Combination of antibody-drug conjugate and blood brain barrier-penetrant parp1 selective inhibitor

Abstract

A pharmaceutical product for administration of an antibody-drug conjugate in combination with a blood brain barrier-penetrant PARP1 selective inhibitor is provided. The antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula (wherein A represents the connecting position to an antibody) is conjugated to an anti-HER2 or anti-TROP2 antibody via a thioether bond. The antibody-drug conjugate is in particular trastuzumab deruxtecan (DS-8201) or datopotamab deruxtecan (DS-1062). The PARP1 selective inhibitor is in particular AZD 9574. Also provided is a therapeutic use and method wherein the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor are administered in combination to a subject:

Description

[0001] COMBINATION OF ANTIBODY-DRUG CONJUGATE AND BLOOD BRAIN BARRIER-PENETRANT PARP1 SELECTIVE INHIBITOR [Technical Field] The present disclosure relates to a pharmaceutical product for administration of a specific antibody-drug conjugate, having an antitumor drug conjugated to an anti-HER2 or anti- TROP2 antibody via a linker structure, in combination with a blood brain barrier-penetrant PARP1 selective inhibitor, and to a therapeutic use and method wherein the specific antibody- drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor are administered in combination to a subject. [Background] The Poly (ADP-ribose) polymerase (PARP) family of enzymes plays an important role in a number of cellular processes, such as replication, recombination, chromatin remodeling, andDNA damage repair (M^Akjjkn KH, Kkh Aahh (2015) 60(4), 547-560). Single-strand break and double-strand break, as types of DNA damage, each have a repair mechanism. If the type of DNA damage is single-strand break, it will be repaired through base excision repair predominantly by PARP (poly[adenosine-5'- diphosphate (ADP)-ribose]polymerase) acting thereon. If the type of DNA damage is double-strand break, it will be repaired through homologous recombination repair predominantly by BRCA, ATM, RAD51, and the like, acting thereon (Lord CJ, et al., Nature (2012) 481, 287-294). PARP1 and PARP2 are the most extensively studied PARPs for their role in DNA damage repair. PARP1 is activated by DNA damage breaks and functions to catalyse the addition of poly (ADP-ribose) (PAR) chains to target proteins. This post- translational modification, known as PARylation, mediates the recruitment of additional DNA repair factors to DNA lesions. Following completion of this recruitment role, PARP auto- PARylation triggers the release of bound PARP from DNA to allow access to other DNA repair proteins to complete repair. Thus, the binding of PARP to damaged sites, its catalytic activity, and its eventual release from DNA are all important steps for a cancer cell to respond to DNA damage caused by chemotherapeutic agents and radiation therapy (Bai P., Mol Cell (2015) 58, 947^958). Inhibition of PARP family enzymes has been exploited as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. A number of pre-clinical and clinical studies have demonstrated that tumor cells bearing deleterious alterations of BRCA1 or BRCA2, key tumor suppressor proteins involved in double-strand DNA break (DSB) repair by homologous recombination (HR), are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes. Such tumors have deficient homologous recombination repair (HRR) pathways and are dependent on PARP enzymes function for survival. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, PARP inhibitors have been tested clinically in non-BRCA-mutant tumors, those which exhibit homologous recombination deficiency (HRD) (Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer 2004;4: 814^9). PARP inhibitors are drugs that have the function of inhibiting PARP (particularly PARP1 and PARP2), and thus preventing single-strand break repair. Some cancers including breast cancer and ovarian cancer are known to have an abnormality in double-strand break repair, and PARP inhibitors have been revealed to have antitumor effects due to synthetic lethality against these cancers (Benafif S, et al., Onco. Targets Ther. (2015) 8, 519-528; Fong PC, et al., N. Engl. J. Med. (2009) 361, 123-134; Fong PC, et al., J. Clin. Oncol. (2010) 28, 2512-2519; Gelmon KA, et al., Lancet Oncol. (2011) 12, 852-861). Examples of PARP inhibitors and their mechanism of action are taught in e.g. WO2004 / 080976. Known PARP inhibitors include olaparib (Menear KA, et al., J. Med. Chem. (2008) 51, 6581-6591), rucaparib (Gillmore AT, et al., Org. Process Res. Dev. (2012) 16, 1897-1904), niraparib (Jones P, et al., J. Med. Chem. (2009) 52, 7170-7185), and talazoparib (Shen Y, et al., Clin. Cancer Res. (2013) 19(18), 5003-15). It is believed that PARP inhibitors having improved selectivity for PARP1 may possess improved efficacy and reduced toxicity compared to non-selective PARP inhibitors. It is believed also that selective strong inhibition of PARP1 would lead to trapping of PARP1 on DNA, resulting in DNA double-strand breaks (DSBs) through collapse of replication forks in S-phase. It is believed also that PARP1-DNA trapping is an effective mechanism for selectively killing tumor cells having HRD. WO2021 / 013735 and WO2021 / 260092 disclose azaquinolones that have PARP inhibitory activity, with high selectivity for PARP1 over other PARP family members such as PARP2, PARP3, PARP5a, and PARP6. WO2021 / 260092 discloses azaquinolones that are inhibit PARP1 selectively and are capable of penetrating the blood brain barrier (BBB). Antibody-drug conjugates (ADCs), which are composed of a cytotoxic drug conjugated to an antibody, can deliver the drug selectively to and within cancer cells, leading to cancer cell death (Ducry, L., et al., Bioconjugate Chem. (2010) 21, 5-13; Alley, S. C., et al., Current Opinion in Chemical Biology (2010) 14, 529-537; Damle N. K. Expert Opin. Biol. Ther. (2004) 4, 1445-1452; Senter P. D., et al., Nature Biotechnology (2012) 30, 631-637; Burris HA., et al., J. Clin. Oncol. (2011) 29(4): 398-405). One such antibody-drug conjugate is trastuzumab deruxtecan, which is composed of a HER2-targeting antibody and a derivative of exatecan (Ogitani Y. et al., Clinical Cancer Research (2016) 22(20), 5097-5108; Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046). Trastuzumab deruxtecan (Enhertu®, DS-8201) has shown significant clinical efficacy in HER2-expressing solid tumors, including breast cancer, gastric cancer, colorectal cancer and non-small cell lung cancer. Significantly, DS-8201 has demonstrated promising activity in HER2 low tumors in the above indications. Another such antibody-drug conjugate is datopotamab deruxtecan (DS-1062), which is composed of a TROP2-targeting antibody and a derivative of exatecan. In particular, WO2015 / 098099 and WO2020 / 240467 provide detailed descriptions of exemplary TROP2-targeting antibody-drug conjugates, including datopotamab deruxtecan (DS-1062). Datopotamab deruxtecan has shown clinical efficacy in multiple tumor types, including lung cancer and breast cancer. References disclosing combined administration of an antibody-drug conjugate and an immune checkpoint inhibitor include Müller P. et al., Science Translational Medicine (2015) 7(315), 315ra188) (trastuzumab emtansine (T-DM1) combined with both anti-CTLA-4 and anti-PD-1 antibodies); and WO2018 / 110515 (trastuzumab deruxtecan (DS-8201) combined with anti-PD-1, anti-PD-L1, anti-CD4 and anti-CD8 antibodies). However, there is a need to identify further combination partners for antibody-drug conjugates, including for anti-HER2 antibody-drug conjugates such as DS-8201 and for anti-TROP2 antibody-drug conjugates such as DS-1062, to enhance their therapeutic potential. Despite the therapeutic potential of antibody-drug conjugates such as DS-8201 and DS-1062 as monotherapy or in combination with a checkpoint inhibitor, and the therapeutic potential of PARP1 selective inhibitors, a need remains for improved therapeutic compositions and methods that can enhance efficacy of existing cancer treating agents, increase durability of therapeutic response, improve tolerance to patients, reduce dose-dependent toxicity, and / or provide an alternative treatment of cancers exhibiting resistance or refractoriness to a previous cancer treatment. For example, there is a need to provide a cancer treatment that can offer an improved safety profile and / or reduced side effects such as neutropenia. [Summary of Disclosure] An antibody-drug conjugate (for example an anti-HER2 or anti-TROP2 antibody-drug conjugate) used in the present disclosure that includes a derivative of the topoisomerase I inhibitor exatecan as a component, has been confirmed to exhibit an excellent antitumor effect in the treatment of certain cancers such as breast cancer, when administered singly or in combination with a checkpoint inhibitor. Furthermore, a blood brain barrier-penetrant PARP1 selective inhibitor has been confirmed to exhibit an antitumor effect in the treatment of certain cancers. However, it is desired to provide a medicine and treatment which can obtain a superior antitumor effect in the treatment of cancers, such as enhanced efficacy, increased durability of therapeutic response and / or reduced dose-dependent toxicity, and / or an improved safety profile and / or reduced side effects such as neutropenia. The present disclosure provides a pharmaceutical product which can exhibit an excellent antitumor effect in the treatment of cancers, through administration of an anti-HER2 or anti-TROP2 antibody-drug conjugate, in combination with a blood brain barrier-penetrant PARP1 selective inhibitor, in particular in combination with an azaquinolone compound of formula (I) as described herein. The present disclosure also provides a therapeutic use and method wherein the antibody- drug conjugate and blood brain barrier-penetrant PARP1 selective inhibitor are administered in combination to a subject. Specifically, the present disclosure relates to the following [1] to

[0073] : [1] a pharmaceutical product comprising an antibody-drug conjugate and a blood brain barrier-penetrant PARP1 selective inhibitor for administration in combination, wherein the antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula: wherein A represents the connecting position to an antibody, is conjugated to an anti-HER2 or anti-TROP2 antibody via a thioether bond; [2] the pharmaceutical product according to [1], wherein the drug-linker is conjugated to an anti-HER2 antibody; [3] the pharmaceutical product according to [2], wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 16, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 17 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 18, and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 19, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 1 to 3 of SEQ ID NO: 20 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 21; [4] the pharmaceutical product according to [3], wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 22 and a light chain comprising a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 23; [5] the pharmaceutical product according to [4], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 14 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 15; [6] the pharmaceutical product according to [4], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 24 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 15; [7] the pharmaceutical product according to any one of [2] to [6], wherein the average number of units of the drug-linker conjugated per anti-HER2 antibody molecule in the antibody- drug conjugate is in the range of from 7 to 8; [8] the pharmaceutical product according to any one of [2] to [7], wherein the average number of units of the drug-linker conjugated per anti-HER2 antibody molecule in the antibody- drug conjugate is in the range of from 7.5 to 8; [9] the pharmaceutical product according to [8], wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201);

[0010] the pharmaceutical product according to [1], wherein the drug-linker is conjugated to an anti-TROP2 antibody;

[0011] the pharmaceutical product according to

[0010] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 4 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 7 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 8;

[0012] the pharmaceutical product according to

[0011] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 9 and a light chain comprising a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 10;

[0013] the pharmaceutical product according to

[0012] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 12 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 13;

[0014] the pharmaceutical product according to

[0012] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 11 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 13;

[0015] the pharmaceutical product according to any one of

[0010] to

[0014] , wherein the average number of units of the drug-linker conjugated per anti-TROP2 antibody molecule in the antibody- drug conjugate is in the range of from 3.5 to 4.5;

[0016] the pharmaceutical product according to

[0015] , wherein the anti-TROP2 antibody-drug conjugate is datopotamab deruxtecan (DS-1062);

[0017] the pharmaceutical product according to any one of [1] to

[0016] , wherein the blood brain barrier-penetrant PARP1 selective inhibitor is a compound represented by the following formula (I): (I) wherein: R1is independently selected from H, C1-4alkyl, C3-6cycloalkyl, C1-4fluoroalkyl, and C1-4alkyloxy; R2is independently selected from H, halo, C1-4alkyl, and C1-4fluoroalkyl; R3is H or C1-4alkyl; and R4is halo or C1-4alkyl, or a pharmaceutically acceptable salt thereof;

[0018] the pharmaceutical product according to

[0017] , wherein R1in formula (I) is selected from any one of methyl, ethyl, isopropyl, cyclopropyl, 1,1-difluoroethyl, 1-fluoroethyl, trifluoromethyl, difluoromethyl, and methoxy; [18a] the pharmaceutical product according to

[0017] , wherein R1in formula (I) is methyl or ethyl;

[0019] the pharmaceutical product according to

[0017] ,

[0018] or [18a], wherein R2in formula (I) is selected from any one of H, chloro, fluoro, methyl, and difluoromethyl; [19a] the pharmaceutical product according to

[0017] ,

[0018] or [18a], wherein R2in formula (I) is fluoro or methyl;

[0020] the pharmaceutical product according to any one of

[0017] to [19a], wherein R3in formula (I) is methyl or ethyl;

[0021] the pharmaceutical product according to any one of

[0017] to

[0020] , wherein R4in formula (I) is selected from any one of chloro, fluoro and methyl; [21a] the pharmaceutical product according to any one of

[0017] to

[0020] , wherein R4in formula (I) is fluoro;

[0022] the pharmaceutical product according to

[0017] , wherein in formula (I), R1is C1-4alkyl, R2is halo, R3is C1-4alkyl, and R4is halo or C1-4alkyl;

[0023] the pharmaceutical product according to any one of

[0017] to

[0022] , wherein the compound of formula (I) is in the free base form;

[0024] the pharmaceutical product according to

[0017] , wherein the compound of formula (I) is 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine- 2-carboxamide or a pharmaceutically acceptable salt thereof;

[0025] the pharmaceutical product according to

[0017] , wherein the compound of formula (I) is 6-fluoro-5-[4-[(5-fluoro-2-methyl- 3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof;

[0026] the pharmaceutical product according to

[0017] , wherein the compound of formula (I) is 6-fluoro-5-[4-[(5-fluoro-2-methyl- 3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide (AZD9574);

[0027] the pharmaceutical product according to

[0017] , wherein the compound of formula (I) is 6-fluoro-5-[4-[(5-fluoro-2-methyl- 3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide crystalline Form D or a pharmaceutically acceptable salt thereof;

[0028] the pharmaceutical product according to any one of [1] to

[0027] , wherein the product is a composition comprising the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor, for simultaneous administration;

[0029] the pharmaceutical product according to any one of [1] to

[0027] , wherein the product is a combined preparation comprising the antibody-drug conjugate and the blood brain barrier- penetrant PARP1 selective inhibitor, for sequential or separate simultaneous administration;

[0030] the pharmaceutical product according to any one of [1] to

[0029] , wherein the product is for treating cancer;

[0031] the pharmaceutical product according to

[0030] , wherein the cancer is at least one selected from the group consisting of breast cancer, lung cancer, colorectal cancer, gastric cancer, esophageal cancer, head-and-neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, endometrial cancer, gastrointestinal stromal tumor, digestive tract stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, cervical cancer, uterine cancer, testicular cancer, and renal cell carcinoma;

[0032] the pharmaceutical product according to

[0031] , wherein the cancer is breast cancer;

[0033] the pharmaceutical product according to

[0032] , wherein the breast cancer is HER2 positive breast cancer;

[0034] the pharmaceutical product according to

[0032] , wherein the breast cancer is HER2 low breast cancer;

[0035] the pharmaceutical product according to

[0032] , wherein the breast cancer is triple negative breast cancer;

[0036] the pharmaceutical product according to

[0032] , wherein the breast cancer is hormone receptor (HR)-positive, HER2-negative breast cancer;

[0037] the pharmaceutical product according to

[0031] , wherein the cancer is lung cancer;

[0038] the pharmaceutical product according to

[0037] , wherein the lung cancer is non-small cell lung cancer;

[0039] the pharmaceutical product according to

[0038] , wherein the non-small cell lung cancer is non-small cell lung cancer with actionable genomic alterations;

[0040] the pharmaceutical product according to

[0038] , wherein the non-small cell lung cancer is non-small cell lung cancer without actionable genomic alterations;

[0041] the pharmaceutical product according to

[0031] , wherein the cancer is colorectal cancer;

[0042] the pharmaceutical product according to

[0031] , wherein the cancer is gastric cancer;

[0043] the pharmaceutical product according to

[0031] , wherein the cancer is pancreatic cancer;

[0044] the pharmaceutical product according to

[0031] , wherein the cancer is ovarian cancer;

[0045] the pharmaceutical product according to

[0031] , wherein the cancer is prostate cancer;

[0046] the pharmaceutical product according to

[0031] , wherein the cancer is kidney cancer;

[0047] the pharmaceutical product according to

[0031] , wherein the cancer is bladder cancer;

[0048] the pharmaceutical product according to

[0031] , wherein the cancer is endometrial cancer;

[0049] the pharmaceutical product according to

[0031] , wherein the cancer is biliary tract cancer;

[0050] a pharmaceutical product as defined in any one of [1] to

[0029] , for use in treating cancer;

[0051] the pharmaceutical product for the use according to

[0050] , wherein the cancer is as defined in any one of

[0031] to

[0049] ;

[0052] use of an antibody-drug conjugate in the manufacture of a medicament for use in combination with a blood brain barrier- penetrant PARP1 selective inhibitor, wherein the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor are as defined in any one of [1] to

[0027] , for treating cancer;

[0053] the use according to

[0052] wherein the medicament is for use in combination with the blood brain barrier-penetrant PARP1 selective inhibitor by sequential administration;

[0054] the use according to

[0052] wherein the medicament is for use in combination with the blood brain barrier-penetrant PARP1 selective inhibitor by separate simultaneous administration;

[0055] the use according to any one of

[0052] to

[0054] , wherein the cancer is as defined in any one of

[0031] to

[0049] ;

[0056] use of a blood brain barrier-penetrant PARP1 selective inhibitor in the manufacture of a medicament for use in combination with an antibody-drug conjugate, wherein the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor are as defined in any one of [1] to

[0027] , for treating cancer;

[0057] the use according to

[0056] wherein the medicament is for use in combination with the antibody-drug conjugate by sequential administration;

[0058] the use according to

[0056] wherein the medicament is for use in combination with the antibody-drug conjugate by separate simultaneous administration;

[0059] the use according to any one of

[0056] to

[0058] , wherein the cancer is as defined in any one of

[0031] to

[0049] ;

[0060] an antibody-drug conjugate for use, in combination with a blood brain barrier-penetrant PARP1 selective inhibitor, in the treatment of cancer, wherein the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor are as defined in any one of [1] to

[0027] ;

[0061] the antibody-drug conjugate for the use according to

[0060] , wherein the cancer is as defined in any one of

[0031] to

[0049] ;

[0062] the antibody-drug conjugate for the use according to

[0060] or

[0061] , wherein the use comprises administration of the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor sequentially;

[0063] the antibody-drug conjugate for the use according to

[0060] or

[0061] , wherein the use comprises administration of the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor separately and simultaneously;

[0064] an antibody-drug conjugate for use in the treatment of cancer in a subject, wherein said treatment comprises the sequential or separate simultaneous administration of i) the antibody-drug conjugate, and ii) a blood brain barrier- penetrant PARP1 selective inhibitor to said subject, wherein the antibody-drug conjugate and the blood brain barrier- penetrant PARP1 selective inhibitor are as defined in any one of [1] to

[0027] ;

[0065] a blood brain barrier-penetrant PARP1 selective inhibitor for use, in combination with an antibody-drug conjugate, in the treatment of cancer, wherein the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor are as defined in any one of [1] to

[0027] ;

[0066] the blood brain barrier-penetrant PARP1 selective inhibitor for the use according to

[0065] , wherein the cancer is as defined in any one of

[0031] to

[0049] ;

[0067] the blood brain barrier-penetrant PARP1 selective inhibitor for the use according to

[0065] or

[0066] , wherein the use comprises administration of the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor sequentially;

[0068] the blood brain barrier-penetrant PARP1 selective inhibitor for the use according to

[0065] or

[0066] , wherein the use comprises administration of the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor separately and simultaneously;

[0069] a blood brain barrier-penetrant PARP1 selective inhibitor for use in the treatment of cancer in a subject, wherein said treatment comprises the sequential or separate simultaneous administration of i) the blood brain barrier-penetrant PARP1 selective inhibitor, and ii) an antibody-drug conjugate to said subject, wherein the blood brain barrier-penetrant PARP1 selective inhibitor and the antibody-drug conjugate are as defined in any one of [1] to

[0027] ;

[0070] a method of treating cancer comprising administering an antibody-drug conjugate and a blood brain barrier-penetrant PARP1 selective inhibitor as defined in any one of [1] to

[0027] in combination to a subject in need thereof;

[0071] the method according to

[0070] , wherein the cancer is as defined in any one of

[0031] to

[0049] ;

[0072] the method according to

[0070] or

[0071] , wherein the method comprises administering the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor sequentially; and

[0073] the method according to

[0070] or

[0071] , wherein the method comprises administering the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor separately and simultaneously. [Advantageous Effects of Disclosure] The present disclosure provides a pharmaceutical product comprising a specified antibody-drug conjugate, having an antitumor drug conjugated to an anti-HER2 or anti-TROP2 antibody via a linker structure, and a blood brain barrier- penetrant PARP1 selective inhibitor, for administration in combination, and a therapeutic use and method wherein the specified antibody-drug conjugate and the blood brain barrier- penetrant PARP1 selective inhibitor are administered in combination to a subject. Thus, the present disclosure provides a medicine and treatment which can obtain a superior antitumor effect in the treatment of cancers. [Brief Description of Drawings] [anti-HER2 antibody]: Figure 1 is a diagram showing the amino acid sequence of a heavy chain of an anti-HER2 antibody (SEQ ID NO: 14). Figure 2 is a diagram showing the amino acid sequence of a light chain of an anti-HER2 antibody (SEQ ID NO: 15). Figure 3 is a diagram showing the amino acid sequence of a heavy chain CDRH1 (SEQ ID NO: 16 [= amino acid residues 26 to 33 of SEQ ID NO: 14]). Figure 4 is a diagram showing the amino acid sequence of a heavy chain CDRH2 (SEQ ID NO: 17 [= amino acid residues 51 to 58 of SEQ ID NO: 14]). Figure 5 is a diagram showing the amino acid sequence of a heavy chain CDRH3 (SEQ ID NO: 18 [= amino acid residues 97 to 109 of SEQ ID NO: 14]). Figure 6 is a diagram showing the amino acid sequence of a light chain CDRL1 (SEQ ID NO: 19 [= amino acid residues 27 to 32 of SEQ ID NO: 15]). Figure 7 is a diagram showing an amino acid sequence comprising the amino acid sequence of a light chain CDRL2 (SAS) (SEQ ID NO: 20 [= amino acid residues 50 to 56 of SEQ ID NO: 15]). Figure 8 is a diagram showing the amino acid sequence of a light chain CDRL3 (SEQ ID NO: 21 [= amino acid residues 89 to 97 of SEQ ID NO: 15]). Figure 9 is a diagram showing the amino acid sequence of a heavy chain variable region (SEQ ID NO: 22 [= amino acid residues 1 to 120 of SEQ ID NO: 14]). Figure 10 is a diagram showing the amino acid sequence of a light chain variable region (SEQ ID NO: 23 [= amino acid residues 1 to 107 of SEQ ID NO: 15]). Figure 11 is a diagram showing the amino acid sequence of a heavy chain (SEQ ID NO: 24 [= amino acid residues 1 to 449 of SEQ ID NO: 14]). [anti-TROP2 antibody]: Figure 12 is a diagram showing the amino acid sequence of a heavy chain of an anti-TROP2 antibody (SEQ ID NO: 1). Figure 13 is a diagram showing the amino acid sequence of a light chain of an anti-TROP2 antibody (SEQ ID NO: 2). Figure 14 is a diagram showing the amino acid sequence of a heavy chain CDRH1 (SEQ ID NO: 3 [= amino acid residues 50 to 54 of SEQ ID NO: 1]). Figure 15 is a diagram showing the amino acid sequence of a heavy chain CDRH2 (SEQ ID NO: 4 [= amino acid residues 69 to 85 of SEQ ID NO: 1]). Figure 16 is a diagram showing the amino acid sequence of a heavy chain CDRH3 (SEQ ID NO: 5 [= amino acid residues 118 to 129 of SEQ ID NO: 1]). Figure 17 is a diagram showing the amino acid sequence of a light chain CDRL1 (SEQ ID NO: 6 [= amino acid residues 44 to 54 of SEQ ID NO: 2]). Figure 18 is a diagram showing the amino acid sequence of a light chain CDRL2 (SEQ ID NO: 7 [= amino acid residues 70 to 76 of SEQ ID NO: 2]). Figure 19 is a diagram showing the amino acid sequence of a light chain CDRL3 (SEQ ID NO: 8 [= amino acid residues 109 to 117 of SEQ ID NO: 2]). Figure 20 is a diagram showing the amino acid sequence of a heavy chain variable region (SEQ ID NO: 9 [= amino acid residues 20 to 140 of SEQ ID NO: 1]). Figure 21 is a diagram showing the amino acid sequence of a light chain variable region (SEQ ID NO: 10 [= amino acid residues 21 to 129 of SEQ ID NO: 2]). Figure 22 is a diagram showing the amino acid sequence of a heavy chain (SEQ ID NO: 11 [= amino acid residues 20 to 469 of SEQ ID NO: 1]). [Experimental]: Figure 23 is a graph showing tumor volumes for treatments with DS-1062 or AZD9574 alone, or with DS-1062 in combination with AZD9574, in an in vivo NCI-N87 xenograft model. Figure 24 is a graph showing tumor volumes for treatments with DS-8201 or AZD9574 alone, or with DS-8201 in combination with AZD9574, in an in vivo KPL-4 xenograft model. Figure 25 shows efficacy and safety data for exatecan in combination with AZD9574 or AZD5305. [Detailed Description] In order that the present disclosure can be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Units, prefixes, and symbols are denoted in their Système International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. It is understood that wherever aspects are described herein with the language "comprising", otherwise analogous aspects described in terms of "consisting of" and / or "consisting essentially of" are also provided. The terms "inhibit" and "inhibition" can refer to a decrease of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% in biological activity. Cellular proliferation can be assayed using art recognized techniques which measure rate of cell division, and / or the fraction of cells within a cell population undergoing cell division, and / or rate of cell loss from a cell population due to terminal differentiation or cell death (e.g., thymidine incorporation). The term "subject" refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject. The term "pharmaceutical product" refers to a preparation which is in such form as to permit the biological activity of the active ingredients, either as a composition containing all the active ingredients (for simultaneous administration), or as a combination of separate compositions (a combined preparation) each containing at least one but not all of the active ingredients (for administration sequentially or simultaneously), and which contains no additional components which are unacceptably toxic to a subject to which the product would be administered. Such product can be sterile. By^oeiqhp]jakqo ]`iejeopn]pekj^ eo ia]jp pd]p pda ]_peraejcna`eajpo ]na ]`iejeopana` ]p pda o]ia peia. @u ^oequential]`iejeopn]pekj^ eo ia]jp pd]p pda ]_pera ejcna`eajpo ]naadministered one after the other, in either order, at a time interval between the individual administrations. The time interval can be, for example, less than 24 hours, less than 6 hours, or less than 2 hours. Terms such as "treating" or "treatment" or "to treat" or "alleviating" or "to alleviate" refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and / or halt progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that prevent and / or slow the development of a targeted pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented. In certain aspects, a subject is successfully "treated" for cancer according to the methods of the present disclosure if the patient shows, e.g., total, partial, or transient remission of a certain type of cancer. The terms "cancer", "tumor", "cancerous", and "malignant" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancers include but are not limited to, breast cancer (including HER2 positive, HER2 low, or triple negative breast cancer), lung cancer (including non-small cell lung cancer, with or without actionable genomic alterations), colorectal cancer, gastric cancer, esophageal cancer, head- and-neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, endometrial cancer, gastrointestinal stromal tumor, digestive tract stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, cervical cancer, uterine cancer, testicular cancer, and renal cell carcinoma. Cancers include hematological malignancies such as acute myeloid leukemia, multiple myeloma, chroniclymphocytic leukemia, diffuse h]nca @ _ahh huildki], @qngepp^olymphoma, follicular lymphoma and solid tumors such as breast cancer, lung cancer, neuroblastoma and colon cancer. The term "cytotoxic drug" as used herein is defined broadly and refers to a substance that inhibits or prevents the function of cells and / or causes destruction of cells (cell death), and / or exerts anti-neoplastic / anti-proliferative effects. For example, a cytotoxic drug prevents directly or indirectly the development, maturation, or spread of neoplastic tumor cells. The term also includes such agents that cause a cytostatic effect only and not a mere cytotoxic effect. The term includes chemotherapeutic agents as specified below. The term "chemotherapeutic agent" is a subset of the term "cytotoxic drug" comprising natural or synthetic chemical compounds. In accordance with the methods or uses of the present disclosure, compounds of the present disclosure may be administered to a patient to promote a positive therapeutic response with respect to cancer. The term "positive therapeutic response" with respect to cancer treatment refers to an improvement in the symptoms associated with the disease. For example, an improvement in the disease can be characterized as a complete response. The term "complete response" refers to an absence of clinically detectable disease with normalization of any previous test results. Alternatively, an improvement in the disease can be categorized as being a partial response. A "positive therapeutic response" encompasses a reduction or inhibition of the progression and / or duration of cancer, the reduction or amelioration of the severity of cancer, and / or the amelioration of one or more symptoms thereof resulting from the administration of compounds of the present disclosure. In specific aspects, such terms refer to one, two or three or more results following the administration of compounds of the instant disclosure: (1) a stabilization, reduction or elimination of the cancer cell population; (2) a stabilization or reduction in cancer growth; (3) an impairment in the formation of cancer; (4) eradication, removal, or control of primary, regional and / or metastatic cancer; (5) a reduction in mortality; (6) an increase in disease-free, relapse-free, progression- free, and / or overall survival, duration, or rate; (7) an increase in the response rate, the durability of response, or number of patients who respond or are in remission; (8) a decrease in hospitalization rate, (9) a decrease in hospitalization lengths, (10) the size of the cancer is maintained and does not increase or increases by less than 10%, preferably less than 5%, preferably less than 4%, preferably less than 2%, and (11) an increase in the number of patients in remission. (12) a decrease in the number of adjuvant therapies (e.g., chemotherapy or hormonal therapy) that would otherwise be required to treat the cancer. Clinical response can be assessed using screening techniques such as PET, magnetic resonance imaging (MRI) scan, x-radiographic imaging, computed tomographic (CT) scan, flow cytometry or fluorescence-activated cell sorter (FACS) analysis, histology, gross pathology, and blood chemistry, including but not limited to changes detectable by ELISA, RIA, chromatography, and the like. In addition to these positive therapeutic responses, the subject undergoing therapy can experience the beneficial effect of an improvement in the symptoms associated with the disease. The term "antibody" as used herein refers to a protein that is capable of recognizing and specifically binding to an antigen. Ordinary or conventional mammalian antibodies comprise a tetramer, which is typically composed of two identical pairs of polypeptide chains, each pair consisting of one "light" chain (typically having a molecular weight of about 25 kDa) and one "heavy" chain (typically having a molecular weight of about 50-70 kDa). The terms "heavy chain" and "light chain", as used herein, refer to any immunoglobulin polypeptide having sufficient variable domain sequence to confer specificity for a target antigen. The amino-terminal portion of each light and heavy chain typically includes a variable domain of about 100 to 110 or more amino acids that typically is responsible for antigen recognition. As useddanaej, pda panio ^r]ne]^ha nacekj^ kn ^r]ne]^ha `ki]ej^ ]naused interchangeably and are common in the art. The carboxyl- terminal portion of each chain typically defines a constant domain responsible for effector function. Thus, in a naturally occurring antibody, a full-length heavy chain immunoglobulin polypeptide includes a variable domain (VH) and three constant domains (CH1, CH2, and CH3) and a hinge region between CH1and CH2, wherein the VH domain is at the amino-terminus of the polypeptide and the CH3domain is at the carboxyl-terminus, and a full-length light chain immunoglobulin polypeptide includes a variable domain (VL) and a constant domain (CL), wherein the VLdomain is at the amino-terminus of the polypeptide and the CLdomain is at the carboxyl-terminus. Those of skill in the art, however, would appreciate that the locations of the domains in a naturally occurring antibody can be modified in certain antibody-like binding protein formats without a loss of antigen-binding capability. Classes of human light chains are termed kappa and lambda light chains. Within full-length light and heavy chains, the variable and constant domains typically are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 more amino acids. The variable regions of each light / heavy chain pair typically form an antigen-binding site. The variable domains of naturally occurring antibodies typically exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. The CDRs from the two chains of each pair typically are aligned by the framework regions, which may enable binding to a specific epitope. From the amino-terminus to the carboxyl-terminus, both light and heavy chain variable domains typically comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The term "antibody fragment" refers to a portion of an intact or full-length chain or an antibody, generally the target binding or variable region. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2and Fvfragments. As used herein, the term "functional fragment" is generally synonymous with "antibody fragment", and with respect to antibodies, can refer to antibody fragments such as Fv, Fab, F(ab')2. Reference to the numbering of amino acid residues described herein is performed according to the EU numbering system (also described in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). ?^ikjk_hkj]h^ ]jpe^k`u kn ]jpecaj-binding fragmentthereof refers to a homogeneous antibody or antigen-binding fragment population involved in the highly specific binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies that typically include different antibodies directed against different antigenic`apaniej]jpo. Rda pani ^ikjk_hkj]h^ ]jpe^k`u kn ]jpecaj- binding fragment thereof encompasses both intact and full- length monoclonal antibodies as well as antibody fragments(oq_d ]o D]^, D]^^, D(]^^)2, Dr), oejcha _d]ej (o_Dr) iqp]jpo,fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigenna_kcjepekj oepa. Dqnpdanikna, ^ikjk_hkj]h^ ]jpe^k`u knantigen-binding fragment thereof refers to such antibodies and antigen-binding fragments thereof made in manner including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals. The term "human antibody", as used herein, includes antibodies having variable and constant regions substantially corresponding to human germline immunoglobulin sequences. In some aspects, human antibodies are produced in non-human mammals, including, but not limited to, rodents, such as mice and rats, and lagomorphs, such as rabbits. In other aspects, human antibodies are produced in hybridoma cells. In still other aspects, human antibodies are produced recombinantly. The term "antigen" or "target antigen" as used herein refers to a molecule or a portion of a molecule that is capable of being recognized by and bound by binding proteins of the disclosure. The target antigen is capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen. A target antigen may have one or more epitopes. The term "epitope" as used herein refers to a region or structural element of an antigen that is recognized and bound by a binding protein of the disclosure. More precisely, the epitope is the specific structure that is bound by the CDRs of the binding protein. Epitopes can comprise protein structural elements, carbohydrates or even portions of lipid structures found in membranes. A binding protein is said to specifically bind an antigen when it preferentially recognizes its antigen target in a complex mixture of proteins and / or macromolecules. The term "specifically binds" refers to a binding protein that specifically binds to a molecule or a fragment thereof (e.g., antigen). A binding protein that specifically binds a molecule or a fragment thereof may bind to other molecules with lower affinity as determined by, for example, immunoassays, BIAcore, or other assays known in the art. In particular, antibodies or fragments that specifically bind to at least one molecule or a fragment thereof can compete off molecules that bind non- specifically. The term "antigen binding site" as used herein refers to a site created on the surface of a binding protein of the disclosure where an antigen or an epitope on an antigen is bound. The antigen binding site of the binding protein is typically described by reference to the loop structures created by complementarity determining regions (CDRs) of the binding protein. [Description of Embodiments] Hereinafter, preferred modes for carrying out the present disclosure are described. The embodiments described below are given merely for illustrating one example of a typical embodiment of the present disclosure and are not intended to limit the scope of the present disclosure. 1. Antibody-drug conjugate The antibody-drug conjugate used in the present disclosure is an antibody-drug conjugate in which a drug-linker represented by the following formula: wherein A represents the connecting position to an antibody, is conjugated to an anti-HER2 or anti-TROP2 antibody via a thioether bond. In the present disclosure, the partial structure consisting of a linker and a drug in the antibody-drug conjugate is referred to as a "drug-linker". The drug-linker is connected to a thiol group (in other words, the sulfur atom of a cysteine residue) formed at an interchain disulfide bond site (two sites between heavy chains, and two sites between a heavy chain and a light chain) in the antibody. The drug-linker of the present disclosure includes exatecan (IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro- 1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H- benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10,13- dione, (also expressed as chemical name: (1S,9S)-1-amino-9- ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H- benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin- 10,13(9H,15H)-dione)), which is a topoisomerase I inhibitor, as a component. Exatecan is a camptothecin derivative having an antitumor effect, represented by the following formula: The antibody-drug conjugate used in the present disclosure can be also represented by the following formula: Here, the drug-linker is conjugated to an antibody(^?jpe^k`u-^), which is an anti-HER2 or anti-TROP2 antibody,via a thioether bond. The meaning of n is the same as that of what is called the average number of conjugated drug molecules (DAR; Drug-to-Antibody Ratio), and indicates the average number of units of the drug-linker conjugated per antibody molecule. After migrating into cancer cells, the antibody-drug conjugate used in the present disclosure is cleaved at the linker portion to release a compound represented by the following formula: 2. Antibody in antibody-drug conjugate The antibody in the antibody-drug conjugate used in the present disclosure is an anti-HER2 or anti-TROP2 antibody, and may be derived from any species, preferably from a human, a rat, a mouse, or a rabbit. In cases when the antibody is derived from species other than human species, it is preferably chimerized or humanized using a well-known technique. The antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The antibody in the antibody-drug conjugate used in the present disclosure is an antibody preferably having a characteristic of being capable of targeting cancer cells, and is preferably an antibody possessing, for example, a property of recognizing a cancer cell, a property of binding to a cancer cell, a property of internalizing in a cancer cell, and / or cytocidal activity against cancer cells. The binding activity of the antibody against cancer cells can be confirmed using flow cytometry. The internalization of the antibody into cancer cells can be confirmed using (1) an assay of visualizing an antibody incorporated in cells under a fluorescence microscope using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay of measuring a fluorescence intensity incorporated in cells using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Molecular Biology of the Cell, Vol. 15, 5268-5282, December 2004), or (3) a Mab-ZAP assay using an immunotoxin binding to the therapeutic antibody wherein the toxin is released upon incorporation into cells to inhibit cell growth (Bio Techniques 28: 162-165, January 2000). As the immunotoxin, a recombinant complex protein of a diphtheria toxin catalytic domain and protein G may be used. The antitumor activity of the antibody can be confirmed in vitro by determining inhibitory activity against cell growth. For example, a cancer cell line overexpressing a target protein for the antibody is cultured, and the antibody is added at varying concentrations into the culture system to determine inhibitory activity against focus formation, colony formation, and spheroid growth. The antitumor activity can be confirmed in vivo, for example, by administering the antibody to a nude mouse with a transplanted cancer cell line highly expressing the target protein, and determining change in the cancer cell. Since the compound conjugated in the antibody-drug conjugate exerts an antitumor effect, it is preferred but not essential that the antibody itself should have an antitumor effect. For the purpose of specifically and selectively exerting the cytotoxic activity of the antitumor compound against cancer cells, it is important and also preferred that the antibody should have the property of internalizing to migrate into cancer cells. The anti-HER2 or anti-TROP2 antibody in the antibody-drug conjugate used in the present disclosure can be obtained by a procedure known in the art. For example, the antibody of the present disclosure can be obtained using a method usually carried out in the art, which involves immunizing animals with an antigenic polypeptide and collecting and purifying antibodies produced in vivo. The origin of the antigen is not limited to humans, and the animals may be immunized with an antigen derived from a non-human animal such as a mouse, a rat and the like. In this case, the cross-reactivity of antibodies binding to the obtained heterologous antigen with human antigens can be tested to screen for an antibody applicable to a human disease. Alternatively, antibody-producing cells which produce antibodies against the antigen are fused with myeloma cells according to a method known in the art (e.g., Kohler and Milstein, Nature (1975) 256, p. 495-497; and Kennet, R. ed., Monoclonal Antibodies, p. 365-367, Plenum Press, N.Y. (1980)) to establish hybridomas, from which monoclonal antibodies can in turn be obtained. The antigen can be obtained by genetically engineering host cells to produce a gene encoding the antigenic protein. Specifically, vectors that permit expression of the antigen gene are prepared and transferred to host cells so that the gene is expressed. The antigen thus expressed can be purified. The antibody can also be obtained by a method of immunizing animals with the above-described genetically engineered antigen-expressing cells or a cell line expressing the antigen. The anti-HER2 or anti-TROP2 antibody in the antibody-drug conjugate used the present disclosure is preferably a recombinant antibody obtained by artificial modification for the purpose of decreasing heterologous antigenicity to humans such as a chimeric antibody or a humanized antibody, or is preferably an antibody having only the gene sequence of an antibody derived from a human, that is, a human antibody. These antibodies can be produced using a known method. As the chimeric antibody, an antibody in which antibody variable and constant regions are derived from different species, for example, a chimeric antibody in which a mouse- or rat-derived antibody variable region is connected to a human- derived antibody constant region can be exemplified (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)). As the humanized antibody, an antibody obtained by integrating only the complementarity determining region (CDR) of a heterologous antibody into a human-derived antibody (Nature (1986) 321, pp. 522-525), and an antibody obtained by grafting a part of the amino acid residues of the framework of a heterologous antibody as well as the CDR sequence of the heterologous antibody to a human antibody by a CDR-grafting method (WO90 / 07861), and an antibody humanized using a gene conversion mutagenesis strategy (U.S. Patent No. 5,821,337) can be exemplified. As the human antibody, an antibody generated by using a human antibody-producing mouse having a human chromosome fragment including genes of a heavy chain and light chain of a human antibody (see Tomizuka, K. et al., Nature Genetics (1997) 16, p.133-143; Kuroiwa, Y. et. al., Nucl. Acids Res. (1998) 26, p.3447-3448; Yoshida, H. et. al., Animal Cell Technology: Basic and Applied Aspects vol.10, p.69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et. al., Proc. Natl. Acad. Sci. USA (2000) 97, p.722-727, etc.) can be exemplified. As an alternative, an antibody obtained by phage display, the antibody being selected from a human antibody library (see Wormstone, I. M. et. al, Investigative Ophthalmology & Visual Science. (2002)43 (7), p.2301-2308; Carmen, S. et. al., Briefings in Functional Genomics and Proteomics (2002), 1(2), p.189-203; Siriwardena, D. et. al., Ophthalmology (2002) 109(3), p.427-431, etc.) can be exemplified. In the antibody in the antibody-drug conjugate used in present disclosure, modified variants of the antibody are also included. The modified variant refers to a variant obtained by subjecting the antibody according to the present disclosure to chemical or biological modification. Examples of the chemically modified variant include variants including a linkage of a chemical moiety to an amino acid skeleton, variants including a linkage of a chemical moiety to an N- linked or O-linked carbohydrate chain, etc. Examples of the biologically modified variant include variants obtained by post-translational modification (such as N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, or oxidation of methionine), and variants in which a methionine residue has been added to the N terminus by being expressed in a prokaryotic host cell. Further, an antibody labeled so as to enable the detection or isolation of the antibody or an antigen according to the present disclosure, for example, an enzyme-labeled antibody, a fluorescence-labeled antibody, and an affinity-labeled antibody are also included in the meaning of the modified variant. Such a modified variant of the antibody according to the present disclosure is useful for improving the stability and blood retention of the antibody, reducing the antigenicity thereof, detecting or isolating an antibody or an antigen, and so on. Further, by regulating the modification of a glycan which is linked to the antibody according to the present disclosure (glycosylation, defucosylation, etc.), it is possible to enhance antibody-dependent cellular cytotoxic activity. As the technique for regulating the modification of a glycan of antibodies, those disclosed in WO99 / 54342, WO00 / 61739, WO02 / 31140, WO2007 / 133855, WO2013 / 120066, etc. are known. However, the technique is not limited thereto. In the antibody (an anti-HER2 or anti-TROP2 antibody) according to the present disclosure, antibodies in which the modification of a glycan is regulated are also included. It is known that a lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell is deleted (Journal of Chromatography A, 705: 129-134 (1995)), and it is also known that two amino acid residues (glycine and lysine) at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell are deleted and a proline residue newly located at the carboxyl terminus is amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, such deletion and modification of the heavy chain sequence do not affect the antigen-binding affinity and the effector function (the activation of complement, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Therefore, in the antibody (an anti-HER2 or anti-TROP2 antibody) according to the present disclosure, antibodies subjected to such modification and functional fragments of the antibody are also included, and deletion variants in which one or two amino acids have been deleted at the carboxyl terminus of the heavy chain, variants obtained by amidation of deletion variants (for example, a heavy chain in which the carboxyl terminal proline residue has been amidated), and the like are also included. The type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the antibody according to the present disclosure is not limited to the above variants as long as the antigen-binding affinity and the effector function are conserved. The two heavy chains constituting the antibody according to the present disclosure may be of one type selected from the group consisting of a full-length heavy chain and the above-described deletion variant, or may be of two types in combination selected therefrom. The ratio of the amount of each deletion variant can be affected by the type of cultured mammalian cells which produce the antibody according to the present disclosure and the culture conditions; however, an antibody in which one amino acid residue at the carboxyl terminus has been deleted in both of the two heavy chains in the antibody according to the present disclosure can be exemplified as preferred. As isotypes of the antibody (an anti-HER2 or anti-TROP2 antibody) according to the present disclosure, for example, IgG (IgG1, IgG2, IgG3, IgG4) can be exemplified, and IgG1 or IgG2 can be exemplified as preferred. In the present disclosure, the term "anti-TROP2 antibody" refers to an antibody which binds specifically to TROP2 (TACSTD2: Tumor-associated calcium signal transducer 2; EGP-1), and preferably has an activity of internalization in TROP2-expressing cells by binding to TROP2. Examples of the anti-TROP2 antibody include hTINA1-H1L1 (WO2015 / 098099), and datopotamab can be exemplified as preferred. In the present disclosure, the term "anti-HER2 antibody" refers to an antibody which specifically binds to HER2 (Human Epidermal Growth Factor Receptor Type 2; ErbB-2), and preferably has an activity of internalizing in HER2-expressing cells by binding to HER2. Examples of the anti-HER2 antibody include trastuzumab (U.S. Patent No. 5821337) and pertuzumab (WO01 / 00245), and trastuzumab can be exemplified as preferred. 3. Production of antibody-drug conjugate A drug-linker intermediate for use in production of the antibody-drug conjugate according to the present disclosure is represented by the following formula: The drug-linker intermediate can be expressed as the chemical name N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanoyl]glycylglycyl-L-phenylalanyl-N-[(2-{[(1S,9S)-9- ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15- hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2- b]quinolin-1-yl]amino}-2-oxoethoxy)methyl]glycinamide, and can be produced with reference to descriptions in WO2014 / 057687, WO2015 / 098099, WO2015 / 115091, WO2015 / 155998, WO2019 / 044947 and so on. The antibody-drug conjugate used in the present disclosure can be produced by reacting the above-described drug-linker intermediate and an antibody (an anti-HER2 or anti-TROP2 antibody) having a thiol group (also referred to as a sulfhydryl group). An anti-HER2 or anti-TROP2 antibody having a sulfhydryl group can be obtained by a method well known in the art (Hermanson, G. T, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). For example, by using 0.3 to 3 molar equivalents of a reducing agent such as tris(2- carboxyethyl)phosphine hydrochloride (TCEP) per interchain disulfide within the antibody and reacting with the antibody in a buffer solution containing a chelating agent such as ethylenediamine tetraacetic acid (EDTA), an antibody having a sulfhydryl group with partially or completely reduced interchain disulfides within the antibody can be obtained. Further, by using 2 to 20 molar equivalents of the drug- linker intermediate per antibody (an anti-HER2 or anti-TROP2 antibody) having a sulfhydryl group, an antibody-drug conjugate in which 2 to 8 drug molecules are conjugated per antibody molecule can be produced. The average number of conjugated drug molecules per antibody (an anti-HER2 or anti-TROP2 antibody) molecule of the antibody-drug conjugate produced can be determined, for example, by a method of calculation based on measurement of UV absorbance for the antibody-drug conjugate and the conjugation precursor thereof at two wavelengths of 280 nm and 370 nm (UV method), or a method of calculation based on quantification through HPLC measurement for fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method). Conjugation between the antibody (an anti-HER2 or anti- TROP2 antibody) and the drug-linker intermediate and calculation of the average number of conjugated drug molecules per antibody molecule of the antibody-drug conjugate can be performed with reference to descriptions in WO2014 / 057687, WO2015 / 098099, WO2015 / 115091, WO2017 / 002776, and so on. In the present disclosure, the term "anti-TROP2 antibody- drug conjugate" refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate is an anti-TROP2 antibody. The anti-TROP2 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 3 [= an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 1], CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 4 [= an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 1], and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 5 [= an amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO: 1], and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 6 [= an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 2], CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 7 [= an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 2], and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 8 [= an amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO: 2], more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 9 [= an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 1], and a light chain comprising a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 10 [= an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 2], and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 12 [= an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1] and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 13 [= amino acid residues 21 to 234 of SEQ ID NO: 2], or an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 11 [= an amino acid sequence consisting of amino acid residues 20 to 469 of SEQ ID NO: 1] and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 13 [= amino acid residues 21 to 234 of SEQ ID NO: 2]. The average number of units of the drug-linker conjugated per antibody molecule in the anti-TROP2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, even more preferably 3.5 to 4.5, and even more preferably about 4. The anti-TROP2 antibody-drug conjugate can be produced with reference to descriptions in WO2015 / 098099, WO2017 / 002776 and WO2022 / 014698. In preferred embodiments, the anti-TROP2 antibody-drug conjugate is datopotamab deruxtecan (DS-1062). In the present disclosure, the term "anti-HER2 antibody- drug conjugate" refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate according to the present disclosure is an anti-HER2 antibody. The anti-HER2 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 14, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 14 and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 14, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 15, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 15 and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 15, and more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 14 and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 15, and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 14 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 15, or an antibody comprising a heavy chain consisting of amino acid residues 1 to 449 of SEQ ID NO: 14 and a light chain consisting of an amino acid sequence consisting of all amino acid residues 1 to 214 of SEQ ID NO: 15. The average number of units of the drug-linker conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8. The anti-HER2 antibody-drug conjugate used in the present disclosure can be produced with reference to descriptions in WO2015 / 115091 and so on. In preferred embodiments, the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201). 4. Blood brain barrier-penetrant PARP1 selective inhibitor In the present disclosure, the term "PARP1 selective inhibitor" refers to a PARP inhibitor that exhibits selectivity for PARP1 over other PARP family members such as PARP2, PARP3, PARP5a, and PARP6, advantageously selectivity for PARP1 over PARP2, preferably at least 10-fold selectivity for PARP1 over PARP2, and more preferably at least 100-fold selectivity for PARP1 over PARP2. In the present disclosure, the term "blood brain barrier-lajapn]jp N?PN1 oaha_pera ejde^epkn^ nabano pk N?PN1 oaha_pera inhibitor that is capable of penetrating the blood brain barrier (BBB). Preferably, the blood brain barrier-penetrant PARP1 selective inhibitor is a PARP1 selective inhibitor for which the ratio of compound that penetrates the BBB is >0.1, more preferably the ratio is >0.2, yet more preferably the ratio is >0.3, wherein 1 is complete BBB penetration, and 0 is no penetration, as measured using the rat kpuu assay. Examples of blood brain barrier-penetrant PARP1 selective inhibitors which may be used according to the present disclosure include azaquinolone compounds of formula (I). Azaquinolone compounds of formula (I) described herein have surprisingly high selectivity for PARP1 over other PARP family members such as PARP2, PARP3, PARP5a, and PARP6. Advantageously, compounds of formula (I) described herein have low hERG activity. It is well known that blockade of the cardiac ion channel coded by human ether-à-gogo-related gene (hERG) is a risk factor in drug discovery and development, and that blockage of hERG can cause safety problems such as cardiac arrhythmia. Moreover, azaquinolone compounds of formula (I) are capable of penetrating the blood brain barrier, and therefore may be useful for the treatment of diseases and conditions occurring in tissues in the central nervous system, such as the brain and spinal cord. Accordingly, in preferred embodiments of the blood brain barrier-penetrant PARP1 selective inhibitor used in the present disclosure, the blood brain barrier-penetrant PARP1 selective inhibitor is a compound represented by the following formula (I): (I) wherein: R1is independently selected from H, C1-4alkyl, C3-6cycloalkyl, C1-4fluoroalkyl, and C1-4alkyloxy; R2is independently selected from H, halo, C1-4alkyl, and C1-4fluoroalkyl; R3is H or C1-4alkyl; and R4is halo or C1-4alkyl, or a pharmaceutically acceptable salt thereof. Preferably, R1is selected from any one of methyl, ethyl, isopropyl, cyclopropyl, 1,1-difluoroethyl, 1-fluoroethyl, trifluoromethyl, difluoromethyl, and methoxy, more preferably R1is methyl or ethyl. Preferably, R2is selected from any one of H, chloro, fluoro, methyl, and difluoromethyl, more preferably R2is fluoro or methyl. Preferably, R3is methyl or ethyl. Preferably, R4is selected from any one of chloro, fluoro and methyl, for example R4is fluoro. In an embodiment, R1is C1-4alkyl, R2is halo, R3is C1-4alkyl, and R4is halo or C1-4alkyl. In further embodiments, the compound of formula (I) is in the free base form. In further embodiments, the compound of formula (I) is selected from: 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2- carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 6-chloro-5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridine-2-carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2-carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2-carboxamide, 6-chloro-5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2- carboxamide, 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, 6-fluoro-5-[4-[[5-fluoro-2-[(1S and 1R)-1-fluoroethyl]-3- oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide, 5-[4-[[5-fluoro-2-[(1S and 1R)-1-fluoroethyl]-3-oxo-4H- quinoxalin-6-yl]methyl]piperazin-1-yl]-N,6-dimethyl-pyridine- 2-carboxamide, 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2- carboxamide, 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, 5-[4-[[2-(1,1-difluoroethyl)-5-fluoro-3-oxo-4H-quinoxalin- 6-yl]methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 6-(difluoromethyl)-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, 6-(difluoromethyl)-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2-carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2- carboxamide, 6-chloro-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 6-chloro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]-N-methyl-pyridine-2-carboxamide, 6-chloro-5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]-N,6-dimethyl-pyridine-2-carboxamide, 6-fluoro-5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[[2-(difluoromethyl)-5-fluoro-3-oxo-4H-quinoxalin-6- yl]methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, 5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 6-fluoro-5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, 6-chloro-5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2- carboxamide, 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, N-ethyl-6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, N-ethyl-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2-carboxamide, 5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6- yl]methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, 6-fluoro-5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H- quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 6-chloro-5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H- quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6- yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 6-fluoro-5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin- 6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, 5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2- carboxamide, 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, 6-fluoro-5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 6-(difluoromethyl)-5-[4-[(2-methoxy-5-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, and 6-(difluoromethyl)-5-[4-[(2,5-dimethyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound of formula (I) is 6- fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound of formula (I) is 6- fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide. In a further embodiment, the compound of formula (I) is 6- fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide crystalline Form B or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound of formula (I) is 6- fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide crystalline Form D or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound of formula (I) is 6- fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide mesylate, optionally as crystalline Form C. 5. Combination of antibody-drug conjugate and blood brain barrier-penetrant PARP1 selective inhibitor In a first combination embodiment of the disclosure, the antibody-drug conjugate which is combined with the blood brain barrier-penetrant PARP1 selective inhibitor is an antibody- drug conjugate in which the antibody is an anti-HER2 antibody. In an embodiment of the first combination embodiment described above, the anti-HER2 antibody comprises a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 16, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 17 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 18, and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 19, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 1 to 3 of SEQ ID NO: 20 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 21. In another embodiment of the first combination embodiment described above, the anti- HER2 antibody comprises a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 22 and a light chain comprising a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 23. In another embodiment of the first combination embodiment described above, the anti- HER2 antibody comprises a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 14 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 15. In another embodiment of the first combination embodiment described above, the anti-HER2 antibody comprises a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 24 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 15. In another embodiment of the first combination embodiment described above, the anti- HER2 antibody is trastuzumab deruxtecan (DS-8201). In another preferred embodiment of the first combination embodiment described above, the blood brain barrier-penetrant PARP1 selective inhibitor is 6-fluoro-5-[4-[(5-fluoro-2- methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl-pyridine-2-carboxamide or a pharmaceutically acceptable salt thereof. In a particularly preferred embodiment of the first combination embodiment described above, the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201) and the blood brain barrier-penetrant PARP1 selective inhibitor is 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide or a pharmaceutically acceptable salt thereof. In a second combination embodiment of the disclosure, the antibody-drug conjugate which is combined with the blood brain barrier-penetrant PARP1 selective inhibitor is an antibody- drug conjugate in which the antibody is an anti-TROP2 antibody. In an embodiment of the second combination embodiment described above, the anti-TROP2 antibody comprises a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 3 [= amino acid residues 50 to 54 of SEQ ID NO: 1], CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 4 [= amino acid residues 69 to 85 of SEQ ID NO: 1] and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 5 [= amino acid residues 118 to 129 of SEQ ID NO: 1], and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 6 [= amino acid residues 44 to 54 of SEQ ID NO: 2], CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 7 [= amino acid residues 70 to 76 of SEQ ID NO: 2] and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 8 [= amino acid residues 109 to 117 of SEQ ID NO: 2]. In another embodiment of the second combination embodiment described above, the anti-TROP2 antibody comprises a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 9 [= amino acid residues 20 to 140 of SEQ ID NO: 1] and a light chain comprising a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 10 [= amino acid residues 21 to 129 of SEQ ID NO: 2]. In another embodiment of the second combination embodiment described above, the anti- TROP2 antibody comprises a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 12 [= amino acid residues 20 to 470 of SEQ ID NO: 1] and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 13 [= amino acid residues 21 to 234 of SEQ ID NO: 2]. In another embodiment of the second combination embodiment described above, the anti-TROP2 antibody comprises a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 11 [= amino acid residues 20 to 469 of SEQ ID NO: 1] and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 13 [= amino acid residues 21 to 234 of SEQ ID NO: 2]. In another embodiment of the second combination embodiment described above, the anti-TROP2 antibody is datopotamab deruxtecan (DS-1062). In another preferred embodiment of the second combination embodiment described above, the blood brain barrier-penetrant PARP1 selective inhibitor is 6-fluoro-5-[4-[(5-fluoro-2- methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl-pyridine-2-carboxamide or a pharmaceutically acceptable salt thereof. In a particularly preferred embodiment of the second combination embodiment described above, the anti-TROP2 antibody-drug conjugate is datopotamab deruxtecan (DS-1062) and the blood brain barrier-penetrant PARP1 selective inhibitor is 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide or a pharmaceutically acceptable salt thereof. 6. Therapeutic combined use and method Described in the following are a pharmaceutical product and a therapeutic use and method wherein the anti-HER2 or anti-TROP2 antibody-drug conjugate according to the present disclosure and a blood brain barrier-penetrant PARP1 selective inhibitor are administered in combination. The pharmaceutical product and therapeutic use and method of the present disclosure may be characterized in that the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor are separately contained as active components in different formulations, and are administered simultaneously or at different times, or characterized in that the antibody-drug conjugate and the blood brain barrier- penetrant PARP1 selective inhibitor are contained as active components in a single formulation and administered. In the pharmaceutical product and therapeutic method of the present disclosure, a single blood brain barrier-penetrant PARP1 selective inhibitor used in the present disclosure can be administered in combination with the antibody-drug conjugate, or two or more different blood brain barrier- penetrant PARP1 selective inhibitors can be administered in combination with the antibody-drug conjugate. The pharmaceutical product and therapeutic method of the present disclosure can be used for treating cancer, and can be preferably used for treating at least one cancer selected from the group consisting of breast cancer (such as HER2 positive, HER2 low, or triple negative breast cancer), lung cancer (such as non-small cell lung cancer, with or without actionable genomic alterations), colorectal cancer, gastric cancer, esophageal cancer, head-and-neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, endometrial cancer, gastrointestinal stromal tumor, digestive tract stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, cervical cancer, uterine cancer, testicular cancer, and renal cell carcinoma. The presence or absence of tumor markers such as HER2 or TROP2 tumor markers can be determined, for example, by collecting tumor tissue from a cancer patient to prepare a formalin-fixed, paraffin-embedded (FFPE) specimen and subjecting the specimen to a test for gene products (proteins), for example, with an immunohistochemical (IHC) method, a flow cytometer, or Western blotting, or to a test for gene transcription, for example, with an in situ hybridization (ISH) method, a quantitative PCR method (q-PCR), or microarray analysis, or by collecting cell-free circulating tumor DNA (ctDNA) from a cancer patient and subjecting the ctDNA to a test with a method such as next-generation sequencing (NGS). The pharmaceutical product and therapeutic method of the present disclosure, when comprising anti-HER2 antibody-drug conjugate, can be used for HER2-expressing cancer, which may be HER2-overexpressing cancer (high or moderate) or may be HER2 low-expressing cancer. In the present disclosure, the term "HER2-overexpressing cancer" is not particularly limited as long as it is recognized as HER2-overexpressing cancer by those skilled in the art. Preferred examples of the HER2-overexpressing cancer can include cancer given a score of 3+ for the expression of HER2 in an IHC method, and cancer given a score of 2+ for the expression of HER2 in an IHC method and determined as positive for the expression of HER2 in an in situ hybridization method (ISH). The in situ hybridization method of the present disclosure includes a fluorescence in situ hybridization method (FISH) and a dual color in situ hybridization method (DISH). In the present disclosure, the term "HER2 low-expressing cancer" is not particularly limited as long as it is recognized as HER2 low-expressing cancer by those skilled in the art. Preferred examples of the HER2 low-expressing cancer can include cancer given a score of 2+ for the expression of HER2 in an IHC method and determined as negative for the expression of HER2 in an in situ hybridization method, and cancer given a score of 1+ for the expression of HER2 in an IHC method. The method for scoring the degree of HER2 expression by the IHC method, or the method for determining positivity or negativity to HER2 expression by the in situ hybridization method is not particularly limited as long as it is recognized by those skilled in the art. Examples of the method can include a method described in the 4th edition of the guidelines for HER2 testing, breast cancer (developed by the Japanese Pathology Board for Optimal Use of HER2 for Breast Cancer). The cancer, particularly in regard to the treatment of breast cancer, may be HER2-overexpressing (high or moderate) or low-expressing breast cancer, or triple-negative breast cancer, and / or may have a HER2 status score of IHC 3+, IHC 2+, IHC 1+ or IHC >0 and <1+. In some aspects, the methods of the present disclosure comprise identifying a patient as having a PD-L1 positive tumor prior to the administration of the blood brain barrier- penetrant PARP1 selective inhibitor. The pharmaceutical product and therapeutic method of the present disclosure can be preferably used for a mammal, but are more preferably used for a human. The antitumor effect of the pharmaceutical product and therapeutic method of the present disclosure can be confirmed by transplanting cancer cells to a test subject animal to prepare a model and measuring reduction in tumor volume or life-prolonging effect by application of the pharmaceutical product and therapeutic method of the present disclosure. And then, the effect of combined use of the antibody-drug conjugate used in the present disclosure and a blood brain barrier-penetrant PARP1 selective inhibitor can be confirmed by comparing antitumor effect with single administration of the antibody-drug conjugate used in the present disclosure and that of the blood brain barrier-penetrant PARP1 selective inhibitor. The antitumor effect of the pharmaceutical product and therapeutic method of the present disclosure can be confirmed in a clinical trial using any of an evaluation method with Response Evaluation Criteria in Solid Tumors (RECIST), a WHO evaluation method, a Macdonald evaluation method, body weight measurement, and other approaches, and can be determined on the basis of indexes of complete response (CR), partial response (PR), progressive disease (PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). By using the above methods, the superiority in antitumor effect of the pharmaceutical product and therapeutic method of the present disclosure to existing pharmaceutical products and therapeutic methods for cancer treatment can be confirmed. The pharmaceutical product and therapeutic method of the present disclosure can delay development of cancer cells, inhibit growth thereof, and further kill cancer cells. These effects can allow cancer patients to be free from symptoms caused by cancer or achieve improvement in quality of life (QOL) of cancer patients and attain a therapeutic effect by sustaining the lives of the cancer patients. Even if the pharmaceutical product and therapeutic method of the present disclosure do not accomplish killing cancer cells, they can achieve higher QOL of cancer patients while achieving longer- term survival, by inhibiting or controlling the growth of cancer cells. The pharmaceutical product of the present disclosure can be expected to exert a therapeutic effect by application as systemic therapy to patients, and additionally, by local application to cancer tissues. The pharmaceutical product and therapeutic method of the present disclosure, in another aspect, provides for use as an adjuct in cancer therapy with ionizing radiation or other chemotherapeutic agents. For example, in the treatment of cancer, the treatment may comprise administering to a subject in need of treatment a therapeutically-effective amount of the pharmaceutical product, simultaneously or sequentially with ionizing radiation or other chemotherapeutic agents. The pharmaceutical product and therapeutic method of the present disclosure can be used as adjuvant chemotherapy combined with surgery operation. The pharmaceutical product of the present disclosure may be administered for the purpose of reducing tumor size before surgical operation (referred to as preoperative adjuvant chemotherapy or neoadjuvant therapy), or may be administered for the purpose of preventing recurrence of tumor after surgical operation (referred to as postoperative adjuvant chemotherapy or adjuvant therapy). In further aspects, the pharmaceutical product of the present disclosure may be used for the treatment of cancer which is deficient 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 reform a continuous DNA helix (K.K. Khanna and S.P. Jackson, Nat. Genet. 27(3): 247-254 (2001)). The 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, et al., Cell, 115, pp523-535). HR components are also described in Wood, et al., Science, 291, 1284-1289 (2001). A cancer which is deficient in HR dependent DNA DSB repair may comprise or consist of one or more cancer cells which have a reduced or abrogated ability to repair DNA DSBs through that pathway, relative to normal cells i.e. the activity of the HR dependent DNA DSB repair pathway may be reduced or abolished in the one or more cancer cells. The activity of one or more components of the HR dependent DNA DSB repair pathway may be abolished in the one or more cancer cells of an individual having a cancer which is deficient in HR dependent DNA DSB repair. Components of the HR dependent DNA DSB repair pathway are well characterised in the art (see for example, Wood, et al., Science, 291, 1284-1289 (2001)) and include the components listed above. In some embodiments, the cancer cells may have a BRCA1 and / or a BRCA2 deficient phenotype i.e. BRCA1 and / or BRCA2 activity is reduced or abolished in the cancer cells. Cancer cells with this phenotype may be deficient in BRCA1 and / or BRCA2, i.e. expression and / or activity of BRCA1 and / or BRCA2 may be reduced or abolished in the cancer cells, for example by means of mutation or polymorphism in the encoding nucleic acid, or by means of amplification, mutation or polymorphism in a gene encoding a regulatory factor, for example the EMSY gene which encodes a BRCA2 regulatory factor (Hughes-Davies,et al., Cell, 115, 523-535). BRCA1 and BRCA2 are known tumorsuppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers (Jasin M., Oncogene, 21(58), 8981-93 (2002); Tutt, et al., Trends Mol Med., 8 (12), 571-6, (2002)). The association of BRCA1 and / or BRCA2 mutations with breast cancer is well-characterised in the art (Radice, P.J., Exp Clin Cancer Res., 21(3 Suppl), 9-12 (2002)). Amplification of the EMSY gene, which encodes a BRCA2 binding factor, is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA1 and / or BRCA2 are also at elevated risk of certain cancers, including breast, ovary, pancreas, prostate, hematological, gastrointestinal and lung cancer. In some embodiments, the individual is heterozygous for one or more variations, such as mutations and polymorphisms, in BRCA1 and / or BRCA2 or a regulator thereof. The detection of variation in BRCA1 and BRCA2 is well-known in the art and is described, for example in EP 699 754, EP 705903, Neuhausen, S.L. and Ostrander, E.A., Genet. Test, 1, 75-83 (1992); Chappnis, P.O. and Foulkes, W.O., Cancer Treat Res,107, 29-59 (2002); Janatova M., et al., Neoplasma, 50(4), 246- 505 (2003); Jancarkova, N., Ceska Gynekol., 68{1), 11-6 (2003)). Determination of amplification of the BRCA2 binding factor EMSY is described in Hughes-Davies, et al., Cell, 115, 523-535). Mutations and polymorphisms associated with cancer may be detected at the nucleic acid level by detecting the presence of a variant nucleic acid sequence or at the protein level by detecting the presence of a variant (i.e. a mutant or allelic variant) polypeptide. The pharmaceutical product of the present disclosure can be administered containing at least one pharmaceutically suitable ingredient. Pharmaceutically suitable ingredients can be suitably selected and applied from formulation additives or the like that are generally used in the art, in accordance with the dosage, administration concentration, or the like of the antibody-drug conjugate used in the present disclosure and the blood brain barrier-penetrant PARP1 selective inhibitor. The antibody-drug conjugate used in the present disclosure can be administered, for example, as a pharmaceutical product containing a buffer such as histidine buffer, a vehicle such as sucrose and trehalose, and a surfactant such as Polysorbates 80 and 20. The antibody-drug conjugate used in the pharmaceutical product of the present disclosure can be preferably used as an injection, can be more preferably used as an aqueous injection or a lyophilized injection, and can be even more preferably used as a lyophilized injection. In the case that the pharmaceutical product containing the antibody- drug conjugate used in the present disclosure is an aqueous injection, the aqueous injection can be preferably diluted with a suitable diluent and then given as an intravenous infusion. Examples of the diluent can include dextrose solution and physiological saline, dextrose solution can be preferably exemplified, and 5% dextrose solution can be more preferably exemplified. In the case that the pharmaceutical product of the present disclosure is a lyophilized injection, a required amount of the lyophilized injection dissolved in advance in water for injection can be preferably diluted with a suitable diluent and then given as an intravenous infusion. Examples of the diluent can include dextrose solution and physiological saline, dextrose solution can be preferably exemplified, and 5% dextrose solution can be more preferably exemplified. Examples of the administration route applicable to administration of the pharmaceutical product of the present disclosure can include intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, and intravenous routes are preferred. The size of the dose required for the therapeutic treatment of a particular disease state will necessarily be varied depending on the subject treated, the route of administration and the severity of the illness being treated. For further information on routes of administration and dosage regimes, reference may be made to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The anti-HER2 antibody-drug conjugate used in the present disclosure can be administered to a human with intervals of 1 to 180 days, can be preferably administered with intervals of a week, two weeks, three weeks, or four weeks, and can be more preferably administered with intervals of three weeks. The anti-HER2 antibody-drug conjugate used in the present disclosure can be administered in a dose of about 0.001 to 100 mg / kg per administration, and can be preferably administered in a dose of 0.8 to 12.4 mg / kg per administration. For example, the anti-HER2 antibody-drug conjugate can be administered once every three weeks at a dose of 0.8 mg / kg, 1.6 mg / kg, 3.2 mg / kg, 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg, and can be preferably administered once every three weeks at a dose of 5.4 mg / kg or 6.4 mg / kg. The anti-TROP2 antibody-drug conjugate used in the present disclosure can be administered to a human once at intervals of 1 to 180 days, and can be preferably administered once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks, and can be even more preferably administered once every 3 weeks. Also, the antibody-drug conjugate used in the present disclosure can be administered at a dose of about 0.001 to 100 mg / kg, and can be preferably administered at a dose of 0.8 to 12.4 mg / kg. For example, the anti-TROP2 antibody-drug conjugate can be administered once every 3 weeks at a dose of 0.27 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 4.0 mg / kg, 6.0 mg / kg, or 8.0 mg / kg, and can be preferably administered once every 3 weeks at a dose of 4.0 or 6.0 mg / kg. The blood brain barrier-penetrant PARP1 selective inhibitor may be administered in a suitable dose by any suitable route of administration. The blood brain barrier-penetrant PARP1 selective inhibitor, particularly when it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, will normally be administered via the oral route in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, the compositions may be administered at varying doses. The pharmaceutical formulations of the compound of formula(I) described above may be prepared for oral administration, particularly in the form of tablets or capsules, and especially involving technologies aimed at furnishing colon- targeted drug release (Patel, M. M. Expert Opin. Drug Deliv. 2011, 8 (10), 1247-1258). The pharmaceutical formulations of the compound of formula(I) described above may conveniently be administered in unitdosage form and may be prepared by any of the methods well- known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985). Pharmaceutical formulations of a compound of formula (I) suitable for oral administration may comprise one or more physiologically compatible carriers and / or excipients and may be in solid or liquid form. Tablets and capsules may be prepared with binding agents, fillers, lubricants and / or surfactants, such as sodium lauryl sulfate. Liquid compositions may contain conventional additives such as suspending agents, emulsifying agents and / or preservatives. Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form. Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. Such two-piece hard shell capsules may be made for example by filling a compound of formula (I) into a gelatin or hydroxypropyl methylcellulose (HPMC) shell. A dry shell formulation of a compound of formula (I) typically comprises of about 40% to 60% w / w concentration of gelatin, about a 20% to 30% concentration of plasticizer (such as glycerin, sorbitol or propylene glycol) and about a 30% to 40% concentration of water. Other materials such as preservatives, dyes, opacifiers and flavours also may be present. The liquid fill material comprises a solid drug that has been dissolved, solubilized or dispersed (with suspending agents such as beeswax, hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug in vehicles or combinations of vehicles such as mineral oil, vegetable oils, triglycerides, glycols, polyols and surface-active agents. Suitable daily doses of the compounds of formula (I), or a pharmaceutically acceptable salt thereof, in therapeutic treatment of humans are about 0.0001-100 mg / kg body weight. Oral formulations are preferred, particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.1 mg to 1000 mg. [Examples] The present disclosure is specifically described in view of the examples shown below. However, the present disclosure is not limited to these. Further, it is by no means to be interpreted in a limited way. Synthesis of blood brain barrier-penetrant PARP1 selective inhibitors Syntheses of exemplary blood brain barrier-penetrant PARP1 selective inhibitors are described in Examples 1 to 60 of WO2021 / 260092, including the preparation of intermediate compounds, and the general experimental conditions used. In Example 61, method 1, of WO2021 / 260092, 6-fluoro-5-[4-[(5- fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-N-methyl-pyridine-2-carboxamide Form B was obtained as white solid. Form B from method 1 exhibited peaks under XRPD analysis as follows: XRPD Peaks for Form B Angle Intensity (2+±0.2°) (%) 18.2 100.0 9.6 86.7 9.1 80.7 18.7 55.8 12.7 24.1 8.5 23.9 10.0 15.6 20.1 14.8 21.7 13.9 23.2 12.3 12.4 12.2 16.1 9.6 14.3 9.2 6.2 8.9 15.6 7.7 27.4 6.9 26.4 6.6 29.7 6.2 27.1 6.0 25.0 5.0 Form B is characterized in providing at least one of thebkhhksejc 2^ r]hqao ia]oqna` qoejc AqI^ n]`e]pekj: 6.2°,14.3°, and 15.6°. DSC analysis indicated that Form B has a melting point with an onset at 275 °C and a peak at 276 °C. TGA indicated that Form B exhibits a mass loss of about 0.2 % upon heating from about 25 °C to about 100 °C. In Example 62, of WO2021 / 260092, 6-fluoro-5-[4-[(5-fluoro-2- methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl-pyridine-2-carboxamide Form D was obtained as white solid. Form D exhibited peaks under XRPD analysis as follows: XRPD Peaks for Form D Angle Intensity (2+±0.2°) (%) 9.6 100.0 18.4 43.0 13.1 32.0 19.9 17.9 27.1 17.3 9.2 15.9 21.7 14.0 23.4 11.2 24.5 9.6 19.3 8.8 16.8 8.7 22.2 8.3 16.3 8.0 18.8 7.6 25.4 6.9 10.2 6.6 33.0 6.3 22.5 5.8 12.6 5.7 7.9 4.5 Form D is characterized in providing at least one of thefollowing 2G r]hqao ia]oqna` qoejc AqI^ n]`e]pekj: 7.9°, 13.1° and 16.3°. Single crystal structure analysis confirmed that Form D is an anhydrous form. In Example 63, method 1, of WO2021 / 260092, 6-fluoro-5-[4-[(5- fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-N-methyl-pyridine-2-carboxamide mesylate salt Form C (MSA- Form C) was obtained as an off-white solid. MSA-Form C from method 1 exhibited peaks under XRPD analysis as follows: XRPD Peaks for MSA-Form C Angle Intensity (2+±0.2°) (%) 17.5 100.0 24.6 95.7 25.4 75.8 16.0 73.8 22.5 72.6 19.4 72.5 24.3 71.6 13.6 65.6 19.0 61.3 20.4 53.3 21.5 43.4 15.5 43.2 22.0 40.2 28.8 35.8 14.6 34.2 26.9 29.7 21.0 29.4 18.3 29.1 31.4 26.8 16.8 26.0 DSC analysis indicated that MSA-Form C begins melting and decomposition at the temperature with an onset at 254°C and a peak at 258°C. TGA indicated that MSA-Form C exhibits a mass loss of about 0.3 % upon heating from about 25°C to about 100°C. Biological Assays for blood brain barrier-penetrant PARP1 selective inhibitors Test procedures as described in WO2021 / 260092 (PARP Fluorescence Anisotropy binding assays; PARP Proliferation Assay (7 day compound dosing); In vitro human transporter efflux; Unbound fraction determinations in plasma and in brain slice; Kpuu determination in rat) may be employed to determine the properties of blood brain barrier-penetrant PARP1 selective inhibitor compounds described herein. Biological data obtained for blood brain barrier-penetrant PARP1 selective inhibitors as described in Examples 1 to 60 of WO2021 / 260092 are shown as follows: BRCA2 WO2021 / WT MDCK- PARP - / - 260092 1 PARP2 PARP3 PARP6 hERG DLD-1 MDR1- IC50 IC50 IC50 PARP5a IC50 IC50 DLD-1 Rat Example IC50 (µM) prolif.7 prolif.7 BCRP (µM) (µM) (µM) (µM) (µM) d IC50 Efflux Kpuu No. d IC50 (µM) (µM) Ratio 1 0.004 >70 >100 >100 >100 >40 0.014 24 0.7 0.07 2 0.011 15 >40 0.734 3 0.003 >100 >100 >100 >100 >40 0.008 25 1.3 4 0.005 >83 78 >100 >100 >40 0.081 >14 0.80.135 0.005 >63 2.89 6 0.004 >100 7 0.006 58 8.43 >30 8 0.004 >66 >100 >100 >100 >40 0.012 >7.9 9 0.004 >100 >100 >100 >100 >40 0.01 >10 0.4 100.013 >100 >100 >100 >100 >40 >30.0 >30 11 0.003 >100 >100 >100 >100 >40 0.009 >30 120.015 85 >100 >100 >40 0.008 4.2 0.009 >100 62 >100 >100 >40 0.019 22 3.0 0.013 >83 52 >100 >100 >40 0.015 3.7 0.012 >100 43 >100 >100 >38 0.014 3.7 0.01 >100 >100 >29 >100 >40 3.62 >30 0.006 >100 >100 >100 >100 >40 1.05 >10 0.005 >100 >100 >100 >100 14 4.33 21 0.013 40 >40 0.006 2.4 <0.005 >93 >100 >100 >100 >40 0.008 >30 1.1 0.27 0.007 >100 5.8 >100 >100 >40 1.42 1.6 0.006 87 0.005 >67 >100 >100 >100 >40 0.003 >30 0.8 0.62 0.006 >81 >100 >100 >100 >36 0.003 >30 1.1 0.005 >100 0.297 0.005 88 0.004 >64 >100 >100 >100 >40 0.006 6.3 0.8 0.43 0.005 >100 >100 >100 >100 >38 0.004 0.8 0.015 >100 >100 >100 >100 >40 0.005 >10 0.7 0.33 0.006 >100 >100 >100 >100 >40 0.003 >30 1.8 0.007 >100 >100 >100 >100 >40 0.007 >30 1.6 0.19 0.007 >100 >100 >100 >100 >40 1.08 23 0.167 >100 >30.0 0.026 >100 29 8.44 0.03 >100 10.3 >30 0.022 >100 16.2 0.026 57 0.01 5.0 0.012 21 >100 >100 >100 >40 0.547 0.006 >100 >100 >100 >100 >40 0.008 1.9 0.011 >100 >100 13 >100 >40 0.007 2.0 0.005 >100 >100 >100 >100 >40 0.007 2.4 0.005 >88 0.006 0.005 >100 0.01 0.128 >100 >30.0 0.006 >100 0.006 1.5 0.01 >100 0.013 0.076 >100 >100 >100 >100 >40 0.058 0.039 26 >100 >100 >100 >40 0.018 27 8.8 0.043 11 >29 >100 >100 >40 0.041 0.060 35 >40 0.136 0.006 1.2 0.085 3.8 0.026 >100 0.111 >100 0.005 >100 56 0.008 >100 57 0.011 >100 580.008 >100 59 0.006 2.1 600.023 >100 Example 1A: Production of anti-HER2 antibody-drug conjugate In accordance with a production method described in WO2015 / 115091 and using an anti-HER2 antibody (an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 24 (amino acid residues 1 to 449 of SEQ ID NO: 14) and a light chain consisting of an amino acid sequence consisting of all amino acid residues 1 to 214 of SEQ ID NO: 15), an anti-HER2 antibody-drug conjugate in which a drug-linker represented by the following formula: wherein A represents the connecting position to an antibody, is conjugated to the anti-HER2 antibody via a thioether bond was produced (DS-8201: trastuzumab deruxtecan). The DAR of the antibody-drug conjugate is 7.7 or 7.8. Example 1B: Production of anti-TROP2 antibody-drug conjugate In accordance with a production method described in WO2015 / 098099, WO2017 / 002776 and WO2022 / 014698 and using an anti-TROP2 antibody (an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 12 [= amino acid residues 20 to 470 of SEQ ID NO: 1] and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 13 [= amino acid residues 21 to 234 of SEQ ID NO: 2]), an anti-TROP2 antibody-drug conjugate in which a drug-linker represented by the following formula: wherein A represents the connecting position to an antibody, is conjugated to the anti-TROP2 antibody via a thioether bond was produced (DS-1062: datopotamab deruxtecan). The DAR of the antibody-drug conjugate is ~4. Example 2: Production of blood brain barrier-penetrant PARP1 selective inhibitor In accordance with the method of Example 20 of WO2021 / 260092, a blood brain barrier-penetrant PARP1 selective inhibitor of formula (I), specifically 6-fluoro-5-[4-[(5- fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-N-methyl-pyridine-2-carboxamide (AZD9574), was produced.Example 3: Antitumor test – in vivo – NCI-N87 xenograftmodel Combination of antibody-drug conjugate DS-1062 (datopotamab deruxtecan) with blood brain barrier-penetrant PARP1 selective inhibitor AZD9574 Method: Female Nude mice (Charles River) aged 5-8 weeks were used, following 7 days acclimatisation before entry into the study. 5x106NCI-N87 tumor cells (gastric cancer cell line) (1:1 in Matrigel) were implanted subcutaneously onto the flank of the female Nude mice. When tumors reached approximately 250 mm3, similar-sized tumors were randomly assigned to treatment groups as shown in Table 1: Table 1 Treatment Dose Route ofDosing Schedule administration Vehicle 0 mg / kg IV + PO Single dose + QD(D8-D14, D29-D35) DS-1062 10 mg / kg IV Single dose AZD9574 3 mg / kg PO QD (D8-D14, D29- D35) DS-1062 + 10 mg / kg + IV + PO Single dose + QD AZD9574 3 mg / kg (D8-D14, D29-D35) DS-1062 + 10 mg / kg + IV + PO Single dose + QD AZD9574 1 mg / kg (D8-D14, D29-D35) DS-1062 + 10 mg / kg + IV + PO Single dose + QD AZD9574 0.3 mg / kg (D8-D14, D29-D35) DS-1062 + 10 mg / kg + IV + PO Single dose + QD AZD9574 0.1 mg / kg (D8-D14, D29-D35) DS-1062 + 10 mg / kg + IV + PO Single dose + QD AZD5305 0.1 mg / kg (D8-D14, D29-D35) PO: oral (per os) dosing QD: once per day (quaque die) dosing The dose of compound for each animal was calculated based on the individual body weight on the day of dosing. DS-1062 was administered as a single dose at 10 mg / kg on day 1, and AZD9574 was administered at 3,1,0.3 and 0.1 mg / kg QD from Day 8-14 and Day 29-35. DS-1062 was administered as a single dose at 10 mg / kg on day 1, and AZD5305 was administered at 0.1 mg / kg QD from Day 8-14 and Day 29-35. AZD5305 was prepared and used as described (WO 2022 / 074617). An example of such preparation is provided in Example 4 below. Formulation of DS-1062 at 10 mg / kg The dosing solutions for DS-1062 were prepared on the day of dosing by diluting the DS-1062 stock (20.1 mg / ml) in 25 mM histidine buffer, 9% sucrose (pH5.5) to 0.6 mg / ml, and 2 mg / ml for the 3 mg / kg and 10 mg / kg dosing solutions, respectively. Each dosing solution was mixed well using a pipette before administration via IV injection at a dosing volume of 5 ml / kg. Formulation of AZD9574 at 3,1,0.3 and 0.1 mg / kg To formulate for a 3 mg / kg dosing solution, a concentration of 0.3 mg / ml AZD9574 was prepared which resulted in a dosing volume of 10 ml / kg for PO dosing. To formulate for a 1 mg / kg dosing solution, a concentration of 0.1 mg / ml AZD9574 was prepared which resulted in a dosing volume of 10 ml / kg for PO dosing. To formulate for a 0.3 mg / kg dosing solution, a concentration of 0.03 mg / ml AZD9574 was prepared which resulted in a dosing volume of 10 ml / kg for PO dosing. To formulate for a 0.1 mg / kg dosing solution, a concentration of 0.01 mg / ml AZD9574 was prepared which resulted in a dosing volume of 10 ml / kg for PO dosing. A total of 230 ml of vehicle was required. A volume of 32.2 ml of 1M MSA was added to the compound in glss vial and mixed well by vortexing. A volume of 184 ml of sterile water was added to the compound and mixed well using a sonicator to facilitate compound dissolution. The remaining volume of sterile water (13.8 ml) was added to the glass bottle and mixed well using a magnetic stirrer. 1M MSA was added to adjust the pH to 3.2. The dosing solution was protected from light and a small aliquot was taken daily for dosing. All remaining dosing solution was kept for up to 7 days in the fridge. The final dosing matrix for AZD9574 was a clear solution. Measurements Tumor growth inhibition (TGI) was calculated as follows: TGI% = {1-(MTV treated / MTV control)}*100 where MTV = mean tumor volume. Statistical significance was evaluated using one-tailed t-test of (log(relative tumor volume) = log(final vol / start vol)) at the day of final measure, comparing to vehicle control. Results Tumor volumes for treatments with DS-1062 or AZD9574 alone or with DS-1062 in combination with AZD9574 are shown in Figure 23. Data represents change in tumor volume over time for treatment groups. The highlighted area in Figure 23 represents the dosing period of AZD9574. For full dose andschedule information, refer to Table 1 above. Values shown aremean ±SEM; n=8 for all treatment groups. TGI responses (Day 42 TGI%) following treatment with DS-1062 or AZD9574 alone or with DS-1062 in combination with AZD9574, in NCI-N87 xenograft, are shown in Table 2: Table 2 Treatment group TGI% day 42 p-valueSignificance vs. vehicle DS-1062 10 mg / kg65%0.0001 ****AZD9574<10%0.3394 }joDS-1062 + AZD9574 **** 3 mg / kg76%0.0001DS-1062 + AZD9574 **** 1 mg / kg76%0.0001DS-1062 + AZD9574 **** 0.3 mg / kg71%0.0001DS-1062 + AZD9574 **** 0.1 mg / kg80%0.0001†not significantMonotherapy with DS-1062 at 10 mg / kg showed TGI value of 65% at day 42 post treatment. AZD9574 monotherapy at 3 mg / kg achieved a TGI of <10% at day 42 post treatment. Combination treatment of DS-1062 with AZD9574 at 3 mg / kg resulted in a TGI of 76% at 42 days post treatment; combination treatment of DS- 1062 with AZD9574 at 1 mg / kg resulted in a TGI of 76% at 42 days post treatment; combination treatment of DS-1062 with AZD9574 at 0.3 mg / kg resulted in a TGI of 71% at 42 days post treatment; combination treatment of DS-1062 with AZD9574 at 0.1 mg / kg resulted in a TGI of 80% at 42 days post treatment, indicating the combination showed better response than either respective monotherapies and AZD9574 dose titration does not impact combination efficacy. Treatment groups were generally well tolerated and average bodyweights of all treatment groups remained stable during the study.Example 4: Antitumor test – in vivo – KPL-4 xenograft modelCombination of antibody-drug conjugate DS-8201 (trastuzumab deruxtecan) with blood brain barrier-penetrant PARP1 selective inhibitor AZD9574 Method: Female Balb / c nude mice (aged 6-8 weeks) were acquired from Charles River Laboratories and acclimatized for 7 days. 1x107KPL-4 breast cancer cells (suspended in 1:1 PBS / Matrigel) were implanted subcutaneously into the right flank of the mice. Tumor volume was monitored via caliper measurements, and calculated using the formula (width2×length) / 2. Mice were randomized into treatment groups once tumor size reached an average of 298 mm3. Mice were assigned into treatment groups as shown in Table 3: Table 3 Dose Route of Treatment (mg / kg)administration Dosing ScheduleVehicle 0 mg / kg IV Q3W (days 1,22) DS-8201 10 mg / kg IV Q3W (days 1,22) AZD9574 3 mg / kg PO Day 8-14 PO QD DS-8201 + 10 mg / kg + IV+PO Q3W (days 1,22) + AZD9574 3 mg / kg Day 8-14 PO QD DS-8201 + 10 mg / kg + ZD9574 1mg / kg IV Q3W (days 1,22) + A +PO Day 8-14 PO QD DS-8201 + 10 mg / kg + D9574 0.3 mg / kg IV+ Q3W (days 1,22) + AZ PO Day 8-14 PO QD DS-8201 + 10 mg / kg + ZD9574 0.1 mg / kg IV Q3W (days 1,22) + A +PO Day 8-14 PO QD DS-8201 + 10 mg / kg + IV+P Q3W (days 1,22) + AZD5305 0.1 mg / kg O Day 8-14 PO QD PO: oral dosing IV: intravenous QD: once per day Q3W: once every 3 weeks AZD9574 and AZD5305 were dosed 7 days after T-DXd administration for 7 days on / 14 days off. All treatment mice were dosed for two full cycles of dose schedules. Formulation of DS-8201 at 10 mg / kg The dosing solution for DS-8201 was prepared by diluting the master stock (20 mg / ml) in 25 mM histidine buffer, 9% sucrose (pH 5.5) to 2 mg / ml. The dosing solution was injected IV at a dose volume of 5 ml / kg. Formulation of AZD9574 To formulate AZD9574 for 3 mg / kg, 1 mg / kg, 0.3 mg / kg, and 0.1 mg / kg dose concentrations, 0.3 mg / ml, 0.1 mg / ml, 0.03 mg / ml, and 0.01 mg / ml dosing solutions were prepared respectively. All dosing solutions were administered at a volume of 10 ml / kg. AZD9574 was prepared by weighing the desired amount of compound into an appropriately sized amber glass vial, and adding 1M MSA at 1:1.2 drug:acid molar ratio. The volume of 1M MSA required was calculated using the following equation: Volume of 1N MSA required (mL) =1.2×concentration (mg / mL)×final volume (mL) / 428.4(g / mole) / 1M 80% of the final volume of sterile deionized water was added, and the glass bottle was vortexed to facilitate dissolution. The pH was measured and adjusted to 3-3.2 if necessary. The remaining 20% of deionized water was added to obtain the final volume. Final pH was measured and recorded. Prepared AZD9574 dosing solutions were stored at 4°C for 7 days (protected from light). Compound was allowed to reach room temperature prior to dosing. Formulation of AZD5305 To formulate AZD5305 for a 0.1 mg / kg dose concentration, 0.01 mg / ml dosing solution was prepared to be administered at a volume of 10 ml / kg. AZD5305 was prepared by weighing the desired amount of compound into an appropriately sized amber glass vial, and adding 1N HCl at a 1:1.25 drug / HCl molar ratio, and 80% of final volume of dionized water. The required amount of 1N HCl to add was calculated as follows: Volume of 1N HCl added (mL) =1.25 x [concentration (mg / mL) / 406.48(g / mole) / 1M] x final volume(mL) The glass bottle was vortexed until a solution was obtained, and pH was measured and adjusted to 3.5-4, if necessary, by gradually adding 1N HCl or 1N NaOH. The remaining 20% of dionized water was added to obtain the final volume, and final pH was recorded. The prepared dosing solution was stored at 4°C for 7 days (protected from light). Measurements Tumor growth inhibition (TGI) was caclulated using the following formula: %TGI = 100 * (geometric mean control RTV ^ geometric mean treated RTV) / (geometric mean control RTV ^ 1) where RTV = relative tumor volume. TGI was calculated on the final day that Vehicle control group mice were on study (50 days post implant). Where TGI >100%, %regression was calculated using the formula: %Regression = 100* (1-geometric mean treated RTV). Significant p-values for differences in TGI were calculated using a one-tailed t test. Results Tumor volumes for treatments with DS-8201 and AZD9574 (as monotherapies and combination partners) are shown in Figure 24. Data represents change in tumor volume over time. Vertical dotted lines in Figure 24 represent IV dosing of DS-8201. Shaded regions indicate 7 day dosing periods for AZD9574 and AZD5305. Values plotted represent mean +SEM; n=10 mice per group. Tumor growth inhibition (TGI) versus Vehicle is shown in Table 4: Table 4 TGI vs. p-value Vehicle vs. Treatment group (%) vehicle %Regression Vehicle 0.0 N / A N / A DS-8201 10 mg / kg 102.9 <0.0001 24.2 AZD9574 3 mg / kg 0.0 N / A N / A DS-8201 10 mg / kg + 108.4 <0.0 69.5 AZD9574 3 mg / kg 001 DS-8201 10 mg / kg+ ZD9574 1 mg / kg 101.3 10.6 A <0.0001 DS-8201 10 mg / kg + 1 73.6 AZD9574 0.3 mg / kg 08.8 <0.0001 DS-8201 10 mg / kg + 1 mg / kg 98.4 N / A AZD9574 0. <0.0001 DS-8201 10 mg / kg + 99.9 <0.0 N / A AZD5305 0.1 mg / kg 001 For treatments resulting in >100% TGI, % regression is also indicated in Table 4. DS-8201 dosed as a single agent resulted in 102.9% TGI, and 24% regression. As a monotherapy, AZD9574 did not exhibit tumor growth control. The combination of DS- 8201 with AZD9574 at 3 mg / kg and 0.3 mg / kg demonstrated the best anti-tumor responses (108.4% TGI; 69.5% regression and 108.8% TGI; 73.6% regression respectively). Similar tumor growth inhibition was observed when DS-8201 was dosed in combination with either AZD9574 or AZD5305 at 0.1 mg / kg. DS- 8201 dosed in combination with AZD9574 0.1mg / kg and AZD5305 0.1 mg / kg resulted in 98.4% TGI and 99.9% TGI, respectively. Example 5: Antitumor test Efficacy and safety of exatecan with AZD9574 or AZD5305. Method ^ Efficacy: A549 cells were grown in their respective condition and plated in 96-well plates at low density to allow linear proliferation for the duration of the assay (7 days). The day after plating cells were dosed with a concentration range of 0.1 nM to 100 nM exatecan in combination with 10nM or 100nM of PARP1-selective inhibitors AZD5305 or AZD9574 and placed in the incubator. At the endpoint, cells were fixed in 4 % PFA for 20 min. at room temperature. After a PBS wash, cells were incubated in Hoeschst for 1 hour at room temperature. After two washes in PBS, cells were imaged on a Cellinsight microscope with a 10x objective and 9 fields / well. Images were anaylsed using cell insight count based on nuclear Hoeschst staining in order to determine the total cell count / well. Results – efficacy: The results (Fig. 25) demonstrate that both PARP1 selective inhibition with AZD9574 or AZD5305 enhances the antitumor efficacy of exatecan in the A549 cell line in vitro. Results indicate that both compounds, at the concentrations tested, cause an equal 2-fold reduction in the exatecan IC50(half maximal (50%) inhibitory concentration) when compared with exatecan monotherapy. Method ^ Safety: CD34+ hematopoietic stem and progenitor cells (Lonza; 2M-101) were cultured overnight in StemSpan SFEM II media (StemCellTechnologies; 09655) supplemented with 25 ng / mL SCF, 50 ng / mL TPO, and 50 ng / ml Flt3-L (PeptroTech; PEPTR300-07-10, PEPTR300-18-10, PEPTR300-19-10) at 37°C, 5% CO2. The following`]u, _ahho sana naoqolaj`a` ej AahhCtl]j`^ - SuspensionCtl]joekj Aqhpqna^ (QCA^) ia`e] EK-CFC 1 (#SECSF-GM1-40H,Preferred Cell Systems) at a concentration of 15x103cells / mL, plated at 450 cells per well in flat-bottom 384-well plates, and technical replicates were treated with vehicle (DMSO) or a concentration range of exatecan from 3.3x10-3nM to 1.67 nM in the presence of 0, 16.7 or 167 nM AZD5305 or AZD9574. Compounds were dispensed into an empty 384-well plate using the Echo (Beckman Coulter), and cells were overlaid using Multidrop (ThermoFisher Scientific). After 5 days of incubation, the number of viable cells per well was determined using CellTiter-Glo 2.0 (G9242, Promega; used at 1:10) with the luminescence readout being performed on an Envision plate reader (PerkinElmer). Data analysis was performed using GeneData software for synergy analysis, data were normalized to vehicle controls and dose-response curves generated using non-linear regression (curvefit) analysis using GraphPad Prism (v9). The experiment was repeated twice using distinct CD34+ hematopoietic stem and progenitor cell donors. Results – Safety: The results shown in Fig. 25 demonstrate that PARP1 selective inhibition with blood brain barrier penetrant (BBB) AZD9574 sensitize myeloid progenitor cells to exatecan in vitro to a lesser degree than with PARP1 selective inhibitor non-BBB AZD5305. At 16.7 nM, AZD5305 provides a 12-fold sensitisation of myeloid progenitor cells to exatecan, whereas AZD9574 provides a 5-fold sensitisation at an equal concentration. Increasing the concentration of PARP1 selective inhibitors to 167 nM resulted in minimal further sensitization to exatecan with either compounds (7-fold sensitization with 167 nM AZD9574 and 13-fold sensitization with AZD5305, compared to exatecan monotherapy). Haematological toxicities, such as anaemia, thrombocytopenia, and neutropenia where a reduction in the number of certain types of haematopoietic cells is observed, are well established problems associated with PARP inhibitor administration. In an assay using myeloid progenitor cells (a type of haematopoietic cell), it is observed that exatecan alone (surrogate for Enhertu free payload) results in a reduction in the numbers of these cells, which is exacerbated when combined with a PARP inhibitor. However, Fig. 25 indicates that combining exatecan with AZD9574 results in a reduction in myeloid progenitor cell numbers that is less severe, than when exatecan is combined with AZD5305. The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the embodiments. The foregoing description and Examples detail certain embodiments and describe the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the embodiments may be practiced in many ways and the claims include any equivalents thereof.

[0002] Free Text of Sequence Listing SEQ ID NO: 1 - Amino acid sequence of a heavy chain of anti- TROP2 antibody SEQ ID NO: 2 - Amino acid sequence of a light chain of anti- TROP2 antibody SEQ ID NO: 3 - Amino acid sequence of a heavy chain CDRH1 [= amino acid residues 50 to 54 of SEQ ID NO: 1] SEQ ID NO: 4 - Amino acid sequence of a heavy chain CDRH2 [= amino acid residues 69 to 85 of SEQ ID NO: 1] SEQ ID NO: 5 - Amino acid sequence of a heavy chain CDRH3 [= amino acid residues 118 to 129 of SEQ ID NO: 1] SEQ ID NO: 6 - Amino acid sequence of a light chain CDRL1 [= amino acid residues 44 to 54 of SEQ ID NO: 2] SEQ ID NO: 7 - Amino acid sequence of a light chain CDRL2 [= amino acid residues 70 to 76 of SEQ ID NO: 2] SEQ ID NO: 8 - Amino acid sequence of a light chain CDRL3 [= amino acid residues 109 to 117 of SEQ ID NO: 2] SEQ ID NO: 9 - Amino acid sequence of a heavy chain variable region [= amino acid residues 20 to 140 of SEQ ID NO: 1] SEQ ID NO: 10 - Amino acid sequence of a light chain variable region [= amino acid residues 21 to 129 of SEQ ID NO: 2] SEQ ID NO: 11 - Amino acid sequence of a heavy chain [= amino acid residues 20 to 469 of SEQ ID NO: 1] SEQ ID NO: 12 - Amino acid sequence of a heavy chain [= amino acid residues 20 to 470 of SEQ ID NO: 1] SEQ ID NO: 13 - Amino acid sequence of a light chain [= amino acid residues 21 to 234 of SEQ ID NO: 2] SEQ ID NO: 14 - Amino acid sequence of a heavy chain of an anti-HER2 antibody SEQ ID NO: 15 - Amino acid sequence of a light chain of an anti-HER2 antibody SEQ ID NO: 16 - Amino acid sequence of a heavy chain CDRH1 [= amino acid residues 26 to 33 of SEQ ID NO: 14] SEQ ID NO: 17 - Amino acid sequence of a heavy chain CDRH2 [= amino acid residues 51 to 58 of SEQ ID NO: 14] SEQ ID NO: 18 - Amino acid sequence of a heavy chain CDRH3 [= amino acid residues 97 to 109 of SEQ ID NO: 14] SEQ ID NO: 19 - Amino acid sequence of a light chain CDRL1 [= amino acid residues 27 to 32 of SEQ ID NO: 15] SEQ ID NO: 20 - Amino acid sequence comprising amino acid sequence of a light chain CDRL2 (SAS) [= amino acid residues 50 to 56 of SEQ ID NO: 15] SEQ ID NO: 21 - Amino acid sequence of a light chain CDRL3 [= amino acid residues 89 to 97 of SEQ ID NO: 15] SEQ ID NO: 22 - Amino acid sequence of a heavy chain variable region [= amino acid residues 1 to 120 of SEQ ID NO: 14] SEQ ID NO: 23 - Amino acid sequence of a light chain variable region [= amino acid residues 1 to 107 of SEQ ID NO: 15] SEQ ID NO: 24 - Amino acid sequence of a heavy chain [= amino acid residues 1 to 449 of SEQ ID NO: 14]

Claims

CLAIMS 1. A pharmaceutical product comprising an antibody-drug conjugate and a blood brain barrier-penetrant PARP1 selective inhibitor for administration in combination, wherein the antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula:wherein A represents the connecting position to an antibody, is conjugated to an anti-HER2 or anti-TROP2 antibody via a thioether bond.

2. The pharmaceutical product according to claim 1, wherein the drug-linker is conjugated to an anti-HER2 antibody.

3. The pharmaceutical product according to claim 2, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 16, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 17 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 18, and a light chain comprising CDRL1 consisting of an aminoacid sequence represented by SEQ ID NO: 19, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 1 to 3 of SEQ ID NO: 20 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO:

21.

4. The pharmaceutical product according to claim 3, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 22 and a light chain comprising a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO:

23.

5. The pharmaceutical product according to claim 4, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 14 and a light chain consisting of an amino acid sequence represented by SEQ ID NO:

15.

6. The pharmaceutical product according to claim 4, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 24 and a light chain consisting of an amino acid sequence represented by SEQ ID NO:

15.

7. The pharmaceutical product according to any one of claims 2 to 6, wherein the average number of units of the drug-linker conjugated per anti-HER2 antibody molecule in the antibody- drug conjugate is in the range of from 7 to 8.

8. The pharmaceutical product according to any one of claims 2 to 7, wherein the average number of units of the drug-linker conjugated per anti-HER2 antibody molecule in the antibody- drug conjugate is in the range of from 7.5 to 8.

9. The pharmaceutical product according to claim 8, wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201).

10. The pharmaceutical product according to claim 1, wherein the drug-linker is conjugated to an anti-TROP2 antibody.

11. The pharmaceutical product according to claim 10, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 4 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 7 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO:

8.

12. The pharmaceutical product according to claim 11, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting ofan amino acid sequence represented by SEQ ID NO: 9 and a light chain comprising a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO:

10.

13. The pharmaceutical product according to claim 12, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 12 and a light chain consisting of an amino acid sequence represented by SEQ ID NO:

13.

14. The pharmaceutical product according to claim 12, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 11 and a light chain consisting of an amino acid sequence represented by SEQ ID NO:

13.

15. The pharmaceutical product according to any one of claims 10 to 14, wherein the average number of units of the drug- linker conjugated per anti-TROP2 antibody molecule in the antibody-drug conjugate is in the range of from 3.5 to 4.

5.

16. The pharmaceutical product according to claim 15, wherein the anti-TROP2 antibody-drug conjugate is datopotamab deruxtecan (DS-1062).

17. The pharmaceutical product according to any one of claims 1 to 16, wherein the blood brain barrier-penetrant PARP1selective inhibitor is a compound represented by the following formula (I):(I) wherein: R1is independently selected from H, C1-4alkyl, C3-6cycloalkyl, C1-4fluoroalkyl, and C1-4alkyloxy; R2is independently selected from H, halo, C1-4alkyl, and C1-4fluoroalkyl; R3is H or C1-4alkyl; and R4is halo or C1-4alkyl, or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical product according to claim 17, wherein R1in formula (I) is selected from any one of methyl, ethyl, isopropyl, cyclopropyl, 1,1-difluoroethyl, 1-fluoroethyl, trifluoromethyl, difluoromethyl, and methoxy.

19. The pharmaceutical product according to claim 17 or 18, wherein R2in formula (I) is selected from any one of H, chloro, fluoro, methyl, and difluoromethyl.

20. The pharmaceutical product according to any one of claims 17 to 19, wherein R3in formula (I) is methyl or ethyl.

21. The pharmaceutical product according to any one of claims 17 to 20, wherein R4in formula (I) is selected from any one of chloro, fluoro and methyl.

22. The pharmaceutical product according to claim 17, wherein in formula (I), R1is C1-4alkyl, R2is halo, R3is C1-4alkyl, and R4is halo or C1-4alkyl.

23. The pharmaceutical product according to any one of claims 17 to 22, wherein the compound of formula (I) is in the free base form.

24. The pharmaceutical product according to claim 17, wherein the compound of formula (I) is 5-[4-[(2-ethyl-5-fluoro-3-oxo- 4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- pyridine-2-carboxamide or a pharmaceutically acceptable salt thereof.

25. The pharmaceutical product according to claim 17, wherein the compound of formula (I) is 6-fluoro-5-[4-[(5-fluoro-2- methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl-pyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical product according to claim 17, wherein the compound of formula (I) is 6-fluoro-5-[4-[(5-fluoro-2- methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl-pyridine-2-carboxamide (AZD9574).

27. The pharmaceutical product according to claim 17, wherein the compound of formula (I) is 6-fluoro-5-[4-[(5-fluoro-2- methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl-pyridine-2-carboxamide crystalline Form D or a pharmaceutically acceptable salt thereof.

28. The pharmaceutical product according to any one of claims 1 to 27, wherein the product is a composition comprising the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor, for simultaneous administration.

29. The pharmaceutical product according to any one of claims 1 to 27, wherein the product is a combined preparation comprising the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor, for sequential or separate simultaneous administration.

30. The pharmaceutical product according to any one of claims 1 to 29, wherein the product is for treating cancer.

31. The pharmaceutical product according to claim 30, wherein the cancer is at least one selected from the group consisting of breast cancer, lung cancer, colorectal cancer, gastric cancer, esophageal cancer, head-and-neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladdercancer, endometrial cancer, gastrointestinal stromal tumor, digestive tract stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, cervical cancer, uterine cancer, testicular cancer, and renal cell carcinoma.

32. The pharmaceutical product according to claim 31, wherein the cancer is breast cancer.

33. The pharmaceutical product according to claim 32, wherein the breast cancer is HER2 positive breast cancer.

34. The pharmaceutical product according to claim 32, wherein the breast cancer is HER2 low breast cancer.

35. The pharmaceutical product according to claim 32, wherein the breast cancer is triple negative breast cancer.

36. The pharmaceutical product according to claim 32, wherein the breast cancer is hormone receptor (HR)-positive, HER2- negative breast cancer.

37. The pharmaceutical product according to claim 31, wherein the cancer is lung cancer.

38. The pharmaceutical product according to claim 37, wherein the lung cancer is non-small cell lung cancer.

39. The pharmaceutical product according to claim 38, wherein the non-small cell lung cancer is non-small cell lung cancer with actionable genomic alterations.

40. The pharmaceutical product according to claim 38, wherein the non-small cell lung cancer is non-small cell lung cancer without actionable genomic alterations.

41. The pharmaceutical product according to claim 31, wherein the cancer is colorectal cancer.

42. The pharmaceutical product according to claim 31, wherein the cancer is gastric cancer.

43. The pharmaceutical product according to claim 31, wherein the cancer is pancreatic cancer.

44. The pharmaceutical product according to claim 31, wherein the cancer is ovarian cancer.

45. The pharmaceutical product according to claim 31, wherein the cancer is prostate cancer.

46. The pharmaceutical product according to claim 31, wherein the cancer is kidney cancer.

47. The pharmaceutical product according to claim 31, wherein the cancer is bladder cancer.

48. The pharmaceutical product according to claim 31, wherein the cancer is endometrial cancer.

49. The pharmaceutical product according to claim 31, wherein the cancer is biliary tract cancer.

50. A pharmaceutical product as defined in any one of claims 1 to 29, for use in treating cancer.

51. The pharmaceutical product for the use according to claim 50, wherein the cancer is as defined in any one of claims 31 to 49.

52. Use of an antibody-drug conjugate in the manufacture of a medicament for use in combination with a blood brain barrier- penetrant PARP1 selective inhibitor, wherein the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor are as defined in any one of claims 1 to 27, for treating cancer.

53. The use according to claim 52 wherein the medicament is for use in combination with the blood brain barrier-penetrant PARP1 selective inhibitor by sequential administration.

54. The use according to claim 52 wherein the medicament is for use in combination with the blood brain barrier-penetrant PARP1 selective inhibitor by separate simultaneous administration.

55. The use according to any one of claims 52 to 54, wherein the cancer is as defined in any one of claims 31 to 49.

56. Use of a blood brain barrier-penetrant PARP1 selective inhibitor in the manufacture of a medicament for use in combination with an antibody-drug conjugate, wherein the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor are as defined in any one of claims 1 to 27, for treating cancer.

57. The use according to claim 56 wherein the medicament is for use in combination with the antibody-drug conjugate by sequential administration.

58. The use according to claim 56 wherein the medicament is for use in combination with the antibody-drug conjugate by separate simultaneous administration.

59. The use according to any one of claims 56 to 58, wherein the cancer is as defined in any one of claims 31 to 49.

60. An antibody-drug conjugate for use, in combination with a blood brain barrier-penetrant PARP1 selective inhibitor, inthe treatment of cancer, wherein the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor are as defined in any one of claims 1 to 27.

61. The antibody-drug conjugate for the use according to claim 60, wherein the cancer is as defined in any one of claims 31 to 49.

62. The antibody-drug conjugate for the use according to claim 60 or 61, wherein the use comprises administration of the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor sequentially.

63. The antibody-drug conjugate for the use according to claim 60 or 61, wherein the use comprises administration of the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor separately and simultaneously.

64. An antibody-drug conjugate for use in the treatment of cancer in a subject, wherein said treatment comprises the sequential or separate simultaneous administration of i) the antibody-drug conjugate, and ii) a blood brain barrier- penetrant PARP1 selective inhibitor to said subject, wherein the antibody-drug conjugate and the blood brain barrier- penetrant PARP1 selective inhibitor are as defined in any one of claims 1 to 27.

65. A blood brain barrier-penetrant PARP1 selective inhibitor for use, in combination with an antibody-drug conjugate, in the treatment of cancer, wherein the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor are as defined in any one of claims 1 to 27.

66. The blood brain barrier-penetrant PARP1 selective inhibitor for the use according to claim 65, wherein the cancer is as defined in any one of claims 31 to 49.

67. The blood brain barrier-penetrant PARP1 selective inhibitor for the use according to claim 65 or 66, wherein the use comprises administration of the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor sequentially.

68. The blood brain barrier-penetrant PARP1 selective inhibitor for the use according to claim 65 or 66, wherein the use comprises administration of the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor separately and simultaneously.

69. A blood brain barrier-penetrant PARP1 selective inhibitor for use in the treatment of cancer in a subject, wherein said treatment comprises the sequential or separate simultaneous administration of i) the blood brain barrier-penetrant PARP1 selective inhibitor, and ii) an antibody-drug conjugate to said subject, wherein the blood brain barrier-penetrant PARP1selective inhibitor and the antibody-drug conjugate are as defined in any one of claims 1 to 27.

70. A method of treating cancer comprising administering an antibody-drug conjugate and a blood brain barrier-penetrant PARP1 selective inhibitor as defined in any one of claims 1 to 27 in combination to a subject in need thereof.

71. The method according to claim 70, wherein the cancer is as defined in any one of claims 31 to 49.

72. The method according to claim 70 or 71, wherein the method comprises administering the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor sequentially.

73. The method according to claim 70 or 71, wherein the method comprises administering the antibody-drug conjugate and the blood brain barrier-penetrant PARP1 selective inhibitor separately and simultaneously.

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