Combination therapy for treating cancer

Abstract

The present invention provides a method of 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. Compositions and kits comprising a PARP inhibitor and an ATR inhibitor are also disclosed.

Description

Technical Field

[0001] The present disclosure relates to a method 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 play a role in promoting DNA repair by "trapping" PARP1-DNA complexes that slow down the progression of DNA replication forks, induce replication stress, and result in DNA lesions that activate the ataxia telangiectasia and Rad3-related (ATR)-dependent replication stress response (RSR) pathway (Non-Patent Document 1, Non-Patent Document 2).

[0003] ATR is a serine / threonine protein kinase, and a number of 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 inhibition (Non-Patent Document 3, Non-Patent Document 4).

[0004] In particular, ATR inhibition is expected to act synergistically in combination with PARP inhibition, resulting in increased DNA damage and enhanced antitumor activity. Extensive preclinical studies of first-generation clinical PARP inhibitors, such as olaparib, talazoparib, niraparib, rucaparib, in combination with ATR inhibitors, such as ceralasertib, elimusertib, bezosertib, galatasertib, VE-821, RP-3500, have demonstrated greater antitumor activity than can be achieved 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 first approved for use in the recurrent setting as single-agent therapies for platinum-tolerant disease (Non-Patent Documents 5, 6), and subsequently approved as maintenance after chemotherapy for platinum-sensitive disease (Non-Patent Document 7). PARPi is currently FDA-approved as frontline maintenance. Olaparib received FDA approval in 2018 as maintenance after response to frontline platinum-based therapy for patients with germline or somatic BRCA-mutated EOC. In April 2020, niraparib received FDA approval as maintenance after response to frontline platinum, regardless of HR status, and the combination of olaparib / bevacizumab received FDA approval in May 2020 as maintenance for patients with HRD EOC.

[0006] Combinations of PARP inhibitors and certain ATR inhibitors have been demonstrated across a range of PARPi-insensitive models or PARPi-resistant BRCA1-mutated EOC models (VE-821, Non-Patent Document 8; AZD6738, Non-Patent Document 9), breast cancer models (BAY-1895344, Non-Patent Document 10; AZD6738, Non-Patent Document 11; RP-3500, Non-Patent Document 12), and lung cancer models (berzosertib, Non-Patent Document 13; AZD6738, Non-Patent Document 14; M4344, Non-Patent Document 15). In addition, the combinations have shown the ability to overcome mechanisms of congenital or acquired PARP inhibitor resistance, for example, through BRCA reversion (Non-Patent Document 16), homologous recombination (HR) rewiring (loss of the 53BP1 / Shieldin complex), and fork protection pathways (repairing partially HR function (Non-Patent Document 17) or loss of SLFN11 (Non-Patent Document 18)) (Non-Patent Document 19).

[0007] The increasing use of PARPi is expected to be approximated by the increasing number of patients found to have de novo or acquired resistance to PARPi.

[0008] Small-scale clinical trials of olaparib and selarasib in patients with recurrent platinum-resistant BRCA-mutated EOC (CAPRI trial, Non-Patent Document 20) and reports from patients with BRCA-mutated PARP inhibitor-resistant HGSOC (OLAPCO trial, Non-Patent Document 21) have shown signs of clinical activity.

[0009] However, recently, it has been reported that the combination of olaparib and selarasib did not improve the outcome in previously treated metastatic triple-negative breast cancer compared to olaparib alone (Non-Patent Document 22).

Prior Art Documents

Non-Patent Documents

[0010]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

Non-Patent Document 16

Non-Patent Document 17

Non-Patent Document 18

Non-Patent Document 19

Non-Patent Document 20

Non-Patent Document 21

Non-Patent Document 22

Summary of the Invention

Problems to be Solved by the Invention

[0011] While many advances have been made in the treatment of ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer, or prostate cancer, many patients with such cancers are living with incurable diseases. Therefore, it is important to continue to find new treatments for patients with incurable cancers.

Means for Solving the Problems

[0012] In some embodiments, disclosed is a method of 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.

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

[0014] In some embodiments, disclosed is an ATR inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer in a subject, wherein the treatment comprises i) separate, sequential or simultaneous administration to the subject of the ATR inhibitor or a pharmaceutically acceptable salt thereof and ii) a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, and is an ATR inhibitor or a pharmaceutically acceptable salt thereof.

[0015] 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 use in the treatment of ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer, wherein the treatment comprises i) separate, sequential or simultaneous administration to the subject of the medicament comprising the selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof and ii) an ATR inhibitor or a pharmaceutically acceptable salt thereof, and is the use.

[0016] In some embodiments, disclosed is a medicament comprising i) a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof and ii) an ATR inhibitor or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, disclosed is 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 and second pharmaceutical compositions in combination.

[0018] A combination of a selective PARP1 inhibitor and an ATR inhibitor may have fewer side effects or be more effective than current monotherapies or combination therapies. This may be due to the selective nature of the PARP1 inhibitor.

Brief Description of the Drawings

[0019]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0020] Selective PARP1 inhibitor A selective PARP1 inhibitor is a compound that inhibits PARP1 more selectively than other members of the PARP family including PARP2, PARP3, PARP5a, and PARP6. Advantageously, the selective PARP1 inhibitor has selectivity for PARP1 over PARP2. In one embodiment, the selective PARP1 inhibitor has 10 - fold selectivity for PARP1 over PARP2. In a further embodiment, the selective PARP1 inhibitor has 100 - fold selectivity for PARP1 over PARP2. In a further embodiment, the selective PARP1 inhibitor has 500 - fold selectivity for PARP1 over PARP2.

[0021] In some embodiments, the selective PARP1 inhibitor is a compound disclosed in WO 2021 / 013735 A1. These compounds have the formula (I): [Chemical formula] (wherein, X 1 and X 2 are each independently selected from N and C(H), X 3 is independently selected from N and C(R 4 ), R 4 is H or fluoro, R 1 is C 1~4 alkyl or C 1~4 fluoroalkyl, R 2 are each 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, provided that when X 1 is N, X 2 is C(H), and X 3 is C(R 4 ), when X 2 is N, X 1 is C(H), and X 3 is C(R 4 ), and when X 3 is N, X 1 and X 2 are both C(H) is a condition.

[0022] Alkyl groups and alkyl moieties are straight-chain or branched-chain, for example C 1~8 alkyl, C 1~6 alkyl, C 1~4 alkyl or C 5~6It is alkyl. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl, such as methyl or n-hexyl.

[0023] A fluoroalkyl group is an alkyl group in which one or more H atoms are replaced by one or more fluoro 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-).

[0024] Halo means fluoro, chloro, bromo and iodo. In one embodiment, halo is fluoro or chloro.

[0025] In some embodiments, the selective PARP1 inhibitor is "AZD5305", which has 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 the structure shown below: [Chemical formula] refers to a compound having. AZD5305 is a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy. AZD5305 is highly selective for PARP1 over other PARP family members, has good secondary pharmacological and physicochemical properties in preclinical species, has excellent pharmacokinetics, and has reduced effects on human bone marrow progenitor cells in vitro.

[0026] The synthesis of AZD5305 is described in Johannes 2021 and International Publication No. 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 a subject. In some embodiments, a pharmaceutically acceptable salt of AZD5305 is administered to a subject. In some embodiments, crystalline AZD5305 or a pharmaceutically acceptable salt of AZD5305 is administered to a subject.

[0027] In some embodiments, the selective PARP1 inhibitor is a compound disclosed in International Publication No. WO 2021 / 260092A1. These compounds have the formula (II):

Chemical formula

[0028] An alkyloxy group is an alkyl group bonded to the remainder of the molecule through an oxygen atom. Examples of suitable C 1~4 alkyloxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy and t-butoxy.

[0029] In some embodiments, the selective PARP1 inhibitor is "AZD9574", which has 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 the structure shown below: [Chemical formula] refers to a compound having the same. AZD9574 is a blood-brain barrier permeable PARP1 selective inhibitor. The synthesis of AZD9574 is described in WO 2021 / 260092A1 (Example 20), the content of which is incorporated herein by reference in its 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.

[0030] In some embodiments, the selective PARP1 inhibitor is "AZ14114554", which has the chemical name 7-((4-(1,5-dimethyl-1H-imidazol-2-yl)piperazin-1-yl)methyl)-3-ethylquinolin-2(1H)-one and the structure shown below: [Chemical formula] refers to a compound having the same. The synthesis of AZ14114554 is described in Johannes 2021 (Compound 16), the content of which is incorporated herein by reference in its 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.

[0031] 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 herein by reference. These selective PARP1 inhibitors are [Chemical formula] and, in some embodiments, [Chemical formula] have a core that is

[0032] Particularly notable compounds are the following.

[0033] [Table 1]

[0034] ATR inhibitor Ataxia telangiectasia and Rad3 related (ATR) kinase plays a central role in the DNA damage response (DDR) by activating an essential signaling pathway for DNA damage repair. Many ATR inhibitors are known, and · Ceralasertib · Berzosertib · Eribulin · VE-821 · Galcitibine · Camonsertib · AZ20 · ATRN-119 · ART-0380 · IMP-9064 · SC-0245 · ATG-018 · LR-02 include.

[0035] 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. ·IC 50 ≦100 nM ·PI3K > 10-fold, e.g., > 100-fold selectivity ·ATM > 10-fold, e.g., > 100-fold selectivity ·DNA-PK > 10-fold, e.g., > 100-fold selectivity

[0036] "Ceralasertib" refers to the compound with the chemical name 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine and the chemical structure shown below:

Chemical formula

[0037] The synthesis of seliciclib is described in WO 2011 / 154737 (Example 2.02), WO 2020 / 127208 and Foote 2018, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the free base seliciclib is administered to a subject. In some embodiments, a pharmaceutically acceptable salt of seliciclib is administered to a subject. In some embodiments, crystalline seliciclib or a pharmaceutically acceptable salt of seliciclib is administered to a subject.

[0038] "Benzoselciclib" refers to the compound with the chemical name 3-(3-(4-((methylamino)methyl)phenyl)-1,2-oxazol-5-yl)-5-(4-(propan-2-sulfonyl)phenyl)pyrazin-2-amine and the structure shown below:

Chemical formula

[0039] The synthesis of benzoselciclib is described in WO 2010 / 071837 (Example 57a - Compound IIA-7) and Knegtel 2019, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the free base benzoselciclib is administered to a subject. In some embodiments, a pharmaceutically acceptable salt of benzoselciclib is administered to a subject. In some embodiments, crystalline benzoselciclib or a pharmaceutically acceptable salt of benzoselciclib is administered to a subject.

[0040] "Elimuselciclib" refers to the compound with the chemical name 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine and the structure shown below:

Chemical formula

[0041] "VE-821" refers to the chemical name 3-amino-N,6-diphenylpyrazine-2-carboxamide and the structure shown below:

Chemical formula

[0042] "Galcitinib" refers to the chemical name 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 the structure shown below:

Chemical formula

[0043] "Camonsertib" refers to 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 the structure shown below:

Chemical Structure

[0044] "AZ20" refers to the chemical name 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole and the structure shown below:

Chemical Structure

[0045] "ATRN-119" refers to a compound derived from ATRIN, which is available for clinical trials (NCT04905914) and is described in International Publication No. 2016 / 061097 pamphlet. This is also discussed, for example, in Gilad 2020 and George 2018.

[0046] "ART-0380" refers to a compound derived from Artios, which is in a Phase 1 clinical trial (NCT04657068). This is also discussed, for example, in Patel 2022.

[0047] "IMP-9064" refers to a compound derived from IMPACT, which is in clinical trials (NCT05269316; CXHL2101780).

[0048] "SC-0245" refers to a compound derived from Wuxi Apptec, which is in a clinical trial (CTR20210769) and is described in International Publication No. 2021 / 023272 pamphlet. This is also discussed, for example, in Wang 2020.

[0049] "ATG-018" refers to a compound derived from Antegene, which is in a clinical trial (NCT05338346). This is also discussed, for example, in Yuwen 2022.

[0050] "LR-02" refers to a compound derived from Laevoroc Oncology, which is discussed, for example, in Koul 2021.

[0051] In some embodiments, the selective PARP1 inhibitor is AZD5305 or AZD9574, and the ATR inhibitor is ceralasertib. In some of these embodiments, the selective PARP1 inhibitor is AZD5305 and the ATR inhibitor is ceralasertib. In other of these embodiments, the selective PARP1 inhibitor is AZD9574 and the ATR inhibitor is ceralasertib.

[0052] The term "pharmaceutical composition" includes compositions containing 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 use in contact with human and animal tissues within the scope of sound medical judgment, without undue toxicity, irritation, allergic reaction or other problems or complications, as determined by those skilled in the art. In some embodiments, the pharmaceutical composition is in 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 can be a sterile 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 suitable dispersing or wetting agents and suspending agents. The pharmaceutical composition can be a solution for iv bolus / infusion injection or a lyophilized system (with or without excipients) for reconstitution with a buffer system with or without other excipients. The lyophilized 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 infusions.

[0053] The terms "treat", "treating", and "treatment" include reducing or inhibiting PARP-1, ATR, or enzyme or protein activity associated with ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer, or prostate cancer in a subject, alleviating 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 tumor growth or cancer cell proliferation in a subject.

[0054] The terms "inhibit", "inhibition", or "inhibiting" include reducing the baseline activity of a biological activity or process.

[0055] 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.

[0056] The term "therapeutically effective amount" together includes the amount of a selective PARP1 inhibitor and the amount of an ATR inhibitor that together elicit a biological or medical response in a subject, such as a reduction or inhibition of PARP1, ATR, or enzyme or protein activity associated with cancer, alleviation of 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 the amount of a selective PARP1 inhibitor and an ATR inhibitor together that is effective to at least partially alleviate, inhibit, and / or remit ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer, or prostate cancer, or to inhibit PARP1 or ATR, and / or to reduce or inhibit tumor growth or cancerous cell proliferation in a subject.

[0057] Although not wishing to be bound by theory, the combination of a selective PARP1 inhibitor with an ATR inhibitor may achieve greater antitumor efficacy and a more promising tolerance profile leading to combination options, higher drug exposure, and more persistent target inhibition than the combination of a first-generation PARP inhibitor with an ATR inhibitor.

[0058] In some embodiments, disclosed is a method of 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.

[0059] In some embodiments, disclosed is 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 in a subject, the treatment comprising separate, sequential, or simultaneous administration to the subject of i) the selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof and ii) an ATR inhibitor or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, disclosed is 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, the treatment comprising separate, sequential, or simultaneous administration to the subject of i) the ATR inhibitor or a pharmaceutically acceptable salt thereof and ii) a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, disclosed is the use of a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for use in the treatment of ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer in a subject, wherein the treatment comprises i) separate, sequential or simultaneous administration to the subject of the pharmaceutical comprising the selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof and ii) an ATR inhibitor or a pharmaceutically acceptable salt thereof.

[0062] 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 in a treatment cycle. In some embodiments, the selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof is administered continuously in a treatment cycle, and the ATR inhibitor or a pharmaceutically acceptable salt thereof is also administered continuously in a treatment cycle.

[0063] The term "continuous" or "continuously" refers to administering a therapeutic agent, such as a selective PARP1 inhibitor, at regular intervals without interruption or break, i.e., without providing a drug-free day. A "drug-free day" means a day on which the therapeutic agent is not administered.

[0064] As used herein, the term "intermittent" or "intermittently" means starting and stopping the administration of a therapeutic agent at either regular or irregular intervals in a treatment cycle. For continuous administration, there is at least one drug-free day in the treatment cycle.

[0065] As used herein, "cycle", "treatment cycle" or "dosing schedule" refers to a period of combination treatment repeated on a regular schedule. For example, the treatment can be given over 1 week, 2 weeks or 3 weeks, and the selective PARP1 inhibitor and 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 period of rest in the treatment cycle, i.e., the drug holiday, is from about 1 day to about 1 month. In some embodiments, the period of rest in the treatment cycle is about 1 day, about 3 days, about 5 days, about 1 week, about 2 weeks or about 3 weeks.

[0066] 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 to a human subject in one or more treatment cycles, e.g., a treatment course. A "treatment course" includes a number of treatment cycles, which can be repeated on a regular schedule or can be gradually adjusted while monitoring the disease progression of the patient. For example, the patient's treatment cycle can have a longer treatment period and / or a shorter rest period at the start of the treatment course (e.g., when the patient is first diagnosed), and as the cancer enters remission, the length of one treatment cycle can be increased by increasing the rest period. The periods of treatment and rest in the treatment cycle, the number of treatment cycles, and the length of time of the treatment course can be determined and adjusted by those skilled in the art throughout the treatment course based on the patient's disease progression, treatment tolerance and prognosis. In some embodiments, the method includes 1 to 10 treatment cycles. In some embodiments, the method includes 2 to 8 treatment cycles.

[0067] Dosing of AZD5305 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 dosed on an interrupted schedule.

[0068] 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 of AZD5305). In some embodiments, AZD5305 is administered once daily (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.

[0069] 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 of 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.

[0070] Dosing of PARP1 Selective Inhibitor In some embodiments, the PARP1 selective inhibitor can be dosed in the same manner as AZD5305 described above.

[0071] Dosing of ATR Inhibitor In some embodiments, the ATR inhibitor is dosed on an intermittent schedule, such as for 7 or 14 consecutive days in a 28-day treatment cycle, i.e., with a rest period of 3 or 2 weeks, or for 3 consecutive days in a 7- or 14-day treatment cycle, i.e., with a rest period of 4 or 11 days, etc.

[0072] Dosing of Seralasecib In some embodiments, seralasecib or a pharmaceutically acceptable salt thereof is administered for 7 or 14 consecutive days in a 28-day treatment cycle, i.e., with a rest period of 3 or 2 weeks.

[0073] In some embodiments, seralasecib or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, seralasecib or a pharmaceutically acceptable salt thereof is in tablet form. In some embodiments, seralasecib or a pharmaceutically acceptable salt thereof is administered orally at a dose of up to about 320 mg per day (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 of seralasecib). In some embodiments, seralasecib is administered twice a day (BID). In some embodiments, seralasecib 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, the 160 mg dose comprises 80 mg or 160 mg tablets.

[0074] Dosing of Elimesecib In some embodiments, elimesecib 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.

[0075] In some embodiments, eribulin or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, eribulin or a pharmaceutically acceptable salt thereof is in tablet form. In some embodiments, eribulin or a pharmaceutically acceptable salt thereof is administered at a dose of up to about 80 mg (e.g., orally at up to about 20 mg, up to about 40 mg, up to about 60 mg, or up to about 80 mg per day).

[0076] Dosing of camonsertib In some embodiments, camonsertib or a pharmaceutically acceptable salt thereof is administered for 3 consecutive days in a 7-day treatment cycle.

[0077] In some embodiments, camonsertib or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, camonsertib or a pharmaceutically acceptable salt thereof is in tablet form. In some embodiments, camonsertib or a pharmaceutically acceptable salt thereof is administered at a dose of up to about 200 mg (e.g., orally at 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).

[0078] Combination dosing In some embodiments, AZD5305 and seralasecib are taken separately. A single dose of AZD5305 is taken on an empty stomach without food intake 2 hours prior, and a single dose of seralasecib is taken with one cup (about 250 ml) of water at the same time as AZD5305.

[0079] In some embodiments, AZD5305 is administered at a single dose of about 2.5 mg QD, and seralasecib is administered at a single dose of about 120 mg BID.

[0080] In some embodiments, AZD5305 is administered at a single dose of about 2.5 mg QD, and seralasecib is administered at a single dose of about 160 mg BID.

[0081] In some embodiments, AZD5305 is administered as a single dose of about 5 mg QD, and ceralasertib is administered as a single dose of about 160 mg BID.

[0082] In some embodiments, disclosed is a pharmaceutical 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.

[0083] In some embodiments, disclosed is 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 and second pharmaceutical compositions in combination.

[0084] Cancer In some embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is advanced epithelial ovarian cancer. In certain embodiments, the cancer is high-grade serous ovarian cancer. In certain embodiments, the cancer is high-grade endometrioid ovarian cancer. In certain 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 certain embodiments, the ovarian cancer is platinum-sensitive recurrent ovarian cancer after treatment with a PARP inhibitor. In some of these embodiments, there is no intervening chemotherapy after treatment with the PARP inhibitor.

[0085] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is a gBRCAm, HER2-negative metastatic breast cancer that is deleterious or suspected of being deleterious. In some embodiments, the cancer is a gBRCAm, HER2-negative metastatic breast cancer that is deleterious or suspected of being deleterious and is in a situation where it has been treated with neoadjuvant or adjuvant chemotherapy or has metastasized. In some embodiments, the cancer is a gBRCAm, HER2-negative, hormone receptor (HR)-positive breast cancer that is deleterious or suspected of being deleterious, is in a situation where it has been treated with neoadjuvant or adjuvant chemotherapy or has metastasized, and has been treated with previous endocrine therapy or is considered inappropriate for endocrine therapy. In certain embodiments, the breast cancer is triple-negative breast cancer.

[0086] In some embodiments, the cancer is a gastrointestinal cancer. In some of these embodiments, the gastrointestinal cancer is gastric cancer. In some of these embodiments, the gastrointestinal cancer is colorectal cancer. In some of these embodiments, the gastrointestinal cancer is stomach cancer. In some of these embodiments, the gastrointestinal cancer is liver cancer. In some of these embodiments, the gastrointestinal cancer is gallbladder cancer. In some of these embodiments, the gastrointestinal cancer is anal cancer. In some embodiments, the gastrointestinal cancer is pancreatic cancer. In some embodiments, the gastrointestinal cancer is a gBRCAm pancreatic cancer that is deleterious or suspected of being deleterious. In some embodiments, the gastrointestinal cancer is a gBRCAm pancreatic cancer that is deleterious or suspected of being deleterious and the disease has not progressed for at least 16 weeks for a first-line platinum-based chemotherapy regimen.

[0087] In some embodiments, the cancer is lung cancer. In some of these embodiments, the lung cancer is small cell lung cancer. In some further embodiments, the lung cancer is non-small cell lung cancer.

[0088] In some embodiments, the cancer is a brain cancer. In some of these embodiments, the brain cancer is a glioma. In some of these further embodiments, the brain cancer is a glioblastoma. In some embodiments, the brain cancer is a metastatic cancer resulting from tumors in other parts of the body, such as 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 lung cancer or non-small cell lung cancer.

[0089] In some embodiments, the cancer is platinum-resistant.

[0090] In some embodiments, the prostate cancer is metastatic prostate cancer, hormone-sensitive prostate cancer (HSPC), or castration-resistant prostate cancer (CRPC). In some embodiments, the 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.

[0091] Hormone-sensitive prostate cancer (HSPC) refers to prostate cancer whose growth is inhibited by a decrease in androgen levels or inhibition of androgen action.

[0092] Castration-resistant prostate cancer (CRPC) refers to prostate cancer that continues to grow even when androgen levels in the body are extremely low or undetectable.

[0093] 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 inhibited by a decrease in androgen levels or inhibition of androgen action.

[0094] Metastatic castration-resistant prostate cancer (mCRPC) refers to 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 extremely low or undetectable.

[0095] In some embodiments of treating prostate cancer, especially when the patient has not undergone orchiectomy or subcapsular orchiectomy, treatment with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist can be administered simultaneously. Examples of LHRH agonists include leuprorelin / leuprolide, goserelin, triptorelin, histrelin, and buserelin. Examples of LHRH antagonists include degarelix, relugolix, bicalutamide, flutamide, and cyproterone acetate. Such additional treatment can be administered during current standard treatment.

[0096] In some embodiments, the cancer being treated may have a deficiency in homologous recombination (HR)-dependent DNA DSB repair activity. The HR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA through a homologous mechanism to reform continuous DNA helices (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), 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). The HR components are also described in Wood 2001.

[0097] Cancers lacking HR-dependent DNA DSB repair may comprise or consist of one or more cancer cells that have a reduced or absent ability to repair DNA DSBs by that repair pathway, compared to normal cells. That is, the activity of the HR-dependent DNA DSB repair pathway may be reduced or absent in one or more cancer cells.

[0098] The activity of one or more components of the HR-dependent DNA DSB repair pathway may be absent in one or more cancer cells of an individual having prostate cancer lacking HR-dependent DNA DSB repair. The components of the HR-dependent DNA DSB repair pathway are well-characterized in the art (see, e.g., Wood 2001), and include those listed above.

[0099] In some embodiments, the cancer cells may have a BRCA1 and / or BRCA2-deficient phenotype. That is, BRCA1 and / or BRCA2 activity is reduced or absent in prostate cancer cells. Cancer cells having this phenotype may be deficient in BRCA1 and / or BRCA2. That is, the expression and / or activity of BRCA1 and / or BRCA2 may be reduced or absent in prostate cancer cells, for example, by a mutation or polymorphism in the coding nucleic acid, or an amplification, mutation or polymorphism in a gene encoding a regulatory factor (e.g., the EMSY gene encoding a BRCA2 regulatory factor) (Hughes-Davies 2003).

[0100] BRCA1 and BRCA2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers (Jasin 2002; Tutt 2002).

[0101] In some embodiments, the individual is heterozygous for one or more variants (e.g., mutations and polymorphisms) in BRCA1 and / or BRCA2 or a regulator thereof. Detection of variants in BRCA1 and BRCA2 is well known in the art and is described, for example, in European Patent No. 699754; European Patent No. 705903; Neuhausen and Nder 1992; Chappuis and Foulkes 2002; Janatova et al., 2003; Jancarkova 2003. Determination of amplification of the BRCA2 binding factor EMSY is described in Hughes-Davies 2003.

[0102] 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 (i.e., mutant or allelic variant) polypeptides.

[0103] In some embodiments, the cancer to be treated may not have a defect in homologous recombination (HR)-dependent DNA DSB repair activity.

[0104] In some embodiments, cancer treatment may be resistant 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.

[0105] In some of these embodiments, the patient will demonstrate continued disease progression from the clinical benefit of treatment with a PARP inhibitor by the initial response to PARP inhibitor treatment or the clinical benefit of PARP inhibitor treatment as maintenance therapy. The clinical benefit for maintenance is defined as: · after previous maintenance with a PARP inhibitor following at least 12 months of first-line chemotherapy, or · after previous maintenance with a PARP inhibitor following > 6 months of first-line chemotherapy.

[0106] In some of these embodiments, resistance can be caused by: (a) Epithelial-mesenchymal transition (EMT), (b) Loss of expression of the Schlafen 11 (SLFN11) gene, (c) ATP-binding cassette (ABC) drug efflux transporter P-glycoprotein, ABCB1, also known as MDR1, overexpression, (d) Loss of poly(ADP-ribose) glycohydrolase (PARG), (e) PARP1 mutation, (f) BRCA / HRR-dependent mechanism.

[0107] PARP inhibitor resistance has been discussed in Prados Carvajal 2022.

Examples

[0108] Here, the compounds of the present application will be further described with reference to the following non-limiting examples.

[0109] HSA Synergy Score Using the highest single agent (HSA) model (and based on the intuitive knowledge that if the effect of a combination simply exceeds the effect levels of each of its components, there must be some combination interaction), the synergy score of the combination is determined. Mathematically, the HSA model describes the simple superposition of single-agent curves. I HSA (C X ,C Y ) = max(I X ,I Y ) where C X,Y is the concentration of compounds X and Y, and I X and I Y are C X,YIt is the inhibition of a single agent. This is also useful for calculating the volume score (HSA volume) between the data and the HSA surface to characterize the overall strength of the combined effect. The combined matrix derived experimentally is compared with each HSA addition model constructed from the experimentally collected single-agent dose-response curves. The sum of the excess additions across the dose-response matrix indicates the HSA volume. A positive HSA volume suggests a potential synergistic effect, while a negative HSA volume suggests potential antagonism.

[0110] Combination Index (CI) Potency shift can also be scored using the combination index (CI). For the selected isoeffect level (ICut), Ci is calculated as follows. CI=(C X / EC X )+(C Y / EC Y ) Where (C X / EC X ) for a particular data point is the ratio of the measured concentration of the X compound to its effective concentration at the selected effect level. CI is a rough estimate of how much drug was needed in combination compared to the single-agent doses required to achieve the selected effect level. CI values in the range of 0.5 - 0.7 are typical for in vitro measurements of current clinical combinations. The CI error (σCI) is calculated using standard error propagation from the CI calculation based on the isobologram error.

[0111] Example 1 - In Vitro Combination Assay This combination screen was a 10-day assay using Cell Titre Glo as a readout for viability.

[0112] The assay was performed in 384-well plates, dosing 1 cell line and 4 drug-drug combinations in a 6×6 matrix per plate. Zero-day readings were measured to determine growth inhibition. Using Genedata Screener, raw values were entered for each well and the software was programmed to normalize the values against zero-day and DMSO control values.

[0113] The CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneous method for determining the number of viable cells in culture based on the quantification of ATP present, which signals the presence of metabolically active cells. This is due to the properties of the proprietary thermostable luciferase (Ultra-Glo® Recombinant Luciferase), which generates a stable "glow-type" luminescence signal and improves performance across a wide range of assay conditions.

[0114] The following information was reported: the synergy score (HSA), combination index value, AC 50 (Maximum half-maximal activity concentration) monotherapy value.

[0115] [Table 2]

[0116] [Table 3]

[0117] [Table 4]

[0118] Example 2 - In Vitro Combination Assay Combinatorial profiling was performed on a panel of cancer cell lines using Horizon Discovery's High Throughput Screening platform. Growth inhibition was determined using the 144-hour CellTiter-Glo® 2.0 proliferation assay.

[0119] Thaw cell lines stored in liquid nitrogen and grow them in growth medium (see Table 1). When the cells reach the expected doubling, begin screening. Seed the cells in 25 μl of growth medium in a black 384-well tissue culture-treated plate (seeding density shown in Table 1I).

[0120] Equilibrate the cells in the assay plate via centrifugation and place them at 37 °C, 5% CO2 for 24 hours prior to treatment. At the time of treatment, collect one set of assay plates (untreated) and measure the ATP levels by adding the luminescence read on a CellTiter-Glo 2.0 (Promega) and an Envision plate reader (Perkin Elmer).

[0121] Transfer the compounds and assay the plates using an Echo acoustic liquid handling system. Add 25 nl of each compound at the appropriate concentration for all combinatorial dose points. Thus, the final assay volume was 25.05 μl. Incubate the assay plates with the compounds for 6 days and then analyze using CellTiter-Glo 2.0. Collect all data points via an automated process and subject them to quality control for analysis.

[0122] Report growth inhibition (GI) as a measure of cell growth. Calculate the GI percentage using the following test and formula. IF T < V_0: 100*(1 - (T - V_0) / V_0) IF T ≥ V_0: 100*(1 - (T - V_0) / (V - V_0)) In the formula, T is the signal scale for the test article, V is the untreated / vehicle-treated control scale, and Vo is the untreated / vehicle control scale at time zero (also referred to colloquially as the T0 plate). This formula is derived from the calculation of growth inhibition used in the National Cancer Institute's NCI-60 high-throughput screen. For this report, all data analyses were performed in terms of growth inhibition (except where indicated).

[0123]

Table 5

[0124]

Table 6

[0125]

Table 7

[0126]

Table 8

[0127]

Table 9

[0128]

Table 10

[0129]

Table 11

[0130]

Table 12

[0131]

Table 13

[0132] [Table 14]

[0133] Example 3 - In Vitro Combination Assay The assay was performed using AZD6738 and AZD9574 in the following glioblastoma cell lines: ·U87 ·U87 R132H ·T98G ·SJ-G2 ctrl ·SJ-G2 IDH The cells were seeded at 150 μl per well in a 96-well plate the day before drug treatment. For SJ-G2 cells, the plates were coated with poly-lysine solution for 15 minutes, washed twice with sterile water, and dried for 1 hour. The seeding numbers were as follows (cells per well): U87 - 500; T98G - 500; SJ-G2 ctrl - 1000; SJ-G2 IDH.

[0134] Treatment: 7-day treatment Method The cells were seeded at 150 μl per well in a 96-well plate the day before drug treatment. For SJ-G2 cells, the plates were coated with poly-lysine solution for 15 minutes, washed twice with sterile water, and dried for 1 hour. The seeding numbers were as follows (cells per well): U87 - 500; T98G - 500; SJ-G2 ctrl - 1000; SJ-G2 IDH.

[0135] The compounds were added via a drug dispenser according to the following scheme.

[0136] [Table 15]

[0137] After 7 days: (a) For SJ-G2, 75 μl of Cell Titer Glow 2.0 solution (Promega) was added and incubated at 37 °C for 15 minutes. Subsequently, the cells were read using a plate reader. (b) For U87 and T98G, 75 μl of 37% formaldehyde was added and fixed at room temperature for 20 minutes. Subsequently, this was washed twice with PBS followed by Hoeschst staining for 1 hour at room temperature (Hoeschst 1:10000 in PBS). Subsequently, this was washed twice in PBS and the plate was sealed. Subsequently, the plate was imaged at 10× magnification at position 25 on the Cell Insight. Hoeschst-positive nuclei were identified and the cell viability was analyzed by counting the corresponding objects (Hoeschst-positive nuclei) for U87 or T98G in the corresponding situation.

[0138] Subsequently, an analysis of drug synergistic effect was performed to obtain the HSA score.

[0139] Results

[0140]

Table 16

[0141] Example 4 - In Vitro Combinations in Isogenic PARP Inhibitor-Resistant Cell Line Pairs Many of the described BRCA / HRR-dependent mechanisms of acquired PARP inhibitor resistance converge on the repair of HRR by reversion mutations or HR rewiring, for example, through alterations in other DDR components, such as loss of the 53BP1 / Shieldin complex (Prados Carvajal 2021). Knockout of the TP53BP1 gene (53BP1 protein) by CRISPR-Cas9 technology in BRCA1-mutant breast cancer cell lines resulted in resistance to PARP inhibitor monotherapy but remained sensitive to the combination of AZD5305 with ceralasertib, overcoming this resistance mechanism.

[0142] Methods Generation of CRISPR-Cas9 TP53BP1 WT and Knockout (KO) Cell Lines The parental BRCA1 mutant SUM149PT breast cancer cell line (Elstrodt 2006) was obtained from the AstraZeneca Cell Bank, Alderley Park, Macclesfield. Cells were routinely grown in Ham’s F12 medium containing 5% fetal bovine serum, 1% glutamine (2 mM), 500 ng / ml hydrocortisone and 5% insulin. SUM149PT 53BP1 WT (CNTR) and 53BP1 null (KO) cell pools were generated by CRISPR-Cas9 technology. Short guide RNAs (sg) targeting TP53BP1 (GAGTAGATCGGAAAGCATC) and non-targeting CNTR guide (GAGTAGATCGGAAAGCATC) on exon 10 were designed and cloned into a lentiviral vector (pKLV2-U6gRNA(BbsI)-EF1a-mClover3-T2A-HygR-W) containing an mClover3 cassette for green fluorescent signal and a hygromycin cassette for selection. Lentiviruses were generated from both KO and CNTR (sg) RNAs, and the Cas9 (pKLVEF1a-Cas9Bsd-W) plasmid and parental cells were first transduced with the Cas9 lentivirus, followed by blasticidin selection, and then transduced with KO and CNTR lentiviruses, followed by hygromycin selection. Loss of 53BP1 was demonstrated by Western blotting by analyzing 53BP1 protein expression from whole cell lysates (Novus, NB100-304, 1:1000 dilution).

[0143] Clonogenic growth assays for single-agent therapy and combination treatments Cells were seeded on 6-well plates (3 replicates per cell line), and after 24 hours, the cells were dosed with AZD6738 / AZD5305. For monotherapy, the cells were dosed with 6-point concentration-response AZD6738 (0 - 0.64 μM) or AZD5305 (0 - 1 μM). For combination treatment, a single dose of AZD5305 (10 nM) was used with 5-point concentration-response AZD6738 (0 - 0.64 μM) for 53BP1 KO cells. The cells were grown for 14 days without medium change for colony formation. The cells were fixed with 10% TCA (trichloroacetic acid). 14 days after dosing, any colonies formed were stained with 0.057% SRB (sulforhodamine B acid), imaged with GelCount™ (Oxford OPTRONIX) at a resolution of 600 dpi, and the growth intensity of the stained colonies was measured at OD@510 nm using a plate reader. A dose-response curve was generated, and the IC 50 concentration was calculated using GraphPad PRISM software.

[0144] Results CRISPR-Cas9 technology was used to knockout (KO) TP53BP1 in the SUM149PT cell line, and simultaneously, a control (CNTR) cell line was generated using a non-targeting guide.

[0145] Figure 1 confirms that the SUM149PT 53BP1 KO cell pool is null for 53BP1 protein expression when compared to the CNTR cell pool. GAPDH protein expression indicates that protein lysate loading was equal for both cell pools.

[0146] Figure 2 shows a clonogenic growth assay, confirming that loss of 53BP1 in SUM149PT cells causes a significant increase in resistance to AZD5305. SUM149PT 53BP1 WT (CNTR) cells are highly sensitive to AZD5305 (IC 50(about 6 nM). In contrast, the SUM149PT 53BP1-1 KO cell pool becomes completely resistant to AZD5305.

[0147] Figure 3 shows a clonogenic growth assay in which PARP inhibitor-resistant SUM149PT 53BP1 KO cell pools are sensitive to the combination of AZD6738 with AZD5305. Single-agent AZD6738 shows modest activity with an IC 50 of about 0.63 μM in both the CNTR and 53BP1 KO cell pools (53BP1 does not affect single-agent AZD6738 sensitivity). However, the combination of a single fixed low dose of 10 nM AZD5305 (a dose as a single agent that shows no growth inhibition) with the AZD6738 dose response shows a strong, synergistic enhancement of growth inhibition with an IC 50 that is reduced by about 6-fold in both the CNTR (IC50 about 0.11 μM) and 53BP1 KO (IC50 about 0.097 μM) cell pools.

[0148] The objective of the study is to determine the maximum tolerated dose (MTD), which is determined as the highest dose at which the predicted probability of dose-limiting toxicity (DLT) is 30% (±5%) during the DLT review period.

[0149] DLT is defined as any toxicity during cycles 0 and 1 (i.e., from dosing on day 1 of cycle 0 to the last day of dosing in cycle 1) and includes the following: 1. Hematological toxicities such as the following: · Grade 4 neutropenia lasting continuously for more than 4 days (ANC (absolute neutrophil count) < 500 cells / mm 3 ) · Grade 3 neutropenia for any period with fever of ≧ 38.5 °C and / or systemic infection (ANC ≧ 500 to < 1000 cells / mm 3 ) · Grade 3 thrombocytopenia with bleeding (25,000 to < 50,000 / mm 3 ) ·Any other confirmed hematologic toxicity (clinical signs, symptoms, or other abnormal tests, i.e., requiring repeat to confirm a single abnormality in the absence of suspect false values) of grade 4 according to CTCAE (Common Terminology Criteria for Adverse Events) version 5. 2. Non-hematologic toxicities of grade 3 according to CTCAE version 5 include the following: ·Laboratory abnormalities (clinical signs, symptoms, or other abnormal tests, i.e., requiring repeat to confirm a single abnormality in the absence of suspect false values). ·Nausea, vomiting, or diarrhea lasting ≥72 hours despite administration of maximal supportive therapy. ·The following cardiac DLTs: - Symptomatic or sustained tachycardia with a resting supine heart rate >125 beats per minute lasting at least 10 minutes. - Medical intervention, e.g., hypotension requiring IV fluids. - Any other cardiac toxicity with CTCAE >grade 2. - QTcF (QT interval corrected for heart rate using Fridericia's formula) interval values <340 milliseconds confirmed by at least two separate ECGs (electrocardiograms) recorded 5 minutes apart. - QTcF prolongation >500 milliseconds confirmed by at least two separate ECGs recorded 5 minutes apart or QTcF prolongation >60 milliseconds from baseline in units. 3. Any other toxicity that exceeds baseline toxicity, is clinically significant, and / or intolerable and does not respond to supportive therapy. 4. Any event including significant dose reduction or omission determined to be a DLT.

[0150] Examples may include confirmed laboratory abnormalities (CTCAE grade ≥3), CTCAE grade 2 toxicities that are clinically important and / or intolerable according to the investigator, and toxicities for which it is not possible to administer at least 75% of the study treatment during cycle 1 or to delay the administration of study treatment in subsequent cycles by ≥7 consecutive days. ·Any death not clearly attributable to underlying disease or external causes.

[0151] DLT excluded the following: · Alopecia of all severities.

[0152] For Part B, if the dose level 2 escalation (160 mg BID for 14 days in combination with continuous AZD5305 2.5 mg QD) is tolerable, the first expansion cohort is initiated while further dose escalation continues concurrently. If the dose of seliciclib of 160 mg BD for 14 days in combination with continuous AZD5305 5 mg (dose level 3) is tolerable, the second expansion cohort is triggered and the first expansion cohort at dose level 2 can be stopped.

[0153] After the study is completed, the recommended Phase 2 dose is determined.

[0154] AZD5305 and seliciclib are taken as separate tablets on an empty stomach without food 2 hours prior, followed by at least 1 hour. Seliciclib is dosed using film-coated tablets containing 20 or 80 mg of seliciclib. AZD5305 is dosed using film-coated tablets containing 0.5 or 5 mg of AZD5305.

[0155]

Table 17

[0156]

Table 18

[0157] If possible, the following PK parameters are determined for seliciclib and AZD5305 at the time points outlined previously.

[0158] After a single dose: · AUC (0-t) [Area under the plasma concentration-time curve from zero to the last measurable time point] · AUC (0-6)(Only part B)[Area under the plasma concentration-time curve from zero to 6 hours] ·AUC (0-24) [Area under the plasma concentration-time curve from zero to 24 hours] ·AUC inf [Area under the plasma concentration-time curve from zero to infinity] ·AUC τ [Area under the plasma concentration-time curve from zero to the end of the dosing interval] ·C max [Maximum plasma concentration] ·t max [Time to reach the maximum plasma concentration] ·CL / F[Apparent plasma clearance] ·λ z [Elimination rate constant of the terminal phase] ·t 1 / 2,λz [Drug elimination in the terminal phase] ·V z / F[Volume of distribution]

[0159] After multiple dosing: ·C ss max [Maximum plasma concentration at steady state] ·t ss max [Time to reach the maximum plasma concentration at steady state] ·C ss min [Minimum plasma concentration at steady state] ·AUC ss [Area under the plasma concentration-time curve from zero to the end of the dosing interval] ·AUC (0-t) ·AUC (0-6) (Only part B) ·AUC (0-24) ·AUC inf ·AUC τ ·CL ss / F[Apparent plasma clearance at steady state] ·R AC [Degree of accumulation for multiple dosing] ·λ z ·t1 / 2,λz ·V ss / F [Distribution volume] ·Time-dependence of PK

[0160] C max 、C ss max 、t max and t ss max are determined by investigation of the concentration-time profile. If possible, λ z is calculated by logarithmic linear regression of the terminal part of the concentration-time profile when sufficient data exist, and t 1 / 2λz is calculated as ln 2 / λ z . All AUC-related parameters after single-dose and multiple-dose are calculated using the linear-up / log-down trapezoidal method. If appropriate, AUC is extrapolated to infinity using λ z to obtain AUC inf . CL / F after single-dose and CL ss / F after multiple-dose are determined from the ratio of dose / AUC or dose / AUC ss . V ss / F or V z / F is determined from MRT×CL / F and / or R AC , and R AC is calculated as the ratio of AUC (0-24) and / or C max on day 8 of cycle 1 and day 1 of cycle 1. The time-dependence of PK for multiple-dose is evaluated by calculation of the ratio of AUC τ , AUC inf on day 8 of cycle 1 and day 1 of cycle 1.

[0161] Antitumor activity Baseline tumor evaluation should cover all areas of known bias regarding metastases in the disease under evaluation and additionally investigate areas that may be affected based on the signs and symptoms of individual participants. The baseline evaluation should be performed within 28 days prior to the start of the study treatment and ideally as close as possible to the start of the study treatment. The evaluation methods used at baseline should be used for each subsequent follow-up evaluation. Follow-up evaluations should be performed every 8 weeks (±1 week) after the start of combination treatment (day 1 of cycle 1) until objective disease progression or withdrawal of consent as defined by RECIST version 1.1 (Eisenhauer 2009). When participants have received selumetinib for more than 2 years and the tumor size (SD, PR or CR) has not changed, the frequency of RECIST version 1.1 evaluations may be adjusted by the investigator at the local site based on the overall benefit / risk, e.g., evaluation of radiation exposure, to every 16 weeks (±1 week). This decision should be documented in the participant's medical record.

[0162] The categorization of objective tumor response assessment is based on the RECIST version 1.1 guidelines regarding response: CR (complete response), PR (partial response), SD (stable disease) and PD (progressive disease).

[0163] To reach "clear progression" based on non-target disease, even if there is SD or PR in the target disease, the overall level in non-target disease must have substantially worsened to the extent that the total tumor burden has increased sufficiently to warrant treatment interruption. A modest "increase" in the size of one or more NTLs is usually not sufficient to qualify for a situation of clear disease progression.

[0164] Calculation or origin of tumor response variables At each tumor evaluation visit, participants are programmatically assigned a RECIST version 1.1 visit response of CR, PR, SD or PD according to the disease status compared to baseline and previous visit evaluations.

[0165] The progression of the TL (target lesion) is calculated compared to the time point when the tumor burden was minimal (i.e., the smallest sum of diameters recorded to date, including the baseline, at the time of the study). If there is no progression, tumor response (CR, PR, SD) is calculated compared to the baseline tumor measurements obtained before treatment initiation.

[0166] If the tumor evaluation of a participant cannot be evaluated, the participant is assigned a NE in - hospital response as long as there is no evidence of progression (in which case, the response is assigned as PD).

[0167] For TL measurements, when ≤ 1 / 3 of the TL size has disappeared, the up - scaling rule is used as follows: · When ≤ 1 / 3 of the lesions recorded at baseline have disappeared, the result is up - scaled (based on the nadir size including the baseline) to give an estimated total diameter, which is used in the calculation (this is equivalent to comparing the sum of the diameters of the lesions that have not disappeared at the hospital with the nadir sum of the diameters excluding the disappeared lesions and determining what percentage the lesions have changed). · When > 1 / 3 of the lesions recorded at baseline have disappeared, the TL response is NE. · However, if the sum of the TL diameters that have not disappeared ends up as PD (i.e., using a value of 0 for the disappeared lesions, the sum of the diameters is still > 20% increased compared to the smallest sum of diameters at the time of the study), PD takes precedence over NE.

[0168] CR is defined as the disappearance of all TL and NTL lesions present at baseline (excluding lymph nodes that must be <10 mm and are considered non-pathological) and no new lesions developing from baseline. PR is defined as a ≥30% decrease in the sum diameter of TLs (without evidence of progression) compared to baseline and NTL being at least stable without evidence of new lesions. For the assignment of PR or CR status, the change in tumor measurements must be confirmed by repeated evaluations that are performed within ≤4 weeks after the criteria for response are first met.

[0169] Stable is defined as no shrinkage sufficient to qualify for PR and no increase sufficient to qualify for PD. For SD, follow-up measurements must meet the SD criteria at least once after study registration at a minimum interval of at least 35 days.

[0170] Objective response rate The objective response rate is defined as the percentage of participants with at least one response of CR or PR 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), a population of "evaluable for response" is derived and participants with no measurable disease at baseline are excluded.

[0171] Duration of response The duration of response is defined as the time from the date of the first documented response to the date of documented progression or death in the absence of disease progression, and the duration of response must coincide with the date of progression or death from any cause used for the PFS endpoint. The time of the first response is defined as the most recent date contributing to the first on-study response of PR or CR.

[0172] If a participant does not progress after response, the DoR is the PFS cutoff time.

[0173] Progression-free survival Progression-free survival is defined as the time from the start of treatment (first dose of selicrelumab) until the date of objective disease progression or death (from any cause in the absence of progression), whether the participant discontinues treatment prior to progression or receives another anti-cancer treatment. Patients who have not progressed or died at the time of analysis are censored at the time of the last evaluable RECIST version 1.1 assessment from the last assessment date. However, if the participant progresses or dies after two or more missed visits, the participant is censored at the time of the latest evaluable RECIST version 1.1 assessment. Participants who do not have an evaluable visit or have no baseline data are censored at day 0 unless they die within two baseline visits.

[0174] PFS time is always derived based on the scan / assessment date (not the visit date). RECIST version 1.1 assessments / scans contributing to a particular visit may be performed on different dates. The following rules apply: · The date of progression is determined based on the earliest date of the component that triggered the progression. · When censoring a participant for PFS, the participant is censored at the latest date contributing to the overall particular visit assessment.

[0175] Survival status is obtained from all participants who received selicrelumab and AZD5305 until the data cut-off for the final analysis. Survival status is collected every 12 weeks (±1 week) for all participants. To assist in the interpretation of survival rate analysis, the use of subsequent anti-cancer therapies after the interruption of the study treatment is also recorded in the eCRF (electronic case report form) for participants who received selicrelumab and AZD5305. Survival status is collected until 24 months before the last participant was randomized to part B or until 80% of the participants in each of the part B cohorts are deceased.

[0176] Overall survival Overall survival is defined as the time from the date of day 1 of cycle 0 to death from any cause. Any participant known to have died at the time of analysis is censored based on the last recorded date that the participant was known to be alive.

[0177] Inclusion Criteria 1. Histologically / cytologically confirmed high-grade epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Eligible histologies include high-grade serous and high-grade endometrioid. Ineligible histologies include low-grade serous, low-grade endometrioid, mucinous carcinoma, and carcinosarcoma.

[0178] 2. Platinum-sensitive recurrent ovarian cancer: · Platinum-sensitive disease is defined as no clinical or radiographic evidence of disease progression for >6 months (or 182 days) after the last platinum-based treatment. The date needs to be calculated from the last dose of platinum therapy.

[0179] 3. Participants must not have been previously treated with a PARPi. a) Dose escalation (Part A): Not a requirement for response to prior PARPi, a minimum treatment duration of 8 months (first choice) or 4 months (second choice) with prior PARPi. b) Dose expansion (Part B): CR or PR with PARPi treatment or a minimum PARPi treatment duration of 8 months (first choice) or 4 months (second choice).

[0180] 4. A washout period of 14 days or 5 half-lives (whichever is longer) is required for any PARPi.

[0181] 5. Progressive cancer at the time of study enrollment.

[0182] 6. It can be accurately measured at baseline within the longest diameter by CT or MRI as ≥ 10 mm (excluding lymph nodes that must have a short axis of ≥ 15 mm), and is suitable for accurate repeated evaluation, preferably at least one lesion that has not been previously irradiated. Lesions that have been previously irradiated may be considered if there is disease progression from radiotherapy.

[0183] 7. Dose escalation only (Part B): Documentation of PALB2 or RAD51C / D mutations (germline or somatic) for known or suspected pathogenic BRCA mutations (germline or somatic) or other validated assays appropriate for the jurisdiction according to CAP / CLIA or local testing or HRD positive status (Myriad MyChoice HRD+ assay using GIS ≥ 42 or FMI F1CDx assay using gLOH ≥ 16). Submission of a copy of the test results is mandatory for eligibility criteria and registration. Future central HRD testing may be offered at sites depending on local testing availability.

[0184] 8. Female participants must use adequate contraception, must not be breastfeeding, and if there is a possibility of pregnancy, must have a negative pregnancy test before starting administration or must have evidence of no possibility of pregnancy by meeting one of the following criteria at screening: a) Postmenopausal - defined as being over 50 years of age and having been amenorrheic for at least 12 months after stopping all exogenous hormonal treatments. b) Documentation of irreversible sterilization surgery by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy (but not tubal ligation). c) Amenorrheic for 12 months and with serum FSH, LH, and plasma estradiol levels within the postmenopausal range for the facility.

[0185] 9. Participants on NOAC (international normalized ratio) can be registered (INR (international normalized ratio) < 2). Participants with other clinical causes of increased INR (e.g., bleeding disorders, impaired hepatic synthesis) need to be excluded.

[0186] References In order to more specifically explain and disclose the present invention and the prior art related to the present invention, several publications are cited above. The complete citations of these references are shown below. The entirety of each of these references is incorporated herein by reference.

[0187] [Table 19]

[0188] [Table 20]

[0189] [Table 21]

[0190] [Table 22]

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, 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 selective PARP1 inhibitor is (a) Formula (I): 【Chemical 1】 (wherein X １ and X ２ are each independently selected from N and C(H), X ３ is independently selected from N and C(R ４ ), where R ４ is H or fluoro, R １ is C １～４ alkyl or C １～４ fluoroalkyl, and R ２ is independently selected from H, halo, C １～４ alkyl and C １～４ fluoroalkyl, and R ３ is H or C １～４ alkyl) a compound of or a pharmaceutically acceptable salt thereof, provided that X １ When X is N, ２ X is C(H), and ３ X is C(R ４ ), X ２ When X is N, １ X is C(H), and ３ X is C(R ４ ), and X ３ When X is N, １ X ２ and X are both C(H), provided that it is a compound or a pharmaceutically acceptable salt thereof, and (b) Formula (II): [Chemical 2] (wherein R １ is independently selected from H, C １～４ alkyl, C １～４ fluoroalkyl and C １～４ alkyloxy, R ２ is independently selected from H, halo, C １～４ alkyl and C １～４ fluoroalkyl, and R ３ is H or C １～４ and is alkyl, R ４ is a halo or C １～４ alkyl) a compound of or a pharmaceutically acceptable salt thereof selected from the group consisting of. The method according to claim 1.

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

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

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

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

7. The ATR inhibitor is ceralasertib. The method according to claim 6.

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

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

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

11. The gastrointestinal cancer is (a) Gastric cancer (b) Colorectal cancer (c) Gastric cancer (d) Liver cancer (e) Gallbladder cancer (f) Anal cancer (g) Pancreatic cancer (h) gBRCAm pancreatic cancer suspected of being harmful or deleterious (i) gBRCAm pancreatic cancer suspected of being harmful or deleterious, where the disease has not progressed for at least 16 weeks for a first-choice platinum-based chemotherapy regimen The method according to any one of claims 1 to 7, selected from the group consisting of

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

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

14. The prostate cancer is (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 The method according to any one of claims 1 to 7, selected from the group consisting of

15. A selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer, wherein the treatment comprises i) separate, sequential or simultaneous administration to the subject of 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 is (a) Formula (I): [Chemical Formula 3] (wherein X １ and X ２ are each independently selected from N and C(H), X ３ is independently selected from N and C(R ４ ), R ４ is H or fluoro, R １ is C １～４ alkyl or C １～４ fluoroalkyl, and R ２ is independently selected from H, halo, C １～４ alkyl and C １～４ fluoroalkyl, and R ３ is H or C １～４ alkyl) a compound of or a pharmaceutically acceptable salt thereof, provided that X １ When X is N, ２ X is C(H), and ３ X is C(R ４ ), X ２ When X is N, １ X is C(H), and ３ X is C(R ４ ), and X ３ When X is N, １ X ２ and X are both C(H), provided that, a compound or a pharmaceutically acceptable salt thereof, and (b) Formula (II): 【Chemical Formula 4】 (wherein R １ is independently selected from H, C １～４ alkyl, C １～４ fluoroalkyl and C １～４ alkyloxy, and R ２ is 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 a halo or C １～４ alkyl) a compound of or a pharmaceutically acceptable salt thereof A selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof for use according to claim 15, selected from the group consisting of.

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

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

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

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

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

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

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

24. The breast cancer is (a) harmful or suspected to be harmful gBRCAm, HER2-negative metastatic breast cancer, (b) A selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 15 to 21, selected from the group consisting of gBRCAm, HER2-negative metastatic breast cancer that is neoadjuvant, treated with chemotherapy with an adjuvant, or in a metastatic situation and is suspected of being harmful or deleterious. (c) A selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 15 to 21, selected from the group consisting of gBRCAm, HER2-negative, hormone receptor (HR)-positive breast cancer that is neoadjuvant, treated with chemotherapy with an adjuvant, or in a metastatic situation and has been treated with previous endocrine therapy or is considered inappropriate for endocrine therapy and is suspected of being harmful or deleterious. (d) Triple-negative breast cancer A selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 15 to 21, selected from the group consisting of [

25. ] The gastrointestinal cancer is (a) Gastric cancer (b) Colorectal cancer (c) Gastric cancer (d) Liver cancer (e) Gallbladder cancer (f) Anal cancer (g) Pancreatic cancer (h) gBRCAm pancreatic cancer suspected of being harmful or deleterious (i) gBRCAm pancreatic cancer suspected of being harmful or deleterious where the disease has not progressed for at least 16 weeks for a first-line platinum-based chemotherapy regimen A selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 15 to 21, selected from the group consisting of [

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

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

28. ] The prostate cancer is (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 A selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 15 to 21, selected from the group consisting of [

29. ] An ATR inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer in a subject, wherein the treatment comprises: i) separate, sequential or simultaneous administration to the subject of 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 is (a) ceralasertib, (b) bezosertib, (c) elimusertib, (d) VE-821, (e) galatasertib, (f) camonsertib, (g) AZ20, (h) ATRN-119, (i) ART-0380, (j) IMP-9064, (k) SC-0245, (l) ATG-018, and (m) LR-02 An ATR inhibitor or a pharmaceutically acceptable salt thereof for use according to claim 29, selected from the group consisting of

31. The ATR inhibitor is ceralasertib, an ATR inhibitor or a pharmaceutically acceptable salt thereof for use according to claim 30.

32. The selective PARP1 inhibitor is (a) formula (I): 【Chemical Formula 5】 (wherein X １ and X ２ are each independently selected from N and C(H), X ３ is independently selected from N and C(R ４ ), where R ４ is H or fluoro, R １ is C １～４ alkyl or C １～４ fluoroalkyl, and R ２ is independently selected from H, halo, C １～４ alkyl and C １～４ fluoroalkyl, and R ３ is H or C １～４ alkyl) a compound of or a pharmaceutically acceptable salt thereof, provided that X １ When X is N, ２ X is C(H), and ３ X is C(R ４ ), X ２ When X is N, １ X is C(H), and ３ X is C(R ４ ), and X ３ When X is N, １ X and ２ both are C(H), provided that, a compound or a pharmaceutically acceptable salt thereof, and (b) formula (II): [Chemical Formula 6] (wherein R １ is independently selected from H, C １～４ alkyl, C １～４ fluoroalkyl and C １～４ alkyloxy, and R ２ is independently selected from H, halo, C １～４ alkyl and C １～４ fluoroalkyl, and R ３ is H or C １～４ and is alkyl, R ４ is a halo or C １～４ alkyl) a compound of or a pharmaceutically acceptable salt thereof An ATR inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 29 to 31, selected from the group consisting of

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

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

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

36. The ovarian cancer is (a) advanced epithelial ovarian cancer, (b) high-grade serous ovarian cancer, (c) high-grade endometrial ovarian cancer, (d) epithelial ovarian cancer containing gBRCA1 or gBRCA2 mutations, and (e) platinum-sensitive recurrent ovarian cancer after treatment with a PARP inhibitor An ATR inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 29 to 35, selected from the group consisting of

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

38. The breast cancer is (a) harmful or suspected to be harmful gBRCAm, HER2-negative metastatic breast cancer, (b) harmful or suspected to be harmful gBRCAm, HER2-negative metastatic breast cancer that has been treated with neoadjuvant or adjuvant chemotherapy or is in a metastatic situation, (c) harmful or suspected to be harmful gBRCAm, HER2-negative, hormone receptor (HR)-positive breast cancer that has been treated with neoadjuvant or adjuvant chemotherapy or is in a metastatic situation and has been treated with previous endocrine therapy or is considered inappropriate for endocrine therapy, and (d) triple-negative breast cancer An ATR inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 29 to 35, selected from the group consisting of

39. The gastrointestinal cancer is (a) gastric cancer, (b) colorectal cancer, (c) gastric cancer, (d) liver cancer, (e) gallbladder cancer, (f) anal cancer, (g) pancreatic cancer, (h) harmful or suspected to be harmful gBRCAm pancreatic cancer, and (i) harmful or suspected to be harmful gBRCAm pancreatic cancer in which the disease has not progressed for at least 16 weeks for a first-choice platinum-based chemotherapy regimen An ATR inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 29 to 35, selected from the group consisting of

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

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

42. The prostate cancer is (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 An ATR inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 29 to 35, selected from the group consisting of

43. Use of a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, brain cancer or prostate cancer, said treatment comprising: i) said medicament comprising said selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof; and ii) separate, sequential or simultaneous administration to the subject of an ATR inhibitor or a pharmaceutically acceptable salt thereof.

44. Said selective PARP1 inhibitor is (a) AZD5305, and (b) AZD9574 selected from, and said ATR inhibitor is ceralasertib, use of a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof according to claim 43.

45. i) A selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof; and ii) A medicament comprising 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 said first and second pharmaceutical compositions in combination.

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