subject.

[0089] "Bezosertinib" refers to a compound whose chemical name is 3-(3-(4-((methylamino)methyl)phenyl)-1,2-oxazol-5-yl)-5-(4-(propane-2-sulfonyl)phenyl)pyrazin-2-amine, and its structure is shown below:

[0090]

[0091] It was previously known as M-6620 and VX-970. It is a potent ATR inhibitor and a weaker inhibitor of ATM serine / threonine kinase (ATM).

[0092] The synthesis of berzosertib is described in WO2010 / 071837 (Example 57a-Compound IIA-7) and Knegtel2019, the contents of which are hereby incorporated by reference in their entirety. In some embodiments, free base berzosertib is administered to a subject. In some embodiments, a pharmaceutically acceptable salt of berzosertib is administered to a subject. In some embodiments, crystalline berzosertib or a pharmaceutically acceptable salt of berzosertib is administered to a subject.

[0093] "Elimositib" refers to a compound whose chemical name is 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine, and its structure is shown below:

[0094]

[0095] The synthesis of Elimosinib (formerly known as BAY-1895344) is described in WO 2016 / 020320 (Example 111), the contents of which are hereby incorporated by reference in their entirety. In some embodiments, free base Elimosinib is administered to a subject. In some embodiments, a pharmaceutically acceptable salt of Elimosinib is administered to a subject. In some embodiments, a pharmaceutically acceptable salt of crystalline Elimosinib or Elimosinib is administered to a subject.

[0096] "VE-821" refers to a compound whose chemical name is 3-amino-N,6-diphenylpyrazine-2-carboxamide, and whose structure is shown below:

[0097]

[0098] The synthesis of VE-821 is described in Charrier 2011 (Compound 6), the contents of which are hereby incorporated by reference in their entirety. In some embodiments, free base VE-821 is administered to a subject. In some embodiments, a pharmaceutically acceptable salt of VE-821 is administered to a subject. In some embodiments, crystalline VE-821 or a pharmaceutically acceptable salt of VE-821 is administered to a subject.

[0099] "Geti Seti" refers to a compound with the chemical name of 2-amino-6-fluoro-N-[5-fluoro-4-(4-{[4-(3-oxetanyl)-1-piperazinyl]carbonyl}-1-piperidinyl)-3-pyridinyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, and its structure is shown below:

[0100]

[0101] Geti color (formerly known as M4344 and VX-803) is described in Zenke 2019 and Jo 2021, the contents of which are hereby incorporated by reference in their entirety. In some embodiments, the free base Geti color is administered to the subject. In some embodiments, a pharmaceutically acceptable salt of Geti color is administered to the subject. In some embodiments, a pharmaceutically acceptable salt of crystalline Geti color or Geti color is administered to the subject.

[0102] "Camonseti" refers to a compound with the chemical name (1R, 3R, 5S)-3-6-[(3R)-3-methylmorpholin-4-yl]-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl-8-oxabicyclo[3.2.1]octan-3-ol, and its structure is shown below:

[0103]

[0104] Camoser (formerly known as RP-3500) is described in Roulston 2022, the contents of which are hereby incorporated by reference in their entirety. In some embodiments, the free base Camoser is administered to the subject. In some embodiments, a pharmaceutically acceptable salt of Camoser is administered to the subject. In some embodiments, crystalline Camoser or a pharmaceutically acceptable salt of Camoser is administered to the subject.

[0105] "AZ20" refers to a compound whose chemical name is 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole, and its structure is shown below:

[0106]

[0107] AZ20 is described in Foote 2013, the contents of which are hereby incorporated by reference in their entirety. In some embodiments, the free base AZ20 is administered to the subject. In some embodiments, a pharmaceutically acceptable salt of AZ20 is administered to the subject. In some embodiments, crystalline AZ20 or a pharmaceutically acceptable salt of AZ20 is administered to the subject.

[0108] "ATRN-119" refers to a compound from ATRIN that is about to undergo clinical trials (NCT04905914) and is described in WO 2016 / 061097. It is also discussed in, for example, Gilad 2020 and George 2018.

[0109] “ART-0380” refers to a compound from Artios that is in Phase 1 clinical trials (NCT04657068). It is also discussed in, for example, Patel 2022.

[0110] “IMP-9064” refers to a compound from IMPACT that is in clinical trials (NCT05269316; CXHL2101780).

[0111] "SC-0245" refers to a compound from Wuxi Apptec that is in clinical trials (CTR20210769) and is described in WO 2021 / 023272. It is also discussed in, for example, Wang 2020.

[0112] “ATG-018” refers to a compound from Antegene that is in clinical trials (NCT05338346). It is also discussed in Yuwen 2022, for example.

[0113] “LR-02” refers to a compound from Laevoroc Oncology, which is discussed, for example, in Koul 2021.

[0114] In some embodiments, the selective PARP1 inhibitor is AZD5305 or AZD9574, and the ATR inhibitor is serasetin. In some of these embodiments, the selective PARP1 inhibitor is AZD5305, and the ATR inhibitor is serasetin. In other embodiments, the selective PARP1 inhibitor is AZD9574, and the ATR inhibitor is lasetin.

[0115] The term "pharmaceutical composition" includes: a composition comprising an active ingredient and a pharmaceutically acceptable excipient, carrier or diluent, wherein the active ingredient is a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, or an ATR inhibitor or a pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable excipient, carrier or diluent" includes compounds, materials, compositions and / or dosage forms that are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic response or other problems or complications, as determined by those skilled in the art, within the scope of reasonable medical judgment. In some embodiments, the pharmaceutical composition is a solid dosage form, such as a capsule, tablet, granule, powder or sachet. In some embodiments, the pharmaceutical composition is in the form of a sterile injectable solution in one or more aqueous or non-aqueous non-toxic parenterally acceptable buffer systems, diluents, solubilizers, co-solvents or carriers. The sterile injectable preparation may also be a sterile injectable aqueous or oily suspension or a suspension in a non-aqueous diluent, carrier or co-solvent, which can be formulated according to known procedures using one or more appropriate dispersants or wetting agents and suspending agents. The pharmaceutical composition can be a solution for intravenous (iv) bolus / infusion, or a lyophilized system (alone or with excipients) reconstituted with a buffer system with or without other excipients. The lyophilized freeze-dried material can be prepared from a non-aqueous solvent or an aqueous solvent. The dosage form can also be a concentrate for further dilution for subsequent infusion.

[0116] The terms "treat," "treating," and "treatment" include reducing or inhibiting the activity of an enzyme or protein associated with PARP-1, ATR, or ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer, or prostate cancer in a subject, improving one or more symptoms of ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer, or prostate cancer in a subject, or slowing or delaying the progression of ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer, or prostate cancer in a subject. The terms "treat," "treating," and "treatment" also include reducing or inhibiting the growth of a tumor or the proliferation of cancer cells in a subject.

[0117] The terms "inhibit," "inhibition," or "inhibiting" include a decrease in the baseline activity of a biological activity or process.

[0118] The term "subject" includes warm-blooded mammals, such as primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, such as a human. In some embodiments, the subject has ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer, or prostate cancer.

[0119] The term "therapeutically effective amount" includes an amount of a selective PARP1 inhibitor and an amount of an ATR inhibitor that together will cause a biological or medical response in a subject, for example, reducing or inhibiting the activity of an enzyme or protein associated with PARP1, ATR or cancer; improving symptoms of ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer; or slowing or delaying the progression of ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer. In some embodiments, the term "therapeutically effective amount" includes an amount of a selective PARP1 inhibitor and an ATR inhibitor that together are effective to at least partially alleviate, inhibit and / or alleviate ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer, or inhibit PARP1 or ATR, and / or reduce or inhibit the growth of a tumor or the proliferation of cancerous cells in a subject.

[0120] Without wishing to be bound by theory, the combination of a selective PARP1 inhibitor with an ATR inhibitor may provide more favorable tolerability, higher drug exposure, and more durable target inhibition compared to the combination of first generation PARP inhibitors with ATR inhibitors, resulting in greater anti-tumor efficacy and combination options.

[0121] In some embodiments, a method of treating ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer in a subject in need thereof is disclosed, the method comprising administering to the subject a first amount of a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, and a second amount of an ATR inhibitor or a pharmaceutically acceptable salt thereof. In the method, the first amount and the second amount together constitute a therapeutically effective amount.

[0122] In some embodiments, a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof is disclosed for use in treating ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer in a subject, wherein the treatment comprises separately, sequentially or simultaneously administering to the subject i) the selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, and ii) an ATR inhibitor or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, an ATR inhibitor or a pharmaceutically acceptable salt thereof is disclosed for use in treating ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer in a subject, wherein the treatment comprises administering to the subject separately, sequentially or simultaneously i) the ATR inhibitor or a pharmaceutically acceptable salt thereof, and ii) a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, disclosed is the use of a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer in a subject, wherein the treatment comprises administering to the subject separately, sequentially or simultaneously i) the medicament comprising the selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, and ii) an ATR inhibitor or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof and the ATR inhibitor or a pharmaceutically acceptable salt thereof are administered separately, sequentially or simultaneously during a treatment cycle. In some embodiments, the selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof is administered continuously during a treatment cycle, and the ATR inhibitor or a pharmaceutically acceptable salt thereof is also administered continuously during the treatment cycle.

[0126] The term "continuously" or "continuously" refers to administration of a therapeutic agent, such as a selective PARP1 inhibitor, at regular intervals without cessation or interruption (ie, no blank days). A "blank day" means a day on which no therapeutic agent is administered.

[0127] As used herein, the term "intermittent" or "intermittently" means stopping and starting administration of a therapeutic agent at regular or irregular intervals during a treatment cycle. For intermittent administration, there is at least one blank day during a treatment cycle.

[0128] As used herein, a "cycle," "treatment cycle," or "dosing schedule" refers to a period of time for a combination therapy that is repeated on a regular schedule. For example, treatment may be administered for one week, two weeks, or three weeks, wherein the selective PARP1 inhibitor and the ATR inhibitor are administered in a coordinated manner. In some embodiments, the treatment cycle is from about 1 week to about 3 months. In some embodiments, the treatment cycle is from about 5 days to about 1 month. In some embodiments, the treatment cycle is from about 1 week to about 3 weeks. In some embodiments, the treatment cycle is about 1 week, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, or about 3 months. In some embodiments, the rest period (i.e., one or more blank days) in the treatment cycle is from about 1 day to about 1 month. In some embodiments, the rest period in the treatment cycle is about 1 day, about 3 days, about 5 days, about 1 week, about 2 weeks, or about 3 weeks.

[0129] In some embodiments, a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof and an ATR inhibitor or a pharmaceutically acceptable salt thereof are administered to a human subject in one or more treatment cycles (e.g., a course of treatment). A "course of treatment" comprises multiple treatment cycles, which can be repeated on a regular schedule, or adjusted to a gradually decreasing schedule based on the monitored patient's disease progression. For example, at the beginning of a course of treatment (e.g., when a patient is first diagnosed), a patient's treatment cycle may have a longer treatment period and / or a shorter rest period, and as the cancer begins to ease, the rest period is extended, thereby increasing the length of a treatment cycle. Throughout the course of treatment, a technician can determine and adjust the time periods used for treatment and rest in the treatment cycle, the number of treatment cycles, and the length of the course of treatment based on the patient's disease progression, treatment tolerance, and prognosis. In some embodiments, the method comprises 1 to 10 treatment cycles. In some embodiments, the method comprises 2 to 8 treatment cycles.

[0130] AZD5305 administration

[0131] In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof is administered for 28 days in a 28 day treatment cycle. In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof is administered on an intermittent schedule.

[0132] In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof is in tablet dosage form. In some embodiments, AZD5305 is administered at a dose of up to about 60 mg per day (e.g., up to 0.5 mg, up to 1 mg, up to about 2.5 mg, up to about 5 mg, up to about 10 mg, up to about 15 mg, up to about 20 mg, up to about 25 mg, up to about 30 mg, up to about 35 mg, up to about 40 mg, up to about 45 mg, up to about 50 mg, up to about 55 mg or up to about 60 mg AZD5305). In some embodiments, AZD5305 is administered once a day (QD). In some embodiments, AZD5305 is administered at a dose of about 0.5 mg Qd, about 1 mg Qd, about 2.5 mg Qd, about 5 mg QD, about 10 mg QD, about 15 mg QD, about 20 mg QD, about 25 mg QD, about 30 mg QD, about 35 mg QD, about 40 mg QD, about 45 mg QD, about 50 mg QD, about 55 mg QD or about 60 mg QD.

[0133] In some further embodiments, AZD5305 is administered at a dose of up to about 140 mg per day (e.g., up to about 80 mg, up to about 90 mg, up to about 100 mg, up to about 110 mg, up to about 120 mg or up to about 140 mg AZD5305). In some further embodiments, AZD5305 is administered at a dose of about 80 mg QD, about 90 mg QD, about 100 mg QD, about 110 mg QD, about 120 mg QD or about 140 mg QD.

[0134] PARP1 selective inhibitor administration

[0135] In some embodiments, the PARP1 selective inhibitor may be administered in the same manner as described above for AZD5305.

[0136] ATR inhibitor administration

[0137] In some embodiments, the ATR inhibitor is administered on an intermittent schedule, for example, 7 or 14 consecutive days in a 28-day treatment cycle, i.e., with a three-week or two-week rest period, or 3 consecutive days in a 7-day or 14-day treatment cycle, i.e., with a 4-day or 11-day rest period.

[0138] Celasetib administration

[0139] In some embodiments, celasetil or a pharmaceutically acceptable salt thereof is administered continuously for 7 or 14 days in a 28-day treatment cycle, ie, with a three-week or two-week rest period.

[0140] In some embodiments, celaseti or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, celaseti or a pharmaceutically acceptable salt thereof is in tablet dosage form. In some embodiments, celaseti or a pharmaceutically acceptable salt thereof is orally administered at a dose of up to about 320 mg (e.g., up to about 120 mg, up to about 140 mg, up to about 160 mg, up to about 180 mg, up to about 200 mg, up to about 220 mg, up to about 240 mg, up to about 280 mg, or up to about 320 mg celaseti) per day. In some embodiments, celaseti is administered twice a day (BID). In some embodiments, celaseti is administered at a dose of about 60 mg BID, about 80 mg BID, about 100 mg BID, about 120 mg BID, about 140 mg BID, or about 160 mg BID. In some embodiments, a 160 mg dose comprises an 80 mg or 160 mg tablet.

[0141] Elimosinib administration

[0142] In some embodiments, elimostibin or a pharmaceutically acceptable salt thereof is administered for 3 consecutive days in a 7-day treatment cycle or for 3 consecutive days in a 14-day treatment cycle.

[0143] In certain embodiments, elimostibu or its pharmaceutically acceptable salt is orally administered. In certain embodiments, elimostibu or its pharmaceutically acceptable salt is in tablet dosage form. In certain embodiments, elimostibu or its pharmaceutically acceptable salt is administered with a dosage of up to about 80 mg (e.g., oral administration of up to about 20 mg, up to about 40 mg, up to about 60 mg or up to about 80 mg per day).

[0144] Camosertib administration

[0145] In some embodiments, camencetib or a pharmaceutically acceptable salt thereof is administered for 3 consecutive days in a 7-day treatment cycle.

[0146] In some embodiments, camonseti or its pharmaceutically acceptable salt is orally administered. In some embodiments, camonseti or its pharmaceutically acceptable salt is in tablet dosage form. In some embodiments, camonseti or its pharmaceutically acceptable salt is administered at a dosage of up to about 200 mg (e.g., up to about 40 mg, up to about 60 mg, up to about 80 mg, up to about 100 mg, up to about 120 mg, up to about 140 mg, up to about 160 mg, up to about 180 mg, or up to about 200 mg per day).

[0147] Combination drug administration

[0148] In some embodiments, AZD5305 and celaxetib are taken separately, wherein the dose of AZD5305 is taken on an empty stomach, without food for two hours prior to taking it, and the dose of celaxetib is taken simultaneously with AZD5305 and with a glass (about 250 ml) of water.

[0149] In some embodiments, AZD5305 is administered at a dose of about 2.5 mg QD and selasetin is administered at a dose of about 120 mg BID.

[0150] In some embodiments, AZD5305 is administered at a dose of about 2.5 mg QD and selasetin is administered at a dose of about 160 mg BID.

[0151] In some embodiments, AZD5305 is administered at a dose of about 5 mg QD and selasetin is administered at a dose of about 160 mg BID.

[0152] In some embodiments, a pharmaceutical product is disclosed, comprising i) a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, and ii) an ATR inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof and the ATR inhibitor or a pharmaceutically acceptable salt thereof are present in a single dosage form. In some embodiments, the selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof and the ATR inhibitor or a pharmaceutically acceptable salt thereof are present in separate dosage forms.

[0153] In some embodiments, a kit is disclosed, comprising: a first pharmaceutical composition comprising a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising an ATR inhibitor or a pharmaceutically acceptable salt thereof; and instructions for using the first pharmaceutical composition and the second pharmaceutical composition in combination.

[0154] cancer

[0155] In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is advanced epithelial ovarian cancer. In some embodiments, the cancer is high-grade serous ovarian cancer. In some embodiments, the cancer is high-grade endometrioid ovarian cancer. In some embodiments, the cancer is epithelial ovarian cancer comprising a gBRCA1 or gBRCA2 mutation, or a mutation in any one of ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L. In some embodiments, the ovarian cancer is platinum-sensitive recurrent ovarian cancer after treatment with a PARP inhibitor. In some of these embodiments, no intervening chemotherapy is performed after treatment with a PARP inhibitor.

[0156] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is harmful or suspected harmful gBRCAm, HER2 negative metastatic breast cancer. In some embodiments, the cancer is harmful or suspected harmful gBRCAm, HER2 negative metastatic breast cancer, and has been treated with chemotherapy in a neoadjuvant, adjuvant or metastatic setting. In some embodiments, the cancer is harmful or suspected harmful gBRCAm, HER2 negative, hormone receptor (HR) positive breast cancer, and has been treated with chemotherapy in a neoadjuvant, adjuvant or metastatic setting, and has been previously treated with endocrine therapy or is considered unsuitable for endocrine therapy. In certain embodiments, the breast cancer is triple negative breast cancer.

[0157] In some embodiments, the cancer is a gastrointestinal cancer. In some of these embodiments, the gastrointestinal cancer is a stomach cancer. In some of these embodiments, the gastrointestinal cancer is a colorectal cancer. In some of these embodiments, the gastrointestinal cancer is a stomach cancer. In some of these embodiments, the gastrointestinal cancer is a liver cancer. In some of these embodiments, the gastrointestinal cancer is a gallbladder cancer. In some of these embodiments, the gastrointestinal cancer is an anal cancer. In some embodiments, the gastrointestinal cancer is a pancreatic adenocarcinoma. In some embodiments, the gastrointestinal cancer is a deleterious or suspected deleterious gBRCAm pancreatic adenocarcinoma. In some embodiments, the gastrointestinal cancer is a deleterious or suspected deleterious gBRCAm pancreatic adenocarcinoma and the disease has not progressed for at least 16 weeks on a first-line platinum-based chemotherapy regimen.

[0158] In some embodiments, the cancer is lung cancer. In some of these embodiments, the lung cancer is small cell lung cancer. Further in these embodiments, the lung cancer is non-small cell lung cancer.

[0159] In some embodiments, the cancer is brain cancer. In some of these embodiments, the brain cancer is a glioma. Further in these embodiments, the brain cancer is a glioblastoma. In some embodiments, the brain cancer is a metastatic cancer caused by a tumor elsewhere in the body (e.g., breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer such as gastric cancer and colorectal cancer, or lung cancer such as small cell or non-small cell lung cancer).

[0160] In some embodiments, the cancer is platinum-resistant.

[0161] In some embodiments, prostate cancer is metastatic prostate cancer, hormone-sensitive prostate cancer (HSPC) or castration-resistant prostate cancer (CRPC). In some embodiments, metastatic prostate cancer can be metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC). Metastatic prostate cancer refers to prostate cancer that has spread or metastasized to another part of the body.

[0162] Hormone-sensitive prostate cancer (HSPC) refers to prostate cancer whose growth is inhibited by reduced androgen levels or by inhibition of androgen action.

[0163] Castration-resistant prostate cancer (CRPC) is a type of prostate cancer that continues to grow even when androgen levels in the body are extremely low or undetectable.

[0164] Metastatic hormone-sensitive prostate cancer (mHSPC) refers to prostate cancer that has spread, or metastasized, to another part of the body and whose growth is suppressed by low androgen levels or by blocking the action of androgens.

[0165] Metastatic castration-resistant prostate cancer (mCRPC) is prostate cancer that has spread, or metastasized, to another part of the body and continues to grow even when androgen levels in the body are very low or undetectable.

[0166] In some embodiments where prostate cancer is being treated, a luteinizing hormone releasing hormone (LHRH) agonist or antagonist treatment may be administered concurrently, especially if the patient has not undergone orchiectomy or subcapsular orchiectomy. LHRH agonists include leuprolide / leuprolide, goserelin, triptorelin, histrelin, and buserelin. LHRH antagonists include degarelix, reglioxan, bicalutamide, flutamide, and cyproterone acetate. Such additional treatments may be administered by current standard of care.

[0167] In some embodiments, the cancer being treated may be defective in homologous recombination (HR) dependent DNA DSB repair activity. The HR dependent DNA DSB repair pathway repairs double strand breaks (DSBs) in DNA via homologous mechanisms to reconstruct a continuous DNA helix (Khanna and Jackson 2001). Components of the HR dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_000051), RAD51 (NM_002875), RAD51L1 (NM_002877), RAD51C (NM_002876), RAD51L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), and XRCC4 (NM_005433). 005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE11A (NM_005590) and NBS1 (NM_002485). Other proteins involved in the HR-dependent DNA DSB repair pathway include regulatory factors such as EMSY (Hughes-Davies 2003). HR components are also described in Wood 2001.

[0168] A cancer defective in HR-dependent DNA DSB repair may comprise or consist of one or more cancer cells having a reduced or abolished ability to repair DNA DSBs via this pathway relative to normal cells, i.e., the activity of the HR-dependent DNA DSB repair pathway may be reduced or abolished in one or more cancer cells.

[0169] The activity of one or more components of the HR-dependent DNA DSB repair pathway can be abolished in one or more cancer cells of an individual with prostate cancer that is defective in HR-dependent DNA DSB repair. Components of the HR-dependent DNA DSB repair pathway are well characterized in the art (see, e.g., Wood 2001) and include the components listed above.

[0170] In some embodiments, the cancer cells may have a BRCA1 and / or BRCA2 deficient phenotype, i.e., the activity of BRCA1 and / or BRCA2 is reduced or eliminated in prostate cancer cells. Cancer cells with this phenotype may have a defect in BRCA1 and / or BRCA2, i.e., the expression and / or activity of BRCA1 and / or BRCA2 may be reduced or eliminated in prostate cancer cells, for example, by means of mutations or polymorphisms in the encoding nucleic acid, or by means of amplification, mutations or polymorphisms in genes encoding regulatory factors (e.g., the EMSY gene encoding a BRCA2 regulatory factor) (Hughes-Davies 2003).

[0171] BRCA1 and BRCA2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers (Jasin 2002; Tutt 2002).

[0172] In some embodiments, the individual is heterozygous for one or more variations (such as mutations and polymorphisms) in BRCA1 and / or BRCA2 or their regulators. Detection of variations in BRCA1 and BRCA2 is well known in the art and is described, for example, in EP 699754, EP 705903, Neuhausen and Nder 1992; Chappuis and Foulkes 2002; Janatová 2003; Jancárková 2003. Determination of amplification of the BRCA2 binding factor EMSY is described in Hughes-Davies 2003.

[0173] Cancer-associated mutations and polymorphisms can be detected at the nucleic acid level by detecting the presence of variant nucleic acid sequences, or at the protein level by detecting the presence of variant (ie, mutant or allelic variant) polypeptides.

[0174] In some embodiments, the cancer being treated may not be defective in homologous recombination (HR)-dependent DNA DSB repair activity.

[0175] In some embodiments, cancer treatment may develop resistance to treatment with a PARP inhibitor alone. When treated with a PARP inhibitor alone, resistance to the PARP inhibitor alone may be characterized by disease progression.

[0176] In some of these embodiments, the patient will demonstrate clinical benefit from treatment with the PARP inhibitor by achieving an initial response to PARP inhibitor treatment or developing a clinical benefit from PARP inhibitor treatment as maintenance therapy followed by disease progression. Clinical benefit for maintenance therapy is defined as:

[0177] Prior maintenance therapy with a PARP inhibitor for at least 12 months after first-line chemotherapy, or

[0178] Prior maintenance therapy with a PARP inhibitor for at least 6 months after >1 line of chemotherapy.

[0179] In some of these embodiments, resistance may be caused by:

[0180] (a) Epithelial-mesenchymal transition (EMT);

[0181] (b) Loss of Schlafen 11 (SLFN11) gene expression;

[0182] (c) overexpression of the ATP-binding cassette (ABC) drug efflux transporter P-glycoprotein ABCB1, also known as MDR1;

[0183] (d) loss of poly(ADP-ribose) glycohydrolase (PARG);

[0184] (e) PARP1 mutation;

[0185] (f) BRCA / HRR-dependent mechanism.

[0186] PARP inhibitor resistance is discussed in Prados Carvajal 2022.

[0187] Examples

[0188] The compounds of the present application will now be further explained by reference to the following non-limiting examples.

[0189] HSA Collaborative Scoring

[0190] The Highest Single Agent (HSA) model is used to determine the synergy score of a combination (and is based solely on the intuition that if the effect of the combination exceeds the level of the effect of each of its components, then there must be some combination interaction). Mathematically, the HSA model describes a simple superposition of the single agent curves:

[0191] I HSA (C X , C Y )=mX(I X , I Y )

[0192] Among them C X,Y are the concentrations of compounds X and Y, I X and I Y Is a single agent in C X,Y Inhibition under the condition of . It is also useful to calculate the volume score (HSA volume) between the data and the HSA surface to characterize the overall strength of the combination effect. The empirically derived combination matrix is ​​compared with its respective HSA additive model, which is constructed from the single drug response curves collected experimentally. The sum of this additional addition in the dose response matrix is ​​called HSA volume. Positive HSA volume indicates potential synergy, while negative HSA volume indicates potential antagonism.

[0193] Combination Index (CI)

[0194] Efficacy shifts can also be scored using a combination index (CI). For a selected iso-effect level (ICut), the CI is calculated as:

[0195] CI=(C X / EC X )+(C Y / EC Y )

[0196] For a specific data point, (C X / EC X ) is the ratio of the measured concentration of compound X to its effective concentration at the selected effect level. The CI is a rough estimate of how much drug is needed relative to the single agent dose required to achieve the selected effect level. CI values ​​in the range of 0.5-0.7 are typical of current in vitro measurements of clinical combinations. The CI error (σCI) is calculated using standard error propagation by calculating the CI based on the error of the equivalent dose analysis method.

[0197] Example 1 - In vitro combination assay

[0198] The combined screen was a 10-day assay using CellTitreGlo as a viability readout.

[0199] The assay was performed in 384-well plates, with each plate containing 1 cell line and 4 drug-drug combinations in a 6x6 matrix. Day zero readings were measured to determine growth inhibition. GenedataScreener was used to input the raw values ​​for each well, and the software was programmed to normalize the values ​​to day zero and DMSO control values.

[0200] The luminescent cell viability assay is a homogeneous method for determining the number of viable cells in culture based on the quantification of the ATP present, which indicates the presence of metabolically active cells. It relies on a proprietary thermostable luciferase (Ultra-Glo TMrecombinant luciferase) that produces a robust “glow-type” luminescent signal and improves performance under a variety of assay conditions.

[0201] The following information is reported: Synergy score (HSA); Combination index value; AC 50 (Concentration at half maximal activity) monotherapy value.

[0202] Breast cell lines (AZD5305 and AZD6738)

[0203]

[0204]

[0205] Lung cell lines (AZ14114554 and AZD6736)

[0206]

[0207]

[0208] Lung cell lines (AZ14114554 and AZD6736)

[0209]

[0210]

[0211] Example 2 - In vitro combination assay

[0212] Combinatorial analysis was performed on a panel of cancer cell lines using Horizon Discovery's high-throughput screening platform. 2.0 Growth inhibition was determined by proliferation assay.

[0213] Cell lines stored in liquid nitrogen were thawed and expanded in growth medium (see Table 1). Screening began once the cells had reached the desired doubling times. Cells were seeded in 25 μl of growth medium in black 384-well tissue culture treated plates (seeding density as shown in Table II).

[0214] Cells were equilibrated in assay plates via centrifugation and placed at 37°C 5% CO2 for 24 hours prior to treatment. At the time of treatment, one set of assay plates (not receiving treatment) was collected and ATP levels were measured by adding CellTiter-Glo 2.0 (Promega) and luminescence reading on an Envision plate reader (Perkin Elmer).

[0215] Compounds were transferred to the assay plate using the Echo acoustic liquid handling system. All combined dose points of 25 nl of each compound were added at the appropriate concentration. Therefore, the final assay volume was 25.05 μl. The assay plate was incubated with the compound for 6 days and then analyzed using CellTiter-Glo 2.0. All data points were collected via an automated process and quality controlled and analyzed.

[0216] Growth inhibition (GI) is reported as a measure of cell growth. The GI percentage is calculated by applying the following test and formula:

[0217] If T <V_0:100*(1-(T-V_0) / V_0)

[0218] If T ≥ V_0: 100*(1-(T-V_0) / (V-V_0))

[0219] Wherein T is the signal measurement of the test article, V is the control measure of untreated / vehicle-treated, and Vo is the measurement of untreated / vehicle-treated at time zero (commonly known as T0 plate). This formula is derived from the growth inhibition calculation used in the National Cancer Institute (National Cancer Institute) NCI-60 high-throughput screening. For the purpose of this report, all data analyses are performed in growth inhibition (unless otherwise stated).

[0220] Table 1

[0221]

[0222]

[0223]

[0224] Pancreatic cell lines (AZD9574 and AZD6738)

[0225]

[0226] Pancreatic cell lines (AZD5305 and AZD6738)

[0227]

[0228] Ovarian cell lines (AZD9574 and AZD6738)

[0229]

[0230]

[0231] Ovarian cell lines (AZD5305 and AZD6738)

[0232]

[0233] Gastric cell lines (AZD9574 and AZD6738)

[0234]

[0235] Gastric cell lines (AZD5305 and AZD6738)

[0236]

[0237] Colorectal cell lines (AZD9574 and AZD6738)

[0238]

[0239] Colorectal cell lines (AZD5305 and AZD6738)

[0240]

[0241]

[0242] Example 3 - In vitro combination assay

[0243] The assay was performed in the following glioblastoma cell lines:

[0244] ·U87

[0245] ·U87 R132H

[0246] ·T98G

[0247] ·SJ-G2 ctrl

[0248] ·SJ-G2 IDH

[0249] Use of AZD6738 and AZD9574

[0250] Processing: 7 days processing

[0251] method

[0252] Cells were seeded in 96-well plates with 150 μl per well one day before drug treatment. For SJ-G2 cells, plates were coated with poly-lysine solution for 15 min, washed twice with sterile water and dried for 1 h.

[0253] The seeding numbers were (cells per well): U87–500; T98G–500; SJ-G2 control–1000; SJ-G2 IDH.

[0254] Compounds were added via the drug dispenser according to the following protocol:

[0255]

[0256]

[0257]

[0258] Compound C1 – AZD6738; Compound C2 – AZD9574

[0259] After 7 days:

[0260] (a) For SJ-G2, 75 μl of Cell Titer Glow 2.0 solution (Promega) was added and incubated at 37° C. for 15 minutes. The cells were then read using a plate reader.

[0261] (b) For U87 and T98G, 75 μl 37% formaldehyde was added and fixed at room temperature for 20 minutes. It was then washed twice with PBS, followed by Hoeschst staining for 1 hour at room temperature (Hoeschst 1:10000 in PBS). It was then washed twice in PBS and the plate was sealed. The plate was then imaged at 10x magnification on CellInsight at position 25. Hoeschst-positive nuclei were identified as targets, and cell viability was analyzed by counting targets (Hoeschst-positive nuclei) in the case of corresponding settings for U87 or T98G.

[0262] Drug synergy was then analyzed to derive the HSA score

[0263] result

[0264]

[0265] Example 4 - In vitro combination of isogenic PARP inhibitor-resistant cell line pairs

[0266] Many described BRCA / HRR-dependent mechanisms of acquired resistance to PARP inhibitors focus on restoring HRR through reversion mutations or HR rearrangement, for example by altering other DDR components such as loss of the 53BP1 / Shieldin complex (Prados Carvajal 2021). In BRCA1 mutant breast cancer cell lines, knockout of the TP53BP1 gene (53BP1 protein) by CRISPR-Cas9 technology conferred resistance to PARP inhibitor monotherapy while remaining sensitive to the combination of AZD5305 and seraceptin, overcoming this resistance mechanism.

[0267] method

[0268] CRISPR-Cas9 TP53BP1 WT and knockout (KO) cell line generation

[0269] The parental BRCA1 mutant SUM149PT breast cancer cell line (Elstrodt 2006) was obtained from the AstraZeneca Cell Bank at Alderley Park, Macclesfield. Cells were routinely grown in Ham's F12 medium containing 5% fetal calf serum, 1% glutamine (2mM), 500ng / ml hydrocortisone and 5% insulin. SUM149PT 53BP1 WT (CNTR) and 53BP1 null (KO) cell pools were generated by CRISPR-Cas9 technology. Short guide (sg) RNA (GAGTAGATCGGAAAGCATC) targeting TP53BP1 on exon 10 and non-targeting CNTR guide (GAGTAGATCGGAAAGCATC) were designed and cloned into a lentiviral vector containing an mClover3 cassette for green fluorescent signal and a hygromycin cassette for selection (pKLV2-U6gRNA (BbsI)-EF1a-mClover3-T2A-HygR-W). Lentivirus was generated from KO and CNTR (sg) RNA and Cas9 (pKLVEF1a-Cas9Bsd-W) plasmids, and parental cells were first transduced with Cas9 lentivirus, followed by blasticidin selection, and then transduced with KO and CNTR lentivirus, followed by hygromycin selection. Loss of 53BP1 was verified by analyzing 53BP1 protein expression in whole cell lysates by Western blot (Novus, NB100-304, 1:1000 dilution).

[0270] Clonal proliferation assays for monotherapy and combination treatments

[0271] Cells were seeded onto 6-well plates with three replicates per cell line and 24 hours later the cells were dosed with AZD6738 / AZD5305. For monotherapy, cells were dosed with a 6-point concentration response of AZD6738 (0 to 0.64 μM) or AZD5305 (0 to 1 μM). For combination treatment, a single dose of AZD5305 (10 nM) was used with a 5-point concentration response of AZD6738 (0 to 0.64 μM) for 53BP1KO cells. Cells were grown for 14 days to form colonies without changing the medium. Cells were fixed with 10% TCA (trichloroacetic acid). 14 days after dosing, any colonies formed were stained with 0.057% SRB (sulforhodamine B acid) and analyzed with GelCount TM(Oxford OPTRONIX) was imaged at 600 dpi resolution and the growth intensity of the stained colonies was measured using a plate reader at OD@510 nM. Dose response curves were generated and IC was calculated using GraphPad PRISM software. 50 concentration.

[0272] result

[0273] We used CRISPR-Cas9 technology to knock out (KO) TP53BP1 in the SUM149PT cell line, and generated a control (CNTR) cell line in parallel using a non-targeting guide.

[0274] Figure 1 The SUM149PT 53BP1 KO cell pool confirmed that 53BP1 protein expression was null compared to the CNTR cell pool. GAPDH protein expression indicated that protein lysate loading was equal between the two cell pools.

[0275] Figure 2 Figure 5 shows a clonal growth assay demonstrating that loss of 53BP1 in SUM149PT cells resulted in a significant increase in resistance to AZD5305. 50 In contrast, the SUM149PT 53BP1-1 KO cell pool was completely resistant to AZD5305.

[0276] Figure 3 Figure 3 shows a clonal growth assay in which the PARP inhibitor-resistant SUM149PT53BP1 KO cell pool was sensitive to the combination of AZD6738 and AZD5305. AZD6738 monotherapy showed modest activity in both CNTR and 53BP1 KO cell pools, with IC 50 However, the combination of a single fixed low dose of 10 nM AZD5305 (a dose that showed no growth inhibition as a monotherapy) with the AZD6738 dose response showed a strong, synergistic enhancement of growth inhibition, with IC50 of approximately 0.63 μM for both CNTR (IC50 approximately 0.11 μM) and 53BP1KO (IC50 approximately 0.097 μM) cell pools. 50 Reduced by about 6 times.

[0277] The objective of the study was to determine the maximum tolerated dose (MTD), which would be determined as the highest dose at which the predicted probability of DLT was 30% (±5%) during the dose-limiting toxicity (DLT) review period.

[0278] DLT was defined as any toxicity during cycle 0 and cycle 1 (i.e., dosing from day 1 of cycle 0 until the last day of dosing of cycle 1), which included:

[0279] 1. Hematotoxicity, as follows:

[0280] Grade 4 neutropenia (ANC (absolute neutrophil count) < 500 cells / mm 3 ) lasts for more than 4 consecutive days

[0281] Grade 3 neutropenia (ANC ≥500 to <1000 cells / mm3) with fever ≥38.5°C and / or systemic infection of any duration 3 )

[0282] Grade 3 thrombocytopenia (25,000 to <50,000 / mm2) with bleeding 3 )

[0283] Any other confirmed hematologic toxicity ≥ CTCAE (Common Terminology Criteria for Adverse Events) version 5 grade 4 (may require repeat to confirm isolated abnormalities in the absence of clinical signs, symptoms or other abnormal investigations, i.e. suspected spurious values)

[0284] 2. Non-hematologic toxicity ≥CTCAE 5th edition grade 3, including:

[0285] Laboratory abnormalities (may need to be repeated to confirm isolated abnormalities in the absence of clinical signs, symptoms, or other abnormal investigations, i.e. suspected spurious values)

[0286] Nausea, vomiting, or diarrhea persisting for ≥ 72 hours despite maximal supportive care

[0287] Cardiac DLTs, which include:

[0288] o Symptomatic tachycardia or tachycardia with a resting supine heart rate > 125 beats / minute for at least 10 minutes

[0289] o Hypotension requiring medical intervention (such as IV fluids)

[0290] o Any other cardiotoxicity with CTCAE grade > 2.

[0291] o QTcF (QT interval corrected for heart rate using Fridericia's formula) interval value <340 msec, confirmed by at least 2 independent ECGs (recorded 5 minutes apart)

[0292] o QTcF prolongation >500 msec or QTcF prolongation >60 msec relative to baseline, confirmed by at least 2 independent ECGs (recorded 5 minutes apart)

[0293] 3. Any other toxicity greater than baseline and clinically significant and / or unacceptable and not responsive to supportive care

[0294] 4. Any event judged as a DLT, including major dose reductions or omissions. Examples may include confirmed laboratory abnormalities (CTCAE ≥ grade 3), CTCAE grade 2 toxicity considered by the investigator to be clinically significant and / or unacceptable, toxicity that resulted in the inability to administer at least 75% of the study treatment in cycle 1 or delayed administration of study treatment for ≥ 7 consecutive days in subsequent cycles.

[0295] Any death not clearly attributable to an underlying disease or to an external cause.

[0296] DLT does not include:

[0297] Any degree of hair loss.

[0298] For Part B, once a dose level 2 escalation is tolerated (160 mg BID for 14 days in combination with continuous AZD5305 2.5 mg QD), the first expansion cohort will be initiated while further dose escalation continues in parallel. Once a dose of 160 mg BD for 14 days of celaxetib in combination with continuous AZD5305 5 mg (dose level 3) is tolerated, the second expansion cohort will be initiated and the first expansion cohort at dose level 2 may be stopped.

[0299] At the end of the study, the recommended Phase 2 dose will be determined.

[0300] AZD5305 and celaxetib are taken as separate tablets on an empty stomach, without food for two hours before and at least one hour after taking it. Celaxetib will be administered using film-coated tablets containing 20 or 80 mg celaxetib. AZD5305 will be administered using film-coated tablets containing 0.5 or 5 mg AZD5305.

[0301] Celasetib and AZD5305 PK blood sampling schedule for Part A

[0302]

[0303] a The time of samples relative to dose was measured relative to the morning dose on C0D1, C1D1, C1D8, and C2D15.

[0304] b For serase only.

[0305] c No celatinib dose on D15. Sample should be collected 30 min before AZD5305 dose.

[0306] d Where relevant, the 24 h sample from D1 should be collected prior to the D2 dose.

[0307] e Withdrawal samples should be collected between 0 and 96 hours after the last dose whenever possible.

[0308] C = cycle; D = day; disc. = withdrawal; h = hour; IP = investigational product; min = minute; PK = pharmacokinetics.

[0309] Celase and AZD5305 PK blood sampling schedule for Part B

[0310]

[0311]

[0312] a The time of samples relative to dose was measured relative to the morning dose on C1D1, C1D15, and C2D15.

[0313] b No celatinib dose on D15. Sample should be collected 30 min before AZD5305 dose.

[0314] c For AZD5305 only.

[0315] d Where relevant, the 24 h sample from D1 should be collected prior to the D2 dose.

[0316] e Withdrawal samples should be collected between 0 and 96 hours after the last dose whenever possible.

[0317] Where possible, the following PK parameters for celacotene and AZD5305 will be determined at the above time points.

[0318] After a single dose:

[0319] AUC (0-t) [Area under the plasma concentration-time curve from time zero to the last measurable time point]

[0320] AUC (0-6) (Part B only) [Area under the plasma concentration-time curve from time zero to 6 hours]

[0321] AUC (0-24)[Area under the plasma concentration-time curve from time zero to 24 hours]

[0322] AUC inf [Area under the plasma concentration-time curve from time zero to infinity]

[0323] AUC τ [Area under the plasma concentration-time curve from time zero to the end of the dosing interval]

[0324] ·C max [Maximum plasma concentration]

[0325] ·t max [Time to reach maximum plasma concentration]

[0326] CL / F [apparent plasma clearance]

[0327] ·Λz z [Terminal elimination rate constant]

[0328] ·t 1 / 2,λz [Drug elimination during terminal period]

[0329] ·V z / F[Volume of distribution]

[0330] Multiple doses of the following:

[0331] ·C ssmax [Maximum plasma concentration at steady state]

[0332] ·t ssmax [Time to reach maximum plasma concentration at steady state]

[0333] ·C ssmin [Minimum plasma concentration at steady state]

[0334] AUC ss [Area under the plasma concentration-time curve from time zero to the end of the dosing interval]

[0335] AUC (0-t)

[0336] AUC (0-6) (Part B only)

[0337] AUC (0-24)

[0338] AUC inf

[0339] AUC τ

[0340] ·CL ss / F[Apparent plasma clearance at steady state]

[0341] ·R AC [Accumulation after multiple administrations]

[0342] ·λ z

[0343] ·t 1 / 2,λz

[0344] ·V ss / F[Volume of distribution]

[0345] Time dependence of PK

[0346] C max , C ss max ,t max and t ss max This will be determined by observing the concentration-time curve. Where possible, λ z will be calculated by log-linear regression of the terminal portion of the concentration-time curve (where sufficient data are available), t 1 / 2λz will be calculated as ln 2 / λ z All AUC-related parameters after single and multiple doses will be calculated using the linear ascending / descending trapezoidal rule. Where appropriate, the λ z Extrapolate the AUC to infinity to get the AUC inf CL / F after a single dose and CL after multiple doses ss / F will be based on dose / AUC or dose / AUC ss The ratio of V ss / F or V z / F will be determined based on MRT×CL / F, and / or R AC Will be calculated as AUC on Cycle 1 Day 8 and Cycle 1 Day 1 (0-24) and / or C max The time dependence of PK on multiple dosing will be determined by calculating the AUC on day 8 of cycle 1. τ and AUC on day 1 of cycle 1 inf ratio to evaluate.

[0347] Antitumor activity

[0348] Baseline tumor assessments should cover all known areas of the disease being evaluated that are known to be metastatically predisposed, and areas of possible involvement should be additionally investigated based on the individual participant's signs and symptoms. Baseline assessments should be performed no more than 28 days before the start of study treatment and, ideally, as close to the start of study treatment as possible. The assessment method used at baseline should be used at each subsequent follow-up assessment. Follow-up assessments should be performed every 8 weeks (±1 week) after the start of combination therapy (Day 1 of Cycle 1) until objective disease progression as defined by RECIST version 1.1 (Eisenhauer 2009) or withdrawal of consent. Once participants have received seracept for more than 2 years and their tumor size has not changed (SD, PR, or CR), the frequency of their RECIST version 1.1 assessments can be modified to every 16 weeks (±1 week) at the discretion of the investigator locally based on the overall assessment of benefit / risk (e.g., exposure to radiation). This decision should be recorded in the participant's medical record.

[0349] The classification of objective tumor response assessment will be based on the RECIST version 1.1 response guidelines: CR (complete response), PR (partial response), SD (stable disease), and PD (progressive disease).

[0350] To achieve 'clear progression' on the basis of non-target disease, the overall level of non-target disease must have worsened sufficiently such that the overall tumor burden has increased sufficiently to warrant discontinuation of therapy even in the presence of SD or PR in target disease. A modest 'increase' in the size of one or more NTLs is generally insufficient to demonstrate a state of clear disease progression.

[0351] Calculation or derivation of tumor response variables

[0352] At each tumor assessment visit, participants will be programmatically assigned a RECIST version 1.1 visit response of CR, PR, SD, or PD based on their disease status compared with baseline and previous visit assessments.

[0353] The progression of TL (target lesion) will be calculated by comparison with the minimum tumor burden (i.e. the sum of the smallest diameters previously recorded in the study, including the baseline). In the absence of progression, the tumor response (CR, PR, SD) will be calculated compared to the baseline tumor measurement obtained before the start of treatment.

[0354] If a participant had a tumor assessment that was not evaluable, the participant would be assigned a NE response unless there was evidence of progression (in which case the response would be designated as PD).

[0355] For TL measurements, if ≤ 1 / 3 of the TL size is missing, the upscaling rule will be applied as follows:

[0356] If ≤ 1 / 3 of the baseline recorded lesions are missing, the result will be scaled up (based on the nadir size, including the baseline) to give an estimated sum of diameters, and this will be used in the calculation (this is equivalent to comparing the sum of diameters of non-missing lesions across visits to the nadir sum of diameters excluding missing lesions, and determining the rate of lesion change).

[0357] If >1 / 3 of the baseline documented lesions are missing, the TL response will be NE.

[0358] • However, if the sum of the non-missing TL diameters would result in PD (i.e., if a value of 0 is used for the missing lesions, the sum of diameters is still increased by >20% or more compared to the smallest sum of diameters under study), PD is preferred over NE.

[0359] A visit response of CR was defined when all TL and NTL lesions present at baseline disappeared (except for lymph nodes, which had to be <10 mm to be considered nonpathological) and no new lesions appeared since baseline. A visit response of PR was defined when the sum of the diameters of the TLs decreased by 30% or more from baseline (no evidence of progression) and the NTLs were at least stable (no evidence of new lesions). To be assigned a PR or CR status, changes in tumor measurements must be confirmed by repeat assessments that should be performed no less than 4 weeks after the response criteria were first met.

[0360] Stable disease was defined as neither sufficient shrinkage to qualify as a PR nor sufficient gain to qualify as a PD. In the case of SD, follow-up measurements had to meet SD criteria at least once after study entry (with an interval of at least 35 days).

[0361] Objective response rate

[0362] The objective response rate is defined as the percentage of participants with at least one CR or PR response before any evidence of progression (as defined by RECIST version 1.1) confirmed at least 4 weeks later. For the analysis of ORR (overall response rate), the "response evaluable" population will be derived and participants without measurable disease at baseline will be excluded.

[0363] Response Duration

[0364] Duration of response will be defined as the time from the date of first documented response to the date of documented progression or death in the absence of disease progression, with the end of response to coincide with the date of progression or death from any cause for the PFS endpoint. Time to initial response will be defined as the latest date leading to a response of PR or CR at the first visit.

[0365] If a participant did not progress after responding, their DoR was censored using the PFS dropout time.

[0366] Progression-free survival

[0367] Progression-free survival is defined as the time from the start of treatment (first dose of celasetil) until objective disease progression or death (by any reason in the absence of progression), regardless of whether the participant withdraws from treatment or receives another anticancer therapy before progression. Subjects who did not progress or die at the time of analysis will be censored from their last evaluable RECIST 1.1 version assessment at the last assessment date. However, if a participant progresses or dies after two or more missed visits, the participant will be assessed at the time of the latest evaluable RECIST 1.1 version assessment. If a participant does not have an evaluable visit or does not have baseline data, it will be censored on day 0 unless they die within 2 visits at baseline.

[0368] PFS times will always be based on the review / assessment date and not the visit date. The RECIST version 1.1 assessment / review leading up to a particular visit may have occurred on a different date. The following rules will apply:

[0369] The date of progression will be determined based on the earliest date of the component that triggered the progression.

[0370] When participants were censored for PFS, they were censored at the latest date to result in a specific overall visit assessment.

[0371] Survival status will be obtained from all participants receiving celaseti and AZD5305 until data cutoff for the final analysis. Survival status will be collected every 12 weeks (±1 week) for all participants. To aid in the interpretation of the survival analysis, the use of subsequent anticancer therapy after discontinuation of study treatment will also be recorded on the eCRF (electronic case report form) for participants receiving celaseti and AZD5305. Survival status will continue to be collected until 24 months after the last participant is recruited to Part B or 80% of the participants in each Part B group have died, whichever comes first.

[0372] Overall survival

[0373] Overall survival was defined as the time from cycle 0 day 1 to death from any cause. Any participant who was not known to have died at the time of the analysis was censored according to the last recorded date that the participant was known to be alive.

[0374] Inclusion criteria

[0375] 1. Histologically / cytologically confirmed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Eligible histologies include high-grade serous and high-grade endometrioid. Ineligible histologies include low-grade serous, low-grade endometrioid, mucinous, and carcinosarcoma.

[0376] 2. Platinum-sensitive recurrent ovarian cancer:

[0377] Platinum-sensitive disease is defined as the absence of clinical or radiographic evidence of disease progression for >6 months (or 182 days) after the last platinum-based therapy. Dates should be calculated from the last dose of platinum therapy administered.

[0378] 3. Participants must have been treated with prior PARPi.

[0379] a) Dose escalation (Part A): There is no requirement for previous PARPi response, but the minimum duration of previous PARPi treatment is 8 months (first-line) or 4 months (second-line).

[0380] b) Dose expansion (Part B): CR or PR to PARPi treatment, or a minimum duration of PARPi treatment of 8 months (first-line) or 4 months (second-line).

[0381] 4. The mandatory clearance period for any PARPi should be 14 days or 5 half-lives (whichever is longer).

[0382] 5. Have progressive cancer at the time of entering the study.

[0383] 6. At least 1, preferably previously unirradiated, lesion that can be accurately assessed by CT or MRI at baseline with a longest diameter ≥10 mm (excluding lymph nodes, which must have a short axis ≥15 mm) and is amenable to accurate repeat assessment. Previously irradiated lesions may be considered if there has been disease progression since radiotherapy.

[0384] 7. Dose Expansion Only (Part B): Known or suspected pathogenic BRCA mutation (germline or somatic), or PALB2 mutation or RAD51C / D mutation (germline or somatic) documented on CAP / CLIA or other jurisdictionally appropriate certified testing based on local testing or HRD-positive status (Myriad MyChoice HRD+ assay with GIS at 42 or higher or FMIF1CDx assay with gLOH ≥16). A copy of test results must be submitted for eligibility and enrollment. Prospective central HRD testing may be offered to sites, depending on local testing availability.

[0385] 8. Female participants must use appropriate contraceptive measures, must not breastfeed, and if of childbearing potential, must have a negative pregnancy test prior to starting dosing, or must meet one of the following criteria at screening to demonstrate no childbearing potential:

[0386] a) Postmenopausal, defined as age 50 years or older and amenorrhoea for at least 12 months after cessation of all exogenous hormone therapy.

[0387] b) Have a record of irreversible surgical infertility by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.

[0388] c) Amenorrhea for 12 months and serum FSH, LH and plasma estradiol levels within the conventional postmenopausal range.

[0389] 9. Participants receiving NOACs (international normalized ratio) may be enrolled with an INR (international normalized ratio) <2; participants with increased INR for other clinical reasons (e.g., bleeding disorders, impaired hepatic synthesis) should be excluded.

[0390] References

[0391] Many publications are cited above to more fully describe and disclose the present invention and the state of the art in the field to which the present invention belongs. The complete citations of these references are provided below. The full text of each reference in these references is incorporated herein.

[0392]

[0393]

[0394]

[0395]

[0396]

Claims

1. A method for treating ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer in a subject in need thereof, the method comprising administering to the subject a first amount of a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, and a second amount of an ATR inhibitor or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together constitute a therapeutically effective amount.

2. The method according to claim 1, wherein the selective PARP1 inhibitor is selected from the group consisting of: (a) a compound having the formula (I): in: X 1 and X 2 are each independently selected from N and C(H), X 3 are independently selected from N and C(R 4 ), where R 4 is H or fluorine, R 1 It is C 1-4 Alkyl or C 1-4 Fluoroalkyl, R 2 are independently selected from H, halo, C 1-4 Alkyl, and C 1-4 fluoroalkyl, and R 3 Is H or C 1-4 alkyl, or a pharmaceutically acceptable salt thereof The conditions are: When X 1 When it is N, then X 2 is C(H), and X 3 is C(R 4 ), When X 2 When it is N, then X 1 =C(H), and X 3 is C(R 4 ),and When X 3 When it is N, then X 1 and X 2 are C(H); and (b) a compound having the formula (II): in: R 1 Independently selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl, and C 1-4 Alkoxy; R 2 are independently selected from H, halo, C 1-4 Alkyl, and C 1-4 fluoroalkyl; and R 3 Is H or C 1-4 alkyl; R 4 Is halogenated or C 1-4 alkyl, or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 or claim 2, wherein the selective PARP1 inhibitor is selected from: (a) AZD5305; and (b) AZD9574.

4. The method according to any one of claims 1 to 3, wherein the selective PARP1 inhibitor is AZD5305.

5. The method according to any one of claims 1 to 3, wherein the selective PARP1 inhibitor is AZD9574.

6. The method according to any one of claims 1 to 5, wherein the ATR inhibitor is selected from the group consisting of: (a) Celaseti; (b) berzosertib; (c) Elimostibin; (d) VE-821; (e) Getiseti; (f) Camonseti; (g) AZ20; (h) ATRN-119; (i) ART-0380; (j) IMP-9064; (k) SC-0245; (l) ATG-018; and (m)LR-02.

7. The method of claim 6, wherein the ATR inhibitor is seraceptin.

8. The method according to any one of claims 1 to 7, wherein the ovarian cancer is selected from the group consisting of: (a) Advanced epithelial ovarian cancer; (b) high-grade serous ovarian cancer; (c) high-grade endometrioid ovarian cancer; (d) epithelial ovarian cancer harboring a gBRCA1 or gBRCA2 mutation; and (e) Platinum-sensitive recurrent ovarian cancer after treatment with a PARP inhibitor.

9. The method according to any one of claims 1 to 7, wherein the ovarian cancer is platinum-sensitive recurrent ovarian cancer following treatment with a PARP inhibitor.

10. The method according to any one of claims 1 to 7, wherein the breast cancer is selected from the group consisting of: (a) deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer; (b) deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer that has been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting; (c) deleterious or suspected deleterious gBRCAm, HER2-negative, hormone receptor (HR)-positive breast cancer who has been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting and has been previously treated with endocrine therapy or is considered a ineligible for endocrine therapy; and (d) Triple-negative breast cancer.

11. The method according to any one of claims 1 to 7, wherein the gastrointestinal cancer is selected from the group consisting of: (a) Gastric cancer; (b) Colorectal cancer (c) Gastric cancer; (d) liver cancer; (e) Gallbladder cancer; (f) anal cancer; (g) pancreatic adenocarcinoma; (h) deleterious or suspected deleterious gBRCAm pancreatic adenocarcinoma; and (i) Patients with deleterious or suspected deleterious gBRCAm pancreatic adenocarcinoma whose disease has not progressed for at least 16 weeks on first-line platinum-based chemotherapy.

12. The method according to any one of claims 1 to 7, wherein the lung cancer is selected from the group consisting of: (a) small cell lung cancer; and (b) Non-small cell lung cancer.

13. The method according to any one of claims 1 to 7, wherein the brain cancer is selected from the group consisting of: (a) glioma; and (b) Glioblastoma.

14. The method according to any one of claims 1 to 7, wherein the prostate cancer is selected from the group consisting of: (a) Metastatic prostate cancer; (b) hormone-sensitive prostate cancer; (c) castration-resistant prostate cancer; (d) metastatic hormone-sensitive prostate cancer; and (e) Metastatic castration-resistant prostate cancer.

15. A selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof for use in treating ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer, wherein the treatment comprises administering to the subject separately, sequentially or simultaneously i) the selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, and ii) an ATR inhibitor or a pharmaceutically acceptable salt thereof.

16. The selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof for use according to claim 15, wherein the selective PARP1 inhibitor is selected from the group consisting of: (a) a compound having the formula (I): in: X 1 and X 2 are each independently selected from N and C(H), X 3 are independently selected from N and C(R 4 ), where R 4 is H or fluorine, R 1 It is C 1-4 Alkyl or C 1-4 Fluoroalkyl, R 2 are independently selected from H, halo, C 1-4 Alkyl, and C 1-4 fluoroalkyl, and R 3 Is H or C 1-4 alkyl, or a pharmaceutically acceptable salt thereof The conditions are: When X 1 When it is N, then X 2 is C(H), and X 3 is C(R 4 ), When X 2 When it is N, then X 1 =C(H), and X 3 is C(R 4 ),and When X 3 When it is N, then X 1 and X 2 are C(H); and (b) a compound having the formula (II): in: R 1 Independently selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl, and C 1-4 Alkoxy; R 2 are independently selected from H, halo, C 1-4 Alkyl, and C 1-4 fluoroalkyl; and R 3 Is H or C 1-4 alkyl; R 4 Is halogenated or C 1-4 alkyl, or a pharmaceutically acceptable salt thereof.

17. The selective PARP1 inhibitor for use according to claim 15 or 16, or a pharmaceutically acceptable salt thereof, wherein the selective PARP1 inhibitor is selected from: (a) AZD5305; and (b) AZD9574.

18. The selective PARP1 inhibitor for use according to any one of claims 15 to 17, or a pharmaceutically acceptable salt thereof, wherein the selective PARP1 inhibitor is AZD5305.

19. The selective PARP1 inhibitor for use according to any one of claims 15 to 17, or a pharmaceutically acceptable salt thereof, wherein the selective PARP1 inhibitor is AZD9574.

20. The selective PARP1 inhibitor for use according to any one of claims 15 to 19, or a pharmaceutically acceptable salt thereof, wherein the ATR inhibitor is selected from the group consisting of: (a) Celaseti; (b) berzosertib; (c) Elimostibin; (d) VE-821; (e) Getiseti; (f) Camonseti; (g) AZ20; (h) ATRN-119; (i) ART-0380; (j) IMP-9064; (k) SC-0245; (l) ATG-018; and (m)LR-02.

21. The selective PARP1 inhibitor for use according to claim 20 or a pharmaceutically acceptable salt thereof, wherein the ATR inhibitor is seraceptin.

22. The selective PARP1 inhibitor for use according to any one of claims 15 to 21 or a pharmaceutically acceptable salt thereof, wherein the ovarian cancer is selected from the group consisting of: (a) Advanced epithelial ovarian cancer; (b) high-grade serous ovarian cancer; (c) high-grade endometrioid ovarian cancer; (d) epithelial ovarian cancer harboring a gBRCA1 or gBRCA2 mutation; and (e) Platinum-sensitive recurrent ovarian cancer after treatment with a PARP inhibitor.

23. The selective PARP1 inhibitor for use according to any one of claims 15 to 21 or a pharmaceutically acceptable salt thereof, wherein the ovarian cancer is platinum-sensitive recurrent ovarian cancer after treatment with a PARP inhibitor.

24. The selective PARP1 inhibitor for use according to any one of claims 15 to 21 or a pharmaceutically acceptable salt thereof, wherein the breast cancer is selected from the group consisting of: (a) deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer; (b) deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer that has been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting; (c) deleterious or suspected deleterious gBRCAm, HER2-negative, hormone receptor (HR)-positive breast cancer who has been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting and has been previously treated with endocrine therapy or is considered a ineligible for endocrine therapy; and (d) Triple-negative breast cancer.

25. The selective PARP1 inhibitor for use according to any one of claims 15 to 21 or a pharmaceutically acceptable salt thereof, wherein the gastrointestinal cancer is selected from the group consisting of: (a) Gastric cancer; (b) Colorectal cancer (c) Gastric cancer; (d) liver cancer; (e) Gallbladder cancer; (f) anal cancer; (g) pancreatic adenocarcinoma; (h) deleterious or suspected deleterious gBRCAm pancreatic adenocarcinoma; and (i) Patients with deleterious or suspected deleterious gBRCAm pancreatic adenocarcinoma whose disease has not progressed for at least 16 weeks on first-line platinum-based chemotherapy.

26. The selective PARP1 inhibitor for use according to any one of claims 15 to 21 or a pharmaceutically acceptable salt thereof, wherein the lung cancer is selected from the group consisting of: (a) small cell lung cancer; and (b) Non-small cell lung cancer.

27. The selective PARP1 inhibitor for use according to any one of claims 15 to 21 or a pharmaceutically acceptable salt thereof, wherein the brain cancer is selected from the group consisting of: (a) glioma; and (b) Glioblastoma.

28. The selective PARP1 inhibitor for use according to any one of claims 15 to 21 or a pharmaceutically acceptable salt thereof, wherein the prostate cancer is selected from the group consisting of: (a) Metastatic prostate cancer; (b) hormone-sensitive prostate cancer; (c) castration-resistant prostate cancer; (d) metastatic hormone-sensitive prostate cancer; and (e) Metastatic castration-resistant prostate cancer.

29. An ATR inhibitor or a pharmaceutically acceptable salt thereof for use in treating ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer in a subject, wherein the treatment comprises administering to the subject separately, sequentially or simultaneously i) the ATR inhibitor or a pharmaceutically acceptable salt thereof, and ii) a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof.

30. The ATR inhibitor for use according to claim 29 or a pharmaceutically acceptable salt thereof, wherein the ATR inhibitor is selected from the group consisting of: (a) Celaseti; (b) berzosertib; (c) Elimostibin; (d) VE-821; (e) Getiseti; (f) Camonseti; (g) AZ20; (h) ATRN-119; (i) ART-0380; (j) IMP-9064; (k) SC-0245; (l) ATG-018; and (m)LR-02.

31. The ATR inhibitor for use according to claim 30 or a pharmaceutically acceptable salt thereof, wherein the ATR inhibitor is seraceptin.

32. The ATR inhibitor for use according to any one of claims 29 to 31 or a pharmaceutically acceptable salt thereof, wherein the selective PARP1 inhibitor is selected from the group consisting of: (a) a compound having the formula (I): in: X 1 and X 2 are each independently selected from N and C(H), X 3 are independently selected from N and C(R 4 ), where R 4 is H or fluorine, R 1 It is C 1-4 Alkyl or C 1-4 Fluoroalkyl, R 2 are independently selected from H, halo, C 1-4 Alkyl, and C 1-4 fluoroalkyl, and R 3 Is H or C 1-4 alkyl, or a pharmaceutically acceptable salt thereof The conditions are: When X 1 When it is N, then X 2 is C(H), and X 3 is C(R 4 ), When X 2 When it is N, then X 1 =C(H), and X 3 is C(R 4 ),and When X 3 When it is N, then X 1 and X 2 are C(H); and (b) a compound having the formula (II): in: R 1 Independently selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl, and C 1-4 Alkoxy; R 2 are independently selected from H, halo, C 1-4 Alkyl, and C 1-4 fluoroalkyl; and R 3 Is H or C 1-4 alkyl; R 4 Is halogenated or C 1-4 alkyl, or a pharmaceutically acceptable salt thereof.

33. The ATR inhibitor for use according to claim 32 or a pharmaceutically acceptable salt thereof, wherein the selective PARP1 inhibitor is selected from: (a) AZD5305; and (b) AZD9574.

34. An ATR inhibitor for use according to claim 32 or 33, or a pharmaceutically acceptable salt thereof, wherein the selective PARP1 inhibitor is AZD5305.

35. An ATR inhibitor for use according to claim 32 or 33, or a pharmaceutically acceptable salt thereof, wherein the selective PARP1 inhibitor is AZD9574.

36. The ATR inhibitor for use according to any one of claims 29 to 35, or a pharmaceutically acceptable salt thereof, wherein the ovarian cancer is selected from the group consisting of: (a) Advanced epithelial ovarian cancer; (b) high-grade serous ovarian cancer; (c) high-grade endometrioid ovarian cancer; (d) epithelial ovarian cancer harboring a gBRCA1 or gBRCA2 mutation; and (e) Platinum-sensitive recurrent ovarian cancer after treatment with a PARP inhibitor.

37. The ATR inhibitor for use according to any one of claims 29 to 35, or a pharmaceutically acceptable salt thereof, wherein the ovarian cancer is platinum-sensitive recurrent ovarian cancer after treatment with a PARP inhibitor.

38. The ATR inhibitor for use according to any one of claims 29 to 35, or a pharmaceutically acceptable salt thereof, wherein the breast cancer is selected from the group consisting of: (a) deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer; (b) deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer that has been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting; (c) deleterious or suspected deleterious gBRCAm, HER2-negative, hormone receptor (HR)-positive breast cancer who has been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting and has been previously treated with endocrine therapy or is considered a ineligible for endocrine therapy; and (d) Triple-negative breast cancer.

39. The ATR inhibitor for use according to any one of claims 29 to 35 or a pharmaceutically acceptable salt thereof, wherein the gastrointestinal cancer is selected from the group consisting of: (a) Gastric cancer; (b) Colorectal cancer (c) Gastric cancer; (d) liver cancer; (e) Gallbladder cancer; (f) anal cancer; (g) pancreatic adenocarcinoma; (h) deleterious or suspected deleterious gBRCAm pancreatic adenocarcinoma; and (i) Patients with deleterious or suspected deleterious gBRCAm pancreatic adenocarcinoma whose disease has not progressed for at least 16 weeks on first-line platinum-based chemotherapy.

40. The ATR inhibitor for use according to any one of claims 29 to 35 or a pharmaceutically acceptable salt thereof, wherein the lung cancer is selected from the group consisting of: (a) small cell lung cancer; and (b) Non-small cell lung cancer.

41. The ATR inhibitor for use according to any one of claims 29 to 35 or a pharmaceutically acceptable salt thereof, wherein the brain cancer is selected from the group consisting of: (a) glioma; and (b) Glioblastoma.

42. The ATR inhibitor for use according to any one of claims 29 to 35 or a pharmaceutically acceptable salt thereof, wherein the prostate cancer is selected from the group consisting of: (a) Metastatic prostate cancer; (b) hormone-sensitive prostate cancer; (c) castration-resistant prostate cancer; (d) metastatic hormone-sensitive prostate cancer; and (e) Metastatic castration-resistant prostate cancer.

43. Use of a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer, wherein the treatment comprises administering to the subject separately, sequentially or simultaneously i) the medicament comprising the selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, and ii) an ATR inhibitor or a pharmaceutically acceptable salt thereof.

44. The use of a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof according to claim 43, wherein the selective PARP1 inhibitor is selected from: (a) AZD5305; and (b) AZD9574; And the ATR inhibitor is serasertib.

45. A pharmaceutical product comprising i) a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, and ii) an ATR inhibitor or a pharmaceutically acceptable salt thereof.

46. ​​A kit comprising: a first pharmaceutical composition comprising a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising an ATR inhibitor or a pharmaceutically acceptable salt thereof; and instructions for using the first pharmaceutical composition and the second pharmaceutical composition in combination.

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