[177lu]lu-psma-617 and a dna damage response inhibitor

Abstract

Described herein are combination therapies featuring 177 Lu]Lu-PSMA-617 and a DNA damage response inhibitor (DDRi), and their use in the treatment of cancer, e.g., like PSMA-expressing cancer.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 575,373, filed April 5, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to a combination therapy featuring a radiopharmaceutical targeting prostate-specific membrane antigen (PSMA) and a DNA damage response inhibitor (DDRi), and its use in increasing the therapeutic efficacy of cancers, such as those expressing PSMA. Background Technology

[0004] Prostate cancer (PC) is a leading cause of cancer-related deaths in men worldwide, with an estimated 1.4 million new cases and 375,000 deaths in 2020 (Wang et al. 2022, Prostate Cancer Incidence and Mortality: Global Status and Temporal Trends in 89 Countries From 2000 to 2019). Frontiers in Public Health. 10-20% of prostate cancer patients develop tumors that become refractory to drug or surgical castration and androgen deprivation therapy, progressing to metastatic castration-resistant prostate cancer (mCRPC) (Juzeniene et al. 2021, Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer).

[0005] Over the past decade, new treatment options such as anti-hormonal therapy, poly(ADP-ribose) polymerase (PARP) inhibitors, radiopharmaceuticals, immunotherapy, and chemotherapy have been approved for patients with mCRPC. Despite these advances, mCRPC remains incurable; this can be partly attributed to the heterogeneity of the disease both between and within patients. Therefore, there is an urgent need for personalized and highly effective targeted therapies for patients with mCRPC.

[0006] Targeted radioligand therapy (RLT) offers the possibility of treating cancerous lesions in a specific and tumor-selective manner by utilizing cell surface receptors primarily expressed in malignant cells, such as prostate-specific membrane antigen (PSMA). Systemically administered RLT concentrates at the target site and surrounding cells through radioligand binding. Targeted RLT delivers DNA strand break radiation by binding with high affinity to lesions expressing biomarkers, ligands, and / or receptors. PSMA is an attractive target for prostate cancer therapy because it is highly expressed in cancer cells, including mCRPC cells, but much lower in normal tissues. Therefore, PSMA has the potential to be a viable target for RLT, minimizing radiation-related side effects. Pluvicto® ([ 177 Lu-PSMA-617 is an example of an FDA-approved PSMA-based RLT for the treatment of PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).

[0007] Despite the clinical success of targeting RLTs, there are still opportunities to improve various aspects of treatment efficacy, such as enhancing the duration or extent of response in a broader patient population. Summary of the Invention

[0008] In one aspect, this disclosure provides a method for treating a subject in need of a cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617 was administered to the subject, along with a therapeutically effective dose of a DNA damage response inhibitor (DDRi).

[0009] In some embodiments, DDRi may be selected from the group consisting of: ataxia-telangiectasia mutant (ATM) inhibitors, ataxia-telangiectasia and Rad3-associated (ATR) inhibitors, poly(ADP-ribose) polymerase (PARP) inhibitors, DNA-dependent protein kinase (DNA-PK) inhibitors, WEE1 protein kinase family inhibitors, checkpoint kinase (CHK) inhibitors, DNA polymerase θ (Polθ) inhibitors, RAD51 recombinase (RAD51) inhibitors, ubiquitin-specific protease 1 (USP1) inhibitors, Polo-like serine / threonine kinase 1 (PLK1) inhibitors, Aurora kinase inhibitors, mutant p53 reactivators, poly(ADP-ribose) hydrolase (PARG) inhibitors, Werner syndrome protein (WRN) inhibitors, and combinations thereof. Optionally, DDRi is not olaparib.

[0010] In some embodiments, DDRi may be selected from the group consisting of: ATM inhibitors, ATR inhibitors, PARP inhibitors, DNA-PK inhibitors, WEE1 protein kinase family inhibitors, CHK1 inhibitors, and Polθ inhibitors. Optionally, the PARP inhibitor is not olaparib.

[0011] In some embodiments, DDRi may include at least one DNA-PK inhibitor listed in Table 4, at least one of XRD-0394, SN-39536, BY101298, XZP-6877, and IMP-11, or a pharmaceutically acceptable salt thereof. In some cases, at least one DNA-PK inhibitor may include:

[0012] (7-Methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(oxan-4-yl)purine-8-one (AZD7648)) or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, DDRi may include at least one ATM inhibitor listed in Table 1, at least one of XRD-0394 and SX-RDS1, or a pharmaceutically acceptable salt thereof. In some cases, at least one ATM inhibitor may include:

[0014] (8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinoline-2-one (AZD0156)) or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, DDRi may include at least one ATR inhibitor listed in Table 2, at least one of LF0397, IMP-9064, ART0380, SC0245, and ATRN-119, or a pharmaceutically acceptable salt thereof. In some cases, at least one ATR inhibitor may include ART0380 or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, DDRi may include at least one PARP inhibitor listed in Table 3 or a pharmaceutically acceptable salt thereof. Optionally, the PARP inhibitor is not olaparib. In some cases, at least one PARP inhibitor may include:

[0017] ((11S,12R)-7-fluoro-11-(4-fluorophenyl)-12-(2-methyl-1,2,4-triazol-3-yl)-2,3,10-triazatricyclic [7.3.1.0] 5,13[13-carbo-1,5(13),6,8-tetraen-4-one (tarazopanib) or a pharmaceutically acceptable salt thereof.]

[0018] In some embodiments, DDRi may include at least one WEE1 protein kinase family inhibitor selected from the group consisting of: Wee1-like protein kinase inhibitors (WEE1) and membrane-associated tyrosine / threonine protein kinase 1 (PKMYT1) inhibitors.

[0019] In some embodiments, DDRi may include at least one WEE1 inhibitor listed in Table 5, at least one of SC0191, SY-4835, and IMP7068, or a pharmaceutically acceptable salt thereof. In some cases, at least one WEE1 inhibitor may include:

[0020] (1-[6-(2-hydroxypropyl-2-yl)pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-propyl-2-enylpyrazolo[3,4-d]pyrimidin-3-one (Adavosertib or MK-1775) or a pharmaceutically acceptable salt thereof.)

[0021] In some embodiments, DDRi may include at least one PKMYT1 inhibitor listed in Table 6, ACR-2316, or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, DDRi may include at least one CHK inhibitor selected from the group consisting of: a CHK1 selective inhibitor, a CHK2 selective inhibitor, and a CHK1 / 2 dual inhibitor.

[0023] In some embodiments, DDRi may include at least one CHK1 selective inhibitor listed in Table 7, VER250840, or a pharmaceutically acceptable salt thereof. In some cases, at least one CHK1 selective inhibitor may include:

[0024] (1-[5-bromo-4-methyl-2-[[(2S)-morpholin-2-yl]methoxy]phenyl]-3-(5-methylpyrazin-2-yl)urea (Rabusertib or LY2603618) or a pharmaceutically acceptable salt thereof.)

[0025] In some embodiments, DDRi may include at least one CHK2 selective inhibitor listed in Table 8 or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, DDRi may include at least one CHK1 / 2 dual inhibitor listed in Table 9 or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, DDRi may include at least one Polθ inhibitor listed in Table 10, at least one of ART4215, ART6043, RP-3467, and GSK101 (GSK4524101 / IDE705), or a pharmaceutically acceptable salt thereof. In some cases, at least one Polθ inhibitor may include: ((2S,3R)-1-[3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl]-3-hydroxy-N-methyl-N-(3-methylphenyl)pyrrolidine-2-carboxamide (ART558), ART6043 or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, DDRi may include at least one RAD51 inhibitor listed in Table 11 or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, DDRi may include at least one of the following listed in Table 12: a USP1 inhibitor, TNG348, HSK39775, FT-3171 (Debio 0432), and ISM3091, or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, DDRi may include at least one PLK1 inhibitor listed in Table 13 or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, DDRi may include at least one Aurora kinase inhibitor selected from the group consisting of: Aurora A inhibitors and Aurora B inhibitors listed in Table 14, WJ05129, or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, DDRi may include at least one PARG inhibitor listed in Table 16, IDE161, or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, DDRi may include at least one WRN inhibitor listed in Table 17, RO7589831, HRO761, or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, DDRi may include at least one mutant p53 reactivator listed in Table 15, PC14586, or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, DDRi and [ 177 Lu]Lu-PSMA-617 can be administered via the same route of application.

[0036] In some embodiments, DDRi and [ 177 Lu]Lu-PSMA-617 is formulated in the same dosage form.

[0037] In some embodiments, DDRi and [ 177 Lu]Lu-PSMA-617 can be formulated into individual dosage forms.

[0038] In some embodiments, DDRi can be via [ 177 Lu]Lu-PSMA-617 can be administered via different routes.

[0039] In some embodiments, DDRi can be [ 177 Lu]Lu-PSMA-617 should be applied within 24 hours.

[0040] In some embodiments, a therapeutically effective amount of DDRi may be administered over a course of treatment of approximately or at least approximately 5 days.

[0041] In some embodiments, DDRi can be [ 177 Lu]Lu-PSMA-617 should be applied within 20 hours.

[0042] In some embodiments, DDRi can be [ 177 Lu]Lu-PSMA-617 should be applied within 4 hours.

[0043] In some embodiments, DDRi can be [ 177 Lu]Lu-PSMA-617 is administered at least 16 hours after administration, in one or more doses.

[0044] In some embodiments, [ 177 The effective dose of Lu]Lu-PSMA-617, DDRi, or both is lower than the dose required for a single-therapy response. In some cases, a single-therapy response can be objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, changes in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers relative to baseline, or a combination thereof. In some cases, [ 177 The effective dose of Lu]Lu-PSMA-617, DDRi, or both is at least about 10% to about 50% lower than the dose required for a monotherapy response. In some cases, [ 177 The therapeutically effective dose of Lu-PSMA-617 is higher than that required for a monotherapy response. 177The amount of Lu]Lu-PSMA-617 is approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or approximately 50%.

[0045] In some cases, the effective dose of DDRi is about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or about 50% lower than the dose of DDRi required for a monotherapy response.

[0046] In some embodiments, with the application of [ 177 Compared to Lu]Lu-PSMA-617 or DDRi as monotherapy, the anticancer response generated by practicing this method is synergistically enhanced.

[0047] In some embodiments, [ 177 The therapeutically effective doses of Lu-PSMA-617 are as follows: approximately 10 MBq to approximately 10 GBq, approximately 100 MBq to approximately 10 GBq, approximately 1 GBq to approximately 10 GBq, approximately 3 GBq to approximately 10 GBq, approximately 5 GBq to approximately 9 GBq, approximately 6 GBq to approximately 8 GBq, or approximately 7.4 GBq.

[0048] In some embodiments, the cancer expressing PSMA is PSMA-positive prostate cancer, optionally PSMA-positive metastatic castration-resistant prostate cancer (mCRPC), optionally PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC), optionally PSMA-positive oligometastatic prostate cancer (OMPC), optionally PSMA-positive cancer in biochemical relapse (BCR) status, optionally PSMA-positive cancer in high-risk BCR status.

[0049] On the other hand, this disclosure provides a method that includes [ 177The combination of Lu-PSMA-617 and DDRi, for use in the treatment of PSMA-expressing cancers, wherein the DDRi is selected from the group consisting of: ataxia-telangiectasia mutant (ATM) inhibitors, ataxia-telangiectasia and Rad3-associated (ATR) inhibitors, poly(ADP-ribose) polymerase (PARP) inhibitors, DNA-dependent protein kinase (DNA-PK) inhibitors, WEE1 protein kinase family inhibitors, checkpoint kinase (CHK) inhibitors, DNA polymerase θ (Polθ) inhibitors, RAD51 recombinase (RAD51) inhibitors, ubiquitin-specific protease 1 (USP1) inhibitors, Polo-like serine / threonine kinase 1 (PLK1) inhibitors, Aurora kinase inhibitors, mutant p53 reactivators, poly(ADP-ribose) hydrolase (PARG) inhibitors, and Werner syndrome protein (WRN) inhibitors, and combinations thereof. Optionally, DDRi is not olaparib.

[0050] In some embodiments, the combination with [ 177 Lu-PSMA-617 monotherapy or DDRi monotherapy can have an enhanced therapeutic index compared to other treatments. In some cases, the combined therapeutic index is higher than [ 177 The treatment index width of Lu]Lu-PSMA-617 monotherapy or DDRi monotherapy is at least about 10% to about 50%.

[0051] In some embodiments, DDRi may include at least one DNA-PK inhibitor listed in Table 4, at least one of XRD-0394, SN-39536, BY101298, XZP-6877 and IMP-11, or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, DDRi may include at least one ATM inhibitor listed in Table 1, at least one of XRD-0394 and SX-RDS1, or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, DDRi may include at least one of the ATR inhibitors listed in Table 2, at least one of LF0397, IMP-9064, SC0245 and ATRN-119, or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, DDRi may include at least one PARP inhibitor listed in Table 3 or a pharmaceutically acceptable salt thereof. Optionally, the PARP inhibitor is not olaparib.

[0055] In some embodiments, DDRi may include at least one WEE1 protein kinase family inhibitor selected from the group consisting of: Wee1-like protein kinase inhibitors (WEE1) and membrane-associated tyrosine / threonine protein kinase 1 (PKMYT1) inhibitors.

[0056] In some embodiments, DDRi may include at least one of the WEE1 inhibitors listed in Table 5, at least one of SC0191, SY-4835 and IMP7068, or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, DDRi may include at least one PKMYT1 inhibitor listed in Table 6, ACR-2316, or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, DDRi may include at least one CHK inhibitor selected from the group consisting of: a CHK1 selective inhibitor, a CHK2 selective inhibitor, and a CHK1 / 2 dual inhibitor.

[0059] In some embodiments, DDRi may include at least one CHK1 selective inhibitor listed in Table 7, VER250840, or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, DDRi may include at least one CHK2 selective inhibitor listed in Table 8 or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, DDRi may include at least one CHK1 / 2 dual inhibitor listed in Table 9 or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, DDRi may include at least one Polθ inhibitor listed in Table 10, at least one of ART4215, ART6043, RP-3467 and GSK101 (GSK4524101 / IDE705), or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, DDRi may include at least one RAD51 inhibitor listed in Table 11 or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, DDRi may include at least one of the following listed in Table 12: a USP1 inhibitor, TNG348, HSK39775, FT-3171 (Debio 0432), and ISM3091, or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, DDRi may include at least one PLK1 inhibitor listed in Table 13 or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, DDRi may include at least one Aurora kinase inhibitor selected from the group consisting of: Aurora A inhibitors and Aurora B inhibitors listed in Table 14, WJ05129, or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, DDRi may include at least one PARG inhibitor listed in Table 16, IDE161, or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, DDRi may include at least one WRN inhibitor listed in Table 17, RO7589831, HRO761, or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, DDRi may include at least one mutant p53 reactivator listed in Table 15, PC14586, or a pharmaceutically acceptable salt thereof.

[0070] On the other hand, this disclosure provides a method for treating a subject with prostate-specific membrane antigen (PSMA)-expressing cancer, the method comprising administering to the subject a therapeutically effective dose of […]. 177 Lu]Lu-PSMA-617, and administer a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject, wherein the DDRi is: ((S)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol (M3814)) or a pharmaceutically acceptable salt thereof, thereby relating to [ 177 Compared to monotherapy responses with Lu-PSMA-617 or the aforementioned DDRi, the anticancer response was synergistically enhanced. In some cases, [ 177The therapeutically effective dose of Lu-PSMA-617 is approximately 10 MBq to 10 GBq, for example, approximately 100 MBq to approximately 10 GBq, approximately 1 GBq to approximately 10 GBq, approximately 3 GBq to approximately 10 GBq, approximately 5 GBq to approximately 9 GBq, approximately 6 GBq to approximately 8 GBq, or approximately 7.4 GBq. The therapeutically effective dose of DDRi is approximately 1 to 1000 mg / kg, approximately 10 to 900 mg / kg, approximately 15 to 800 mg / kg, approximately 20 to 700 mg / kg, approximately 25 to 600 mg / kg, approximately 30 mg to 500 mg / kg, approximately 35 to 400 mg / kg, approximately 40 to 300 mg / kg, approximately 45 to 200 mg / kg, approximately 50 to 100 mg / kg, optionally approximately 100 mg / kg, administered twice daily for approximately 5 days, or approximately 50 mg, approximately 100 mg, approximately 150 mg / kg, etc. mg or approximately 250 mg, and the initial dose of DDRi is administered at [ 177 Lu]Lu-PSMA-617 was applied less than 1 hour prior.

[0071] On the other hand, this disclosure provides a method for treating a subject with prostate-specific membrane antigen (PSMA)-expressing cancer, the method comprising administering to the subject a therapeutically effective dose of […]. 177 Lu]Lu-PSMA-617, and administered a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject, wherein the DDRi is ((7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(oxan-4-yl)purine-8-one (AZD7648)) or a pharmaceutically acceptable salt thereof, thereby relating to [ 177 Compared to monotherapy with Lu-PSMA-617 or DDRi, the anticancer response was synergistically enhanced. In some cases, [ 177The therapeutically effective dose of Lu-PSMA-617 is approximately 10 mBq to 10 GBq, for example, approximately 100 MBq to approximately 10 GBq, approximately 1 GBq to approximately 10 GBq, approximately 3 GBq to approximately 10 GBq, approximately 5 GBq to approximately 9 GBq, or approximately 6 GBq to approximately 8 GBq, and optionally approximately 7.4 GBq. The therapeutically effective dose of DDRi is approximately 1 to 1000 mg / kg, approximately 10 to 900 mg / kg, approximately 15 to 800 mg / kg, approximately 20 to 700 mg / kg, approximately 25 to 600 mg / kg, approximately 30 mg to 500 mg / kg, approximately 35 to 400 mg / kg, approximately 40 to 300 mg / kg, approximately 45 to 200 mg / kg, or approximately 50 to 100 mg / kg, optionally approximately 100 mg / kg, administered once daily for approximately 5 days. The initial dose of DDRi is administered at […]. 177 Lu]Lu-PSMA-617 was applied less than 1 hour prior.

[0072] On the other hand, this disclosure provides a method for treating a subject in need of cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is:

[0073] (8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one (AZD0156)) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy response to Lu]Lu-PSMA-617 or this DDRi, the anticancer response was synergistically enhanced.

[0074] On the other hand, this disclosure provides a method for treating a subject in need of cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is:

[0075] (1-[5-bromo-4-methyl-2-[[(2S)-morpholin-2-yl]methoxy]phenyl]-3-(5-methylpyrazin-2-yl)urea (LY2603618, labusetetibr)) or a pharmaceutically acceptable salt thereof, thereby being used with [177 Compared with monotherapy response to Lu]Lu-PSMA-617 or this DDRi, the anticancer response was improved or synergistically enhanced.

[0076] On the other hand, this disclosure provides a method for treating a subject in need of cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is:

[0077] (1-[6-(2-hydroxypropyl-2-yl)pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-propyl-2-enylpyrazolo[3,4-d]pyrimidin-3-one (Adavocetib or MK-1775) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy responses to Lu]Lu-PSMA-617 or the aforementioned DDRi, the anticancer response was improved or synergistically enhanced.

[0078] On the other hand, this disclosure provides a method for treating a subject in need of cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is: 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one (olaparib) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared to monotherapy with Lu-PSMA-617 or this DDRi, the anticancer response was synergistically enhanced, optionally wherein the DDRi was administered in combination with […]. 177 Lu]Lu-PSMA-617 is administered within 24 hours, and / or the DDRi is administered within 24 hours of administration and for a course of treatment of at least 48 hours.

[0079] On the other hand, this disclosure provides a method for treating a subject in need of cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is:

[0080] ((11S,12R)-7-fluoro-11-(4-fluorophenyl)-12-(2-methyl-1,2,4-triazol-3-yl)-2,3,10-triazatricyclic [7.3.1.0] 5,13 [13-carbohydrate-1,5(13),6,8-tetraen-4-one (tapazopanib) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy response to Lu]Lu-PSMA-617 or this DDRi, the anticancer response was synergistically enhanced.

[0081] On the other hand, this disclosure provides a method for treating a subject in need of cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is:

[0082] ((2S,3R)-1-[3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl]-3-hydroxy-N-methyl-N-(3-methylphenyl)pyrrolidine-2-carboxamide (ART558) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy response to Lu]Lu-PSMA-617 or this DDRi, the anticancer response was synergistically enhanced.

[0083] On the other hand, this disclosure provides a method for treating a subject in need of cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and administered to the subject a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is ART6043 or a pharmaceutically acceptable salt thereof, thereby in conjunction with [ 177 Compared with monotherapy response to Lu]Lu-PSMA-617 or this DDRi, the anticancer response was synergistically enhanced.

[0084] On the other hand, this disclosure provides a method for treating a subject in need of cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and administered a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject, wherein the DDRi is ART0380 or a pharmaceutically acceptable salt thereof, thereby in conjunction with [ 177Compared with monotherapy response to Lu]Lu-PSMA-617 or this DDRi, the anticancer response was synergistically enhanced. Attached Figure Description

[0085] Figure 1 The time-dependent induction of γH2AX and 53BP1 in DLD-1 cells treated with 2.5 MBq / ml 177Lu-DOTA was depicted.

[0086] Figure 2 The induction of DDR markers in DLD-1 cells treated with increased activity of 177Lu-DOTA was depicted.

[0087] Figure 3 The quantification of representative DDR markers induced in LNCaP cells treated with 177Lu-PSMA-617 for 4 h was characterized.

[0088] Figure 4A -B depicts the results of viability assays, showing induced sensitization to 177Lu-DOTA and 177Lu-PSMA-617 in the absence of PRKDC. (A) HCT-116 (PSMA negative) and (B) DU-145 PSMA-overexpressing cells (engineered to express PSMA at high levels) were treated with 177Lu-DOTA for 8 days or with 177Lu-PSMA-617 for 24 h, respectively. Viability was measured after 8 days of incubation. The X-axis represents the activity of 177Lu-DOTA (A) or 177Lu-PSMA-617 (B) (in MBq / mL), and the Y-axis represents the relative viability normalized to the mediator. Solid lines represent cells expressing PRKDC, while dashed lines represent cells with PRKDC knockout.

[0089] Figure 5 Viability curves (EC50) of a group of cell lines continuously treated with 177Lu-DOTA were plotted based on an 8-day viability assay. 50 The values ​​are provided in Table 23.

[0090] Figure 6A-C The time-course analysis of DU145 PSMA-high expressing cells treated with 177Lu-PSMA-617 with increased activity for 24 h was depicted. (A) Consolidation percentage analysis. (B) Cytotoxicity and (C) Apoptosis analysis were performed using Cytotox or Caspase 3 / 7 dyes, respectively. Measurements were performed using IncuCyte.

[0091] Figure 7 A graphical representation of the 177Lu operating mode is shown.

[0092] Figure 8A-CThe results of viability assays in the following syngeneic models were described: (A) homologous recombination (HR) defect; (B) non-homologous end joining (NHEJ) defect; or (C) a combination of DNA-PK inhibitor (AZD7648) and 177Lu-DOTA.

[0093] Figure 9A -D depicts the results of gene screening to identify sensitizers for radioligand therapy. (A) is a diagram summarizing the experiment; (B, C, D) provide representative volcano plots of the sensitizers identified by CRISPR / Cas9 KO screening in three cell lines.

[0094] Figure 10A -B depicts the results of continuous treatment for 8 days with the following specified compounds (followed by measurement of viability in specified cells) in the presence (dashed line) or absence (solid line) of 177Lu-DOTA: (A) PARP, ATM, CHK1, and WEE1 inhibitors, and (B) Polθ and ATR inhibitors. The x-axis represents the concentration of each compound, and the y-axis represents the normalized relative viability relative to the medium (solid line) or 177Lu-DOTA alone (dashed line).

[0095] Figure 11A-F The results of the combination of the DNA-PK inhibitor AZD7648 and 177Lu-DOTA in a group of cancer cell lines are depicted. Cell lines were treated with 177Lu-DOTA alone (solid line) or in combination with 1 µM DNA-PK inhibitor (dashed line) for 8 days until the viability assay endpoint was reached. The X-axis represents the activity of 177Lu-DOTA (in MBq / mL), and the Y-axis represents the relative activity normalized to the mediator.

[0096] Figure 12A-D The results of combining 177Lu-PSMA-617 with the indicated DDRi in PSMA-expressing cell lines are depicted. (A, B, and C) LNCaP cells were treated with 177Lu-PSMA-617 alone (solid line) for 24 h or in combination with an ATR inhibitor and a Polθ inhibitor for 8 days until the viability assay endpoint was read out. DU 145 engineered cells expressing PSMA (D) were treated with 177Lu-PSMA-617 alone (solid line) for 24 h or in combination with an ATM inhibitor for 8 days until the viability assay endpoint was read out. The x-axis represents the concentration of 177Lu-PSMA-617 (MBq / ml), and the y-axis represents the relative viability normalized to the mediator.

[0097] Figure 13A-GThe results of the combination of the DNA-PK inhibitor AZD7648 and 177Lu-PSMA-617 in PSMA-expressing cell lines are depicted. DU-145 (A) and PC-3 (D) PSMA-negative cells were engineered to express low (B, E) or high (C, F) levels of PSMA. LNCaP FGC cells (G) expressed high levels of endogenous PSMA. Cells were treated with 177Lu-PSMA-617 alone (solid line) or in combination with a DNA-PK inhibitor (dashed line). The X-axis represents the activity of 177Lu-PSMA-617 (in MBq / mL), and the Y-axis represents the normalized relative activity compared to the mediator (solid line) or the DNA-PK inhibitor alone (dashed line). Cells were exposed to 177Lu-PSMA-617 for 4 h and to the DNA-PK inhibitor for 8 days.

[0098] Figures 14A-F The results of viability assays were depicted, showing that the DNA-PK inhibitor AZD7648 produced a synergistic effect with 177Lu-PSMA-617 when administered before or concurrently. Viability assays were performed in DU145 PSMA-overexpressing cells (AE) using different DNA-PK inhibitor administration schedules (as outlined in (F): (A) - 24 h of DNA-PK inhibitor administration, (B) - 1 h of DNA-PK inhibitor administration, (C) 0 h of DNA-PK inhibitor administration, (D) 4 h of DNA-PK inhibitor administration, and (E) 24 h of DNA-PK inhibitor administration.

[0099] Figures 15A-F The results of viability assays were depicted, showing that the maximum synergistic effect between the DNA-PK inhibitors AZD7648 and 177Lu-PSMA-617 was achieved by prolonged inhibition of DDR. Viability assays were performed in DU145 PSMA-overexpressing cells (AE) with different DNA-PK inhibitor administration schedules (as outlined in (F): (A) removal of DNA-PK inhibitor at 4 h, (B) removal of DNA-PK inhibitor at 16 h, (C) removal of DNA-PK inhibitor at 24 h, (D) removal of DNA-PK inhibitor at 48 h, and (E) continuous DNA-PK inhibitor treatment.

[0100] Figure 16Normalized quantifications of γ-H2AX focal immunofluorescence (top plot) or 53BP1 focal immunofluorescence (bottom plot) were plotted. Statistical analysis was performed using one-way ANOVA and Dunnett's post-hoc test (asterisk above the column) or two-tailed t-test (asterisk above parentheses), comparing the summation of combinations with predictions. Solid columns represent 24-hour time points, and dashed columns represent 96-hour time points.

[0101] Figure 17A -C depicts the accumulation of DDR markers and cell cycle alterations: (A) Time course of γH2AX focal induction in PC-3 MP9 cells after treatment with 177Lu-PSMA-617 alone (solid column) or in combination with DNA-PKi (1 µM AZD7648 – dashed column). Micronucleus induction (B) or cell cycle alterations (C) in DU 145 PSMA-overexpressing cells after 4 h of treatment with 177Lu-PSMA-617 alone or in combination with DNA-PKi (1 µM AZD7648). Statistical analysis of the mediator treatments at corresponding time points was performed using one-way ANOVA and Dunnett's post-hoc test.

[0102] Figure 18A-B The effects of the combination of the Polθ inhibitor ART6043 and 177Lu-PSMA-617 in vivo were depicted. (A) Body weight over time (mean ± SEM). (B) Survival curves for the four experimental groups. When the tumor volume exceeded 1500 mm... 3 The mice were terminated at that time. Statistical analysis was performed using a log-rank test.

[0103] Figure 19 Depicting a single [ 177 Biodistribution of Lu]Lu-PSMA-617 or in combination with the two DDRi compounds disclosed herein in PC3FOLH1 MP9 PSMA-high tumors at 4 h and 24 h (pi).

[0104] Figure 20A -D describes the individual [ 177 Experimental protocols and effects of Lu-PSMA-617 or in combination with the two DDRi disclosed herein in female nude mice carrying PC3FOLH1 MP9 PSMA tumors: (A) is a schematic illustration of the protocol; (B) and (C) show the individual [ 177 The effect of Lu]Lu-PSMA-617 or in combination with DDRi (AZD7648); and (D) displaying the effect of [ 177 The effect of Lu]Lu-PSMA-617 or in combination with DDRi (M3814). Detailed Implementation

[0105] PSMA is a transmembrane glycoprotein of approximately 100 kDa with folate hydrolase, carboxypeptidase, and internalization activities. It is expressed at low levels in normal prostate tissue, kidney, duodenum, salivary and lacrimal glands, brain, and intestine. Increased PSMA expression is significantly associated with the differentiation and progression of mCRPC. Therefore, PSMA-targeting ligands can selectively accumulate in malignant cells, thus providing developmental opportunities for the imaging and treatment of mCRPC. Systemic administration of PSMA-targeting RLTs allows for the simultaneous treatment of extensive bone and extra-bone metastases, thereby limiting radiotoxicity to healthy tissues.

[0106] Radioligand therapy (RLT) is emerging as a safe and effective targeted treatment for several types of cancer. Pluvicto® ([ 177 Lu-PSMA-617 is an FDA-approved drug for the treatment of PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). 177 An example of Lu's RLT drugs. Although 177 Lu-RLT has achieved clinical success, but a portion of patients still fail to achieve complete and durable remission. Therefore, there are opportunities to improve patient treatment.

[0107] In one aspect, this disclosure provides methods for treating subjects with PSMA-expressing cancers, including administering a therapeutically effective amount of [177Lu]Lu-PSMA-617 to the subject and administering a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject.

[0108] In one aspect, this disclosure provides a combination of [177Lu]Lu-PSMA-617 and a DNA damage response inhibitor (DDRi) for use in the treatment of PSMA-expressing cancers. Treatment may include […]. 177 Lu]Lu-PSMA-617 was applied within 24 hours of DDRi, in [ 177 DDRi may be administered at one or more doses within at least 16 hours after Lu]Lu-PSMA-617 administration, and / or DDRi may be administered over a course of approximately or at least approximately 5 days.

[0109] [ 177 The effective therapeutic dose of Lu-PSMA-617, DDRi, or a combination of both can be lower than [ 177 The amount required for a single therapy response of Lu]Lu-PSMA-617 and / or DDRi. The required amount can be based on individual 177Lu]Lu-PSMA-617 and / or DDRi achieve quantities of the following: predetermined objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, changes in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers relative to baseline, or combinations thereof, or improvements in one or more of these responses compared to a single therapy response.

[0110] The combination of [177Lu]Lu-PSMA-617 and a DNA damage response inhibitor (DDRi) for use in the treatment of PSMA-expressing cancers can have a broader therapeutic index when used for the treatment of PSMA-expressing cancers compared to [177Lu]Lu-PSMA-617 monotherapy and / or DDRi monotherapy.

[0111] Combination therapy can provide synergistic effects in the treatment of cancers expressing PSMA. For example, one or more anticancer effects of DDRi can be achieved through combination with […]. 177 Synergistic enhancement is achieved through the combination of Lu]Lu-PSMA-617, or [ 177 One or more anticancer effects of Lu]Lu-PSMA-617 can be synergistically enhanced by combination with DDRi.

[0112] Detailed statements of this disclosure are set forth in the specification appended below. While methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, illustrative methods and materials are described hereafter. Other features, objectives, and advantages of this disclosure will be apparent from the specification and the claims. In this specification and the claims, the singular form also includes the plural form unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents and publications cited in this specification are incorporated herein by reference in their entirety.

[0113] definition

[0114] Unless specifically defined, the nomenclature, procedures, and techniques used in conjunction with the analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are those well-known and commonly used in the art. Standard techniques are available for chemical synthesis and chemical analysis. Some of these techniques and procedures can be found, for example, in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pennsylvania, 21st edition, 2005, which is hereby incorporated by reference for any purpose. Where permitted, all patents, applications, published applications, and other publications, as well as other data cited throughout this disclosure, are incorporated herein by reference in their entirety.

[0115] The term "radiopharmaceutical" is used herein to refer to a pharmaceutical compound radiolabeled with a radionuclide, such as peptides, oligonucleotides, small molecules, and antibodies. A radiopharmaceutical may be a radioligand. In some embodiments, a radiopharmaceutical refers to […]. 177 Lu]Lu-PSMA-617, that is, 177 Lu-labeled PSMA-617. In other embodiments, the radiopharmaceutical refers to a radiolabeled compound known in the art.

[0116] As used herein, the term "target-binding organic moiety" refers to an organic moiety that has a specific binding affinity for a target protein (typically a cell surface receptor or cellular protein). In a particular embodiment, the target-binding receptor moiety is an organic moiety that has a specific binding affinity for prostate-specific membrane antigen (PSMA).

[0117] As used herein, the term "chelate moiety" refers to an organic moiety containing a functional group that forms a non-covalent bond with a radionuclide during the reaction steps of the method, thereby forming a stable radionuclide complex. In the context of this invention, the chelate moiety may be or may contain 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), which is directly linked to the target-bound organic moiety via covalent bonding.

[0118] As used herein, the term "radiolabeled" (or "chelated" or "complexed") means that a non-radioactive compound is labeled with a radioactive isotope. Radiolabeling can be achieved, for example, via chelation or complexation of a chelating agent with a suitable radionuclide. Radiolabeling can also refer to the chemical substitution of a group on a compound with a radionuclide, for example, as in... 18 In the case of F.

[0119] Furthermore, it is intended that, within the scope of this invention, any element, particularly when mentioned in relation to compounds disclosed herein, should comprise all isotopes and mixtures of isotopes of the element, whether naturally occurring or synthetically produced, having natural abundance or being in isotopically enriched form. For example, reference to hydrogen within its scope includes... 1 H, 2 H (i.e., deuterium or D) and 3 H (i.e., tritium or T). In some embodiments, the compounds described herein contain... 2 H (deuterium) isotope. For example, it is represented as -C. (1-6) Alkyl groups include not only -CH3, but also CD3; not only CH2CH3, but also CD2CD3, etc. Similarly, references to carbon and oxygen within their respective ranges include... 12 C 13 C and 14 C and 15 O and 16 O and 17 O and 18 O. Isotopes may be radioactive or non-radioactive. The radiolabeled compounds disclosed herein may include radioactive isotopes selected from the group consisting of: 3 H, 11 C 18 F, 35 S, 122 I, 123 I, 125 I, 131 I, 75 Br、 76 Br、 77 Br and 82 Br. In some embodiments, the radioactive isotope is selected from the group consisting of: 3 H, 11 C and 18 F.

[0120] As used herein, the term "reaction solution" refers to a solution containing radioactive nuclide ions, target-binding organic molecules suitable for chelating the radioactive nuclide ions, and one or more stabilizers resistant to radiodegradation. Target-binding organic molecules include target-binding organic moieties directly or indirectly connected to the chelating moiety.

[0121] As used herein, the term "radiodegradation resistant stabilizer" refers to a stabilizer that protects organic molecules from radiodegradation. For example, when gamma rays emitted from a radionuclide break the bonds between atoms in an organic molecule and form free radicals, those free radicals are then scavenged by a stabilizer, preventing them from undergoing any other chemical reactions that could lead to undesirable, potentially ineffective, or even toxic molecules. Therefore, such stabilizers are also called "free radical scavengers" or simply "radioactive scavengers." Other alternative terms for these stabilizers are "radiostability enhancers," "radiodegradation stabilizers," or simply "quenchers."

[0122] As used in this article, "multivalent chelating agent" refers to a chelating agent suitable for chelating free radioactive nuclide metal ions (not chelated with radiolabeled peptides) in a complexing preparation.

[0123] As used herein, the term "mother liquor" refers to a solution obtained when the above-described reaction solution has completed the reaction to form a radionuclide complex, which has been further processed as described below (if applicable) and has been mixed with and diluted with water for injection (WFI) (if applicable).

[0124] As used herein, the term "dispensing solution" refers to the solution obtained when the aforementioned stock solution is further mixed with a diluent. A dispensing solution comprises all components and activities suitable for patient administration. A dispensing solution is a solution dispensed into multiple patient doses (vials) for subsequent administration to patients without further material alteration.

[0125] As used herein, the term “DNA damage response inhibitor” or “DDRi” refers to a compound that can block a cellular surveillance and signaling network that responds to DNA damage and maintains genomic stability by one or more of the following: (1) sensing and recognizing DNA damage; (2) recruiting repair mechanisms; (3) pausing the cell cycle to provide an opportunity for repair; (4) activating programmed cell death or inactivating cell replication; and (5) repairing DNA damage. Exemplary DDRi compounds include, but are not limited to, inhibitors of ataxia-telangiectasia mutant (ATM), inhibitors of ataxia-telangiectasia and Rad3-related (ATR), poly(ADP-ribose) polymerase (PARP) inhibitors, DNA-dependent protein kinase (DNA-PK) inhibitors, WEE1 protein kinase family inhibitors, checkpoint kinase (CHK) inhibitors, DNA polymerase θ (Polθ) inhibitors, RAD51 recombinase (RAD51) inhibitors, ubiquitin-specific protease 1 (USP1) inhibitors, Polo-like serine / threonine kinase 1 (PLK1) inhibitors, Aurora kinase inhibitors, mutant p53 reactivators, poly(ADP-ribose) hydrolase (PARG) inhibitors, and Werner syndrome protein (WRN) inhibitors.

[0126] As used herein, the phrase “pharmaceutically acceptable” means those compounds, materials, compositions, and / or dosage forms that are suitable for contact with human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications (in proportion to a reasonable benefit / risk ratio).

[0127] As used in this article, the term "treatment" means to reduce, inhibit, weaken, decrease, halt, or stabilize the development or progression of a symptom or disease.

[0128] As used herein, the term "prevent" means the absence of disease or illness if the disease or illness does not occur, or the absence of further disease or illness if the disease or illness has already developed. The ability to prevent some or all of the symptoms associated with the disease or illness is also considered.

[0129] As used herein, the term "synergistic effect" refers to two therapeutic agents (e.g., like […]) 177The effect produced by the action of Lu-PSMA-617 and DDRi is greater than the simple sum of the effects when each compound is administered as a single therapy. The synergistic effect can be calculated, for example, using appropriate methods such as the Sigmoid-Emax equation (Holford, NHG and Scheiner, LB, Clin. Pharmacokinet. [Clinical Pharmacokinetics] 6:429-453 (1981)), the Loewe additive equation (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. [Archives of Experimental Pathology and Pharmacology] 114: 313-326 (1926)) and the intermediate-effect equation (Chou, TC and Talalay, P., Adv. Enzyme Regul. [Advances in Enzyme Regulation Research] 22: 27-55 (1984)).

[0130] The terms "administer," "administering," and "administration" refer to the administration of the disclosed compound or another specified compound to a patient via any appropriate route. Specifically, the disclosed compounds may be administered orally or parenterally, for example, via injection or infusion via a parenteral route, wherein the injection or infusion may be intravenous, intramuscular, intra-arterial, subcutaneous, intradermal, intraperitoneal, etc. Depending on the route of administration, the disclosed compounds may be administered in the form of a pharmaceutical composition further comprising suitable components, such as carriers, solvents, and excipients commonly known in the art.

[0131] The term “pharmaceutical composition” is defined herein as a mixture (e.g., a solution or emulsion) containing at least one active ingredient or therapeutic agent to be administered to a subject (e.g., a human) in order to prevent or treat a specific disease or condition affecting that subject.

[0132] As used herein, the term "carrier" or "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delay agents, salts, preservatives, pharmaceuticals, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pp. 1289-1329). Except where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions should be considered.

[0133] As used herein, the term “parenteral” refers to administration methods including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal, and intra-articular injections and infusions.

[0134] Unless otherwise stated, the conventional definitions of terms and the valence of conventional stable atoms are assumed and are reflected in the full formula and groups.

[0135] As used herein, the term “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. As used herein, when referring to measurable values ​​such as quantities and time intervals, the term “about” means covering a variation of ±10% (inclusive) from the specified value, because such variation is suitable for performing the disclosed methods, and when “about” precedes a numerical value or range, “about” indicates a deviation of ±20%, ±10%, or ±5% from that value or range, unless a specific deviation is described. In some contexts, the deviation indicated by “about” may be ±2% or ±1%.

[0136] The article “a / an” as used in this disclosure refers to one or more (e.g., at least one) grammatical object of the article. For example, “a / an element” means one or more elements.

[0137] compound

[0138] This disclosure provides therapeutic combinations for the treatment or prevention of cancers expressing PSMA, including [177Lu]Lu-PSMA-617 and DNA damage response inhibitors (DDRi).

[0139] [ 177 Lu]Lu-PSMA-617

[0140] [ 177Lu]Lu-PSMA-617 can be used in the drug product PLUVICTO ([INN] lutetium ( 177 Lu) terciviride was obtained. [The following text appears to be incomplete and requires further context: "Produced [...]"] 177 The method described in Lu-PSMA-617 is published in WO 2023 / 148680 A1, dated August 10, 2023, and follows the methods disclosed in WO 2020 / 089379 A1, dated May 7, 2020; US 2020 / 131224A1, dated April 30, 2020; US 2021 / 0316019 A1, dated October 14, 2021; and US 2022 / 0041649A1, dated February 10, 2022. The contents of those patent applications are incorporated herein by reference in their entirety.

[0141] Throughout this disclosure, [ 177 Lu]Lu-PSMA-617 can also be called lutetium ( 177 Lu) Tercivitin, lutetium ( 177 Lu) Tercivirpeptide [INN] or Lu 177 Tercivirpeptide [USAN], PLUVICTO, or 2-[4-[2-[[4-[[(2S)-1-[[(5S)-5-carboxy-5-[[(1S)-1,3-dicarboxy-propyl]carbamoylamino]pentyl]amino]-3-naphth-2-yl-1-oxopropyl-2-yl]carbamoyl]cyclohexyl]methylamino]-2-oxoethyl]-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]acetate; Lu-177(3+). The molecular weight is 1216.06 g / mol and the molecular formula is C 49 H 68 177 LuN9O 16 [ 177 The chemical structure of Lu-PSMA-617 is shown below:

[0142]

[0143] Preparation and use [ 177 The method of Lu]Lu-PSMA-617 can also be found, for example, in the examples of this application (see, for example, Examples 1-3).

[0144] DDRi

[0145] In some embodiments, the DDRi of the treatment combination is selected from the group consisting of: ataxia-telangiectasia mutant (ATM) inhibitors listed in Table 1 or pharmaceutically acceptable salts thereof:

[0146] Table 1: Inhibitors of Ataxia-Telangiopalatine Mutant (ATM) (ATMi)

[0147]

[0148] In addition to the ATM inhibitors listed above, the ATM inhibitor group may include one or more of XRD-0394, which is being developed by XRad Therapeutics Inc., and SX-RDS1, which was originally developed by Serometrix LLC, or pharmaceutically acceptable salts thereof.

[0149] In some embodiments, DDRi is selected from the group consisting of: ataxia-telangiectasia and Rad3-related (ATR) inhibitors listed in Table 2, or pharmaceutically acceptable salts thereof:

[0150] Table 2: Ataxia-telangiectasia and Rad3-related inhibitors (ATRi)

[0151]

[0152] In addition to the ATR inhibitors listed above, the ATR inhibitor group may include one or more of the following, or pharmaceutically acceptable salts thereof: LF0397 developed by Shenzhen Lingfang Biomedical Technology Co., Ltd.; IMP-9064 developed by IMPACT Therapeutics, Inc.; SC0245 developed by Shijiazhuang Zhikang Hongren New Drug Development Co., Ltd.; and ATRN-119 developed by Aprea Therapeutics.

[0153] In some embodiments, DDRi is selected from the group consisting of: poly(ADP-ribose) polymerase (PARP) inhibitors listed in Table 3 or pharmaceutically acceptable salts thereof:

[0154] Table 3: Poly(ADP-ribose) polymerase inhibitors (PARPi)

[0155]

[0156] In some embodiments, DDRi is not olaparib. In some embodiments, DDRi is not a poly(ADP-ribose) polymerase (PARP) inhibitor.

[0157] In some embodiments, DDRi is selected from the group consisting of DNA-dependent protein kinase (DNA-PK) inhibitors listed in Table 4 or pharmaceutically acceptable salts thereof:

[0158] Table 4: DNA-dependent protein kinase inhibitors (DNA-PKi)

[0159]

[0160] In addition to the DNA-PK inhibitors mentioned above, the DNA-PK inhibitor group may include one or more of the following: XRD-0394 developed by XRad Therapeutics, Inc.; SN-39536 developed by Auckland Uniservices Limited; BY101298 developed by Chengdu Baiyu Pharmaceutical Co., Ltd.; XZP-6877 developed by Xuanzhu Biopharm Co., Ltd.; and IMP-11 developed by Yingpai Pharmaceutical Co., Ltd., or pharmaceutically acceptable salts thereof.

[0161] In some embodiments, DDRi is selected from the group consisting of: WEE1 protein kinase family inhibitors listed in Table 5 or pharmaceutically acceptable salts thereof:

[0162] Table 5: WEE1 protein kinase family inhibitors (WEE1i)

[0163]

[0164] In addition to the WEE1 inhibitors mentioned above, the WEE1 inhibitor group may include one or more of the following: SC0191 developed by Biocity Biopharmaceutics, IMP7068 developed by Yingpai Pharmaceutical Co., Ltd., and SY-4835 developed by Shouyao Holdings, or pharmaceutically acceptable salts thereof.

[0165] In some embodiments, DDRi is selected from the group consisting of the PKMYT1 inhibitors listed in Table 6:

[0166] Table 6: PKMYT1 Inhibitors (PKMYT1i)

[0167]

[0168] In addition to lenrescitebrate, the PKMYT1 inhibitor group may include ACR-2316 developed by Acrivon Therapeutics or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, DDRi is a checkpoint kinase (CHK) inhibitor. In some embodiments, the CHK inhibitor is selected from the group consisting of: CHK1 selective inhibitors, CHK2 selective inhibitors, or CHK1 / 2 inhibitors. In some embodiments, DDRi is selected from the group consisting of: CHK1 selective inhibitors listed in Table 7 or pharmaceutically acceptable salts thereof.

[0170] Table 7: CHK1 Inhibitors (CHK1i)

[0171]

[0172] In addition to the CHK1 selective inhibitors listed above, the CHK1 selective inhibitor group may include VER250840, which is being developed by Cumulus Oncology, or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, DDRi is selected from the group consisting of: CHK2 selective inhibitors in Table 8 or pharmaceutically acceptable salts thereof:

[0174] Table 8: Selective Inhibitors of CHK2 (CHK2i)

[0175]

[0176] In some embodiments, DDRi is selected from the group consisting of CHK1 / 2 inhibitors in Table 9 or pharmaceutically acceptable salts thereof:

[0177] Table 9: CHK1 / 2 Inhibitors (CHK1 / 2i)

[0178]

[0179] In some embodiments, DDRi is selected from the group consisting of DNA polymerase θ (Polθ) inhibitors listed in Table 10 or pharmaceutically acceptable salts thereof:

[0180] Table 10: DNA polymerase θ (Polθ) inhibitors (Polθi)

[0181]

[0182] In addition to the Polθ inhibitors mentioned above, the Polθ inhibitor group may include one or more of the following: ART4215 and ART6043 developed by Artios Pharma, RP-3467 developed by Repare Therapeutics, and GSK101 (GSK4524101 / IDE705) developed by Ideaya Biosciences, or pharmaceutically acceptable salts thereof.

[0183] In some embodiments, DDRi is selected from the group consisting of: RAD51 recombinase (RAD51) inhibitors listed in Table 11 or pharmaceutically acceptable salts thereof:

[0184] Table 11: RAD51 Inhibitors (RAD51i)

[0185]

[0186] In some embodiments, DDRi is selected from the group consisting of ubiquitin-specific protease 1 (USP1) inhibitors listed in Table 12 or pharmaceutically acceptable salts thereof:

[0187] Table 12: USP1 Inhibitors

[0188]

[0189] In addition to the USP1 inhibitors listed above, the USP1 inhibitor group may include one or more of the following: TNG348 developed by Tango Therapeutics, Inc.; ISM3091 (XL309) developed by Exelixis; HSK39775 developed by Haisco Pharmaceutical; and FT-3171 (Debio 0432) developed by Forma Therapeutics, or pharmaceutically acceptable salts thereof.

[0190] In some embodiments, DDRi is selected from the group consisting of: Polo-like serine / threonine kinase 1 (PLK1) inhibitors listed in Table 13 or pharmaceutically acceptable salts thereof:

[0191] Table 13: PLK1 Inhibitors (PLK1i)

[0192]

[0193] In some embodiments, DDRi is selected from the group of Aurora kinase inhibitors. In some embodiments, DDRi is selected from the group of: Aurora A and Aurora B inhibitors listed in Table 14, or pharmaceutically acceptable salts thereof:

[0194] Table 14: Inhibitors of Aurora A and Aurora B

[0195]

[0196] In addition to the Aurora kinase inhibitors listed above, the Aurora A and Aurora B inhibitor groups may include WJ05129 or a pharmaceutically acceptable salt thereof developed by Suzhou Junjing BioSciences Co., Ltd.

[0197] In some embodiments, DDRi is selected from the group consisting of mutant p53 reactivators listed in Table 15 or pharmaceutically acceptable salts thereof:

[0198] Table 15: Mutant p53 reactivators

[0199]

[0200] In addition to the mutant p53 reactivators listed above, the mutant p53 reactivator group may include PC14586 developed by PMV Pharmaceuticals or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, DDRi is selected from the group consisting of: poly(ADP-ribose) hydrolase (PARG) inhibitors listed in Table 16 or pharmaceutically acceptable salts thereof:

[0202] Table 16: PARG Inhibitors (PARGi)

[0203]

[0204] In addition to the PARG inhibitors listed above, the PARG inhibitor group may include IDE161 developed by Adidas Biosciences or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, DDRi is selected from the group consisting of: Werner syndrome protein (WRN) inhibitors listed in Table 17 or pharmaceutically acceptable salts thereof:

[0206] Table 17: WRN Inhibitors

[0207]

[0208] In addition to the WRN inhibitors listed above, the WRN inhibitor group may include RO7589831 developed by Hoffmann-Roche and HRO761 developed by Novartis.

[0209] Treatment

[0210] This disclosure provides a method for treating or preventing PSMA-expressing cancer in a subject of need, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of a DNA damage response inhibitor (DDRi). [177Lu]Lu-PSMA-617 and DDRi may be as described above. In some embodiments, DDRi is not olaparib.

[0211] In the method of this invention, the amount of [177Lu]Lu-PSMA-617 and the amount of DDRi administered include amounts effective for combination therapy against PSMA-expressing cancers. The amounts of [177Lu]Lu-PSMA-617 and DDRi administered can be administered as a single formulation or unit dosage form, simultaneously (but optionally separately), or sequentially via any suitable route. In some embodiments, DDRi can be administered via […]. 177 Lu]Lu-PSMA-617 can be administered via different routes.

[0212] In some embodiments, this disclosure provides a method of treating a subject with PSMA-expressing cancer, wherein the method includes administering a therapeutically effective amount of [177Lu]Lu-PSMA-617 to the subject and administering a therapeutically effective amount of DDRi selected from the previously described group to the subject. In some embodiments, DDRi is selected from the group consisting of: ataxia-telangiectasia mutant (ATM) inhibitors, ataxia-telangiectasia and Rad3-associated (ATR) inhibitors, poly(ADP-ribose) polymerase (PARP) inhibitors, DNA-dependent protein kinase (DNA-PK) inhibitors, WEE1 protein kinase family inhibitors, checkpoint kinase (CHK) inhibitors, DNA polymerase θ (Polθ) inhibitors, RAD51 recombinase (RAD51) inhibitors, ubiquitin-specific protease 1 (USP1) inhibitors, Polo-like serine / threonine kinase 1 (PLK1) inhibitors, Aurora kinase inhibitors, mutant p53 reactivators, poly(ADP-ribose) hydrolase (PARG) inhibitors, Werner syndrome protein (WRN) inhibitors, and combinations thereof. In some embodiments, the PARP inhibitor is not olaparib.

[0213] Typically, the amount of radiopharmaceutical (e.g., [177Lu]Lu-PSMA-617) to be administered to a subject in need is based on the radiation dose to be administered to the subject. The radiation dose can be expressed as a unit dose (in MBq) or radiation dose per kg of body weight (in kBq / kg). When referring to values ​​associated with radioactivity, such as 7.4 GBq (200 mCi) of radioactivity, this amount can refer to the radioactivity at the date and time of administration.

[0214] In the method of the present invention, [177Lu]Lu-PSMA-617 can be administered in unit doses of about 3 GBq to about 10 GBq, such as about 3 GBq, about 4 GBq, about 5 GBq, about 6 GBq, about 7 GBq, about 8 GBq, about 9 GBq, or about 10 GBq. In some embodiments, the amount of [177Lu]Lu-PSMA-617 administered in combination with DDRi can be reduced compared to a monotherapy approach without reducing therapeutic efficacy. In some embodiments, [177Lu]Lu-PSMA-617 can be administered in unit doses of about 6 GBq to about 8 GBq. In some embodiments, [177Lu]Lu-PSMA-617 can be administered in combination with DDRi in unit doses of about 7.4 GBq (e.g., 7.4 GBq (+ / - 10%)), achieving one or more improvements in therapeutic efficacy compared to [177Lu]Lu-PSMA-617 monotherapy.

[0215] Typically, the amount of DDRi to be administered to a subject in need is based on factors such as: the severity of the PSMA-expressing cancer, characteristics of the subject being treated (e.g., the specific animal or human subject being treated, age, weight, and health status), frequency of treatment, route of administration, severity of side effects from one or more DDRi compounds, and / or the amount of 177Lu]Lu-PSMA-617 being administered. In some embodiments, a therapeutically effective dose may be the maximum dose or dosing regimen that avoids significant side effects or toxicity, or results in unacceptable toxicity. In some embodiments, a therapeutically effective dose is the minimum dose that provides improvement in: degree of response, slowing of cancer or its symptoms progression, duration of remission, progression-free survival, prostate-specific antigen (PSA) levels, alkaline phosphatase (ALP) levels, lactate dehydrogenase (LDH) levels, pain intensity, Functional Assessment of Cancer Therapy (FACT) score, health-related quality of life, number of hospitalizations, improvement in duration of hospitalization and / or overall survival, or improvement in another clinical indicator or parameter. Improvement in a clinical indicator or parameter can be at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, where 100% is defined as a clinical indicator or parameter exhibited by a healthy subject.

[0216] In some embodiments, the amount of DDRi administered in combination with [177Lu]Lu-PSMA-617 can be reduced compared to monotherapy without reducing therapeutic efficacy. In some embodiments, the amount of DDRi is a synergistically effective amount. Improvement in a clinical indicator or parameter can be at least 100%, at least 105%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, at least 170%, at least 175%, at least 180%, at least 185%, at least 190%, at least 195%, at least 200%, at least 205%, at least 210%, at least 215%, at least 220%, at least 225%, at least 230%, at least 235%, of which 240% or at least 250%, wherein 100% can be defined as a clinical indicator or parameter observed after DDRi monotherapy or [177Lu]Lu-PSMA-617 monotherapy.

[0217] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the ATM inhibitors listed in Table 1, XRD-0394 and SX-RDS1, or pharmaceutically acceptable salts thereof.

[0218] In some embodiments, the ATM inhibitor is:

[0219] ,

[0220] 7-Fluoro-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]-1-propane-2-ylimidazo[4,5-c]quinoline-2-one (AZD1390), and the dosage can be about 10 mg, 40 mg or 80 mg.

[0221] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the ATR inhibitors listed in Table 2, LF0397, IMP-9064, SC0245 and ATRN-119, or a pharmaceutically acceptable salt thereof.

[0222] In some embodiments, the ATR inhibitor is:

[0223] ,

[0224] Imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-λ 6 -Thiocarbazine (celasetebuconazole (AZD6738)), and the dosage can be about 160 mg.

[0225] In some embodiments, the ATR inhibitor is:

[0226] ,

[0227] 2-Amino-6-fluoro-N-[5-fluoro-4-[4-[4-(oxecyclobutane-3-yl)piperazin-1-carbonyl]piperidin-1-yl]pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, plus tesetephthalamide (M4344, VX-803), and the dosage can be about 10 mg, 20 mg or 40 mg.

[0228] Specifically, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the PARP inhibitors listed in Table 3, or a pharmaceutically acceptable salt thereof. In some embodiments, PARPs do not include olaparib.

[0229] In some embodiments, the PARP inhibitor is:

[0230] ,

[0231] 6-Fluoro-2-[4-(methylaminomethyl)phenyl]-3,10-diazatricyclo[6.4.1.0] 4,13 [13-C-1,4,6,8(13)-Tetraen-9-one (Lucapani (PF-01367338)), and the dosage can be about 600 mg.

[0232] In some embodiments, the PARP inhibitor is:

[0233] ,

[0234] 4-[(4-hydroxypiperidin-1-yl)methyl]-8-oxa-15,16-diazatetracyclo[7.7.1.] 2,7 .0 13,17 [Heptadec-1(16),2(7),3,5,9,11,13(17)-heptaen-14-one (E7016), and the dosage can be about 320 mg.]

[0235] In some embodiments, the PARP inhibitor is:

[0236] ,

[0237] 2-[(2R)-2-methylpyrrolidone-2-yl]-1H-benzimidazole-4-carboxamide (Vilipanib (ABT-888)), and the dosage can be about 40, 80 and 120 mg.

[0238] In some embodiments, the PARP inhibitor is:

[0239] ,

[0240] 2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide (nirapanib (ZL-2306)), and the dosage can be approximately 300 mg once daily.

[0241] In some embodiments, the PARP inhibitor is:

[0242] ,

[0243] 4-Iodo-3-nitrobenzamide (Iniparib (BSI-201)), and the dosage can be about 5.6 mg / kg.

[0244] In some embodiments, the PARP inhibitor is:

[0245] ,

[0246] (11S,12R)-7-fluoro-11-(4-fluorophenyl)-12-(2-methyl-1,2,4-triazol-3-yl)-2,3,10-triazatricyclic [7.3.1.0] 5,13 [Tetrazol-1,5(13),6,8-tetraen-4-one (tarazopanib (BMN 673)), and the dosage can be about 0.5 or 1 mg.]

[0247] In some embodiments, the PARP inhibitor is:

[0248] ,

[0249] 11-(1,3-dihydroisoindole-2-ylmethyl)-2,3,10,12-tetraazatricyclic[7.3.1.05,13]tetane-1,5(13),6,8,11-pentaen-4-one (Stenoparib (2X-121 / E7449)), and the dosage may be about 100 mg.

[0250] In some embodiments, the PARP inhibitor is:

[0251] ,

[0252] 14-Methoxy-9-[(4-methylpiperazin-1-yl)methyl]-9,19-diazapentacyclo[10.7.0.0] 2,6 .0 7, 11 .0 13,18 [Ninedeca-1(12),2(6),7(11),13(18),14,16-hexane-8,10-dione (CEP-9722), and the dosage can be about 150 mg.]

[0253] In some embodiments, the PARP inhibitor is:

[0254] ,

[0255] 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazine-1- (olaparib (KU-0059436, AZD2281)), and the dosage can be about 300 mg.

[0256] In some embodiments, the PARP inhibitor is:

[0257] ,

[0258] 6-Fluoro-5-[4-[(5-Fluoro-2-methyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-N-methylpyridine-2-carboxamide (AZD9574), and the dosage can be about 440 μg.

[0259] In some embodiments, the PARP inhibitor is:

[0260] ,

[0261] 5-Fluoro-1-[[4-Fluoro-3-(4-pyrimidin-2-ylpiperazin-1-carbonyl)phenyl]methyl]quinazolin-2,4-dione (Senaparib (IMP4297)), and the dosage can be about 100 mg.

[0262] In some embodiments, the PARP inhibitor is:

[0263] ,

[0264] 4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one (fluzoparib (SHR-3162)), and the dosage can be about 100 or 150 mg.

[0265] In some embodiments, the PARP inhibitor is:

[0266] ,

[0267] 2-(1-Cyclohexylpiperidin-4-yl)-3-oxoisoindoline-4-carboxamide (NMS-293), and the dosage can be about 100 mg.

[0268] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the DNA-PK inhibitors listed in Table 4, XRD-0394, SN-39536, XZP-6877 and IMP-11, or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, the DNA-PK inhibitor is:

[0270] ,

[0271] 8-[(2S)-1-[[6-(4,6-dideuter-2-methylpyrimidin-5-yl)pyrimidin-4-yl]amino]propane-2-yl]-N-methylquinoline-4-carboxamide (VX-984 (M9831)), and the dosage can be about 120 mg, 240 mg, 480 mg or 720 mg.

[0272] In some embodiments, the DNA-PK inhibitor is:

[0273] ,

[0274] (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazine-3-yl)methanol (dexamethasone / pepositeb (M3814)), and the dosage can be about 50 mg, 100 mg, 150 mg or 250 mg.

[0275] In some embodiments, the DNA-PK inhibitor is

[0276]

[0277] 5-Ethyl-3-[2-methyl-6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl]-7,8-dihydropyrazino[2,3-b]pyrazin-6-one (CC-115), and the dosage may be about 7.5 or 10 mg.

[0278] In some embodiments, the DNA-PK inhibitor is:

[0279] ,

[0280] (E)-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinoline-6-yl]-4-(dimethylamino)but-2-enamide (lenatinib), and the dosage can be about 240 mg.

[0281] In some embodiments, the DNA-PK inhibitor is:

[0282] ,

[0283] (3S)-3-amino-4-[5-[bis(2-chloroethyl)amino]-2-methylphenyl]butyric acid (QBS10072S), and the dosage can be approximately 12 mg / m³. 2 injection.

[0284] In some embodiments, the DNA-PK inhibitor is:

[0285] ,

[0286] (2S)-2-amino-5-[[(2R)-3-[2-[bis[bis(2-chloroethyl)amino]phosphoryloxy]ethylsulfonyl]-1-[[(R)-carboxy(phenyl)methyl]amino]-1-oxopropyl-2-yl]amino]-5-oxovaleric acid (canphosphoramide (TLK-286, TER286)), and the dosage can be approximately 1000 mg / m 2 .

[0287] In some embodiments, the DNA-PK inhibitor is XRD-0394 from XRad Therapeutics, and the dosage may be about 40 mg, 80 mg or 160 mg.

[0288] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the WEE1 inhibitors listed in Table 5, SC0191, SY-4835 and IMP7068, or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, the WEE1 inhibitor is:

[0290] ,

[0291] 1-[6-(2-hydroxypropyl-2-yl)pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-propyl-2-enylpyrazolo[3,4-d]pyrimidin-3-one (Adavocetib (AZD1775, MK-1775)), and the dosage can be about 300 mg.

[0292] In some embodiments, the WEE1 inhibitor is:

[0293] ,

[0294] 4-(2,4-dichloro-5-methoxyaniline)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carboxylonitrile (bosutinib), and the dosage can be about 400 mg.

[0295] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the PKMYT1 inhibitors and ACR-2316 listed in Table 6, or a pharmaceutically acceptable salt thereof.

[0296] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the CHK1 selective inhibitors listed in Table 7 and VER250840, or pharmaceutically acceptable salts thereof.

[0297] In some embodiments, the CHK1 selective inhibitor is:

[0298] ,

[0299] (2S,3R,4R,6R,18R)-18-hydroxy-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.1] 2,6 .0 7,28 .0 8,13 .0 15,19 .0 20,27 .0 21,26 ] 8,10,12,14,19,21,23,25,27-nonaen-16-one (7-hydroxyastrosporin (UNC-01)), and the dosage can be approximately 68 or 135 mg / m 2 .

[0300] In some embodiments, the CHK1 selective inhibitor is:

[0301] ,

[0302] (2R)-2-amino-2-cyclohexyl-N-[2-(1-methylpyrazol-4-yl)-9-oxo-3,10,11-triazatricyclo[6.4.1.0] 4,13[13,11-pentaen-6-yl]acetamide (PF477736), and the dosage can be approximately 750 to 1250 mg / m³. 2 .

[0303] In some embodiments, the CHK1 selective inhibitor is:

[0304] ,

[0305] 6-Bromo-3-(1-methylpyrazol-4-yl)-5-[(3R)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidine-7-amine (MK8776 / SCH900776), and the dosage can be about 10, 20, 40 or 56 mg / m 2 .

[0306] In some embodiments, the CHK1 selective inhibitor is:

[0307] ,

[0308] 5-[[4-[[(2R)-morpholin-2-yl]methylamino]-5-(trifluoromethyl)pyridin-2-yl]amino]pyrazine-2-carboxylonitrile (CCT245737 (SRA737, PNT-737)), and the dosage can be about 500 mg.

[0309] In some embodiments, the CHK1 selective inhibitor is:

[0310] ,

[0311] 1-[5-bromo-4-methyl-2-[[(2S)-morpholin-2-yl]methoxy]phenyl]-3-(5-methylpyrazin-2-yl)urea (LY2603618, rabucetibu), and the dosage can be about 230-275 mg.

[0312] In some embodiments, the CHK1 selective inhibitor is:

[0313] ,

[0314] 5-[[5-[2-(3-aminopropoxy)-6-methoxyphenyl]-1H-pyrazol-3-yl]amino]pyrazine-2-carboxynitrile (Presetex (LY2606368)), and the dosage can be about 105, 150 or 170 mg / m³. 2 .

[0315] In some embodiments, the CHK1 selective inhibitor is:

[0316] ,

[0317] N-[4-[(3R)-3-aminopiperidin-1-yl]-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]cyclopropanecarboxamide (ARRY575, GDC-0575), and the dosage can be about 45 or 80 mg.

[0318] In some embodiments, the CHK1 selective inhibitor is:

[0319] ,

[0320] 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide (AZD7762), and the dosage can be about 6, 9, 14, 21, 30, 32 or 40 mg.

[0321] In some embodiments, the CHK1 selective inhibitor is:

[0322] ,

[0323] 3-(1-Ethylpiperidin-4-yl)oxy-5,8,10-triazatricyclic [7.4.0.0] 2,7 [Tweldecarbon-1(9),2,4,6,10,12-hexene-4-carboxynitrile (GDC0425), and the dosage can be about 60-80 mg.]

[0324] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the CHK2 selective inhibitors listed in Table 8, or a pharmaceutically acceptable salt thereof.

[0325] In some embodiments, the CHK2 selective inhibitor is:

[0326] ,

[0327] 3-(carbamoylamino)-5-[2-(3-fluorophenyl)ethynyl]-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide (PHI-101), and the dosage can be about 40, 80, 120, 160, 200 or 240 mg.

[0328] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the dual CHK1 / 2 inhibitors listed in Table 9, or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, the dual CHK1 / 2 inhibitors are:

[0330] ,

[0331] 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide (AZD7762), and the dosage can be about 6, 9, 14, 21, 30, 32 or 40 mg.

[0332] In some embodiments, the dual CHK1 / 2 inhibitors are:

[0333] ,

[0334] 5-[[5-[2-(3-aminopropoxy)-6-methoxyphenyl]-1H-pyrazol-3-yl]amino]pyrazine-2-carboxynitrile (Presetex (LY2606368)), and the dosage can be about 105, 150 or 170 mg / m³. 2 .

[0335] In some embodiments, the dual CHK1 / 2 inhibitors are:

[0336] ,

[0337] (2R)-2-[[(2R)-2-[[(2R)-5-amino-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-amino-3-(4-benzoylphenyl)propionyl]amino]-3-hydroxypropionyl]amino]-3-(1H-indole-3-yl) [Propionyl]amino]-3-hydroxypropionyl]amino]-3-(2,3,4,5,6-pentafluorophenyl)propionyl]amino]-3-cyclohexylpropionyl]amino]-5-aminoformamidinyl]amino]-5-aminoformamidinyl]amino]-5-aminoformamidinyl]amino]-5-oxovaleryl]amino]-5-aminoformamidinyl]amino]-5-aminoformamidinyl]amino]-5-aminoformamidinyl acid (CBP501), and the dosage can be about 16 or 25 mg / m 2 .

[0338] In some embodiments, the dual CHK1 / 2 inhibitors are:

[0339] ,

[0340] 1-[2-(3-aminopropoxy)phenyl]-3-pyrazin-2-ylurea (XL844), and the dosage can be about 5, 25 or 100 mg.

[0341] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject one or more of the Polθ inhibitors listed in Table 10, ART4215, ART6043, RP-3467 and GSK101 (GSK4524101 / IDE705), or a pharmaceutically acceptable salt thereof.

[0342] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the RAD51 inhibitors listed in Table 11, or a pharmaceutically acceptable salt thereof.

[0343] In some embodiments, the RAD51 inhibitor is:

[0344] ,

[0345] N-[3-(tert-butylaminosulfonyl)-4-[2-[4-(propane-2-yloxycarbonylamino)cyclohexyl]-1,3-thiazolyl-5-yl]phenyl]carbamate propane-2-yl ester (CYT0851), and the dosage can be about 300 or 400 mg.

[0346] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the USP1 inhibitors listed in Table 12, TNG348, HSK39775, FT-3171 (Debio 0432) and ISM3091 (XL309), or a pharmaceutically acceptable salt thereof.

[0347] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the PLK1 inhibitors in Table 13, or a pharmaceutically acceptable salt thereof.

[0348] In some embodiments, the PLK1 inhibitor is:

[0349] ,

[0350] 1-(2-hydroxyethyl)-8-[5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)anilino]-4,5-dihydropyrazolo[4,3-h]quinazolin-3-carboxamide (Olvancetib), and the dosage can be about 12, 15 or 18 mg / m². 2 .

[0351] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the Aurora kinase inhibitors listed in Table 14 and WJ05129, or a pharmaceutically acceptable salt thereof.

[0352] In some embodiments, the Aurora kinase inhibitor is the Aurora kinase A inhibitor WJ05129, and the dosage may be about 1.25, 2.5, 5, 7.5 or 10 mg.

[0353] In some embodiments, the Aurora kinase inhibitor is an Aurora kinase A inhibitor:

[0354] ,

[0355] 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimidino[5,4-d][2]benzozaza-2-yl]amino]-2-methoxybenzoic acid (alicetebuconazole (MLN8237)), and the dosage can be about 50 mg.

[0356] In some embodiments, the Aurora kinase inhibitor is an Aurora kinase B inhibitor:

[0357]

[0358] 2-[ethyl-[3-[4-[[5-[2-(3-fluoroaniline)-2-oxoethyl]-1H-pyrazol-3-yl]amino]quinazolin-7-yl]oxypropyl]amino]ethyl dihydrogen phosphate (balaseteb (AZD1152)), and the dosage can be about 200 mg.

[0359] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the mutant p53 reactivators and PC14586 listed in Table 15, or pharmaceutically acceptable salts thereof.

[0360] In some embodiments, the mutant p53 reactivator is:

[0361]

[0362] 2-(hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octane-3-one (APR246), and the dosage can be about 60 mg / kg.

[0363] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the PARG inhibitors and IDE161 listed in Table 16, or a pharmaceutically acceptable salt thereof.

[0364] In particular, this disclosure provides a method for treating a subject with PSMA-expressing cancer, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the WRN inhibitors listed in Table 17, RO7589831 and HRO761, or a pharmaceutically acceptable salt thereof.

[0365] In one or more of the above embodiments, [ 177 The effective dose of Lu]Lu-PSMA-617, DDRi, or both is lower than the amount required for a single-therapy response to objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, changes in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers relative to baseline, or a combination thereof. For example, [ 177The effective dose of Lu]Lu-PSMA-617, DDRi, or both may be at least 10% to about 50% lower than the dose required for a monotherapy response.

[0366] In some embodiments, [ 177 The therapeutically effective dose of Lu-PSMA-617 can be compared with [ 177 The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, changes in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers relative to baseline, or combinations thereof, required for Lu-PSMA-617 monotherapy. 177 The amount of Lu]Lu-PSMA-617 is approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or approximately 50%.

[0367] In some embodiments, the therapeutically effective dose of DDRi may be approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or approximately 50% lower than the amount of DDRi required to achieve objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, changes in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers relative to baseline, or combinations thereof, as observed with DDRi monotherapy.

[0368] In some embodiments, with the application of [ 177 Compared to monotherapy, Lu]Lu-PSMA-617 or DDRi, the methods described above produce synergistic responses in subjects, such as synergistic anticancer responses.

[0369] In some embodiments, implementing the method described above broadens the application [ 177 Lu]Lu-PSMA-617 or DDRi can be used as a therapeutic index for monotherapy. For example, implementing the method described above can [ 177 The treatment index of Lu]Lu-PSMA-617 monotherapy or DDRi monotherapy is broadened by at least about 10% to about 50%.

[0370] As is common in radiotherapy, to deliver the total radiation dose required to eradicate PSMA-expressing cancer, the method may include administering [177Lu]Lu-PSMA-617 approximately every 4 to 8 weeks for multiple cycles. In the method of the present invention, a therapeutically effective dose of [177Lu]Lu-PSMA-617 (e.g., approximately 3 GBq to approximately 10 GBq as described above) may be administered to the subject approximately every 4 to 8 weeks (e.g., approximately every 4 to 6 weeks, approximately every 6 to 8 weeks, approximately every 4 to 5 weeks, approximately every 5 to 8 weeks, approximately every 4 to 7 weeks, approximately every 5 to 6 weeks, approximately every 5 to 7 weeks, and approximately every 6 to 7 weeks).

[0371] In some embodiments, the number of weeks and / or cycles of [177Lu]Lu-PSMA-617 administration in the method of the present invention can be reduced compared to [177Lu]Lu-PSMA-617 monotherapy without compromising therapeutic efficacy. In some embodiments, the number of weeks and / or cycles of [177Lu]Lu-PSMA-617 administration required to achieve the desired clinical endpoints or parameters can be reduced compared to [177Lu]Lu-PSMA-617 monotherapy. In some embodiments, a therapeutically effective amount (e.g., about 3 GBq to about 10 GBq as described above) of [177Lu]Lu-PSMA-617 may be administered to the subject once every about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks.

[0372] In some embodiments, a therapeutically effective amount (e.g., about 3 GBq to about 10 GBq as described above) of [177Lu]Lu-PSMA-617 may be administered to the subject for a duration of 4 to 6 cycles as described above. For example, a therapeutically effective amount of [177Lu]Lu-PSMA-617 may be administered approximately every 4 to 8 weeks for 4, 5, or 6 cycles.

[0373] In some embodiments, a therapeutically effective amount of [177Lu]Lu-PSMA-617 may be administered approximately every 4 to 6 weeks for 4 to 6 cycles; approximately every 6 to 8 weeks for 4 to 6 cycles; approximately every 6 to 8 weeks for 4 cycles; approximately every 6 to 8 weeks for 5 cycles; approximately every 6 to 8 weeks for 6 cycles; approximately every 4 to 5 weeks for 4 to 6 cycles; approximately every 4 to 7 weeks for 4 to 6 cycles; approximately every 5 to 8 weeks for 4 to 6 cycles; approximately every 5 to 6 weeks for 4 to 6 cycles; approximately every 5 to 7 ... Use once, for 4 to 6 cycles; apply approximately every 6 to 7 weeks, for 4 to 6 cycles; apply approximately every 4 weeks, for 4 to 6 cycles; apply approximately every 5 weeks, for 4 to 6 cycles; apply approximately every 6 weeks, for 4 to 6 cycles; apply approximately every 7 weeks, for 4 to 6 cycles; apply approximately every 8 weeks, for 4 to 6 cycles; apply approximately every 4 weeks, for 4 cycles; apply approximately every 4 weeks, for 6 cycles; apply approximately every 6 weeks, for 4 cycles; apply approximately every 6 weeks, for 6 cycles; apply approximately every 8 weeks, for 4 cycles; or apply approximately every 8 weeks, for 6 cycles.

[0374] In some embodiments, a therapeutically effective amount of [177Lu]Lu-PSMA-617 may be administered approximately every 5 weeks for 4 cycles; approximately every 5 weeks for 6 cycles; approximately every 7 weeks for 4 cycles; approximately every 7 weeks for 6 cycles; approximately every 4 weeks for 5 cycles; approximately every 6 weeks for 5 cycles; approximately every 8 weeks for 5 cycles; approximately every 5 weeks for 5 cycles; or approximately every 7 weeks for 5 cycles.

[0375] The duration or frequency of administration of a therapeutically effective dose of DDRi can vary depending on the compound used, the subject being treated, and the specific PSMA-expressing cancer being treated. In some embodiments, the duration or frequency may be the maximum duration or frequency regimen to avoid significant side effects or toxicity or unacceptable toxicity. In some embodiments, the duration or frequency may be the shortest duration or lowest frequency providing improvement in the clinical indicators or parameters described above, or the shortest duration or lowest frequency of synergistic effects.

[0376] In some embodiments, the therapeutically effective amount of DDRi is in [ 177 Lu]Lu-PSMA-617 was administered within 24 hours, in [ 177 Lu]Lu-PSMA-617 was administered within 22 hours, in [ 177 Lu]Lu-PSMA-617 was administered within 20 hours, in [ 177Lu]Lu-PSMA-617 was administered within 18 hours, in [ 177 Lu]Lu-PSMA-617 was administered within 16 hours, in [ 177 Lu]Lu-PSMA-617 was administered within 14 hours, in [ 177 Lu]Lu-PSMA-617 was administered within 12 hours, in [ 177 Lu]Lu-PSMA-617 was administered within 10 hours, in [ 177 Lu]Lu-PSMA-617 was administered within 8 hours, in [ 177 Lu]Lu-PSMA-617 was administered within 6 hours, in [ 177 Lu]Lu-PSMA-617 was administered within 4 hours, in [ 177 Lu]Lu-PSMA-617 was administered within 3 hours, in [ 177 Lu]Lu-PSMA-617 was administered within 2 hours, in [ 177 Lu]Lu-PSMA-617 was administered within 1 hour or [ 177 Lu-PSMA-617 is administered within 30 minutes at one or more doses. In some embodiments, a therapeutically effective amount of DDRi is administered at one or more doses, and a therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 is administered simultaneously (optionally in separate dosage forms) at one or more doses.

[0377] In some embodiments, a therapeutically effective amount of DDRi is administered [ 177 At least 16 hours after application of Lu-PSMA-617, […] 177 At least 20 hours after applying Lu-PSMA-617, […] 177 At least 24 hours after application of Lu-PSMA-617, […] 177 At least 28 hours after application of Lu-PSMA-617, […] 177 At least 32 hours after application of Lu-PSMA-617, […] 177 At least 36 hours after application of Lu-PSMA-617, […] 177 At least 40 hours after application of Lu-PSMA-617, […] 177 At least 44 hours after application of Lu-PSMA-617, […] 177 At least 48 hours after application of Lu-PSMA-617, […] 177 At least 52 hours after application of Lu-PSMA-617, […] 177 At least 56 hours after application of Lu-PSMA-617, […]177 At least 60 hours after application of Lu-PSMA-617, […] 177 At least 64 hours after application of Lu-PSMA-617, […] 177 At least 68 hours after application of Lu-PSMA-617, […] 177 At least 72 hours after application of Lu-PSMA-617, […] 177 At least 76 hours after application of Lu-PSMA-617, […] 177 At least 80 hours after application of Lu-PSMA-617, […] 177 At least 84 hours after application of Lu-PSMA-617, […] 177 At least 88 hours after application of Lu-PSMA-617, […] 177 At least 92 hours after application of Lu-PSMA-617, […] 177 At least 98 hours after application of Lu-PSMA-617, […] 177 At least 102 hours after application of Lu-PSMA-617, […] 177 At least 106 hours after application of Lu-PSMA-617, […] 177 At least 110 hours after application of Lu-PSMA-617, […] 177 At least 114 hours after application of Lu-PSMA-617, […] 177 Lu]Lu-PSMA-617 for at least 118 hours after administration, or after [ 177 Lu]Lu-PSMA-617 is administered at least 122 hours after treatment with one or more doses. In some embodiments, a therapeutically effective amount of DDRi is administered at one or more doses over a course of treatment of about or at least about 5 days.

[0378] "At least about 5 days" can encompass at least 1, 2, 3, or 4 weeks, or at least 1, 2, 3, 4, 5, or 6 months. In some cases, at least about 5 days can be 4 to 8 weeks, lasting for one or more cycles. These cycles can have the same periodicity as the 177Lu]Lu-PSMA-617 cycle, or they can occur at different treatment intervals.

[0379] In application [ 177 Lu-PSMA-617 can be administered at regular intervals (e.g., once, twice, three times, or every few days) at least 16 hours after administration or within a course of approximately 5 days. 177 The Lu]Lu-PSMA-617 cycle is performed on a specific date, or continuously.

[0380] In some embodiments, DDRi in [ 177 Lu]Lu-PSMA-617 was applied within 24 hours and during the application of [ 177 At least 16 hours after application of Lu-PSMA-617 (e.g., after administration of […]). 177 Lu]Lu-PSMA-617 within approximately or at least 5 days of treatment, or during the administration of [ 177 Lu-PSMA-617 is administered at any time interval between 16 hours and approximately or at least 5 days. In some embodiments, DDRi is administered within […]. 177 Lu]Lu-PSMA-617 was applied within 22 hours and during the application of [ 177 At least 16 hours after application of Lu-PSMA-617 (e.g., after administration of […]). 177 Lu]Lu-PSMA-617 within approximately or at least 5 days of treatment, or during the administration of [ 177 Lu-PSMA-617 is administered at any time interval between 16 hours and approximately 5 days after administration. In some embodiments, DDRi is administered within […]. 177 Lu]Lu-PSMA-617 was applied within 20 hours and during the application of [ 177 At least 16 hours after application of Lu-PSMA-617 (e.g., after administration of […]). 177 Lu]Lu-PSMA-617 within approximately or at least 5 days of treatment, or during the administration of [ 177 Lu-PSMA-617 is administered at any time interval between 16 hours and approximately 5 days after administration. In some embodiments, DDRi is administered within […]. 177 Lu]Lu-PSMA-617 was applied within 18 hours and during the application of [ 177 At least 16 hours after application of Lu-PSMA-617 (e.g., after administration of […]). 177 Within approximately 5 days of a course of treatment following the administration of Lu-PSMA-617, or during the application of […] 177 Lu-PSMA-617 is administered at any time interval between 16 hours and approximately or at least 5 days. In some embodiments, DDRi is administered within […]. 177 Lu]Lu-PSMA-617 was applied within 16 hours and during the application of [ 177 At least 16 hours after application of Lu-PSMA-617 (e.g., after administration of […]). 177 Within approximately 5 days of a course of treatment following the administration of Lu-PSMA-617, or during the application of […] 177 Lu-PSMA-617 is administered at any time interval between 16 hours and approximately or at least 5 days. In some embodiments, DDRi is administered within […]. 177Lu]Lu-PSMA-617 was applied within 14 hours and during the application [ 177 At least 16 hours after application of Lu-PSMA-617 (e.g., after administration of […]). 177 Lu]Lu-PSMA-617 within approximately or at least 5 days of treatment, or during the administration of [ 177 Lu-PSMA-617 is administered at any time interval between 16 hours and approximately or at least 5 days. In some embodiments, DDRi is administered within […]. 177 Lu]Lu-PSMA-617 was applied within 12 hours and during the application of [ 177 At least 16 hours after application of Lu-PSMA-617 (e.g., after administration of […]). 177 Lu]Lu-PSMA-617 within approximately or at least 5 days of treatment, or during the administration of [ 177 Lu-PSMA-617 is administered at any time interval between 16 hours and approximately or at least 5 days. In some embodiments, DDRi is administered within […]. 177 Lu]Lu-PSMA-617 was applied within 10 hours and during the application of [ 177 At least 16 hours after application of Lu-PSMA-617 (e.g., after administration of […]). 177 Lu]Lu-PSMA-617 within approximately or at least 5 days of treatment, or during the administration of [ 177 Lu-PSMA-617 is administered at any time interval between 16 hours and approximately or at least 5 days. In some embodiments, DDRi is administered within […]. 177 Lu]Lu-PSMA-617 was applied within 8 hours and during the application [ 177 At least 16 hours after application of Lu-PSMA-617 (e.g., after administration of […]). 177 Lu]Lu-PSMA-617 within approximately or at least 5 days of treatment, or during the administration of [ 177 Lu-PSMA-617 is administered at any time interval between 16 hours and approximately 5 days after administration. In some embodiments, DDRi is administered within […]. 177 Lu]Lu-PSMA-617 was applied within 6 hours and during the application [ 177 At least 16 hours after application of Lu-PSMA-617 (e.g., after administration of […]). 177 Lu]Lu-PSMA-617 within approximately or at least 5 days of treatment, or during the administration of [ 177 Lu-PSMA-617 is administered at any time interval between 16 hours and approximately 5 days after administration. In some embodiments, DDRi is administered within […]. 177 Lu]Lu-PSMA-617 was applied within 4 hours and during the application [ 177At least 16 hours after application of Lu-PSMA-617 (e.g., after administration of […]). 177 Lu]Lu-PSMA-617 within approximately or at least 5 days of treatment, or during the administration of [ 177 Lu-PSMA-617 is administered at any time interval between 16 hours and approximately or at least 5 days. In some embodiments, DDRi is administered within […]. 177 Lu]Lu-PSMA-617 was applied within 2 hours and during the application [ 177 At least 16 hours after application of Lu-PSMA-617 (e.g., after administration of […]). 177 Lu]Lu-PSMA-617 within approximately or at least 5 days of treatment, or during the administration of [ 177 Lu-PSMA-617 is administered at any time interval between 16 hours and approximately 5 days after administration. In some embodiments, DDRi is administered within […]. 177 Lu]Lu-PSMA-617 was applied within 1 hour and during the application [ 177 At least 16 hours after application of Lu-PSMA-617 (e.g., after administration of […]). 177 Lu]Lu-PSMA-617 within approximately or at least 5 days of treatment, or during the administration of [ 177 Lu-PSMA-617 can be administered at any time interval between 16 hours and approximately 5 days after administration.

[0381] In some embodiments, when applying [ 177 Lu]Lu-PSMA-617 is administered concurrently with at least one dose of DDRi (optionally alone), and one or more additional doses of DDRi are administered at least 16 hours after concurrent administration (e.g., within a treatment course of about or at least about 5 days after concurrent administration, or at any time interval between 16 hours and about or at least about 5 days after concurrent administration).

[0382] In the methods described herein, the PSMA-expressing cancer can be any cancer exhibiting high PSMA expression compared to corresponding healthy cells or tissues. For example, in various prostate and salivary gland cancers, the PSMA expression level in malignant cells is significantly increased compared to the expression level in healthy cells. In some embodiments, the PSMA-expressing cancer is a PSMA-positive cancer in a biochemical relapse (BCR) state, such as a PSMA-positive cancer in a high-risk BCR state.

[0383] In one or more embodiments of the methods described herein, the cancer expressing PSMA is prostate cancer. In some embodiments, the prostate cancer is PSMA-positive oligometastatic prostate cancer (OMPC). In some embodiments, when the cancer expressing PSMA is prostate cancer, the prostate cancer is metastatic prostate cancer. In some embodiments, the metastatic prostate cancer is metastatic castration-resistant prostate cancer (mCRPC). In some embodiments, the metastatic prostate cancer is PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC).

[0384] Specific embodiments of the treatment method

[0385] In particular, this article provides a method for treating a subject with prostate-specific membrane antigen (PSMA)-expressing cancer, comprising administering to the subject a therapeutically effective dose of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is: (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazoline-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol (M3814) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy response to Lu]Lu-PSMA-617 or this DDRi, the anticancer response is synergistically enhanced. The therapeutically effective dose of DDRi may be the following: about 1 to 1000 mg / kg, about 10 to 900 mg / kg, about 15 to 800 mg / kg, about 20 to 700 mg / kg, about 25 to 600 mg / kg, about 30 mg to 500 mg / kg, about 35 to 400 mg / kg, about 40 to 300 mg / kg, about 45 to 200 mg / kg, or about 50 to 100 mg / kg, optionally about 100 mg / kg, administered twice daily for about or at least about 5 days; or about 50 mg, about 100 mg, about 150 mg, or about 250 mg daily.

[0386] In embodiments, this document provides methods for treating prostate cancer in a subject of need, methods including administering a therapeutically effective dose of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is ((7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(oxan-4-yl)purine-8-one (AZD7648)) or a pharmaceutically acceptable salt thereof. In the examples, the prostate cancer is prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer (PSMA-positive mCRPC).

[0387] In particular, this article provides methods for treating PSMA-expressing cancers in subjects of need, methods including administering a therapeutically effective dose of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is ((7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(oxan-4-yl)purine-8-one (AZD7648)) or a pharmaceutically acceptable salt thereof, thereby relating to [ 177 Compared with monotherapy with Lu-PSMA-617 or this DDRi, the anticancer response was synergistically enhanced. The therapeutically effective dose of DDRi may be the following: about 1 to 1000 mg / kg, about 10 to 900 mg / kg, about 15 to 800 mg / kg, about 20 to 700 mg / kg, about 25 to 600 mg / kg, about 30 mg to 500 mg / kg, about 35 to 400 mg / kg, about 40 to 300 mg / kg, about 45 to 200 mg / kg, or about 50 to 100 mg / kg, optionally about 100 mg / kg, administered once daily.

[0388] In particular, this article provides a method for treating PSMA-expressing cancers in subjects of need, the method comprising administering a therapeutically effective dose of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is:

[0389] (8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one (AZD0156)) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy response to Lu]Lu-PSMA-617 or this DDRi, the anticancer response was synergistically enhanced.

[0390] In particular, this article provides a method for treating PSMA-expressing cancers in subjects of need, the method comprising administering a therapeutically effective dose of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is:

[0391] 1-[5-bromo-4-methyl-2-[[(2S)-morpholin-2-yl]methoxy]phenyl]-3-(5-methylpyrazin-2-yl)urea (LY2603618, labusetetiba) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy response to Lu]Lu-PSMA-617 or this DDRi, the anticancer response was improved or synergistically enhanced.

[0392] In particular, this article provides a method for treating PSMA-expressing cancers in subjects of need, the method comprising administering a therapeutically effective dose of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is:

[0393] (1-[6-(2-hydroxypropyl-2-yl)pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-propyl-2-enylpyrazolo[3,4-d]pyrimidin-3-one (Adavocetib or MK-1775) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy responses to Lu]Lu-PSMA-617 or the aforementioned DDRi, the anticancer response was improved or synergistically enhanced.

[0394] In particular, this article provides a method for treating PSMA-expressing cancers in subjects of need, the method comprising administering a therapeutically effective dose of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is: 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one (olaparib) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared to monotherapy with Lu-PSMA-617 or this DDRi, the anticancer response was synergistically enhanced, optionally wherein the DDRi was administered in combination with […]. 177Lu]Lu-PSMA-617 is administered within 24 hours, and / or the DDRi is administered within 24 hours of administration and for a course of treatment of at least 48 hours.

[0395] In particular, this article provides a method for treating PSMA-expressing cancers in subjects of need, the method comprising administering a therapeutically effective dose of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is:

[0396] ((11S,12R)-7-fluoro-11-(4-fluorophenyl)-12-(2-methyl-1,2,4-triazol-3-yl)-2,3,10-triazatricyclic [7.3.1.0] 5,13 [13-carbohydrate-1,5(13),6,8-tetraen-4-one (tapazopanib) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy responses to Lu]Lu-PSMA-617 or the aforementioned DDRi, the anticancer response was synergistically enhanced.

[0397] In particular, this article provides a method for treating PSMA-expressing cancers in subjects of need, the method comprising administering a therapeutically effective dose of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is:

[0398] ((2S,3R)-1-[3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl]-3-hydroxy-N-methyl-N-(3-methylphenyl)pyrrolidine-2-carboxamide (ART558) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy response to Lu]Lu-PSMA-617 or this DDRi, the anticancer response was synergistically enhanced.

[0399] In embodiments, this document provides methods for treating prostate cancer in a subject of need, methods including administering a therapeutically effective dose of […]. 177Lu]Lu-PSMA-617, and administering a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject, wherein the DDRi is ART6043 or a pharmaceutically acceptable salt thereof. In the examples, the prostate cancer is prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer (PSMA-positive mCRPC). In particular, this document provides methods for treating PSMA-expressing cancers in subjects of need, methods comprising administering a therapeutically effective amount of [Lu-PSMA-617] to the subject. 177 Lu]Lu-PSMA-617, and administered to the subject a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is ART6043 or a pharmaceutically acceptable salt thereof, thereby in conjunction with [ 177 Compared with monotherapy with Lu-PSMA-617 or this DDRi, the anticancer response was improved or synergistically enhanced. 177 Compared to monotherapy response to Lu-PSMA-617 or DDRi, improvement may include prolonged response (e.g., prolonged survival). A therapeutically effective dose of DDRi may be approximately 100 mg / kg. DDRi may be administered daily for at least approximately 5 days (e.g., at least approximately 20 days).

[0400] In particular, this article provides methods for treating PSMA-expressing cancers in subjects of need, methods including administering a therapeutically effective dose of […]. 177 Lu]Lu-PSMA-617, and the subject was given a therapeutically effective amount of a DNA damage response inhibitor (DDRi), wherein the DDRi is ((S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methyl-morpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -Thiodanone (ART0380) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy response to Lu]Lu-PSMA-617 or this DDRi, the anticancer response was synergistically enhanced.

[0401] In any of the specific embodiments described above, the cancer expressing PSMA can be prostate cancer (e.g., metastatic prostate cancer or metastatic castration-resistant prostate cancer (mCRPC), optionally PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC), optionally PSMA-positive oligometastatic prostate cancer (OMPC)) and / or PSMA-positive cancer in a biochemical relapse (BCR) state, optionally PSMA-positive cancer in a high-risk BCR state, [ 177The therapeutically effective dose of Lu-PSMA-617 can be approximately 10 MBq to 10 GBq, such as approximately 0.1 GBq to 10 GBq, approximately 1 GBq to 10 GBq, approximately 3 GBq to 10 GBq, approximately 5 GBq to approximately 9 GBq, or approximately 6 GBq to approximately 8 GBq (optionally approximately 7.4 GBq). DDRi can be administered for approximately, or at least approximately, 5 days, and / or the initial dose of DDRi can be […]. 177 Apply Lu]Lu-PSMA-617 less than 1 hour before application.

[0402] Pharmaceutical Composition

[0403] This document also provides pharmaceutical compositions for use in the methods described above, these pharmaceutical compositions comprising [ 177 Lu]Lu-PSMA-617 and / or DDRi, and pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, [ 177 Lu]Lu-PSMA-617 and / or DDRi are not formulated together and may be supplied separately, for example, as separate pharmaceutical compositions.

[0404] It can be combined with pharmaceutically acceptable carriers, diluents, or excipients to produce a single dosage form. 177 The amount of Lu]Lu-PSMA-617 and / or DDRi will vary depending on the individual subject and the specific method of administration. In some embodiments, it contains [as described above] 177 The unit dosage form of the combination of Lu-PSMA-617 and DDRi will contain the amount of each compound in the combination that would be administered when the compounds are administered alone, or [ 177 The amount of Lu]Lu-PSMA-617 and / or DDRi may be less than the amount of each compound when the compound is applied alone, or [ 177 The amount of Lu]Lu-PSMA-617 and / or DDRi may be greater than the amount of each compound when the compound is administered alone. Pharmaceutically acceptable carriers, diluents, or excipients may be solid, semi-solid, or liquid fillers, diluents, encapsulating materials, or any type of formulation aid.

[0405] The pharmaceutical composition can be administered parenterally. Therefore, in some embodiments, the composition is formulated for delivery via any of these routes of administration. The pharmaceutical composition can be formulated for parenteral administration and administered via parenteral administration. In particular, the pharmaceutical compositions disclosed herein can be formulated for intravenous administration and administered via intravenous administration.

[0406] In some embodiments, pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders reconstituted into sterile injectable solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or mediators include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, β-cyclodextrin, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Appropriate flowability can be maintained, for example, by using coating materials (such as lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants. These compositions may also contain additives such as preservatives, wetting agents, emulsifiers, chelating agents, buffers, and dispersants.

[0407] In some embodiments, the pharmaceutical composition comprises a chelating agent to isolate internally deposited radionuclides. Any chelating agent known in the art that complexes with alpha-emitting radionuclides may be included in the pharmaceutical compositions described herein. In various embodiments, the pharmaceutical composition comprises DTPA. Further exemplary chelating agents that may be included in the pharmaceutical compositions disclosed herein are described in Holik et al., “The Chemical Scaffold of Theranostic Radiopharmaceuticals: Radionuclide, Bifunctional Chelator, and Pharmacokinetics Modifying Linker.” Molecules 27,10 (2022): 3062 and Kostelnik, Thomas I. and Chris Orvig. “Radioactive main group and rare earthmetals for imaging and therapy.” Chemical Reviews 119.2 (2018): 902-956, both of which are incorporated herein by reference in their entirety.

[0408] The pharmaceutical composition may further include stabilizers, such as free radical scavengers or radiostability enhancers, to prevent the autoradiolytic degradation of radioligands. Stabilizers present in the solution disclosed herein may be selected from gentianic acid (2,5-dihydroxybenzoic acid) or salts thereof, ascorbic acid (L-ascorbic acid, vitamin C) or salts thereof (e.g., sodium ascorbate), methionine, histidine, melatonin, ethanol, and Se-methionine. In some cases, the stabilizer may include gentianic acid or a salt thereof instead of ethanol. Suitable stabilizers included in the disclosed pharmaceutical compositions include, but are not limited to, 2,5-dihydroxybenzoic acid or salts thereof, ascorbic acid or a salt thereof, gentianic acid or a salt thereof, methionine, histidine, melatonin, N-acetylmethionine, ethanol, amino acid infusion solutions, or any combination thereof. In some embodiments, the pharmaceutical composition includes a gentianic acid stabilizer. In some embodiments, the pharmaceutical composition includes an ascorbic acid stabilizer. In some embodiments, the pharmaceutical composition includes a stabilizer comprising gentianic acid and ascorbic acid.

[0409] In some embodiments, the pharmaceutical composition comprises one or more buffers to maintain a pH of about 3 to 5. Suitable buffers include, but are not limited to, acetates, citrates, Tris, lactates, and tartrates, and their acidic forms.

[0410] In some embodiments, [ 177 Lu]Lu-PSMA-617 pharmaceutical composition is an aqueous pharmaceutical solution.

[0411] In certain embodiments, this disclosure provides the following aqueous solutions:

[0412] (A) [ 177 Lu]Lu-PSMA-617, with an activity range of 800 to 1200 MBq / ml, 900 to 1100 MBq / ml, 950 to 1050 MBq / ml, or about 1000 MBq / mL (27 mCi / mL).

[0413] (B + C) buffer solution, providing a pH range of 4.5 to 7.0;

[0414] (D) Gentianic acid or its salts, in concentrations ranging from 0.3 to 1.0, 0.3 to 0.5, 0.31 to 0.47 mg / mL, 0.35 to 0.43 mg / mL, 0.37 to 0.41, or about 0.39 mg / mL relative to the free acid;

[0415] (E) Ascorbic acid or its salts, such as its sodium salt, in concentrations ranging from 20 to 52.5 mg / mL, 47.5 to 52.5 mg / mL, 48 to 52 mg / mL, or about 50 mg / mL relative to the sodium salt;

[0416] (F) Penteacin or its salts, in concentrations ranging from 0.08 to 0.12 mg / mL, 0.09 to 0.11 mg / mL, 0.095 to 0.105 mg / mL, or about 0.1 mg / mL relative to the free acid.

[0417] In certain embodiments, this disclosure provides the following aqueous solutions:

[0418] (A) [ 177 Lu]Lu-PSMA-617, with an activity range of 800 to 1200 MBq / ml, 900 to 1100 MBq / ml, 950 to 1050 MBq / ml, or about 1000 MBq / mL (27 mCi / mL).

[0419] (B) Acetic acid, in concentrations ranging from 0.24 to 0.36 mg / mL, 0.27 to 0.33 g / mL, 0.285 to 0.315 mg / mL, or about 0.3 mg / mL;

[0420] (C) Acetates, such as their sodium salts, in concentrations ranging from 0.33 to 0.49 mg / mL, 0.37 to 0.45 mg / mL, 0.39 to 0.43 mg / mL, or about 0.41 mg / mL relative to the sodium salt;

[0421] (D) Gentianic acid or its salts, in concentrations ranging from 0.3 to 1.0, 0.3 to 0.5, 0.31 to 0.47 mg / mL, 0.35 to 0.43 mg / mL, 0.37 to 0.41, or about 0.39 mg / mL relative to the free acid;

[0422] (E) Ascorbic acid or its salts, such as its sodium salt, in concentrations ranging from 20 to 52.5 mg / mL, 47.5 to 52.5 mg / mL, 48 to 52 mg / mL, or about 50 mg / mL relative to the sodium salt;

[0423] (F) Penteacin or its salts, in concentrations ranging from 0.08 to 0.12 mg / mL, 0.09 to 0.11 mg / mL, 0.095 to 0.105 mg / mL, or about 0.1 mg / mL relative to the free acid.

[0424] In some embodiments, the aqueous solution comprises, contains, or consists of: about [ 177Lu-PSMA-617 (approximately 1,000 MBq / mL, approximately 27 mCi / mL), acetic acid (approximately 0.30 mg / mL), sodium acetate (approximately 0.41 mg / mL), gentic acid (approximately 0.39 mg / mL), sodium ascorbate (approximately 50.0 mg / mL), pentimic acid (approximately 0.10 mg / mL), and water for injection (e.g., up to 1 mL), with a pH range of approximately 4.5 to approximately 7.0. The term "approximately" here means ±10% of all components, or ±10% of the radioactive components and ±5% of the non-radioactive components.

[0425] In some embodiments, any of the aqueous solutions of the above embodiments can maintain a radiochemical purity (RCP, determined by HPLC) of ≥ 95% for at least 120 hours when stored at 30°C or below. Therefore, the shelf life of the aqueous solutions disclosed herein is about 120 hours or about 5 days, and in some cases, storage conditions below 30°C (86°F), without freezing, from the calibration date and time.

[0426] In some embodiments, any of the aqueous solutions described above may include no more than 5% (w / w) ethanol or no more than 1% ethanol. In some cases, the solution is substantially free of ethanol.

[0427] In some embodiments, any of the aqueous solutions in the above embodiments may include a total peptide content of 10 to 20 micrograms / mL, 13 to 17 micrograms / mL, 14 to 16 micrograms / mL, or 15 micrograms / mL.

[0428] In some embodiments, any of the aqueous solutions described above may be provided as sterile, preservative-free, transparent, colorless to slightly yellow solutions. In some embodiments, the aqueous solutions are provided as ready-to-use solutions.

[0429] This disclosure further provides individual patient dose units containing a volume of any of the aqueous solutions as described in any of the above embodiments. In some embodiments, the individual patient dose unit volume is about 7.5 to about 12.5 mL of any of the aqueous solutions as described in any of the above embodiments.

[0430] Patient dosage units may be in the form of vials, such as single-dose vials, such as colorless borosilicate (Type I) glass vials, for example, about 30 mL in size, sealed, for example, with a bromobutyl rubber stopper (a stopper with silicate filler and an inorganic coloring system) and a seal (e.g., an aluminum seal), or in the form of pre-filled syringes or cartridges, such as cartridges that can be loaded into devices for infusion / injection, such as cartridges for syringes or infusion systems. The aqueous solutions disclosed herein may be dispensed in vials and then transferred to syringes.

[0431] Dosage units can be supplied in lead-shielded containers. Lead-shielded containers can be placed inside sealed plastic containers. Dosage units can be transported in Type A packaging systems (in accordance with the relevant regulations of the International Air Transport Association (IATA) and the International Road Transport of Dangerous Goods (ADR)). Type A packaging can be designed to meet radiation protection requirements.

[0432] The aqueous solution of any of the above embodiments can be administered intravenously (IV, by bolus injection or infusion), intra-arterially, or intratumorally. The aqueous solution of any of the above embodiments can be administered to the patient by slow intravenous bolus injection (using an infusion pump or manually) over approximately 1 to 10 minutes, for example, through an intravenous catheter pre-filled with, for example, 0.9% sterile sodium chloride solution.

[0433] The aqueous solution of any of the above embodiments may be administered at the above dosage / follow-up amounts and for any of the above durations or number of cycles. In some embodiments, the dosage / follow-up amount is about 7.4 (±10%) GBq (200 (±10%) mCi), once every about 6 weeks, for up to about 6 doses. The dose may be temporarily interrupted (e.g., by extending the dosing interval from about 6 weeks to about 7, 8, 9, or 10 weeks), or the dose may be reduced or increased, for example, by about 20% to about 5.9 (±10%) GBq (160 (±10%) mCi).

[0434] [177Lu] Manufacturing method of Lu-PSMA-617

[0435] The lutetium-177 used in the embodiments of this disclosure can be prepared using two different stable isotope sources (lutetium-176 or ytterbium-176). Lutetium-177 can be obtained via an (n,γ) reaction. Both are present in a nuclear reactor. 177 Methods for producing Lu. One method includes irradiation. 176 Lu, leading to the direct formation 177 Lu. However, this method leads to metastable states. 177m The co-formation of Lu isotopes and other lutetium isotopes. Due to the difficulty and challenge of isotope separation, methods containing... 177 Lu and 177m Lu and other compositions. Such a composition. 177 Combinations of Lu and related isotopes are referred to as carrier-added. 177 Lu source or 177 Lu (CA) source.

[0436] The second method involves short-lived radioisotopes. 177 The β decay of Yb (with a half-life of 1.9 hours) is caused by enrichment. 176 Neutron capture from a Yb (>99%) target. However, 176 Yb (n,γ) 177The low thermal neutron cross-section of the Yb reaction (2.1 target) results in the production of only a very small amount of the desired neutrons compared to the total mass of the target. 177 Lu. However. 177 Lu and 176 The separation of Yb is feasible, resulting in only containing 177 Compositions of Lu isotopes. Such compositions provide additive-free... 177 Lu, abbreviated as Lu 177 Lu (NCA).

[0437] Radioactive nuclides can be in the form of 177 Lutetium-177 in the form of Lu(III) ions 177 Lu). For example, radioactive nuclide ions may originate from HCl solution. 177 LuCl3. The reaction solution may contain... 177 Lu(III) ions with a volumetric activity of at least 17 GBq / mL, 18 GBq / mL, 19 GBq / mL, 20 GBq / mL, 25 GBq / mL, 28 GBq / mL, or at least 30 GBq / mL. The upper limit for radionuclides may be 30, 40, or 50 GBq / mL.

[0438] This disclosure provides a method for producing radionuclide complexes via a reaction, such as a reaction comprising... 177 Lu(III) ions (radioactive nuclides) and PSMA-617 (target-bound organic molecules). The reaction is also known as radiolabeling.

[0439] In some embodiments, it includes [ 177 The radiopharmaceutical solution of Lu-PSMA-617 can be prepared by the following method, thereby obtaining the solution and container respectively, the method comprising the following steps:

[0440] (1) Provide a reaction solution comprising:

[0441] a. 177 Lu(III) ions with a volume activity of at least 17 GBq / mL

[0442] b. A target-binding organic molecule comprising an organic moiety having a binding affinity for prostate-specific membrane antigens and a chelating moiety for chelating Lu(III) ions (i.e., a compound according to formula (I)).

[0443]

[0444] (I), and

[0445] c. One or more stabilizers resistant to radioactive degradation; and

[0446] (2) At sub-atmospheric pressure, optionally in the presence of an inert gas, the target binds organic molecules to... 177 Lu(III) ion reaction to obtain radionuclide complexes in a single container used for radiolabeling.

[0447] Even when 177 Lu(III) ions are derived from unloaded (NCA) 177 When using a Lu(III) ion source (i.e., molar ratio > 1), the reaction solution may include, relative to... 177 Lu(III) ions in molar excess of target-bound organic molecules. Target-bound organic molecules and 177 The molar ratio between Lu(III) ions can be at least 1.2, or between 1.5 and 3.5.

[0448] When using carrier-added (CA) 177 Lu(III) as 177 When using a Lu(III) ion source, the reaction solution can contain, relative to, ions including 177 Lu(III) ions, 176 Lu(III) ions, 175 Lu(III) and metastable state 177m All Lu(III) ions (present in the solution provided for immediate reaction with the volume activities given above) 177 The composition of Lu(III) ions contains a molar excess of target-bound organic molecules. The target-bound organic molecules include... 177 Lu(III) ions, 176 Lu(III) ions, 175 Lu(III) and metastable state 177m The molar ratio between all groups of Lu(III) ions can be at least 1.2, or between 1.5 and 3.5.

[0449] The reaction solution may include a pharmaceutically acceptable buffer solution to provide a pH in the range of 2 to 8, which is suitable for... 177 The reaction between Lu(III) ions and target-bound organic molecules. In some cases, pharmaceutically acceptable buffers provide a pH in the range of 4 to 6.

[0450] Pharmaceutically acceptable buffer solutions may include acetate buffer, citrate buffer, or phosphate buffer. Acetate buffer may include acetic acid and sodium acetate. Citrate buffer may include citrate and HCl and / or citric acid. Phosphate buffer may include sodium dihydrogen phosphate and disodium hydrogen phosphate.

[0451] In some embodiments, step (1) may include adding a stabilizer resistant to radioactive degradation to the target-binding organic molecule before adding it. 177 Lu(III) ions are mixed. The components of the reaction solution can be mixed under ambient atmosphere and pressure.

[0452] In some embodiments, step (1) may include mixing the components described herein at sub-atmospheric pressure to form a reaction solution. The sub-atmospheric pressure may be within a range suitable for removing gaseous components from the container up to removing them from the solution, but minimizing or avoiding significant evaporation of the solvent (water). The pressure may be at least 150 mbar, 200 mbar, 250 mbar, or 300 mbar below atmospheric pressure. The pressure may be up to 400 mbar, 500 mbar, 650 mbar, or 700 mbar below atmospheric pressure. The pressure may be at least about 250 mbar and up to 500 mbar below atmospheric pressure.

[0453] In some embodiments, step (1) may include degassing the solutions of the components described herein by passing inert gas bubbles through the solution or purging the headspace above each solution with inert gas and then mixing the solutions in an inert gas atmosphere.

[0454] In some embodiments, step (1) may include degassing the solutions of the components by passing inert gas bubbles through the solutions or by purging the headspace above the solutions with inert gas and then mixing the solutions at below atmospheric pressure to form a reaction solution. Below atmospheric pressure may include the pressure described above.

[0455] Mixing and / or degassing at below atmospheric pressure reduces the oxygen concentration in the reaction solution, thereby reducing radioactive degradation.

[0456] In some embodiments, step (1) may include providing the reaction solution in a container (e.g., a single container). Providing the reaction solution in the container may include applying a pressure below atmospheric pressure as described above prior to the mixing step.

[0457] In step (1), the reaction solution may have the following activities: at least 5 Ci, for example about 5 to 20 Ci, about 5 to 15 Ci, about 5 to 12 Ci, about 5.4 to 12 Ci, about 7 to 12 Ci, or about 8 to 12 Ci.

[0458] In step (2), the target-binding organic molecules contained in the reaction solution are made to... 177 Lu(III) ions react with each other at sub-atmospheric pressure to obtain target-bound organic molecules and... 177A radionuclide complex composed of Lu(III) ions. Below atmospheric pressure includes applying the pressure described above in step (1). Reaction at below atmospheric pressure reduces radioactive degradation. Step (2) may include the reaction being carried out in a single container.

[0459] In step (2), the individual containers used for radiolabeling may include oxygen concentrations of less than 7 mg / L, or 6 mg / L, or 5 mg / L, or 4 mg / L, or 3 mg / L, or 2 mg / L, or 1 mg / L (all values ​​at 25°C). Oxygen may be substantially absent in the individual container. The low oxygen concentration in the individual container reduces radioactive degradation. Due to the low oxygen concentration, the individual container may contain a volumetric activity of at least 17 GBq / ml, at least 18 GBq / ml, at least 19 GBq / ml, at least 20 GBq / ml, at least 25 GBq / mL, or at least 30 GBq / mL. 177 Lu(III) ions. 177 The upper limit of the volume activity of Lu(III) ions can be 20, 25, 30, 40, or 50 GBq / mL.

[0460] In step (2), the situation is made as described above relative to... 177 A molar excess of Lu(III) ions is used to target and bind organic molecules to ensure high radiochemical labeling yields. In some embodiments, the method requires no or excludes any purification steps to remove free (i.e., non-chelated) molecules. 177 Lu(III) ions. For example, a solid-phase extraction (SPE) purification step using a tC18 adsorbent column can be used to remove free (non-chelated) Lu(III) ions. 177 Lu(III) ions can be elute using this adsorbent column, however, which may require eluting the product with ethanol, potentially undesirable (A. Mathur et al., Cancer Biother. Radiopharm. 2017, 32, 266-273). Using a tC18 adsorbent column may also result in the removal of the stabilizer, requiring its re-addition (S. Maus et al., Int. J. Diagnostic imaging, 2014, 1, 5-12).

[0461] In step (2), the target binds organic molecules to the target at a pressure below atmospheric pressure. 177 The step of reacting Lu(III) ions to obtain radionuclide complexes can be carried out for 2 to 15 minutes, 4 to 10 minutes, or 5 min ± 0.5 min.

[0462] In step (2), the target binds organic molecules to the target at a pressure below atmospheric pressure. 177 The Lu(III) ion reaction to obtain radionuclide complexes can be carried out at 80°C to 100°C, 90°C to 98°C, or 94°C ± 4°C. Generally, temperatures below 90°C cannot guarantee quantitative labeling yields.

[0463] In step (2), a radionuclide complex solution with a volume of 15 to 19 ml can be obtained.

[0464] Used for manufacturing [ 177 The method for using Lu-PSMA-617 solution may further include the following steps:

[0465] (3) The radionuclide complex formed in step (2) is recovered to obtain the mother liquor.

[0466] The stock solution can be used and is suitable for preparing dispensing solutions that can be dispensed into multiple patient doses (vials) for subsequent administration to patients without further material alteration. In some embodiments, the stock solution contains a volumetric activity of at least 10 GBq / mL. 177 Lu(III) ions, [ 177 Lu]Lu-PSMA-617 radionuclide complex, one or more stabilizers resistant to radioactive degradation, and oxygen at a concentration of less than 50 mg / L. The mother liquor may include... 177 Lu(III) ions with a volumetric activity of at least 10 GBq / ml, at least 11 GBq / ml, at least 12 GBq / ml, at least 13 GBq / ml, at least 15 GBq / ml, or at least 16 GBq / ml.

[0467] One or more stabilizers resistant to radioactive degradation and their properties may be those described above regarding the reaction solution. One or more stabilizers may include gentianic acid or its salts, and their concentration ranges are as described above regarding the reaction solution. In certain embodiments, the reaction solution and mother liquor do not contain ascorbic acid; for example, they contain gentianic acid as a stabilizer but not ascorbic acid. In certain embodiments, the reaction solution and mother liquor do not contain ethanol as a stabilizer. In certain embodiments, the reaction solution and mother liquor do not contain either ascorbic acid or ethanol as a stabilizer.

[0468] Oxygen concentrations can be below 20 mg / L, below 10 mg / L, below 7 mg / L, below 5 mg / L, below 4 mg / L, below 3 mg / L, below 2, or below 1 mg / L (all values ​​are at 25°C). In some cases, the mother liquor is essentially oxygen-free.

[0469] The mother liquor may further include nitrogen at a concentration of up to 20 ml / L at 25°C or argon at a concentration of up to 60 ml / L at 25°C. The presence of an inert gas such as nitrogen or argon in the mother liquor is a result of the steps leading to the formation of the mother liquor, which is part of the method further described below. The concentration of the inert gas in the mother liquor can reduce the radioactive decomposition and degradation of the components in the mother liquor. The mother liquor may include nitrogen at a concentration ranging from 3 to 20 ml / L at 25°C, or from 5 to 15 ml / L or 10 to 15 ml / L at 25°C.

[0470] Alternatively, the mother liquor may include nitrogen gas at a concentration ranging from 3 to 20 mg / L at 25°C, 5 to 15 ml / L at 25°C, or 10 to 15 mg / L. Alternatively, the mother liquor may include argon gas at a concentration ranging from 3 to 60 mg / L at 25°C, or 10 to 50 mg / L or 20 to 40 mg / L at 25°C.

[0471] Methods for determining the concentrations and contents of oxygen, nitrogen, and / or argon in aqueous or gaseous solutions are well-known and have been described in the literature and encyclopedias (see, for example, Determination of Argon in Air and Water, J. Lasa et al., Chem. Anal. (Warsaw), 47, 839 (2002); HH Willard et al., Instrumental methods of analysis, 6th ed., D. Van Norstrand, New York, 1981, pp. 910-912; ML Hitchman, Measurement of dissolved oxygen, John Wiley & Sons, New York, 1978; Ullmann's Encyclopedia of Industrial Chemistry; S. Uchiyama, Analysis of Dissolved Argon, Oxygen, and Nitrogen in Solutions, Shimadzu Corporation publication). [Shimadzu Corporation Publication], July 2021.

[0472] The above descriptions of the ascorbic acid or its salt and ethanol, the target-bound organic molecules, the molar excess of the target-bound organic molecules relative to Lu(III) ions, pH, and pharmaceutically acceptable buffer solutions also apply to the mother liquor. In certain embodiments, the mother liquor may contain radionuclide complexes. 177 Lu PSMA-617, with volumetric activities of 10 to 30, 10 to 25, 15 to 25, 17 to 25, 17 to 20, or 18 to 19 GBq / ml.

[0473] Step (3) may include recovering the radionuclide complex at sub-atmospheric pressure, wherein the pressure range is as given above. Step (3) may also include recovering the radionuclide complex under an inert gas atmosphere. In some embodiments, the step of recovering the radionuclide complex may be performed under an inert gas atmosphere.

[0474] The inert gas atmosphere can be provided by nitrogen or argon. In step (3), due to purging with nitrogen and argon respectively, the mother liquor may include nitrogen at a concentration of up to 20 ml / L at 25°C or argon at a concentration of up to 60 ml / L at 25°C. The mother liquor may include nitrogen at a concentration range of 3 to 20 ml / L at 25°C, or 5 to 15°C or 10 to 15 ml / L at 25°C. The mother liquor may include argon at a concentration range of 3 to 60 ml / L at 25°C, or 10 to 50 ml / L or 20 to 40 ml / L at 25°C.

[0475] In some embodiments, step (3) of recovering the radionuclide complex may include purging the mother liquor container with an inert gas before and during the introduction or transfer of the mother liquor into or from the mother liquor container. Purging the mother liquor container with an inert gas before and during the introduction or transfer of the mother liquor into the mother liquor container reduces the radioactive degradation of the components contained in the mother liquor container.

[0476] In some embodiments, step (3) of recovering the radionuclide complex may include purging the mother liquor container with an inert gas at a pressure at least 250 mbar above atmospheric pressure before and during the introduction or transfer of the mother liquor into or from the mother liquor container. The atmospheric pressure may be at least 300 mbar, 350 mbar, or 400 mbar and up to 450 mbar or 500 mbar.

[0477] The transfer from the single container in step (2) to the mother liquor container in step (3) can be performed at pressure above atmospheric pressure or by syringe. In step (3), the recovery of the radionuclide complex may include rinsing with water for injection (WFI). For example, WFI can be added to the single container in step (2) after the reaction is complete and the solution formed in the single container can be introduced into or transferred to the mother liquor container as described above. This ensures complete (or almost complete) transfer of the solution containing the radionuclide complex while maintaining a relatively high volumetric activity concentration.

[0478] In step (3), the final volume of the mother liquor can be between 20 and 23 ml.

[0479] The method, including steps (1), (2), and (3) above, offers the following technical advantages: maximizing volumetric activity while keeping radioactive degradation to a minimum. This method delivers multiple patient doses per given time unit through large-scale synthesis to meet the growing global demand for radiochemicals used in radiotherapy and diagnostic radiotherapy.

[0480] In some embodiments, step (3) may include introducing or transferring the mother liquor into a single container to obtain a mother liquor container. The mother liquor container may be used to collect solutions formed during the radiolabeling reaction, for example, after the radiolabeling reaction is completed. The mother liquor container may include the aforementioned mother liquor. The mother liquor container may further include a headspace volume above the mother liquor.

[0481] In some embodiments, the mother liquor container for collecting the solution formed in the radiolabeled reaction contains: a mother liquor containing a volumetric activity of at least 10 GBq / mL. 177 Lu(III) ions, target-bound organic molecules (including target-bound organic moieties linked to the chelate moiety), and 177 The product contains a radioactive nuclide complex formed by Lu(III) ions, and one or more stabilizers resistant to radioactive degradation, and also contains a headspace volume above the mother liquor, wherein the headspace volume contains no more than 10 vol% oxygen.

[0482] The headspace gas volume can contain less than 10 vol%, less than 7 vol%, less than 5 vol%, or less than 3 vol% oxygen. The headspace gas volume can also contain essentially 0 vol% oxygen. A low volume percentage of oxygen in the headspace gas volume can reduce the radioactive degradation of components in the mother liquor.

[0483] The mother liquor container may include the mother liquor described above; therefore, all the features and embodiments described above under the mother liquor section can also be applied to the mother liquor container.

[0484] In an embodiment, the method may further include the following steps:

[0485] (4) Dilute the mother liquor from step (3) with a diluent to obtain a partition solution at a defined volumetric activity, and

[0486] (5) Dispense the dispensing solution into each patient dose unit.

[0487] The diluent may include stabilizers resistant to radioactive degradation, multivalent chelating agents, and optionally isotonic agents. Stabilizers resistant to radioactive degradation may be selected from the above-mentioned stabilizers. In some embodiments, the stabilizer is selected from ascorbic acid and its salts, diethylenetriaminepentaacetic acid (DTPA, also known as pentiacin), or combinations thereof.

[0488] The optional isotonic agent may be a salt or mixture of such salts selected from sodium chloride, potassium chloride, calcium chloride or magnesium chloride, or monosodium phosphate or disodium phosphate. In some embodiments, the isotonic agent may be sodium chloride.

[0489] In some embodiments, the diluent includes ascorbic acid or a salt thereof, DTPA, and optionally NaCl.

[0490] The diluent may include ethanol of the concentrations described above. For example, the diluent may be substantially ethanol-free.

[0491] Perform steps (4) and (5) to obtain individual patient doses, which are to be subsequently administered to patients without further material alteration. Individual patient doses may include the volumetric activity required for therapeutic or diagnostic purposes. The defined volumetric activity of the dispensing solution may be adjusted to provide a volumetric activity of 1000 MBq / mL ± 5%. 177 Patient dose units of Lu]Lu-PSMA-617.

[0492] The method disclosed herein can be advantageously used for the synthesis of [ 177 Lu-PSMA-617, especially for the production of mother liquor, which is used to produce [ 177 Lu]Lu-PSMA-617 Patient Dosage (Ready-to-Use).

[0493] In another specific embodiment of the method, the dispensing solution obtained in step (4) above comprises:

[0494] (A)[ 177 Lu]Lu-PSMA-617, with an activity range of 800 to 1200 MBq / ml, 900 to 1100 MBq / ml, 950 to 1050 MBq / ml, or about 1000 MBq / mL (27 mCi / mL).

[0495] (B) Acetic acid, in concentrations ranging from 0.24 to 0.36 mg / mL, 0.27 to 0.33 mg / mL, 0.285 to 0.315 mg / mL, or about 0.3 mg / mL;

[0496] (C) Acetates, such as their sodium salts, in concentrations ranging from 0.33 to 0.49 mg / mL, 0.37 to 0.45 mg / mL, 0.39 to 0.43 mg / mL, or about 0.41 mg / mL relative to the sodium salt;

[0497] (D) Gentianic acid or its salts, in concentrations ranging from 0.3 to 1.0 mg / mL, 0.3 to 0.5 mg / mL, 0.31 to 0.47 mg / mL, 0.35 to 0.43 mg / mL, 0.37 to 0.41, or about 0.39 mg / mL relative to the free acid;

[0498] (E) Ascorbic acid or its salts, in concentrations ranging from 20 to 52.5 mg / mL, 47.5 to 52.5 mg / mL, 48 to 52 mg / mL, or about 50 mg / mL relative to the sodium salt;

[0499] (F) Penteacin or its salts, in concentrations ranging from 0.08 to 0.12 mg / mL, 0.09 to 0.11 mg / mL, 0.095 to 0.105 mg / mL, or about 0.1 mg / mL relative to the free acid.

[0500] The above method can be implemented in a sealed device (e.g., a synthesis module) including an inlet for inert gas and an adapter for applying pressure to the device. Furthermore, a container containing the above-described reactants and water for injection (WFI) is provided and connected to the device. Additionally, a container suitable for receiving the reaction solution and mother liquor is provided and connected to the device. All connections to the device are equipped with valves, thereby enabling direct transfer of solution to or from the container, depending on the step, by applying pressure or inert gas. Alternatively or concurrently, transfer can be achieved using a syringe that can be connected to the container and device via an adapter. All equipment components are made of materials compatible with the reagents used in the method.

[0501] The above method can be advantageously automated and implemented in a synthesis module employing a disposable kit (e.g., a kit for preparing fluorine-18 labeled radiopharmaceuticals). An example kit may include a reaction vial (reactor) and connectors for inflow and outflow of fluids, a puncture connector for connecting the reagent vial, and optionally a solid-phase column. For example, the disposable kit may be mounted in front of a synthesis module containing a fluid path (pipeline), a reactor vial, and a sealed reagent vial. The disposable kit components may be made of specially selected materials to be compatible with the reagents used in the method. In particular, the components may be designed to minimize potential leaching from surfaces in contact with the fluids of the method, while maintaining the mechanical properties and integrity of the kit. The method is fully automated and implemented within a computer-aided system.

[0502] In a particular embodiment, the synthesis module may include: positioning for inserting a radioactive material. 177 A first needle at the top of a first vial of Lu(III) solution, a second needle positioned for insertion into the top of a vial containing a solution comprising a target-bound organic portion linked to a chelating agent, a bag containing water for injection for a rinsing step, a solution containing one or more stabilizers resistant to radioactive degradation, and one or more additional needles positioned for insertion into the top of one or more other vials (e.g., mother liquor containers) or conduits for transfer from the synthesis module to a dispensing isolator.

[0503] This disclosure is further illustrated by the following examples and synthetic methods, which should not be construed as limiting the scope or spirit of this disclosure. Those skilled in the art will readily recognize that several non-critical parameters can be altered or modified to produce substantially the same or similar results. The example compounds have shown efficacy in the treatment of prostate cancer, and particularly metastatic resistant prostate cancer (mCRPC).

[0504] Example

[0505] Example 1: Preparations containing [177Lu]Lu-PSMA-617

[0506] [177Lu]Lu-PSMA-617 was synthesized as described in WO 2023 / 148680 to produce a radioactive raw material as a sterile aqueous concentrate (the so-called mother liquor).

[0507] The synthesis steps were carried out in an automated, self-contained, closed-system synthesis module, remotely controlled by GMP-compliant software that automatically monitored and recorded process parameters. Active pharmaceutical ingredient (API) synthesis was performed at scales of 200 GBq or 400 GBq using MinAio (Trasis) kits.

[0508] Step 1: Remove the HCl (0.05 N)177 LuCl3 is transferred into the reactor using a vacuum pump.

[0509] Step 2: Draw up the reaction buffer using a syringe and transfer it to... 177 In a small vial of LuCl3.

[0510] Step 3: Transfer the reaction buffer into the reactor using a vacuum pump.

[0511] Step 4: Draw water for injection (WFI) using a syringe and transfer it to... 177 In a small vial of LuCl3.

[0512] Step 5: Transfer WFI into the reactor using a vacuum pump.

[0513] Step 6: Transfer the PSMA-617 compound into the reactor using a vacuum pump.

[0514] Step 7: Allow the reaction mixture to react at 94°C (±4°C) for 5±0.5 minutes, thereby allowing... 177 Lu chelates to the DOTA moiety of the PSMA-617 peptide. In the reaction mixture, DOTA-PSMA is expressed relative to... 177 An excess of Lu molars is present to ensure acceptable radiochemical labeling yields. The nitrogen pressure in the mother liquor container is above 250 mbar at the start and end of the labeling reaction. Used for the production of the active pharmaceutical ingredient […]. 177 The chemical reaction scheme for Lu-PSMA-617 is shown below:

[0515]

[0516] Step 8: Transfer the [177Lu]Lu-PSMA-617 active pharmaceutical ingredient to an intermediate mother liquor vial located in the dispensing isolator.

[0517] Step 9: Draw WFI with a syringe, transfer it to the reactor, and then transfer it twice to the intermediate mother liquor vial.

[0518] Drug product preparation, sterilization filtration, and dispensing are carried out in a Class A dispensing isolator.

[0519] Step 10: Sterilize the [177Lu]Lu-PSMA-617 active pharmaceutical ingredient solution through a 0.20 µm filter into an intermediate mother liquor vial.

[0520] Step 11: Add the filtered diluent solution to achieve a volumetric activity of 1000 MBq / mL at calibration time (Tc). The diluent solution is prepared by dissolving appropriate amounts of sodium ascorbate and pentilic acid (DTPA) in WFI.

[0521] Step 12: Sterilize the [177Lu]Lu-PSMA-617 solution for injection using a 0.20 µm filter and aseptically dispense it into open-top drug product vials (sealed by capping).

[0522] Table 18: PSMA-617 Experimental Information

[0523]

[0524] Mother liquor holding time: 60 min

[0525] Typical yield of the method: 92%-95%

[0526] The theoretical batch formulation of the active pharmaceutical ingredient [177Lu]Lu-PSMA-617 solution is described in Table 19. The ratios of acetic acid, sodium acetate, gentian acid, sodium ascorbate, pentiformic acid, and WFI are maintained regardless of the batch size of the pharmaceutical product.

[0527] Table 19: Batch formulations of [177Lu]Lu-PSMA-617 solution for injection / infusion

[0528]

[0529] Tc: Calibration time; DTPA: Diethylenetriaminepentaacetic acid

[0530] Depending on the batch size, a batch can contain 1-40 customer vials.

[0531] Table 20: Composition of per mL of [177Lu]Lu-PSMA-617 solution for injection / infusion

[0532]

[0533] Tc: Calibration time = End of production; 2: Includes all water, as well as a small amount of water that may remain during sterilization; 3: Calculated and rounded value.

[0534] Due to the natural decay of radionuclides, the total radioactivity and radioactivity concentration (volume activity) of the pharmaceutical product change over time. Table 21 describes the composition of each single dose of the pharmaceutical product with reference to the minimum (7.5 mL) and maximum (12.5 mL) fill contents.

[0535] Table 21: Drug Products Per Single Dosage

[0536]

[0537] Tc: Calibration time = End of production; 2: Includes all water, as well as a small amount of water that may remain during the sterilization process.

[0538] Example 2: [ 177 Mechanism of action and cellular response of Lu-PSMA-617

[0539] Radioligand therapy (RLT) is emerging as a safe and effective targeted treatment for several types of cancer. Pluvicto® ([ 177 Lu-PSMA-617 is an FDA-approved drug for the treatment of PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). 177 An example of Lu's RLT drugs. Although 177 Lu-RLT has achieved clinical success, but a subset of patients still fail to achieve complete and durable remission. Elucidating the cellular response to RLT and its mechanisms of action could reveal potential opportunities to improve treatment and patient outcomes.

[0540] The following examples describe multiple 177 Phenotypic and response of Lu-RLT-treated cell lines. Results from the following methods showed that: (1) 177Lu induced DNA damage response (DDR) biomarkers in a time- and dose-dependent manner, particularly those indicating repair of double-strand breaks (DSBs) via non-homologous end joining (NHEJ) or homologous recombination (HR). Figure 1-3 (2) Sensitization to 177Lu induced by PRKDC gene deletion or DNA-PKcs inhibitors (i.e., NHEJ core factors, such as the catalytic subunit of DNA-PK (PRKDC)). Figure 4A -B); (3) The viability of a group of cell lines treated with 177Lu was reduced ( Figure 5 (and Table 23); (4) 177Lu-PSMA-RLT-induced apoptosis and cell death ( Figure 6A-C (5) 177Lu mode of action ( Figure 7 ), indicating that DSB is 177 Lu-RLT-induced DNA damage is the most cytotoxic form; (6) DDR defects (i.e., homologous recombination (HR) or non-homologous end joining (NHEJ) defects, or syngeneic models of DNA-PK repression) sensitize cells to 177Lu ( Figure 8A-C (7) Identification of radioligand therapy sensitizers through gene screening ( Figure 9A -D), of which PRKDC was found to be a hit; (8) 177Lu-DOTA with DDRi (e.g., PARP, ATM, CHK1 and WEE1 inhibitors ( Figure 10A ) and Polθ and ATR inhibitors ( Figure 10B This can generate a synergistic effect, which can also... 177Lu-RLT sensitization; DNA-PK inhibitor (AZD7648) synergistically interacted with 177Lu-DOTA in a group of cancer cell lines. Figure 11A-F (9) 177Lu-PSMA-617 exhibits synergistic effects with Polθ, ATR, and ATM inhibitors in PSMA-expressing cell lines. Figure 12A-D ); and (10) the DNA-PK inhibitor (AZD7648) synergistically interacted with 177Lu-PSMA-617 in PSMA-expressing cell lines. Figure 13A-G ).

[0541] Furthermore, the results showed that in cells with high DU145 PSMA expression (such as...) Figure 13A-G In the study, using different DNA-PK inhibitor administration schedules (as shown in Figures 14F and 15F), the DNA-PK inhibitor AZD7648 and 177Lu-PSMA-617 produced a synergistic effect when administered before or simultaneously with 177Lu-PSMA-617, but no synergistic effect was observed when added 24 h after 177Lu-PSMA-617 treatment. Figures 14A-F Furthermore, the maximum synergistic effect between the DNA-PK inhibitor AZD7648 and 177Lu-PSMA-617 is achieved by prolonging DNA-PK inhibition. Figures 15A-F Furthermore, combined treatment with the DNA-PK inhibitor AZD7648 and 177Lu-PSMA-617 induced an increase in DDR marker accumulation. Figure 16 ).

[0542] also, 177 Lu-RLT treatment leads to cell cycle alterations, micronucleus accumulation, and cell death. Figure 17A -C). In summary, these studies provide insights into cell-targeted... 177 A better understanding of the Lu-RLT response, and the notion that NHEJ is a key pathway promoting cell survival after treatment and forms the basis of the combination therapy disclosed herein.

[0543] Materials and Methods

[0544] 1. Cell lines and cell viability assays

[0545] Cells were cultured under normal growth conditions (37°C, 5% CO2) and passaged at 80% confluence. Details of the cell lines and seeding densities used for viability assays are listed in Table 22.

[0546] Table 22: Cell lines and seeding densities for viability assay

[0547]

[0548] Table 23: Figure 5 EC curve in 50 Values ​​were obtained from an 8-day viability assay of a group of cell lines continuously treated with 177Lu-DOTA.

[0549]

[0550] Viability assays were performed as previously described (PG Pilie et al., Clin Cancer Res. 2024 Feb 28). Briefly, cells in the exponential growth phase were seeded at the density indicated above in 100 µL of medium in 96-well plates (VWR, catalog 734-1660). The day after seeding, the cells were […]. 177 Treatment with a dilution of Lu-PSMA-617 and / or the DDR inhibitor AZD7648 or a matching medium, to a final volume of 150 µL. For timed protocols, wash out the medium containing the compound at selected time points according to the experimental protocol and replace with fresh medium containing the desired compound at matching concentrations. After 8 days of treatment, add 50 µL of Cell Titre Glow (Promega, G7570) to each well, incubate according to the manufacturer's instructions, and read using a GloMax microplate reader (Promega). Viability readings are normalized relative to the medium control (or single-drug control, for combinations). Viability curves and EC50 are generated using GraphPad Prism. 50 The data were fitted using a log(inhibitor) versus response-variable slope (four parameters), with upper and lower limits set to 1 and 0, respectively. Each data point was generated in technical triplicate. The mean and mean standard error of each data point are shown on the viability curve. Detailed information on the DNA damage response inhibitors used for the assay is summarized in Table 24.

[0551] Table 24: Tested DNA damage response inhibitors

[0552]

[0553] 2. Immunofluorescence and cell cycle analysis of biomarkers for DNA damage response

[0554] The day before treatment, cells were technically seeded in quadruplicate in 96-well plates (PerkinElmer, 6055300) at the seeding density indicated below.

[0555] Table 25: Immunofluorescence inoculation density

[0556]

[0557] The day after inoculation, the cells were treated with serially diluted indicated compounds ([ 177 Cells were treated with Lu-PSMA-617, AZD7648, or a combination thereof. Following the experimental protocol, after 4 h of incubation, the culture medium containing the compounds was washed off and replaced with fresh culture medium containing the desired concentration of the compound. At the experimental endpoint, cells were fixed for 10 min with 4% paraformaldehyde in PBS (Santa Cruz Biotechnology, sc-281692), blocked for 1 h in blocking buffer (0.5% Triton™ X-100 / 0.5% BSA / PBS), and incubated overnight at 4°C with the primary antibody diluted in the blocking buffer (dilutions indicated in Table 26). (The nonionic surfactant sold under the trade name Triton™ X-100 is 2-[4-(2,4,4-trimethylpentane-2-yl)phenoxy]ethanol).

[0558] Table 26: Primary Antibody

[0559]

[0560] The next day, excess primary antibody was washed with 0.1% Triton™ X-100 / PBS and the sample was incubated at room temperature with matched secondary antibody and DAPI diluted in blocking buffer for 1 h (see below for dilutions used).

[0561] Table 27: Secondary Antibodies

[0562]

[0563] Excess antibody was washed with 0.1% Triton™ X-100 / PBS, and the sample was stored in PBS for imaging. Imaging was performed using the Operetta CLS high-content analysis system with a 20x air objective. The acquired images were analyzed using Harmony 4.9 software to determine the percentage of cells displaying at least 5 or 10 DDR focal points (depending on the marker). The obtained values ​​were normalized relative to the mean induction in the vector-treated sample to obtain the fold change in induction. The cumulativeity of the predictions was calculated by multiplying by the induction of a single agent. The significance of induction by any single agent or combination on the vector-treated sample was assessed using one-way ANOVA and Dunnett's post-hoc test, while the significance of the cumulativeity of the observed inductions from the combination on the predictions was assessed using a two-tailed t-test.

[0564] For cell cycle analysis, the Click-iT EdU Imaging Kit with Alexa Fluor 647 (Fisher Scientific, C10340) was used. Cells were incubated with 10 µM EdU to label actively replicating cells for 30 minutes, then fixed with 4% PFA / PBS. The Click-iT reaction for detecting EdU was performed according to the manufacturer's protocol, followed by staining DNA with DAPI. After imaging the samples using the same setup described above, the intensities of EdU and DAPI staining were calculated using Harmony 4.9 software and plotted to obtain the cell cycle profiles of the samples.

[0565] Example 3: 177 In vivo efficacy of the combination of Lu]Lu-PSMA-617 and DDRi

[0566] The combination of both 177Lu-RLT and a Polθ inhibitor (ART6043) was well tolerated and effective in vivo, significantly prolonging the survival of tumor-bearing mice (LNCaP xenografts, results are outlined in Figure 18A-B ).

[0567] The combination of both 177Lu-RLT and a DNA-PK inhibitor does not affect the biodistribution of 177Lu-RLT. The biodistribution of 177 Lu]Lu-PSMA-617 alone or in combination with DDRi AZD7648 or peposertib (M3814) in PC3 FOLH1 MP9PSMA high-expression tumors was evaluated at 4 h and 24 h. The results are shown in Table 27 and Figure 19 .

[0568] Table 28: Biodistribution study

[0569]

[0570] The combination of both 177Lu-RLT and a DNA-PK inhibitor provides beneficial tumor growth inhibition in vivo. The effect of 177 Lu]Lu-PSMA-617 alone or in combination with AZD7648 or M3814 in female nude mice bearing PC3 FOLH1 MP9 PSMA tumors was evaluated. The results are shown in Figure 20A -D.

[0571] Materials and Methods

[0572] Table 29: Abbreviations used

[0573]

[0574] 1. Animals and maintenance conditions:

[0575] The experiment was conducted in female naked Cr1:NU(NCr)-Foxn1nu- homozygous mice (Charles River, Germany). Animals were 14 weeks old at the time of compound administration. Animals were housed in XJ-type cages (maximum 5 animals per cage) under optimized hygienic conditions, with free access to food and water and a 12-hour light-dark cycle. They were allowed at least 7 days to acclimatize before the start of the experiment.

[0576] 2. Cell lines and cell cultures:

[0577] PC3, FOLH1, MP9, and PSMA-overexpressing cells were grown in 500 mL of Kaighn's modified F-12K nutrient mixture medium (Gibco, 21127-022, 500 mL) + 50 mL of FCS (Bio Concept, 2-01F30-I) and incubated at 37°C under a humidified atmosphere of 5% CO2. Cells were harvested with trypsin-EDTA, resuspended in medium (with additives), and counted using a NucleoCounter® NC-200™ system. Finally, cells were centrifuged and resuspended in ice-cold Hank's balanced salt solution (HBSS) and Matrigel® matrix (Corning, 354234) (1:1).

[0578] 3. Establishment of in vivo tumor xenografts:

[0579] By using 200 μL HBSS (Sigma, No. H8264):Matrigel® matrix (Corning, 354234) (50%:50%) in 5 x 10 6 PC3 FOLH1 MP9 PSMA tumors were established by subcutaneous injection of cells into the right flank of nude mice.

[0580] 4. Compound formulation and animal treatment:

[0581] AZD7648 was prepared as a homogeneous suspension in 0.5% MC + 0.1% polysorbate 80 (Tween 80™) for administration. M3814 was prepared as a homogeneous suspension in 0.5% Methocel™ + 0.25% polysorbate 20 (Tween 20™) in 300 mM sodium citrate buffer (pH 2.5) for administration. Fresh suspensions were prepared every 7 days and stored at room temperature.

[0582] In terms of biodistribution, AZD7648 and M3814 were administered intravenously at 4 MBq.177 Lu]Lu-PSMA-617 (0.1 nmol) was administered orally 10 minutes before the first dose.

[0583] In efficacy studies, AZD7648 was administered orally at a volume of 10 mL / kg, once daily (qd), for 5 days, and M3814 was administered orally at a volume of 10 mL / kg, twice daily (bid), for 5 days. 177 Lu-PSMA-617 was prepared in PBS and administered intravenously in a volume of 100 μL, with a total activity of 10 MBq (0.1 nmol / single injection). The mediator control was administered intravenously once in a volume of 100 μL PBS.

[0584] 5. Statistical Analysis:

[0585] The absolute values ​​of radioactive uptake in tissues and tumor growth were compared between groups using a two-way ANOVA following Dunnett's multiple comparison test. The significance level was set at p < 0.05. All statistical calculations were performed using GraphPad Prism 10.1.2 (324). For efficacy studies, the last date of the mediator control group was used to assess significance.

[0586] 6. Assessment of biological distribution:

[0587] When the tumor volume is approximately 200 mm 3 Biological distribution studies were conducted. Tumor volume was measured using calipers and calculated according to the formula (length x diameter). 2 x π ⁄ 6) Determine the volume. Values ​​are mean ± SEM. Mice were randomly divided into groups of three, and freshly prepared test samples were injected or gavaged at a volume of 10 mL / kg via the lateral tail vein. Mice were euthanized at 4 h and 24 h after radioactive dose administration, and organs (blood, liver, spleen, kidney, and tumor) were collected, weighed, and placed in counting vials. Each tissue sample was counted for the activity of the radioactive element using a gamma counter. The injected sample was used as an attenuation correction standard. The final bar graph is expressed as injected dose % / g tissue.

[0588] 7. Evaluation of antitumor activity:

[0589] When the average tumor volume in mice was approximately 210 mm 3 Efficacy therapy was initiated 26 days after tumor cell injection. Values ​​are mean ± SEM; sample size (n = 8 mice / group).

[0590] Measure the tumor volume using calipers and calculate it according to the formula (length x diameter). 2x π ⁄ 6) Determine the volume. A "carry-forward" process was used for the mean plot when animals were euthanized; tumor mean plots were stopped when fewer than four animals remained in each group. Body weight and tumor volume were recorded two to three times per week.

[0591] 8.[ 177 In vivo efficacy study of LNCaP FGC xenografts combining Lu-PSMA-617 with the Polθ inhibitor ART6043.

[0592] Male NMRI nude mice carrying subcutaneous LNCaP FGC tumors (see cell lines in Table 22 above) were treated with the following: a mediator (PO, BID), ART6043 (PO, 100 mg / kg BID), and a single dose of 10 MBq. 177 Lu-PSMA-617 (iv) or 10 MBq [ 177 The combination of Lu-PSMA-617 (iv) + ART6043 (PO, 100 mg / kg BID) was administered. Each experimental group consisted of six mice. Mice were then given either the mediator or ART6043 for 20 days. Tumor volume exceeding 1500 mm was considered normal. 3 Mice were terminated at the designated time, and this termination point was used for survival analysis. Body weight and tumor volume were measured twice weekly. All drug treatments were well tolerated. (Compared to individual...) 177 Compared to Lu-PSMA-617, ART6043+ 177 The combination of Lu-PSMA-617 treatment significantly prolonged survival. 177 Compared to the 31 days in the Lu-PSMA-617 group, the median survival in the combination group increased to 47 days. Figure 18A-B These results indicate that the Polθ inhibitor ART6043 is associated with... 177 The combination of Lu-PSMA-617 was well tolerated and increased in vivo survival.

Claims

1. A method for treating a subject with cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and administered a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject.

2. The method of claim 1, wherein the DDRi is selected from the group consisting of: ataxia-telangiectasia mutant (ATM) inhibitors, ataxia-telangiectasia and Rad3-related (ATR) inhibitors, poly(ADP-ribose) polymerase (PARP) inhibitors, DNA-dependent protein kinase (DNA-PK) inhibitors, WEE1 protein kinase family inhibitors, checkpoint kinase (CHK) family inhibitors, DNA polymerase θ (Polθ) inhibitors, RAD51 recombinase (RAD51) inhibitors, ubiquitin-specific protease 1 (USP1) inhibitors, Polo-like serine / threonine kinase 1 (PLK1) inhibitors, Aurora kinase inhibitors, mutant p53 reactivators, poly(ADP-ribose) hydrolase (PARG) inhibitors, Werner syndrome protein (WRN) inhibitors, and combinations thereof, optionally wherein the DDRi is not olaparib.

3. The method of claim 1 or 2, wherein the DDRi is selected from the group consisting of: ataxia-telangiectasia mutant (ATM) inhibitors, ataxia-telangiectasia and Rad3-related (ATR) inhibitors, poly(ADP-ribose) polymerase (PARP) inhibitors, DNA-dependent protein kinase (DNA-PK) inhibitors, WEE1 protein kinase family inhibitors, checkpoint kinase (CHK1) inhibitors, and DNA polymerase θ (Polθ) inhibitors, optionally wherein the DDRi is not olaparib.

4. The method of any one of claims 1-3, wherein the DDRi comprises at least one DNA-PK inhibitor listed in Table 4, at least one of XRD-0394, SN-39536, BY101298, XZP-6877 and IMP-11, or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, wherein the at least one DNA-PK inhibitor comprises: (7-Methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(oxan-4-yl)purine-8-one (AZD7648)) or a pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1-5, wherein the DDRi comprises at least one ATM inhibitor listed in Table 1, at least one of XRD-0394 and SX-RDS1, or a pharmaceutically acceptable salt thereof.

7. The method of claim 6, wherein the at least one ATM inhibitor comprises: (8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinoline-2-one (AZD0156)) or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1-7, wherein the DDRi comprises at least one ATR inhibitor listed in Table 2, at least one of LF0397, IMP-9064, SC0245 and ATRN-119, or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the at least one ATR inhibitor comprises ((S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methyl-morpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 - Thionyl ketone (ART0380) or a pharmaceutically acceptable salt thereof.

10. The method of any one of claims 1-8, wherein the DDRi comprises at least one PARP inhibitor listed in Table 3 or a pharmaceutically acceptable salt thereof, optionally wherein the PARP inhibitor is not olaparib.

11. The method of claim 10, wherein the at least one PARP inhibitor comprises: ((11S,12R)-7-fluoro-11-(4-fluorophenyl)-12-(2-methyl-1,2,4-triazol-3-yl)-2,3,10-triazatricyclic [7.3.1.0] 5,13 [13-carbo-1,5(13),6,8-tetraen-4-one (tarazopanib) or a pharmaceutically acceptable salt thereof.] 12. The method of any one of claims 1-11, wherein the DDRi comprises at least one WEE1 protein kinase family inhibitor selected from the group consisting of: Wee1-like protein kinase (WEE1) inhibitors and membrane-associated tyrosine / threonine protein kinase 1 (PKMYT1) inhibitors.

13. The method of claim 12, wherein the DDRi comprises at least one WEE1 inhibitor listed in Table 5, at least one of SC0191, SY-4835 and IMP7068, or a pharmaceutically acceptable salt thereof.

14. The method of claim 13, wherein the at least one WEE1 inhibitor comprises: (1-[6-(2-hydroxypropyl-2-yl)pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-propyl-2-enylpyrazolo[3,4-d]pyrimidin-3-one (Adavocetib or MK-1775) or a pharmaceutically acceptable salt thereof.) 15. The method of claim 12, wherein the DDRi comprises at least one PKMYT1 inhibitor listed in Table 6, ACR-2316, or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 1-15, wherein the DDRi comprises at least one CHK family inhibitor selected from the group consisting of: a CHK1 selective inhibitor, a CHK2 selective inhibitor, and a CHK1 / 2 dual inhibitor.

17. The method of claim 16, wherein the DDRi comprises at least one CHK1 selective inhibitor listed in Table 7, VER250840, or a pharmaceutically acceptable salt thereof.

18. The method of claim 17, wherein the at least one CHK1 selective inhibitor comprises: (1-[5-bromo-4-methyl-2-[[(2S)-morpholin-2-yl]methoxy]phenyl]-3-(5-methylpyrazin-2-yl)urea (rabucetebru or LY2603618) or a pharmaceutically acceptable salt thereof.) 19. The method of claim 16, wherein the DDRi comprises at least one CHK2 selective inhibitor listed in Table 8 or a pharmaceutically acceptable salt thereof.

20. The method of claim 16, wherein the DDRi comprises at least one CHK1 / 2 dual inhibitor listed in Table 9 or a pharmaceutically acceptable salt thereof.

21. The method of any one of claims 1-20, wherein the DDRi comprises at least one Polθ inhibitor listed in Table 10, at least one of ART4215, ART6043, RP-3467 and GSK101 (GSK4524101 / IDE705), or a pharmaceutically acceptable salt thereof.

22. The method of claim 21, wherein the at least one Polθ inhibitor comprises: ((2S,3R)-1-[3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl]-3-hydroxy-N-methyl-N-(3-methylphenyl)pyrrolidine-2-carboxamide (ART558), ART6043 or a pharmaceutically acceptable salt thereof.

23. The method of any one of claims 1-22, wherein the DDRi comprises at least one RAD51 inhibitor listed in Table 11 or a pharmaceutically acceptable salt thereof.

24. The method of any one of claims 1-23, wherein the DDRi comprises at least one of the following listed in Table 12: a USP1 inhibitor, TNG348, HSK39775, FT-3171 (Debio 0432), and ISM3091, or a pharmaceutically acceptable salt thereof.

25. The method of any one of claims 1-24, wherein the DDRi comprises at least one PLK1 inhibitor listed in Table 13 or a pharmaceutically acceptable salt thereof.

26. The method of any one of claims 1-25, wherein the DDRi comprises at least one Aurora kinase inhibitor selected from the group consisting of: Aurora A inhibitors and Aurora B inhibitors listed in Table 14, WJ05129 or a pharmaceutically acceptable salt thereof.

27. The method of any one of claims 1-26, wherein the DDRi comprises at least one PARG inhibitor listed in Table 16, IDE161, or a pharmaceutically acceptable salt thereof.

28. The method of any one of claims 1-27, wherein the DDRi comprises at least one WRN inhibitor listed in Table 17, RO7589831, HRO761, or a pharmaceutically acceptable salt thereof.

29. The method of any one of claims 1-28, wherein the DDRi comprises at least one mutant p53 reactivator listed in Table 15, PC14586, or a pharmaceutically acceptable salt thereof.

30. The method of any one of claims 1-29, wherein the DDRi and [ 177 Lu]Lu-PSMA-617 is administered via the same route of administration.

31. The method of any one of claims 1-30, wherein the DDRi and [ 177 Lu]Lu-PSMA-617 is available in a single dosage form.

32. The method of any one of claims 1-31, wherein the DDRi and [ 177 Lu]Lu-PSMA-617 has the same dosage form.

33. The method of any one of claims 1-32, wherein the DDRi is transmitted via [ 177 Lu]Lu-PSMA-617 can be administered via different routes.

34. The method of any one of claims 1-33, wherein the DDRi is in [ 177 Lu]Lu-PSMA-617 should be applied within 24 hours.

35. The method of any one of claims 1-34, wherein the therapeutically effective amount of DDRi is administered over a course of treatment of about or at least about 5 days.

36. The method of any one of claims 1-35, wherein the DDRi is in [ 177 Lu]Lu-PSMA-617 should be applied within 20 hours.

37. The method of any one of claims 1-36, wherein the DDRi is in [ 177 Lu]Lu-PSMA-617 should be applied within 4 hours.

38. The method of any one of claims 1-37, wherein the DDRi is in [ 177 Lu]Lu-PSMA-617 is administered at least 16 hours after administration, in one or more doses.

39. The method according to any one of claims 1-38, wherein [ 177 The therapeutically effective dose of Lu]Lu-PSMA-617, the DDRi, or both is lower than the dose required for a single therapy response.

40. The method of claim 39, wherein the monotherapy response is selected from the group consisting of: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, changes in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers relative to baseline, or combinations thereof.

41. The method of claim 39 or 40, wherein [ 177 The effective dose of Lu]Lu-PSMA-617, the DDRi, or both is at least about 10% to about 50% lower than the dose required for a response to the single therapy.

42. The method of any one of claims 39-41, wherein [ 177 The therapeutically effective dose of Lu-PSMA-617 is higher than that required for a response to the monotherapy. 177 The amount of Lu]Lu-PSMA-617 is approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or approximately 50%.

43. The method of any one of claims 39-42, wherein the therapeutically effective amount of DDRi is about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or about 50% lower than the amount of DDRi required for a monotherapy response.

44. The method as described in any one of claims 1-43, thereby applying the [ 177 Compared to Lu]Lu-PSMA-617 or the aforementioned DDRi as a monotherapy, the anticancer response was synergistically enhanced.

45. The method of any one of claims 1-44, wherein [ 177 The therapeutically effective dose of Lu]Lu-PSMA-617 is approximately 3 GBq to approximately 10 GBq.

46. ​​The method of any one of claims 1-45, wherein the PSMA-expressing cancer is PSMA-positive prostate cancer, optionally PSMA-positive metastatic castration-resistant prostate cancer (mCRPC), optionally PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC), optionally PSMA-positive oligometastatic prostate cancer (OMPC), optionally PSMA-positive cancer in biochemical relapse (BCR) state, optionally PSMA-positive cancer in high-risk BCR state.

47. A kind of [ 177 The combination of Lu]Lu-PSMA-617 and DDRi is intended for use in the treatment of cancers expressing prostate-specific membrane antigen (PSMA), wherein the DDRi is selected from the group consisting of: ataxia-telangiectasia mutant (ATM) inhibitors, ataxia-telangiectasia and Rad3-associated (ATR) inhibitors, poly(ADP-ribose) polymerase (PARP) inhibitors, DNA-dependent protein kinase (DNA-PK) inhibitors, WEE1 protein kinase family inhibitors, checkpoint kinase (CHK) inhibitors, DNA polymerase θ (Polθ) inhibitors, RAD51 recombinase (RAD51) inhibitors, ubiquitin-specific protease 1 (USP1) inhibitors, Polo-like serine / threonine kinase 1 (PLK1) inhibitors, Aurora kinase inhibitors, mutant p53 reactivators, poly(ADP-ribose) hydrolase (PARG) inhibitors, and Werner syndrome protein (WRN) inhibitors, and combinations thereof, optionally wherein the DDRi is not olaparib.

48. The combination as described in claim 47, wherein it is combined with [ 177 Lu]Lu-PSMA-617 monotherapy has an enhanced therapeutic index compared to DDRi monotherapy.

49. The combination of claim 48, wherein the therapeutic index of the combination is higher than that of the [ 177 The therapeutic index of Lu]Lu-PSMA-617 monotherapy or the DDRi monotherapy is at least about 10% to about 50%.

50. The combination of any one of claims 47-49, wherein the DDRi comprises at least one DNA-PK inhibitor listed in Table 4, at least one of XRD-0394, SN-39536, BY101298, XZP-6877 and IMP-11, or a pharmaceutically acceptable salt thereof.

51. The combination of any one of claims 47-50, wherein the DDRi comprises at least one ATM inhibitor listed in Table 1, at least one of XRD-0394 and SX-RDS1, or a pharmaceutically acceptable salt thereof.

52. The combination of any one of claims 47-51, wherein the DDRi comprises at least one ATR inhibitor listed in Table 2, at least one of LF0397, IMP-9064, SC0245 and ATRN-119, or a pharmaceutically acceptable salt thereof.

53. The combination of any one of claims 47-52, wherein the DDRi comprises at least one PARP inhibitor listed in Table 3 or a pharmaceutically acceptable salt thereof, optionally wherein the PARP inhibitor is not olaparib.

54. The combination of any one of claims 47-53, wherein the DDRi comprises at least one WEE1 protein kinase family inhibitor selected from the group consisting of: Wee1-like protein kinase (WEE1) inhibitors and membrane-associated tyrosine / threonine protein kinase 1 (PKMYT1) inhibitors.

55. The combination of claim 54, wherein the DDRi comprises at least one WEE1 inhibitor listed in Table 5, at least one of SC0191, SY-4835 and IMP7068, or a pharmaceutically acceptable salt thereof.

56. The combination of claim 54, wherein the DDRi comprises at least one PKMYT1 inhibitor listed in Table 6, ACR-2316, or a pharmaceutically acceptable salt thereof.

57. The combination of any one of claims 47-56, wherein the DDRi comprises at least one CHK inhibitor selected from the group consisting of: a CHK1 selective inhibitor, a CHK2 selective inhibitor, and a CHK1 / 2 dual inhibitor.

58. The combination of claim 57, wherein the DDRi comprises at least one CHK1 selective inhibitor listed in Table 7, VER250840, or a pharmaceutically acceptable salt thereof.

59. The combination of claim 57, wherein the DDRi comprises at least one CHK2 selective inhibitor listed in Table 8 or a pharmaceutically acceptable salt thereof.

60. The combination of claim 57, wherein the DDRi comprises at least one CHK1 / 2 dual inhibitor listed in Table 9 or a pharmaceutically acceptable salt thereof.

61. The combination of any one of claims 47-60, wherein the DDRi comprises at least one Polθ inhibitor listed in Table 10, at least one of ART4215, ART6043, RP-3467 and GSK101 (GSK4524101 / IDE705), or a pharmaceutically acceptable salt thereof.

62. The combination of any one of claims 47-61, wherein the DDRi comprises at least one RAD51 inhibitor listed in Table 11 or a pharmaceutically acceptable salt thereof.

63. The combination of any one of claims 47-62, wherein the DDRi comprises at least one of the following listed in Table 12: a USP1 inhibitor, TNG348, HSK39775, FT-3171 (Debio 0432), and ISM3091, or a pharmaceutically acceptable salt thereof.

64. The combination of any one of claims 47-63, wherein the DDRi comprises at least one PLK1 inhibitor listed in Table 13 or a pharmaceutically acceptable salt thereof.

65. The combination of any one of claims 47-64, wherein the DDRi comprises at least one Aurora kinase inhibitor selected from the group consisting of: Aurora A inhibitors and Aurora B inhibitors listed in Table 14, WJ05129 or a pharmaceutically acceptable salt thereof.

66. The combination of any one of claims 47-65, wherein the DDRi comprises at least one PARG inhibitor listed in Table 16, IDE161, or a pharmaceutically acceptable salt thereof.

67. The combination of any one of claims 47-66, wherein the DDRi comprises at least one WRN inhibitor listed in Table 17, RO7589831, HRO761, or a pharmaceutically acceptable salt thereof.

68. The combination of any one of claims 47-67, wherein the DDRi comprises at least one mutant p53 reactivator listed in Table 15, PC14586, or a pharmaceutically acceptable salt thereof.

69. A method for treating a subject with cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and administer a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject, wherein the DDRi is: ((S)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol (M3814)) or a pharmaceutically acceptable salt thereof, thereby relating to [ 177 Compared with monotherapy responses to Lu]Lu-PSMA-617 or the aforementioned DDRi, the anticancer response was synergistically enhanced.

70. The method of claim 69, wherein [ 177 The therapeutically effective dose of Lu-PSMA-617 is the following: about 10 MBq to 10 GBq, optionally about 100 MBq to about 10 GBq, about 1 GBq to about 10 GBq, about 3 GBq to about 10 GBq, about 5 GBq to about 9 GBq, about 6 GBq to about 8 GBq, optionally about 7.4 GBq, and the therapeutically effective dose of the DDRi is the following: about 1 to 1000 mg / kg, optionally about 100 mg / kg, administered twice daily for about or at least about 5 days, or about 50 mg, about 100 mg, about 150 mg, or about 250 mg, and wherein the initial dose of the DDRi is [ 177 Apply Lu]Lu-PSMA-617 less than 1 hour before application.

71. A method for treating a subject with cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and administer a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject, wherein the DDRi is ((7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(oxan-4-yl)purine-8-one (AZD7648)) or a pharmaceutically acceptable salt thereof, thereby relating to [ 177 Compared with monotherapy responses to Lu]Lu-PSMA-617 or the aforementioned DDRi, the anticancer response was synergistically enhanced.

72. The method of claim 71, wherein [ 177 The therapeutically effective dose of Lu-PSMA-617 is approximately 10 MBq to 10 GBq, optionally approximately 100 MBq to approximately 10 GBq, approximately 1 GBq to approximately 10 GBq, approximately 3 GBq to approximately 10 GBq, approximately 5 GBq to approximately 9 GBq, or approximately 6 GBq to approximately 8 GBq, optionally approximately 7.4 GBq, and the therapeutically effective dose of the DDRi is approximately 1 to 1000 mg / kg, optionally approximately 100 mg / kg, administered once daily for approximately or at least approximately 5 days, and the initial dose of the DDRi is […]. 177 Apply Lu]Lu-PSMA-617 less than 1 hour before application.

73. A method for treating a subject with cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and administer a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject, wherein the DDRi is: (8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one (AZD0156)) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy responses to Lu]Lu-PSMA-617 or the aforementioned DDRi, the anticancer response was synergistically enhanced.

74. A method for treating a subject with cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and administer a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject, wherein the DDRi is: (1-[5-bromo-4-methyl-2-[[(2S)-morpholin-2-yl]methoxy]phenyl]-3-(5-methylpyrazin-2-yl)urea (LY2603618, labusetetibr)) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy responses to Lu]Lu-PSMA-617 or the aforementioned DDRi, the anticancer response was improved or synergistically enhanced.

75. A method for treating a subject with cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and administer a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject, wherein the DDRi is: (1-[6-(2-hydroxypropyl-2-yl)pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-propyl-2-enylpyrazolo[3,4-d]pyrimidin-3-one (Adavocetib or MK-1775) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy responses to Lu]Lu-PSMA-617 or the aforementioned DDRi, the anticancer response was improved or synergistically enhanced.

76. A method for treating a subject with cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and administer a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject, wherein the DDRi is: 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one (olaparib) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared to monotherapy responses to Lu-PSMA-617 or the DDRi, the anticancer response is synergistically enhanced, optionally wherein the DDRi is administered in […]. 177 Lu]Lu-PSMA-617 is administered within 24 hours, and / or the DDRi is administered within 24 hours of administration and for a course of treatment of at least 48 hours.

77. A method for treating a subject with cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and administer a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject, wherein the DDRi is: ((11S,12R)-7-fluoro-11-(4-fluorophenyl)-12-(2-methyl-1,2,4-triazol-3-yl)-2,3,10-triazatricyclic [7.3.1.0] 5,13 [13-carbohydrate-1,5(13),6,8-tetraen-4-one (tapazopanib) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy responses to Lu]Lu-PSMA-617 or the aforementioned DDRi, the anticancer response was synergistically enhanced.

78. A method for treating a subject with cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and administer a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject, wherein the DDRi is: ((2S,3R)-1-[3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl]-3-hydroxy-N-methyl-N-(3-methylphenyl)pyrrolidine-2-carboxamide (ART558) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy responses to Lu]Lu-PSMA-617 or the aforementioned DDRi, the anticancer response was synergistically enhanced.

79. A method for treating a subject with cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and administer a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject, wherein the DDRi is ART6043 or a pharmaceutically acceptable salt thereof, thereby in conjunction with [ 177 Compared with monotherapy responses to Lu]Lu-PSMA-617 or the aforementioned DDRi, the anticancer response was synergistically enhanced.

80. A method of treating a subject with cancer expressing prostate-specific membrane antigen (PSMA), the method comprising administering to the subject a therapeutically effective amount of […]. 177 Lu]Lu-PSMA-617, and administer a therapeutically effective amount of a DNA damage response inhibitor (DDRi) to the subject, wherein the DDRi is ((S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methyl-morpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -Thiodanone (ART0380) or a pharmaceutically acceptable salt thereof, thereby being used with [ 177 Compared with monotherapy responses to Lu]Lu-PSMA-617 or the aforementioned DDRi, the anticancer response was synergistically enhanced.

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