Combination therapies with ar-degrading agents and PSMA-targeting radioligands

Abstract

Described herein are combination therapies featuring a Prostate- Specific Membrane Antigen (PSMA)-targeting radiopharmaceutical, in particular [177Lu]Lu-PSMA-617, and an Androgen Receptor (AR) -degrading agent, in particular luxdegalutamide, and their use in treating cancers, such as, e.g., PSMA-expressing cancers.

Description

[0001] COMBINATION THERAPIES WITH

[0002] AR-DEGRADING AGENTS AND PSMA-TARGETING RADIOLIGANDS

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 710,938, filed October 23, 2024, which is incorporated herein in its entirety.

[0005] FIELD

[0006] This disclosure relates to combination therapies featuring a radioligand targeting the prostate specific membrane antigen (PSMA) and an androgen receptor (AR)-degrading agent, and their use in increasing treatment efficacy for cancers, such as, e.g., PSMA-expressing cancers.

[0007] BACKGROUND

[0008] Prostate cancer (PC) is a leading cause of cancer-related death among men around the world, 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). The tumors of 10-20% of prostate cancer patients become refractory to androgen-deprivation therapy by pharmaceutical or surgical castration, and progress as 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. Cancers).

[0009] During the past decade, new therapeutic options such as antihormonal therapies, poly(ADP-ribose) polymerase (PARP) inhibitors, radiopharmaceuticals, immunotherapies, and chemotherapies have been approved for mCRPC patients. Despite these developments, mCRPC remains incurable, which may be explained, in part, by the inter- and intra-patient heterogeneity of the disease. Thus, there is an urgent need for personalized, highly effective targeted therapies for mCRPC patients.

[0010] Targeted radioligand therapy (RLT) offers the possibility to treat cancer lesions in a specific and tumor-selective manner by exploiting cell surface receptors that are mainly expressed in malignant cells, such as, e.g., prostate specific membrane antigen (PSMA).

[0011] Systemically administered RLT is concentrated at target sites and surrounding cells through radioligand binding. Targeted RLTs bind with high affinity to biomarker-expressing, ligandexpressing, and / or receptor-expressing lesions, delivering DNA strand-breaking radiation. PSMA is an attractive target for prostate cancer therapy because, while it is highly expressed in cancerous cells, including mCRPC cells, it has much lower expression in normal tissues.

[0012] Accordingly, PSMA has the potential to be a viable target for RLT with minimized radioactivity-related side effects. Pluvicto® ([177Lu]Lu-PSMA-617) is one example of an FDA-approved PSMA-based RLT drug for the treatment of PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).

[0013] Despite the clinical success of targeted RLT, there are opportunities for improving aspects of therapeutic efficacy, such as enhancing the duration and / or extent of the response for a wider population of patients.

[0014] SUMMARY

[0015] Described herein are combination therapies featuring a Prostate-Specific Membrane Antigen (PSMA)-targeting radiopharmaceutical and an Androgen Receptor (AR)-degrading agent, and their use in treating cancers, such as, e.g., prostate cancer, PSMA-positive cancer, and / or a PSMA-expressing cancer. In particular aspects described herein, combination therapies featuring a PSMA-targeting radiopharmaceutical and an AR-degrading agent, and their use in treating prostate cancers, PSMA-positive cancers, PSMA-expressing cancers, and PSMA-positive / PSMA-expressing prostate cancers are provided.

[0016] In one aspect, the present disclosure provides a method of treating a prostate specific membrane antigen (PSMA)-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a PSMA-targeting radioligand and administering to the subject a therapeutically effective amount of an androgen receptor (AR)-degrading agent.

[0017] In certain embodiments, the PSMA-targeting radioligand can include a PSMA-binding ligand selected from the group consisting of PSMA binding ligands comprising a glutamate-urea-lysine binding motif and a chelator; PSMA binding ligands comprising a glutamate-urea-lysine binding motif, a chelator and a linker comprising a hydrophobic side chain, optionally the hydrophobic side chain comprises an amino acid linker comprising amino acid residues selected from phenylalanine, tyrosine and naphthylalanine, wherein the amino acid residues are independently optionally substituted. In certain embodiments, the PSMA-targeting radioligand can include PSMA-617 (INN: vipivotide tetraxetan), PSMA l&T (INN: zadavotide guraxetan), PSMA-R2 (Novartis), MIP-1095 (Lantheus), MIP-1545 (Lantheus), MIP-1555 (Lantheus), MIP-1557 (Lantheus), MIP-1558 (Lantheus), CTT1403 (Cancer Targeted Technology), FC705 (FC-KR), BAY-2315497 (Bayer), BAY-2315487 (Bayer), BAY-356254 (Bayer), BAY-354682 (Bayer), TLX591 (Telix), TLX592 (Telix), PSMA-TCC, rhPSMA (Blue Earth Diagnostics), rhPSMA-7 (Blue Earth Diagnostics), rhPSMA-7.3 (Blue Earth Diagnostics), rhPSMA-10.1 (Blue Earth Diagnostics), Ludotadipep, PNT2001 (PSMA-062 (Point Biopharma)), PNT2002 (Point Biopharma), PSMA-7 l&T, EB-PSMA-617 (National Institute For Biomedical Imaging And Bioengineering (Nibib), PSMA-ALB-02 (ITM Radiopharma), PSMA-ALB-53 (ITM Radiopharma), PSMA-ALB-56 (ITM Radiopharma), P16-093 (Five Eleven Pharma (PSMA-093)), PSMA-1 (RadioMedix), PSMA-1-DOTA (Case Western Reserve), SAR-bisPSMA (Clarity), ITM-22 (ITM Radiopharma), ITM-24D (ITM Radiopharma), PMI-21 (Precision Molecular), D0TA-h11B6 (Janssen Research & Development), FPI-1434 (Fusion Pharmaceuticals), pelgifatamab, NG001 / AB001 (ArtBio), ADVC001 (AdvanCell), RPS-072 (Cornell University), RPS-074 (Cornell University), FL-020 (Full Life Technologies), FPI-2265 (Fusion), CONV01 (Convergent), JNJ-6420 (J&J), LNC-1003 (Yantai LNC). In certain embodiments, the

[0018] PSMA binding ligand is PSMA-617 (INN: vipivotide tetraxetan) or PSMA l&T (INN: zadavotide guraxetan).

[0019] In certain embodiments, the PSMA-targeting radioligand can include a beta-minus-, positron-, or alpha-particle emitting radionuclide. In a further embodiment, the PSMA-targeting radioligand comprises an alpha-particle emitting radionuclide. In still a further embodiment, the alpha-particle emitting radionuclide is225Ac or212Pb. In a further embodiment, the PSMA-targeting radioligand comprises a beta-minus-particle emitting radionuclide. In still a further embodiment, the beta-minus-particle emitting radionuclide is177Lu or161Tb.

[0020] In certain embodiments, the PSMA-targeting radioligand can include a radiohybrid (rh) ligand or radiolabeled anti-PSMA antibody. In further embodiments, the PSMA-targeting radioligand comprises a radiohybrid (rh) ligand labeled with177Lu, or225Ac. In further embodiments, the PSMA-targeting radioligand comprises an anti-PSMA Monoclonal Antibody J591 labeled with177Lu,161Tb or225Ac, an anti-PSMA monoclonal antibody BAY 2315497 (Pelgifatamab Corixetan) labeled with227Th, or DOTA-rosopatamab (TLX591) labeled with177Lu.

[0021] In certain embodiments, the PSMA-targeting radioligand can include177Lu-Ludotadipep,177Lu-labeled Evans blue-modified PSMA 617 (EB-PSMA-617), or177Lu-DGUL.

[0022] In certain embodiments, the PSMA-targeting radioligand can be selected from the group consisting of compounds of formulae (I), (II), (III), (IV), and (V):

[0023]

[0024] (I)

[0025]

[0026]

[0027] (V) wherein the compounds of formulae (I), (II), (III), (IV), and (V) are radiolabeled with an alpha-particle emitting radionuclide or a beta-minus-particle emitting radionuclide. In certain embodiments, the glutamic acid and the lysine adjacent to the urea of the compound of formula (II) are in the L-configuration. In certain embodiments, the glutamic acid of the DOTAGA chelator of the compound of formula (IV) is in the unnatural D-configuration.

[0028] In further embodiments, the compounds of formulae (I), (II), (III), (IV), and (V) are radiolabeled with an alpha-particle emitting radionuclide selected from the group consisting of225Ac,211At,213Bi,212Bi,212Pb,223Ra,224Ra,149Tb, and227Th. In a further embodiment, the alphaparticle emitting radionuclide is selected from the group consisting of225Ac,212Pb, and227Th. In still a further embodiment, the alpha-particle emitting radionuclide is225Ac. In further embodiments, the compounds of formulae (I), (II), (III), (IV), and (V) are radiolabeled with a beta-minus-particle emitting radionuclide selected from the group consisting of177Lu,169Er,161Tb,131l,90Y,67Cu, and47Sc. In a further embodiment, the beta-minus-particle emitting radionuclide is177Lu or161Tb. In a further embodiment, the beta-minus-particle emitting radionuclide is177Lu. In certain embodiments, the PSMA-targeting radioligand is [177Lu]Lu-PSMA l&T (also referred to as 177Lu-PSMA l&T; INN: lutetium (177Lu) zadavotide guraxetan; in certain embodiments, [177Lu]Lu-PSMA l&T is the compound of formula (IV) with the glutamic acid of the DOTAGA chelator being in the unnatural D-configuration). In certain embodiments, the PSMA-targeting radioligand is [177Lu]Lu-PSMA-617 (also referred to as177Lu-PSMA-617; INN: lutetium (177Lu) vipivotide tetraxetan; commercial name: PLUVICTO).

[0029] In one or more of the forgoing embodiments, the non-steroidal AR-degrading agent can be selected from the group consisting of PROteolysis-TArgeting chimera (PROTAC) AR degraders, selective AR degraders (SARDs), hydrophobic tag-based degraders (HyTs), nonsteroidal CYP11A1 inhibitors, dual-action AR inhibitors (DAARIs), N-terminal domain AR degraders, ligand-directed degraders, chaperone protein dissociating AR degraders, autophagy promoting AR degraders, and combinations thereof.

[0030] In certain embodiments, the non-steroidal AR-degrading agent comprises a PROTAC AR degrader selected from the group consisting of luxdegalutamide (ARV-766), bavdegalutamide (ARV-110), gridegalutamide (BMS-986365), AC-0176 under development by Accutar Biotechnology, and HP518 under development by Hinova Pharmaceuticals Inc., or a combination thereof. In further embodiments, the PROTAC AR degrader comprises luxdegalutamide.

[0031] In certain embodiments, the non-steroidal AR-degrading agent comprises a nonsteroidal CYP11A1 inhibitor. In further embodiments, the non-steroidal CYP11A1 inhibitor comprises opevesostat.

[0032] In certain embodiments, the non-steroidal AR-degrading agent comprises a DAARI. In further embodiments, the DAARI can be (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluoropyrazol-1-yl)-2-hydroxy-2-methylpropanamide, or a pharmaceutically acceptable salt thereof.

[0033] In certain embodiments, the non-steroidal AR-degrading agent comprises a ligand directed degrader. In further embodiments, the ligand directed degrader can be 2-[(2R)-4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl]-2-ethylphenoxy]ethyl]-2-methylpiperazin-1-yl]-N-[3-[(2,6-dioxopiperidin-3-yl)amino]phenyl]acetamide, or a pharmaceutically acceptable salt thereof.

[0034] In certain embodiments, the non-steroidal AR-degrading agent comprises an N-terminal domain AR degrader. In further embodiments, the N-terminal domain AR degrader comprises Masofaniten or EPI-8207, under development by Essa Pharma.

[0035] In certain embodiments, the non-steroidal AR-degrading agent comprises a chaperone protein dissociating AR degrader. In further embodiments, the chaperone protein dissociating AR degrader can include Dimethylcurcumin, Niclosamide or derivatives thereof (ARVibs), or a pharmaceutical salt thereof, or a combination thereof.

[0036] In certain embodiments, the non-steroidal AR-degrading agent comprises an autophagy promoting AR degrader. In further embodiments, the autophagy promoting AR degrader comprises Riluzole, ora pharmaceutical salt thereof.

[0037] In certain embodiments, the non-steroidal AR-degrading agent comprises a hydrophobic tag-based degrader (HyT). In further embodiments, the HyT comprises N-(2-(2-(2-(2-((Adamantan-1-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)butanamide, ora pharmaceutically acceptable salt thereof. In one or more of the forgoing embodiments, the therapeutically effective amount of the PSMA-targeting radioligand, the non-steroidal AR-degrading agent, or both in the combination is lower than the amount required for a monotherapy response for the PSMA-targeting radioligand and / or the non-steroidal AR-degrading agent. In further embodiments, the monotherapy response is an objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (OR), partial response (PR), PSA response rate, radiographic response rate, AR-protein level, tumor growth rate, PSMA-expression level, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.

[0038] In one or more of the forgoing embodiments, the combination of the PSMA-targeting radioligand and the non-steroidal AR-degrading agent achieves an improved anti-cancer response in the treatment of a PSMA-expressing cancer than the anti-cancer response achieved by PSMA-targeting radioligand monotherapy and / or AR-degrading agent monotherapy.

[0039] In one or more of the forgoing embodiments, the combination of the PSMA-targeting radioligand and the non-steroidal AR-degrading agent provides a synergistic effect in the treatment of the PSMA-expressing cancer.

[0040] In one or more of the forgoing embodiments, the therapeutically effective amount of the PSMA-targeting radioligand is a dose of from about 6 MBq to about 10 GBq.

[0041] In one or more of the forgoing embodiments, 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 a biochemical recurrence (BCR) setting, optionally PSMA-positive cancer in a high-risk BCR setting.

[0042] In another aspect, the present disclosure provides a method of treating a prostate specific membrane antigen (PSMA)-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and a therapeutically effective amount of a nonsteroidal androgen receptor (AR)-degrading agent.

[0043] In certain embodiments, the non-steroidal AR-degrading agent is selected from the group consisting of PROteolysis-TArgeting chimera (PROTAC) AR degraders, selective AR degraders (SARDs), hydrophobic tag-based degraders (HyTs), non-steroidal CYP11A1 inhibitors, dual-action AR inhibitors (DAARIs), N-terminal domain AR degraders, ligand-directed degraders, chaperone protein dissociating AR degraders, autophagy promoting AR degraders, and combinations thereof. In certain embodiments, the non-steroidal AR-degrading agent is a PROTAC AR degrader selected from the group consisting of luxdegalutamide (ARV-766), bavdegalutamide (ARV-110), gridegalutamide (BMS-986365), AC-0176 under development by Accutar Biotechnology, and HP518 under development by Hinova Pharmaceuticals Inc., or a combination thereof, and optionally the PROTAC AR degrader is luxdegalutamide.

[0044] In certain embodiments, the non-steroidal AR-degrading agent is a non-steroidal CYP11A1 inhibitor, and optionally the non-steroidal CYP11A1 inhibitor comprise opevesostat.

[0045] In certain embodiments, the non-steroidal AR-degrading agent is a DAARI, and optionally the DAARI is (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluoropyrazol-1-yl)-2-hydroxy-2-methylpropanamide, or a pharmaceutically acceptable salt thereof.

[0046] In certain embodiments, the non-steroidal AR-degrading agent is a ligand directed degrader, and optionally the ligand directed degrader is 2-[(2R)-4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl]-2-ethylphenoxy]ethyl]-2-methylpiperazin-1-yl]-N-[3-[(2,6-dioxopiperidin-3-yl)amino]phenyl]acetamide, or a pharmaceutically acceptable salt thereof.

[0047] In certain embodiments, the non-steroidal AR-degrading agent is an N-terminal domain AR degrader, and optionally wherein the N-terminal domain AR degrader is Masofaniten or EPI-8207.

[0048] In certain embodiments, the non-steroidal AR-degrading agent is a chaperone protein dissociating AR degrader, and optionally the chaperone protein dissociating AR degrader is Dimethylcurcumin, Niclosamide or a derivative thereof (ARVibs), or pharmaceutical salts thereof, or combinations thereof.

[0049] In certain embodiments, the non-steroidal AR-degrading agent is an autophagy promoting AR degrader, and optionally the autophagy promoting AR degrader is Riluzole, or a pharmaceutical salt thereof.

[0050] In certain embodiments, the non-steroidal AR-degrading agent is a hydrophobic tag-based degrader (HyT), and optionally the HyT is N-(2-(2-(2-(2-((Adamantan-1-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)butanamide, or a pharmaceutically acceptable salt thereof.

[0051] In any one or more of the embodiments of the above method, the therapeutically effective amount of the [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), the non-steroidal AR-degrading agent, or both in the combination is lower than the amount required for a monotherapy response for [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and / or the non-steroidal AR-degrading agent. In a further aspect, the monotherapy response is an objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (OR), partial response (PR), PSA response rate, radiographic response rate, AR-protein level, tumor growth rate, PSA expression level, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.

[0052] In any one or more of the embodiments of the above aspect, the combination of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and the non-steroidal AR-degrading agent achieves an improved anti-cancer response for use in the treatment of a PSMA-expressing cancer than the anti-cancer response achieved by [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) monotherapy and / or AR-degrading agent monotherapy.

[0053] In any one or more of the embodiments of the above aspect, wherein the combination of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and the non-steroidal AR-degrading agent provides a synergistic effect in the treatment of the PSMA-expressing cancer.

[0054] In any one or more of the embodiments of the above aspect, the therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) is a dose of from about 3 GBq to about 10 GBq.

[0055] In any one or more of the embodiments of the above aspect, the PSMA-expressing cancer is PSMA-positive prostate cancer, optionally PSMA-positive metastatic castrationresistant prostate cancer (mCRPC), optionally PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC), optionally PSMA-positive oligometastatic prostate cancer (OMPC), optionally PSMA-positive cancer in a biochemical recurrence (BCR) setting, optionally PSMA-positive cancer in a high-risk BCR setting.

[0056] In another aspect, the present disclosure provides a method of treating a prostate specific membrane antigen (PSMA)-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a therapeutically effective amount of luxdegalutamide and a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan).

[0057] In another aspect, the present disclosure provides a method of treating a prostate specific membrane antigen (PSMA)-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a therapeutically effective amount of luxdegalutamide and a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan); wherein the therapeutically effective amount of luxdegalutamide is administered at least 24 hours prior to administration of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan); wherein the therapeutically effective amount of luxdegalutamide is about 20 mg / kg to about 30 mg / kg body weight of the subject daily or about 100 mg / day to 300 mg / day; wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) is a dose of from about 3 GBq to about 10 GBq; whereby an anti-cancer response in the subject is improved as compared to a monotherapy response with [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) or

[0058] luxdegalutamide. In certain embodiments, the therapeutically effective amount of luxdegalutamide is administered about 3, 4, or 5 days before administering the therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan).

[0059] In certain embodiments, the therapeutically effective amount of luxdegalutamide is administered for at least one week after the [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) is administered.

[0060] In any one or more of the embodiments of the above aspect, the improvement in the at least one anti-cancer response is at least additive or greater than additive.

[0061] In another aspect, the present disclosure provides a combination comprising a nonsteroidal Androgen Receptor (AR)-degrading agent and a Prostate Specific Membrane Antigen (PSMA)-targeting radioligand for use in treating a PSMA-expressing cancer.

[0062] In certain embodiments, the non-steroidal AR-degrading agent is selected from the group consisting of PROteolysis-TArgeting chimera (PROTAC) AR degraders, selective AR degraders (SARDs), hydrophobic tag-based degraders (HyTs), non-steroidal CYP11A1 inhibitors, dual-action AR inhibitors (DAARIs), N-terminal domain AR degraders, ligand-directed degraders, chaperone protein dissociating AR degraders, autophagy promoting AR degraders, and combinations thereof.

[0063] In certain embodiments, the PSMA-targeting radioligand comprises a radiohybrid (rh) ligand, a radiolabeled anti-PSMA antibody, Ludotadipep, Evans blue-modified PSMA 617 (EB-PSMA-617), or177Lu-DGUL, or is a compound of formula (I), (II), (III), (IV), or (V), as defined above.

[0064] In certain embodiments, the PSMA-targeting radioligand is radiolabeled with an alphaparticle emitting radionuclide or a beta-minus-particle emitting radionuclide, optionally an alphaparticle emitting radionuclide selected from the group consisting of225Ac,211At,213Bi,212Bi,212Pb,223Ra,224Ra,149Tb, and227Th, or a beta-minus-particle emitting radionuclide selected from the group consisting of177Lu,169Er,161Tb,1311,90Y,67Cu, and47Sc.

[0065] In certain embodiments, the PSMA-targeting radioligand is [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) or [177Lu]Lu-PSMA l&T (INN: lutetium (177Lu) zadavotide guraxetan). In a further embodiment, the combination achieves an enhanced anti-cancer response in the subject as compared with a [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) or [177Lu]Lu-PSMA- l&T (INN: lutetium (177Lu) zadavotide guraxetan) monotherapy or non-steroidal AR-degrading agent monotherapy. In still a further embodiment, the anti-cancer response of the combination is at least about 10% to about 50% greater than the anti-cancer response of the [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) or [177Lu]Lu-PSMA l&T (INN: lutetium (177Lu) zadavotide guraxetan) monotherapy or the nonsteroidal AR-degrading agent monotherapy. In another aspect, the present disclosure provides a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a AR-degrading agent and administering a therapeutically effective amount of a PSMA-targeting radiopharmaceutical.

[0066] In certain embodiments, the PSMA-targeting radiopharmaceutical comprises [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and / or the AR-degrading agent comprises luxdegalutamide.

[0067] In certain embodiments, the cancer comprises a prostate cancer, a prostate specific membrane antigen (PSMA)-positive cancer, a PSMA-expressing cancer, a PSMA-positive / PSMA-expressing prostate cancer, a metastatic castration resistant prostate cancer (mCRPC), and / or PSMA-positive or PSMA-expressing mCRPC that has been confirmed by radiographical imaging.

[0068] In certain embodiments, the cancer is a progressive PSMA-positive or PSMA-expressing mCRPC.

[0069] In certain embodiments, the therapeutically effective amount of luxdegalutamide comprises a dose of at least about 100 mg, a dose of from about 100 mg to about 300 mg, or from about 200 mg to about 300 mg.

[0070] In certain embodiments, the therapeutically effective amount of luxdegalutamide comprises a dose of about 300 mg.

[0071] In certain embodiments, the therapeutically effective amount of luxdegalutamide is administered daily, such as once daily.

[0072] In certain embodiments, the therapeutically effective amount of luxdegalutamide is administered orally.

[0073] In certain embodiments, the therapeutically effective amount of luxdegalutamide is administered with food, such as with a daily meal comprising a mixture of macronutrients, particularly the largest meal of the day, e.g., dinner with food(s) comprising a mixture of fat, carbohydrates and protein, and / or any food comprising 400 or more calories from a mixture of fat, carbohydrates and protein.

[0074] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 comprises a dose of from about 3 GBq to about 10 GBq, from about 4 GBq to about 9 GBq or from about 5.9 GBq to about 7.4 GBq.

[0075] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 5.9 GBq or a dose of about 7.4 GBq.

[0076] In certain embodiments, the method comprises adjusting the therapeutically effective amount of [177Lu]Lu-PSMA-617 over a course of therapy (e.g., reducing the dose).

[0077] In certain embodiments, the [177Lu]Lu-PSMA-617 dose is administered intravenously. In certain embodiments, the therapeutically effective amount of luxdegalutamide is a dose of at least about 100 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of: from about 3 GBq to about 10 GBq; from about 5.9 GBq to about 7.4 GBq; about 7.4 GBq; or about 5.9 GBq.

[0078] In certain embodiments, the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of: from about 3 GBq to about 10 GBq; from about 5.9 GBq to about 7.4 GBq; about 7.4 GBq; or about 5.9 GBq.

[0079] In certain embodiments, the therapeutically effective amount of luxdegalutamide is a dose of from about 200 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of: from about 3 GBq to about 10 GBq; from about 5.9 GBq to about 7.4 GBq; about 7.4 GBq; or about 5.9 GBq.

[0080] In certain embodiments, the therapeutically effective amount of luxdegalutamide is a dose of about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of: from about 3 GBq to about 10 GBq; from about 5.9 GBq to about 7.4 GBq; about 7.4 GBq; or about 5.9 GB.

[0081] In certain embodiments, a first dose of luxdegalutamide is administered less than or equal to about 17 days prior to administering a first dose of [177Lu]Lu-PSMA-617.

[0082] In certain embodiments, the first dose of [177Lu]Lu-PSMA-617 is administered within about two weeks after the first dose of luxdegalutamide.

[0083] In certain embodiments, the first dose of [177Lu]Lu-PSMA-617 is administered less than or equal to about 14 days after the first dose of luxdegalutamide.

[0084] In certain embodiments, the first dose of luxdegalutamide is formulated an oral tablet and the first dose of [177Lu]Lu-PSMA-617 is formulated as an intravenous solution.

[0085] In certain embodiments, the method comprises an on-treatment period comprising at least about 14 consecutive days of luxdegalutamide and at least one dose of [177Lu]Lu-PSMA-617.

[0086] In certain embodiments, the first day of the on-treatment period can include administering an initial dose of the therapeutically effective amount of luxdegalutamide at time To and administering an initial dose of the therapeutically effective amount of [177Lu]Lu-PSMA-617 at time Tn, wherein the Tn-To interval is greater than about 10 days and less than or equal to about 17 days. In certain embodiments, the Tn-To interval is greater than or equal to about 1.5 weeks and less than or equal to about two weeks, or the Tn-To interval is greater than or equal to about 12 days and less than or equal to about 14 days.

[0087] In certain embodiments, the initial dose of the therapeutically effective amount of luxdegalutamide is administered orally and the initial dose of the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered intravenously. In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered as a course of treatment comprising at least one cycle. In certain embodiments, the course of treatment comprises at least two cycles, at least three cycles, at least four cycles or at least five cycles. In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be administered once per cycle for 2 to 10 cycles or for 4 to 8 cycles.

[0088] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 6 cycles.

[0089] In certain embodiments, one cycle has a duration of about 4 weeks to about 8 weeks, about 5 weeks duration to about 7 weeks, or of about 6 weeks.

[0090] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for at least two cycles and each cycle is about 4 weeks to about 8 weeks, each cycle is about 5 weeks to about 7 weeks, or each cycle is about 6 weeks.

[0091] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 2 to 10 cycles and each cycle is about 4 weeks to about 8 weeks, each cycle is about 5 weeks to about 7 weeks or each cycle is about 6 weeks.

[0092] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 4 to 8 cycles and each cycle is about 4 weeks to about 8 weeks, about 5 weeks to about 7 weeks, or each cycle is about 6 weeks.

[0093] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 6 cycles and each cycle is about 4 weeks to about 8 weeks, about 5 weeks to about 7 weeks, or each cycle is about 6 weeks.

[0094] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 6 cycles and each cycle is about 6 weeks.

[0095] In certain embodiments, the subject is selected from a group of subjects who have had prior exposure to at least one Androgen Receptor Pathway Inhibitor (ARPI). The least one ARPI can have been one or more of enzalutamide, abiraterone, apalutamide, darolutamide, cimetidine, orteronel, galeterone, seviteronel, topilutamide, bicalutamide, fluamide, nilutamide, and Hsp90 inhibitors, and combinations thereof. The subject can have been exposed to the least one ARPI in a metastatic or advanced setting.

[0096] In certain embodiments, the subject has had prior exposure to at least one ARPI selected from the group consisting of abiraterone, enzalutamide, darolutamide, and apalutamide, or the subject has had prior exposure to two or more of abiraterone, enzalutamide, darolutamide, and apalutamide.

[0097] In certain embodiments, the subject is selected from a group of subjects:

[0098] (a) with no prior exposure to a taxane regimen;

[0099] (b) with prior exposure to no more than two taxane regimens; (c) with prior exposure to one or two taxane regimens in a previous treatment in a Hormone Sensitive Prostate Cancer (HSPC) or a castration resistant prostate cancer (CRPC) setting;

[0100] (d) who have not received prior chemotherapy;

[0101] (e) who have not received prior chemotherapy other than a taxane regimen. (f) who have not been treated with one or more of platinum, estramustine, vincristine, methotrexate, and cyclophosphamide, or who have not been treated with any of platinum, estramustine, vincristine, methotrexate, and cyclophosphamide;

[0102] (g) who have been treated with an immunotherapy agent, e.g., sipuleucel-T; (h) who have not been exposed to a radioligand therapy (RLT) prior to receiving a first dose of [177Lu]Lu-PSMA-617;

[0103] (i) who have been treated with a poly (ADP-ribose) polymerase (PARP) inhibitor, an immune checkpoint inhibitor, or a combination thereof;

[0104] (j) who have had prior exposure to radiation therapy;

[0105] (k) who are not exhibiting or experiencing a sign or symptom of toxicity from a prior treatment;

[0106] (l) who are not exhibiting or experiencing a sign or symptom of toxicity from a prior therapy of less than or equal to grade 1 ;

[0107] (m) who are not exhibiting alopecia less than or equal to grade 2 toxicity from a prior therapy;

[0108] (n) who are not experiencing peripheral neuropathy less than or equal to grade 2 toxicity from a prior therapy;

[0109] (o) with a castrate level of serum / plasma testosterone;

[0110] (p) with a serum / plasma testosterone level less than <50 ng / dL or <1.7 nmol / L; (q) receiving Androgen Deprivation Therapy (ADT);

[0111] (r) receiving concurrent ADT selected from the group consisting of gonadotropin releasing hormone analogues / antagonists, e.g:, abarelix, degarelix, and relugolix;

[0112] (s) who underwent an orchiectomy; and / or

[0113] (t) receiving a proton-pump inhibitor.

[0114] In certain embodiments, the subject is selected from a group of subjects:

[0115] (a) with prior exposure to:

[0116] (i) at least one ARPI selected from the group consisting of abiraterone, enzalutamide, darolutamide, and apalutamide in a metastatic or advanced setting; and

[0117] (ii) no more than two taxane regimens in a previous treatment in a Hormone Sensitive Prostate Cancer (HSPC) or a castration resistant prostate cancer (CRPC) setting;

[0118] (b) who have not received prior chemotherapy other than a taxane regimen; (c) with a castrate level of serum / plasma testosterone; and

[0119] (d) receiving Androgen Deprivation Therapy (ADT);

[0120] In another aspect, the present disclosure provides a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of luxdegalutamide and administering a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), wherein:

[0121] the cancer is metastatic castration resistant prostate cancer (mCRPC);

[0122] the subject has had prior exposure to at least one ARPI and prior exposure to no more than two taxane regimes; and

[0123] the therapeutically effective amount of luxdegalutamide comprises a dose of at least about 100 mg.

[0124] In certain embodiments, the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg, a dose of from about 200 mg to about 300 mg, a dose of about 300 mg, a dose of about 200 mg, or a dose of about 100 mg.

[0125] In certain embodiments, the therapeutically effective amount of luxdegalutamide is administered daily; continuously; orally; and / or with food.

[0126] In certain embodiments, luxdegalutamide is administered with food of 400 or more calories comprising a mixture of fat, carbohydrates and protein; such as the largest meal of the day or dinner.

[0127] In certain embodiments, the therapeutically effective amount of luxdegalutamide is administered for at least about 14 days or for at least about 4 weeks.

[0128] In certain embodiments, the therapeutically effective amount of luxdegalutamide is administered continuously for about 4 weeks to about 38 weeks.

[0129] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 3 GBq to about 10 GBq; from about 5.9 GBq to about 7.4 GBq; about 7.4 GBq; or about 5.9 GBq.

[0130] In certain embodiments, the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of: from about 3 GBq to about 10 GBq; from about 5.9 GBq to about 7.4 GBq; about 7.4 GBq; or about 5.9 GBq.

[0131] In certain embodiments, the therapeutically effective amount of luxdegalutamide is a dose of from about 200 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of: from about 3 GBq to about 10 GBq; from about 5.9 GBq to about 7.4 GBq; about 7.4 GBq; or about 5.9 GBq. In certain embodiments, the therapeutically effective amount of luxdegalutamide is a dose of about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of: from about 3 GBq to about 10 GBq; from about 5.9 GBq to about 7.4 GBq; about 7.4 GBq; or about 5.9 GB.

[0132] In certain embodiments, a first dose of luxdegalutamide is administered less than or equal to about 17 days prior to administering a first dose of [177Lu]Lu-PSMA-617.

[0133] In certain embodiments, the first dose of [177Lu]Lu-PSMA-617 is administered within about two weeks after the first dose of luxdegalutamide.

[0134] In certain embodiments, the first dose of [177Lu]Lu-PSMA-617 is administered less than or equal to about 14 days after the first dose of luxdegalutamide.

[0135] In certain embodiments, the first dose of luxdegalutamide is formulated an oral tablet and the first dose of [177Lu]Lu-PSMA-617 is formulated as an intravenous solution.

[0136] In certain embodiments, the method comprises an on-treatment period comprising at least about 14 consecutive days of luxdegalutamide and at least one dose of [177Lu]Lu-PSMA-617.

[0137] In certain embodiments, the first day of the on-treatment period can include administering an initial dose of the therapeutically effective amount of luxdegalutamide at time To and administering an initial dose of the therapeutically effective amount of [177Lu]Lu-PSMA-617 at time Tn, wherein n is an integer within a range of about 10 to about 17 days (i.e. , wherein the Tn-To interval is greater than about 10 days and less than or equal to about 17 days). In certain embodiments, the Tn-To interval is greater than or equal to about 1.5 weeks and less than or equal to about two weeks, or the Tn-To interval is greater than or equal to about 12 days and less than or equal to about 14 days

[0138] In certain embodiments, the initial dose of the therapeutically effective amount of luxdegalutamide is administered orally and the initial dose of the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered intravenously.

[0139] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered as a course of treatment comprising at least one cycle. In certain embodiments, the course of treatment comprises at least two cycles, at least three cycles, at least four cycles or at least five cycles. In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be administered once per cycle for 2 to 10 cycles or for 4 to 8 cycles.

[0140] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 6 cycles.

[0141] In certain embodiments, one cycle has a duration of about 4 weeks to about 8 weeks, about 5 weeks duration to about 7 weeks, or of about 6 weeks. In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for at least two cycles and each cycle is about 4 weeks to about 8 weeks, each cycle is about 5 weeks to about 7 weeks, or each cycle is about 6 weeks.

[0142] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 2 to 10 cycles and each cycle is about 4 weeks to about 8 weeks, each cycle is about 5 weeks to about 7 weeks or each cycle is about 6 weeks.

[0143] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 4 to 8 cycles and each cycle is about 4 weeks to about 8 weeks, about 5 weeks to about 7 weeks, or each cycle is about 6 weeks.

[0144] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 6 cycles and each cycle is about 4 weeks to about 8 weeks, about 5 weeks to about 7 weeks, or each cycle is about 6 weeks.

[0145] In certain embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 6 cycles and each cycle is about 6 weeks.

[0146] In certain embodiments, the subject is selected from a group of subjects who have had prior exposure to at least one Androgen Receptor Pathway Inhibitor (ARPI). The least one ARPI can have been one or more of enzalutamide, abiraterone, apalutamide, darolutamide, cimetidine, orteronel, galeterone, seviteronel, topilutamide, bicalutamide, fluamide, nilutamide, and Hsp90 inhibitors, and combinations thereof. The subject can have been exposed to the least one ARPI in a metastatic or advanced setting.

[0147] In certain embodiments, the subject has had prior exposure to at least one ARPI selected from the group consisting of abiraterone, enzalutamide, darolutamide, and apalutamide, or the subject has had prior exposure to two or more of abiraterone, enzalutamide, darolutamide, and apalutamide.

[0148] In certain embodiments, the subject is selected from a group of subjects:

[0149] (a) with no prior exposure to a taxane regimen;

[0150] (b) with prior exposure to one or two taxane regimens in a previous treatment in a Hormone Sensitive Prostate Cancer (HSPC) or a castration resistant prostate cancer (CRPC) setting;

[0151] (d) who have not received prior chemotherapy;

[0152] (e) who have not received prior chemotherapy other than a taxane regimen. (f) who have not been treated with one or more of platinum, estramustine, vincristine, methotrexate, and cyclophosphamide, or who have not been treated with any of platinum, estramustine, vincristine, methotrexate, and cyclophosphamide;

[0153] (g) who have been treated with an immunotherapy agent, e.g., sipuleucel-T; (h) who have not been exposed to a radioligand therapy (RLT) prior to receiving a first dose of [177Lu]Lu-PSMA-617; (i) who have been treated with a poly (ADP-ribose) polymerase (PARP) inhibitor, an immune checkpoint inhibitor, or a combination thereof;

[0154] (j) who have had prior exposure to radiation therapy;

[0155] (k) who are not exhibiting or experiencing a sign or symptom of toxicity from a prior treatment;

[0156] (l) who are not exhibiting or experiencing a sign or symptom of toxicity from a prior therapy of less than or equal to grade 1 ;

[0157] (m) who are not exhibiting alopecia less than or equal to grade 2 toxicity from a prior therapy;

[0158] (n) who are not experiencing peripheral neuropathy less than or equal to grade 2 toxicity from a prior therapy;

[0159] (o) with a castrate level of serum / plasma testosterone;

[0160] (p) with a serum / plasma testosterone level less than <50 ng / dL or <1.7 nmol / L; (q) receiving Androgen Deprivation Therapy (ADT);

[0161] (r) receiving concurrent ADT selected from the group consisting of gonadotropin releasing hormone analogues / antagonists, e.g:, abarelix, degarelix, and relugolix;

[0162] (s) who underwent an orchiectomy; and / or

[0163] (t) receiving a proton-pump inhibitor.

[0164] In certain embodiments, the subject is selected from a group of subjects:

[0165] (a) with prior exposure to:

[0166] (i) at least one ARPI selected from the group consisting of abiraterone, enzalutamide, darolutamide, and apalutamide in a metastatic or advanced setting; and

[0167] (ii) no more than two taxane regimens in a previous treatment in a Hormone Sensitive Prostate Cancer (HSPC) or a castration resistant prostate cancer (CRPC) setting;

[0168] (b) who have not received prior chemotherapy other than a taxane regimen; (c) with a castrate level of serum / plasma testosterone; and

[0169] (d) receiving Androgen Deprivation Therapy (ADT).

[0170] In another aspect, the present disclosure provides a combination for use treating cancer, the combination comprising a therapeutically effective amount of an AR-degrading agent and a therapeutically effective amount of a PSMA-targeting radiopharmaceutical, wherein the combination has improved efficacy as compared with the efficacy of the PSMA-targeting radiopharmaceutical alone. In certain embodiments, the AR-degrading agent comprises luxdegalutamide and the PSMA-targeting radiopharmaceutical comprises [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan).

[0171] In certain embodiments, the combination is for use treating a prostate cancer, a prostate specific membrane antigen (PSMA)-positive cancer, a PSMA-expressing cancer, a PSMA-positive / PSMA-expressing prostate cancer, a metastatic castration resistant prostate cancer (mCRPC), and / or PSMA-positive or PSMA-expressing mCRPC that has been confirmed by radiographical imaging.

[0172] In certain embodiments, the combination is for use treating a progressive PSMA-positive or PSMA-expressing mCRPC.

[0173] In certain embodiments, the combination is for use treating a in treating mCRPC in a subject who has had prior exposure to at least one Androgen Receptor Pathway Inhibitor (ARPI). The at least one ARPI can be selected from the group consisting of abiraterone, enzalutamide, darolutamide, and apalutamide, or a combination thereof. The subject can have been exposed to two or more of abiraterone, enzalutamide, darolutamide, and apalutamide.

[0174] In certain embodiments, the combination is for use treating mCRPC in a subject who has had prior exposure to at least one ARPI and no more than two taxane regimens, who has a castrate level of serum / plasma testosterone; and is receiving concurrent Androgen Deprivation Therapy (ADT), such as gonadotropin releasing hormone analogues / antagonists, or has undergone an orchiectomy.

[0175] In certain embodiments, luxdegalutamide of the combination improves an anti-cancer response to [177Lu]Lu-PSMA-617 for use treating cancer as compared with the anti-cancer response to a [177Lu]Lu-PSMA-617 monotherapy.

[0176] In another aspect, the present disclosure provides a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of luxdegalutamide and administering a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), wherein:

[0177] the cancer is metastatic castration resistant prostate cancer (mCRPC);

[0178] the subject has had prior exposure to at least one ARPI;

[0179] the subject has: (i) no prior exposure to a taxane regime or chemotherapy, or (ii) prior exposure to no more than two taxane regimens;

[0180] the therapeutically effective amount of luxdegalutamide comprises a dose of about 100 mg or about 300 mg, formulated for oral administration; and

[0181] the therapeutically effective amount of [177Lu]Lu-PSMA-617 comprises a dose of about 7.4 GBq administered once per a six-week cycle, for about six cycles,

[0182] wherein the first dose of [177Lu]Lu-PSMA-617 is administered intravenously without about 14 to about 17 days after administration of the first dose of luxdegalutamide. In another aspect, the present disclosure provides a method of improving the effectiveness of a cancer treatment in a subject in need thereof, the method comprising providing a combination therapy to the subject;

[0183] wherein the combination therapy comprises administering at least one cycle of a PSMA-targeting radioligand therapy (RLT) and administering a daily dose of an AR-degrading agent;

[0184] whereby the combination therapy improves at least one efficacy endpoint for the subject as compared with a corresponding efficacy endpoint achieved in subjects receiving the PSMA-targeting RLT as a monotherapy.

[0185] In certain embodiments, the at least one efficacy endpoint is selected from the group consisting of Radiographic progression-free survival (rPFS), Overall survival (OS), Complete response (OR), Partial response (PR), Stable response (SD), Best Overall response (BOR), Duration of radiographic response (DOR), Time to response (TTR), Time to soft tissue progression (TTSTP), PSA value less than 0.2 ng / ml at any time point, % decrease in a PSA value from a baseline, Duration of biochemical response (DBR), Time to first symptomatic skeletal event (TTSSE), and combinations thereof.

[0186] In certain embodiments, the efficacy endpoint is improved by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, or at least 250% as compared with an average value for the corresponding efficacy endpoint achieved in subjects receiving the PSMA-targeting RLT as a monotherapy.

[0187] In certain embodiments, a first dose of the AR-degrading agent is administered about two weeks before a first cycle of the PSMA-targeting RLT.

[0188] In certain embodiments of this aspect, the daily dose of the AR-degrading agent is administered continuously during the at least one cycle.

[0189] In certain embodiments, one cycle is about 6 weeks in duration, and the PSMA-targeting RLT comprises 6 cycles.

[0190] In certain embodiments, the daily dose of the AR-degrading agent comprises at least about 100 mg of luxdegalutamide and the PSMA-targeting RLT comprises administering a dose of about 7.4 GBq of [177Lu]Lu-PSMA-617 per cycle.

[0191] In another aspect, the present disclosure provides a method of prolonging the rPFS, OS, and / or TTSTP of a subject with cancer, the method comprising providing a combination therapy to the subject;

[0192] wherein the combination therapy comprises administering at least one cycle of a PSMA-targeting radioligand therapy (RLT) and administering a daily dose of an AR-degrading agent;

[0193] whereby the combination therapy prolongs the subject’s rPFS, OS, and / or TTSTP as compared with an average rPFS, OS, and / or TTSTP for subjects receiving the PSMA-targeting RLT as a monotherapy. In certain embodiments, the subject’s rPFS, OS, and / or TTSTP is prolonged by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, or at least 250%, as compared with the average rPFS, OS, and / or TTSTP for subjects receiving the PSMA-targeting RLT monotherapy;

[0194] the first dose of the AR-degrading agent is administered about two weeks before a first cycle of the PSMA-targeting RLT;

[0195] the daily dose of the AR-degrading agent is administered continuously during the at least one cycle; and / or one cycle is about 6 weeks in duration, and the PSMA-targeting RLT comprises 6 cycles; and / or

[0196] the daily dose of the AR-degrading agent comprises at least about 100 mg of luxdegalutamide and the PSMA-targeting RLT comprises administering a dose of about 7.4 GBq of [177Lu]Lu-PSMA-617 per cycle.

[0197] In another aspect, the present disclosure provides a method of reducing a TTR of a cancer therapy comprising providing a combination therapy to a subject in need thereof;

[0198] wherein the combination therapy comprises administering at least one cycle of a PSMA-targeting radioligand therapy (RLT) and administering a daily dose of an AR-degrading agent;

[0199] whereby the combination therapy reduces the TTR as compared with an average TTR in subjects receiving the PSMA-targeting RLT as monotherapy.

[0200] In certain embodiments, the TTR is reduced by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, or at least 250%, in the subject as compared with the average TTR in subjects receiving the PSMA-targeting RLT as monotherapy;

[0201] the first dose of the AR-degrading agent is administered about two weeks before a first cycle of the PSMA-targeting RLT;

[0202] the daily dose of the AR-degrading agent is administered continuously during the at least one cycle; and / or one cycle is about 6 weeks in duration, and the PSMA-targeting RLT comprises 6 cycles; and / or

[0203] the daily dose of the AR-degrading agent comprises at least about 100 mg of luxdegalutamide and the PSMA-targeting RLT comprises administering a dose of about 7.4 GBq of [177Lu]Lu-PSMA-617 per cycle.

[0204] In another aspect, the present disclosure provides a method of improving the rate of PSA50, ORR, DCR, PSA90, PSA30 and / or PSA0 of a cancer therapy, the method comprising administering at least one cycle of a PSMA-targeting radioligand therapy (RLT) to a population of subjects receiving a daily dose of an AR-degrading agent;

[0205] whereby the proportion of subjects who achieve: a decrease of > about 30% in PSA from baseline at any timepoint;

[0206] a PSA value <0.2 ng / ml at any timepoint after start of treatment;

[0207] a confirmed complete response (CR) or partial response (PR); and / or

[0208] a CR, PR or stable disease (SD),

[0209] is increased as compared with a corresponding population of subjects who have not received the AR-degrading agent.

[0210] In certain embodiments, wherein the rate is increased by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, or at least 250% in the population as compared to the rate of the PSMA-targeting radioligand used as a monotherapy;

[0211] the first dose of the AR-degrading agent is administered about two weeks before a first cycle of the PSMA-targeting RLT;

[0212] the daily dose of the AR-degrading agent is administered continuously during the at least one cycle; and / or one cycle is about 6 weeks in duration, and the PSMA-targeting RLT comprises 6 cycles; and / or

[0213] the daily dose of the AR-degrading agent comprises at least about 100 mg of luxdegalutamide and the PSMA-targeting RLT comprises administering a dose of about 7.4 GBq of [177Lu]Lu-PSMA-617 per cycle.

[0214] BRIEF DESCRIPTION OF THE DRAWINGS FIGs. 1A-B depict western blots showing dose-dependent induction of AR degradation in LNCaP cells treated for 24h (A) and 72h (B) with luxdegalutamide (ARV766).

[0215] FIG. 2A depicts dose-dependent growth inhibition of LNCaP cells by luxdegalutamide (ARV766) (squares) or enzalutamide (circles), showing a growth inhibition 50% (GI50) of 33 nm and 284 nm, respectively.

[0216] FIG. 2B depicts dose-dependent inhibition of KLK3 mRNA in LNCaP cells by luxdegalutamide (ARV766) (squares) or enzalutamide (circles).

[0217] FIG. 3 depicts results of in vivo studies showing the time course analysis of AR degradation in LNCaP tumor xenografts after a single treatment with luxdegalutamide (ARV766 (NVP-BUO652)). Tumor-bearing female mice with testosterone pellets were treated with a single dose (20mg / kg p.o. in 20% caprylocaproyl macrogol-8 glyceride (LABRASOL®) / 80% water vehicle).

[0218] FIGs. 4A-B depict the results of the combination of luxdegalutamide (ARV766) and [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan; commercial name: PLUVICTO) on LNCaP tumor xenograft volume over time in female mice with testosterone pellets. Average fold changes in tumor volume were plotted at each measurement point and the antitumor efficacy was evaluated by the percentage of tumor growth inhibition (TGI%): (A) shows the fold-change of tumor volume and TGI% following treatment with vehicle (upper circles), 10 MBq 177Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) (triangles), 10 mg / kg p.o. QD luxdegalutamide (diamonds), or a combination of 10 MBq [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and 10 mg / kg p.o. QD luxdegalutamide (lower circles) and (B) shows the fold-change of tumor volume and TGI% following treatment with vehicle (upper circles), 10 MBq [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) (upper triangles), 30 mg / kg p.o. QD luxdegalutamide (lower circles), or a combination of 10 MBq [177Lu]Lu--PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and 30 mg / kg p.o. QD luxdegalutamide (lower triangles). Treatment with luxdegalutamide began on day 18 post inoculation. [177Lu]Lu--PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) was dosed on day 22 post inoculation.

[0219] FIG. 5 shows the structure (upper) and mode of action (lower) of the androgen receptor PROteolysis-TArgeting Chimera (AR PROTAC) molecule luxdegalutamide (ARV-766), which simultaneously binds the E3 ligase cereblon and the ligand binding domain of AR, enabling the cereblon ligase complex to ubiquitinate AR.

[0220] FIG. 6A shows western blotting results analyzed as part of a preclinical study with noncastrated male NOD scid gamma (NSG) mice bearing AR-amplified patient-derived xenografts 30158-HX, after 14 days of repeated p.o. daily treatment with a single p.o. dose of luxdegalutamide in vivo at 10 mg / kg. Luxdegalutamide demonstrated sustained reductions in AR expression and an upregulation of PSMA expression, whereas enzalutamide was associated with compensatory upregulation of AR expression and non-sustained upregulation of PSMA expression.

[0221] FIG. 6B is a graphical representation of degradation of AR proteins harboring clinically relevant point mutations in stably transfected into HEK293 cells expressing androgen receptor wild-type (AR WT) or the indicated AR mutants treated with indicated concentrations of luxdegalutamide for 24 hours.

[0222] FIG. 6C shows western blotting AR degradation in castrated CB17 / SCID male mice bearing VCaP xenografts treated with a single dose of luxdegalutamide (upper) and analysis thereof (lower). Tumors were harvested 16 hours post-dose and tumor AR level was established by western blotting. Antibody recognizing human Mito.C was employed as a loading control. The quantitation of AR levels from the western blot is shown. AR = androgen receptor; Mito.C = mitochondria specific antibody; PO = oral; scid = severe combined immune deficiency; VCaP = vertebral-cancer of the prostate.

[0223] FIG. 6D is a graphical representation of tumor growth inhibition in castrated CB17 / SCID male mice bearing VCaP xenografts treated with luxdegalutamide (ARV-766) or enzalutamide (enza). Treatment groups (n=10 per group) were compared by one-way analysis of variance (ANOVA) with Tukey’s multiple comparisons test. PO = oral; QD = once daily; scid = severe combined immune deficiency; VCaP = vertebral-cancer of the prostate. Note: ns: not significant, **: p < 0.01, ****: p<0.0001.

[0224] DETAILED DESCRIPTION PSMA is a transmembrane glycoprotein of about 100 kDa with folate hydrolase, carboxypeptidase, and internalization activities that exhibits low expression in normal prostate tissue, kidneys, duodenum, salivary and lacrimal glands, brain, and intestines. Increased PSMA expression is significantly associated with the degree of differentiation and progression of mCRPC. Accordingly, PSMA-targeting ligands may selectively accumulate in malignant cells, allowing development opportunities for imaging and treating mCRPC. The systemic administration of PSMA-targeted RLT allows the simultaneous treatment of wide-spread bone and extraskeletal metastases, thereby limiting radiotoxicity to healthy tissues.

[0225] Radioligand therapy (RLT) is emerging as a safe and effective targeted approach for treating several types of cancers. Pluvicto® ([177Lu]Lu-PSMA-617) (INN: lutetium (177Lu) vipivotide tetraxetan) is one example of an FDA-approved177Lu-based RLT drug for the treatment of PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Despite the clinical success of177Lu-RLT, a subset of patients do not achieve a complete, durable response. Thus, there is an opportunity for improving patient therapy.

[0226] In view of the foregoing, the present disclosure provides combination therapy for the treatment of PSMA-expressing cancers featuring PSMA upregulating agents and PSMA-targeting radioligands and / or Androgen Receptor (AR)-degrading agents and PSMA-targeting radioligands.

[0227] Definitions

[0228] Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques may be used for chemical synthesis, and chemical analysis. Certain such techniques and procedures may be found for example in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., 21st edition, 2005, which is hereby incorporated by reference for any purpose. Where permitted, all patents, applications, published applications and other publications and other data referred to throughout in the disclosure are incorporated by reference herein in their entirety.

[0229] Unless otherwise specified, conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups. The term “radiopharmaceutical” is used herein to refer to pharmaceutical compounds, e.g., peptides, oligonucleotides, small molecules, and antibodies, that are radiolabeled with a radionuclide. In some embodiments, radiopharmaceutical refers to a radiolabeled compound of the present disclosure ( / .e., a compound of formula (I), (II), (III), (IV), or (V)). In other embodiments, radiopharmaceutical refers to a radiolabeled compound known in the art.

[0230] A radiopharmaceutical may be a “radioligand”, i.e., a compound comprising a target binding organic moiety (e.g., a ligand, small molecule, peptide, or monoclonal antibody capable of binding to a specific marker on a cancer cell), a linker for stable attachment of the target binding moiety and a radioisotope.

[0231] The term “radiolabeled” (or “chelated,” or “complexed”) as used herein means that a non-radioactive compound is labeled with a radioisotope. Radiolabeling can be achieved, e.g., via chelation or complexation of a chelator with an appropriate radionuclide. Radiolabeling can also refer to chemically substituting one group on a compound for a radionuclide, such as, e.g., in the case of18F.

[0232] As used herein, the term “chelating moiety” refers to an organic moiety comprising functional groups that form non-covalent bonds with a radionuclide during a reacting step of the radioligand synthesis and thereby, form a stable radionuclide complex. The chelating moiety in the context of the present invention may be or may comprise, e.g., 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), which is directly linked to the target binding organic moiety via covalent bonding.

[0233] As used herein, the term “reaction solution” refers to a solution comprising ions of a radionuclide, a target binding organic molecule which is suitable for chelating the radionuclide ions, and one or more stabilizers against radiolytic degradation. The target binding organic molecule comprises a target binding organic moiety linked directly or indirectly to a chelating moiety.

[0234] As used herein, the term “stabilizer against radiolytic degradation” refers to a stabilizing agent which protects organic molecules against radiolytic degradation, e.g., when a gamma ray emitted from the radionuclide is cleaving a bond between the atoms of an organic molecules and radicals are forms, those radicals are then scavenged by the stabilizer which avoids the radicals undergo any other chemical reactions which might lead to undesired, potentially ineffective or even toxic molecules. Therefore, those stabilizers are also referred to as “free radical scavengers” or in short “radical scavengers”. Other alternative terms for those stabilizers are “radiation stability enhancers”, “radiolytic stabilizers”, or simply “quenchers”.

[0235] As used herein, “sequestering agent” refers to a chelating agent suitable to complex free radionuclide metal ions in the formulation (which are not complexed with the radiolabeled peptide). As used herein, the term “target binding ligand” refers to an organic moiety which has specific binding affinity to a target protein, typically a cell surface receptor or cellular protein. In specific embodiments, said target binding receptor moiety is an organic moiety which has specific binding affinity to prostate specific membrane antigen (PSMA).

[0236] As used herein, the terms “alpha-particle emitting radionuclide” and “alpha-emitter” include radionuclides that decay primarily via a decay (e.g.,225Ac) and radionuclides that decay via branching decay (e.g.,213Bi, which decays via p-and a decay).

[0237] The term “beta-minus-particle emitting radionuclide” as used herein refers to radionuclides that, during the process of natural decay, emit beta particles. Exemplary beta-minus-particle emitting radionuclides for use in a radioligand of the present disclosure include, but are not limited to,177Lu,169Er,161Tb,1311,90Y,67Cu, and47Sc.

[0238] Furthermore, it is intended that within the scope of the present invention, any element, in particular when mentioned in relation to a compound of the disclosure, shall comprise all isotopes and isotopic mixtures of said element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope1H,2H ( / .e., deuterium or D), and3H ( / .e., tritium or T). In some embodiments, the compounds described herein include a2H ( / .e., deuterium) isotope. By way of example, the group denoted -C<1 -ejalkyl includes not only -CH3, but also CD3; not only CH2CH3, but also CD2CD3, etc. Similarly, references to carbon and oxygen include within their scope respectively12C,13C and14C and15O and16O and17O and18O. The isotopes may be radioactive or non-radioactive. Radiolabeled compounds of the disclosure may include a radioactive isotope selected from the group comprising3H,11C,18F,35S,122l,123l,125l,131l,75Br,76Br,77Br and82Br. In some embodiments, the radioactive isotope is selected from the group of3H,11C and18F.

[0239] The term “androgen receptor (AR)-degrading agent” as used herein refers to a compound that binds to the AR receptor and causes degradation and downregulation of AR signaling. As used herein, an AR-degrading agent is distinct from AR antagonists and inverse agonists, or other compounds which reduce receptor signaling but do not induce or otherwise cause degradation of the AR receptor. In some cases, an AR-degrading agent is a nonsteroidal AR-degrading agent. In some cases, an AR-degrading agent can cause the degradation of a wild type AR and / or AR mutants, such as AR splice variants. In some cases, an AR-degrading agent exhibits a preference for an AR over other receptors (i.e. , a Selective AR Degrader (SARD)). Non-limiting examples of SARDs can include PROteolysis-TArgeting chimeras (PROTACs), hydrophobic tagged chimeric degraders (HyTs), and N-terminal domain AR degraders. A “chimera” as used in reference to an AR-degrading agent refers to a multifunctional (e.g., bi-functional) small molecule compound that selectively targets AR protein for degradation by cellular protein disposal pathways. In some cases, an AR-degrading agent is a non-steroidal CYP11A1 inhibitor or a dual-action AR inhibitor (DAARI). As used herein, “DAARI” refers to a compound that targets and binds more than one domain of the AR, e.g., the ligand-binding domain (LBD) and the N-terminal domain (NTD) of the AR, and induces the degradation of AR and AR splice variant (AR-SV) proteins.

[0240] As used herein, the term “treat,” “treatment,” or “treating” means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disorder or disease.

[0241] As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

[0242] As used herein, “PSMA-expressing cancer" refers to cancers that overexpress PSMA. As used herein, "PSMA-positive cancer" refers to cancer, particularly in prostate cancer, comprising cells that express PSMA. PSMA expression in prostate cancer can be heterogeneous, varying both within and between subjects, and within the same tumor lesion. PSMA expression in tumor lesions can be assessed with positron emission tomography (PET) scans using [68Ga]Ga-FAPI-46, 2-[18F]FDG and [68Ga]Ga- / [18F]F-PSMA-11 / -1007 PET, for example.

[0243] The expression, “in a metastatic or advanced setting” as used herein refers to the context of a therapeutic intervention for cancer no longer confined to its original location, spreading to nearby lymph nodes or tissue (i.e., locally advanced) or to distant parts of the body, such as bones, distant lymph nodes, and other organs (i.e., metastatic).

[0244] The phrase “pharmaceutically acceptable” as employed herein refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0245] As used herein, the expression, “anti-cancer response” refers to a measurable outcome used to evaluate the efficacy of an anti-cancer treatment. Suitable metrics for assessing efficacy include, but are not limited to PSA levels (e.g., PSA50, PSA90, PSA30, PSAO), tumor size (Overall Response Rate (ORR)), progression-free survival (radiographic progression-free survival (rPFS)), overall survival (OS), time to PSA progression (TTPSAP), and / or time to symptomatic tumor progression (TTSTP).

[0246] As used herein, the term “synergistic effect” as used herein refers to the action of two therapeutic agents such as, for example, [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), or any PSMA targeting radioligand described herein, and an AR-degrading agent described herein, wherein the two therapeutic agents produce an effect that is greater than the simple addition of the effects of each compound administered as a monotherapy. A synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)).

[0247] The term “biochemical recurrence” or “BCR” refers to a rise in prostate-specific antigen (PSA) levels in subjects (e.g., patients) who have been treated for prostate cancer. BCR can be stratified into low- and high-risk groups. A low-risk BCR setting can include monitoring and testing biochemical markers of recurrence. A high-risk BCR setting can include systemic therapy, androgen receptor signaling inhibitors and / or androgen depravation therapy.

[0248] The expression, “best overall response,” as used herein, refers to the best response recorded from the start of the treatment until disease progression / recurrence (taking as reference for progressive disease (PD) the smallest measurements recorded since the treatment started). The best overall response can be determined from response assessments undertaken while on treatment. A response (partial response (PR) or complete response (CR)) can be confirmed after the response criteria is met by measuring changes in tumor size over various intervals (e.g., less than about 6, 5, 4, 3, or 2 weeks after the response criteria is met). In certain embodiments, the best overall response for each subject can be determined from the sequence of overall (lesion) responses according to the following rules:

[0249] CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required;

[0250] PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required;

[0251] Stable disease (SD) = at least one SD assessment (or better) > 6 weeks after random ization / start of treatment (and not qualifying for CR or PR); and

[0252] PD = progression ~ 12 weeks after start of treatment (and not qualifying for CR, PR or SD).

[0253] The time durations above are based on a 6-week tumor assessment frequency.

[0254] However, these may be modified for specific indications which are more or less aggressive. It is envisaged that the time duration may also take into account assessment windows. E.g., if the assessment occurs every 6 weeks with a time window of + / - 7 days, a BOR of SD would require a SD or better response longer than 5 weeks after random ization / start of treatment.

[0255] For example, in a case where confirmation of response is required the sum of lesion diameters is 200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent visits, the overall lesion response would be PR - SD - PR - PR - PR, with the second assessment with 140 mm confirming the PR for this subject. All subsequent assessments can be considered PR even if tumor measurements decrease only by 20% compared to baseline (200 mm to 160 mm) at subsequent assessments.

[0256] As used herein, “overall response rate” or “ORR” refers to the proportion of subjects with a best overall response of CR or PR.

[0257] As used herein, “disease control rate” or “DCR” refers to the proportion of subjects with a best overall response of CR or PR or SD. The DCR can be used to classify subjects with signs of “activity” defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.

[0258] As used herein, “clinical benefit rate” or “CBR” refers to the proportion of subjects with a best overall response of CR or PR, or an overall lesion response of SD or Non-CR / Non-PD which lasts for a minimum time duration, and measures signs of activity taking into account duration of disease stabilization.

[0259] As used herein, “early progression rate” or “EPR” refers to the proportion of subjects with progressive disease (i.e. , subjects who do not have an overall lesion response of SD, PR or CR, where the cancer grows despite treatment) at a specific early timepoint (e.g., within 8 weeks ± window of the start of treatment).

[0260] As used herein, the “time to overall response (CR or PR)” refers to the time between the date treatment is started until first documented response (CR or PR).

[0261] As used herein, the “duration of response” or “DOR” refers to the time between first documented CR / PR and disease progression or death due to any cause per PCWG3-modified RECIST v1.1.

[0262] As used herein, “PSA50 rate,” “PSA90 rate,” and “PSA30 rate” refer to the proportion of subjects in need of treatment of a cancer, who achieve a >50%, >90%, or >30% decrease, in Prostate Specific Antigen (PSA) from baseline at any timepoint, respectively. The decrease can be confirmed by a second PSA measurement >3 weeks without any PSA progression in between. In certain embodiments, the baseline of any of the PSA50 rate, PSA90 rate, and PSA30 rate is determined when treatment is initiated (i.e., when the first dose of the AR-degrading agent is administered).

[0263] As used herein, “PSA0 rate” refers to the proportion of subjects who achieve a PSA value <0.2 ng / ml at any timepoint after start of treatment, confirmed by a second PSA measurement >3 weeks without any PSA progression in between.

[0264] As used herein, “duration of biochemical response” refers to time between PSA50 and PSA progression or death due to any cause.

[0265] As used herein, “radiographic progression-free survival” or “rPFS” refers to time between treatment initiation and the first occurrence of disease progression as per Prostate Cancer Working Group 3 (PCWG3)-modified Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or death due to any cause. “rPFS at x weeks” is an additional measure used to quantify rPFS endpoint.

[0266] As used herein, “time to response” or “TTR” refers to the time from start of treatment to the date of first documented CR or PR per PCWG3-modified RECIST v1.1.

[0267] As used herein, “time to first symptomatic skeletal event” or “TTSSE” refers to the date of treatment is initiated to the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or death from any cause, whichever occurs first.

[0268] As used herein, “time to soft tissue progression” or “TTPSAP” refers to time from treatment initiation to PSA progression. “PSA progression” refers to an increase >25% in PSA and an absolute increase of >2 ng / mL above the NADIR confirmed by a second value >3 weeks later if there is PSA decline from baseline, or a >25% increase and a >2 ng / mL increase from baseline beyond 12 weeks if there is no PSA decline from baseline.

[0269] The terms “administer,” “administering,” and “administration” refer to the giving of a compound disclosed herein, or another indicated compound, to a patient by any appropriate route. In particular, the compounds disclosed herein may be administered by oral or parenteral route, such as via a parenteral route by injection or infusion, wherein the injection or infusion may be made intravenously, intramuscularly, intra-arterially, subcutaneously, intra-dermally, intraperitoneally, etc. Depending on the administration route, the compounds of the present disclosure can be administered in a pharmaceutical composition that further comprises appropriate constituents, such as carriers, solvents, and excipients generally known in the art.

[0270] As used herein, the term “cycle” refers to the number and timing or recommended repetitions of therapy, which can be expressed as a number of days (e.g., every (q) 28 days) or a number of weeks (e.g., q 6 weeks).

[0271] The term “pharmaceutical composition” is defined herein to refer to a mixture (e.g., a solution or an 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 particular disease or condition affecting the subject.

[0272] 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 delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

[0273] The term “parenteral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal and intraarticular injection and infusion.

[0274] Unless otherwise specified, conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups.

[0275] As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, timeframe, and the like, the term “about” is meant to encompass variations of ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods, and when a numerical value or range is preceded by “about”, the “about” indicates a deviation of the value or range by ± 20%, ± 10%, or ± 5%, unless a specific deviation is described. In some contexts, the deviation indicated by “about” can be ± 2% or ± 1%. When timeframes are specified in weeks, “about” indicates a deviation of ±1 week. When timeframes are specified in days, “about” indicates a deviation of ±3 days, preferably ± 2 days, even more preferably ±1 day. In the context of radioactive dose of a PSMA-targeting radioligand, the deviation indicated by “about” can be ±30%, preferably ±20%, and more preferably ±10%. In the context of a dose of an AR-degrading agent, e.g., Luxdegalutamide, the deviation indicated by “about” can be ±50%, ±40%, ±30%, ±20%, ±10%, ±5%, ±2% or ±1%.

[0276] The articles “a” and “an” are used in this disclosure to refer to one or more than one {e.g., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0277] Disclosures of ranges in the present disclosure are, unless specified

[0278] otherwise, inclusive of endpoints and include all distinct values and further divided ranges within the entire range. Thus, for example, a range of “from ValueA to Values” or “from ValueA to Values” is inclusive of ValueA and Values. Disclosure of values and ranges of values for specific parameters (such as amounts, weight percentages, etc.) are not exclusive of other values and ranges of values useful herein. It is envisioned that two or more specific exemplified values for a given parameter may define endpoints for a range of values that may be claimed for the parameter. For example, if Parameter X is exemplified herein to have ValueA and also exemplified to have Valuez, it is envisioned that Parameter X may have a range of values from about ValueA to about Valuez”. Similarly, it is envisioned that disclosure of two or more ranges of values for a parameter (whether such ranges are nested, overlapping, or distinct) subsume all possible combination of ranges for the value that might be claimed

[0279] using endpoints of the disclosed ranges. For example, if Parameter X is exemplified herein to have values in the range of 1-10, or 2-9, or 3-8, it is also envisioned that Parameter X may have other ranges of values including 1-9, 1-8, 1-3, 1-2, 2-10, 2-8, 2-3, 3-10, 3-9, and so on.

[0280] Compounds

[0281] PSMA-targeting radioligands

[0282] Described herein are PSMA-targeting radiopharmaceuticals such as PSMA-targeting radioligands and their use in treating cancers, such as, e.g., prostate cancer, PSMA-positive cancer, and / or a PSMA-expressing cancer. In particular aspects described herein, a PSMA-targeting radioligand can be used for treatment of prostate cancers, PSMA-positive cancers, PSMA-expressing cancers, and PSMA-positive / PSMA-expressing prostate cancers.

[0283] In certain embodiments, the present disclosure provides PSMA-targeting radioligands for the treatment of PSMA-expressing cancers. A PSMA-targeting radioligand can include a PSMA-binding ligand and a radionuclide.

[0284] In certain embodiments, the PSMA-binding ligand can comprise a glutamate-urea-lysine binding motif and a chelator. In further embodiments, the PSMA binding ligands can comprise a glutamate-urea-lysine binding motif, a chelator and a linker. In still further embodiments, the linker can include a hydrophobic side chain. In still further embodiments, the hydrophobic side chain comprises amino acid residues selected from phenylalanine, tyrosine and naphthylalanine, which amino acid residues can be independently optionally substituted.

[0285] Non-limiting examples of PSMA-binding ligands include “cold” ligand (i.e. , ligand without radionuclide) selected from the group consisting of PSMA-617 (INN: vipivotide tetraxetan), PSMA l&T (INN: zadavotide guraxetan), PSMA-R2 (Novartis), MIP-1095 (Lantheus), MIP-1545 (Lantheus), MIP-1555 (Lantheus), MIP-1557 (Lantheus), MIP-1558 (Lantheus), CTT1403 (Cancer Targeted Technology), FC705 (FC-KR), BAY-2315497 (Bayer), BAY-2315487 (Bayer), BAY-356254 (Bayer), BAY-354682 (Bayer), TLX591 (Telix), TLX592 (Telix), PSMA-TCC, rhPSMA (Blue Earth Diagnostics), rhPSMA-7 (Blue Earth Diagnostics), rhPSMA-7.3 (Blue Earth Diagnostics), rhPSMA-10.1 (Blue Earth Diagnostics), Ludotadipep, PNT2001 (PSMA-062 (Point Biopharma)), PNT2002 (Point Biopharma), PSMA-7 l&T, EB-PSMA-617 (National Institute For Biomedical Imaging And Bioengineering (Nibib), PSMA-ALB-02 (ITM Radiopharma), PSMA-ALB-53 (ITM Radiopharma), PSMA-ALB-56 (ITM Radiopharma), P16-093 (Five Eleven Pharma (PSMA-093)), PSMA-1 (RadioMedix), PSMA- 1-DOTA (Case Western Reserve), SAR-bisPSMA (Clarity), ITM-22 (ITM Radiopharma), ITM-24D (ITM Radiopharma), PMI-21 (Precision Molecular), DOTA-h11B6 (Janssen Research & Development), FPI-1434 (Fusion Pharmaceuticals), pelgifatamab, NG001 / AB001 (ArtBio), ADVC001 (AdvanCell), RPS-072 (Cornell University), RPS-074 (Cornell University), FL-020 (Full Life Technologies), FPI-2265 (Fusion), CONV01 (Convergent), JNJ-6420 (J&J), LNC-1003 (Yantai LNC). In some embodiments, the PSMA-binding ligand is selected from the group consisting of PSMA-617 (INN: vipivotide tetraxetan), PSMA l&T (INN: zadavotide guraxetan), PSMA-62 POINT Biopharma, PSMA-1-DOTA (Case Western Reserve), and PSMA-R2 (Novartis). In certain embodiments, the PSMA-binding ligand is selected from the group consisting of PSMA-617 (INN: vipivotide tetraxetan), PSMA l&T (INN: zadavotide guraxetan), and PSMA-R2.

[0286] The present disclosure provides PSMA-targeting radioligands radiolabeled with beta-minus-, positron-, or alpha-particle emitting radionuclides. In certain embodiments, the PSMA-targeting radioligand comprises an alpha-particle emitting radionuclide or a beta-minus-particle emitting radionuclide. In certain embodiments, the PSMA-targeting radioligand includes an alpha-particle emitting radionuclide selected from the group consisting of225Ac,211At,213Bi,212Bi,212Pb,223Ra,224Ra,149Tb, and227Th. In further embodiments, the alpha-particle emitting radionuclide is selected from the group consisting of225Ac,212Pb, and227Th. In certain embodiments, the PSMA-targeting radioligand includes a p-emitting radionuclide selected from the group consisting of177Lu,169Er,161Tb,131l,90Y,67Cu, and47Sc. In some embodiments, the PSMA-targeting radioligand comprises177Lu.

[0287] In some embodiments, the PSMA-targeting radioligand is a radiohybrid (rh) ligand or radiolabeled anti-PSMA antibody. In certain embodiments, the PSMA-targeting radioligand is a radiohybrid (rh) ligand labeled with177Lu, or225Ac. In certain embodiments, the PSMA-targeting radioligand is a radiolabeled Anti-PSMA Monoclonal Antibody J591, labeled with177Lu,161Tb or225Ac, a227Th-labeled Anti-PSMA monoclonal antibody BAY 2315497 (Pelgifatamab Corixetan), or177Lu-DOTA-rosopatamab (TLX591).

[0288] In some embodiments, the PSMA-targeting radioligand comprises177Lu-Ludotadipep,177Lu-labeled Evans blue-modified PSMA 617 (EB-PSMA-617), or177Lu-DGUL (PSMA-targeting tracer based on Glu-Urea-Lys derivatives conjugated to a DOTA chelator).

[0289] In certain embodiments, a PSMA-targeting radioligand includes one or more compounds of formulae (I), (II), (III), (IV), and (V):

[0290]

[0291]

[0292] (V) wherein the compounds of formulae (I), (II), (III), (IV), and (V) are radiolabeled with an alpha-particle emitting radionuclide or a beta-minus-particle emitting radionuclide. In certain embodiments, the glutamic acid and the lysine adjacent to the urea of the compound of formula (II) are in the L-configuration. In certain embodiments, the glutamic acid of the DOTAGA chelator of the compound of formula (IV) is in the unnatural D-configuration. In some embodiments, the compounds of formulae (I), (II), (III), (IV), and (V) are radiolabeled with an alpha-particle emitting radionuclide selected from the group consisting of225Ac,211At,213Bi,212Bi,212Pb,223Ra,224Ra,149Tb, and227Th. In further embodiments, the alphaparticle emitting radionuclide is selected from the group consisting of225Ac,212Pb, and227Th. In still further embodiments, the alpha-particle emitting radionuclide is225Ac.

[0293] Methods of making and using the compound of formula (I) can be found, for example, in U.S. Patent No. 10,398,791, which is incorporated herein by reference in its entirety.

[0294] Methods of making and using the compound of formula (II) (e.g., 225Ac-PSMA-R2) can be found, for example, in International Stage Application No. PCT / IB2024 / 057048, Examples 1-3, which is incorporated herein by reference in its entirety.

[0295] Methods of making and using the compound of formula (III) can be found, for example, in WO 2019 / 115547 (compound of formula (III) is therein referred to PSMA-62 and DOTAGA-F(4-NH2)y-2-nal-k(d[N5-orn-C4-EuE]-TMA)), which is incorporated herein by reference in its entirety.

[0296] Methods of making and using the compound of formula (IV) can be found, for example, in Weineisen et al. J Nucl Med 2015; 56:1169-1176; and Chatalic, Theranostics, 6(6), 849-861 (2016), which is incorporated herein by reference in its entirety.

[0297] Methods of making and using the compound of formula (V) can be found, for example, in Wang et al. Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer. Cancers (Basel). 2021 13(3):417, which is incorporated herein by reference in its entirety.

[0298] In some embodiments, the compounds of formulae (I), (II), (III), (IV), and (V) are radiolabeled with a p-emitting radionuclide selected from the group consisting of177Lu,169Er,161Tb,131l,90Y,67Cu, and47Sc, In further embodiments, the p-emitting radionuclide is177Lu.

[0299] In some embodiments, the PSMA-targeting radioligand is [177Lu]Lu-PSMA l&T ( / .e., Formula (IV) radiolabeled with177Lu (INN: lutetium (177Lu) zadavotide guraxetan) (also referred to as 177Lu-PSMA l&T; INN: lutetium (177Lu) zadavotide guraxetan; in certain embodiments, [177Lu]Lu-PSMA l&T is the compound of formula (IV) with the glutamic acid of the DOTAGA chelator being in the unnatural D-configuration).

[0300] In further embodiments, the PSMA-targeting radioligand is [177Lu]Lu-PSMA-617, available under the drug product name PLUVICTO ([INN] lutetium (177Lu) vipivotide tetraxetan). Methods for the production of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) are described in WO2023 / 148680 A1, published on 10 August 2023, and following the methods as disclosed in WO 2020 / 089379 A1, published on 7 May 2020, US 2020 / 131224 A1, published on 30 April 2020, US 2021 / 0316019 A1, published on 14 October 2021, US 2022 / 0041649 A1, published on 10 February 2022. The content of those patent application publications are incorporated herein by reference in their entireties.

[0301] Throughout the entire present disclosure, [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) may be also referred to as Lutetium (177Lu) vipivotide tetraxetan, Lutetium (177Lu) vipivotide tetraxetan [INN] or Lutetium Lu 177 vipivotide tetraxetan [USAN], PLUVICTO, or 2- [4-[2-[[4-[[(2 S)-1-[[(5 S)-5-carboxy-5-[[(1 S)- 1,3-dicarboxy-propyl]carbamoylamino]pentyl]amino]-3-naphthalen-2-y1-1-oxopropan-2-yl] carbamoyl] cyclohexyl]methylamino]-2-oxoethy1]-4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraza cyclododec- 1-yl]acetate; lutetium-177(3+). The molecular mass is 1216.06 g / mol and the molecular formula is C49H68177LuNgOi6. The chemical structure for [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) is shown below:

[0302]

[0303] PSMA Upregulating Agents

[0304] Described herein are PSMA upregulating agents and their use in treating cancers, such as, e.g., prostate cancer, PSMA-positive cancer, and / or a PSMA-expressing cancer. In particular aspects described herein, a PSMA upregulating agent can be used in treating prostate cancers, PSMA-positive cancers, PSMA-expressing cancers, and PSMA-positive / PSMA-expressing prostate cancers in combination with PSMA-targeting radioligands.

[0305] In certain embodiments, the present disclosure provides PSMA upregulating agents for the treatment of PSMA-expressing cancers, in combination with a PSMA-targeting radioligand described above.

[0306] In certain embodiments, the PSMA upregulating agent is selected from the group consisting of luteinizing hormone-releasing hormone (LHRH) agonists, LHRH antagonists, androgen receptor pathway inhibitors (ARPIs), and combinations thereof. In certain embodiments the PSMA upregulating agent is an AR-degrading agent. In certain embodiments, the PSMA upregulating agent is a LHRH agonist selected from the group consisting of leuprolide, goserelin, triptorelin, histrelin, buserelin, nafarelin, deslorelin, and combinations thereof.

[0307] In certain embodiments, the PSMA upregulating agent is s a LHRH antagonists selected from the group consisting of degarelix, cetrorelix, abarelix, ganirelix, and combinations thereof.

[0308] In certain embodiments, the PSMA upregulating agent is an androgen receptor pathway inhibitor (ARPI) selected from the group consisting of enzalutamide, abiraterone, apalutamide, darolutamide, cimetidine, orteronel, galeterone, seviteronel, topilutamide, bicalutamide, fluamide, nilutamide, Hsp90 inhibitors, and combinations thereof. In further embodiments, the PSMA upregulating agent is a Hsp90 inhibitor selected from the group consisting of geldanamycin, 17-allylamino-17-demethoxygeldanamycin, genistein, and combinations thereof.

[0309] AR-Degrading Agents

[0310] Described herein are AR-degrading agents and their use in treating cancers, such as, e.g., prostate cancer, PSMA-positive cancer, and / or a PSMA-expressing cancer. In particular aspects described herein, an AR-degrading agent can be used in treating prostate cancers, PSMA-positive cancers, PSMA-expressing cancers, and PSMA-positive / PSMA-expressing prostate cancers in combination with PSMA-targeting radioligands.

[0311] In certain embodiments, the present disclosure provides AR-degrading agents for the treatment of PSMA-expressing cancers, in combination with a PSMA-targeting radioligand described above. In certain embodiments, an AR-degrading agent is a non-steroidal AR-degrading agent.

[0312] In certain embodiments, a non-steroidal AR-degrading agent can be selected from the group consisting of PROteolysis-TArgeting chimeras (PROTACs), selective AR degraders (SARDs), hydrophobic tag-based degraders (HyTs), non-steroidal CYP11A1 inhibitors, dualaction AR inhibitors (DAARIs), N-terminal domain AR degraders, ligand-directed degraders, chaperone protein dissociating AR degraders, autophagy promoting AR degraders, and combinations thereof.

[0313] In some embodiments, a non-steroidal AR-degrading agent comprises a PROTAC AR degrader selected from the group consisting of luxdegalutamide (ARV-766), bavdegalutamide (ARV-110), gridegalutamide (BMS-986365), AC-0176 underdevelopment by Accutar Biotechnology, and HP518 underdevelopment by Hinova Pharmaceuticals Inc., ora combination thereof. In a further embodiment, the PROTAC AR degrader is luxdegalutamide, which has the structure:

[0314]

[0315] Luxdegalutamide (JSB462 and formerly known as ARV-766) is described in WO 2021 / 127443, which is incorporated herein by reference in its entirety.

[0316] In some embodiments, a non-steroidal AR-degrading agent comprises a non-steroidal CYP11A1 inhibitor, such as opevesostat (ODM-208 / MK5684).

[0317] In some embodiments, a non-steroidal AR-degrading agent comprises a DAARI, such as (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluoropyrazol-1-yl)-2-hydroxy-2-methylpropanamide (ONCT-534 from Oncternal Therapeutics), which has the structure:

[0318]

[0319] , and pharmaceutically acceptable salts thereof.

[0320] In some embodiments, a non-steroidal AR-degrading agent comprises a ligand directed degrader, such as 2-[(2R)-4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl]-2-ethylphenoxy]ethyl]-2-methylpiperazin-1-yl]-N-[3-[(2,6-dioxopiperidin-3-yl)amino]phenyl]acetamide (BMS-986365, from Bristol Myers Squibb), which has the structure:

[0321] o

[0322] n MH

[0323] o

[0324]

[0325] , and pharmaceutically acceptable salts thereof.

[0326] In some embodiments, a non-steroidal AR-degrading agent comprises an N-terminal domain AR degrader, such as Masofaniten and EPI-8207 under development by Essa Pharma.

[0327] In some embodiments, a non-steroidal AR-degrading agent comprises a chaperone protein dissociating AR degrader, such as Dimethylcurcumin, Niclosamide and derivatives thereof (ARVibs), and pharmaceutical salts thereof, and combinations thereof.

[0328] In some embodiments, a non-steroidal AR-degrading agent comprises an autophagy promoting AR degrader, such as Riluzole, and pharmaceutical salts thereof.

[0329] In some embodiments, a non-steroidal AR-degrading agent comprises a hydrophobic tag-based degrader (HyT), the HyT comprising an AR agonist conjugated to a hydrophobic degron, such as N-(2-(2-(2-(2-((Adamantan-1-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)butanamide, which has the structure:

[0330]

[0331] , and pharmaceutically acceptable salts thereof.

[0332] The present disclosure provides combinations of PSMA-targeting radioligands and AR-degrading agents for use in the treatment of a PSMA-expressing cancer.

[0333] The therapeutically effective amount of the PSMA-targeting radioligand, the AR-degrading agent, or both in the combination can be lower than the amount required for a monotherapy response for the PSMA-targeting radioligand and / or the AR-degrading agent. The amount required can be based upon the amount of PSMA-targeting radioligand and / or AR-degrading agent alone that achieves a predetermined objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (OR), partial response (PR), PSA response rate, radiographic response rate, AR-protein level, tumor growth rate, PSMA-expression level, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination thereof, or an improvement in one or more of these responses as compared to the monotherapy response.

[0334] In certain embodiments, the therapeutically effective amount of the PSMA-targeting radioligand and / or the therapeutically effective amount of the AR-degrading agent in the combination can be based upon the minimum amount that achieves an improvement in efficacy in comparison to the efficacy of the monotherapy. An improvement in efficacy over the monotherapy can be determined if there is a beneficial change in one or more of the following response assessments: Best Overall Response (BOR), overall lesion response, overall response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), early progression rate (EPR), radiographic progression-free survival (rPFS), overall survival (OS), time to progression (TTP), time to first symptomatic skeletal event (TTSSE), time to PSA progression (TTPSAP), duration of overall response, duration of overall complete response, duration of stable disease, time to overall response, time to overall complete response, PSA50 rate, PSA90 rate, PSA30 rate, and PSAO rate, which differs from an observed monotherapy response. The observed response can be characterized quantitatively, semi-quantitatively, and / or qualitatively. The improvement can be demonstrated by comparing an observed response with an expected response. The observed response and / or expected response can be a single data point, or a value based on a descriptive statistic representing a set of a plurality of data points. In certain embodiments, an improvement in efficacy for the combination therapy described herein can be demonstrated by an increase in the rate of overall response, disease control, clinical benefit, PSA50, PSA90, and / or PSA30, and / or a decrease in the PSAO rate from baseline at any timepoint in comparison to the respective rate of the monotherapy at the same timepoint. For example, in certain embodiments, the disease control, clinical benefit, PSA50, PSA90, and / or PSA30 rate of the combination therapy can be increased by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, at least 250%, as compared to the monotherapy rate, and / or the PSAO rate of the combination therapy can be decreased by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, at least 250%, as compared to the monotherapy rate.

[0335] In certain embodiments, an improvement in efficacy for the combination therapy described herein can be demonstrated by a prolonged rPFS, OS, TTPSAP, and / or TTSTP time period in comparison to the respective time period of the monotherapy. In certain embodiments, the rPFS, OS, and / or TTSTP time period of the combination therapy as described can be prolonged by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, at least 250% as compared to the monotherapy time period.

[0336] In certain embodiments, an improvement in efficacy for the combination therapy described herein can be demonstrated by a reduction in EPR and / or time to overall response in comparison to the monotherapy. In certain embodiments, EPR and / or time to overall response of the combination therapy can be reduced by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, at least 250%, as compared to the monotherapy EPR and / or time to overall response.

[0337] Combinations of PSMA-targeting radioligand and AR-degrading agent(s) for use in the treatment of a PSMA-expressing cancer can achieve a greater anti-cancer response in a subject being treated for the PSMA-expressing cancer than PSMA-targeting radioligand monotherapy and / or AR-degrading agent monotherapy.

[0338] Use of the combination can provide a synergistic effect in the treatment of the PSMA-expressing cancer. For example, one or more anti-cancer effects of the AR-degrading agent can be synergized by combination with a PSMA-targeting radioligand, or one or more anticancer effects of the PSMA-targeting radioligand can be synergized by combination with an AR-degrading agent. The details of the disclosure are set forth in the accompanying description below.

[0339] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

[0340] In certain embodiments, the PSMA-targeting radioligand of the therapeutic combination is radiolabeled with an alpha-particle emitting radionuclide or a beta-minus-particle emitting radionuclide. In certain embodiments, the PSMA-targeting radioligand includes an alphaparticle emitting radionuclide selected from the group consisting of225Ac,211At,213Bi,212Bi,212Pb,223Ra,224Ra,149Tb, and227Th. In further embodiments, the alpha-particle emitting radionuclide is selected from the group consisting of225Ac,212Pb, and227Th. In certain embodiments, the PSMA-targeting radioligand includes a b-emitting radionuclide selected from the group consisting of177Lu,169Er,161Tb,131l,90Y,67Cu, and47Sc. In some embodiments, the PSMA-targeting radioligand comprises177Lu.

[0341] In certain embodiments, the PSMA-targeting radioligand of the therapeutic combination is a radiohybrid (rh) ligand or radiolabeled anti-PSMA antibody. In certain embodiments, the radiohybrid (rh) ligand is labeled with177Lu, or225Ac. In certain embodiments, the radiolabeled anti-PSMA antibody is monoclonal antibody J591, labeled with177Lu,161Tb or225Ac,227Th-labeled Anti-PSMA monoclonal antibody BAY 2315497 (Pelgifatamab Corixetan), or ^Lu-labeled monoclonal antibody rosopatamab (TLX591).

[0342] In certain embodiments, the PSMA-targeting radioligand of the therapeutic combination is177Lu-Ludotadipep,177Lu-labeled Evans blue-modified PSMA 617 (EB-PSMA-617), or177Lu-DGUL (PSMA-targeting tracer based on Glu-Urea-Lys derivatives conjugated to a DOTA chelator). In certain embodiments, a PSMA-targeting radioligand of the therapeutic combination is a compound of Formula (I):

[0343]

[0344] (I)

[0345] radiolabeled with an alpha-particle emitting radionuclide selected from the group consisting of225Ac,211At,213Bi,212Bi,212Pb,223Ra,224Ra,149Tb, and227Th, or a b-emitting radionuclide selected from the group consisting of177Lu,169Er,161Tb,131l,90Y,67Cu, and47Sc. In further embodiments, the alpha-particle emitting radionuclide is selected from the group consisting of225Ac,212Pb, and227Th. In still further embodiments, the alpha-particle emitting radionuclide is225Ac. In still further embodiments, the beta-minus-particle emitting radionuclide is177Lu (e.g., [177Lu]Lu-PSMA-617, available under the drug product name PLUVICTO ([INN] lutetium (177Lu) vipivotide tetraxetan).

[0346] In certain embodiments, a PSMA-targeting radioligand of the therapeutic combination is a compound of Formula (II):

[0347]

[0348] (H)

[0349] radiolabeled with an alpha-particle emitting radionuclide selected from the group consisting of225Ac,211At,213Bi,212Bi,212Pb,223Ra,224Ra,149Tb, and227Th, or a b-emitting radionuclide selected from the group consisting of177Lu,169Er,161Tb,131l,90Y,67Cu, and47Sc. In further embodiments, the alpha-particle emitting radionuclide is selected from the group consisting of225Ac,212Pb, and227Th. In still further embodiments, the alpha-particle emitting radionuclide is225Ac. In still further embodiments, the b-emitting radionuclide is177Lu. In still further embodiments, the glutamic acid and the lysine adjacent to the urea of the compound of formula (II) are in the L-configuration.

[0350] In certain embodiments, a PSMA-targeting radioligand of the therapeutic combination is a compound of Formula (III):

[0351]

[0352] radiolabeled with an alpha-particle emitting radionuclide selected from the group consisting of225Ac,211At,213Bi,212Bi,212Pb,223Ra,224Ra,149Tb, and227Th, or a b-emitting radionuclide selected from the group consisting of177Lu,169Er,161Tb,131l,90Y,67Cu, and47Sc. In further embodiments, the alpha-particle emitting radionuclide is selected from the group consisting of225Ac,212Pb, and227Th. In still further embodiments, the alpha-particle emitting radionuclide is225Ac. In still further embodiments, the beta-minus-particle emitting radionuclide is177Lu.

[0353] In certain embodiments, a PSMA-targeting radioligand of the therapeutic combination is a compound of Formula (IV):

[0354]

[0355] radiolabeled with an alpha-particle emitting radionuclide selected from the group consisting of225Ac,211At,213Bi,212Bi,212Pb,223Ra,224Ra,149Tb, and227Th, or a b-emitting radionuclide selected from the group consisting of177Lu,169Er,161Tb,131l,90Y,67Cu, and47Sc. In further embodiments, the alpha-particle emitting radionuclide is selected from the group consisting of225Ac,212Pb, and227Th. In still further embodiments, the alpha-particle emitting radionuclide is225Ac (e.g., 225Ac-PSMA l&T). In still further embodiments, the beta-minus-particle emitting radionuclide is177Lu (e.g., [177Lu]Lu-PSMA l&T (INN: lutetium (177Lu) zadavotide guraxetan)) or161Tb (e.g.,161Tb-PSMA l&T). In still further embodiments, the glutamic acid of the DOTAGA chelator of the compound of formula (IV) is in the unnatural D-configuration.

[0356] In certain embodiments, a PSMA-targeting radioligand of the therapeutic combination is a compound of Formula (V):

[0357]

[0358] (V) radiolabeled with an alpha-particle emitting radionuclide selected from the group consisting of225Ac,211At,213Bi,212Bi,212Pb,223Ra,224Ra,149Tb, and227Th, or a b-emitting radionuclide selected from the group consisting of177Lu,169Er,161Tb,131l,90Y,67Cu, and47Sc. In further embodiments, the alpha-particle emitting radionuclide is selected from the group consisting of225Ac,212Pb, and227Th. In still further embodiments, the alpha-particle emitting radionuclide is225Ac. In still further embodiments, the beta-minus-particle emitting radionuclide is177Lu.

[0359] In certain embodiments, the AR-degrading agent of the therapeutic combination is a non-steroidal AR-degrading agent.

[0360] In certain embodiments, the non-steroidal AR-degrading agent is selected from the group consisting of selective AR degraders (SARDs), PROteolysis-TArgeting chimera (PROTAC) AR degraders, non-steroidal CYP11A1 inhibitors, hydrophobic tag-based degraders (HyTs), dual-action AR inhibitors (DAARIs), N-terminal domain AR degraders, ligand-directed degraders, chaperone protein dissociating AR degraders, autophagy promoting AR degraders, and combinations thereof.

[0361] In certain embodiments, the AR-degrading agent of the therapeutic combination is a PROTAC selected from the group consisting of luxdegalutamide (ARV-766), bavdegalutamide (ARV-110), gridegalutamide (BMS-986365), AC-0176 from Accutar Biotechnology, and HP518 from Hinova Pharmaceuticals Inc., or a combination thereof. In a further embodiment, the PROTAC is luxdegalutamide, which has the structure:

[0362]

[0363] In certain embodiments, the AR-degrading agent of the therapeutic combination is a non-steroidal CYP11A1 inhibitor, such as opevesostat (ODM-208 / MK5684).

[0364] In certain embodiments, the AR-degrading agent of the therapeutic combination is a DAARI, such as (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluoropyrazol-1-yl)-2-hydroxy-2-methylpropanamide (ONCT-534 from Oncternal Therapeutics), which has the structure:

[0365]

[0366] , and pharmaceutically acceptable salts thereof.

[0367] In certain embodiments, the AR-degrading agent of the therapeutic combination is a ligand directed degrader, such as 2-[(2R)-4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl]-2-ethylphenoxy]ethyl]-2-methylpiperazin-1-yl]-N-[3-[(2,6-dioxopiperidin-3-yl)amino]phenyl]acetamide (BMS-986365, from Bristol Myers Squibb), which has the structure:

[0368] s I

[0369]

[0370] , and pharmaceutically acceptable salts thereof.

[0371] In certain embodiments, the AR-degrading agent of the therapeutic combination is an N-terminal domain AR degrader, such as Masofaniten and EPI-8207 from Essa Pharma.

[0372] In certain embodiments, the AR-degrading agent of the therapeutic combination is a chaperone protein dissociating AR-degrader, such as Dimethylcurcumin, Niclosamide and derivatives thereof (ARVibs), and pharmaceutical salts thereof, and combinations thereof.

[0373] In certain embodiments, the AR-degrading agent of the therapeutic combination is an autophagy promoting AR degrader, such as Riluzole, and pharmaceutical salts thereof.

[0374] In certain embodiments, the AR-degrading agent of the therapeutic combination is a hydrophobic tag-based degrader (HyT), the HyT comprising an AR agonist conjugated to a hydrophobic degron, such as N-(2-(2-(2-(2-((Adamantan-1-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)butanamide, which has the structure:

[0375]

[0376] N , and pharmaceutically acceptable salts thereof.

[0377] In further embodiments, the PSMA-targeting radioligand of the therapeutic combination is [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), and the AR-degrading agent of the therapeutic combination is non-steroidal AR-degrading agent selected from SARDs, PROTAC AR degraders, HyTs, non-steroidal CYP11A1 inhibitors, DAARIs, N-terminal domain AR degraders, ligand-directed degraders, chaperone protein dissociating AR-degraders, autophagy promoting AR degraders, and combinations thereof. In still further embodiments, the PSMA-targeting radioligand is [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), and the AR-degrading agent is a PROTAC AR degrader. In still further embodiments, the PSMA-targeting radioligand is [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), and the AR-degrading agent is luxdegalutamide (ARV-766), bavdegalutamide (ARV-110), gridegalutamide (BMS-986365), AC-0176 under development by Accutar Biotechnology, HP518 under development by Hinova Pharmaceuticals Inc., or a combination thereof. In still further embodiments, the PSMA-targeting radioligand is [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), and the AR-degrading agent is luxdegalutamide (ARV-766).

[0378] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. C / s and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0379] Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as p-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, / V-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

[0380] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

[0381] In some embodiments, the compounds of the invention have the (R)-configuration. In other embodiments, the compounds have the (S)-configuration. In compounds with more than one chiral centers, each of the chiral centers in the compound may be independently ( / ?) or (S), unless otherwise indicated.

[0382] Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g., 1 / 7- and 3 / 7-imidazole, 1 / 7- , 2 / 7- and 4 / 7- 1 ,2,4-triazole, 1 / 7- and 2 / 7-isoindole and 1 / 7- and 2 / 7-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0383] Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can used in various studies such as NMR spectroscopy, metabolism experiments, and / or assays.

[0384] Substitution with heavier isotopes such as deuterium, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. (A.

[0385] Kerekes et.al. J. Med. Chem. 2011, 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm.

[0386] 2015, 58, 308-312).

[0387] Methods of Treatment

[0388] The present disclosure provides methods of treating or preventing a PSMA-expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a PSMA-targeting radioligand and administering to the subject a therapeutically effective amount of an AR-degrading agent. The PSMA-targeting radioligand and the AR-degrading agent can be as previously described. In certain embodiments, the AR-degrading agent is a non-steroidal AR-degrading agent (e.g., the AR-degrading agent is not galeterone or an analogue of galeterone).

[0389] In certain embodiments, the present disclosure provides methods of treating or preventing a PSMA-expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and administering to the subject a therapeutically effective amount of an AR-degrading agent. The [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and the AR-degrading agent can be as previously described. In certain embodiments, the AR-degrading agent is a PROTAC AR degrader.

[0390] In the present methods, the amount of PSMA-targeting radioligand administered and the amount of AR-degrading agent administered comprise quantities that are

[0391] jointly therapeutically effective against a PSMA-expressing cancer. The amount of PSMA-targeting radioligand administered and the amount of AR-degrading agent administered can be administered in a single formulation or unit dosage form, administered concurrently, but optionally separately, or administered sequentially by any suitable route. In certain embodiments, the AR-degrading agent can be administered via a different route than PSMA-targeting radioligand.

[0392] In certain embodiments, the present disclosure provides methods of treating a PSMA-expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of PSMA-targeting radioligand and administering to the subject a therapeutically effective amount of an AR-degrading agent selected from the group as previously described. In certain embodiments, the AR-degrading agent is a non- steroidal AR-degrading agent selected from SARDs, PROTAC AR degraders, HyTs, nonsteroidal CYP11A1 inhibitors, DAARIs, N-terminal domain AR degraders, ligand-directed degraders, chaperone protein dissociating AR degraders, autophagy promoting AR degraders, and combinations thereof.

[0393] Typically, the amount of a radiopharmaceutical, e.g., [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), to be administered to a subject in need thereof, is based on the amount of radiation that will be administered to the subject. The amount of radiation may be reflected as a unitary dose (in MBq or GBq) or as an amount of radiation per kg bodyweight (in kBq / kg). When referring to a radioactivity-related value, e.g., 7.4 GBq (200 mCi) of radioactivity, the amount can refer to the radioactivity at the date and time of administration.

[0394] In the present methods, the PSMA-targeting radioligand is administered at a dose of from about 6 MBq to about 10 GBq. For example, In certain embodiments, a compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of from about 6 MBq to about 8 MBq, or about 8 MBq to about 10 MBq, or from about 3 GBq to about 10 GBq. In certain embodiments, the amount of the PSMA-targeting radioligand administered in combination with the AR-degrading agent can be reduced as compared to a monotherapy method without a reduction in therapeutic efficacy. In certain embodiments, the PSMA-targeting radioligand can be administered in a unitary dose of from about 6 MBq to about 8 GBq, while achieving one or more improvements in therapeutic efficacy as compared with PSMA-targeting radioligand monotherapy.

[0395] In certain embodiments, the PSMA-targeting radioligand is [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), administered in a unitary dose of from about 3 GBq to about 10 GBq, such as, for example, 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 certain embodiments, amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) administered in combination with the AR-degrading agent can be reduced as compared to a monotherapy method without a reduction in therapeutic efficacy. In certain embodiments, [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) can be administered in a unitary dose of from about 6 GBq to about 8 GBq. In certain embodiments, [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) can be administered in combination with the AR-degrading agent in a unitary dose of about 7.4 GBq, such as 7.4 GBq (+ / - 10%), while achieving one or more improvements in therapeutic efficacy as compared with [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) monotherapy.

[0396] Typically, the amount of an AR-degrading agent to be administered to a subject in need thereof is based on factors such as the severity of the PSMA-expressing cancer, the characteristics of the subject being treated, e.g., the particular animal or human subject treated, age, weight, and health, frequency of treatments, the route of administration, the severity of side effects of the one or more AR-degrading agent and / or the amount of PSMA-targeting radioligand being administered. In certain embodiments, the therapeutically effective amount is the minimal dose that provides an improvement in the extent of response, slowing the symptomatic progression of the cancer, or symptoms thereof, duration of response, progression-free survival, Prostate-Specific Antigen (PSA) level, Alkaline Phosphatase (ALP) level, Lactate Dehydrogenase (LDH) level, pain Intensity, Functional Assessment of Cancer Therapy (FACT) score, health-related quality of life, number of hospitalizations, duration of hospitalization, and / or improvement in overall survival, or an improvement in another clinical measure or parameter. The improvement of a clinical measure or parameter can be by 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 the clinical measure or parameter shown by a healthy subject.

[0397] In certain embodiments, amount of an AR-degrading agent administered in combination with the PSMA-targeting radioligand can be reduced as compared to a monotherapy method without a reduction in therapeutic efficacy. In certain embodiments, the amount of the AR-degrading agent is a synergistically effective amount. The improvement of a clinical measure or parameter can be by 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%, where 240% or at least 250%, where 100% can be defined as the clinical measure or parameter observed after AR-degrading agent monotherapy or PSMA-targeting radioligand monotherapy.

[0398] In one or more of the above embodiments, the therapeutically effective amount of PSMA-targeting radioligand, the AR-degrading agent, or both, is lower than the amount required for a monotherapy response of objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (OR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, tumor growth rate, PSMA-expression level, or a combination thereof. For example, the therapeutically effective amount of PSMA-targeting radioligand, the AR-degrading agent, or both can be at least about 10% lower to about 50% lower than the amount required for the monotherapy response.

[0399] In certain embodiments, the therapeutically effective amount of PSMA-targeting radioligand can be about 10%, 15%, 20%, 25%, 30% 35%, 40%, 45% or about 50% lower than the amount of PSMA-targeting radioligand required for an 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, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, tumor growth rate, PSMA-expression level or a combination thereof observed with PSMA-targeting radioligand monotherapy.

[0400] In certain embodiments, the therapeutically effective amount of the AR-degrading agent can be about 10%, 15%, 20%, 25%, 30% 35%, 40%, 45% or about 50% lower than the amount of the AR-degrading agent required for an 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, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, tumor growth rate, PSMA-expression level or a combination thereof observed with AR-degrading agent monotherapy.

[0401] In certain embodiments, practicing a method as described above produces a synergistic response in the subject, such as a synergistic anti-cancer response, as compared to a method of administering the PSMA-targeting radioligand or the AR-degrading agent as monotherapy. In further embodiments, practicing a method as described above produces a synergistic response in the subject, such as a synergistic anti-cancer response, as compared to a method of administering [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) or a PROTAC such as luxdegalutamide, as monotherapy

[0402] In certain embodiments, practicing a method as described above improves an anticancer response achieved by administering the PSMA-targeting radioligand or the AR-degrading agent as monotherapy. For example, practicing a method as described above can improve an anti-cancer response of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) monotherapy or AR-degrading agent monotherapy by at least about 10% to about 50%.

[0403] As is common with radiation therapy, in order to deliver the total dose of radiation required to eradicate the PSMA-expressing cancer, the method may include administering the PSMA-targeting radioligand, about every 4 to 8 weeks for a number of cycles. In the present methods, the therapeutically effective amount of PSMA-targeting radioligand, e.g., about 6 MBq to about 10 GBq as described above, can be administered to the subject about every 4 to 8 weeks, such as about every 4 to 6 weeks, about every 6 to 8 weeks, about every 4 to 5 weeks, about every 5 to 8 weeks, about every 4 to 7 weeks, about every 5 to 6 weeks, about every 5 to 7 weeks, and about every 6 to 7 weeks.

[0404] In certain embodiments, the number of weeks and / or number of cycles of PSMA-targeting radioligand administration in the present methods can be reduced as compared to PSMA-targeting radioligand monotherapy without a reduction in therapeutic efficacy. In certain embodiments, the number of weeks and / or number of cycles of PSMA-targeting radioligand administration required to achieve desired clinical measure or parameter can be reduced as compared to PSMA-targeting radioligand monotherapy. In some embodiments, the therapeutically effective amount of PSMA-targeting radioligand, e.g., about 6 M Bq to about 10 GBq as described above, can be administered to the subject about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, or about every 8 weeks.

[0405] In some embodiments, the therapeutically effective amount of PSMA-targeting radioligand, e.g., about 6 M Bq to about 10 GBq as described above, can be administered to the subject for a duration as described above for 4 to 6 cycles. For example, the therapeutically effective amount of PSMA-targeting radioligand can be administered about every 4 to 8 weeks for 4 cycles, for 5 cycles, or for 6 cycles.

[0406] In some embodiments, the therapeutically effective amount of PSMA-targeting radioligand can be administered about every 4 to 6 weeks for 4 to 6 cycles, about every 6 to 8 weeks for 4 to 6 cycles, about every 6 to 8 weeks for 4 cycles, about every 6 to 8 weeks for 5 cycles, about every 6 to 8 weeks for 6 cycles, about every 4 to 5 weeks for 4 to 6 cycles, about every 4 to 7 weeks for 4 to 6 cycles, about every 5 to 8 weeks for 4 to 6 cycles, about every 5 to 6 weeks for 4 to 6 cycles, about every 5 to 7 weeks for 4 to 6 cycles, about every 6 to 7 weeks for 4 to 6 cycles, about every 4 weeks for 4 to 6 cycles, about every 5 weeks for 4 to 6 cycles, about every 6 weeks for 4 to 6 cycles, about every 7 weeks for 4 to 6 cycles, about every 8 weeks for 4 to 6 cycles, about every 4 weeks for 4 cycles, about every 4 weeks for 6 cycles, about every 6 weeks for 4 cycles, about every 6 weeks for 6 cycles, about every 8 weeks for 4 cycles, or about every 8 weeks for 6 cycles.

[0407] In some embodiments, the therapeutically effective amount of PSMA-targeting radioligand can be administered about every 5 weeks for 4 cycles, about every 5 weeks for 6 cycles, about every 7 weeks for 4 cycles, about every 7 weeks for 6 cycles, about every 4 weeks for 5 cycles about every 6 weeks for 5 cycles, about every 8 weeks for 5 cycles, about every 5 weeks for 5 cycles, or about every 7 weeks for 5 cycles.

[0408] Duration or frequency of administering the therapeutically effective amount of the AR-degrading agent can vary depending on the compound used, the subject being treated and the particular PSMA-expressing cancer being treated. In certain embodiments, the duration or frequency can be the maximal duration or frequency protocol that avoids significant side effects or toxic effects or an occurrence of unacceptable toxicity. In certain embodiments, the duration or frequency is the minimal duration or frequency that provides an improvement in the clinical measure or parameter, as described above, or the minimal duration or frequency for a synergistic effect.

[0409] In certain embodiments, the therapeutically effective amount of the AR-degrading agent is administered in one or more doses within 24 hours of PSMA-targeting radioligand administration, within 48 hours of PSMA-targeting radioligand administration, within 96 hours of PSMA-targeting radioligand administration, within 1 week of PSMA-targeting radioligand, within 2 weeks of PSMA-targeting radioligand administration. In certain embodiments, the therapeutically effective amount of the AR-degrading agent is administered in one or more doses within 14 hours of PSMA-targeting radioligand administration, within 12 hours of PSMA-targeting radioligand administration, within 10 hours of PSMA-targeting radioligand administration, within 8 hours of PSMA-targeting radioligand administration, within 6 hours of PSMA-targeting radioligand administration, within 4 hours of PSMA-targeting radioligand administration, within 3 hours of PSMA-targeting radioligand administration, within 2 hours of PSMA-targeting radioligand administration, within 1 hour of PSMA-targeting radioligand administration, or within 30 minutes of PSMA-targeting radioligand administration. In certain embodiments, the therapeutically effective amount of the AR-degrading agent is administered in one or more doses and the therapeutically effective amount of PSMA-targeting radioligand is administered in one or more doses concurrently (optionally in separate dosage forms).

[0410] In certain embodiments, the therapeutically effective amount of the AR-degrading agent is administered in one or more doses at least 16 hours prior to PSMA-targeting radioligand administration, at least 24 hours prior to PSMA-targeting radioligand administration, at least 36 hours prior to PSMA-targeting radioligand administration, at least 48 hours prior to PSMA-targeting radioligand administration, at least 60 hours prior to PSMA-targeting radioligand administration, at least 72 hours prior to PSMA-targeting radioligand administration, at least 84 hours prior to PSMA-targeting radioligand administration, at least 96 hours prior to PSMA-targeting radioligand administration, or at least 108 hours prior to PSMA-targeting radioligand administration. In certain embodiments, the therapeutically effective amount of the AR-degrading agent is administered in one or more doses over a course of about, or at least about, 5 days.

[0411] The one or more doses of AR-degrading agent can include one or more daily doses, e.g., b.i.d. t.i.d., and q.d. In certain embodiments, administration at least 16 hours prior to PSMA-targeted radioligand administration or administration over at least about 5 days can occur at regular intervals (e.g., q.d., b.i.d., t.i.d., or on alternating days), on specific days of a PSMA-targeted radioligand cycle, or continuously.

[0412] The range encompassed by “at least about 5 days” can include at least about 1, 2, 3, or 4 weeks, at least about 1, 2, 3, 4, 5, or 6 months. In some cases, at least about 5 days can be 4 to 8 weeks, for one or more cycles. The cycles can occur with the same periodicity as a PSMA-targeting radioligand cycle, or can occur at different intervals of therapy.

[0413] In the methods described herein, the PSMA-expressing cancer can be any cancer that exhibits high PSMA expression compared to corresponding healthy cells or tissues. For example, in various prostate cancers and salivary gland cancers, the level of PSMA expression of the malignant cells is markedly increased compared to that of healthy cells. In certain embodiments, the PSMA-expressing cancer is PSMA-positive cancer in the biochemical recurrence (BCR) setting, such as PSMA-positive cancer in a high-risk BCR setting.

[0414] In one or more embodiments of the methods described herein, the PSMA-expressing cancer is prostate cancer. In some embodiments, the prostate cancer is PSMA-positive oligometastatic prostate cancer (OMPC). In some embodiments, when the PSMA-expressing cancer is prostate cancer, then the prostate cancer is metastatic prostate cancer. In certain embodiments, the metastatic prostate cancer is metastatic castration-resistant prostate cancer (mCRPC). In certain embodiments, the metastatic prostate cancer is PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC).

[0415] Particular Embodiments of the Methods of Treatment

[0416] In particular, provided herein are methods of treating a prostate specific membrane antigen (PSMA)-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and administering to the subject a therapeutically effective amount of a AR-degrading agent, wherein the AR-degrading agent is luxdegalutamide (ARV766), or a pharmaceutically acceptable salt thereof. In certain embodiments, the method of treating a prostate specific membrane antigen (PSMA)-expressing cancer in a subject in need thereof comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and administering to the subject a therapeutically effective amount of a AR-degrading agent, wherein the AR-degrading agent is luxdegalutamide (ARV766), or a pharmaceutically acceptable salt thereof, and wherein an anti-cancer response is improved or synergized in the subject as compared to a monotherapy response with [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) or the AR-degrading agent. The therapeutically effective amount of the AR-degrading agent can be a dose of from 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 1-3 times daily for at least about, 5 days, or about 50 mg, about 100 mg, about 150 mg, about 300 mg daily, about 600 mg, about 1200 mg, or about 1500 mg daily. A therapeutically effective amount of the AR-degrading agent can be delivered before administration of a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), such as at least 3, 4, or 5 days before, or within a timeframe sufficient for AR-degrading agent-induced degradation of AR proteins and / or induction of PSMA expression in a cancer cell of the subject.

[0417] In any of the particular embodiments described above, the PSMA-expressing cancer 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 the biochemical recurrence (BCR) setting, optionally PSMA-positive cancer in a high-risk BCR setting, the therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) can be a dose of from about 10 MBq to 10 GBq, such as from about 0.1 GBq to 10 GBq, from about 1 GBq to 10 GBq, from about 3 GBq to 10 GBq, from about 5 GBq to about 9 GBq, or from about 6 GBq to about 8 GBq (optionally about 7.4 GBq), the AR-degrading agent can be administered for about, or at least about, 5 days, and / or the initial dose of the AR-degrading agent can be administered less than 7 days prior to [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) administration.

[0418] In a further particular embodiment, the present disclosure describes a method of treating a cancer, in particular a prostate cancer, preferably a prostate specific membrane antigen (PSMA)-positive cancer and / or a prostate specific membrane antigen (PSMA)-expressing cancer, in particular a PSMA+ / PSMA-expressing prostate cancer, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of luxdegalutamide and administering a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan).

[0419] The cancer can be metastatic castration resistant prostate cancer (mCRPC). In particular embodiments the mCRPC has been confirmed by radiographical imaging, such as by CT / MRI or bone scan. In a particular embodiment, the cancer can have progressed while the subject was receiving Androgen Deprivation Therapy (ADT) and at least one prior ARPI. The ADT received by the subject can be abarelix, degarelix, and / or relugolix. The subject can have undergone ADT through orchiectomy (e.g., bilateral orchiectomy).

[0420] The subject can be selected from a group of adult subjects (e.g., >18 years of age) who have had prior exposure to at least one Androgen Receptor Pathway Inhibitor (ARPI). The prior exposure can have been in the metastatic or advanced setting, e.g., received after the cancer metastasized. The least one ARPI can be selected from the group consisting of enzalutamide, abiraterone, apalutamide, darolutamide, cimetidine, orteronel, galeterone, seviteronel, topilutamide, bicalutamide, fluamide, nilutamide, Hsp90 inhibitors, and combinations thereof, or from the group consisting of abiraterone, enzalutamide, darolutamide, and apalutamide, or a combination thereof. The subject can have had prior exposure to two or more of abiraterone, enzalutamide, darolutamide, and apalutamide. In particular embodiments, prior ARPI exposure does not include prior exposure to a first generation ARPI (e.g., bicalutamide, flutamide, nilutamide, or a combination thereof).

[0421] The subject can be selected from a group of adult subjects with a castrate level of serum / plasma testosterone, a serum / plasma testosterone level less than <50 ng / dL or <1.7 nmol / L, subjects receiving an ADT, subjects receiving a gonadotropin releasing hormone analogues / antagonists, e.g., selected from abarelix, degarelix, and relugolix, and / or subjects who have undergone an orchiectomy.

[0422] The subject can be selected from a group of adult subjects without prior exposure to a taxane regimen.

[0423] The subject can be selected from a group of adult subjects who have had prior exposure to no more than two taxane regimens, such as subjects who have had prior exposure to one or two taxane regimens in a previous treatment in a Hormone Sensitive Prostate Cancer (HSPC) or a castration resistant prostate cancer (CRPC) setting.

[0424] The subject can be selected from a group of adult subjects who have not received prior chemotherapy or who have not received prior chemotherapy other than a taxane regimen.

[0425] The subject can be selected from a group of subjects who have not been treated with one or more of platinum, estramustine, vincristine, methotrexate, and cyclophosphamide.

[0426] The subject can be selected from a group of subjects who have previously been treated with an immunotherapy agent, such as sipuleucel-T.

[0427] The subject can be selected from a group of adult subjects who have previously been treated with an immunotherapy agent subject has been treated with a poly (ADP-ribose) polymerase (PARP) inhibitor, an immune checkpoint inhibitor, or a combination thereof.

[0428] The subject can be selected from a group of adult subjects with no prior exposure to a radioligand therapy (RLT) before administration of the first dose of [177Lu]Lu-PSMA-617 in the combination therapy.

[0429] The subject can be selected from a group of adult subjects who have had prior exposure to radiation therapy.

[0430] The subject can be selected from a group of adult subjects exhibiting or experiencing no signs or symptoms of toxicity from a prior treatment, exhibiting or experiencing toxicity from a prior therapy of less than or equal to grade 1, exhibiting alopecia less than or equal to grade 2 toxicity from a prior therapy, or experiencing peripheral neuropathy less than or equal to grade 2 toxicity from a prior therapy.

[0431] In a particular embodiments, the subject is selected from a group of adult subjects who have had prior exposure to at least one second-generation ARPI selected from abiraterone, enzalutamide, darolutamide, apalutamide, and combinations thereof in the metastatic or advanced setting, with a castrate level of serum / plasma testosterone, a serum / plasma testosterone level less than <50 ng / dL or <1.7 nmol / L, receiving an ADT and / or who have undergone an orchiectomy, and who have had prior exposure to no more than two taxane regimens in a Hormone Sensitive Prostate Cancer (HSPC) or a castration resistant prostate cancer (CRPC) setting.

[0432] In the therapeutic method above, the therapeutically effective amount of luxdegalutamide can include a dose of at least about 100 mg; a dose of from about 100 mg to about 300 mg; a dose of from about 200 mg to about 300 mg; or a dose of about 300 mg. The therapeutically effective amount of luxdegalutamide can be administered daily, such as once per day. The therapeutically effective amount of luxdegalutamide can be administered orally. The therapeutically effective amount of luxdegalutamide can be administered as one or more tablets. The luxdegalutamide can be taken with food. The food can include 400 or more calories of a mixture of fat, carbohydrates and protein. The luxdegalutamide can be taken with the largest meal of the day. For example, luxdegalutamide can be taken with dinner.

[0433] In the therapeutic method above, the therapeutically effective amount of luxdegalutamide can be administered for at least about 4 weeks, preferably continuously for at least about 4 weeks. Daily administration over a period of one or more weeks can be considered “continuous” administration.

[0434] In a particular embodiment, the therapeutically effective amount of luxdegalutamide is administered orally by one to three tablets of about 100 mg taken with a large meal comprising 400 or more calories of a mixture of fat, carbohydrates and protein, daily and continuously for about 4 weeks to about 38 weeks, such as about 6 weeks, about 12 weeks, about 18 weeks, about 24 weeks, about 30 weeks, about 36 weeks, or about 38 weeks.

[0435] The therapeutically effective amount of [177Lu]Lu-PSMA-617 can include a dose of from about 3 GBq to about 10 GBq; a dose of from about 5.9 GBq to about 7.4 GBq; a dose of about 7.4 GBq; or a dose of about 5.9 GBq. The dose can be administered intravenously.

[0436] The therapeutically effective amount of [177Lu]Lu-PSMA-617 can be administered as a course of treatment comprising at least one cycle, such as a cycle as described above. In particular embodiments, one cycle can be about 4 weeks to about 8 weeks or about 5 weeks to about 7 weeks. In particular embodiments, one cycle is about 6 weeks.

[0437] The therapeutically effective amount of [177Lu]Lu-PSMA-617 can be administered for at least two cycles. In particular embodiments, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 2 to 10 cycles or for 4 to 8 cycles. In a particular embodiment, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for about 6 cycles.

[0438] In a particular embodiment, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for at least two cycles and each cycle is about 4 weeks to about 8 weeks; the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for at least two cycles and each cycle is about 5 weeks to about 7 weeks; the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for at least two cycles and each cycle is about 6 weeks; the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 2 to 10 cycles and each cycle is about 4 weeks to about 8 weeks; the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 2 to 10 cycles and each cycle is about 5 weeks to about 7 weeks; the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 2 to 10 cycles and each cycle is about 6 weeks; the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 4 to 8 cycles and each cycle is about 4 weeks to about 8 weeks; the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 4 to 8 cycles and each cycle is about 5 weeks to about 7 weeks; the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 4 to 8 cycles and each cycle is about 6 weeks; the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 6 cycles and each cycle is about 4 weeks to about 8 weeks; the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 6 cycles and each cycle is about 5 weeks to about 7 weeks; or the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 6 cycles and each cycle is about 6 weeks.

[0439] In the therapeutic method above, a therapeutically effective amount of luxdegalutamide can be a dose of at least about 100 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be a dose of from about 3 GBq to about 10 GBq; the therapeutically effective amount of luxdegalutamide is a dose of at least about 100 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be a dose of from about 5.9 GBq to about 7.4 GBq; the therapeutically effective amount of luxdegalutamide can be a dose of at least about 100 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be a dose of about 7.4 GBq; the therapeutically effective amount of luxdegalutamide can be a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be a dose of from about 3 GBq to about 10 GBq; the therapeutically effective amount of luxdegalutamide can be a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be a dose of from about 5.9 GBq to about 7.4 GBq; the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be a dose of about 7.4 GBq; the therapeutically effective amount of luxdegalutamide can be a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be a dose of about 5.9 GBq; the therapeutically effective amount of luxdegalutamide can be a dose of from about 200 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be a dose of from about 3 GBq to about 10 GBq; the therapeutically effective amount of luxdegalutamide can be a dose of from about 200 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be a dose of from about 5.9 GBq to about 7.4 GBq; the therapeutically effective amount of luxdegalutamide can be a dose of from about 200 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be a dose of about 7.4 GBq; the therapeutically effective amount of luxdegalutamide can be a dose of from about 200 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu- PSMA-617 can be a dose of about 5.9 GBq; the therapeutically effective amount of luxdegalutamide can be a dose of about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be a dose of from about 3 GBq to about 10 GBq; the therapeutically effective amount of luxdegalutamide can be a dose of about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be a dose of from about 5.9 GBq to about 7.4 GBq; the therapeutically effective amount of luxdegalutamide can be a dose of about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be a dose of about 7.4 GBq; or the therapeutically effective amount of luxdegalutamide can be a dose of about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be a dose of about 5.9 GBq.

[0440] In a particular embodiment, a method as described herein can include administering the AR-degrader and the PSMA-targeting radiopharmaceutical in a specific order.

[0441] In a particular embodiment, the method can include administering a first dose of luxdegalutamide (or other AR-degrader) and then administering of a first dose of [177Lu]Lu-PSMA-617 (or other PSMA-targeting agent). The interval between administering the first dose of luxdegalutamide and the first dose of [177Lu]Lu-PSMA-617 can be at least about one week. The interval between administering the first dose of luxdegalutamide and the first dose of [177Lu]Lu-PSMA-617 can be a timeframe sufficient for luxdegalutamide-induced degradation of AR proteins and / or induction of PSMA expression in a cancer cell of the subject. The timeframe can be about two weeks.

[0442] In a particular embodiment, the first dose of luxdegalutamide can be administered about two weeks prior to administering a first dose of [177Lu]Lu-PSMA-617, such as about 17, about 16, about 15, or about 14 days prior to administering the first dose of [177Lu]Lu-PSMA-617.

[0443] In a particular embodiment, a first dose of [177Lu] Lu- PSMA-617 can be administered within about 2 weeks of luxdegalutamide administration. For example, a first dose of [177Lu]Lu-PSMA-617 can be administered about 17 days after the initial dose of luxdegalutamide is administered about 14 days after the initial dose of luxdegalutamide is administered.

[0444] In a particular embodiment of the method above, the cancer is mCRPC, the subject has had prior exposure to at least one ARPI and no prior exposure to a taxane regimen or chemotherapy; the therapeutically effective amount of luxdegalutamide comprises a dose of at least about 100 mg, administered daily, preferably orally, with the first dose of luxdegalutamide being administered about two weeks before the first dose of [177Lu]Lu-PSMA-617 is administered. The dose of luxdegalutamide can be administered continuously over a course of treatment lasting about 2 weeks to about 38 weeks. The therapeutically effective amount of [177Lu]Lu-PSMA-617 can be administered intravenously once per cycle for about 6 cycles, wherein each cycle is about 6 weeks. In a particular embodiment of the method above, the cancer is mCRPC; the subject has had prior exposure to at least one ARPI, the subject has either no prior exposure to a taxane regimen or chemotherapy, or has prior exposure to no more than two taxane regimens, the therapeutically effective amount of luxdegalutamide comprises a dose of about 100 mg or about 300 mg, the therapeutically effective amount of [177Lu]Lu-PSMA-617 comprises a dose of about 7.4 GBq administered once per a six-week cycle, for about six cycles, and the dose of luxdegalutamide is administered daily starting about two weeks before the first dose of [177Lu]Lu-PSMA-617 is administered.

[0445] The present disclosure contemplates practicing any of the particular embodiments above with a PSMA targeting agent other than [177Lu]Lu-PSMA-617, as described above, and / or an AR-degrading agent other than luxdegalutamide, as described above.

[0446] In a particular embodiment, the group of other PSMA targeting agents (i.e., other than [177Lu]Lu-PSMA-617) includes PSMA-binding ligands including “cold” ligand (i.e., ligand without radionuclide) selected from the group consisting of any compound of Formulae I l-V described above, PSMA l&T (INN: zadavotide guraxetan), PSMA-R2 (Novartis), MIP-1095 (Lantheus), MIP-1545 (Lantheus), MIP-1555 (Lantheus), MIP-1557 (Lantheus), MIP-1558 (Lantheus), CTT1403 (Cancer Targeted Technology), FC705 (FC-KR), BAY-2315497 (Bayer), BAY-2315487 (Bayer), BAY-356254 (Bayer), BAY-354682 (Bayer), TLX591 (Telix), TLX592 (Telix), PSMA-TCC, rhPSMA (Blue Earth Diagnostics), rhPSMA-7 (Blue Earth Diagnostics), rhPSMA-7.3 (Blue Earth Diagnostics), rhPSMA-10.1 (Blue Earth Diagnostics), Ludotadipep, PNT2001 (PSMA-062 (Point Biopharma)), PNT2002 (Point Biopharma), PSMA-7 l&T, EB-PSMA-617 (National Institute For Biomedical Imaging And Bioengineering (Nibib), PSMA-ALB-02 (ITM Radiopharma), PSMA-ALB-53 (ITM Radiopharma), PSMA-ALB-56 (ITM Radiopharma), P16-093 (Five Eleven Pharma (PSMA-093)), PSMA-1 (RadioMedix), PSMA-1-DOTA (Case Western Reserve), SAR-bisPSMA (Clarity), ITM-22 (ITM Radiopharma), ITM-24D (ITM Radiopharma), PMI-21 (Precision Molecular), DOTA-h11B6 (Janssen Research & Development), FPI-1434 (Fusion Pharmaceuticals), pelgifatamab, NG001 / AB001 (ArtBio), ADVC001 (AdvanCell), RPS-072 (Cornell University), RPS-074 (Cornell University), FL-020 (Full Life Technologies), FPI-2265 (Fusion), CONV01 (Convergent), JNJ-6420 (J&J), LNC-1003 (Yantai LNC), and radiolabeled anti-PSMA antibodies as described above, such as PSMA l&T, PSMA-62, PSMA-1-DOTA, and PSMA-R2, or PSMA l&T (INN: zadavotide guraxetan), and PSMA-R2.

[0447] In further particular embodiments, the present disclosure contemplates practicing the methods above with a radionuclide other than117Lu, such as161Tb or225Ac. For example, the radionuclide can be an alpha-particle emitting radionuclide selected from the group consisting of225Ac,211At,213Bi,212Bi,212Pb,223Ra,224Ra,149Tb, and227Th or a p-emitting radionuclide selected from the group consisting of169Er,161Tb,1311,90Y,67Cu, and47Sc. An AR-degrading agent other than luxdegalutamide can be selected from the group consisting of PROteolysis-TArgeting chimeras (PROTACs), selective AR degraders (SARDs), hydrophobic tag-based degraders (HyTs), non-steroidal CYP11A1 inhibitors, dual-action AR inhibitors (DAARIs), N-terminal domain AR degraders, ligand-directed degraders, chaperone protein dissociating AR degraders, autophagy promoting AR degraders, and combinations thereof described above, or a PROTAC AR degrader selected from the group consisting of bavdegalutamide (ARV-110), gridegalutamide (BMS-986365), AC-0176 under development by Accutar Biotechnology, and HP518 under development by Hinova Pharmaceuticals Inc., or a combination thereof.

[0448] The present disclosure also describes methods of improving effectiveness of a PSMA-targeting radioligand therapy (RLT) for treating a cancer in a subject in need thereof. Improving effectiveness can include providing a combination therapy to the subject which includes administering a therapeutically effective amount of a PSMA-targeting radioligand and an efficacy-enhancing amount of an AR-degrading agent to the subject, wherein the efficacyenhancing amount is an amount of the AR-degrading agent that improves the effectiveness in the subject in at least one efficacy endpoint, The improved effectiveness of the combination therapy can be demonstrated by comparison with a corresponding efficacy endpoint of a monotherapy using the PSMA-targeting radioligand. The at least one efficacy endpoint can be selected from the group consisting of Radiographic progression-free survival (rPFS), Overall survival (OS), Complete response (OR), Partial response (PR), Stable response (SD), Best Overall response (BOR), Duration of radiographic response (DOR), Time to response (TTR), Time to soft tissue progression (TTSTP), PSA value less than 0.2 ng / ml at any time point, % decrease in a PSA value from a baseline, Duration of biochemical response (DBR), Time to first symptomatic skeletal event (TTSSE), and combinations thereof.

[0449] The present disclosure also describes methods of prolonging the timeframe of rPFS, OS, and / or TTSTP of a PSMA-targeting radioligand therapy (RLT) for use in treating a subject with cancer, wherein the method comprises combining the PSMA-targeting RLT with an AR-degrading therapy, whereby the combined therapy prolongs the rPFS, OS, and / or TTSTP assessed in the subject as compared with the corresponding rPFS, OS, and / or TTSTP assessed in subjects receiving the PSMA-targeting RLT as monotherapy. The method can prolong the rPFS, OS, and / or TTSTP assessed in the subject by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, or at least 250%.

[0450] The present disclosure also describes methods of reducing the TTR timeframe of a PSMA-targeting radioligand therapy (RLT) for use in treating a subject with cancer, wherein the method comprises combining the PSMA-targeting RLT with an AR-degrading therapy, whereby the combined therapy reduces TTR assessed in the subject as compared with the corresponding TTR assessed in subjects receiving the PSMA-targeting RLT as monotherapy. The method can reduce the TTR assessed in the subject by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, or at least 250%.

[0451] The present disclosure also describes methods of improving the rate of PSA50, ORR, DCR, PSA90, PSA30 and / or PSA0 of a PSMA-targeting RLT. A method of improving a PSA50, ORR, DCR, PSA90, PSA30, and / or PSA0 rate can include providing, to a population of subjects with a cancer, a combination therapy that includes administering a therapeutically effective amount of a PSMA-targeting radioligand and an efficacy-enhancing amount of an AR-degrading agent to the subject, wherein the efficacy-enhancing amount is the amount that achieves an increase the proportion of subjects who achieve a >30% decrease in PSA from baseline at any timepoint, the proportion of subjects who achieve a PSA value <0.2 ng / ml at any timepoint after start of treatment, the proportion of subjects achieving a confirmed complete response (CR) or partial response (PR), and the proportion of subjects achieving a CR, PR or stable disease (SD). The method can increase the rate by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, or at least 250%.

[0452] PSA can be measured every 2 weeks during the initial period of treatment. The initial period can include 18 weeks, and include 1 to 3 RLT cycles as described above. PSA can be measured after every 3 weeks after the initial period, until the end of treatment. An improvement in the PSA50 rate can be any statistically significant increase in the proportion of subjects who achieve a >50% decrease in PSA from baseline at any timepoint that is assessed in the population of subjects receiving the combination therapy as compared with the monotherapy PSA50 rate. The proportion can be confirmed by a second PSA measurement >3 weeks later, which shows a lack of PSA progression in between.

[0453] In the methods of improving a PSMA-targeting RLT described above, the cancer can be a prostate cancer, preferably a prostate specific membrane antigen (PSMA)-positive cancer and / or a prostate specific membrane antigen (PSMA)-expressing cancer, in particular a PSMA+ / PSMA-expressing prostate cancer. The cancer can be metastatic castration resistant prostate cancer (mCRPC). The cancer can have progressed while the subject(s) was / were receiving Androgen Deprivation Therapy (ADT) and at least one prior ARPI. The ADT received by the subject(s) can be abarelix, degarelix, and / or relugolix. The subject(s) can have undergone ADT through orchiectomy (e.g., bilateral orchiectomy).

[0454] The subject(s) can be selected from a group of adult subjects (e.g., >18 years of age) defined by one or more of the inclusion or exclusion factors described above. In a particular embodiment, the subject(s) have had prior exposure to at least one second generation ARPI, in the metastatic or advanced setting and combinations thereof, or from the group consisting of abiraterone, enzalutamide, darolutamide, and apalutamide, or a combination thereof; the subject(s) have a castrate level of serum / plasma testosterone, a serum / plasma testosterone level less than <50 ng / dL or <1.7 nmol / L, are receiving an ADT and / or subjects who have undergone an orchiectomy; and / or the subject(s) have had prior exposure to no more than two taxane regimens, such as subjects who have had prior exposure to one or two taxane regimens in a previous treatment in a Hormone Sensitive Prostate Cancer (HSPC) or a castration resistant prostate cancer (CRPC) setting.

[0455] In a particular embodiment, the AR-degrading therapy includes administering a dose of the AR-degrading agent, luxdegalutamide, of at least about 100 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, or a dose of about 300 mg. The AR-degrading agent can be administered daily, such as once per day. The AR-degrading agent, luxdegalutamide, can be administered as one or more tablets, taken with food, as described above.

[0456] The AR-degrading therapy can include administering the dose of AR-degrading agent (e.g., luxdegalutamide) for at least about 4 weeks, preferably continuously for at least about 4 weeks, e.g., daily and continuously for about 4 weeks to about 38 weeks, such as about 6 weeks, about 12 weeks, about 18 weeks, about 24 weeks, about 30 weeks, about 36 weeks, or about 38 weeks.

[0457] In a particular embodiment, the PSMA-targeting RLT includes administering a therapeutically effective amount of [177Lu]Lu-PSMA-617, selected from a dose of from about 3 GBq to about 10 GBq; a dose of from about 5.9 GBq to about 7.4 GBq; a dose of about 7.4 GBq; or a dose of about 5.9 GBq. The dose can be administered intravenously.

[0458] The therapeutically effective amount of [177Lu]Lu-PSMA-617 can be administered as a course of treatment comprising at least one cycle, such as a cycle as described above. In particular embodiments, one cycle can be about 4 weeks to about 8 weeks or about 5 weeks to about 7 weeks. In particular embodiments, one cycle is about 6 weeks.

[0459] The therapeutically effective amount of [177Lu]Lu-PSMA-617 can be administered for at least two cycles, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 2 to 10 cycles or for 4 to 8 cycles. In a particular embodiment, the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for about 6 cycles.

[0460] In a particular embodiment, the first dose of luxdegalutamide (or other AR-degrader) is administered before administering the first dose of [177Lu]Lu-PSMA-617 (or other PSMA-targeting RLT). The interval between administering the first dose of luxdegalutamide and the first dose of [177Lu]Lu-PSMA-617 can be at least about 10 days, such as about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, or about 17 days. The interval between administering the first dose of luxdegalutamide and the first dose of [177Lu]Lu-PSMA-617 can be a timeframe sufficient for luxdegalutamide-induced degradation of AR proteins and / or induction of PSMA expression in a cancer cell of the subject(s). The timeframe can be about two weeks.

[0461] In a particular embodiment, the first dose of luxdegalutamide can be administered about two weeks prior to administering a first dose of [177Lu]Lu-PSMA-617, such as about 17, about 16, about 15, or about 14 days prior to administering the first dose of [177Lu]Lu-PSMA-617.

[0462] In a particular embodiment, a first dose of [177Lu]Lu-PSMA-617 can be administered within about 2 weeks of luxdegalutamide administration. For example, a first dose of [177Lu]Lu-PSMA-617 can be administered about 17 days after the initial dose of luxdegalutamide is administered about 14 days after the initial dose of luxdegalutamide is administered.

[0463] The efficacy endpoints described above can be assessed using conventional methods. Imaging assessments to monitor radiographic progression can be based on PCWG3-modified RECIST v1.1 guidelines. Periodic radiographic imaging can include contrast-enhanced CT / MRI and / or bone scans with technetium-99m labeled diphosphonates. CT / MRI with contrast assessments can include evaluations of the chest, abdomen, and pelvis. Screening / baseline imaging can include chest, abdomen, and pelvis CT or MRI; whole body bone scan, with technetium-99m labeled diphosphonates; brain CT or MRI, CT or MRI of other metastatic sites (e.g., neck), and [68Ga]Ga-PSMA-11 PET scan.

[0464] Sites of “soft tissue” disease can be characterized as either target or non-target lesions based on CT / MRI images. The distribution of target and non-target lesions can be representative of the subject’s overall disease. Site of metastatic spread can include lung, liver, adrenal glands, lymph nodes, etc. Target lesions can be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs / sites of metastatic spread, and be amenable to reproducible repeated measurements. Preferably, a target lesion is measurable at screening / baseline. Sites of bone disease can be recorded based on bone scan, with exception to bone metastasis with soft tissue component which may qualify for target / non-target when detectable at CT / MRI as described above.

[0465] Disease progression by bone scan criteria can be demonstrated when at least 2 new bone lesions at the first “post treatment” scan persist, with at least two additional lesions on the next (confirmatory) scan outside a flare window of about 12 weeks (2 + 2 PCWG3 criteria). For scans after the flare window, the first observation of at least two new lesions relative to the baseline scan can be confirmed on a subsequent scan at least 6 weeks later (2 + 2 PCWG3 criteria). If the second scan confirms the metastases, then the date of progression is the date of the scan when the first 2 new metastases were documented. Disease progression can be assessed according to PCWG3-modified RECIST. Progression seen on conventional imaging (e.g., PSMA PET / CT imaging) can be considered as an event for rPFS.

[0466] Pharmaceutical Compositions

[0467] Also provided herein are pharmaceutical compositions for use in the methods described above comprising a PSMA-targeting radioligand and / or an AR-degrading agent and a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, a PSMA-targeting radioligand and / or an AR-degrading agent are not formulated together, and can be supplied separately, e.g., as separate pharmaceutical compositions.

[0468] The amount of PSMA-targeting radioligand and / or AR-degrading agent that may be combined with pharmaceutically acceptable carrier, diluent, or excipient to produce a single dosage form will vary depending upon the individual subject and the particular mode of administration. For example, the amount of PSMA-targeting radioligand as described above and / or AR-degrading agent (e.g., a PROteolysis-TArgeting chimera (PROTAC) AR degraders, selective AR degraders (SARDs), hydrophobic tag-based degraders (HyTs), non-steroidal CYP11A1 inhibitors, dual-action AR inhibitors (DAARIs), N-terminal domain AR degraders, ligand-directed degraders, chaperone protein dissociating AR degraders, autophagy promoting AR degraders, and combinations thereof), as described above, that may be combined with pharmaceutically acceptable carrier, diluent, or excipient to produce a single dosage form will vary depending upon the individual subject and the particular mode of administration.

[0469] In some embodiments the unit dosage forms containing the combination of PSMA-targeting radioligand and AR-degrading agent as described above will contain the amounts of each compound in the combination that are administered when the compounds are administered alone, or the amount of PSMA-targeting radioligand and / or AR-degrading agent can be less than the amount of each compound when the compounds are administered alone, or the amount of PSMA-targeting radioligand and / or AR-degrading agent can be greater than the amount of each compound when the compounds are administered alone. The pharmaceutically acceptable carrier, diluent or Also provided herein are pharmaceutical compositions for use in the methods described above comprising PSMA-targeting radioligand and / or an AR-degrading agent and a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, PSMA-targeting radioligand and / or an AR-degrading agent are not formulated together, and can be supplied separately, e.g., as separate pharmaceutical compositions.

[0470] The amount of PSMA-targeting radioligand and / or AR-degrading agent that may be combined with pharmaceutically acceptable carrier, diluent, or excipient to produce a single dosage form will vary depending upon the individual subject and the particular mode of administration. In some embodiments the unit dosage forms containing the combination of PSMA-targeting radioligand and AR-degrading agent as described above will contain the amounts of each compound in the combination that are administered when the compounds are administered alone, or the amount of PSMA-targeting radioligand and / or AR-degrading agent can be less than the amount of each compound when the compounds are administered alone, or the amount of PSMA-targeting radioligand and / or AR-degrading agent can be greater than the amount of each compound when the compounds are administered alone. The pharmaceutically acceptable carrier, diluent or excipient may be a solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.

[0471] The pharmaceutical compositions may be administered parenterally. Accordingly, in certain embodiments, the compositions are formulated for delivery by any of these routes of administration. A pharmaceutical composition may be formulated for and administered by parenteral administration. In particular, a pharmaceutical composition of the present disclosure may be formulated for and administered by intravenous administration.

[0472] In certain embodiments, pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders, for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, p-cyclodextrin, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain additives such as preservatives, wetting agents, emulsifying agents, chelating agents, buffering agents, and dispersing agents.

[0473] In some embodiments, the pharmaceutical composition comprises a chelating agent to sequester internally deposited radionuclides. Any chelating agent known in the art that complexes to alpha-particle emitting radionuclides may be included in pharmaceutical compositions described herein. In various embodiments, the pharmaceutical composition comprises DTPA. Additional exemplary chelating agents that may be included in pharmaceutical compositions of the present disclosure 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 earth metals for imaging and therapy.” Chemical reviews 119.2 (2018): 902-956, both of which are incorporated herein by reference in their entireties.

[0474] Pharmaceutical compositions can further include a stabilizer, such as, for example, a free radical scavenger or radiation stability enhancer, in order to prevent autoradiolysis of the radioligand. Stabilizer(s) present in the solutions of the present disclosure can be selected from gentisic acid (2,5-dihydroxybenzoic acid) or salts thereof, ascorbic acid (L-ascorbic acid, vitamin C) or salts thereof (e.g., sodium ascorbate), methionine, histidine, melatonine, ethanol, and Se-methionine. In some cases, the stabilizer(s) can include gentisic acid or salts thereof, and not ethanol. Suitable stabilizers for inclusion in the disclosed pharmaceutical compositions include, but are not limited to, 2,5-dihydroxybenzoic acid or salts thereof, ascorbic acid or salts thereof, gentisic acid or salts thereof, methionine, histidine, melatonine, N-acetylmethionine, ethanol, an amino acid infusion solution, or any combination thereof. In some embodiments, the pharmaceutical composition includes a gentisic acid stabilizer. In some embodiments, the pharmaceutical composition includes an ascorbic acid stabilizer. In some embodiments, the pharmaceutical composition include stabilizer including gentisic acid and ascorbic acid.

[0475] In some embodiments, the pharmaceutical composition comprises one or more buffering agents to maintain a pH of about 3 to 5. Suitable buffering agents include, but are not limited to acetate, citrate, Tris, lactate, and tartrate, and the acid forms thereof.

[0476] In some embodiments, the pharmaceutical composition is an aqueous pharmaceutical solution including [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan). In a specific embodiment, the aqueous solution includes [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) in an activity in the range from 800 to 1200 MBq / ml, 900 to 1100 MBq / ml, 950 to 1050 MBq / ml, or about 1000 MBq / mL (27 mCi / mL); a buffer to provide a pH in the range of 4.5 to 7.0; gentisic acid or a salt thereof in a concentration in the range 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 with regard to the free acid; ascorbic acid or a salt thereof, such as the sodium salt thereof, in a concentration in the range from 20 to 52.5 mg / mL, 47.5 to 52.5 mg / mL, 48 to 52 mg / mL, or about 50 mg / mL with regard to the sodium salt; and pentetic acid or a salt thereof in a concentration in the range 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 with regard to the free acid.

[0477] In a specific embodiment, the pharmaceutical composition includes an individual patient dose unit containing a volume of an aqueous solution of PSMA-targeting radioligand. In certain embodiments, the individual patient dose unit volume is about 7.5 to about 12.5 mL. The patient dose unit can be in the form of a vial, e.g. a single-dose vial, e.g. a colorless borosilicate (type I) glass vial, e.g. of about 30 mL size, e.g. closed with a bromobutyl rubber stopper (stopper with silicate filler and inorganic coloring system) and a seal, such as an aluminum seal, or in the form of a pre-filled syringe or cartridge, e.g. a cartridge that can be loaded into a device for infusion / injection, e.g. a cartridge for a syringe or an infusion system. The aqueous solutions of the present disclosure can be dispensed in a vial and then transferred into a syringe.

[0478] The dose unit of PSMA-targeting radioligand can be provided in a lead shielded container. The lead shielded container can be placed in a plastic sealed container. The dose unit can be shipped in a Type A packaging system (according to the corresponding regulations of the International Air Transport Association (IATA) and International Carriage of Dangerous Good by Road (ADR)). The Type A packaging can be designed to meet the radiological protection requirements.

[0479] The aqueous solutions of any of the embodiments above can be injected intravenously (IV, by bolus injection or infusion) or intraarterially, or intratumorally. The aqueous solutions of any of the embodiments above can be administered to the patient by slow intravenous push within approximately 1 to 10 minutes (either with a syringe pump or infusion pump or manually), e.g., via an intravenous catheter that is pre-filled with e.g., 0.9% sterile sodium chloride solution.

[0480] The aqueous solutions of any of the embodiments above can be administered at a dosage / dose described above, and for any duration or number of cycles described above. In certain embodiments, the PSMA-targeting radioligand is [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and the dosage / dose is about 7.4 (±10%) GBq (200 (±10%) mCi), to be administered every about 6 weeks for up to about 6 doses. The dose can be temporarily interrupted (e.g., by extending the dosing interval from every about 6 weeks up to every about 7, 8, 9, or 10 weeks), or the dose may be reduced or increased, e.g., by about 20% to about 5.9 (±10%) GBq (160 (±10%) mCi).

[0481] Pharmaceutical compositions provided herein include combinations for use in treating cancer, in particular a prostate cancer, preferably a PSMA-positive cancer and / or a PSMA-expressing cancer, in particular a PSMA+ / PSMA-expressing prostate cancer. In a particular embodiment. In a particular embodiment, the combination can include luxdegalutamide and [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan).

[0482] In particular embodiments, the combination can be for use in treating mCRPC in a subject having prior exposure to at least one Androgen Receptor Pathway Inhibitor (ARPI), such as prior exposure to at least one second generation ARPI selected from the group consisting of abiraterone, enzalutamide, darolutamide, and apalutamide, or a combination thereof, or prior exposure to two or more of abiraterone, enzalutamide, darolutamide, and apalutamide. The presence of metastases can be confirmed by radiographical imaging, optionally by CT / MRI or bone scan.

[0483] In particular embodiments, the combination can be for use in treating a subject having no prior exposure to a taxane regimen, having prior exposure to no more than two taxane regimens; having prior exposure to one or two taxane regimens in a previous treatment in a Hormone Sensitive Prostate Cancer (HSPC) or a castration resistant prostate cancer (CRPC) setting; who has not received prior chemotherapy; and / or who has not received prior chemotherapy other than a taxane regimen. In particular embodiments, the combination can be for use in treating a subject who has not been treated with one or more of platinum, estramustine, vincristine, methotrexate, and cyclophosphamide.

[0484] In particular embodiments, the combination can be for use in treating a subject who has been treated with an immunotherapy agent, such as sipuleucel-T.

[0485] In particular embodiments, the combination can be for use in treating a subject who has had no exposure to a radioligand therapy (RLT) prior to receiving a first dose of [177Lu]Lu-PSMA-617.

[0486] In particular embodiments, the combination can be for use in treating a subject who has been treated with a poly (ADP-ribose) polymerase (PARP) inhibitor, an immune checkpoint inhibitor, or a combination thereof.

[0487] In particular embodiments, the combination can be for use in treating a subject who has had prior exposure to radiation therapy.

[0488] In particular embodiments, the combination can be for use in treating a subject receiving concurrent ADT defined as serum testosterone levels <50 ng / dL induced by orchiectomy and / or a gonadotropin releasing hormone analog or inhibitor.

[0489] In particular embodiments, the combination provides an improved therapeutic effect compared to the therapeutic effect provided by a PSMA-targeting radioligand monotherapy or an AR-degrading agent monotherapy in the treatment of mCRPC.

[0490] In particular embodiments, the combination has an improved risk / benefit ratio as compared to the risk / benefit ratio of a PSMA-targeting radioligand monotherapy or an AR-degrading agent monotherapy in the treatment of mCRPC.

[0491] In particular embodiment, the AR-degrading agent improves an anti-cancer response of the PSMA-targeting radioligand in a subject when used in treating a cancer.

[0492] In further particular embodiments, the present disclosure contemplates combinations comprising a PSMA targeting agent other than PSMA-617 (INN: vipivotide tetraxetan), e.g., any compound of Formulae I l-V described above, PSMA-binding ligands including “cold” ligand (i.e. , ligand without radionuclide) selected from the group consisting of PSMA l&T (INN: zadavotide guraxetan), PSMA-R2 (Novartis), MIP-1095 (Lantheus), MIP-1545 (Lantheus), MIP-1555 (Lantheus), MIP-1557 (Lantheus), MIP-1558 (Lantheus), CTT1403 (Cancer Targeted Technology), FC705 (FC-KR), BAY-2315497 (Bayer), BAY-2315487 (Bayer), BAY-356254 (Bayer), BAY-354682 (Bayer), TLX591 (Telix), TLX592 (Telix), PSMA-TCC, rhPSMA (Blue Earth Diagnostics), rhPSMA-7 (Blue Earth Diagnostics), rhPSMA-7.3 (Blue Earth Diagnostics), rhPSMA-10.1 (Blue Earth Diagnostics), Ludotadipep, PNT2001 (PSMA-062 (Point Biopharma)), PNT2002 (Point Biopharma), PSMA-7 l&T, EB-PSMA-617 (National Institute For Biomedical Imaging And Bioengineering (Nibib), PSMA-ALB-02 (ITM Radiopharma), PSMA-ALB-53 (ITM Radiopharma), PSMA-ALB-56 (ITM Radiopharma), P16-093 (Five Eleven Pharma (PSMA- 093)), PSMA-1 (RadioMedix), PSMA-1-D0TA (Case Western Reserve), SAR-bisPSMA (Clarity), ITM-22 (ITM Radiopharma), ITM-24D (ITM Radiopharma), PMI-21 (Precision Molecular), DOTA-h11B6 (Janssen Research & Development), FPI-1434 (Fusion Pharmaceuticals), pelgifatamab, NG001 / AB001 (ArtBio), ADVC001 (AdvanCell), RPS-072 (Cornell University), RPS-074 (Cornell University), FL-020 (Full Life Technologies), FPI-2265 (Fusion), CONV01 (Convergent), JNJ-6420 (J&J), LNC-1003 (Yantai LNC), and radiolabeled anti-PSMA antibodies as described above, such as PSMA l&T, PSMA-62, PSMA-1-DOTA, and PSMA-R2, or PSMA l&T (INN: zadavotide guraxetan), and PSMA-R2.

[0493] The present disclosure contemplates combinations comprising a radionuclide other than117Lu, such as161Tb or225Ac. For example, the radionuclide can be an alpha-particle emitting radionuclide selected from the group consisting of225Ac,211At,213Bi,212Bi,212Pb,223Ra,224Ra,149Tb, and227Th or a p-emitting radionuclide selected from the group consisting of169Er,161Tb,1311,90Y,67Cu, and47Sc.

[0494] The present disclosure contemplates combinations comprising an AR degrader other than luxdegalutamide, such as a non-steroidal AR-degrading agent selected from the group consisting of PROteolysis-TArgeting chimeras (PROTACs), selective AR degraders (SARDs), hydrophobic tag-based degraders (HyTs), non-steroidal CYP11A1 inhibitors, dual-action AR inhibitors (DAARIs), N-terminal domain AR degraders, ligand-directed degraders, chaperone protein dissociating AR degraders, autophagy promoting AR degraders, and combinations thereof described above, or a PROTAC AR degrader selected from the group consisting of bavdegalutamide (ARV-110), gridegalutamide (BMS-986365), AC-0176 under development by Accutar Biotechnology, and HP518 under development by Hinova Pharmaceuticals Inc., or a combination thereof.

[0495] The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same or similar results. The compounds of the Examples have demonstrated efficacy in the treatment of prostate cancer, and in particular, metastatic resistance prostate cancer (mCRPC).

[0496] EXAMPLES

[0497] Example 1: In vitro / R degradation by luxdegalutamide.

[0498] New interventions are needed to address dysregulated AR signaling in prostate cancer (PCa) and castration-resistant PCa. Androgen ablation by surgical or chemical castration in early-stage patients can provide remission of localized PCa, however high AR expression, including expression of constitutively active AR splice variants, can enhance AR signaling in PCa cells despite low levels of adrenal androgens.

[0499] As shown in FIG. 1A-G AR-degrading agent luxdegalutamide induces concentrationdependent AR degradation in LNCaP cells. LNCaP cells carry a clinically relevant T878A mutation in the AR ligand binding domain. AR protein levels were attenuated in the absence or presence of competing ligand (2.5 nM di-hydro-testosterone (DHT)) as early as 24 hrs after treatment with luxdegalutamide (FIG. 1 A). This effect increased with the duration of exposure, with nearly complete degradation at concentrations above 1,000 nM luxdegalutamide by 72 hrs (FIG. 1B).

[0500] Example 2: Treatment with AR-degrading agent provides superior growth inhibition and reduction in PSA expression in LNCaP cells over treatment with AR inhibitor enzalutamide.

[0501] As shown in FIG. 2A treatment with luxdegalutamide (AVR766) results in potent growth inhibition (approximately 9 times higher potency than enzalutamide (Table, GI50 of 33 nm and 284 nm, respectively)). Inhibition of KLK3 mRNA (AR target gene encoding PSA) by luxdegalutamide is also superior to enzalutamide (FIG. 2B).

[0502] Example 3: In vivo Pharmacokinetics and Pharmacodynamics of a single treatment with luxdegalutamide in LNCaP tumor xenografts.

[0503] Luxdegalutamide (ARV-766) treatment of mice bearing LNCaP tumor xenografts at 20 mg / kg dose in led to AR degradation starting at 4 hours and reaching maximal degradation (-70%) at 8 hrs. Degradation was sustained for 24 hours. These data show that luxdegalutamide has a late absorption. The AUC at 20mg / kg is similar with two different formulations. FIG. 3 depicts results of in vivo studies showing the time course analysis of AR degradation in LNCaP tumor xenografts after a single treatment with luxdegalutamide (ARV766 (NVP-BUO652)). Tumor-bearing female mice with testosterone pellets were treated with a single dose (20 mg / kg p.o. in 20% caprylocaproyl macrogol-8 glyceride (LABRASOL®) / 80% water vehicle).

[0504] Example 4: In vivo combination of (177LulLu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) with luxdegalutamide in LNCaP tumor xenografts.

[0505] Tumor bearing female mice with testosterone pellets were treated as shown in FIGs.

[0506] 4A-B. The combination of 10 mg / kg luxdegalutamide (ARV766) and 10 MBq [177Lu]Lu-PSMA-617 ((INN: lutetium (177Lu) vipivotide tetraxetan, commercial name: PLUVICTO) showed an at least additive reduction in LNCaP xenograft tumor volume over time as compared to monotherapy responses with 10 mg / kg p.o. QD luxdegalutamide or 10 MBq 177Lu-PSMA-617 (FIG. 4A), although the 10 MBq dose of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) exposure was suboptimal. FIG. 4B shows greater than additive reduction in LNCaP xenograft tumor volume was achieved over time with 30 mg / kg p.o. QD luxdegalutamide and 10 MBq [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) as compared to monotherapy responses with 30 mg / kg p.o. QD luxdegalutamide or 10 MBq [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan). A 30 mg / kg dose luxdegalutamide in mice corresponds to an exposure of 300 mg in humans.

[0507] Example 5: In vivo efficacy of the combination of r177l_u]l_u-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and luxdegalutamide in adult male patients with PSMA-positive metastatic castration resistant prostate cancer (mCRPC)

[0508] Overview.

[0509] This example describes a Phase II, randomized, open-label, multi-center study of an Androgen Receptor Pathway Inhibitor (ARPI), luxdegalutamide, in combination with a compound of Formula I, lutetium (177Lu) vipivotide tetraxetan, in adult male patients with PSMA-positive metastatic castration resistant prostate cancer (mCRPC). Where permitted, all publications and other data referred to below are incorporated by reference herein in their entirety.

[0510] Subjects described herein have mCRPC that progressed on Androgen Deprivation Therapy (ADT) and at least 1 prior ARPI. Such subjects have limited treatment options and a poor prognosis (median rPFS around 8-12 months and median OS around 15-19 months) (Rebello et al 2021, Le et al 2023). Therefore, there is a medical need for new effective treatments to improve the survival of these patients.

[0511] This study demonstrates the improved efficacy of the combination of luxdegalutamide at about 100 mg and about 300 mg QD doses + lutetium (177Lu) vipivotide tetraxetan in subjects with mCRPC with prior exposure to at least one ARPI and zero to two taxane regimens compared with the efficacy of lutetium (177Lu) vipivotide tetraxetan monotherapy. The efficacy data from subjects can be used to select the dose of the combination for a phase III study. The study design is shown in TABLE 1.

[0512] Table 1: Study design.

[0513] Key eligibility criteria luxdegalutamide 100 mg QD + N =

[0514] Arm 1

[0515] • >18 years lutetium (177Lu) vipivotide tetraxetan 50 • ECOG 0-2 7.4 GBq q6 weeks

[0516] • mCRPC R luxdegalutamide 300 mg QD + N =

[0517] Arm 2

[0518] • Positive 68 Ga-PSMA-11 5:5:3 lutetium (177Lu) vipivotide tetraxetan 50 • PET / CT scan 7.4 GBq q6 weeks

[0519] • Prior progression on >1 ARPI Arm 3 lutetium (177Lu) vipivotide tetraxetan N =

[0520] 30

[0521]

[0522] • 0-2 prior taxanes 7.4 GBq q6 weeks The study objectives and related endpoints are summarized in TABLE 2. The results demonstrate the clinical benefit for subjects with cancer, such as, e.g., prostate cancer, PSMA-positive cancer, and / or a PSMA-expressing cancer. The clinical benefit of the combination therapy is demonstrated as compared with lutetium (177Lu) vipivotide tetraxetan monotherapy for one or more of the following endpoint measures: PSA50, PSA90, PSA30, PSAO, Overall Response Rate (ORR), Disease Control Rate (DCR), Radiographic Progression Free Survival (rPFS), Time to response (TTR), Overall Survival (OS), time to soft tissue progression (TTSTP), time to first symptomatic skeletal event (TTSSE) and Time To Progression (TTP).

[0523] Table 2: Objectives and related endpoints

[0524] Objective(s) Endpoint(s)

[0525] Primary objective(s) Endpoint(s) for primary objective(s)

[0526] • Determine the optimal dose of • Efficacy: PSA50 rate defined as the luxdegalutamide (100 mg QD vs 300 proportion of subjects who achieve a >50% mg QD) in combination with lutetium decrease in PSA from baseline at any (177Lu) vipivotide tetraxetan based on timepoint, confirmed by a second PSA an integrated assessment of efficacy measurement >3 weeks without any PSA

[0527] • Compare luxdegalutamide (100 mg progression in between.

[0528] QD / 300 mg QD pooled doses or

[0529] best of the two doses) in combination

[0530] with lutetium (177Lu) vipivotide

[0531] tetraxetan versus control (lutetium

[0532] (177Lu) vipivotide tetraxetan alone) in

[0533] terms of efficacy

[0534] Secondary objective(s) Endpoint(s) for secondary objective(s)

[0535] • Evaluate rPFS across treatments • rPFS defined as time between treatment initiation (i.e. , initial dose of luxdegalutamide) and the first occurrence of disease progression as per PCWG3 modified RECIST v1.1 or death due to any cause

[0536] • Evaluate OS across treatments • OS defined as time between treatment initiation and death due to any cause

[0537] • In subjects with evaluable soft tissue ORR defined as proportion of subjects disease by RECIST v1.1 at baseline: achieving a confirmed complete response Objective(s) Endpoint(s)

[0538] evaluate the overall response rate (CR) or partial response (PR) per PCWG3- (ORR), disease control rate (DCR), modified RECIST v1.1;

[0539] duration of response (DOR), time to DCR defined as proportion of subjects response (TTR), and time to soft achieving a CR, PR or stable disease (SD) tissue progression (TTSTP) based on per PCWG3-modified RECIST v1.1;

[0540] PCWG3-modified RECIST v1.1 DOR defined as time between first (Eisenhauer et al 2009) across study documented CR / PR and disease progression treatments or death due to any cause per PCWG3- modified RECIST v1.1;

[0541] TTR defined as the time from treatment initiation to the date of first documented CR or PR per PCWG3-modified RECIST v1.1;

[0542] TTSTP defined as time from treatment initiation to the date of first documented radiographic soft tissue progression per PCWG3-modified RECIST v1.1.

[0543] • To evaluate biochemical response as • PSA90 rate defined as the proportion of measured by PSA across study patients who achieve a >90% decrease from treatments baseline at any timepoint, confirmed by a second PSA measurement >3 weeks without any PSA progression in between;

[0544] PSA30 rate defined as the proportion of patients who achieve a >30% decrease from baseline at any timepoint, confirmed by a second PSA measurement >3 weeks without any PSA progression in between;

[0545] PSA0 rate defined as the proportion of patients who achieve a PSA value <0.2 ng / ml at any timepoint after start of treatment, confirmed by a second PSA measurement >3 weeks without any PSA progression in between. Objective(s) Endpoint(s)

[0546] • To evaluate the durability of • Duration of biochemical response defined biochemical response across study as time between PSA50 and PSA progression treatments or death due to any cause

[0547] • To evaluate the time to first • TTSSE defined as date of treatment initiation symptomatic skeletal event (TTSSE) to the date of first new symptomatic across study treatments pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or death from any cause, whichever occurs first

[0548] • To characterize the PK of • Plasma concentrations of luxdegalutamide luxdegalutamide and its metabolite, and ARV-767 pre and post dose

[0549] ARV-767

[0550] • To characterize the PK of lutetium • Concentrations of lutetium (177Lu) vipivotide (177Lu) vipivotide tetraxetan tetraxetan in blood over time and PK parameters from blood radioactivity data. • To evaluate tumor and organs • Radiation absorbed doses in organs and dosimetry of lutetium (177Lu) tumors for lutetium (177Lu) vipivotide vipivotide tetraxetan across study tetraxetan

[0551] treatments

[0552] • To characterize patient-reported

[0553] outcomes of interest to complement

[0554] evidence of efficacy outcomes

[0555] Exploratory objective(s) Endpoint(s) for exploratory objective(s)

[0556] • To assess luxdegalutamide • Association between luxdegalutamide exposure-response (efficacy) exposure and efficacy (PSA50, ORR) relationships

[0557] • To assess relationships between • Association between absorbed dose and absorbed dose of lutetium (177Lu) efficacy (PSA)

[0558] vipivotide tetraxetan and response

[0559] (efficacy) Objective(s) Endpoint(s)

[0560] • To evaluate the time to PSA TTPSAP defined as time from treatment progression (TTPSAP) across study initiation to PSA progression. PSA treatments progression is defined as an increase >25% in PSA and an absolute increase of >2 ng / mL above the NADIR confirmed by a second value >3 weeks later if there is PSA decline from baseline, or a >25% increase and a >2 ng / mL increase from baseline beyond 12 weeks if there is no PSA decline from baseline

[0561] • To assess molecular and imaging • Association between biomarkers and biomarkers associated with efficacy efficacy (PSA50, ORR), and changes in and / or resistance to study treatment biomarkers before and after study treatment. Biomarkers may include molecular or phenotypic characteristics (such as, but not limited to AR-status, AR or PSMA expression, genomic alterations) derived from tumor tissue, circulating tumor cells and / or liquid biopsy, and imaging parameters derived from PSMA PET imaging

[0562] • Association between molecular response as assessed by ctDNA change from baseline with biochemical and radiographic response and survival (rPFS and OS)

[0563] To assess whether luxdegalutamide Change from baseline PSMA expression as increases the expression of PSMA measured by repeated [68Ga]Ga-PSMA- 11 PET / CT scan

[0564] Background

[0565] PSMA is a transmembrane protein highly expressed in nearly all prostate cancers but with restricted and low expression in some normal tissues, such as the duodenal mucosa, proximal renal tubules, and salivary glands (Bostwick et al 1998, Ghosh and Heston 2004, Mannweiler et al 2009). The differential expression of PSMA from tumor to non-tumor tissue renders PSMA an attractive therapeutic target in patients with prostate cancer.

[0566] In addition to the expression pattern, the functionality of PSMA has value as a tumorspecific targeting mechanism. Specifically, the binding of a high affinity ligand to PSMA leads to internalization through endocytosis and a sustained retention of the ligand within the cancer cell (Rajasekaran et al 2003, Begum et al 2019). This functional feature of PSMA, together with its selective expression on prostate cancer cells, allows for the development of low-molecular-weight targeted radiopharmaceuticals that yield a high radiation uptake by tumor sites with limited off-target uptake (Haberkorn et al 2016).

[0567] Compounds of formula (I), (II), (III), (IV), and (V) described above can exhibit high PSMA binding affinity and internalization. A specific embodiment of a PSMA-targeting radioligand therapy is represented by Formula (I), lutetium (177Lu) vipivotide tetraxetan.

[0568] Lutetium (177Lu) vipivotide tetraxetan consists of the PSMA-binding ligand glutamate-urea-lysine and a DOTA-chelator, which are connected by a naphthyl containing linker. By design, lutetium (177Lu) vipivotide tetraxetan exhibits high PSMA binding affinity and internalization, prolonged tumor retention, and rapid kidney clearance (Benesova et al 2015). Vipivotide tetraxetan was uniquely developed for both imaging and radio ligand therapy of prostate cancer and can be radiolabeled with gallium-68 (68Ga), lutetium-177 (177Lu), indium-111, copper-64, scandium-44, actinium-225, or yttrium-90.

[0569] Lutetium (177Lu) vipivotide tetraxetan delivers the radioactive cargo177Lu.177Lu has physical properties that make it an appropriate radionuclide for the treatment of mCRPC.177Lu is a medium energy P emitter (490 ke V) with a maximum energy of 0.5 Me V and a maximal tissue penetration of <2 mm. The shorter p-range of177Lu provides better irradiation of small tumors, in contrast to the longer P-range of 90Y (Emmett et al 2017). The shorter path length also acts to direct the energy within the tumor rather than in the surrounding normal tissues, while the path length is still sufficient to create bystander and crossfire effects within the tumor lesion.177Lu has a relatively long physical half-life of 6.7 days that combines with the intratumoral retention of177Lu-PSMA-617 to reduce the necessary dosing frequency. These physical properties and the benefit of PSMA targeting allow for the delivery of effective antitumor activity of177Lu against prostate cancer cells.

[0570] Two Phase III trials (VISION and PSMAfore) have demonstrated the benefit of Lutetium (177Lu) vipivotide tetraxetan in patients with mCRPC, pre- and post-taxane exposure (Sartor et al 2021, Morris et al 2024). Overall, Lutetium (177Lu) vipivotide tetraxetan has shown robust antitumor activity and a favorable toxicity profile in these studies, associated with a rPFS improvement (VISION and PSMAfore) and an OS improvement (VISION). These results have led to the approval of Lutetium (177Lu) vipivotide tetraxetan as a new effective treatment option in patients with PSMA-positive mCRPC who have been treated with prior AR pathway inhibition and taxane-based chemotherapy.

[0571] Trials that evaluated Lutetium (177Lu) vipivotide tetraxetan for the treatment of patients with mCRPC suggest that a high PSMA expression as determined by high standardized uptake values (SUVmean) at baseline PSMA-PET imaging was associated with more robust therapeutic benefit from Lutetium (177Lu) vipivotide tetraxetan (Cardenas et al 2024). PSMA expression by IHC scores demonstrates marked heterogeneity in mCRPC, where up to 75% of PSMA-positive biopsies may include zones with no detectable PSMA expression

[0572] (Wang et al 2023).

[0573] AR inhibition via Androgen Receptor Pathway Inhibitors (ARPIs) such as luxdegalutamide can lead to upregulation of PSMA expression in PC cells, albeit transiently, which may be due in part to the compensatory AR upregulation (Sommer et al 2022).

[0574] Luxdegalutamide (also known as JSB462, formerly ARV-766) is a potent, selective, PROTAC® (PROteolysis Targeting Chimera) molecule that targets and induces the degradation of androgen receptor (AR). As a bi-functional small molecule, luxdegalutamide simultaneously binds the AR and cereblon E3 ligase complex, forming what is known as a "trimer complex", which enables a protein-protein interaction between the AR and cereblon, resulting in the accessible lysine residues on the AR protein becoming polyubiquitinated by the ligase complex (FIG. 5). Subsequent degradation of the polyubiquitinated AR by the proteasome results in elimination of the AR protein from cells. In contrast to traditional target inhibition, which is a competitive, occupancy-driven process, PROTAC-mediated degradation is iterative and event (trimer formation)-driven and is therefore less susceptible to increases in endogenous ligand, target protein expression levels, or mutations in the target.

[0575] Luxdegalutamide demonstrated sustained reductions in AR expression and an upregulation of PSMA expression. In a preclinical study with non-castrated male NSG mice bearing AR-amplified patient-derived xenografts 30158-HX, after 14 days of repeated p.o. daily treatment with a single p.o. dose of Luxdegalutamide in vivo at 10 mg / kg, Luxdegalutamide demonstrated sustained reductions in AR expression and an upregulation of PSMA expression, whereas enzalutamide was associated with compensatory upregulation of AR expression and non-sustained upregulation of PSMA expression (FIG. 6A). Without being bound by theory, the transient nature of PSMA upregulation induced by ARPIs may be related to the compensatory upregulation of AR expression (Noss et al 2002, Sommer et al 2022).

[0576] To determine the pharmacological effect of Luxdegalutamide in vitro, AR degradation assays were conducted in vertebral cancer of the prostate (VCaP) cells and lymph node carcinoma of the prostate (LNCaP) PC cells that harbor AR amplification and the AR mutation (T878A), respectively. After 24 hours of treatment, luxdegalutamide effectively degraded the AR in LNCaP (Dmax >91 % with DC50 of <1.3 nM) and VCaP (Dmax >94% with DC50 of <1 nM). A degradation time course experiment also performed in VCaP cells demonstrated that >50% degradation of AR is achieved within 2 hours of Luxdegalutamide treatment of VCaP cells and near complete elimination of AR from the cell is observed by 6 hours. Since Luxdegalutamide is thought to engage the cereblon protein at the same binding site as I M i Ds, such as thalidomide, lenalidomide, and pomalidomide, an excess amount of pomalidomide would compete for the binding of Luxdegalutamide to the cereblon protein. Consistent with the PROTAC’s mode of action, pomalidomide (10 pM) blocked Luxdegalutamide mediated degradation. In addition, a poly-ubiquitination assay was conducted and that demonstrated that ubiquitination of the AR is significantly increased with Luxdegalutamide treatment. These data support the proposed mode of action of Luxdegalutamide in degrading AR via the engagement of E3 ligase cereblon, ubiquitination of AR, and degradation via the proteasome (data not shown).

[0577] To assess the ability of Luxdegalutamide to degrade variants of the AR, vectors expressing wild type (WT) AR or mutant AR proteins harboring clinically observed mutations in the ligand binding domain (13 with single amino acid changes or 4 with 2 amino acid changes) were stably transfected into HEK293 or T-REx™-293 cells, which do not express endogenous AR (Azad et al 2015, Robinson et al 2015, Ledet et al 2020). As shown in FIG. 6B, Luxdegalutamide-mediated degradation of all the clinically relevant AR point mutants tested was comparable to that observed for WT AR.

[0578] Upon castration, prostate tumor cells are able to produce testosterone on their own to enable their growth. The effect of Luxdegalutamide on AR degradation in vivo was evaluated in castrated mice bearing VCaP xenografts. To recapitulate human CRPC, when the implanted tumors reached a volume of approximately 100 mm3, the mice were surgically castrated. Three weeks after castration, mice were administered a single PO dose of Luxdegalutamide at 10, 3, 1, 0.3, 0.1, 0.03, or 0 (vehicle) mg / kg via gavage. Sixteen hours after treatment, the tumor tissues were collected, and lysates were prepared to assess AR expression by western blotting. At Luxdegalutamide doses of 10, 3, 1, 0.3, 0.1, and 0.03 mg / kg, AR was reduced on average by 96%, 91%, 81%, 73%, -5%, and 14%, respectively (FIG. 6C), compared to vehicle control. Thus, robust AR degradation was observed in vivo upon oral dosing of Luxdegalutamide at 1 mg / kg or higher.

[0579] The anti-tumor growth effects of Luxdegalutamide in vivo were evaluated in a castrated mouse VCaP xenograft model. Briefly, 6- to 8-week-old male CB17 / scid mice were implanted with 3 x 106VCaP tumor cells in the flank region. Once the tumors reached a volume of approximately 100 mm3, the mice were surgically castrated. When tumors began to grow again and reached about 150 mm3in castrated animals (approximately 2 to 4 weeks after castration), the mice in each arm of the study (n=10) were treated with 3, 1, 0.3, 0.1, or 0 (vehicle) mg / kg / day Luxdegalutamide, or 20 mg / kg dose of enzalutamide QD for 24 days, via oral gavage. This dose of enzalutamide has been reported to exceed clinical exposure. All treatments were well tolerated including no effect on body weight. As shown in FIG. 6D, treatment with Luxdegalutamide at 3 mg / kg, 1 mg / kg, and enzalutamide at 20 mg / kg resulted in significant tumor growth inhibition (TGI) relative to the vehicle control group (100%, 81 %, 111%, respectively). Luxdegalutamide treatment groups at 0.3 mg / kg (TGI =49%) and 0.1 mg / kg (TGI =45%) exhibited a modest and statistically insignificant TGI relative to the vehicle control group.

[0580] These preclinical data show that Luxdegalutamide induces AR degradation and presents robust antitumor activity not only in prostate cancer cells harboring a broad range of clinically relevant LBD mutations, which are found in around 20-25% of the patients with mCRPC and are typically associated with resistance to ARPIs, but also in prostate cancer cells without LBD mutations (wild type) (Le et al 2023). These results led the present inventors to hypothesize that treatment with luxdegalutamide avoids this compensatory AR upregulation and provides a more sustained upregulation of PSMA expression in PC cells, which creates an opportunity to improve PSMA-targeted therapy.

[0581] The safety, tolerability, PK, PD, and preliminary efficacy of luxdegalutamide as monotherapy are being evaluated in an ongoing study, CJSB462A12101 (NCT05067140, also known as ARV-766-mCRPC-101, and hereafter referred to as CJSB462A12101). Based on the overall safety, tolerability, PK and preliminary efficacy data from Part A of CJSB462A12101, two dose levels (100 mg QD and 300 mg QD) were selected for the Phase II luxdegalutamide monotherapy cohort expansion in patients with mCRPC.

[0582] Preliminary analysis of Parts A and B of the ongoing study CJSB462A12101 demonstrated efficacy and tolerability of luxdegalutamide in monotherapy (with ADT to maintain castrate levels of testosterone) in patients with mCRPC. In terms of efficacy of luxdegalutamide, among the two doses selected for dose expansion (Part B) 300 mg and 100 mg QD, the confirmed PSA50 response rate (defined as a >50% decline in PSA from baseline and confirmed by a second PSA >3 weeks) was 26.4% (14 / 53) in the 100 mg QD dose cohort and 19.1% (9 / 47) in the 300 mg QD dose cohort. The unconfirmed radiographic Overall Response Rate (ORR) (by modified RECIST v1.1 [soft tissue disease)] and PCWG3 [bone disease] criteria) was 19.2% (5 / 26) for the 100 mg QD dose cohort and 13.3% (2 / 15) for the 300 mg QD cohort.

[0583] Among patients whose tumors harbor AR Ligand-Binding Domain (LBD) mutations (any missense mutation between amino acids 671-920 which are typically associated with resistance to ARPIs) (n=31 in 100 mg, n = 25 in 300 mg), the confirmed PSA50 response was 41.9% (13 / 31) in the 100 mg cohort and 32% (8 / 25) in 300 mg cohort, with an unconfirmed radiographic ORR of 21.4% (3 / 14) and 28.6% (2 / 7) in the 100 mg and 300 mg doses, respectively (Kwan and Wyatt 2022).

[0584] Preliminary analysis of safety data of luxdegalutamide in the CJSB462A12101 study showed a tolerable and manageable safety profile, with no unexpected safety findings observed, luxdegalutamide. The overall incidence of grade >3 AEs are broadly comparable to standard of care (SoC) in this treatment setting and within the acceptable limits for the patient population being treated and provide supportive data regarding tolerability in the 300 mg QD cohort as compared to 100 mg QD for the patient population being treated

[0585] (Armstrong et al 2019, Fizazi et al 2017).

[0586] Detailed Description of Treatment Protocol:

[0587] The present Example demonstrates a new effective treatment to improve the survival of patients with prostate cancer by targeting Prostate-Specific Membrane Antigen (PSMA), which is predicated on the Inventors’ discovery that the mechanisms of action of luxdegalutamide and the compound of Formula (I), lutetium (177Lu) vipivotide tetraxetan, are complementary and that the combination of luxdegalutamide and lutetium (177Lu) vipivotide tetraxetan has a favorable risk-benefit ratio for mCRPC patients. In this context, luxdegalutamide can improve the efficacy of lutetium (177Lu) vipivotide tetraxetan by inducing sustained upregulation of PSMA expression on prostate cancer cells. The improvement can be greater than additive. Luxdegalutamide can generate synergistic antitumor activity when combined with lutetium (177Lu) vipivotide tetraxetan.

[0588] This Example describes an open-label, global, multicenter, randomized phase II study demonstrating the efficacy of two dose regimens of luxdegalutamide (100 mg QD and 300 mg QD) combined with lutetium (177Lu) vipivotide tetraxetan as compared to lutetium (177Lu) vipivotide tetraxetan alone (control) in adult patients with PSMA-positive mCRPC. The subjects have a history of progression on Androgen Deprivation Therapy (ADT) and after exposure to at least 1 prior ARPI.

[0589] Approximately 130 eligible subjects are randomized in a 5:5:3 ratio to the following arms:

[0590] ARM 1 : luxdegalutamide 100 mg QD + lutetium (177Lu) vipivotide tetraxetan 7.4 GBq q6 weeks

[0591] ARM 2: luxdegalutamide 300 mg QD + lutetium (177Lu) vipivotide tetraxetan 7.4 GBq q6 weeks

[0592] ARM 3 (control): lutetium (177Lu) vipivotide tetraxetan 7.4 GBq q6 weeks.

[0593] The control arm consisting of lutetium (177Lu) vipivotide tetraxetan is an effective treatment option for subjects with PSMA-positive mCRPC, as described above (Morris et al 2024, Sartor et al 2021). Randomization is stratified by prior taxane (yes vs no), and visceral metastases (yes vs. no). Visceral metastases are defined as soft tissue lesions involving liver, lungs, adrenal glands, peritoneum, pleura, brain and dura (Pezaro et al 2014). The number of subjects with visceral metastases (per screening imaging exams as assessed by the investigator) is capped to a maximum of 39 (30%) overall, to allow adequate representation of subjects with and without visceral metastases in the study. Lutetium (177Lu) vipivotide tetraxetan is administered at 7.4 GBq intravenously about every 6 weeks for up to about 6 doses unless there is disease progression per PCWG3-modified RECIST v1.1 or death. A dose of about 7.4 GBq is equivalent to about 200 mCi or about 7400 MBq. This dose has been previously evaluated and shown to be safe in prior studies (Morris et al 2024) and according to the approved product information. Administration of the radiopharmaceutical can be preceded by a saline flush with >10 mL of normal saline to ensure patency of the intravenous line.

[0594] Lutetium (177Lu) vipivotide tetraxetan can be provided as a clear colorless to yellowish solution, free of visible particles, in a ready-to-use single-dose vial. The amount of radioactivity in the radiopharmaceutical vial can be measured with an appropriate and calibrated device prior to administration in order to confirm that the actual amount of radioactivity to be administered is equal to the planned amount at the time of administration. A saline flush of >10 mL NS (normal saline) can be performed after administration of Lutetium (177Lu) vipivotide tetraxetan to ensure residual radiopharmaceutical has been removed from the intravenous line.

[0595] Luxdegalutamide is administered orally, daily and continuously (100 mg or 300 mg QD) until disease progression per PCWG3-modified RECIST v1.1. In the phase l / ll, open-label, dose-escalation / expansion CJSB462A12101 study, dose proportional increase in luxdegalutamide exposure was observed up to 300 mg QD. Doses greater than 300 mg QD did not result in higher exposures, presumably due to the saturation on absorption. The 100 mg QD dose appeared to represent a minimum efficacy threshold in terms of AR degradation needed to yield antitumor activity based on preclinical PD models (described above). Based on previous results, luxdegalutamide is taken with food to maximize the exposure. More specifically, luxdegalutamide is taking with food comprising 400 or more calories that includes a mixture of fat, carbohydrates and protein, such as the largest meal of the day. The subject can receive concurrent treatment with esomeprazole or other proton-pump inhibitor (PPI). The daily dose of luxdegalutamide is taken at approximately the same time each day, or at least 12 hours prior to the next scheduled dose. Luxdegalutamide tablets are swallowed whole (i.e., not crushed, chewed, or dissolved).

[0596] Although specific dosing is described above, each study treatment component can be dose managed (e.g., adjusted and / or discontinued) independently of the other. For example, dose adjustments of luxdegalutamide can include a reduction from about 300 mg QD to about 200 mg QD, or from about 200 mg QD to about 100 mg QD. A dose adjustment of lutetium (177Lu) vipivotide tetraxetan can include a rejection from about of 7.4 GBq (200 mCi) to about 5.9 GBq (160 mCi).

[0597] One treatment cycle is about 6 weeks (about 42 days). A treatment period can end after a subject has been followed for at least about 42 (±3) days after the last dose of lutetium (177Lu) vipivotide tetraxetan. Luxdegalutamide can be discontinued before (about <7 days before) or after (about ±3 days after) the last dose of lutetium (177Lu) vipivotide tetraxetan is administered to the subject.

[0598] The study includes an interim dose selection analysis. The interim dose selection analysis is performed after ~25 subjects begin treatment in both Arm 1 and Arm 2 and followed for > about 12 weeks to assesses differences in efficacy (PSA50 rate >20%), if any.

[0599] Dose determination comprises identifying which combination arm (Arm 1 or Arm 2) offers the optimal dose in terms of PSA50 rate. The primary treatment effect can be described by the following four attributes:

[0600] 1. Population: Adult subjects with PSMA-positive mCRPC (as determined by [68Ga]Ga- PSMA-11 PET / CT scan) who have progressed on at least one prior ARPI, received up to 2 prior taxane regimens, and no prior RLT.

[0601] 2. Endpoint:

[0602] • Efficacy: PSA50 rate, defined as the proportion of subjects who achieve a >50% decrease in Prostate Specific Antigen (PSA) from baseline at any timepoint, confirmed by a second PSA measurement >3 weeks without any PSA progression in between.

[0603] 3. Treatment of interest: luxdegalutamide 100 mg QD + lutetium (177Lu) vipivotide tetraxetan 7.4 GBq (Arm 1), luxdegalutamide 300 mg QD + lutetium (177Lu) vipivotide tetraxetan 7.4 GBq (Arm 2), lutetium (177Lu) vipivotide tetraxetan 7.4 GBq (Arm 3, control).

[0604] • Summary measure (Efficacy): The PSA50 rate, along with its corresponding two- sided exact binomial 95% confidence interval.

[0605] The primary treatment effect establishes the PSA50 rate of two dose levels (100 mg QD and 300 mg QD, pooled or individually) of luxdegalutamide in combination with lutetium (177Lu) vipivotide tetraxetan, as measured by, in comparison to lutetium (177Lu) vipivotide tetraxetan (control) for the target population. The primary treatment effect can be described by the following four attributes:

[0606] 1. Population: Adult subjects with PSMA-positive mCRPC (as determined by [68Ga]Ga- PSMA-11 PET / CT scan) who have progressed on at least one prior ARPI, received up to 2 prior taxane regimens and no prior RLT.

[0607] 2. Endpoint:

[0608] Efficacy: PSA50 rate, defined as the proportion of subjects who achieve a >50% decrease in PSA from baseline at any timepoint, confirmed by a second PSA measurement >3 weeks without any PSA progression in between. 3. Treatment of interest: luxdegalutamide 100 mg QD + lutetium (177Lu) vipivotide tetraxetan 7.4 GBq (arm 1), luxdegalutamide 300 mg QD + lutetium (177Lu) vipivotide tetraxetan 7.4 GBq (arm 2), lutetium (177Lu) vipivotide tetraxetan 7.4 GBq (arm 3, control).

[0609] 4. Summary measure:

[0610] • Efficacy: The PSA50 rate, along with its corresponding two-sided exact binomial 95% confidence interval, of the combination arms (individual or pooled) are compared with the control arm using the Miettinen-Nurminen (MN) method, stratified as discussed above.

[0611] Additional treatments

[0612] Determining whether a subject meets the inclusion criterion requiring an overall positive [68Ga]Ga-PSMA-11 PET / CT can include administering the [68Ga]Ga-PSMA-11 as a single intravenous (i.v.) dose.

[0613] Androgen deprivation therapy (ADT) is administered to ensure castrate levels of testosterone as per inclusion criteria 12 (<50 ng / dL or <1.7 nmol / L), either by the use of GnRH analog / antagonist or by having had an orchiectomy. Non-limiting examples of GnRH analog / antagonists are provided in TABLE 3.

[0614] Table 3: Additional study treatments

[0615] Treatment Gallium (68Ga) ATC1code abarelix degarelix relugolix Title gozetotide category

[0616] L02AE

[0617] Treatment Single intravenous Gonadotropin Other Other Other Description administration for releasing hormone hormone hormone imaging. hormone antagonists antagonists antagonists analogues and related and related and related agents agents agents

[0618]

[0619] 1Anatomical Therapeutic Chemical

[0620] Key Inclusion criteria

[0621] 1. Adults > 18 years of age.

[0622] 2. Histological and / or cytological confirmation of adenocarcinoma of the prostate.

[0623] 3. At least 1 bone or visceral metastatic lesion (according to local radiology assessment by the investigator) present on baseline CT, MRI, or bone scan imaging, excluding individuals with lymph nodes as only site of metastases. 4. Progressive mCRPC based on at least 1 of the following criteria:

[0624] • Biochemical progression defined as 2 increases in PSA (and an absolute value of at least 2.0 ng / mL) measured at least 1 week apart;

[0625] • Radiographic progression per PCWG3-modified RECIST v1.1.

[0626] 5. A castrate level of serum / plasma testosterone (<50 ng / dL or <1.7 nmol / L).

[0627] 6. Previous exposure to at least one second generation ARPI (e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or any combination of these) in the metastatic / advanced setting.

[0628] • Previous exposure to >2 second generation ARPIs is allowed.

[0629] • Prior use of a first-generation ARPI (e.g. bicalutamide, flutamide, nilutamide) is allowed but not considered as prior ARPI therapy for the purpose of eligibility.

[0630] 7. Previous treatment with a maximum of 2 taxane regimens in HSPC or CRPC setting is allowed.

[0631] 8. Prior treatment with sipuleucel-T is allowed.

[0632] 9. Ongoing ADT (as defined by prior orchiectomy and / or ongoing GnRH analog / antagonist) is allowed prior to randomization.

[0633] Key Exclusion criteria

[0634] 1. Patients with mixed histology (neuroendocrine).

[0635] 2. Prior treatment with any RLT (approved or investigational).

[0636] 3. Prior treatment with chemotherapies other than taxanes (e.g., platinum, estramustine, vincristine, methotrexate, cyclophosphamide).

[0637] 4. Prior treatment with a protein degrader compound that targets the AR.

[0638] 5. Patients with biochemical recurrence only or those without evidence of metastatic disease by radiographical imaging (CT / MRI or bone scan) are not eligible.

[0639] 6. Patients treated with strong CYP3A4 / 5 inhibitors or strong CYP3A inducers that cannot be discontinued 7 days prior to the initiation of treatment and for the duration of the study.

[0640] Other protocol-defined inclusion / exclusion criteria may apply.

[0641] Primary endpoint(s)

[0642] TABLE 4 shows the minimum observed PSA50 rate required for the lower bound of the 95% Cl of the PSA50 rate difference to exceed 0% (clinical benefit) and 10% (strong clinical interest) between the pooled combination arm vs. control arm constructed by stratified Miettinen and Nurminen method.

[0643] A clinical benefit of a selected luxdegalutamide combination arm or pooled combination arms can be established when the lower bound of the 95% confidence interval for the difference of the observed PSA50 rate between luxdegalutamide combination arm vs. the control arm is >0. The selected luxdegalutamide combination arm or pooled combination arms is considered to have strong clinical benefit if the lower bound of the 95% confidence interval for the difference of the observed PSA50 rate between luxdegalutamide combination arm vs. the control arm is >10%. Table 4: Operating Characteristics

[0644] Control arm (N=30) Pooled combination arm (N=100)

[0645] Assumed PSA50 Two-sided 90% Required PSA50 rate for Observed PSA50 rate for rate Cl 95% Cl lower bound of 95% Cl lower bound of A > A > 0%* 10%*

[0646] 37% (11 / 30) [22%, 53%] 54% (54 / 100) 64% (64 / 100)

[0647] 47% (14 / 30) [31%, 63%] 64% (64 / 100) 74% (74 / 100)

[0648] 57% (17 / 30) [40%, 72%] 73% (73 / 100) 83% (83 / 100)

[0649] A is PSA50 rate difference between combination treatment arm and control arm; one-sided unstratified Miettinen and Nurminen (MN) confidence interval (Cl)

[0650] TABLE 5 presents the probabilities of achieving the base (clinical benefit) and higher success criteria (strong clinical interest) at the primary analysis under various true PSA50 rates, as determined through simulation. These simulations replicate the trial process, incorporating both interim and primary analysis outcomes.

[0651] Table 5: Probability of meeting success criteria

[0652] Assumed True Probability (%) of meeting the base Probability (%) of meeting the higher PSA50 rate in success criteria3success criteria15

[0653] combination

[0654] arm

[0655] Assumed true PSA50 rate in the control arm = 37% (11 / 30

[0656] 40% 10.6 1.1

[0657] 45% 18.8 3.6

[0658] 50% 31.2 8.1

[0659] 55% 47.6 16.1

[0660] 60% 63.3 27.5

[0661] 65% 78.6 42.6

[0662] 70% 89.2 59.6

[0663] 75% 96.3 78.0

[0664] 80% 98.6 90.0

[0665] Assumed true PSA50 rate in the control arm = 47% (14 / 30

[0666] 50% 10.3 1.5

[0667] 55% 19.2 4.0

[0668] 60% 31.9 8.6

[0669] 65% 47.7 16.5

[0670] 70% 63.9 28.9

[0671] 75% 81.0 48.1

[0672]

[0673] 80% 92.3 65.4

[0674] 85% 97.9 83.2

[0675] 90% 99.6 95.1

[0676] Assumed true PSA50 rate in the control arm = 57% (17 / 30

[0677] 60% 10.4 1.4

[0678] 65% 19.0 4.2

[0679] 70% 33.3 9.0

[0680] 75% 52.7 19.2

[0681] 80% 71.1 33.8

[0682] 85% 87.6 53.7

[0683] 90% 96.9 77.8

[0684] Based on 5000 simulations.

[0685]

[0686] aObserved PSA50 rate with 95% Cl lower bound of A > 0%;bObserved PSA50 rate with 95% Cl lower bound of A > 10%

[0687] Efficacy and / or pharmacodynamic endpoint(s)

[0688] Radiographic progression-free survival (rPFS)

[0689] rPFS is defined as time between treatment initiation and the first occurrence of disease progression as per PCWG3-modified RECIST v1.1 or death due to any cause. Clinical deterioration is not considered to be documented disease progression. Tumor assessment data collected irrespective of discontinuation of study treatment and initiation of new anti-neoplastic therapy are used for the analysis. rPFS is analyzed based on the Full Analysis Set (FAS) population. The rPFS distribution is estimated using the Kaplan-Meier method, and Kaplan-Meier curves, medians and 95% confidence intervals of the medians are presented for each treatment arm. The hazard ratio for rPFS is calculated, along with its 95% confidence interval, from a stratified Cox model stratified by the stratification factors discussed above.

[0690] Overall Survival (OS)

[0691] OS is defined as the time from date of treatment initiation to date of death due to any cause. OS is analyzed in the Full Analysis Set (FAS) population according to the treatment arm and assigned strata. OS data collected irrespective of discontinuation of study treatment and initiation of new anti-neoplastic therapy are used for the analysis. The OS distribution can be estimated using the Kaplan-Meier method, and Kaplan-Meier curves, medians and 95% confidence intervals of the medians are presented for each treatment arm. The hazard ratio for OS is calculated, along with its 95% confidence interval, from a stratified Cox model stratified by the stratification factors described above.

[0692] Overall response rate (ORR) ORR is evaluated in the RECIST Analysis Set (RAS). ORR is defined as the proportion of subjects achieving a confirmed complete response (CR) or partial response (PR) in soft tissue, according to PCWG3-modified RECIST v1.1 , in the absence of bone progression as per PCWG3. CR and PR is confirmed by repeat assessments that performed not less than 4 weeks after the criteria for response are first met. ORR is calculated based on the RECIST Analysis Set (RAS) and according to the Intent to Treat (ITT) principle. ORR and its 95% confidence interval is presented by treatment arm.

[0693] Best Overall Response (BOR) for each subject is determined from the sequence of overall (lesion) responses according to the following rules:

[0694] • CR = at least two determinations of CR at least 4 weeks apart before progression.

[0695] • PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR).

[0696] • SD = at least one stable disease (SD) assessment (or better) > 8 weeks after treatment start (and not qualifying for CR or PR).

[0697] • Non-CR / Non-Progressive Disease (PD) = at least one non-CR / non-PD assessment (or better) > 8 weeks after treatment start (and not qualifying for CR or PD).

[0698] • PD = progression < 19 weeks after treatment start (and not qualifying for CR, PR or SD). • UNK = all other cases (i.e. , not qualifying for confirmed CR or PR and without SD after more than 8 weeks or early progression within the first 19 weeks)

[0699] As a supplementary analysis, ORR in soft tissue only, as per PCWG3-modified RECIST v1.1 review is presented by treatment arm, along with 95% confidence intervals.

[0700] Disease control rate (DCR)

[0701] DCR is evaluated in the RECIST Analysis Set (RAS). DCR is defined as the proportion of subjects achieving a CR, PR, or stable disease (SD), according to PCWG-modified RECIST v1.1. DCR is calculated based on the RAS. DCR and its 95% confidence interval is presented by treatment arm.

[0702] Duration of radiographic response (DOR)

[0703] DOR is evaluated in the RECIST Analysis Set (RAS). DOR is defined as the duration of time between the date of first documented response (CR or PR) according to PCWG3-modified RECIST v1.1 based on tumor response data and the date of first documented progression or death due to any cause. Subjects who never achieved a BOR of CR or PR are excluded from the analysis. The distribution function of DOR is estimated using the Kaplan-Meier method. The median DOR along with 95% Cis is presented by treatment arm.

[0704] Time to response (TTR)

[0705] TTR is evaluated in the RECIST Analysis Set (RAS). TTR is defined as the time from the date of treatment initiation to the date of first documented CR or PR, which is confirmed subsequently. CR and PR are based on tumor response data according to PCWG3-modified RECIST v1.1. The distribution function of TTR is estimated using the Kaplan-Meier method. The median TTR along with 95% Cis is presented by treatment arm.

[0706] Time to soft tissue progression (TTSTP)

[0707] TTSTP is evaluated in the RECIST Analysis Set (RAS). TTSTP is defined as time from treatment initiation to radiographic soft tissue progression per PCWG3-modified RECIST v1.1. The TTSTP distribution is estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% confidence intervals of the medians is presented for each treatment arm, using RAS population.

[0708] Biochemical response

[0709] Biochemical response is calculated based on the FAS and according to the ITT principle. PSA response along with 95% confidence intervals is presented by treatment arm.

[0710] • PSA90 rate defined as the proportion of subjects who achieve a >90% decrease from baseline at any timepoint, confirmed by a second PSA measurement >3 weeks without any PSA progression in between;

[0711] • PSA30 rate defined as the proportion of subjects who achieve a >30% decrease from baseline at any timepoint, confirmed by a second PSA measurement >3 weeks without any PSA progression in between;

[0712] • PSA0 rate defined as the proportion of subjects who achieve a PSA value <0.2 ng / ml at any timepoint, confirmed by a second PSA measurement >3 weeks without any PSA progression in between.

[0713] As a sensitivity analysis, biochemical response is analyzed using a different baseline which is defined as the values prior to or on the treatment initiation date when calculating PSA90 / PSA30 / PSA0. The same analyses are performed for the new biochemical response, based on this different baseline.

[0714] As a supplementary analysis, biochemical response is analyzed using the PSA evaluable set.

[0715] Duration of biochemical response (DBR)

[0716] Duration of biochemical response defined as time between the first date of PSA50 response and the date of PSA progression (an increase >25% in PSA and an absolute increase of >2 ng / mL above the NADIR confirmed by a second value >3 weeks later if there is PSA decline from baseline, or a >25% increase and a >2 ng / mL increase from baseline beyond 12 weeks if there is no PSA decline from baseline) or death due to any cause. Subjects who never achieved a PSA50 are excluded from the analysis. The duration of biochemical response distribution is estimated using the Kaplan-Meier method, and the Kaplan-Meier curve, medians and 95% confidence intervals of the medians are presented for each treatment arm.

[0717] As a sensitivity analysis, duration of biochemical response is analyzed using a different baseline which is defined as the values prior to or on the treatment initiation date when calculating PSA50. The same analyses are performed for the new duration of biochemical response, based on this different baseline.

[0718] Time to SSE (TTSSE)

[0719] TTSSE is defined as the time from the date of treatment initiation to the date of the first symptomatic skeletal event (SSE) or death from any cause. SSE date is date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain. The FAS is used in TTSSE analysis. The distribution function of TTSSE is estimated using the Kaplan-Meier method. The median TTSSE along with 95% Cis are presented by treatment arm.

[0720] References

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Claims

CLAIMS1. A method of treating a prostate specific membrane antigen (PSMA)-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a non-steroidal Androgen Receptor (AR)-degrading agent and administering to the subject a therapeutically effective amount of a PSMA-targeting radioligand.

2. The method of claim 1, wherein the PSMA-targeting radioligand comprises a PSMA-binding ligand selected from the group consisting of PSMA-binding ligands comprising a glutamate-urea-lysine binding motif and a chelator; PSMA-binding ligands comprising a glutamate-urea-lysine binding motif, a chelator and a linker comprising a hydrophobic side chain, optionally the hydrophobic side chain comprises an amino acid linker comprising amino acid residues selected from phenylalanine, tyrosine and naphthylalanine, wherein the amino acid residues are independently optionally substituted; optionally the PSMA-binding ligand is selected from PSMA-617 (INN: vipivotide tetraxetan), PSMA l&T (INN: zadavotide guraxetan), PSMA-R2 (Novartis), MIP-1095 (Lantheus), MIP-1545 (Lantheus), MIP-1555 (Lantheus), MIP-1557 (Lantheus), MIP-1558 (Lantheus), CTT1403 (Cancer Targeted Technology), FC705 (FC-KR), BAY-2315497 (Bayer), BAY-2315487 (Bayer), BAY-356254 (Bayer), BAY-354682 (Bayer), TLX591 (Telix), TLX592 (Telix), PSMA-TCC, rhPSMA (Blue Earth Diagnostics), rhPSMA-7 (Blue Earth Diagnostics), rhPSMA-7.3 (Blue Earth Diagnostics), rhPSMA-10.1 (Blue Earth Diagnostics), Ludotadipep, PNT2001 (PSMA-062 (Point Biopharma)), PNT2002 (Point Biopharma), PSMA-7 l&T, EB-PSMA-617 (National Institute For Biomedical Imaging And Bioengineering (Nibib), PSMA-ALB-02 (ITM Radiopharma), PSMA-ALB-53 (ITM Radiopharma), PSMA-ALB-56 (ITM Radiopharma), P16-093 (Five Eleven Pharma (PSMA-093)), PSMA-1 (RadioMedix), PSMA-1-DOTA (Case Western Reserve), SAR-bisPSMA (Clarity), ITM-22 (ITM Radiopharma), ITM-24D (ITM Radiopharma), PMI-21 (Precision Molecular), DOTA-h11B6 (Janssen Research & Development), FPI-1434 (Fusion Pharmaceuticals), pelgifatamab, NG001 / AB001 (ArtBio), ADVC001 (AdvanCell), RPS-072 (Cornell University), RPS-074 (Cornell University), FL-020 (Full Life Technologies), FPI-2265 (Fusion), CONV01 (Convergent), JNJ-6420 (J&J), and LNC-1003 (Yantai LNC); optionally the PSMA-binding ligand is PSMA-617 or PSMA l&T.

3. The method of claim 1 or 2, wherein the PSMA-targeting radioligand comprises a beta-minus-, positron-, or alpha-particle emitting radionuclide.

4. The method of any one of claims 1 to 3, wherein the PSMA-targeting radioligand comprises an alpha-particle emitting radionuclide.

5. The method of claim 4, wherein the alpha-particle emitting radionuclide is225Ac or212Pb.

6. The method of any one of claims 1 to 3, wherein the PSMA-targeting radioligand comprises a beta-minus-particle emitting radionuclide.

7. The method of claim 6, wherein the beta-minus-particle emitting radionuclide is177Lu or161Tb.

8. The method of any one of claims 1 to 7, wherein the PSMA-targeting radioligand comprises a radiohybrid (rh) ligand or radiolabeled anti-PSMA antibody.

9. The method of claim 8, wherein the PSMA-targeting radioligand comprises a radiohybrid (rh) ligand labeled with177Lu, or225Ac.

10. The method of claim 8, wherein the PSMA-targeting radioligand comprises an anti-PSMA Monoclonal Antibody J591 labeled with177Lu,161Tb or225Ac, an anti-PSMA monoclonal antibody BAY 2315497 (Pelgifatamab Corixetan) labeled with227Th, or DOTA-rosopatamab (TLX591) labeled with177Lu.

11. The method of claim 1, wherein the PSMA-targeting radioligand comprises177Lu-Ludotadipep,177Lu-labeled Evans blue-modified PSMA 617 (EB-PSMA-617), or177Lu-DGUL.

12. The method of claim 1, wherein the PSMA-targeting radioligand is selected from the group consisting of compounds of formulae (I), (II), (III), (IV), and (V):(I)(V)wherein the compounds of formulae (I), (II), (III), (IV), and (V) are radiolabeled with an alpha-particle emitting radionuclide or a beta-minus-particle emitting radionuclide, optionally wherein the compound of formula (IV) has the glutamic acid of the DOTAGA chelator being in the unnatural D-configuration and / or the compound of formula (II) has the glutamic acid and the lysine adjacent to the urea in the L-configuration.

13. The method of claim 12, wherein the compounds of formulae (I), (II), (III), (IV), and (V) are radiolabeled with an alpha-particle emitting radionuclide selected from the group consisting of225Ac,211At,213Bi,212Bi,212Pb,223Ra,224Ra,149Tb, and227Th.

14. The method of claim 12 or 13, wherein the alpha-particle emitting radionuclide is selected from the group consisting of225Ac,212Pb, and227Th.

15. The method of any one of claims 12 to 14, wherein the alpha-particle emitting radionuclide is225Ac.

16. The method of claim 12, wherein the compounds of formulae (I), (II), (III), (IV), and (V) are radiolabeled with a beta-minus-particle emitting radionuclide selected from the group consisting of177Lu,169Er,161Tb,1311,90Y,67Cu, and47Sc.

17. The method of claim 16, wherein beta-minus-particle emitting radionuclide is177Lu.

18. The method of claim 1, wherein the PSMA-targeting radioligand is [177Lu]Lu-PSMA l&T (INN: lutetium (177Lu) zadavotide guraxetan).

19. The method of claim 1, wherein the PSMA-targeting radioligand is [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan).

20. The method of any one of claims 1 to 19, wherein the non-steroidal AR-degrading agent is selected from the group consisting of PROteolysis-TArgeting chimera (PROTAC) AR degraders, selective AR degraders (SARDs), hydrophobic tag-based degraders (HyTs), nonsteroidal CYP11A1 inhibitors, dual-action AR inhibitors (DAARIs), N-terminal domain AR degraders, ligand-directed degraders, chaperone protein dissociating AR degraders, autophagy promoting AR degraders, and combinations thereof.

21. The method of any one of claims 1 to 20, wherein the non-steroidal AR-degrading agent comprises a PROTAC AR degrader selected from the group consisting of luxdegalutamide (ARV-766), bavdegalutamide (ARV-110), gridegalutamide (BMS-986365), AC-0176, and HP518, or a combination thereof.

22. The method of claim 21 , wherein the PROTAC AR degrader comprisesluxdegalutamide.

23. The method of any one of claims 1 to 20, wherein the non-steroidal AR-degrading agent comprises a non-steroidal CYP11A1 inhibitor.

24. The method of claim 23, wherein the non-steroidal CYP11A1 inhibitor comprises opevesostat.

25. The method of any one of claims 1 to 20, wherein the non-steroidal AR-degrading agent comprises a DAARI.

26. The method of claim 25, wherein the DAARI comprises (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluoropyrazol-1-yl)-2-hydroxy-2-methylpropanamide, or a pharmaceutically acceptable salt thereof.

27. The method of any one of claims 1 to 20, wherein the non-steroidal AR-degrading agent comprises a ligand directed degrader.

28. The method of claim 27, wherein the ligand directed degrader comprises 2-[(2R)-4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl]-2-ethylphenoxy]ethyl]-2-methylpiperazin-1-yl]-N-[3-[(2,6-dioxopiperidin-3-yl)amino]phenyl]acetamide, or a pharmaceutically acceptable salt thereof.

29. The method of any one of claims 1 to 20, wherein the non-steroidal AR-degrading agent comprises an N-terminal domain AR degrader.

30. The method claim of 29, wherein the N-terminal domain AR degrader comprises Masofaniten or EPI-8207.

31. The method of any one of claims 1 to 20, wherein the non-steroidal AR-degrading agent comprises a chaperone protein dissociating AR degrader.

32. The method of claim 31, wherein the chaperone protein dissociating AR degrader comprises Dimethylcurcumin, Niclosamide or derivatives thereof (ARVibs), or a pharmaceutical salt thereof, or a combination thereof.

33. The method of any one of claims 1 to 20, wherein the non-steroidal AR-degrading agent comprises an autophagy promoting AR degrader.

34. The method of claim 33, wherein the autophagy promoting AR degrader comprises Riluzole, or a pharmaceutical salt thereof.

35. The method of any one of claims 1 to 20, wherein the non-steroidal AR-degrading agent comprises a hydrophobic tag-based degrader (HyT).

36. The method of claim 35, wherein the HyT comprises N-(2-(2-(2-(2-((Adamantan-1-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)butanamide, or a pharmaceutically acceptable salt thereof.

37. The method of any one of claims 1 to 36, wherein the therapeutically effective amount of the PSMA-targeting radioligand, the non-steroidal AR-degrading agent, or both in the combination is lower than the amount required for a monotherapy response for the PSMA-targeting radioligand and / or the non-steroidal AR-degrading agent.

38. The method of claim 37, wherein the monotherapy response is an objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (OR), partial response (PR), PSA response rate, radiographic response rate, AR-protein level, tumor growth rate, PSMA-expression level, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.

39. The method of any one of claims 1 to 38, wherein the combination of the PSMA-targeting radioligand and the non-steroidal AR-degrading agent achieves an improved anticancer response in the subject being treated for the PSMA-expressing cancer than the anticancer response achieved by a PSMA-targeting radioligand monotherapy and / or AR-degrading agent monotherapy.

40. The method of any one of claims 1 to 39, wherein the combination of the PSMA-targeting radioligand and the non-steroidal AR-degrading agent provides a synergistic effect in the treatment of the PSMA-expressing cancer.

41. The method of any one of claims 1-40, wherein the therapeutically effective amount of the PSMA-targeting radioligand is a dose of from about 6 MBq to about 10 GBq.

42. The method of any one of claims 1-41, wherein the PSMA-expressing cancer is PSMA-positive prostate cancer, optionally PSMA-positive metastatic castration-resistant prostatecancer (mCRPC), optionally PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC), optionally PSMA-positive oligometastatic prostate cancer (OMPC), optionally PSMA-positive cancer in a biochemical recurrence (BCR) setting, optionally PSMA-positive cancer in a high-risk BCR setting.

43. A method of treating a prostate specific membrane antigen (PSMA)-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and a therapeutically effective amount of a non-steroidal androgen receptor (AR)-degrading agent.

44. The method of claim 43, wherein the non-steroidal AR-degrading agent is selected from the group consisting of PROteolysis-TArgeting chimera (PROTAC) AR degraders, selective AR degraders (SARDs), hydrophobic tag-based degraders (HyTs), non-steroidal CYP11A1 inhibitors, dual-action AR inhibitors (DAARIs), N-terminal domain AR degraders, ligand-directed degraders, chaperone protein dissociating AR degraders, autophagy promoting AR degraders, and combinations thereof.

45. The method of claim 43 or 44, wherein the non-steroidal AR-degrading agent is a PROTAC AR degrader selected from the group consisting of luxdegalutamide (ARV-766), bavdegalutamide (ARV-110), gridegalutamide (BMS-986365), AC-0176, and HP518, ora combination thereof, optionally wherein the PROTAC AR degrader is luxdegalutamide.

46. The method of claim 43 or 44, wherein the non-steroidal AR-degrading agent is a nonsteroidal CYP11A1 inhibitor, optionally wherein the non-steroidal CYP11A1 inhibitor comprise opevesostat.

47. The method of claim 43 or 44, wherein the non-steroidal AR-degrading agent is a DAARI, optionally wherein the DAARI is (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluoropyrazol-1-yl)-2-hydroxy-2-methylpropanamide, or a pharmaceutically acceptable salt thereof.

48. The method of claim 43 or 44, wherein the non-steroidal AR-degrading agent is a ligand directed degrader, optionally wherein the ligand directed degrader is 2-[(2R)-4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl]-2-ethylphenoxy]ethyl]-2-methylpiperazin-1-yl]-N-[3-[(2,6-dioxopiperidin-3-yl)amino]phenyl]acetamide, or a pharmaceutically acceptable salt thereof.

49. The method of claim 43 or 44, wherein the non-steroidal AR-degrading agent is an N-terminal domain AR degrader, optionally wherein the N-terminal domain AR degrader is Masofaniten or EPI-8207.

50. The method of claim 43 or 44, wherein the non-steroidal AR-degrading agent is a chaperone protein dissociating AR degrader, optionally wherein the chaperone protein dissociating AR degrader is Dimethylcurcumin, Niclosamide or a derivative thereof (ARVibs), or a pharmaceutical salt thereof, or a combination thereof.

51. The method of claim 43 or 44, wherein the non-steroidal AR-degrading agent is an autophagy promoting AR degrader, optionally wherein the autophagy promoting AR degrader is Riluzole, or a pharmaceutical salt thereof.

52. The method of claim 43 or 44, wherein the non-steroidal AR-degrading agent is a hydrophobic tag-based degrader (HyT), optionally wherein the HyT is N-(2-(2-(2-(2-((Adamantan-1-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)butanamide, ora pharmaceutically acceptable salt thereof.

53. The method of any one of claims 43 to 52, wherein the therapeutically effective amount of the [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), the non-steroidal AR-degrading agent, or both in the combination is lower than the amount required for a monotherapy response for [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and / or the non-steroidal AR-degrading agent.

54. The method of claim 53, wherein the monotherapy response is an objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (OR), partial response (PR), PSA response rate, radiographic response rate, AR-protein level, tumor growth rate, PSA expression level, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.

55. The method of any one of claims 43 to 54, wherein the combination of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and the non-steroidal AR-degrading agentachieves an improved anti-cancer response in the subject being treated for the PSMA-expressing cancerthan the anti-cancer response achieved by [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) monotherapy and / or AR-degrading agent monotherapy.

56. The method of any one of claims 43 to 55, wherein the combination of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) and the non-steroidal AR-degrading agent provides a synergistic effect in the treatment of the PSMA-expressing cancer.

57. The method of any one of claims 43 to 56, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) is a dose of from about 3 GBq to about 10 GBq.

58. The method of any one of claims 43 to 57, 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 a biochemical recurrence (BCR) setting, optionally PSMA-positive cancer in a high-risk BCR setting.

59. A method of treating a prostate specific membrane antigen (PSMA)-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a therapeutically effective amount of luxdegalutamide and a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan);wherein the therapeutically effective amount of luxdegalutamide is administered at least 24 hours prior to administration of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan);wherein the therapeutically effective amount of luxdegalutamide is about 20 mg / kg to about 30 mg / kg body weight of the subject daily or about 100 mg / day to 300 mg / day;wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) is a dose of from about 3 GBq to about 10 GBq;whereby an anti-cancer response in the subject is improved as compared to a monotherapy response with [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) or luxdegalutamide.

60. The method of claim 59, wherein the therapeutically effective amount of luxdegalutamide is administered about 3, 4, or 5 days before administering the therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan).

61. The method of claim 59 or 60, wherein the therapeutically effective amount of luxdegalutamide is administered for at least one week after the [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) is administered.

62. The method of any one of claims 59 to 61 , wherein the improvement in the at least one anti-cancer response is greater than additive.

63. A combination comprising a non-steroidal Androgen Receptor (AR)-degrading agent and a Prostate Specific Membrane Antigen (PSMA)-targeting radioligand for use in treating a PSMA-expressing cancer.

64. The combination of claim 63, wherein the non-steroidal AR-degrading agent is selected from the group consisting of PROteolysis-TArgeting chimera (PROTAC) AR degraders, selective AR degraders (SARDs), hydrophobic tag-based degraders (HyTs), non-steroidal CYP11A1 inhibitors, dual-action AR inhibitors (DAARIs), N-terminal domain AR degraders, ligand-directed degraders, chaperone protein dissociating AR degraders, autophagy promoting AR degraders, and combinations thereof.

65. The combination of claim 63 or 64, wherein the PSMA-targeting radioligand comprises a radiohybrid (rh) ligand, a radiolabeled anti-PSMA antibody, Ludotadipep, Evans blue-modified PSMA 617 (EB-PSMA-617), or177Lu-DGUL, or is a compound of formula (I), (II), (III), (IV), or (V), as defined in claim 12.

66. The combination of claim 65, wherein the PSMA-targeting radioligand is radiolabeled with an alpha-particle emitting radionuclide or a beta-minus-particle emitting radionuclide, optionally an alpha-particle emitting radionuclide selected from the group consisting of225Ac,211At,213Bi,212Bi,212Pb,223Ra,224Ra,149Tb, and227Th, or a beta-minus-particle emitting radionuclide selected from the group consisting of177Lu,169Er,161Tb,1311,90Y,67Cu, and47Sc.

67. The combination of any one of claims 63 to 66, wherein the PSMA-targeting radioligand is [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) or [177Lu]Lu-PSMA l&T (INN: lutetium (177Lu) zadavotide guraxetan).

68. The combination of claim 67, achieving an enhanced anti-cancer response in a subject as compared with a [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) or[177Lu]Lu-PSMA l&T (INN: lutetium (177Lu) zadavotide guraxetan) monotherapy or non-steroidal AR-degrading agent monotherapy.

69. The combination of claim 68, wherein the anti-cancer response of the combination is at least about 10% to about 50% greater than the anti-cancer response achieved by the [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) or [177Lu]Lu-PSMA l&T (INN: lutetium (177Lu) zadavotide guraxetan) monotherapy or the non-steroidal AR-degrading agent monotherapy.

70. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of luxdegalutamide and administering a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan).

71. The method of claim 70, wherein the cancer comprises a prostate cancer.

72. The method of claim 70 or 71, wherein the cancer comprises a prostate specific membrane antigen (PSMA)-positive cancer and / or a PSMA-expressing cancer.

73. The method of any one of claims 70-72, wherein the cancer comprises a PSMA+ / PSMA-expressing prostate cancer.

74. The method of any one of claims 70-73, wherein the cancer is metastatic castration resistant prostate cancer (mCRPC).

75. The method of any one of claims 70-74, wherein the cancer is a PSMA-positive or PSMA-expressing mCRPC that has been confirmed by radiographical imaging.

76. The method of claim 75, wherein the radiographical imaging comprises CT / MRI and / or bone scan.

77. The method of any one of claims 70-76, wherein the therapeutically effective amount of luxdegalutamide comprises:(a) a dose of at least about 100 mg;(b) a dose of from about 100 mg to about 300 mg;(c) a dose of from about 200 mg to about 300 mg; or(d) a dose of about 300 mg.

78. The method of any one of claims 70-77, wherein the therapeutically effective amount of luxdegalutamide is administered daily.

79. The method of any one of claims 70-78, wherein the therapeutically effective amount of luxdegalutamide is administered once daily.

80. The method of any one of claims 70-79, wherein the therapeutically effective amount of luxdegalutamide is administered orally.

81. The method of any one of claims 70-80, wherein the therapeutically effective amount of luxdegalutamide is administered with food.

82. The method of any one of claims 70-81 , wherein the therapeutically effective amount of luxdegalutamide is administered with food of 400 or more calories comprising a mixture of fat, carbohydrates and protein.

83. The method of any one of claims 70-82, wherein the therapeutically effective amount of luxdegalutamide is administered with a daily meal, optionally the daily meal is the largest meal of the day.

84. The method of any one of claims 70-83, wherein the therapeutically effective amount of luxdegalutamide is administered with the subject’s dinner.

85. The method of any one of claims 70-84, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 comprises:(a) a dose of from about 3 GBq to about 10 GBq;(b) a dose of from about 5.9 GBq to about 7.4 GBq;(c) a dose of about 7.4 GBq; or(d) a dose of about 5.9 GBq.

86. The method of claim 85, wherein said dose is administered intravenously.

87. The method of any one of claims 70-86, wherein the therapeutically effective amount of luxdegalutamide is a dose of at least about 100 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 3 GBq to about 10 GBq.

88. The method of any one of claims 70-87, wherein the therapeutically effective amount of luxdegalutamide is a dose of at least about 100 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 5.9 GBq to about 7.4 GBq.

89. The method of any one of claims 70-88, wherein the therapeutically effective amount of luxdegalutamide is a dose of at least about 100 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 7.4 GBq.

90. The method of claim 87, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 3 GBq to about 10 GBq.

91. The method of claim 90, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 5.9 GBq to about 7.4 GBq.

92. The method of claim 90 or 91 , wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 7.4 GBq.

93. The method of claim 90 or 91 , wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 5.9 GBq.

94. The method of claim 87, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 200 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 3 GBq to about 10 GBq.

95. The method of claim 94, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 200 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 5.9 GBq to about 7.4 GBq.

96. The method of claim 94 or 95, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 200 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 7.4 GBq.

97. The method of claim 94 or 95, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 200 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 5.9 GBq.

98. The method of claim 87, wherein the therapeutically effective amount of luxdegalutamide is a dose of about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 3 GBq to about 10 GBq.

99. The method of claim 98, wherein the therapeutically effective amount of luxdegalutamide is a dose of about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 5.9 GBq to about 7.4 GBq.

100. The method of claim 98 or 99, wherein the therapeutically effective amount of luxdegalutamide is a dose of about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 7.4 GBq.

101. The method of claim 98 or 99, wherein the therapeutically effective amount of luxdegalutamide is a dose of about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 5.9 GBq.

102. The method of any one of claims 70 to 101, wherein administering to the subject a therapeutically effective amount of luxdegalutamide and administering a therapeutically effective amount of [177Lu]Lu-PSMA-617 comprises administering a first dose of luxdegalutamide less than or equal to about 17 days prior to administering a first dose of [177Lu]Lu-PSMA-617.

103. The method of claim 102, wherein the first dose of [177Lu]Lu-PSMA-617 is administered within about two weeks before the first dose of luxdegalutamide.

104. The method of claim 102 or 103, wherein the first dose of [177Lu]Lu-PSMA-617 is administered less than or equal to about 14 days after the first dose of luxdegalutamide.

105. The method of any one of claims 102-104, wherein the first dose of luxdegalutamide is formulated an oral tablet and the first dose of [177Lu]Lu-PSMA-617 is formulated as an intravenous solution.

106. The method of any one of claims 70 to 105, further comprising an on-treatment period comprising at least one dose of [177Lu]Lu-PSMA-617 and at least about 14 consecutive days of luxdegalutamide.

107. The method of claim 106, wherein the on-treatment period begins by administering an initial dose of the therapeutically effective amount of luxdegalutamide at time To and administering an initial dose of the therapeutically effective amount of [177Lu]Lu-PSMA-617 at time Tn, wherein Tn- To is an integer within a range of about 10 to about 17 days.

108. The method of claim 107, wherein Tn- To s to about 1.5 weeks and less than or equal to about two weeks, or Tn-To within a range of about 12 days to about 14 days.

109. The method of claim 107 or 108, wherein the initial dose of the therapeutically effective amount of luxdegalutamide is administered orally and the initial dose of the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered intravenously.

110. The method of any one of claims 70-109, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered as a course of treatment comprising at least one cycle.

111. The method of claim 110, wherein one cycle has a duration of about 4 weeks to about 8 weeks.

112. The method of claim 110 or 111 , wherein one cycle has a duration of about 5 weeks duration to about 7 weeks duration.

113. The method of any one of claims 110-112, wherein one cycle has a duration of about 6 weeks.

114. The method of any one of claims 110-113, wherein the course of treatment comprises at least two cycles.

115. The method of claim 114, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 2 to 10 cycles or for 4 to 8 cycles.

116. The method of claim 114 or 115, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 6 cycles.

117. The method of claim 114, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for at least two cycles and each cycle is about 4 weeks to about 8 weeks.

118. The method of claim 117, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for at least two cycles and each cycle is about 5 weeks to about 7 weeks.

119. The method of claim 117, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for at least two cycles and each cycle is about 6 weeks.

120. The method of claim 117, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 2 to 10 cycles and each cycle is about 4 weeks to about 8 weeks.

121. The method of claim 120, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 2 to 10 cycles and each cycle is about 5 weeks to about 7 weeks.

122. The method of claim 120, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 2 to 10 cycles and each cycle is about 6 weeks.

123. The method of claim 120, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 4 to 8 cycles and each cycle is about 4 weeks to about 8 weeks.

124. The method of claim 123, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 4 to 8 cycles and each cycle is about 5 weeks to about 7 weeks.

125. The method of claim 123, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 4 to 8 cycles and each cycle is about 6 weeks.

126. The method of claim 123, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 6 cycles and each cycle is about 4 weeks to about 8 weeks.

127. The method of claim 123, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 6 cycles and each cycle is about 5 weeks to about 7 weeks.

128. The method of claim 123, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 6 cycles and each cycle is about 6 weeks.

129. The method of any one of claims 70-128, wherein the subject has had prior exposure to at least one Androgen Receptor Pathway Inhibitor (ARPI).

130. The method of claim 129, wherein the subject was exposed to the least one ARPI in a metastatic or advanced setting.

131. The method of claim 129 or 130, wherein the least one ARPI is selected from the group consisting of enzalutamide, abiraterone, apalutamide, darolutamide, cimetidine, orteronel, galeterone, seviteronel, topilutamide, bicalutamide, fluamide, nilutamide, Hsp90 inhibitors, and combinations thereof.

132. The method of any one of claims 129-131, wherein the subject has had prior exposure to at least one ARPI selected from the group consisting of abiraterone, enzalutamide, darolutamide, and apalutamide, or a combination thereof.

133. The method of claim 132, wherein the subject has had prior exposure to two or more of abiraterone, enzalutamide, darolutamide, and apalutamide.

134. The method of any one of claims 129-133, wherein the prior ARPI exposure does not include exposure to bicalutamide, flutamide, nilutamide, and any combination thereof.

135. The method of any one of claims 70-134, wherein the subject:(a) has no prior exposure to a taxane regimen;(b) has had prior exposure to no more than two taxane regimens;(c) has had prior exposure to one or two taxane regimens in a previous treatment in a Hormone Sensitive Prostate Cancer (HSPC) or a castration resistant prostate cancer (CRPC) setting;(d) has not received prior chemotherapy; and / or(e) has not received prior chemotherapy other than a taxane regimen.

136. The method of any one of claims 70-135, wherein the subject has not been treated with one or more of platinum, estramustine, vincristine, methotrexate, and cyclophosphamide, or has not been treated with any of platinum, estramustine, vincristine, methotrexate, and cyclophosphamide.

137. The method of any one of claims 70-136, wherein the subject has previously been treated with an immunotherapy agent.

138. The method of claim 137, wherein the immunotherapy agent comprises sipuleucel-T.

139. The method of any one of claims 70-138, wherein the subject has not been exposed to a radioligand therapy (RLT) prior to receiving a first dose of [177Lu]Lu-PSMA-617.

140. The method of any one of claims 70-139, wherein the subject has been treated with a poly (ADP-ribose) polymerase (PARP) inhibitor, an immune checkpoint inhibitor, or a combination thereof.

141. The method of any one of claims 70-140, wherein the subject has had prior exposure to radiation therapy.

142. The method of any one of claims 70-141, wherein the subject is not exhibiting or experiencing a sign or symptom of toxicity from a prior treatment, or toxicity from a prior therapy of less than or equal to grade 1, and / or the subject is not exhibiting alopecia less than or equal to grade 2 toxicity from a prior therapy, and / or is not experiencing peripheral neuropathy less than or equal to grade 2 toxicity from a prior therapy.

143. The method of any one of claims 70-142, wherein the subject:(a) has a castrate level of serum / plasma testosterone;(b) has a serum / plasma testosterone level less than <50 ng / dL or <1.7 nmol / L;(c) is receiving concurrent Androgen Deprivation Therapy (ADT); and / or(d) is receiving concurrent ADT selected from the group consisting of gonadotropin releasing hormone analogues / antagonists, and / or(e) has undergone an orchiectomy.

144. The method of claim 143, wherein the subject is receiving concurrent ADT selected from the group of gonadotropin releasing hormone analogues / antagonists consisting of abarelix, degarelix, and relugolix.

145. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of luxdegalutamide and administering a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), wherein:the cancer is metastatic castration resistant prostate cancer (mCRPC);the subject has had prior exposure to at least one ARPI;the subject has had prior exposure to no more than two taxane regimes; and the therapeutically effective amount of luxdegalutamide comprises a dose of at least about 100 mg.

146. The method of claim 145, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg, a dose of from about 200 mg to about 300 mg, a dose of about 300 mg, a dose of about 200 mg, or a dose of about 100 mg.

147. The method of claim 145 or 146, wherein the therapeutically effective amount of luxdegalutamide is administered daily.

148. The method of any one of claims 145-147, wherein the therapeutically effective amount of luxdegalutamide is administered once daily.

149. The method of any one of claims 145-148, wherein the therapeutically effective amount of luxdegalutamide is administered orally.

150. The method of any one of claims 145-149, wherein the therapeutically effective amount of luxdegalutamide is administered with food.

151. The method of any one of claims 145-150, wherein the therapeutically effective amount of luxdegalutamide is administered with food of 400 or more calories comprising a mixture of fat, carbohydrates and protein.

152. The method of any one of claims 145-151, wherein the therapeutically effective amount of luxdegalutamide is administered with a daily meal, optionally the daily meal is the largest meal of the day.

153. The method of any one of claims 145-152, wherein the therapeutically effective amount of luxdegalutamide is administered with the subject’s dinner.

154. The method of any one of claims 145-153, wherein the therapeutically effective amount of luxdegalutamide is administered for at least about 2 weeks.

155. The method of any one of claims 145-154, wherein the therapeutically effective amount of luxdegalutamide is administered continuously for at least about 4 weeks, at least about 6 weeks, at least about 12 weeks, at least about 18 weeks, at least about 24 weeks, at least about 30 weak, or at least about 36 weeks.

156. The method of claim 155, wherein the therapeutically effective amount of luxdegalutamide is administered continuously for about 4 weeks to about 38 weeks.

157. The method of any one of claims 145-156, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 comprises:(a) a dose of from about 3 GBq to about 10 GBq;(b) a dose of from about 5.9 GBq to about 7.4 GBq;(c) a dose of about 7.4 GBq; or(d) a dose of about 5.9 GBq.

158. The method of claim 157, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 3 GBq to about 10 GBq.

159. The method of claim 158, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 5.9 GBq to about 7.4 GBq.

160. The method of claim 159, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 7.4 GBq.

161. The method of claim 159, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 5.9 GBq.

162. The method of claim 159, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 3 GBq to about 10 GBq.

163. The method of claim 162 wherein the therapeutically effective amount of luxdegalutamide is a dose of about 100 mg or about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 5.9 GBq to about 7.4 GBq.

164. The method of claim 162, wherein the therapeutically effective amount of luxdegalutamide is a dose of about 100 mg or about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 7.4 GBq.

165. The method of claim 162, wherein the therapeutically effective amount of luxdegalutamide is a dose of about 100 mg or about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 5.9 GBq.

166. The method of any one of claims 145-165, wherein a first dose of [177Lu]Lu-PSMA-617 is administered about two weeks after a first dose of luxdegalutamide.

167. The method of any one of claims 145-166, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered as a course of treatment comprising at least one cycle, wherein the cycle is about 4 weeks to about 8 weeks, about 5 weeks to about 7 weeks, or about 6 weeks.

168. The method of claim 167, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 2 to 10 cycles or for 4 to 8 cycles.

169. The method of claim 167, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle for 6 cycles.

170. The method of any one of claims 145-169, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered as a course of treatment comprising at least two cycles and each cycle is about 4 weeks to about 8 weeks, about 5 weeks to about 7 weeks, or about 6 weeks.

171. The method of any one of claims 145-170, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered as a course of treatment comprising 2 to 10 cycles and each cycle is about 4 weeks to about 8 weeks, about 5 weeks to about 7 weeks, or about 6 weeks.

172. The method of any one of claims 145-171, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered as a course of treatment comprising 4 to 8 cycles and each cycle is about 4 weeks to about 8 weeks, about 5 weeks to about 7 weeks, or about 6 weeks.

173. The method of any one of claims 145-172, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered as a course of treatment comprising 6 cycles and each cycle is about 4 weeks to about 8 weeks, about 5 weeks to about 7 weeks, or about 6 weeks.

174. The method of any one of claims 145-173, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 7.4 GBq administered as a course of treatment comprising about 6 cycles, the dose is administered once per cycle, each cycle is about 6 weeks, and the first dose is administered within about 17 days after a first dose of luxdegalutamide.

175. The method of claim 174, wherein the dose of luxdegalutamide is administered daily for about 36 weeks to about 40 weeks.

176. The method of any one of claims 145-175, wherein the subject has not received prior chemotherapy other than one or two taxane regimens.

177. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of luxdegalutamide and administering a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), wherein:the cancer is metastatic castration resistant prostate cancer (mCRPC);the subject has had prior exposure to at least one ARPI;the subject has no prior exposure to a taxane regime or chemotherapy; andthe therapeutically effective amount of luxdegalutamide comprises a dose of at least about 100 mg.

178. The method of claim 177, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg, a dose of from about 200 mg to about 300 mg, a dose of about 300 mg, a dose of about 200 mg, or a dose of about 100 mg.

179. The method of claim 177 or 178, wherein the therapeutically effective amount of luxdegalutamide is administered daily, orally, and / or with food.

180. The method of any one of claims 177-179, wherein the therapeutically effective amount of luxdegalutamide is administered with food of 400 or more calories comprising a mixture of fat, carbohydrates and protein.

181. The method of any one of claims 177-180, wherein the therapeutically effective amount of luxdegalutamide is administered with a daily meal, optionally the daily meal is the largest meal of the day.

182. The method of any one of claims 177-181, wherein the therapeutically effective amount of luxdegalutamide is administered with the subject’s dinner.

183. The method of any one of claims 177-182, wherein the therapeutically effective amount of luxdegalutamide is administered daily for at least about 4 weeks.

184. The method of claim 183, wherein the therapeutically effective amount of luxdegalutamide is administered daily for about 4 weeks to about 48 weeks.

185. The method of any one of claims 177-184, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 comprises:(a) a dose of from about 3 GBq to about 10 GBq;(b) a dose of from about 5.9 GBq to about 7.4 GBq;(c) a dose of about 7.4 GBq; or(d) a dose of about 5.9 GBq.

186. The method of claim 185, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 3 GBq to about 10 GBq.

187. The method of claim 185, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 5.9 GBq to about 7.4 GBq.

188. The method of claim 185, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 7.4 GBq.

189. The method of claim 185, wherein the therapeutically effective amount of luxdegalutamide is a dose of from about 100 mg to about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 5.9 GBq.

190. The method of claim 185, wherein the therapeutically effective amount of luxdegalutamide is a dose of about 100 mg or about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of from about 5.9 GBq to about 7.4 GBq.

191. The method of claim 185, wherein the therapeutically effective amount of luxdegalutamide is a dose of about 100 mg or about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 7.4 GBq.

192. The method of claim 185, wherein the therapeutically effective amount of luxdegalutamide is a dose of about 100 mg or about 300 mg and the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 5.9 GBq.

193. The method of any one of claims 177-192, wherein a first dose of [177Lu]Lu-PSMA-617 is administered within about two weeks after a first dose of luxdegalutamide is administered.

194. The method of any one of claims 177-193, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered as a course of treatment comprising at least one cycle, wherein one cycle is about 4 weeks to about 8 weeks, about 5 weeks to about 7 weeks, or about 6 weeks and a first cycle starts within about two weeks after a first dose of luxdegalutamide is administered.

195. The method of claim 194, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is administered once per cycle and the course of treatment comprises 6 cycles.

196. The method of claim 195, wherein each cycle is about 6 weeks.

197. The method of claim 196, wherein the therapeutically effective amount of [177Lu]Lu-PSMA-617 is a dose of about 7.4 GBq and the first dose is administered within 17 days after the first dose of luxdegalutamide.

198. The method of claim 197, wherein luxdegalutamide is administered daily for about 38 weeks.

199. The method of any one of claims 177-198, wherein the at least one ARPI is selected from the group consisting of abiraterone, enzalutamide, darolutamide, and apalutamide, or a combination thereof.

200. A combination comprising luxdegalutamide and [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan) for use in treating a cancer.

201. The combination of claim 200, for use in treating mCRPC in a subject having prior exposure to at least one Androgen Receptor Pathway Inhibitor (ARPI).

202. The combination of claim 201 , wherein the subject has had prior exposure to at least one ARPI selected from the group consisting of abiraterone, enzalutamide, darolutamide, and apalutamide, or a combination thereof.

203. The combination of claim 201 or 202, wherein the subject has had prior exposure to two or more of abiraterone, enzalutamide, darolutamide, and apalutamide.

204. The combination of any one of claims 200-203, wherein the subject:(a) has no prior exposure to a taxane regimen;(b) has had prior exposure to no more than two taxane regimens;(c) has had prior exposure to one or two taxane regimens in a previous treatment in a Hormone Sensitive Prostate Cancer (HSPC) or a castration resistant prostate cancer (CRPC) setting;(d) has not received prior chemotherapy; and / or(e) has not received prior chemotherapy other than a taxane regimen.

205. The combination of any one of claims 200-204, wherein the subject:(a) has a castrate level of serum / plasma testosterone;(b) has a serum / plasma testosterone level less than <50 ng / dL or <1.7 nmol / L;(c) is receiving concurrent Androgen Deprivation Therapy (ADT); and / or (d) is receiving concurrent ADT selected from the group consisting of gonadotropin releasing hormone analogues / antagonists, and / or(e) has undergone an orchiectomy.

206. The combination of claim 205, wherein the subject is receiving concurrent ADT selected from the group of gonadotropin releasing hormone analogues / antagonists consisting of abarelix, degarelix, and relugolix.

207. The combination of any one of claims 200-206, wherein the cancer is mCRPC that has been confirmed by radiographical imaging, optionally by CT / MRI or bone scan.

208. The combination of any one of claims 200-207, wherein the combination provides an improvement in efficacy for treating mCRPC as compared to the efficacy of a [177Lu]Lu-PSMA-617 monotherapy or a luxdegalutamide monotherapy.

209. The combination of any one of claims 200-207, wherein luxdegalutamide improves the anti-cancer response of a subject to [177Lu]Lu-PSMA-617 in the combination as compared with the anti-cancer response to a [177Lu]Lu-PSMA-617 monotherapy.

210. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of luxdegalutamide and administering a therapeutically effective amount of [177Lu]Lu-PSMA-617 (INN: lutetium (177Lu) vipivotide tetraxetan), wherein:the cancer is metastatic castration resistant prostate cancer (mCRPC);the subject has had prior exposure to at least one ARPI;the subject has: (i) no prior exposure to a taxane regime or chemotherapy, or (ii) prior exposure to no more than two taxane regimens;the therapeutically effective amount of luxdegalutamide comprises a dose of about 100 mg or about 300 mg; andthe therapeutically effective amount of [177Lu]Lu-PSMA-617 comprises a dose of about 7.4 GBq administered once per a six-week cycle, for about six cycles.

211. A method of improving effectiveness of a cancer treatment in a subject in need thereof, the method comprising providing a combination therapy to the subject;wherein the combination therapy comprises administering at least one cycle of a PSMA-targeting radioligand therapy (RLT) and administering a daily dose of an AR-degrading agent;whereby the combination therapy improves at least one efficacy endpoint for the subject as compared with a corresponding efficacy endpoint achieved in subjects receiving the PSMA-targeting RLT as a monotherapy.

212. The method of claim 211, wherein the at least one efficacy endpoint is selected from the group consisting of Radiographic progression-free survival (rPFS), Overall survival (OS), Complete response (OR), Partial response (PR), Stable response (SD), Best Overall response (BOR), Duration of radiographic response (DOR), Time to response (TTR), Time to soft tissue progression (TTSTP), PSA value less than 0.2 ng / ml at any time point, % decrease in a PSA value from a baseline, Duration of biochemical response (DBR), Time to first symptomatic skeletal event (TTSSE), and combinations thereof.

213. The method of claim 211 or 211, wherein the efficacy endpoint is improved by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, or at least 250% as compared with an average value for the corresponding efficacy endpoint achieved in subjects receiving the PSMA-targeting RLT as a monotherapy.

214. A method of prolonging rPFS, OS, and / or TTSTP of a subject with cancer, the method comprising providing a combination therapy to the subject;wherein the combination therapy comprises administering at least one cycle of a PSMA-targeting radioligand therapy (RLT) and administering a daily dose of an AR-degrading agent;whereby the combination therapy prolongs the subject’s rPFS, OS, and / or TTSTP as compared with an average rPFS, OS, and / or TTSTP for subjects receiving the PSMA-targeting RLT as a monotherapy.

215. The method of claim 214, wherein the subject’s rPFS, OS, and / or TTSTP is prolonged by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, or at least 250%, as compared with the average rPFS, OS, and / or TTSTP for subjects receiving the PSMA-targeting RLT monotherapy.

216. A method of reducing a TTR of a cancer therapy comprising providing a combination therapy to a subject in need thereof;wherein the combination therapy comprises administering at least one cycle of a PSMA-targeting radioligand therapy (RLT) and administering a daily dose of an AR-degrading agent;whereby the combination therapy reduces the TTR as compared with an average TTR in subjects receiving the PSMA-targeting RLT as monotherapy.

217. The method of claim 216, wherein the TTR is reduced by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, or at least 250%, in the subject as compared with the average TTR in subjects receiving the PSMA-targeting RLT as monotherapy.

218. A method of improving a rate of PSA50, ORR, DCR, PSA90, PSA30 and / or PSA0 of a cancer therapy, the method comprising administering at least one cycle of a PSMA-targeting radioligand therapy (RLT) to a population of subjects receiving a daily dose of an AR-degrading agent;whereby the proportion of subjects who achieve at least one of:(a) a decrease of > about 30% in PSA from baseline at any timepoint;(b) a PSA value <0.2 ng / ml at any timepoint after start of treatment;(c) a confirmed complete response (CR) or a partial response (PR); and(d) a CR, a PR, or stable disease (SD),is increased as compared with a corresponding population of subjects who have not received the AR-degrading agent.

219. The method of claim 218, wherein the rate is increased by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, at least 200%, or at least 250% in the population as compared to the rate of the PSMA-targeting radioligand used as a monotherapy.

220. The method of any one of claims 211-219, wherein a first dose of the AR-degrading agent is administered about two weeks before a first cycle of the PSMA-targeting RLT.

221. The method of any one of claims 211-220, wherein the daily dose of the AR-degrading agent is administered continuously during the at least one cycle.

222. The method of any one of claims 211-221 , wherein one cycle is about 6 weeks, and the PSMA-targeting RLT comprises 6 cycles.

223. The method of any one of claims 211-222, wherein the daily dose of the AR-degrading agent comprises at least about 100 mg of luxdegalutamide and the PSMA-targeting RLT comprises administering a dose of about 7.4 GBq of [177Lu]Lu-PSMA-617 per cycle.

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