Use of ATR inhibitors in combination with radioligand therapy for the treatment of cancer

Abstract

Disclosed are methods of treating a cancer in a subject using at least one ATR inhibitor and a radionuclide-containing PSMA targeting agent such as 177Lu vipivotide tetraxetan, wherein the cancer has an over expression of PSMA on its cell membrane. The methods comprise contacting the cell with a therapeutically effective amount of a combination of at least one ATR inhibitor and 177Lu vipivotide tetraxetan.

Description

[0001] USE OF ATR INHIBITORS IN COMBINATION WITH RADIOLIGAND THERAPY FOR THE TREATMENT OF CANCER

[0002] FIELD OF THE DISCLOSURE

[0003] The disclosure relates to combinations of at least one ataxia-telangiectasia and RAD-3-related protein kinase (ATR) inhibitor, pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, and at least one agent for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC), pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, and their use in the treatment of a disease or condition, such as a cancer.

[0004] BACKGROUND

[0005] There is a need for new anti-cancer therapies and, in particular, for ATR inhibitor-based anticancer therapies. These therapies may be useful in combination with therapies which alone increase the reliance of cancer cells on ATR for mitosis, in particular if the combination therapy can be locally delivered.

[0006] SUMMARY

[0007] In general, the present disclosure provides for methods of treating cancers with combination therapies including ataxia telangiectasia and Rad3-related protein (ATR) inhibitors and a radioligand therapy.

[0008] One aspect of the disclosure is a combination of at least one ATR inhibitor, or a pharmaceutically acceptable salt thereof, and177Lu vipivotide tetraxetan (PLUVICTO®), and use thereof in the treatment of cancers or for inducing cell death in cancer cells. The cancers included herein may have an overexpression of PSMA on their cell membranes.

[0009] In another aspect, the disclosure provides a method of treating a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a combination of an ATR inhibitor and177Lu vipivotide tetraxetan , where the cancers included herein can have an over-expression of PSMA on their cell membranes.

[0010] In another aspect, the disclosure provides a method of treating a cancer in a subject, the method comprising:

[0011] (i) identifying a subject having a cancer having an over-expression of PSMA on its cell membrane; and

[0012] (ii) administering to the subject a therapeutically effective amount of a combination of an ATR inhibitor and177Lu vipivotide tetraxetan.

[0013] In another aspect, the disclosure provides a method of inducing cell death in an aberrant cancer cell where the cancer has an over-expression of PSMA on its cell membrane, the method comprising contacting the cell with an effective amount of a combination of an ATR inhibitor and177Lu vipivotide tetraxetan, the effective amount being sufficient to induce cell death in the aberrant cancer cell. In general, the disclosure relates to a combination of an ATR inhibitor, or a pharmaceutically acceptable salt thereof, and177Lu vipivotide tetraxetan, or a pharmaceutically acceptable salt thereof, and use thereof for the treatment of cancers or for inducing cell death in cancer cells.

[0014] In one embodiment, the combinations disclosed herein are used for the treatment of prostatespecific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC).

[0015] In another aspect, the disclosure provides a method of treating a cancer in a subject having a cancer that has an over-expression of PSMA on its cell membranes, comprising: administering a therapeutic combination, wherein the therapeutic combination comprises:

[0016] (i) a therapeutically effective amount of an ATR inhibitor, wherein the ATR inhibitor is camonsertib, or a pharmaceutically acceptable salt thereof; and

[0017] (ii) a therapeutically effective amount of177Lu vipivotide tetraxetan.

[0018] In another aspect, the disclosure provides a method of treating a cancer in a subject having a cancer that has an over-expression of PSMA on its cell membranes, comprising: administering a therapeutic combination, wherein the therapeutic combination comprises:

[0019] (i) a therapeutically effective amount of an ATR inhibitor, wherein the ATR inhibitor is camonsertib hydrogen sulfate salt; and

[0020] (ii) a therapeutically effective amount of177Lu vipivotide tetraxetan.

[0021] In some embodiments, the disclosure provides a method, wherein177Lu vipivotide tetraxetan ® is administered in a dose of about 7.4 GBq. In some embodiments, PLUVICTO® is administered once every 6 weeks. In some embodiments,177Lu vipivotide tetraxetan is administered once every 6 weeks, at a dose of about 7.4 GBq.

[0022] In some embodiments, the disclosure provides a method wherein the subject has one or more DDR pathway mutations. In some embodiments, the disclosure provides a method, wherein the DDR pathway mutation comprises one or more of: oncogenic mutations; dysfunctional G1 / S checkpoint control; (e.g., loss of p53 function); defects in other DNA repair pathways (e.g., ATM) or that are subject to the effects of DNA damaging agents, e.g., radioligand therapy or chemotherapeutic agents.

[0023] In some embodiments, the disclosure provides a method, wherein the dysfunctional G1 / S checkpoint is a loss of p53 function. In some embodiments, the disclosure provides a method, wherein the defect in other DNA repair pathways is ATM. In some embodiments, the disclosure provides a method, wherein the DNA damaging agent comprises radioligand therapy, chemotherapeutic agents, and combinations thereof. In some embodiments, the disclosure provides a method, wherein the subject is free of DDR pathway mutations.

[0024] In some embodiments, the disclosure provides a method, wherein the therapeutically effective dose of the therapeutic combination of an ATR inhibitor and177Lu vipivotide tetraxetan for a subject having one or more DDR pathway mutations is from about 1 % to about 99% of the therapeutically effective dose for a subject that is free of DDR pathway mutations. In some embodiments, the disclosure provides a method, wherein the dose of the ATR inhibitor is reduced by about 1 % to about 99% in response to an adverse toxicological event. In some embodiments, the disclosure provides a method wherein the dose of177Lu vipivotide tetraxetan is reduced by about 1 % to about 99% in response to an adverse toxicological event.

[0025] All of the features disclosed herein on ATR inhibitors (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any embodiments explicitly disclosed herein on ATR inhibitors. Any embodiment described in this application on ATR inhibitors can be combined with any other embodiment.

[0026] DETAILED DESCRIPTION

[0027] The present disclosure provides for methods of treating cancers with combination therapies including ataxia telangiectasia and Rad3-related protein (ATR) inhibitors and a radioligand therapy. The radioligand may include a targeting agent specific for the cancer being treated (e.g., a PSMA targeting agent to target cancers with an overexpression of PSMA, e.g., prostate cancer cells overexpressing PSMA). In certain examples, methods of the present disclosure include the treatment of cancers having an overexpression of PSMA on their cell membranes with compound 121 of the present disclosure (Camonsertib) and177Lu vipivotide tetraxetan (PLUVICTO®).

[0028] Advantageously, an ATR inhibitor and a radioligand (e.g.,177Lu vipivotide tetraxetan) may act synergistically to induce cell death in cancer cells having an over-expression of PSMA on their cell membranes. Advantageously, combination cancer therapies including an ATR inhibitor and177Lu vipivotide tetraxetan may exhibit reduced morbidities, as ATR inhibitor and177Lu vipivotide tetraxetan dosages may be reduced, e.g., relative to those administered in corresponding monotherapies. Thus, the ATR inhibitor and177Lu vipivotide tetraxetan may be used in subtherapeutic regimens in the methods of the disclosure. The present disclosure demonstrates that combination cancer therapies including an ATR inhibitor and177Lu vipivotide tetraxetan may synergistically induce cell death in cancer cells through a combination of DNA damage affected by a radionuclide in close proximity to a cancer cell having an overexpression of PSMA and the interruption of DNA damage pathways by an ATR inhibitor. Thus, the present disclosure examined both the advantages and disadvantages to using either an ATR inhibitor or177Lu vipivotide tetraxetan to treat cancer and determined that a combination of the two agents will induce cell death in cancer cells while exhibiting reduced morbidities due to the use of subtherapeutic dosages of the agents as relative to the dosages administered in the corresponding monotherapies. It is to be understood that based on the present disclosure the skilled person, having the common general knowledge in mind, would derive the provision of a synergistically active combination therapy for prostate cancer as being encompassed by the technical teaching and embodied by the present disclosure. Such a synergistic combination might be an ATR inhibitor with177Lu vipivotide tetraxetan. In particular, provided herein is a synergistically active combination therapy for prostate cancer when combining Camonsertib and177Lu vipivotide tetraxetan. It may remain to post-published evidence to confirm the plausibility of these synergistic effects (US Rule 132 Declaration or evidence under EPO Decision G2 / 21). Definitions

[0029] The term "aberrant," as used herein, refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, where returning the aberrant activity to a normal or non-disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms. The aberrant activity can be measured by measuring the modification of a substrate of the enzyme in question; a difference of greater or equal to a 2-fold change in activity could be considered as aberrant. Aberrant activity could also refer to an increased dependence on a particular signaling pathway as a result of a deficiency in a separate complementary pathway.

[0030] The term “acyl,” as used herein, represents a group -C(=O)-R, where R is alkyl, alkenyl, alky ny I, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclyl. Acyl may be optionally substituted as described herein for each respective R group.

[0031] The term “alkanoyl,” as used herein, represents a hydrogen or an alkyl group that is attached to the parent molecular group through a carbonyl group and is exemplified by formyl (i.e ., a carboxyaldehyde group), acetyl, propionyl, butyryl, and iso-butyryl. Unsubstituted alkanoyl groups contain from 1 to 7 carbons. The alkanoyl group may be unsubstituted of substituted (e.g., optionally substituted C1-7 alkanoyl) as described herein for alkyl group. The ending “-oyl” may be added to another group defined herein, e.g., aryl, cycloalkyl, and heterocyclyl, to define “aryloyl,” “cycloalkanoyl,” and “(heterocyclyl)oyl.” These groups represent a carbonyl group substituted by aryl, cycloalkyl, or heterocyclyl, respectively. Each of “aryloyl,” “cycloalkanoyl,” and “(heterocyclyl)oyl” may be optionally substituted as defined for “aryl,” “cycloalkyl,” or “heterocyclyl,” respectively.

[0032] The term “alkenyl,” as used herein, represents acyclic monovalent straight or branched chain hydrocarbon groups of containing one, two, or three carbon-carbon double bonds. Non-limiting examples of the alkenyl groups include ethenyl, prop-1 -enyl, prop-2-enyl, 1 -methylethenyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylprop-1-enyl, 2-methylprop-1-enyl, and 1-methylprop-2-enyl. Alkenyl groups may be optionally substituted as defined herein for alkyl.

[0033] The term “alkoxy,” as used herein, represents a chemical substituent of formula -OR, where R is a C1-6 alkyl group, unless otherwise specified. In some embodiments, the alkyl group can be further substituted as defined herein. The term “alkoxy” can be combined with other terms defined herein, e.g., aryl, cycloalkyl, or heterocyclyl, to define an “aryl alkoxy,” “cycloalkyl alkoxy,” and “(heterocyclyl)alkoxy” groups. These groups represent an alkoxy that is substituted by aryl, cycloalkyl, or heterocyclyl, respectively. Each of “aryl alkoxy,” “cycloalkyl alkoxy,” and “(heterocyclyl)alkoxy” may optionally substituted as defined herein for each individual portion.

[0034] The term “alkoxyalkyl,” as used herein, represents a chemical substituent of formula -L-O-R, where L is C1-6 alkylene, and R is C1-6 alkyl. An optionally substituted alkoxyalkyl is an alkoxyalkyl that is optionally substituted as described herein for alkyl.

[0035] The term “alkyl,” as used herein, refers to an acyclic straight or branched chain saturated hydrocarbon group, which, when unsubstituted, has from 1 to 12 carbons, unless otherwise specified. In certain preferred embodiments, unsubstituted alkyl has from 1 to 6 carbons. Alkyl groups are exemplified by methyl; ethyl; n- and iso-propyl; n-, sec-, iso- and tert-butyl; neopentyl, and the like, and may be optionally substituted, valency permitting, with one, two, three, or, in the case of alkyl groups of two carbons or more, four or more substituents independently selected from: amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heterocyclyl; (heterocyclyl)oxy; heteroaryl; hydroxy; nitro; thiol; silyl; cyano; alkylsulfonyl; alkylsulfinyl; alkylsulfenyl; =0; =S; -SO2R, where R is amino or cycloalkyl; =NR’, where R’ is H, alkyl, aryl, or heterocyclyl. Each of the substituents may itself be unsubstituted or, valency permitting, substituted with unsubstituted substituent(s) defined herein for each respective group.

[0036] The term “alkylene,” as used herein, refers to a divalent alkyl group. An optionally substituted alkylene is an alkylene that is optionally substituted as described herein for alkyl.

[0037] The term “alkylamino,” as used herein, refers to a group having the formula -N(RN1)2 or -NHRN1, in which RN1is alkyl, as defined herein. The alkyl portion of alkylamino can be optionally substituted as defined for alkyl. Each optional substituent on the substituted alkylamino may itself be unsubstituted or, valency permitting, substituted with unsubstituted substituent(s) defined herein for each respective group.

[0038] The term “alkylsulfenyl,” as used herein, represents a group of formula —S— (alkyl). Alkylsulfenyl may be optionally substituted as defined for alkyl.

[0039] The term “alkylsulfinyl,” as used herein, represents a group of formula -S(O)-(alkyl). Alkylsulfinyl may be optionally substituted as defined for alkyl.

[0040] The term “alkylsulfonyl,” as used herein, represents a group of formula -S(0)2-(alkyl). Alkylsulfonyl may be optionally substituted as defined for alkyl.

[0041] The term “alky ny I,” as used herein, represents monovalent straight or branched chain hydrocarbon groups of from two to six carbon atoms containing at least one carbon-carbon triple bond and is exemplified by ethynyl, 1 -propynyl, and the like. The alkynyl groups may be unsubstituted or substituted (e.g., optionally substituted alkynyl) as defined for alkyl.

[0042] The term “amino,” as used herein, represents -N(RN1)2, where, if amino is unsubstituted, both RN1are H; or, if amino is substituted, each RN1is independently H, -OH, -NO2, -N(RN2)2, -SO2ORN2, -SO2RN2, - SORN2, -C00RN2, an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, cycloalkyl, cycloalkenyl, heteroalkyl, or heterocyclyl, provided that at least one RN1is not H, and where each RN2is independently H, alkyl, or aryl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group. In some embodiments, amino is unsubstituted amino (i.e., -NH2) or substituted amino (e.g., NHRN1), where RN1is independently -OH, - SO2ORN2, -SO2RN2, -SORN2, -COORN2, optionally substituted alkyl, or optionally substituted aryl, and each RN2can be optionally substituted alkyl or optionally substituted aryl. In some embodiments, substituted amino may be alkylamino, in which the alkyl groups are optionally substituted as described herein for alkyl. In some embodiments, an amino group is -NHRN1, in which RN1is optionally substituted alkyl.

[0043] The term “aryl,” as used herein, represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings. Aryl group may include from 6 to 10 carbon atoms. All atoms within an unsubstituted carbocyclic aryl group are carbon atoms. Non-limiting examples of carbocyclic aryl groups include phenyl, naphthyl, 1 ,2-dihydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, etc. The aryl group may be unsubstituted or substituted with one, two, three, four, or five substituents independently selected from: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; hydroxy; nitro; thiol; silyl; and cyano. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group.

[0044] The term “aryl alkyl,” as used herein, represents an alkyl group substituted with an aryl group. The aryl and alkyl portions may be optionally substituted as the individual groups as described herein.

[0045] The term “arylene,” as used herein, refers to a divalent aryl group. An optionally substituted arylene is an arylene that is optionally substituted as described herein for aryl.

[0046] The term “aryloxy,” as used herein, represents a chemical substituent of formula -OR, where R is an aryl group, unless otherwise specified. In optionally substituted aryloxy, the aryl group is optionally substituted as described herein for aryl.

[0047] The term “ATR kinase,” as used herein, refers to Ataxia-telangiectasia and RAD-3-related protein kinase.

[0048] The term “carbocyclic,” as used herein, represents an optionally substituted C3-16 monocyclic, bicyclic, or tricyclic structure in which the rings, which may be aromatic or non-aromatic, are formed by carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, cycloalkynyl, and certain aryl groups.

[0049] The term “carbonyl,” as used herein, represents a -C(O)- group.

[0050] The term “cyano,” as used herein, represents -CN group.

[0051] The term “cycloalkenyl,” as used herein, refers to a non-aromatic carbocyclic group having at least one double bond in the ring and from three to ten carbons (e.g., a C3-10 cycloalkenyl), unless otherwise specified. Non-limiting examples of cycloalkenyl include cycloprop-1 -enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1 -enyl, cyclopent-2-enyl, cyclopent-3-enyl, norbornen-1-yl, norbornen-2-yl, norbornen-5-yl, and norbornen-7-yl. The cycloalkenyl group may be unsubstituted or substituted (e.g., optionally substituted cycloalkenyl) as described for cycloalkyl.

[0052] The term “cycloalkenyl alkyl,” as used herein, represents an alkyl group substituted with a cycloalkenyl group, each as defined herein. The cycloalkenyl and alkyl portions may be substituted as the individual groups defined herein.

[0053] The term “cycloalkoxy,” as used herein, represents a chemical substituent of formula -OR, where R is cycloalkyl group, unless otherwise specified. In some embodiments, the cycloalkyl group can be further substituted as defined herein.

[0054] The term “cycloalkyl,” as used herein, refers to a cyclic alkyl group having from three to ten carbons (e.g., a C3-C10 cycloalkyl), unless otherwise specified. Cycloalkyl groups may be monocyclic or bicyclic. Bicyclic cycloalkyl groups may be of bicyclo[p.q.O]alkyl type, in which each of p and q is, independently, 1 , 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 2, 3, 4, 5, 6, 7, or 8. Alternatively, bicyclic cycloalkyl groups may include bridged cycloalkyl structures, e.g., bicyclo[p.q.r]alkyl, in which r is 1 , 2, or 3, each of p and q is, independently, 1 , 2, 3, 4, 5, or 6, provided that the sum of p, q, and r is 3, 4, 5, 6, 7, or 8. The cycloalkyl group may be a spirocyclic group, e.g., spiro[p.q]alkyl, in which each of p and q is, independently, 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 4, 5, 6, 7, 8, or 9. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1 - bicyclo[2.2.1 Jheptyl, 2-bicyclo[2.2.1 Jheptyl, 5-bicyclo[2.2.1 Jheptyl, 7-bicyclo[2.2.1 Jheptyl, and decalinyl. The cycloalkyl group may be unsubstituted or substituted (e.g., optionally substituted cycloalkyl) with one, two, three, four, or five substituents independently selected from: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; heteroaryl; hydroxy; nitro; thiol; silyl; cyano; =0; =S; -SO2R, where R is amino or cycloalkyl; =NR’, where R’ is H, alkyl, aryl, or heterocyclyl; or - C0N(RA)2, where each RAis independently H or alkyl, or both RA, together with the atom to which they are attached, combine to form heterocyclyl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group.

[0055] The term “cycloalkyl alkyl,” as used herein, represents an alkyl group substituted with a cycloalkyl group, each as defined herein. The cycloalkyl and alkyl portions may be optionally substituted as the individual groups described herein.

[0056] The term “cycloalkylene,” as used herein, represents a divalent cycloalkyl group. An optionally substituted cycloalkylene is a cycloalkylene that is optionally substituted as described herein for cycloalkyl.

[0057] The term “cycloalkynyl,” as used herein, refers to a monovalent carbocyclic group having one or two carbon-carbon triple bonds and having from eight to twelve carbons, unless otherwise specified. Cycloalkynyl may include one transannular bond or bridge. Non-limiting examples of cycloalkynyl include cyclooctynyl, cyclononynyl, cyclodecynyl, and cyclodecadiynyl. The cycloalkynyl group may be unsubstituted or substituted (e.g., optionally substituted cycloalkynyl) as defined for cycloalkyl.

[0058] The term "co-administration," "administration with," "administration in combination with," or the like, as used herein, encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0059] "Disease" or "condition" refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein.

[0060] The term “halo,” as used herein, represents a halogen selected from bromine, chlorine, iodine, and fluorine.

[0061] The term “heteroalkyl,” as used herein refers to an alkyl, alkenyl, or alkynyl group interrupted once by one or two heteroatoms; twice, each time, independently, by one or two heteroatoms; three times, each time, independently, by one or two heteroatoms; or four times, each time, independently, by one or two heteroatoms. Each heteroatom is, independently, O, N, or S. In some embodiments, the heteroatom is O or N. None of the heteroalkyl groups includes two contiguous oxygen or sulfur atoms. The heteroalkyl group may be unsubstituted or substituted (e.g., optionally substituted heteroalkyl). When heteroalkyl is substituted and the substituent is bonded to the heteroatom, the substituent is selected according to the nature and valency of the heteratom. Thus, the substituent bonded to the heteroatom, valency permitting, is selected from the group consisting of =0, -N(RN2)2, -SO2ORN3, -SO2RN2, -SORN3, - COORN3, an N protecting group, alkyl, alkenyl, alky ny I, aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, or cyano, where each RN2is independently H, alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl, and each RN3is independently alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl. Each of these substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group. When heteroalkyl is substituted and the substituent is bonded to carbon, the substituent is selected from those described for alkyl, provided that the substituent on the carbon atom bonded to the heteroatom is not Cl, Br, or I . It is understood that carbon atoms are found at the termini of a heteroalkyl group.

[0062] The term “heteroaryl alkyl,” as used herein, represents an alkyl group substituted with a heteroaryl group, each as defined herein. The heteroaryl and alkyl portions may be optionally substituted as the individual groups described herein.

[0063] The term “heteroarylene,” as used herein, represents a divalent heteroaryl. An optionally substituted heteroarylene is a heteroarylene that is optionally substituted as described herein for heteroaryl.

[0064] The term “heteroaryloxy,” as used herein, refers to a structure -OR, in which R is heteroaryl. Heteroaryloxy can be optionally substituted as defined for heterocyclyl.

[0065] The term “heterocyclyl,” as used herein, represents a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused, bridging, and / or spiro 3-, 4-, 5-, 6-, 7-, or 8-membered rings, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, “heterocyclyl” is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused or bridging 5-, 6-, 7-, or 8-membered rings, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocyclyl can be aromatic or non-aromatic. Nonaromatic 5-membered heterocyclyl has zero or one double bonds, non-aromatic 6- and 7-membered heterocyclyl groups have zero to two double bonds, and non-aromatic 8-membered heterocyclyl groups have zero to two double bonds and / or zero or one carbon-carbon triple bond. Heterocyclyl groups include from 1 to 16 carbon atoms unless otherwise specified. Certain heterocyclyl groups may include up to 9 carbon atoms. Non-aromatic heterocyclyl groups include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolidinyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, thiazolidinyl, tetra hydrofuranyl, di hydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, etc. If the heterocyclic ring system has at least one aromatic resonance structure or at least one aromatic tautomer, such structure is an aromatic heterocyclyl (i.e. , heteroaryl). Non-limiting examples of heteroaryl groups include benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, qunazolinyl, quinolinyl, thiadiazolyl (e.g., 1 ,3,4-thiadiazole), thiazolyl, thienyl, triazolyl, tetrazolyl, etc. The term “heterocyclyl” also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and / or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., 8-oxabicyclo[3,2,1]octane, quinuclidine, tropanes, or diaza-bicyclo[2.2.2]octane. The term “heterocyclyl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring. Examples of fused heterocyclyls include 1 ,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3-dihydrobenzothiophene. The heterocyclyl group may be unsubstituted or substituted with one, two, three, four, five, or six substituents independently selected from: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; hydroxy; nitro; thiol; silyl; cyano; =0; =S; =NR’, where R’ is H, alkyl, aryl, or heterocyclyl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group.

[0066] The term “heterocyclyl alkyl,” as used herein, represents an alkyl group substituted with a heterocyclyl group, each as defined herein. The heterocyclyl and alkyl portions may be optionally substituted as the individual groups described herein.

[0067] The term “heterocyclylene,” as used herein, represents a divalent heterocyclyl. An optionally substituted heterocyclylene is a heterocyclylene that is optionally substituted as described herein for heterocyclyl.

[0068] The term “(heterocyclyl)oxy,” as used herein, represents a chemical substituent of formula -OR, where R is a heterocyclyl group, unless otherwise specified. (Heterocyclyl)oxy can be optionally substituted in a manner described for heterocyclyl.

[0069] The terms “hydroxyl” and “hydroxy,” as used interchangeably herein, represent an -OH group.The term “isotopically enriched,” as used herein, refers to the pharmaceutically active agent with the isotopic content for one isotope at a predetermined position within a molecule that is at least 100 times greater than the natural abundance of this isotope. For example, a composition that is isotopically enriched for deuterium includes an active agent with at least one hydrogen atom position having at least 100 times greater abundance of deuterium than the natural abundance of deuterium. Preferably, an isotopic enrichment for deuterium is at least 1000 times greater than the natural abundance of deuterium. More preferably, an isotopic enrichment for deuterium is at least 4000 times greater (e.g., at least 4750 times greater, e.g., up to 5000 times greater) than the natural abundance of deuterium.

[0070] The term “nitro,” as used herein, represents an -NO2 group.

[0071] The term “oxo,” as used herein, represents a divalent oxygen atom (e.g., the structure of oxo may be shown as =0).

[0072] The term “PSMA,” as used herein and unless specified otherwise, refers to the Prostate Specific Membrane Antigen.

[0073] The term “Ph,” as used herein, represents phenyl. The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein, formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.

[0074] The term “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier,” as used interchangeably herein, refers to any ingredient other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0075] The term “pharmaceutically acceptable salt,” as use herein, represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydrogen sulfate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0076] The term "progression-free survival (PFS)" means time from initiation of therapy to first evidence of disease progression or death due to any cause, whichever occurs first. For the purpose of the clinical trial described in the example, PFS is defined as the time from randomization of study population to the first documented progressive disease or death due to any cause. In some embodiments, administration of an ATR inhibitor and177Lu vipivotide tetraxetan may provide an increase in the progression-free survival of a human subject with cancer (e.g., without limitations, cancer bearing an over-expression of PSMA on its cell membranes), compared to a human subject who is administered an ATR inhibitor alone. The increase in the progression-free survival refers to an increase in PFS in cancer patients (e.g., without limitations, patients with prostate cancer) treated with an ATR inhibitor and177Lu vipivotide tetraxetan relative to PFS in cancer patients treated with an ATR inhibitor only. In some embodiments, the increase in progression-free survival is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, about 36 months, or greater than 36 months increased over that of a subject administered an ATR inhibitor alone.

[0077] The term “prostate cancer,” as used herein, refers to cancer that occurs in the prostate. The prostate is a small walnut-shaped gland in males that produces the seminal fluid that nourishes and transports sperm. Prostate cancer is one of the most common types of cancer. Many prostate cancers grow slowly and are confined to the prostate gland, where they may not cause serious harm. However, while some types of prostate cancer grow slowly and may need minimal or even no treatment, other types are aggressive and can spread quickly.

[0078] The terms “b.i.d.”, “q.d.”, “q.o.d.”, “q.wk.”, and “q.6wk.”, as used herein refer to twice-daily, once- daily, once-weekly, or once every 6 weeks, respectively.

[0079] For the methods disclosed herein, subjects can be ones who have been previously treated with 1 to 3 (or greater) lines of therapy. A line of therapy is defined as one or more cycles of a planned treatment program, which may be one or more planned cycles of single-agent therapy or a combination therapy, or a sequence of treatments administered in a planned manner. A new line of therapy begins when a planned course of therapy is modified to include other treatment agents due to lack of adequate response, disease progression, relapse, or toxicity. Previous lines of treatment include, but are not limited to, therapy comprising an ATR inhibitor (e.g., without limitations, Camonsertib), an antibody therapy, stem cell transplant, or any combination thereof. In some cases, the subject had previously been administered an ATR inhibitor (e.g., without limitations, Camonsertib) either alone or in combination with other cancer treatments (e.g., an antibody therapy).

[0080] The term “RP2D”, as used herein, refers to the recommended phase 2 dose. The RP2D of anticancer agents is determined traditionally by dose-limiting toxicities. Nontoxicity or biological endpoints such as pharmacokinetics, pharmacodynamics, and efficacy can also be used to identify RP2D, which may be relevant to molecularly targeted agents (MTAs) such as, for example, PLUVICTO®.

[0081] The term “tautomer” refers to structural isomers that readily interconvert, often by relocation of a proton. Tautomers are distinct chemical species that can be identified by differing spectroscopic characteristics, but generally cannot be isolated individually. Non-limiting examples of tautomers include ketone - enol, enamine - imine, amide - imidic acid, nitroso - oxime, ketene - ynol, and amino acid - ammonium carboxylate.

[0082] The term “therapeutically effective amount,” as used herein, means the amount of a compound or a pharmaceutically acceptable salt thereof that, in a combination of an ATR inhibitor and177Lu vipivotide tetraxetan, is sufficient to treat cancer. Typically, a therapeutically effective amount is a subtherapeutic regimen.

[0083] The term “subject,” as used herein, represents a human or non-human animal (e.g., a mammal) that is suffering from, or is at risk of, disease or condition, as determined by a qualified professional (e.g., a doctor or a nurse practitioner) with or without known in the art laboratory test(s) of sample(s) from the subject. Preferably, the subject is a human. Non-limiting examples of diseases and conditions include diseases having the symptom of cell hyperproliferation, e.g., a cancer.

[0084] The term “subtherapeutic regimen,” as used herein, refers to a dosing regimen that is at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest standard recommended dosing regimen of a particular compound formulated for a given route of administration for treatment of cancer. A subtherapeutic regimen of a compound may be therapeutically ineffective for the compound in a monotherapy regimen. In the methods of the disclosure, a therapeutically effective amount of ATR inhibitor is preferably a subtherapeutic regimen (e.g., a regimen that is therapeutically ineffective for ATR inhibitor in a monotherapy regimen). A subtherapeutic regimen of ATR inhibitor that is formulated for oral administration may differ from a subtherapeutic regimen of the same agent formulated for intratumoral administration. A subtherapeutic regimen may include a “subtherapeutic starting regimen” and a “subtherapeutic maintenance regimen.” A “subtherapeutic starting regimen” of ATR inhibitor is lower than the lowest standard starting dosage. Similarly, a “subtherapeutic maintenance regimen” of ATR inhibitor) is lower than the lowest standard maintenance regimen. Typically, the subtherapeutic regimen is at least 1% of the lowest standard subtherapeutic regimen.

[0085] “Treatment” and "treating," as used herein, refer to the medical management of a subject with the intent to improve, ameliorate, stabilize, prevent, or cure a disease or condition. This term includes active treatment (treatment directed to improve the disease or condition); causal treatment (treatment directed to the cause of the associated disease or condition); palliative treatment (treatment designed for the relief of symptoms of the disease or condition); preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease or condition); and supportive treatment (treatment employed to supplement another therapy). A disease or condition may be a cancer. .

[0086] ATR Inhibitors

[0087] Ataxia-Telangiectasia-mutated- and Rad-3-related (ATR) inhibitors (ATRi) elicit cell death in rapidly growing tumor cells by exacerbating endogenous replication stress and replication fork collapse, as well as by disabling cell cycle checkpoints. Camonsertib has demonstrated antitumoral-activity in several xenograft models of cancer as a single agent. Pharmacokinetic (PK) and pharmacodynamic (PD) marker analysis from tumor xenografts demonstrates target engagement and a dose-dependent increase in double-strand DNA breaks leading to tumor cell death in vivo.

[0088] An ATR inhibitor is a compound that upon contacting the enzyme ATR kinase, whether in vitro, in cell culture, or in an animal, reduces the activity of ATR kinase, such that the measured ATR kinase IC50 is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain ATR inhibitors, the ATR kinase IC50 may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM . Preferably, the ATR kinase IC50 is 0.1 nM to 1 pM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM).

[0089] Non-limiting examples of ATR inhibitors include, e.g.:

[0090] BA Y1895344 ceralasertib (AZD6738) berzosertib (VE-822) Non-limiting examples of ATR inhibitors include, e.g., those described in, e.g., International Application Publication Nos. WO 2019 / 178590 and WO2018218197; U.S. Patent Nos. 9,663,535, 9,549,932, 8,552,004, 8,841 ,308, 10,800,774, 10,894,052, and 10,421 ,765, each of which is incorporated by reference herein; and U.S. Patent Application Publication No. 2019 / 0055240, which is incorporated by reference herein.

[0091] In one embodiment, an ATR inhibitor is a compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein

[0092] - is a double bond, and each Y is independently N or CR4; or - is a single bond, and each Y is independently NRY, carbonyl, or C(RY)2; where each RYis independently H or optionally substituted Ci -6 alkyl;

[0093] R1is optionally substituted C1-6 alkyl or H;

[0094] R2is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted Ce-io aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, - N(R5)2, -OR5, -CON(R6)2I-SO2N(R6)2, -SO2R5A, or -Q-R5B;

[0095] R3is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R4is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted Ce-io aryl, optionally substituted C1-9 heteroaryl, or -SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted Ce-io aryl;

[0096] R5Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted Ce-io aryl, optionally substituted C1-9 heteroaryl, -N(R5)2, -CON(R6)2, -SO2N(R6)2, -SO2R5A, or optionally substituted alkoxy; each R6is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted Ce-io aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted Ce-io arylene; and

[0097] X is hydrogen or halogen.

[0098] The ATR inhibitor may be, e.g., a compound of formula (IV): or a pharmaceutically acceptable salt thereof, wherein each Y is independently N or CR4;

[0099] R1is optionally substituted C1-6 alkyl or H;

[0100] R2is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted Ce-io aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, - N(R5)2, -OR5, -CON(R6)2I-SO2N(R6)2, -SO2R5A, or -Q-R5B;

[0101] R3is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R4is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted Ce-io aryl, optionally substituted C1-9 heteroaryl, or -SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted Ce-io aryl;

[0102] R5Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted Ce-io aryl, optionally substituted C1-9 heteroaryl, -N(R5)2, -CON(R6)2, -SO2N(R6)2, -SO2R5A, or optionally substituted alkoxy; each R6is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted Ce-io aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;

[0103] Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted Ce-io arylene; and

[0104] X is hydrogen or halogen.

[0105] In some embodiments, in the compound of formula (III), (IV), or (lll-b): each Y is independently N or CR4;

[0106] R1is H or optionally substituted C1-6 alkyl;

[0107] R2is optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted Ce-io aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, -N(R5)2, -CON(R6)2, -SO2N(R6)2, or -SO2R5A;

[0108] R3is optionally substituted C1-9 heteroaryl; each R4is independently H or optionally substituted C1-6 alkyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted Ce-io aryl, optionally substituted C1-9 heteroaryl, or -SO2R5A, where each R5Ais independently optionally substituted C1-6 alkyl or optionally substituted C3-8 cycloalkyl; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl or optionally substituted C3-8 cycloalkyl; and each R6is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted Ce-io aryl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl.

[0109] Methods of making compounds of formula (III) are described, e.g., in U.S. Patent No.12, 264, 155, hereby incorporated by reference.

[0110] The ATR inhibitor may be, e.g., a compound of formula (lll-a): or a pharmaceutically acceptable salt thereof, where Y, R1, R2, R3, and R4are as described for formula (III).

[0111] The ATR inhibitor may be, e.g., a compound of formula (lll-b):

[0112] (Ill-b) or a pharmaceutically acceptable salt thereof, where Y, R1, R2, R3, and R4are as described for formula (III).

[0113] The ATR inhibitor may be, e.g., a compound of formula (IIIA): or a pharmaceutically acceptable salt thereof, where R1, R2, R3, and R4are as described for formula (III).

[0114] The ATR inhibitor may be, e.g., a compound of formula (IIIA-a):

[0115] (IIIA-a) or a pharmaceutically acceptable salt thereof, where R1, R2, R3, and R4are as described for formula (III).

[0116] The ATR inhibitor may be, e.g., a compound of Formula (I I IB) : (IIIB) or a pharmaceutically acceptable salt thereof, where R1, R2, R3, and R4are as described for formula (III).

[0117] The ATR inhibitor may be, e.g., a compound of formula (IIIB-a):

[0118] (IIIB-a) or a pharmaceutically acceptable salt thereof, where R1, R2, R3, and R4are as described for formula V.

[0119] The ATR inhibitor may be, e.g., a compound of Formula (I I IC) : or a pharmaceutically acceptable salt thereof, where R1, R2, R3, and R4are as described for formula (Illi).

[0120] The ATR inhibitor may be, e.g., a compound of formula (IllC-a): or a pharmaceutically acceptable salt thereof, where R1, R2, R3, and R4are as described for formula (HI). The ATR inhibitor may be, e.g., a compound of formula (HID): or a pharmaceutically acceptable salt thereof, where R1, R2, R3, and R4are as described for formula (III).

[0121] The ATR inhibitor may be, e.g., a compound of formula (IIID-a):

[0122] (IIID-a) or a pharmaceutically acceptable salt thereof, where R1, R2, R3, and R4are as described for formula (III).

[0123] Preferably, R1is methyl.

[0124] In some embodiments, R2may be, e.g., optionally substituted C3-8 cycloalkyl. For example, R2may be a group of formula (A): rt / W

[0125] - R7

[0126] 4 )"

[0127] (A) wherein n is 0, 1 , 2, or 3; and

[0128] R7is hydrogen, alkylsulfonyl, cyano, -CON(RA)2, -SON(RA)2, optionally substituted C1-9 heteroaryl, hydroxy, or alkoxy, where each RAis independently H or alkyl; or both RA, together with the atom to which they are attached, combine to form C2-9 heterocyclyl.

[0129] In some embodiments, R2may be, e.g., optionally substituted C1-6 alkyl (e.g., optionally substituted tertiary C3-6 alkyl. For example, R2may be a group of formula (B): where R7is hydrogen, alkylsulfonyl, cyano, -CON(RA)2, -SON(RA)2, optionally substituted C1-9 heteroaryl, hydroxy, or alkoxy, where each RAis independently H or alkyl; or both RA, together with the atom to which they are attached, combine to form C2-9 heterocyclyl.

[0130] In some embodiments, R2may be, e.g., optionally substituted non-aromatic C2-9 heterocyclyl.

[0131] In some embodiments, R2may be, e.g.:

[0132]

[0133] In some embodiments, R2may be a 5-10 membered bicyclic [p.q.r] heterocyclyl.

[0134] In some embodiments, R2may be

[0135] In some

[0136] In some embodiments, R3may be, e.g., optionally substituted, monocyclic C1-9 heteroaryl including at least one nitrogen atom (e.g., two nitrogen atoms). For example, R3may be a group of formula (C): where A is optionally substituted, monocyclic C1-9 heteroaryl ring.

[0137] In some embodiments, A may be, e.g., a group of formula (C1): where R8is hydrogen, halogen, or optionally substituted C1-6 alkyl. In some embodiments, R3may be, e.g.:

[0138] In some embodiments, R3may be, e.g.:

[0139] In some embodiments, R4may be, e.g., hydrogen.

[0140] The ATR inhibitor may be, e.g., a compound listed in Table 1 below or a pharmaceutically acceptable salt thereof.

[0141] Table 1

[0142]

[0143]

[0144] In some embodiments, the ATR inhibitor of the present disclosure may be presented as a salt. In some embodiments, the ATR inhibitor may come in the form of a pharmaceutically acceptable salt. In some embodiments the ATR inhibitor is a hydrogen sulfate salt. In some embodiments, the ATR inhibitor is a phosphate salt. ATR inhibitors may be prepared using reactions and techniques known in the art. For example, certain ATR inhibitors may be prepared using techniques and methods disclosed in, e.g., International Application Publication Nos. WO 2020 / 087170 and WO 2018 / 218197; U.S. Patent Nos. 9,663,535, 9,549,932, 8,552,004, 8,841 ,308, 10,421 ,765, 10,800, 774, and 12,264,155, each of which is incorporated by reference herein; and U.S. Patent Application Publication No. 2019 / 0055240, which is incorporated by reference herein.

[0145] Camonsertib

[0146] Camonsertib is compound 121 of Table 1 , above, and is also known as RP-3500. The terms compound 121 , Camonsertib, and RP-3500 may be used interchangeably herein. In some embodiments, the ATR inhibitor is Camonsertib, or a pharmaceutically acceptable salt thereof. In some embodiments, the ATR inhibitor is Camonsertib hydrogen sulfate salt. The hydrogen sulfate salt form of Camonsertib is previously described as example 121 in U.S. Patent Application Publication No. 2024 / 0294521 , which is incorporated by reference herein in its entirety.

[0147] Camonsertib is an orally bioavailable clinical-stage ATR kinase inhibitor. Camonsertib is highly potent with IC50 values of 1 .0 and 0.33 nmol / L in biochemical and cell-based assays, respectively. Camonsertib is highly selective for ATR with 30-fold selectivity over mammalian target of rapamycin (mTOR) and more than 2,000-fold selectivity over ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and phosphatidylinositol 3-kinase alpha (PI3Ka) kinases. In vivo, Camonsertib treatment results in potent single-agent efficacy and / or tumor regression in multiple xenograft models at minimum effective doses (MED) of 5 to 7 mg / kg once daily. Pharmacodynamic assessments validate target engagement, with dose-proportional tumor inhibition of phosphorylated checkpoint kinase 1 (pCHK1) (ICao = 18.6 nmol / L) and induction of phosphorylated H2A.X variant histone (yH2AX), phosphorylated DNA-PK catalytic subunit (pDNA-PKcs), and phosphorylated KRAB-associated protein 1 (pKAP1). Camonsertib exposure at MED indicates that circulating free plasma levels above the in vivo tumor ICao for 10 to 12 hours are sufficient for efficacy on a continuous schedule. However, short-duration intermittent (weekly 3 days on / 4 days off) dosing schedules as monotherapy or given concomitantly with reduced doses of olaparib or niraparib, maximize tumor growth inhibition while minimizing the impact on red blood cell depletion, emphasizing the reversible nature of erythroid toxicity with Camonsertib and demonstrating superior efficacy compared with sequential treatment. See Roulston, Anne et al. “RP-3500: A Novel, Potent, and Selective ATR Inhibitor that is Effective in Preclinical Models as a Monotherapy and in Combination with PARP Inhibitors.” Molecular Cancer Therapeutics vol. 21 ,2 (2022): 245-256; and NCT04497116.

[0148] Camonsertib has been under development for the treatment of solid tumors. In some embodiments, a solid tumor is selected from ovarian cancer, breast cancer, pancreatic cancer, head and neck cancer squamous cell carcinoma, melanoma, hormone refractory (castration resistant, androgenindependent) prostate cancer, and relapsed and refractory chronic lymphocytic leukemia (CLL). Camonsertib can be administered through oral routes. In some embodiments, Camonsertib is undergoing development for the treatment of various diseases. In embodiments, the various diseases include but are not limited to cancer. In embodiments, the cancer is ovarian cancer, breast cancer, colorectal cancer, endometrial cancer, bladder cancer, cervical cancer, or an advanced solid tumor. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a breast cancer. In some embodiments, the cancer is an ovarian cancer.

[0149] Camonsertib has demonstrated antitumor activity in several xenograft models of cancer as a single agent. Precli nically , PK and PD marker analysis from tumor xenografts demonstrates target engagement and a dose-dependent increase in double-strand DNA breaks leading to tumor cell death in vivo.

[0150] The disclosure includes (where possible) individual diastereomers, enantiomers, epimers, and atropisomers of the compounds disclosed herein, and mixtures of diastereomers and / or enantiomers thereof including racemic mixtures. Although the specific stereochemistries disclosed herein are preferred, other stereoisomers, including diastereomers, enantiomers, epimers, atropisomers, and mixtures of these may also have utility in treating diseases. Inactive or less active diastereoisomers and enantiomers may be useful, e.g., for scientific studies relating to the receptor and the mechanism of activation.

[0151] It is understood that certain molecules can exist in multiple tautomeric forms. This disclosure includes all tautomers even though only one tautomer may be indicated in the examples.

[0152] The disclosure also includes pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions including the compounds and a pharmaceutically acceptable carrier. The compounds are especially useful, e.g., in certain kinds of cancer and for slowing the progression of cancer once it has developed in a patient.

[0153] The compounds disclosed herein may be used in pharmaceutical compositions including (a) the compound(s) or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier. The compounds may be used in pharmaceutical compositions that include one or more other active pharmaceutical ingredients. The compounds may also be used in pharmaceutical compositions in which the compound disclosed herein or a pharmaceutically acceptable salt thereof is the only active ingredient.

[0154] Optical Isomers - Diastereomers - Geometric Isomers - Tautomers

[0155] Compounds disclosed herein may contain, e.g., one or more stereogenic centers and can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, and mixtures of diastereomers and / or enantiomers. The disclosure includes all such isomeric forms of the compounds disclosed herein. It is intended that all possible stereoisomers (e.g., enantiomers and / or diastereomers) in mixtures and as pure or partially purified compounds are included within the scope of this disclosure (i.e. , all possible combinations of the stereogenic centers as pure compounds or in mixtures).

[0156] Some of the compounds described herein may contain bonds with hindered rotation such that two separate rotomers, or atropisomers, may be separated and found to have different biological activity which may be advantageous. It is intended that all of the possible atropisomers are included within the scope of this disclosure. Some of the compounds described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

[0157] Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. An example is a ketone and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed by the disclosure.

[0158] Compounds disclosed herein having one or more asymmetric centers may be separated into diastereoisomers, enantiomers, and the like by methods well known in the art.

[0159] Alternatively, enantiomers and other compounds with chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and / or reagents of known configuration.

[0160] Pharmaceutically Acceptable Salts

[0161] The disclosure also includes pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions including the compounds (e.g., without limitations, camonsertib) and a pharmaceutically acceptable carrier. The disclosure provides pharmaceutically acceptable salts of various compounds disclosed herein. In embodiments, camonsertib is presented in the form of a pharmaceutically acceptable salt. In embodiments, camonsertib is presented in the form of a hydrogen sulfate salt. Although camonsertib may be effective in various forms (including, without limitations, as a free base), it may in practice be administered in the form of a salt of a pharmaceutically acceptable acid or base. In embodiments, the salt form is a hydrogen sulfate salt form or a phosphate salt form. In embodiments, the hydrogen sulfate salt form of camonsertib is significantly more effective than other known forms. In embodiments, the hydrogen sulfate salt form of Camonsertib is significantly more effective than the free base form. The hydrogen sulfate salt form of Camonsertib is previously described as example 121 in U.S. Patent Application Publication No. 2024 / 0294521 , the salt forms of which are incorporated by reference herein. In embodiments, the phosphate salt form of camonsertib is significantly more effective than other known forms. In embodiments, the phosphate salt form of camonsertib is significantly more effective than the free base form. The phosphate salt form of camonsertib is previously described in International Application Publication No. WO 2024 / 123932, the salt forms of which are incorporated by reference.

[0162] Metabolites - Prodrugs

[0163] The disclosure includes therapeutically active metabolites, where the metabolites themselves fall within the scope of the claims. The disclosure also includes prodrugs, which are compounds that are converted to the claimed compounds as they are being administered to a patient or after they have been administered to a patient. The claimed chemical structures of this application in some cases may themselves be prodrugs.

[0164] Isotopically Enriched Derivatives

[0165] The disclosure includes molecules which have been isotopically enriched at one or more position within the molecule. Thus, compounds enriched for deuterium fall within the scope of the claims. Radioligand Therapy

[0166] Radioligand therapy refers to a radiotherapy wherein the ionizing radiation is provided from a radioactive nucleus (i.e., a radionuclide) or a molecule thereof (comprising a radionuclide bound to a ligand molecule). As the radioligand undergoes radioactive decay, ionizing radiation in the form of radioparticles (e.g., a-particles or p-particles) For example, the radiotherapy may include contacting cancerous tissue with a radioligand. In some embodiments, the radioligand includes a radionuclide (i.e., an atom or ion which undergoes radioactive decay). In some embodiments, the radionuclide may be, e.g., an a-emitting radionuclide (i.e., a radionuclide which emits an a particle during radioactive decay). Exemplary a-emitting radionuclides include, e.g.,211At,212Bi,213Bi,225Ac, etc. In some embodiments, a radionuclide may be a p-emitting radionuclide (i.e., a radionuclide which emits an a particle during radioactive decay). Exemplary p-emitting radionuclides include, e.g.,32P,33P,177Lu,67Cu,89Sr,90Y,131l,165Dy,166Ho,186Re,188Re, etc.

[0167] Radioligands may further include a ligand. The ligand may modify the solubility of the radioligand, modify the chemical stability of the radioligand, or enable targeted delivery of the radioligand. A ligand may include a chelating moiety which binds the radioligand. Exemplary chelating moieties include, e.g., e.g., diethylenetriaminepentaacetate (DTPA), 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetate (DOTA), ethylenediamine tetraacetate (EDTA), cis-1 ,3,5-cyclohexantriamine (CHTA), triethylene glycol diamine tetraacetate (EGTA), 1 ,4,8,11 -tetraazacyclotetradecane-1 ,4,8,1 1 -tetraacetate (TETA), 1 ,4,7,10- tetraazacyclododecane-1 ,4,7-triacetate (DO3A), 1 ,4,7-triazacyclononane-1 ,4,7-triacetate (NOTA), 1 ,4,7,10,13,16-hexaazacyclooctadecane-1 ,4,7,10,13,16-hexaacetate (HEHA), N,N’-[(6-carboxy-2- pyridyl(methyl)]-4,13-diaza-18-crown-6 (MACROPA), 1 ,4,7,10-tetraazacyclododecane-1 ,7-diacetate (DO2A), 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic amide (DOTAM), or ethylenediaminetetramethylenephosphonic acid (EDTMP). A ligand may further include a targeting moiety configured to localize the radioligand to cancerous tissue. Exemplary cell-targeting moieties include, e.g., internal receptors, cell-surface receptors, ion-channel receptors, G-Protein coupled receptors, enzyme linked receptors, integrins, phosphonic acid, etc.

[0168] Exemplary radioligands of the present disclosure include "Y-ibritumomab tiuxetan, (ZEVALIN®; formula R1), Lutetium (177Lu) oxodotreotide (177Lu-dotatate; LUTATHERA®; formula (R2))

[0169] 177Lu-vipivotide tetraxetan (PLUVICTO®; Formula (R4)) 212Pb-Dotamtate (ALPHAMEDICX®); (R5))

[0170]

[0171] AAA604, AAA617, AAA817, RYZ801 , RYZ811 , or MC-399. Preferably, the radioligand is177Lu vipivotide tetraxetan.

[0172] 90Y-ibritumomab tiuxetan may be used in the treatment of, e.g., B-cell non-Hodgkin lymphoma (e.g., relapsed or refractory, low-grade or follicular B-cell non-Hodgkin lymphoma, or previously untreated follicular non-Hodgkin lymphoma who achieve a partial or complete response to first-line chemotherapy).177Lu-dotatate may be used in the treatment of, e.g., somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors or unresectable or metastatic progressive well differentiated (G1 and G2) somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (e.g., forgut, midgut, or hindgut neuroendocrine tumors). 131 -iobenguane may be used in the treatment of tumors of the adrenal gland (e.g., pheochromocytomas or paragangliomas; e.g., unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma in patients who require systematic anticancer therapy).177Lu-vipivotide tetraxetan may be used in the treatment of prostate-specific membrane antigen (PSMA) positive metastatic castration-resistant prostate cancers (mCRPC) which have been treated with androgen receptor (AR) pathway inhibition and taxan-based chemotherapy.212Pb- Dotamtate may be used in treatments of inoperable or metastatic, progressive SSTR-expressing GEP- NETs, who have not received treatment with a peptide receptor radionuclide therapy (PPRT).

[0173] 177Lu-NeoB may be used in treatments of patients with advanced solid tumors known to overexpress Gastin-Releasing Peptide Receptor (GRPR) and with 68Ga-NeoN lesion uptake.177Lu PSMA-R2 may be used in the treatment of prostate-specific membrane antigen (PSMA) positive prostate cancers. BAY3563254 may be used in the treatment of prostate-specific membrane antigen (PSMA) positive metastatic castration-resistant prostate cancers (mCRPC). 177Lu-PNT2002 metastatic castration-resistant prostate cancers (mCRPC). RYZ101 may be used in the treatment of advanced metastatic neuroendocrine tumors.212Pb-NG001 metastatic castration-resistant prostate cancers (mCRPC). AAA604 may be used in the treatment of multiple solid tumors including pancreatic cancer. AAA617 may be used in the treatment of metastatic hormone selective prostate cancer (mHSPC), oligometastatic prostate cancer, or metastatic castration-resistant prostate (mCRPC) pre-taxane. AAA817 may be used in the treatment of metastatic castration-resistant prostate cancer. RYZ801 may be used in the treatment of a hepatocellular carcinoma. RYZ811 may be used in the treatment of a hepatocellular carcinoma. MC-399 may be used in the treatment of small cell lung cancer. In some embodiments, the radioligand therapy may be a bone directed therapy. Exemplary radioligands for a bone directed therapy include, e.g.117Sn-DTPA,177Lu-EDTMP,153Sm-EDTMP,188Re- HEDP, a33P-phosphate salt (e.g., Na233PO4), or223Ra-chloride.

[0174] Radioligand-Containing PSMA Targeting Agent

[0175] Preferably, the present disclosure relates to radionuclide-containing PSMA targeting agents. In some embodiments, the radionuclide-containing PSMA Targeting Agent used in the combination therapies disclosed herein is177Lu vipivotide tetraxetan (PLUVICTO®). vipivotide tetraxetan has been approved to treat mCRPC, and is marketed as PLUVICTO®, see prescribing information in Novartis PLUVICTO® package insert revised 3 / 2025.

[0176] Methods of Use

[0177] ATR inhibitors and177Lu vipivotide tetraxetan may be used together for the treatment of a disease or condition having the symptom of cell hyperproliferation. For example, the disclosure described herein may be applicable for treatment of various oncological conditions having an over-expression of PSMA such as, for example, renal cancer, bladder cancer, testicular cancer, prostate cancer, pancreatic cancer, colorectal cancer, and breast cancer. Accordingly, methods of the disclosure are preferably used in the treatment of these cancers. In any and every aspect of the disclosure herein wherein a method of treatment is described, the equivalent use of the compound(s) in treatment, and use of the compound(s) in manufacture of a medicament for treatment use and treatment are contemplated. A combination of an ATR inhibitor and177Lu vipivotide tetraxetan for use in damaging the DNA of cells with an overexpression of PSMA and subsequently preventing the cells from repairing the DNA damage, thus resulting in cell death, is contemplated. Additionally, a combination of an ATR inhibitor and177Lu vipivotide tetraxetan for use in damaging the DNA of cells with an overexpression of PSMA may be used in the manufacture of a medicament for use in damaging the DNA of cells with an overexpression of PSMA and subsequently preventing the cells from repairing the DNA damage, thus resulting in cell death, is contemplated.

[0178] Therapeutic methods of the disclosure include the step of administering a therapeutically effective amount of a combination of an ATR inhibitor and177Lu vipivotide tetraxetan (PLUVICTO®) to a subject in need thereof. The amount of an ATR inhibitor may be, e.g., a subtherapeutic regimen of an ATR inhibitor versus when the ATR inhibitor is used as a monotherapy.

[0179] The disease or condition treated using methods of the disclosure may have the symptom of cell hyperproliferation. For example, the disease or condition may be a cancer. The cancer may be prostate cancer. The prostate cancer may be PSMA-positive metastatic castration-resistant prostate cancer.

[0180] Pharmaceutical Compositions

[0181] The compounds used in the methods described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions typically include a compound as described herein and a pharmaceutically acceptable excipient. Certain pharmaceutical compositions may include one or more additional pharmaceutically active agents described herein.

[0182] The compounds described herein can also be used in the form of the free base, in the form of salts, zwitterions, solvates, or as prodrugs, or pharmaceutical compositions thereof. All forms are within the scope of the disclosure. The compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions thereof, may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds used in the methods described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0183] For human use, a compound of the disclosure can be administered alone or in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present disclosure thus can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of a compound of the disclosure into preparations which can be used pharmaceutically.

[0184] This disclosure also includes pharmaceutical compositions which can contain one or more pharmaceutically acceptable carriers. In making the pharmaceutical compositions of the disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material (e.g., normal saline), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules. As is known in the art, the type of diluent can vary depending upon the intended route of administration. The resulting compositions can include additional agents, e.g., preservatives.

[0185] The excipient or carrier is selected on the basis of the mode and route of administration. Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP / NF (United States Pharmacopeia and the National Formulary). Examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents, e.g., talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents, e.g., methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6th Edition, Rowe et al., Eds., Pharmaceutical Press (2009).

[0186] These pharmaceutical compositions can be manufactured in a conventional manner, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Methods well known in the art for making formulations are found, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York. Proper formulation is dependent upon the route of administration chosen. The formulation and preparation of such compositions is well-known to those skilled in the art of pharmaceutical formulation. In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., 40 mesh.

[0187] Dosages

[0188] The dosage of the compound used in the methods described herein, or pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions thereof, can vary depending on many factors, e.g., the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds used in the methods described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, a suitable daily dose of a compound of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. An ATR inhibitor may be administered to the patient in a single dose or in multiple doses. When multiple doses are administered, the doses may be separated from one another by, for example, 1 -24 hours, 1-7 days, 1-4 weeks, or 1-12 months. The compound may be administered according to a schedule or the compound may be administered without a predetermined schedule. An active compound may be administered, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 times per day, every 2nd, 3rd, 4th, 5th, or 6th day, 1 , 2, 3, 4, 5, 6, or 7 times per week, 1 , 2, 3, 4, 5, or 6 times per month, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 times per year. It is to be understood that, for any particular subject, specific dosage regimes should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0189] While the attending physician ultimately will decide the appropriate amount and dosage regimen of the ATR inhibitor, an effective amount of a compound of the disclosure may be, for example, a total daily dosage of, e.g., between 0.05 mg and 3000 mg of any of the compounds described herein. Alternatively, the dosage amount can be calculated using the body weight of the patient. Such dose ranges may include, for example, between 0.05-1000 mg (e.g., 0.25-800 mg). In some embodiments, 0.05, 0.1 , 0.25, 0.5, 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered.

[0190] Preferably, the subtherapeutic regimen of an ATR inhibitor is a low dosage (e.g., at least 10%, 20%, 50%, 80%, 90%, or 95% less than the lowest standard recommended dosage of the ATR inhibitor for a given route of administration).

[0191] The ATR inhibitor may be administered once daily, 1 day / week, 2 days / week, 3 days / week, or 4 days / week. Preferably, the ATR inhibitor is administered once daily or twice daily.

[0192] In the methods of the disclosure, the time period during which multiple doses of a compound of the disclosure are administered to a patient can vary. For example, in some embodiments, doses of the compounds of the disclosure are administered to a patient over a time period that is 1-7 days; 1-12 weeks; or 1-3 months. In other embodiments, the compounds are administered to the patient over a time period that is, for example, 4-11 months or 1-30 years. In other embodiments, the compounds are administered to a patient at the onset of symptoms. In any of these embodiments, the amount of compound that is administered may vary during the time period of administration. When a compound is administered daily, administration may occur, for example, 1 , 2, or 3 times per day.

[0193] Each therapeutic agent in a combination therapy of the disclosure may be administered either alone or in a medicament (may also referred to herein as a pharmaceutical composition) which comprises the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients and diluents, according to standard pharmaceutical practice.

[0194] Each therapeutic agent in a combination therapy of the disclosure may be administered simultaneously (i.e. , in the same medicament), concurrently (i.e. , in separate medicaments administered one right after the other in any order) or sequentially in any order. Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (one agent is a tablet or capsule and another agent is a sterile liquid) and / or are administered on different dosing schedules, e.g., a chemotherapeutic that is administered at least daily and a biotherapeutic that is administered less frequently, such as once weekly, once every two weeks, or once every three weeks and / or are administered to different parts of the body, e.g., one therapeutic agent is administered intratumorally and one therapeutic agent is administered systemically.

[0195] In some embodiments, camonsertib is administered at a dose of 120 mg orally daily at a frequency of 3 days on, 4 days off per week for weeks 1 , 2, 4, and 5 for a 6 week cycle - i.e., on days 1 , 2, 3, 8, 9, 10, 22, 23, 24, 29, 30, 31 of a 6 week cycle. In some embodiments, camonsertib is administered at a dose of 120 mg orally daily at a frequency of 2 days on, 5 days off per week for weeks 1 , 2, 4, and 5 for a 6 week cycle - i.e., days 1 , 2, 8, 9, 22, 23, 29, and 30 of a 6 week cycle. In some embodiments, camonsertib is administered at a dose of 160 mg orally daily at a frequency of 3 days on, 4 days off per week for weeks 1 , 2, 4, and 5 for a 6 week cycle - i.e., days 1 , 2, 3, 8, 9, 10, 22, 23, 24, 29, 30, and 31 of a 6 week cycle.

[0196] Camonsertib may be self-administered by patients orally (PO) with a 3 days on / 4 days off and 2 weeks on / 1 week off schedule (i.e., Days 1 -3 [Week 1], Days 8-10 [Week 2], Days 22-24 [Week 4], Days 29-31 [Week 5] of each 6-week cycle) for up to 7 cycles. The starting dose of camonsertib is 50 mg per day, and this may be escalated to 80 mg per day, 120 mg per day, and 160 mg per day. The starting dose of camonsertib is about 30% RP2D of the monotherapy and this dose may be escalated to about 50%, about 75%, or about 100% RP2D of the monotherapy. An alternative camonsertib schedule may be explored based on emerging data. The dose of camonsertib can be reduced up to two times for management of drug-related toxicities, and treatment may be temporarily interrupted to manage drug- related toxicities.

[0197] 177Lu vipivotide tetraxetan, sometimes referred to herein as177Lu-PSMA, (7.4 GBq [200 mCi]) will be administered intravenously, as 1 ,000 MBq / ml (27 mCi / ml), in accordance with the local prescribing information (e.g., for PLUVICTO®) and institutional guidelines on Day 1 of each 6-week cycle for up to 6 cycles. The dose of177Lu vipivotide tetraxetan can be reduced once for management of drug-related toxicities, and treatment may be temporarily interrupted to manage drug-related toxicities.

[0198] Dose escalations for camonsertib will follow a Bayessian Optimal Interval (BOIN) design .

[0199] Bayesian Optimal Interval (BOIN) designs are a class of model-assisted dose-finding designs that can be used in oncology trials to determine the maximum tolerated dose (MTD) of a study drug based on safety or the optimal biological dose (OBD) based on safety and efficacy. BOIN designs provide a complete suite for dose finding in early phase trials, as well as a consistent way to explore different scenarios such as toxicity, efficacy, continuous outcomes, delayed toxicity or efficacy and drug combinations in a unified manner with easy access to software to implement most of these designs. Although built upon Bayesian probability models, BOIN designs are operationally simple in general and have good statistical operating characteristics compared to other dose-finding designs. The present study uses an accelerated titration for Dose Level 1 (50 mg) and Dose Level 2 (80 mg) to minimize the exposure of participants at low camonsertib doses. The highest dose of camonsertib in combination with177Lu vipivotide tetraxetan will not exceed 160 mg QD (monotherapy RP2D). Dose escalation may be completed before reaching the Maximum Tolerated Dose (MTD). The Maximum Administered Dosage (MAD) will be defined as the highest dose of camonsertib administered in combination with approved177Lu vipivotide tetraxetan dose. The total duration of study participation for each individual is expected to be approximately 36 months.

[0200] While not wishing to be bound by theory, it is envisaged that fewer instances of hematological toxicity will be observed from administration of the combination of the present disclosure than have been reported from administration of either a monotherapy of camonsertib or a monotherapy of177Lu vipivotide tetraxetan as at least camonsertib will be administered as a reduced amount than when administered as a monotherapy.

[0201] Routes of Administration

[0202] A compound identified as capable of treating any of the conditions described herein, using any of the methods described herein, may be administered to patients or animals with a pharmaceutically- acceptable diluent, carrier, or excipient, in unit dosage form. The chemical compounds for use in such therapies may be produced and isolated by any standard technique known to those in the field of medicinal chemistry. Conventional pharmaceutical practice may be employed to provide suitable compositions to administer the identified compound to subjects in need thereof. Administration may begin before the patient is symptomatic.

[0203] Exemplary routes of administration of the compounds (e.g., a compound of the disclosure), or pharmaceutical compositions thereof, used in the present disclosure include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. The compounds desirably are administered with a pharmaceutically acceptable carrier. Pharmaceutical compositions of the compounds described herein formulated for treatment of the disorders described herein are also part of the present disclosure. Oral administration is a preferred route of administration in the methods of the disclosure.

[0204] Compositions for Oral Administration

[0205] The pharmaceutical compositions contemplated by the disclosure include those formulated for oral administration (“oral dosage forms”). Oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0206] Compositions for oral administration may also be presented as chewable tablets, as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

[0207] Controlled release compositions for oral use may be constructed to release the active drug by controlling the dissolution and / or the diffusion of the active drug substance. Any of a number of strategies can be pursued in order to obtain controlled release and the targeted plasma concentration versus time profile. In one example, controlled release is obtained by appropriate selection of various composition parameters and ingredients, including, e.g., various types of controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. In certain embodiments, compositions include biodegradable, pH, and / or temperature-sensitive polymer coatings.

[0208] Dissolution- or diffusion- controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate composition of compounds, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and / or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl- polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1 ,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbon.

[0209] The liquid forms in which the compounds and compositions of the present disclosure can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0210] Compositions for Parenteral Administration

[0211] The compounds described herein for use in the methods of the disclosure can be administered in a pharmaceutically acceptable parenteral (e.g., intravenous or intramuscular) composition as described herein. The pharmaceutical composition may also be administered parenterally (intravenous, intramuscular, subcutaneous or the like) in dosage forms or compositions containing conventional, nontoxic pharmaceutically acceptable carriers and adjuvants. In particular, compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. For example, to prepare such a composition, the compounds of the disclosure may be dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1 ,3-butanediol, Ringer’s solution and isotonic sodium chloride solution. The aqueous composition may also contain one or more preservatives, for example, methyl, ethyl, or n-propyl p-hydroxybenzoate. Additional information regarding parenteral compositions can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), herein incorporated by reference.

[0212] The parenteral composition can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration:

[0213] (1) “Drug Injection:” a liquid preparation that is a drug substance (e.g., a compound of the disclosure), or a solution thereof;

[0214] (2) “Drug for Injection:” the drug substance (e.g., a compound of the disclosure) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injection;

[0215] (3) “Drug Injectable Emulsion:” a liquid preparation of the drug substance (e.g., a compound of the disclosure) that is dissolved or dispersed in a suitable emulsion medium;

[0216] (4) “Drug Injectable Suspension:” a liquid preparation of the drug substance (e.g., a compound of the disclosure) suspended in a suitable liquid medium; and

[0217] (5) “Drug for Injectable Suspension:” the drug substance (e.g., a compound of the disclosure) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injectable suspension.

[0218] Exemplary compositions for parenteral administration include solutions of the compound prepared in water suitably mixed with a surfactant, e.g., hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[0219] Compositions for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols, e.g., polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Biocompatible, biodegradable lactide polymer, lactide / glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Compositions for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.

[0220] The parenteral composition can be formulated for prompt release or for sustained / extended release of the compound. Exemplary compositions for parenteral release of the compound include: aqueous solutions, powders for reconstitution, cosolvent solutions, oil / water emulsions, suspensions, oilbased solutions, liposomes, microspheres, and polymeric gels.

[0221] The following examples are meant to illustrate the disclosure. They are not meant to limit the disclosure in any way.

[0222] EXAMPLES

[0223] Example 1 : Synergy between ATR inhibitors and177Lu vipivotide tetraxetan in patents with and without various prostate cancer genetic alterations

[0224] Camonsertib may synergize with177Lu vipivotide tetraxetan in metastatic prostate cancer patients with and without genetic alterations (e.g., DNA damage genetic changes).

[0225] 177Lu vipivotide tetraxetan can cause DNA damage to metastatic prostate cancer cells. An ATR inhibitor can prevent the prostate cancer cell from repairing the DNA damage, resulting in tumor cell death. In the absence of the ATR inhibitor, a tumor cell still may be able to survive and produce more tumor cells because of its mutated genetic sequence. The combination of177Lu vipivotide tetraxetan with an ATR inhibitor can improve the tumor response rate to either therapy given alone. This enhanced effect of the combination may exist regardless of the presence of DNA damage repair mutations. In essence,177Lu vipivotide tetraxetan can create the genetic mutation, making the tumor more susceptible to the ATR inhibitor.

[0226] Tolerability of the combination treatment with an ATR inhibitor and177Lu vipivotide tetraxetan can be improved by optimizing dosing schedules, such as those in the following table. Based on the above, tumor cells regardless of their specific genetic makeup, can be treated with177Lu vipivotide tetraxetan and ATR inhibitors, exhibiting augmented efficacy.

[0227] Example 2: Phase Ib / ll study of Camonsertib in combination with177Lu Vipivotide Tetraxetan

[0228] The purpose of this substudy is to assess the safety, efficacy, and pharmacokinetics of camonsertib in combination with lutetium177Lu vipivotide tetraxetan (also referred to herein as177Lu- PSMA) and to determine the recommended Phase II dose for further development of the combination in patients with metastatic castration-resistant prostate cancer (mCRPC). This Phase Ib / ll multicenter, open-label substudy will investigate the safety, efficacy, and pharmacokinetics of camonsertib in combination with177Lu-PSMA in patients with mCRPC who have received at least one line of prior therapy with a second-generation androgen receptor signaling inhibitor.

[0229] The Phase lb dose-escalation part of the substudy will evaluate the safety, tolerability, and pharmacokinetics and determine the maximum tolerated dose / maximum administered dose and schedule of camonsertib in combination with177Lu-PSMA. The Phase lb dose-expansion part of the substudy will further evaluate the safety, tolerability, and efficacy of the study treatment combination and the pharmacokinetics of camonsertib.

[0230] The investigational medicinal products for this study are camonsertib and177Lu-PSMA. Camonsertib will be self-administered by participants orally (PO) at home (except on clinic days) with a 3 days on / 4 days off and 2 weeks on / 1 week off schedule (i.e., Days 1 -3 [Week 1], Days 8-10 [Week 2], Days 22-24 [Week 4], Days 29-31 [Week 5] of each 6-week cycle) for up to 7 cycles. The starting dose of camonsertib is 50 mg per day, and this may be escalated to 80 mg per day, 120 mg per day, and 160 mg per day. An alternative camonsertib schedule may be explored based on emerging data. The dose of camonsertib can be reduced up to two times for management of drug-related toxicities, and treatment may be temporarily interrupted to manage drug-related toxicities.

[0231] 177Lu-PSMA (7.4 GBq [200 mCi]) will be administered intravenously, as 1 ,000 MBq / ml (27 mCi / ml), in accordance with the local prescribing information and institutional guidelines on Day 1 of each 6-week cycle for up to 6 cycles. The dose of177Lu-PSMA can be reduced once for management of drug- related toxicities, and treatment may be temporarily interrupted to manage drug-related toxicities.

[0232] Dose escalations for camonsertib will follow a Bayessian Optimal Interval (BOIN) design .

[0233] Bayesian Optimal Interval (BOIN) designs are a class of model-assisted dose-finding designs that can be used in oncology trials to determine the maximum tolerated dose (MTD) of a study drug based on safety or the optimal biological dose (OBD) based on safety and efficacy. BOIN designs provide a complete suite for dose finding in early phase trials, as well as a consistent way to explore different scenarios such as toxicity, efficacy, continuous outcomes, delayed toxicity or efficacy and drug combinations in a unified manner with easy access to software to implement most of these designs. Although built upon Bayesian probability models, BOIN designs are operationally simple in general and have good statistical operating characteristics compared to other dose-finding designs. The present study uses an accelerated titration for Dose Level 1 (50 mg) and Dose Level 2 (80 mg) to minimize the exposure of participants at low camonsertib doses. The highest dose of camonsertib in combination with177Lu-PSMA will not exceed 160 mg QD. Dose escalation may be completed before reaching the Maximum Tolerated Dose (MTD). The Maximum Administered Dosage (MAD) will be defined as the highest dose of camonsertib administered in combination with approved177Lu-PSMA dose.

[0234] The total duration of study participation for each individual is expected to be approximately 36 months.

[0235] Inclusion criteria include:

[0236] Adenocarcinoma of the prostate without small-cell or neuroendocrine features

[0237] Surgical or ongoing medical castration with testosterone serum levels <50 ng / dL (1 .7 nM). Progression of mCRPC, defined as:

[0238] (a) PSA progression, defined by a minimum of two rising PSA values from three consecutive assessments with an interval of at least 7 days between assessments, and a PSA value of > 1 ng / mL.

[0239] (b) soft tissue disease progression, defined by RECIST 1 .1 .

[0240] (c) bone disease progression, defined by Prostate Cancer Working Group 2 (PCWG3) criteria, with two or more new metastatic bone lesions on a whole-body radionuclide bone scan.

[0241] At least one but no more than two prior lines of second-generation AR-targeted therapy.

[0242] Prior docetaxel or PARPi therapy is allowed.

[0243] Exclusion criteria include:

[0244] Prior treatment with ATRi or DNA-dependent protein kinase inhibitor.

[0245] More than one prior chemotherapy treatment for mCRPC or hormone-sensitive prostate cancer.

[0246] Example 3: Combination Therapy Using an ATR Inhibitor and a Radioligand

[0247] A subject is identified as in need of treatment for a disease or disorder (e.g., cancer). For example, the subject may have gastrointestinal cancer, stomach cancer, colorectal cancer, pancreatic cancer, neuroendocrine cancer, prostate cancer, breast cancer, lung cancer, bladder cancer, or lymphoma. The subject may have one or more tumors (e.g., a pancreatic neuroendocrine tumor a pheochromocytoma, a somatostatinoma, a carcinoid tumor, a neuroendocrine carcinoma, a gastrinoma, a merkel-cell carcinoma, a medullary carcinoma, a glucagonoma, an insulinoma, paraganglioma, adrenal cancer, appendiceal neuroendocrine tumor, a bronchopulmonary neuroendocrine tumor, a multiple endocrine neoplasia type 1 tumor, a pituitary gland tumor, a thymus tumor, etc.).

[0248] The subject is then administered an ATR inhibitor (e.g., an ATR inhibitor selected from any compounds 1 to 152, e.g., compound 121 , or a salt thereof) and a radioligand therapy. The radioligand therapy may include administering a bone-directed agent (e.g.,117Sn-DTPA, sodium33P-phosphate,188Re-HEDP,177Lu-EDTMP,153Sm-EDTMP and223Ra-chloride). The radioligand therapy may include administering a radioligand including a radionuclide (e.g., an a-emitting radionuclides (e.g.,211At,212Bi,213Bi,225Ac, etc.) or a p-emitting radionuclide (e.g.,32P,33P,177Lu,67Cu,89Sr,90Y,131l,165Dy,166Ho,186Re,188Re, etc.)) conjugated to a ligand. The ligand includes a chelating moiety (e.g., DTPA, DOTA, EDTA, CHTA, EGTA, TETA, DO3A, NOTA, HEHA, MACROPA, DO2A, DOTAM, etc.) and a targeting moiety (e.g., internal receptors, cell-surface receptors, ion-channel receptors, G-Protein coupled receptors, enzyme linked receptors, integrins, phosphonic acid etc.). The radioligand may be, e.g., "Y-ibritumomab tiuxetan,177Lu-DOTATATE (e.g., LUTATHERA®),225Ac-pelgifatamab,131l-lobenguane,212Pb-Dotamate,77Lu-NeoB, AAA604, AAA614, AAA617, AAA802, AAA817, BAY 3563254, LNTH-1558, LNTH-1095, PNT-2003, PNT-2002, RYZ101 , RYZ801 , RYZ811 ,212Pb-NG001 , MC-339, or177Lu-vipivotide tetraxetan. Preferably, the radioligand is177Lu-vipivotide tetraxetan.

[0249] Treatment with the combination therapy may treat the disease or disorder (e.g., cancer) in the subject. For example, a tumor in the subject may decrease in size after the subject is administered the combination therapy. Enumerated Embodiments

[0250] E1 . A combination for use in treating a cancer that has an over-expression of PSMA on its cell membranes, wherein the combination comprises

[0251] (i) a therapeutically effective amount of an ATR inhibitor, wherein the ATR inhibitor is camonsertib or a pharmaceutically acceptable salt thereof; and

[0252] (ii) a therapeutically effective amount of177Lu vipivotide tetraxetan.

[0253] E2. A method of treating a cancer that has an over-expression of PSMA on its cell membranes in a subject suffering therefrom comprising administering to the subject a therapeutically effective amount of camonsertib or pharmaceutically acceptable salt and a therapeutically effective amount of177Lu vipivotide tetraxetan.

[0254] E3. A method of treating a cancer in a subject in need thereof, the method comprising:

[0255] (i) identifying a subject having a cancer having an over-expression of PSMA on its cell membrane; and

[0256] (ii) administering to the subject in need thereof a therapeutically effective amount of a combination of an ATR inhibitor and177Lu vipivotide tetraxetan, wherein the ATR inhibitor is camonsertib or a pharmaceutically acceptable salt thereof.

[0257] E4. The combination for use or method of any one of embodiments E1 to E3, wherein camonsertib is administered as camonsertib hydrogen sulfate salt.

[0258] E5. The combination for use or method of any one of embodiments E1 to E4, wherein the therapeutically effective amount comprises a subtherapeutic regimen of the ATR inhibitor.

[0259] E6. The combination for use or method of embodiment E5, wherein the subtherapeutic regimen comprises a starting dosage that is at least 50% less than the lowest standard starting dosage that is used for a monotherapy.

[0260] E7. The combination for use or method of embodiment E5 or E6, wherein the subtherapeutic regimen comprises a maintenance dosage that is at least 50% less than the lowest standard maintenance dosage that is used for a monotherapy.

[0261] E8. The combination for use or method of embodiment E7, wherein the maintenance dosage of the subtherapeutic regimen comprises a first reduced dosage that is at least 50% less than the lowest standard maintenance dosage that is used for a monotherapy. E9. The combination for use or method of embodiment E7 or E8, wherein the maintenance dosage of the subtherapeutic regimen comprises a second reduced dosage that is at least 60% less than the lowest standard maintenance dosage that is used for a monotherapy.

[0262] E10. The combination for use or method of any one of embodiments E8 to E10, wherein the maintenance dosage of the subtherapeutic regimen comprises a third reduced dosage that is at least 70% less than the lowest standard maintenance dosage that is used for a monotherapy.

[0263] E11. The combination for use or method of any one of embodiments E1 to E10, wherein the ATR inhibitor is orally administered.

[0264] E12. The combination for use or method of any one of embodiments E1 to E11 , wherein the ATR inhibitor is administered 1 day / week, 2 days / week, or 3 days / week.

[0265] E13. The combination for use or method of any one of embodiments E1 to E12, wherein the ATR inhibitor is administered on days 1 , 2, 3, 8, 9, 10, 22, 23, 24, 29, 30, and 31 of a 6-week cycle.

[0266] E14. The combination for use or method of any one of embodiments E1 to E13, wherein the ATR inhibitor is administered at a total daily dose of 50 mg.

[0267] E15. The combination for use or method of any one of embodiments E1 to E13, wherein the ATR inhibitor is administered at a total daily dose of 80 mg.

[0268] E16. The combination for use or method of any one of embodiments E1 to E13, wherein the ATR inhibitor is administered at a total daily dose of 120 mg.

[0269] E17. The combination for use or method of any one of embodiments E1 to E13, wherein the ATR inhibitor is administered at a total daily dose of 160 mg.

[0270] E18. The method of any one of embodiments E1 to E17, wherein177Lu vipivotide tetraxetan is administered on day 1 of a 6-week cycle.

[0271] E19. The combination for use or method of any one of embodiments E1 to E18, wherein177Lu vipivotide tetraxetan is administered intravenously at a dose of 7.4 GBq (200 mCi).

[0272] E20. The combination for use or method of any one of embodiments E1 to E19, wherein the subject has received at least one prior line of therapy for the cancer having an over-expression of PSMA on its cell membrane. E21 . The combination for use or method of embodiments E20, wherein at least one prior line of therapy comprised an AR targeted therapy.

[0273] E22. The combination for use or method of any one of embodiments E1 to E21 , wherein the cancer is metastatic castration resistant prostate cancer (mCRPC).

[0274] E23. A method of inducing cell death in aberrant cancer cells having an over-expression of PSMA on their cell membranes, the method comprising contacting the cell with an effective amount of a combination of an ATR inhibitor and177Lu vipivotide tetraxetan, the effective amount being sufficient to induce cell death in the aberrant cancer cell, wherein the ATR inhibitor is camonsertib or a pharmaceutically acceptable salt thereof.

[0275] E24. The method of embodiment E23, wherein the ATR inhibitor is camonsertib hydrogen sulfate salt.

[0276] E25. A method of treating a cancer in a subject having a cancer that has an over-expression of PSMA on its cell membranes, comprising: administering a therapeutic combination, wherein the therapeutic combination comprises

[0277] (i) a therapeutically effective amount of an ATR inhibitor, wherein the ATR inhibitor is camonsertib or a pharmaceutically acceptable salt thereof; and

[0278] (ii) a therapeutically effective amount of177Lu vipivotide tetraxetan.

[0279] E26. The method of embodiment E25, wherein the ATR inhibitor is administered in a daily dose of 50 mg to 160 mg.

[0280] E27. The method of embodiment E26, wherein the daily dose of the ATR inhibitor is 50 mg, 80 mg, 120 mg, or 160 mg.

[0281] E28. The method of embodiment E27, wherein the ATR inhibitor is administered in a daily dose of 120 mg.

[0282] E29. The method of any one of embodiments E25 to E28, wherein the ATR inhibitor is administered on days 1 , 2, 3, 8, 9, 10, 22, 23, 24, 29, 30, and 31 of a 6-week cycle.

[0283] E30. The method of any one of embodiments E25 to E29, wherein177Lu vipivotide tetraxetan is administered intravenously in a dose of 7.4 GBq.

[0284] E31 . The method of any one of embodiments E25 to E30, wherein177Lu vipivotide tetraxetan is administered on day 1 of a 6-week cycle.

[0285] □□ E32. The method of any one of embodiments E25 to E31 , wherein the subject has one or more DDR pathway mutations.

[0286] E33. The method of embodiment E32, wherein the DDR pathway mutation comprises one or more of: oncogenic mutations; dysfunctional G1 / S checkpoint control; (e.g., loss of p53 function); defects in other DNA repair pathways (e.g., ATM) and that are subject to the effects of DNA damaging agents, e.g., radioligand therapy or chemotherapeutic agents.

[0287] E34. The method of embodiment E33, wherein the dysfunctional G1 / S checkpoint is a loss of p53 function.

[0288] E35. The method of embodiment E33, wherein the defect in other DNA repair pathways is ATM.

[0289] E36. The method of embodiment E33, wherein the DNA damaging agent comprises radioligand, chemotherapeutic agents, or combinations thereof.

[0290] E37. The method of any one of embodiment E25 to E31 , wherein the subject is free of DDR pathway mutations.

[0291] E38. The method of any one of embodiments E25 to E37, wherein the therapeutically effective dose of the therapeutic combination of an ATR inhibitor and177Lu vipivotide tetraxetan for a subject having one or more DDR pathway mutations is from about 1 % to about 99% of the therapeutically effective dose for a subject that is free of DDR pathway mutations.

[0292] E39. The method of any one of embodiments E25 to E38, wherein the subject experiences fewer instances of hematological toxicity after administration of the therapeutic combination than after administration of a monotherapy of the ATR inhibitor.

[0293] E40. The method of any one of embodiments E25 to E39, wherein the subject experiences fewer instances of hematological toxicity after administration of the therapeutic combination than after administration of a monotherapy of the177Lu vipivotide tetraxetan.

[0294] OTHER EMBODIMENTS

[0295] Various modifications and variations of the described disclosure will be apparent to those skilled in the art without departing from the scope and spirit of the disclosure. Although the disclosure has been described in connection with specific embodiments, it should be understood that the disclosure as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the disclosure that are obvious to those skilled in the art are intended to be within the scope of the disclosure. Other embodiments are in the claims.

Claims

CLAIMS1 . A combination for use in treating a cancer that has an over-expression of PSMA on its cell membranes, wherein the combination comprises(i) a therapeutically effective amount of an ATR inhibitor, wherein the ATR inhibitor is camonsertib or a pharmaceutically acceptable salt thereof; and(ii) a therapeutically effective amount of177Lu vipivotide tetraxetan.

2. A method of treating a cancer that has an over-expression of PSMA on its cell membranes in a subject suffering therefrom comprising administering to the subject a therapeutically effective amount of camonsertib or pharmaceutically acceptable salt and a therapeutically effective amount of177Lu vipivotide tetraxetan.

3. A method of treating a cancer in a subject in need thereof, the method comprising:(i) identifying a subject having a cancer having an over-expression of PSMA on its cell membrane; and(ii) administering to the subject in need thereof a therapeutically effective amount of a combination of an ATR inhibitor and177Lu vipivotide tetraxetan, wherein the ATR inhibitor is camonsertib or a pharmaceutically acceptable salt thereof.

4. The combination for use or method of any one of claims 1 to 3, wherein camonsertib is administered as camonsertib hydrogen sulfate salt.

5. The combination for use or method of any one of claims 1 to 4, wherein the therapeutically effective amount comprises a subtherapeutic regimen of the ATR inhibitor.

6. The combination for use or method of claim 5, wherein the subtherapeutic regimen comprises a starting dosage that is at least 50% less than the lowest standard starting dosage that is used for a monotherapy.

7. The combination for use or method of claim 5 or 6, wherein the subtherapeutic regimen comprises a maintenance dosage that is at least 50% less than the lowest standard maintenance dosage that is used for a monotherapy.

8. The combination for use or method of claim 7, wherein the maintenance dosage of the subtherapeutic regimen comprises a first reduced dosage that is at least 50% less than the lowest standard maintenance dosage that is used for a monotherapy.

9. The combination for use or method of claim 7 or 8, wherein the maintenance dosage of the subtherapeutic regimen comprises a second reduced dosage that is at least 60% less than the lowest standard maintenance dosage that is used for a monotherapy.

10. The combination for use or method of any one of claims 8 to 10, wherein the maintenance dosage of the subtherapeutic regimen comprises a third reduced dosage that is at least 70% less than the lowest standard maintenance dosage that is used for a monotherapy.11 . The combination for use or method of any one of claims 1 to 10, wherein the ATR inhibitor is orally administered.

12. The combination for use or method of any one of claims 1 to 11 , wherein the ATR inhibitor is administered 1 day / week, 2 days / week, or 3 days / week.

13. The combination for use or method of any one of claims 1 to 12, wherein the ATR inhibitor is administered on days 1 , 2, 3, 8, 9, 10, 22, 23, 24, 29, 30, and 31 of a 6-week cycle.

14. The combination for use or method of any one of claims 1 to 13, wherein the ATR inhibitor is administered at a total daily dose of 50 mg.

15. The combination for use or method of any one of claims 1 to 13, wherein the ATR inhibitor is administered at a total daily dose of 80 mg.

16. The combination for use or method of any one of claims 1 to 13, wherein the ATR inhibitor is administered at a total daily dose of 120 mg.

17. The combination for use or method of any one of claims 1 to 13, wherein the ATR inhibitor is administered at a total daily dose of 160 mg.

18. The method of any one of claims 1 to 17, wherein177Lu vipivotide tetraxetan is administered on day 1 of a 6-week cycle.

19. The combination for use or method of any one of claims 1 to 18, wherein177Lu vipivotide tetraxetan is administered intravenously at a dose of 7.4 GBq (200 mCi).

20. The combination for use or method of any one of claims 1 to 19, wherein the subject has received at least one prior line of therapy for the cancer having an over-expression of PSMA on its cell membrane.

21. The combination for use or method of claim 20, wherein at least one prior line of therapy comprised an AR targeted therapy.

22. The combination for use or method of any one of claims 1 to 21 , wherein the cancer is metastatic castration resistant prostate cancer (mCRPC).

23. A method of inducing cell death in aberrant cancer cells having an over-expression of PSMA on their cell membranes, the method comprising contacting the cell with an effective amount of a combination of an ATR inhibitor and177Lu vipivotide tetraxetan, the effective amount being sufficient to induce cell death in the aberrant cancer cell, wherein the ATR inhibitor is camonsertib or a pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein the ATR inhibitor is camonsertib hydrogen sulfate salt.

25. A method of treating a cancer in a subject having a cancer that has an over-expression of PSMA on its cell membranes, comprising: administering a therapeutic combination, wherein the therapeutic combination comprises(i) a therapeutically effective amount of an ATR inhibitor, wherein the ATR inhibitor is camonsertib or a pharmaceutically acceptable salt thereof; and(ii) a therapeutically effective amount of177Lu vipivotide tetraxetan.

26. The method of claim 25, wherein the ATR inhibitor is administered in a daily dose of 50 mg to 160 mg.

27. The method of claim 26, wherein the daily dose of the ATR inhibitor is 50 mg, 80 mg, 120 mg, or 160 mg.

28. The method of claim 27, wherein the ATR inhibitor is administered in a daily dose of 120 mg.

29. The method of any one of claims 25 to 28, wherein the ATR inhibitor is administered on days 1 , 2, 3, 8, 9, 10, 22, 23, 24, 29, 30, and 31 of a 6-week cycle.

30. The method of any one of claims 25 to 29, wherein177Lu vipivotide tetraxetan is administered intravenously in a dose of 7.4 GBq.31 . The method of any one of claims 25 to 30, wherein177Lu vipivotide tetraxetan is administered on day 1 of a 6-week cycle.

32. The method of any one of claims 25 to 31 , wherein the subject has one or more DDR pathway mutations.

33. The method of claim 32, wherein the DDR pathway mutation comprises one or more of: oncogenic mutations; dysfunctional G1 / S checkpoint control; (e.g., loss of p53 function); defects in other DNA repair pathways (e.g., ATM) and that are subject to the effects of DNA damaging agents, e.g., radioligand therapy or chemotherapeutic agents.

34. The method of claim 33, wherein the dysfunctional G1 / S checkpoint is a loss of p53 function.

35. The method of claim 33, wherein the defect in other DNA repair pathways is ATM.

36. The method of claim 33, wherein the DNA damaging agent comprises radioligand, chemotherapeutic agents, or combinations thereof.

37. The method of any one of claims 25 to 31 , wherein the subject is free of DDR pathway mutations.

38. The method of any one of claims 25 to 37, wherein the therapeutically effective dose of the therapeutic combination of an ATR inhibitor and177Lu vipivotide tetraxetan for a subject having one or more DDR pathway mutations is from about 1% to about 99% of the therapeutically effective dose for a subject that is free of DDR pathway mutations.

39. The method of any one of claims 25 to 38, wherein the subject experiences fewer instances of hematological toxicity after administration of the therapeutic combination than after administration of a monotherapy of the ATR inhibitor.

40. The method of any one of claims 25 to 39, wherein the subject experiences fewer instances of hematological toxicity after administration of the therapeutic combination than after administration of a monotherapy of the177Lu vipivotide tetraxetan.

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