Radiopharmaceuticals for use in the treatment of high-risk localized prostate cancer

Abstract

The disclosure relates to kits of parts and compositions comprising a PSMA-targeted radiopharmaceutical, e.g., PSMA I&T, for the treatment of a cancer, preferably a prostate cancer.

Description

[0001] Attorney Ref: P6973PC00 1

[0002] RADIOPHARMACEUTICALS FOR USE IN THE TREATMENT OF HIGH- RISK LOCALIZED PROSTATE CANCER

[0003] FIELD OF THE INVENTION

[0004] The invention relates to compounds for use in a method of treating a prostate cancer in a subject, wherein the compound is a radiopharmaceutical, preferably a PSMA-targeted radiopharmaceutical, and wherein the prostate cancer is preferably high-risk localized prostate cancer.

[0005] RELATED ART

[0006] Prostate cancer (PC) is an adenocarcinoma of the prostate and is the fourth most common cancer worldwide in men and the fifth most common cause of cancer death among men worldwide (James, N.D., et al., Lancet, 2024. 403(10437): 1683-1722). Early-stage PC is often asymptomatic. In contrast, metastasized PC is typically more aggressive, often associated with significant bone pain and clinically difficult to manage.

[0007] PC cells depend on the androgen signaling via the androgen receptor (AR), a hormone- activated transcription factor that controls expression of numerous genes including prostatespecific antigen (PSA). Most PC patients are initially diagnosed with localized disease and treatment is often limited to active surveillance until PSA levels in the blood increase as an indicator of increased tumor volume.

[0008] Risk stratification of prostate cancers can be determined based on histological, pathological, and / or cytological assessment. High-risk prostate cancer is defined by the American Urological Association (AU A) as a prostate cancer characterized by the presence of any of the following: (i) clinical stage T2c or higher; (ii) Gleason score from 8 to 10; and / or (iii) pre-treatment prostate-specific antigen (PSA) > 20 ng / mL (Thompson, I. et al., J. Urol., (2007), 177:2106-2131; see also D’Amico, A.V. etal, JAMA (1998) 280(11): 969-974). High- risk prostate cancers have the potential to progress to a lethal phenotype that can be fatal (Chang et al., Nat. Rev. Clin. Oncol., (2014) 11 (6): 308-323). Accordingly, there is a need for more effective treatments of high-risk prostate cancers such as high-risk localized prostate cancer beyond radical prostatectomy.

[0009] The CWR22 cell line (also known as “CWR22Pc”) was originally derived from a Gleason score 9 primary (i.e. localized) prostate cancer patient undergoing radical prostatectomy (RPE). CWR22R cells, such as the CWR22Rvl (also known as “22Rvl”) cell Attorney Ref: P6973PC00 2 line, are derived from CWR22 cells after relapse upon androgen deprivation-induced regression of the original CWR22 tumors, which typically occurs within about 7-9 months (Dagvadori et al., Clin. Cancer Res. 2008, 14(19): 6062-6072).

[0010] SUMMARY OF THE INVENTION

[0011] As set forth in the Detailed Description below, the present disclosure provides a compound for use in a method of treating a prostate cancer in a subject, wherein said compound is a radiopharmaceutical. Preferably, the radiopharmaceutical is a PSMA-targeted radiopharmaceutical, and the prostate cancer is high-risk localized prostate cancer.

[0012] Accordingly, in one aspect, the present disclosure provides a compound for use in a method of treating a prostate cancer in a subject, wherein said compound is a radiopharmaceutical .

[0013] In one aspect, the present disclosure provides a compound for use in a method of treating a prostate cancer in a subject, wherein said compound is a PSMA-targeted radiopharmaceutical .

[0014] In one aspect, the present disclosure provides a method of treating a prostate cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a radiopharmaceutical as described herein. Preferably, the radiopharmaceutical is a PSMA-targeted radiopharmaceutical and the prostate cancer is a high-risk localized prostate cancer.

[0015] In one aspect, the present disclosure provides a radiopharmaceutical for use in a method of treating a prostate cancer in a subject. Preferably, the radiopharmaceutical is a PSMA-targeted radiopharmaceutical and the prostate cancer is a high-risk localized prostate cancer.

[0016] In one aspect, the present disclosure provides the use of a radiopharmaceutical in the manufacture of a medicament for treating a prostate cancer in a subject. Preferably, the radiopharmaceutical is a PSMA-targeted radiopharmaceutical and the prostate cancer is a high-risk localized prostate cancer.

[0017] In some embodiments, said PSMA-targeted radiopharmaceutical comprises a DUPA targeting group.

[0018] In some embodiments, said PSMA-targeted radiopharmaceutical is selected from the group consisting of: PSMA I&T, PSMA-11, PSMA-617, PSMA-62, and PSMA-R2.

[0019] In some embodiments, said PSMA-targeted radiopharmaceutical is selected from Attorney Ref: P6973PC00 3

[0020] PSMA I&T and PSMA-617.

[0021] In some embodiments, said PSMA-targeted radiopharmaceutical is selected from

[0022] PSMA I&T.

[0023] In some embodiments, said PSMA-targeted radiopharmaceutical is selected from

[0024] PSMA-617.

[0025] In some embodiments, said PSMA-targeted radiopharmaceutical is chelated to a radionuclide.

[0026] In some embodiments, said PSMA-targeted radiopharmaceutical is chelated to a radionuclide selected from the group consisting of161Tb,177Lu,212Pb, and225Ac.

[0027] In some embodiments, said PSMA-targeted radiopharmaceutical is chelated to a radionuclide selected from the group consisting of161Tb and177Lu, preferably161Tb.

[0028] In some embodiments, said prostate cancer is high-risk localized prostate cancer.

[0029] In some embodiments, said prostate cancer is a very high-risk localized prostate cancer.

[0030] In some embodiments, said prostate cancer is high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA I&T, PSMA-11, PSMA-617, PSMA-62, and PSMA-R2, wherein said PSMA-targeted radiopharmaceutical is chelated to a radionuclide selected from the group consisting of161Tb,177LU,212Pb, and225Ac.

[0031] In some embodiments, said prostate cancer is high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA I&T and PSMA-617, wherein said PSMA-targeted radiopharmaceutical is chelated to a radionuclide selected from the group consisting of161Tb,177Lu,212Pb, and225Ac; preferably chelated to161Tb or177Lu.

[0032] In some embodiments, said prostate cancer is high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177LU, preferably161Tb.

[0033] In some embodiments, said prostate cancer is high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177LU, preferably177Lu.

[0034] In some embodiments, said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) but has not previously been subject to radical prostatectomy.

[0035] In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk Attorney Ref: P6973PC00 4 localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection.

[0036] In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb.

[0037] In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to177Lu.

[0038] In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to177Lu.

[0039] In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb.

[0040] BRIEF DESCRIPTION OF THE FIGURES

[0041] FIG 1 is a plot showing percent survival of 22Rvl cells treated with different concentrations of Compound 1* and Compound 2 for 7 days relative to untreated cells. IC50 values were determined by non-linear regression analysis. Graphs represent the mean of three replicates ± SEM. “PQR309” refers to Compound 1* as disclosed herein. Attorney Ref: P6973PC00 5

[0042] FIG 2A is a plot showing percent survival of 22Rvl cells treated with different concentrations of Compound 1* and Compound 2 in combination with different doses of177LU-PSMA-617 (0, 0.5,1, 2.5, 5, 10, or 20 MBq) for 7 days relative to cells treated with respective dose of177Lu-PSMA-617 only (i.e., not treated with Compound 1* or Compound 2).

[0043] FIG 2B is a synergy analysis of 22Rvl cells treated with different concentrations of Compound 1* in combination with different doses of177Lu-PSMA-617, as described in Example 1. “PQR309” refers to Compound 1* as disclosed herein.

[0044] FIG 2C is a synergy analysis of 22Rvl cells treated with different concentrations of Compound 2 in combination with different doses of177Lu-PSMA-617, as described Example 1.

[0045] FIG 3 A is a plot of body weight in g of female nude mice at start of treatment period (Study day -1) in the indicated treatment groups as described in Example 2. n=8 per group. “PQR309” refers to Compound 1* as disclosed herein.

[0046] FIG 3B is a plot of tumor volume in mm3at start of treatment period (Study day -1) in the indicated treatment groups as described in Example 2. n=8 per group. “PQR309” refers to Compound 1* as disclosed herein.

[0047] FIG 4A is a plot of tumor volume (mm3) over time in mice treated with vehicle; Compound 1*;161Tb-PSMA-I&T (21.8 MBq); or both Compound 1* and161Tb-PSMA-I&T (21.8 MBq). Treatment as indicated started at study day 0. Mice received a single injection of161Tb-PSMA-I&T and / or Compound 1* daily until reaching the endpoint (tumor volume 1500 mm3). Data presented as mean - / +SEM. n=8 per group. “PQR309” refers to Compound 1 * as disclosed herein.

[0048] FIG 4B is a plot of tumor volume (mm3) over time in mice treated with vehicle; Compound 1*;161Tb-PSMA-I&T (43.7 MBq); or both Compound 1* and161Tb-PSMA-I&T (43.7 MBq). Treatment as indicated started at study day 0. Mice received a single injection of161Tb-PSMA-I&T and / or Compound 1* daily until reaching the endpoint (tumor volume 1500 mm3). Data presented as mean - / +SEM. n=8 per group. “PQR309” refers to Compound 1 * as disclosed herein.

[0049] FIG 4C is a plot of tumor volume (mm3) over time in mice treated with vehicle; Compound 1*;177Lu-PSMA-617 (30 MBq); or both Compound 1* and177Lu-PSMA-617 (30 MBq). Treatment as indicated started at study day 0. Mice received a single injection of177Lu- PSMA-617 and / or Compound 1* daily until reaching the endpoint (tumor volume 1500 mm3). Data presented as mean - / +SEM. n=8 per group. “PQR309” refers to Compound 1* as Attorney Ref: P6973PC00 6 disclosed herein.

[0050] FIG 4D is a plot of tumor volume (mm3) over time in mice treated with vehicle; Compound 1*;177Lu-PSMA-617 (60 MBq); or both Compound 1* and177Lu-PSMA-617 (60 MBq). Treatment as indicated started at study day 0. Mice received a single injection of177Lu- PSMA-617 and / or Compound 1* daily until reaching the endpoint (tumor volume 1500 mm3). Data presented as mean - / +SEM. n=8 per group. “PQR309” refers to Compound 1* as disclosed herein.

[0051] FIG 5 is a series of plots of tumor volume (mm3) over time in mice treated with vehicle; Compound 1*;161Tb-PSMA-I&T (21.8 MBq);161Tb-PSMA-I&T (43.7 MBq);177Lu-PSMA- 617 (30 MBq);177Lu-PSMA-617 (60 MBq); or both Compound 1* and161Tb-PSMA-I&T (21.8 MBq) or161Tb-PSMA-I&T (43.7 MBq) or177Lu-PSMA-617 (30 MBq) or177Lu-PSMA- 617 (60 MBq). Treatment as indicated started at study day 0. Mice received a single injection of161Tb-PSMA-I&T (21.8 MBq) or161Tb-PSMA-I&T (43.7 MBq) or177Lu-PSMA-617 (30 MBq) or177Lu-PSMA-617 (60 MBq) and / or Compound 1* daily until reaching the endpoint (tumor volume 1500 mm3). Data presented as individual tumor volumes. n=8 per group. “PQR309” refers to Compound 1* as disclosed herein.

[0052] FIG 6 is a plot of days until endpoint (i.e., number of study days from treatment start until tumors reaching >1500 mm3) from all treatment groups as described in Example 2.

[0053] FIG 7 is a plot showing percent survival of 22Rvl cells treated with different doses of177LU-PSMA-I&T,161Tb-PSMA-I&T, or161Tb-PSMA-617 (0, 2.5, 5, 10, 20, or 40 MBq / mL) for 7 days relative to untreated cells. ** p<0.01.

[0054] FIG 8 is a plot showing percent survival of CWR22 cells treated with different doses of177LU-PSMA-I&T,161Tb-PSMA-I&T, or161Tb-PSMA-617 (0, 2.5, 5, 10, 20, or 40 MBq / mL) for 7 days relative to untreated cells. ** p<0.01.

[0055] DETAILED DESCRIPTION OF THE INVENTION

[0056] Definitions

[0057] As used herein, the term “high-risk localized prostate cancer (HRLPC)” is understood to refer to a localized prostate cancer defined as high-risk by the American Urological Association (AUA) (Thompson, I. et al., J. Urol., (2007), 177:2106-2131; see also D’Amico, A.V. et al, JAMA (1998) 280(11): 969-974; and Chang et al., Nat. Rev. Clin. Oncol., (2014) 11 (6): 308-323). Specifically, a “high-risk localized prostate cancer” as understood herein is a prostate cancer that is nonmetastatic, and that is characterized by the presence of any of the Attorney Ref: P6973PC00 7 following: (i) clinical stage T2c or higher; (ii) Gleason score from 8 to 10; or (iii) pre-treatment prostate-specific antigen (PSA) concentration of > 20 ng / mL. Without wishing to be bound by theory, HRLPC is associated with substantial risk of disease progression (i.e., recurrence) despite local treatment including RPE.

[0058] As used herein, the term “very high-risk localized prostate cancer” is understood to refer to a prostate cancer defined as very high-risk by the National Comprehensive Cancer Network (NCCN) guidelines. Specifically, a very high-risk localized prostate cancer is defined herein as a nonmetastatic prostate cancer characterized by a clinical stage T3b or higher, e.g., T3b or T4 (see Chang et al., Nat. Rev. Clin. Oncol., (2014) ll(6):308-323). Alternatively, in some embodiments, a very high-risk localized prostate cancer is defined as a nonmetastatic prostate cancer characterized exhibiting (i) a primary Gleason pattern 5 (preferably in the most common areas of the cancer in the biopsy); (ii) more than 4 biopsy cores with ISUP GG >4 (Gleason score 8 to 10); and / or (iii) 2 or 3 features found in the high-risk group (see, e.g., Prostate Cancer Early Detection, Diagnosis and Staging, American Cancer Society®, e.g., p. 47). In some embodiments, a very high-risk localized prostate cancer is defined as a nonmetastatic prostate cancer exhibiting at least two of the following characteristics: (i) stage T3 to T4 tumor; (ii) grade group 4 or 5; (iii) PSA greater than 40 ng / mL (see National Comprehensive Cancer Network (NCCN) Guidelines, Early-Stage Prostate Cancer, Version 2.2025, e.g., p. 59).

[0059] As used herein, the term “treatment-naive (very) high-risk localized prostate cancer” is understood to mean a high-risk or very high-risk localized prostate cancer that has not previously been treated with any drug or therapeutic agent (e.g., radioligand therapy or external radiotherapy), or therapeutic intervention (surgical or otherwise) with the intention of treating or slowing the progression of the (very) high-risk localized prostate cancer.

[0060] Accordingly, in some embodiments, said treatment-naive (very) high-risk localized prostate cancer is a (very) high-risk localized prostate cancer that has not been previously treated with a systemic treatment (e.g., a chemotherapy such as taxane; or androgen receptor inhibitors).

[0061] In some embodiments, said treatment-naive (very) high-risk localized prostate cancer is a (very) high-risk localized prostate cancer that has not been subject to surgery, e.g., radical prostatectomy (RPE). In some embodiments, said treatment-naive (very) high-risk localized prostate cancer is a (very) high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE). In some embodiments, said treatment-naive (very) high-risk localized Attorney Ref: P6973PC00 8 prostate cancer is a (very) high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with pelvic lymph node dissection. In some embodiments, said treatment-naive (very) high-risk localized prostate cancer is a (very) high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection.

[0062] As used herein, the term “radical prostatectomy”, abbreviated as “RPE”, is understood as defined in the National Comprehensive Cancer Network (NCCN) Guidelines, Early-Stage Prostate Cancer, Version 2.2025. Accordingly, a “prostatectomy” is understood to mean removing the prostate gland by surgery. A “radical prostatectomy” removes not only the entire prostate but also the surrounding tissue and seminal vesicles.

[0063] As used herein, the term “pelvic lymph node dissection”, abbreviated as “PLND”, is understood as defined in the National Comprehensive Cancer Network (NCCN) Guidelines, Early-Stage Prostate Cancer, Version 2.2025. Accordingly, in preferred embodiments, a pelvic lymph node dissection is an operation to remove lymph nodes in the pelvis and preferably near the prostate; preferably the PLND occurs as part of a radical prostatectomy. In preferred embodiments, a radical prostatectomy with PLND is administered in certain situations, preferably when (i) the tumor has not grown outside the prostate; (ii) the tumor can be removed completely with surgery; (iii) the patient has an estimated life expectancy of 10 or more years; and / or (iv) the patient has no other serious health conditions.

[0064] As used herein, the term “extended pelvic lymph node dissection” is understood as defined by Santucci et al., “Extended vs. Standard Pelvic Lymph Node Dissection in Bladder Cancer Patients Undergoing Radical Cystectomy: Systematic Review and Meta- Analysis”, Soc. Int. Urol. J. 2025, 6(3), 37. Thus, in preferred embodiments, an extended pelvic lymph node dissection is understood to include a pelvic lymph node dissection as defined herein, including at least the obturator and internal and external iliac nodes, plus extended dissection to at least the aortic bifurcation (common iliac, presacral, paracaval, and interaortocaval nodes; wherein the extended pelvic lymph node dissection could extend to include the para-aortal nodes up to the inferior mesenteric artery).

[0065] In some embodiments, said treatment-naive (very) high-risk localized prostate cancer is a (very) high-risk localized prostate cancer that has not been previously treated with a hormone therapy including androgen receptor inhibitors.

[0066] In some embodiments, a treatment-naive (very) high-risk localized prostate cancer is a (very) high-risk localized prostate cancer that has not been subject to androgen deprivation therapy (ADT). Attorney Ref: P6973PC00 9

[0067] In some embodiments, a treatment-naive (very) high-risk localized prostate cancer is a (very) high-risk localized prostate cancer that has not been subjected to radiation therapy.

[0068] As used herein, the term “localized” is understood to mean “nonmetastatic”.

[0069] As used herein, the term “nonmetastatic” is understood to have the definition given by the National Cancer Institute of the United States National Institutes of Health. Thus, “nonmetastatic” is understood to refer to a cancer that has not detectably spread from the primary site (place where it started) to other places in the body (see the NCI’s dictionary of cancer terms at https : / / www. cancer, gov / publications / dictionaries / cancer- terms / def / nonmetastatic). Accordingly, a “nonmetastatic” prostate cancer is understood to refer to a prostate cancer that has not detectably spread from the prostate to other places in the body.

[0070] Accordingly, in preferred embodiments, a nonmetastatic prostate cancer is a prostate cancer (e.g., a high-risk prostate cancer) that presents no detectable metastases, e.g., as assessed by conventional imaging, MRI and / or PET / CT scans (in particular PSMA-PET / CT scans), including whole body PET / CT scans. One of skill in the art will be capable of using techniques such as conventional imaging, MRI, PET, CT and the like to establish the presence or absence of prostate cancer metastases.

[0071] As used herein, the term “hormone-sensitive”, when used in the context of a hormonesensitive prostate cancer, is understood to have the definition given by the National Cancer Institute of the United States National Institutes of Health (see https: / / www.cancer.gov / publications / dictionaries / cancer-terms / def / hormone-sensitive- prostate-cancer). Thus, “hormone-sensitive” is understood to mean a prostate cancer that needs androgens (male hormones) to grow and therefore stops growing when androgens are not present. “Hormone-sensitive” cancers are also known as androgen-dependent prostate cancers, androgen-sensitive prostate cancers, castrate-sensitive prostate cancers, CSPC, and HSPC.

[0072] Accordingly, as used herein a “fully hormone-sensitive” prostate cancer is a prostate cancer that does not exhibit measurable growth (e.g., as evaluated by a clinician) in the absence of androgens.

[0073] As used herein, a “partially hormone-sensitive” prostate cancer is a prostate cancer that exhibits slowed (i.e., less) growth (e.g., as evaluated by a clinician) in the absence of androgens compared to the growth of the prostate cancer in the presence of androgens.

[0074] In some embodiments, the high-risk localized prostate cancer or the very high-risk localized prostate cancer is present in a patient who is eligible for RPE based on the National Attorney Ref: P6973PC00 10

[0075] Comprehensive Cancer Network (NCCN) Guidelines, Early-Stage Prostate Cancer, Version 2.2025; Prostate Cancer, but has not yet undergone RPE. In preferred embodiments, a patient who is eligible for RPE is a patient not on an active surveillance program with clinically localized prostate cancer that can be completely excised surgically, who has a life expectancy of at least 10 years, and who has no serious comorbid conditions that would contraindicate an elective operation. In some embodiments, the high-risk localized prostate cancer or the very high-risk localized prostate cancer is present in a patient who presents with (i.e., exhibits) pretreatment testosterone levels of greater than 50 ng / mL.

[0076] In preferred embodiments, the prostate cancer is newly diagnosed, histologically confirmed prostate adenocarcinoma with no neuroendocrine differentiation or small cell characteristics with localized disease and no detectable metastatic lesions, considered eligible for radical prostatectomy and fulfilling predefined high-risk criteria.

[0077] Each “alkyl” moiety either alone or as part of a larger group such as alkoxy is a straight or branched chain and is preferably Ci-Csalkyl. more preferably Ci-C2alkyl. Examples include in particular methyl, ethyl, w-propyl and prop-2-yl ( / .so-propyl). Examples of an alkoxy include in particular methoxy, ethoxy, w-propoxy and / .so-propoxy. As described herein, alkoxy may include further substituents such as halogen atoms leading to haloalkoxy moieties.

[0078] Each alkylene moiety is a straight or branched chain and is, particularly for example, - CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, or -CH(CH2CH3)-, preferably -CH2-, -CH2-CH2- or -CH(CH3)-.

[0079] As used herein, the term “chelator” is understood to refer to a polydentate chemical residue, preferably an organic polydentate residue, capable of forming two or more coordinate bonds with a metal ion, preferably wherein said metal ion is a radionuclide as described herein.

[0080] Where a group is said to be optionally substituted, preferably there are optionally 1-3 substituents, more preferably optionally 1-2 substituents.

[0081] As used herein, the terms “overexpression” or “overexpressed” refer to the abnormal or artificial expression of a gene or protein in increased quantity, e.g., as compared to wildtype cells. In some embodiments, the expression of the overexpressed gene or protein can be, e.g., 10% higher than the expression of the same gene or protein in a corresponding wild-type cell, as measured by standard techniques used in the art for quantification of gene expression. In some embodiments, the expression of the overexpressed gene or protein can be, e.g., 50% higher, 100% higher, ten times higher, 100 times higher, or 1,000 times higher or more than the expression of the same gene in a corresponding wild-type cell.

[0082] As used herein, the term “PSMA” is understood to mean prostate specific membrane Attorney Ref: P6973PC00 11 antigen. In preferred embodiments, PSMA is a type II membrane protein and is expressed in all forms of prostate tissue, including carcinoma. PSMA is described by Chang, Rev. Urol., 2004 6(Suppl. 10): S13-S18. In preferred embodiments, a (very) high-risk localized prostate cancer as described herein expresses PSMA. As used herein, the term “expresses PSMA” is understood to mean that the (very) high-risk localized prostate cancer expresses detectable amounts of PSMA as measured by one of skill in the art, preferably as measured by PSMA PET / CT (see, e.g., Fanti et al., European Journal of Nuclear Medicine and Molecular Imaging (2021) 48:469-476; Ceci & Fanti, Clinical and Translational Imaging (2019) 7:377-379; Boellard et al. Eur J Nucl Med Mol Imaging (2015) 42:328-354; Fendler c / al. Eur J Nucl Med Mol Imaging (2017) 44:1014-1024). In some embodiments, PSMA is overexpressed in prostate cancer tissue, e.g., high-risk localized prostate cancer tissue, preferably as measured by PSMA PET / CT.

[0083] The phrase “therapeutically effective amount” means an amount of one or more compounds of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer (preferably HRLPC), the therapeutically effective amount of the drug may be reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve to some extent one or more of the symptoms associated with the cancer. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0084] The terms “treatment” / “treating” as used herein include: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereol); and / or (3) relieving the condition (i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a Attorney Ref: P6973PC00 12 patient to treat a disease, the outcome may not always be effective treatment. In one embodiment, the terms “treatment’ ’ / “treating” as used herein, refer to a therapeutic treatment. In another embodiment, the terms “treatment’ ’ / “treating” as used herein, refer to a prophylactic treatment.

[0085] The term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep. The term "mammal", as used herein, preferably refers to humans.

[0086] The terms "individual," "subject" or "patient" are used herein interchangeably. In a preferred embodiment, the subject is a human. In some embodiments, the patient is eligible for RPE based on the National Comprehensive Cancer Network (NCCN) Guidelines, Early- Stage Prostate Cancer, Version 2.2025; Prostate Cancer, but has not yet undergone RPE. In preferred embodiments, a patient who is eligible for RPE is a patient not on an active surveillance program with clinically localized prostate cancer that can be completely excised surgically, who has a life expectancy of at least 10 years, and who has no serious co morbid conditions that would contraindicate an elective operation. In some embodiments, the patient presents with (i.e., exhibits) pre-treatment testosterone levels of greater than 50 ng / mL.

[0087] As used herein, the term "systemic administration" refers to administration of a compound according to the invention, e.g., a PSMA-targeted radiopharmaceutical, such that the compound becomes widely distributed in the body in significant amounts and has a biological effect, e.g. its desired effect, in the blood and / or reaches its desired site of action via the vascular system. Typical systemic routes of administration include administration by (1) introducing the compound directly into the vascular system (e.g., via intravenous administration) or (2) oral, pulmonary, or intramuscular administration wherein the compound is adsorbed, enters the vascular system, and is carried to one or more desired site(s) of action via the blood.

[0088] The terms "oral", "orally", and "oral administration", as used herein, refer to orally ingesting a compound of the present invention.

[0089] The term “parenteral” as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection, or infusion techniques.

[0090] As used herein, the term “androgen receptor inhibitor” is understood to refer to a substance that prevents androgens (male sex hormones) from binding to androgen receptors. Non-limiting examples of androgen receptor inhibitors include apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, and nilutamide. Androgen receptor inhibitors can also be referred to as “androgen receptor blockers”, “androgen receptor antagonists” or Attorney Ref: P6973PC00

[0091] “anti androgens”.

[0092] PSMA-Targeted Radiopharmaceuticals

[0093] As used herein, the term “PSMA-targeted radiopharmaceutical” is understood as a radiopharmaceutical, preferably a radiopharmaceutical that is targeted in vivo or in vitro to PSMA. A “radiopharmaceutical” is understood as a pharmaceutical drug containing a radioactive isotope (also known as a radionuclide as defined herein). In preferred embodiments, the PSMA-targeted radiopharmaceutical comprises a chelating group to chelate the radionuclide. In some embodiments, the chelating group comprises a DOTA chelator or a DOTA residue. In preferred embodiments, the PSMA-targeted radiopharmaceutical comprises a PSMA-targeting fragment. In some embodiments, said targeting fragment is a dipeptide urea based PSMA-targeting fragment, preferably DUPA.

[0094] In preferred embodiments, the PSMA-targeted radiopharmaceuticals of the present disclosure are administered to a subject internally, e.g., via intravenous (IV) administration. In some embodiments, the PSMA-targeted radiopharmaceutical is administered systemically. Accordingly, in preferred embodiments, radiation from a PSMA-targeted radiopharmaceutical as described herein is not administered externally, e.g., as a beam of energy (e.g., X-rays, proton radiation, gamma knife radiation and the like) to the subject.

[0095] As used herein, a “DUPA” is understood to mean a glutamate-urea moiety of formula 1 , preferably of formula 1 * : and enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof; wherein R is preferably substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and any combination thereof; more preferably R is Ci-6-alkyl, preferably C2-C4-alkyl, optionally substituted one or more times, preferably one time with OH, SH, NH2, or COOH, wherein one of said NH2, OH or SH or COOH group serve as the point of covalent attachment to the PSMA-targeted radiopharmaceutical. In preferred embodiments, R is -C4alkylene-NH- , wherein said -NH- forms an amide bond with the remainder of the PSMA-targeted radiopharmaceutical.

[0096] A “DOTA” chelator, also known as “tetraxetan”, as used herein is understood as a Attorney Ref: P6973PC00 14 complexing agent with the formula (C^CftNCftCChH or a residue thereof. In some preferred embodiments, the DOTA chelator, or residue thereof, has the structure below, wherein said DOTA chelator is connected to the remainder of the PSMA-targeted radiopharmaceutical at the position Xi or X2:

[0097] In some embodiments, the DOTA chelator is connected to the remainder of the PSMA- targeted radiopharmaceutical at position X2, and Xi is -OH. In such embodiments, the DOTA chelator is referred to as a “DOTAGA” chelator.

[0098] In some embodiments, the DOTA chelator is connected to the remainder of the PSMA- targeted radiopharmaceutical at position Xi, e.g., by an amide linkage wherein Xi is -NHR-, wherein “R” is the remainder of the PSMA-targeted radiopharmaceutical. In preferred embodiments, X2 is a Ci-Ce alkyl or -H, preferably X2 is -H.

[0099] In preferred embodiments, the PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA-I&T, PSMA-617, PSMA-11, PSMA-62, PSMA-R2, PSMA- ALB-56, EB-PSMA-617, CTT1403, PSMA-617, HTK01169, LI, L14, and SibuDAB. In preferred embodiments, the PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA-I&T, PSMA-617, and PSMA-11. In preferred embodiments, the PSMA- targeted radiopharmaceutical is selected from the group consisting of PSMA-I&T and PSMA- 617.

[0100] In preferred embodiments, the PSMA-targeted radiopharmaceutical is PSMA-I&T. In some embodiments, the PSMA-targeted radiopharmaceutical is PSMA-617. In some embodiments, the PSMA-targeted radiopharmaceutical is PSMA-11. In some embodiments, the PSMA-targeted radiopharmaceutical is PSMA-62. In some embodiments, the PSMA- targeted radiopharmaceutical is PSMA-R2. In some embodiments, the PSMA-targeted radiopharmaceutical is PSMA-ALB-56. In some embodiments, the PSMA-targeted radiopharmaceutical is EB-PSMA-617. In some embodiments, the PSMA-targeted radiopharmaceutical is CTT1403. In some embodiments, the PSMA-targeted radiopharmaceutical is PSMA-617. In some embodiments, the PSMA-targeted radiopharmaceutical is HTK01169. In some embodiments, the PSMA-targeted Attorney Ref: P6973PC00 15 radiopharmaceutical is LI. In some embodiments, the PSMA-targeted radiopharmaceutical is L14. In some embodiments, the PSMA-targeted radiopharmaceutical is SibuDAB.

[0101] The structures for PSMA-I&T, PSMA-617, and PSMA-11 are described below and by Chatalic et al., Theranostics, (2016), 6(6): 849-861. PSMA-I&T

[0102] As used herein, PSMA-I&T has the structure below:

[0103] PSMA I&T has the CAS number 2192281-54-0.

[0104] When PSMA I&T is chelated to a radionuclide such as161Tb, said chelate is referred to as, e.g., “161Tb-PSMA-I&T”

[0105] Attorney Ref: P6973PC00 16

[0106] PSMA-11

[0107] As used herein, “PSMA-11” has the structure below:

[0108] When PSMA-11 is chelated to a radionuclide such as161Tb, said chelate is referred to as, e.g., “161Tb-PSMA-l l”. PSMA-11 has the CAS number 1366302-52-4.

[0109] PSMA-617

[0110] As used herein, “PSMA-617” has the structure below: Attorney Ref: P6973PC00 17

[0111] When PSMA-617 is chelated to a radionuclide such as161Tb, said chelate is referred to as, e.g., “161Tb-PSMA-617”. PSMA-617 has the CAS number 1702967-37-0.

[0112] PSMA-62

[0113] As used herein, “PSMA-62” has the structure below:

[0114] The structure of PSMA-62 is also described by Schmidt, A. (2017). Structural modifications of PSMA ligands to optimize their pharmacokinetics. [Doctoral Dissertation, Technischen Universitat Munchen], https: / / d-nb.info / l 170872573 / 34.

[0115] PSMA-R2

[0116] As used herein, “PSMA-R2” has the structure below:

[0117] The structure of PSMA-R2 is also described in WO 2021 / 001360.

[0118] In some embodiments, the PSMA-targeted radiopharmaceutical comprises an albuminbinding fragment. In preferred embodiments, the PSMA-targeted radiopharmaceutical comprising an albumin-binding fragment is selected from the group consisting of PSMA- ALB-56, EB-PSMA-617, CTT1403, PSMA-617, HTK01169, LI, L14, and SibuDAB. The structures of PSMA-ALB-56, EB-PSMA-617, CTT1403, PSMA-617, HTK01169, LI, and L14, are described by Boinapally, S. et al., Molecules, 2023, 28, 6158; see also Choy et al, Theranoslics. 2017, 7(7): 1928-1939. The structure of SibuDAB is described by Tschan et al., Journal of Nuclear Medicine July 2023, jnumed. 123.265524; DOI: https: / / doi.org / 10.2967 / jnumed.123.265524. Attorney Ref: P6973PC00 18

[0119] In preferred embodiments, the PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA I&T, PSMA-617, and PSMA-11.

[0120] Radionuclides

[0121] As used herein, a “radionuclide” is understood as a nuclide that has excess nuclear energy, making it unstable. The excess energy can be (i) emitted from the nucleus as gamma radiation; (ii) transferred to one of its electrons to release it as a conversion electron; or (iii) used to create and emit a new particle (e.g., an alpha particle or a beta particle) from the nucleus.

[0122] In some embodiments, said PSMA-targeted radiopharmaceutical is chelated to a radionuclide. In some embodiments, said radionuclide is selected from:nC,13N,15O,18F,43Sc,44Sc,47Sc,61Cu,64Cu,67Cu,68Cu,68Ga,89Sr,89Zr,90Y, "mTc,1231,125I,1311,153Sm,149Pm,149Tb,152Tb,155Tb,161Tb,165Dy,166Ho,169Er,177Lu,188Re,198Au,203Pb,212Pb,211At,212BI,213Bi,223Ra,225Ac, and227Th. In some embodiments, said radionuclide is selected from:43Sc,44Sc,47Sc,61Cu,64Cu,67Cu,68Cu,68Ga,89Sr,89Zr,90Y, "mTc,123I,125I,131I,153Sm,149Pm,149Tb,152Tb,155Tb,161Tb,165Dy,166Ho,169Er,177Lu,188Re,198Au,203Pb,212Pb,211At,212BI,213Bi,223Ra,225Ac, and227Th. In some embodiments, said radionuclide is selected from:161Tb,177LU,212Pb, and225Ac. In some embodiments, said radionuclide is selected from:161Tb,177Lu, and225Ac. In some embodiments, said radionuclide is selected from:161Tb,177Lu, and212Pb. In some embodiments, said radionuclide is selected from:161Tb and177Lu.

[0123] In some embodiments, said radionuclide is a beta-emitter. In some embodiments, said radionuclide is a long-range beta emitter, e.g., wherein said long-range beta emitter is selected from the group consisting of90Y,32P,186Re / 188Re;166Ho,76As / 77As,89Sr, and153Sm. In some embodiments, said radionuclide is a medium range beta-emitter, e.g., wherein said medium range beta-emitter is selected from the group consisting of13 JI,177Lu,67Cu,161Tb, and105Rh. In some embodiments, said radionuclide is a low-energy beta-emitter, e.g., wherein said low- energy beta-emitter is selected from the group consisting of45Ca and35S. In some embodiments, said radionuclide is a conversion or Auger-emitter, e.g., wherein said conversion or Auger-emitter is selected from the group consisting of51Cr,67Ga, "Tcm,1 1' in.114mIn,123I,125I, and2O1T1. In some embodiments, said radionuclide is an alpha emitter, e.g., wherein said alpha emitter is selected from the group consisting of212Bi,213Bi,223Ac,225Ac,212Pb,255Fm,223Ra,149Tb and221At.

[0124] In some embodiments, said radionuclide is selected from:161Tb, and177Lu.

[0125] In some embodiments, said radionuclide is "C. In some embodiments, said Attorney Ref: P6973PC00 19 radionuclide is13N. In some embodiments, said radionuclide is15O. In some embodiments, said radionuclide is18F. In some embodiments, said radionuclide is43Sc. In some embodiments, said radionuclide is44Sc. In some embodiments, said radionuclide is47Sc. In some embodiments, said radionuclide is64Cu. In some embodiments, said radionuclide is67Cu. In some embodiments, said radionuclide is68Ga. In some embodiments, said radionuclide is89Sr. In some embodiments, said radionuclide is89Zr. In some embodiments, said radionuclide is90Y. In some embodiments, said radionuclide is "mTc. In some embodiments, said radionuclide is123I. In some embodiments, said radionuclide is131I. In some embodiments, said radionuclide is153Sm. In some embodiments, said radionuclide is149Tb. In some embodiments, said radionuclide is152Tb. In some embodiments, said radionuclide is155Tb. In preferred embodiments, said radionuclide is161Tb. In some embodiments, said radionuclide is165Dy. In some embodiments, said radionuclide is166Ho. In some embodiments, said radionuclide is169Er. In preferred embodiments, said radionuclide is177Lu. In some embodiments, said radionuclide is188Re. In some embodiments, said radionuclide is198Au. In some embodiments, said radionuclide is203Pb. In some embodiments, said radionuclide is212Pb. In some embodiments, said radionuclide is211At. In some embodiments, said radionuclide is212Bi. In some embodiments, said radionuclide is213Bi. In some embodiments, said radionuclide is223Ra. In some embodiments, said radionuclide is225Ac. In some embodiments, said radionuclide is227Th.

[0126] In some embodiments, said PSMA-targeted radiopharmaceutical is chelated to a radionuclide selected from161Tb177Lu,212Pb, and225Ac. In some embodiments, said PSMA- targeted radiopharmaceutical is chelated to a radionuclide selected from161Tb and177Lu. In some embodiments, said PSMA- targeted radiopharmaceutical is chelated to161Tb. In some embodiments, said PSMA- targeted radiopharmaceutical is chelated to177Lu. In some preferred embodiments, said PSMA- targeted radiopharmaceutical is chelated to212Pb. In some preferred embodiments, said PSMA- targeted radiopharmaceutical is chelated to225Ac.

[0127] In some embodiments, said PSMA I&T is chelated to a radionuclide selected from161Tb177LU,212Pb, and225Ac. In some embodiments, said PSMA I&T is chelated to a radionuclide selected from161Tb and177Lu. In preferred embodiments, said PSMA I&T is chelated to161Tb. In some embodiments, said PSMA I&T is chelated to177Lu. In some preferred embodiments, said PSMA I&T is chelated to212Pb. In some preferred embodiments, said PSMA I&T is chelated to225Ac.

[0128] In some embodiments, said PSMA-617 is chelated to a radionuclide selected from161Tb177LU,212Pb, and225Ac. In some embodiments, said PSMA-617 is chelated to a Attorney Ref: P6973PC00 20 radionuclide selected from161Tb and177Lu. In some embodiments, said PSMA-617 is chelated to161Tb. In some embodiments, said PSMA-617 is chelated to177Lu. In some preferred embodiments, said PSMA-617 is chelated to212Pb. In some preferred embodiments, said PSMA-617 is chelated to225Ac.

[0129] Preparation of compounds of the invention

[0130] The compounds of the invention may be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained herein.

[0131] In preparing compounds of the invention, protection of remote functionality (e.g, primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups include / c / 7-butyloxycarbonyl (BOC), bis- / e / 7-butyloxycarbonyl or dimethylaminomethylenyl. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0132] Methods of separation

[0133] In the methods of preparing the compounds of this invention, it may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; high, medium and low-pressure liquid chromatography methods and apparatus; small scale analytical; and preparative thin or thick layer chromatography, as well as techniques of small-scale thin layer and flash chromatography.

[0134] Selection of appropriate methods of separation depends on the nature of the materials involved, for example, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One skilled in the art will apply techniques most likely to achieve the desired separation. Attorney Ref: P6973PC00 21

[0135] Kits of Parts. Compositions, Combinations, and Methods of Treatment

[0136] As used herein, the term "for use" as used in "compound for use in a method of treating a prostate cancer in a subject” shall disclose also the corresponding method of treatment of a prostate cancer in a subject in need thereof, comprising administering the compound to the subject; and the corresponding use of the compound in the manufacture of a medicament for the treatment of a prostate cancer in a subject. Accordingly, embodiments disclosed herein are understood to related to compounds for use, methods of treatment, the use of a compound as described herein in the manufacture of a medicament, and the use of a compound as described herein for treatment.

[0137] In some embodiments, the compound of the present disclosure is administered systemically, orally, or parenterally. In preferred embodiments, the compound of the present disclosure is administered systemically (i.e. , intravenously). In some embodiments, the compound of the present disclosure is administered locally, e.g., into the bladder.

[0138] In one aspect, the present disclosure provides a compound for use in a method of treating a prostate cancer in a subject, wherein said compound is a radiopharmaceutical.

[0139] In one aspect, the present disclosure provides a compound for use in a method of treating a prostate cancer in a subject, wherein said compound is a PSMA-targeted radiopharmaceutical .

[0140] In one aspect, the present disclosure provides a method of treating a prostate cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a radiopharmaceutical as described herein. Preferably, the radiopharmaceutical is a PSMA-targeted radiopharmaceutical and the prostate cancer is a high-risk localized prostate cancer.

[0141] In one aspect, the present disclosure provides a radiopharmaceutical for use in a method of treating a prostate cancer in a subject. Preferably, the radiopharmaceutical is a PSMA-targeted radiopharmaceutical and the prostate cancer is a high-risk localized prostate cancer.

[0142] In one aspect, the present disclosure provides the use of a radiopharmaceutical in the manufacture of a medicament for treating a prostate cancer in a subject. Preferably, the radiopharmaceutical is a PSMA-targeted radiopharmaceutical and the prostate cancer is a high-risk localized prostate cancer.

[0143] In some embodiments, said PSMA-targeted radiopharmaceutical comprises a DUPA targeting group.

[0144] In some embodiments, said PSMA-targeted radiopharmaceutical is selected from the Attorney Ref: P6973PC00 22 group consisting of: PSMA I&T, PSMA-11, PSMA-617, PSMA-62, and PSMA-R2.

[0145] In some embodiments, said PSMA-targeted radiopharmaceutical is selected from

[0146] PSMA I&T and PSMA-617.

[0147] In some embodiments, said PSMA-targeted radiopharmaceutical is selected from

[0148] PSMA I&T.

[0149] In some embodiments, said PSMA-targeted radiopharmaceutical is selected from

[0150] PSMA-617.

[0151] In some embodiments, said PSMA-targeted radiopharmaceutical is chelated to a radionuclide.

[0152] In some embodiments, said PSMA-targeted radiopharmaceutical is chelated to a radionuclide selected from the group consisting of161Tb,177Lu,212Pb, and225Ac.

[0153] In some embodiments, said PSMA-targeted radiopharmaceutical is chelated to a radionuclide selected from the group consisting of161Tb and177Lu, preferably161Tb.

[0154] In some embodiments, said prostate cancer is high-risk localized prostate cancer.

[0155] Accordingly, in some embodiments, said prostate cancer is characterized by the presence of at least one of any of the following criteria:

[0156] (i) clinical stage T2c or higher; (ii) Gleason score from 8 to 10; or (iii) pre-treatment prostate-specific antigen (PSA) concentration of > 20 ng / mL.

[0157] In some embodiments, said prostate cancer is characterized by the presence of at least two of any of the following criteria:

[0158] (i) clinical stage T2c or higher; (ii) Gleason score from 8 to 10; or (iii) pre-treatment prostate-specific antigen (PSA) concentration of > 20 ng / mL.

[0159] In some embodiments, said prostate cancer is characterized by the presence of all three of the following criteria:

[0160] (i) clinical stage T2c or higher; (ii) Gleason score from 8 to 10; or (iii) pre-treatment prostate-specific antigen (PSA) concentration of > 20 ng / mL.

[0161] In some embodiments, the high-risk localized prostate cancer is a treatment-naive high- risk localized prostate cancer. In some embodiments, the high-risk localized prostate cancer is a high-risk localized prostate cancer has been subject to androgen deprivation therapy (ADT). In some embodiments, said high-risk localized prostate cancer expresses PSMA. In some embodiments, said high-risk localized prostate cancer overexpresses PSMA. In some embodiments, said high-risk localized prostate cancer is partially or fully hormone-sensitive (e.g., partially or fully androgen-sensitive). In some embodiments, said high-risk localized prostate cancer is partially hormone-sensitive (e.g., partially androgen-sensitive). In preferred Attorney Ref: P6973PC00 23 embodiments, said high-risk localized prostate cancer is fully hormone-sensitive (e.g., fully androgen-sensitive).

[0162] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that has not previously been subject to radical prostatectomy. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) but has not previously been subject to radical prostatectomy. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high- risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with pelvic lymph node dissection. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection.

[0163] In some embodiments, said prostate cancer is a very high-risk localized prostate cancer. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, i.e., a localized prostate cancercharacterized by a clinical stage T3b or T4. In some embodiments, the very high-risk localized prostate cancer is a treatment-naive very high-risk localized prostate cancer. In some embodiments, the very high-risk localized prostate cancer is a very high-risk localized prostate cancer has been subject to androgen deprivation therapy (ADT). In some embodiments, said very high-risk localized prostate cancer expresses PSMA. In some embodiments, said very high-risk localized prostate cancer overexpresses PSMA. In some embodiments, said very high-risk localized prostate cancer is partially or fully hormonesensitive (e.g., partially or fully androgen-sensitive). In some embodiments, said very high- risk localized prostate cancer is partially hormone-sensitive (e.g., partially androgensensitive). In preferred embodiments, said very high-risk localized prostate cancer is fully hormone-sensitive (e.g., fully androgen-sensitive).

[0164] In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that has not previously been subject to radical prostatectomy. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said Attorney Ref: P6973PC00 24 very high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) but has not previously been subject to radical prostatectomy. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with pelvic lymph node dissection. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive high- risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection.

[0165] In some embodiments, said prostate cancer is high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA I&T, PSMA-11, PSMA-617, PSMA-62, and PSMA-R2, wherein said PSMA-targeted radiopharmaceutical is chelated to a radionuclide selected from the group consisting of161Tb,177LU,212Pb, and225Ac. In some embodiments, said prostate cancer is very high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA I&T, PSMA-11, PSMA-617, PSMA-62, and PSMA-R2, wherein said PSMA-targeted radiopharmaceutical is chelated to a radionuclide selected from the group consisting of161Tb,177Lu,212Pb, and225Ac.

[0166] In some embodiments, said prostate cancer is high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA I&T, and PSMA-617, wherein said PSMA-targeted radiopharmaceutical is chelated to a radionuclide selected from the group consisting of161Tb,177Lu,212Pb, and225Ac. In some embodiments, said prostate cancer is very high-risk localized prostate cancer; and said PSMA- targeted radiopharmaceutical is selected from the group consisting of PSMA I&T and PSMA- 617, wherein said PSMA-targeted radiopharmaceutical is chelated to a radionuclide selected from the group consisting of161Tb,177Lu,212Pb, and225Ac.

[0167] In some embodiments, said prostate cancer is high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA I&T and PSMA-617, wherein said PSMA-targeted radiopharmaceutical is chelated to161Tb or177LU. In some embodiments, said prostate cancer is very high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA I&T and PSMA-617, wherein said PSMA-targeted radiopharmaceutical is chelated to161Tb or Attorney Ref: P6973PC00 25

[0168] 177LU.

[0169] In some embodiments, said prostate cancer is high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177LU, preferably161Tb. In some embodiments, said prostate cancer is very high- risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb.

[0170] In some embodiments, said prostate cancer is high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177LU, preferably177Lu. In some embodiments, said prostate cancer is very high- risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu.

[0171] In some embodiments, said prostate cancer is treatment-naive high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb. In some embodiments, said prostate cancer is treatment-naive high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu.

[0172] In some embodiments, said prostate cancer is treatment-naive very high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb. In some embodiments, said prostate cancer is treatment-naive very high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu.

[0173] In some embodiments, said prostate cancer is high-risk localized prostate cancer that has been subject to androgen deprivation therapy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb. In some embodiments, said prostate cancer is high-risk localized prostate cancer that has been subject to androgen deprivation therapy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu.

[0174] In some embodiments, said prostate cancer is very high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb. In some embodiments, said prostate cancer is very high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is PSMA- Attorney Ref: P6973PC00 26

[0175] 617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu.

[0176] In some embodiments, said prostate cancer is very high-risk localized prostate cancer that has been subject to androgen deprivation therapy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb. In some embodiments, said prostate cancer is very high-risk localized prostate cancer that has been subject to androgen deprivation therapy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu.

[0177] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer has not previously been treated with a systemic treatment, preferably wherein said systemic treatment is chemotherapy (e.g., a taxane), or an androgen receptor inhibitor; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer has not previously been treated with a systemic treatment, preferably wherein said systemic treatment is chemotherapy (e.g., a taxane), or an androgen receptor inhibitor; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb.

[0178] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer has not previously been treated with a systemic treatment, preferably wherein said systemic treatment is chemotherapy (e.g., a taxane), or an androgen receptor inhibitor; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer has not previously been treated with a systemic treatment, preferably wherein said systemic treatment is chemotherapy (e.g., a taxane), or an androgen receptor inhibitor; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu.

[0179] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer has not previously been subject to surgery, preferably wherein said surgery is radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized Attorney Ref: P6973PC00 27 prostate cancer that has not previously been subject to radical prostatectomy; and said PSMA- targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177LU, preferably161Tb. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) but has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection; and said PSMA- targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to177Lu. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high- risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) but has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to177Lu. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA I&T, Attorney Ref: P6973PC00 28 wherein said PSMA I&T is chelated to177Lu. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection; and said PSMA- targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to177Lu.

[0180] In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer has not previously been subject to surgery, preferably wherein said surgery is radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) but has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb. In some embodiments, said prostate cancer is very high- risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA I&T, Attorney Ref: P6973PC00 29 wherein said PSMA I&T is chelated to161Tb. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to177Lu. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) but has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to177LU. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to177Lu. In some embodiments, said prostate cancer is very high- risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to177LU.

[0181] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer has not previously been subject to surgery, preferably wherein said surgery is radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that has not previously been subject to radical prostatectomy; and said PSMA- targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177LU, preferably177Lu. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to177LU. In some embodiments, said prostate cancer is high-risk localized prostate cancer, Attorney Ref: P6973PC00 30 wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) but has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to177Lu. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to177Lu. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection; and said PSMA- targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to177Lu. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high- risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) but has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb. In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is treatment-naive high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection; and said PSMA- targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb.

[0182] In some embodiments, said prostate cancer is very high-risk localized prostate cancer, Attorney Ref: P6973PC00 31 wherein said very high-risk localized prostate cancer has not previously been subject to surgery, preferably wherein said surgery is radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to177Lu. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) but has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to177Lu. In some embodiments, said prostate cancer is very high- risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to177Lu. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to177Lu. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb. In some embodiments, said prostate cancer is very high- risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical Attorney Ref: P6973PC00 32 prostatectomy (RPE) but has not previously been subject to radical prostatectomy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb. In some embodiments, said prostate cancer is very high- risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb.

[0183] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer has not previously been treated with a hormone therapy, preferably wherein said hormone therapy comprises treatment with an androgen receptor inhibitor; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer has not previously been treated with a hormone therapy, preferably wherein said hormone therapy comprises treatment with an androgen receptor inhibitor; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177LU, preferably161Tb.

[0184] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer has not previously been treated with a hormone therapy, preferably wherein said hormone therapy comprises treatment with an androgen receptor inhibitor; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer has not previously been treated with a hormone therapy, preferably wherein said hormone therapy comprises treatment with an androgen receptor inhibitor; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177LU, preferably177Lu. Attorney Ref: P6973PC00 33

[0185] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer has not previously been subject to androgen deprivation therapy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer has not previously been subject to androgen deprivation therapy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177LU, preferably161Tb.

[0186] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer has not previously been subject to androgen deprivation therapy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer has not previously been subject to androgen deprivation therapy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177LU, preferably177Lu.

[0187] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer has not previously been subject to radiation therapy, preferably radioligand therapy or external radiotherapy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer has not previously been subject to radiation therapy, preferably radioligand therapy or external radiotherapy; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177LU, preferably161Tb.

[0188] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer has not previously been subject to radiation therapy, preferably radioligand therapy or external radiotherapy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer has not previously been subject to radiation therapy, preferably radioligand therapy or external radiotherapy; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177LU, preferably177Lu. Attorney Ref: P6973PC00 34

[0189] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is partially hormone-sensitive; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177LU, preferably161Tb. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is partially hormone-sensitive; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb.

[0190] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is partially hormone-sensitive; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177LU, preferably177Lu. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is partially hormone-sensitive; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu.

[0191] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is fully hormone-sensitive; and said PSMA- targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177LU, preferably161Tb. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is fully hormonesensitive; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb.

[0192] In some embodiments, said prostate cancer is high-risk localized prostate cancer, wherein said high-risk localized prostate cancer is fully hormone-sensitive; and said PSMA- targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177LU, preferably177Lu. In some embodiments, said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is fully hormonesensitive; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA- 617 is chelated to161Tb or177Lu, preferably177Lu. Attorney Ref: P6973PC00 35

[0193] EXAMPLES

[0194] The invention will now be illustrated by way of the following non-limiting examples. While particular embodiments of the invention are described below, a skilled person will appreciate that various changes and modifications can be made. References to preparations carried out in a similar manner to, or by the general method of, other preparations, may encompass variations in routine parameters such as time, temperature, workup conditions, minor changes in reagents amounts, and the like.

[0195] CWR22 cells are derived from a primary tumor of a prostate cancer patient with a stage D (according to the Whitmore-Jewett classification system) and Gleason grade 9 primary tumor and with osseous metastases who underwent radical prostatectomy (T.G. Pretlow et al, J. Natl. Cancer Inst., 1993). The stage D classification under the Whitmore-Jewett system corresponds to a clinical T4 classification under the TNM classification system. Mice with CWR22 xenografts are known to exhibit high PSA levels (of 100 ng / mL or higher) (M. A. Wainstein et al, Cancer Res, 1994; M. Nagabhushan et al, Cancer Res, 1996), above the 20 ng / mL threshold to qualify a prostate cancer as a high-risk localized prostate cancer. CWR22 cells thus represent a viable model for early-stage high-risk localized prostate cancer. 22Rvl cells (also referred to as CWR22Rvl) were derived from CWR22 upon castration-induced relapse (R.M. Sramkoski et al, In vitro Cell Dev Biol, 1999) and are partially androgensensitive. Thus, 22Rvl represents a model of early-stage high-risk localized prostate cancer that has undergone androgen deprivation.

[0196] EXAMPLE 1: CO-TREATMENT OF177LU-PSMA-617 AND COMPOUND 1* (PQR309; BIMIRALISIB) OR COMPOUND 2 IN 22RV1 HUMAN PROSTATE CANCER CELLS

[0197] This study determined the anti-proliferative effects of177Lu-PSMA-617 in combination with Compound 1* (PQR309; bimiralisib) and Compound 2 (see, e.g., Borsari et al., Preclinical Development of PQR514, a Highly Potent PI3K Inhibitor Bearing a Difluoromethyl-Pyrimidine Moiety, ACS Med. Chem. Lett., 10(10): 1473-1497 (2019)) on cell survival in the human prostate cancer cell line 22Rvl.

[0198] Cell culture: 22Rvl cells (Sigma Aldrich) were cultured according to standard procedures (growth medium: RPMI-160 ATCC modified supplemented with 10% (v / v) FBS, 2 mM L-glutamine, and 1% (v / v) Pen / Strep; growth at 37 °C with 5 % CO2) and harvested when cells were between 70-90 % confluent.

[0199] Determination of IC50 of Compound 1* (PQR309; bimiralisib) and Compound 2, in Attorney Ref: P6973PC00 36

[0200] 22Ryl cells: 9,000 22Rvl cells per well were seeded in opaque-walled clear botom 96-well plates in growth medium and incubated overnight prior to treatment. Triplicates were seeded for each condition. The next day, medium was replaced with warm medium containing Compound 1* or Compound 2 at different concentrations (10, 3, 1. 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, and 0 pM) and cells were incubated for 7 days. After 7 days, a CellTiter-Glo assay was performed as per manufacturer’s instructions. Luminescence was measured on a Spectramax i3x multi-mode microplate reader and the dose-response curves were determined by non-linear regression analysis in GraphPad Prism, including calculation of the IC50. A plot of percent survival of 22Rvl cells as a function of concentration of Compound 1* or Compound 2 is shown in FIG 1, and the IC50S are given in Table 1, below.

[0201] Table 1: IC50S of Compound 1* and Compound 2, in 22Ryl Cells (pM)

[0202] Compound 1* and Compound 2 dose-dependently inhibited survival of 22Rvl cells.

[0203] Cell survival of 22Ryl cells treated with177Lu-PSMA-617, Compound 1, or Compound 2, as single agents or treated with combinations of177Lu-PSMA-617 and Compound 1* or Compound 2: Different doses of177Lu-PSMA-617 (0 (vehicle), 0.5, 1, 2.5, 5, 10, and 20 MBq / mL; Table 2) were added to tubes containing 22Rvl cells (final volume of 2.5 mL) and then incubated under constant agitation at 37 °C with 5 % CO2 for 4 hours. After incubation, the cells were washed twice with PBS and cells were seeded in opaque-walled clear botom 96-well plate with 9 000 cells per well. Triplicates (3 wells) were seeded for each treatment (Table 2). Compound 1* and Compound 2 were added at the concentrations indicated in Table 2 (i.e., these concentrations corresponded to the ICso, ICeo, IC50, IC40, IC30, IC20 determined in the previous experiment above). Cells were incubated at 37 °C with 5 % CO2 for 7 days. After incubation, CellTiter-Glo was added to all wells as per the manufacturer’s instructions. The plates were placed on a shaker to induce cell lysis and incubated at room temperature to stabilize the signal. Luminescence was measured on a Spectramax i3x multi-mode microplate reader and the dose-response curve was determined by non-linear regression analysis. Attorney Ref: P6973PC00 37

[0204] Table 2: Dosage Combinations for Survival Assay with Compound 1* or Compound 2 and177LU-PSMA-617

[0205] Cell survival decreased with increasing concentrations of Compound 1* (PQR309) or Compound 2 (FIG 2 A). Treatment of cells with177Lu-PSMA-617 in combination with Compound 1* (PQR309) or Compound 2 further decreased survival (FIG 2A). To assess the effect of the combination of177Lu-PSMA-617 with Compound 1* (PQR309) or Compound 2, the Bliss synergy score was calculated using SynergyFinder (https: / / synergyfmder.fimm.fi / synergy / 20241025144228237071 / ). A Bliss synergy score above 10 indicates synergy between two drugs. Combination of177Lu-PSMA-617 with both Compound 1* (PQR309) or Compound 2 was synergistic as evidenced by a Bliss synergy score of 11.145 (FIG 2B) and 12.158 (FIG 2C), respectively.

[0206] EXAMPLE 2: CO-ADMINISTRATION OF161Tb-PSMA-I&T OR177Lu-PSMA-617 AND COMPOUND 1* (PQR309; BIMIRALISIB) IN NUDE MICE BEARING 22RV1 TUMORS

[0207] This study evaluated and compared the anti-tumor efficacy of161Tb-PSMA-I&T and177LU-PSMA-617 as single treatment and in combination with Compound 1* in female NMRI nude mice bearing subcutaneous human prostate carcinoma established with the cell line 22Rvl.

[0208] Study outline and procedures: 8-week-old female NMRI nude mice (80 mice required for the experiment plus extra mice in reserve) from Janvier (France) were implanted with 3x10622Rvl cells (Sigma Aldrich; cultured as described in Example 1) in PBS:Matrigel (1: 1) by subcutaneous injection using a 27G needle and a total injection volume of 100 pL at the flank above the right limb on day -16 (relative to start of treatment, defined as study day 0). On day Attorney Ref: P6973PC00 38

[0209] -1 (i.e., 15 days post-implantation), the mice were randomized based on tumor size and body weight to ensure similar average and variation of the groups. Mice were distributed to the treatment and control groups (8 mice per group). FIG 3A is a plot of average body weight of mice at day -1, and FIG 3B is a plot of tumor volume of mice at day -1. Average body weight was 29 g (range from 25.5 to 33.4 g; FIG 3A) and average tumor volume was 175 mm3(range from 76 to 347 mm3; FIG 3B) for all groups.

[0210] Treatments with radioligands (161Tb-PSMA-I&T and177Lu-PSMA-617) and Compound 1* were initiated on study day 0. Study groups and treatment details are outlined in Table 3.

[0211] 161Tb-PSMA-I&T was intravenously (IV) administered once at a target dose of 21.8 MBq or at a target dose of 43.7 MBq.177Lu-PSMA-617 was intravenously administered once at a target dose of 30 MBq or at a target dose of 60 MBq. The doses of 21.8 MBq and 43.7 MBq161Tb-PSMA-I&T correspond to the same dose (in Gy) of 30 MBq and 60 MBq177Lu- PSMA-617. IV injections were carried out at an injection volume of 100-200 pL at the lateral tail vein.

[0212] Compound 1* was intraperitoneally (IP) administered at 7 mg / kg daily (QD) for 45 days or until mice reached a humane endpoint (see below). Control mice were IV administered with vehicle once. All injections were performed at a dosing volume of 5 mL / kg. Compound 1* was formulated weekly in 7.5% (v / v) SBECD at pH 7.

[0213] Table 3, Study Groups and Treatment Details Attorney Ref: P6973PC00 39

[0214] Mice were checked daily and adverse clinical reactions noted. Animal body weight and tumor size were assessed twice a week. Animals were euthanized at the end of the experiment or upon reaching humane endpoints as listed in Table 4. Euthanasia was performed by cervical dislocation.

[0215] Table 4, Humane endpoints Attorney Ref: P6973PC00 40

[0216] Tumor size was measured by caliper 2x every week and on the day of stratification.

[0217] All treatments were tolerated well and no mice had to be sacrificed before reaching the endpoint of the tumor volume being as big as or bigger than 1500 mm3.

[0218] Treatment with (a) Compound 1* alone; (b) 21.8 MBq161Tb-PSMA-I&T alone; and (c) both 30 and 60 MBq of177Lu-PSMA-617 alone did not reduce tumor growth as single agents up to study day 15 (i.e., the last day on which all mice were still alive, allowing all conditions to be compared directly) compared to treatment with vehicle (FIG 4A, 4C, 4D). All mice that were treated with vehicle alone or Compound 1* alone reached a tumor volume of 1500 mm3by or shortly after day 15 and thus were euthanized on or shortly after day 15.

[0219] In contrast, the combination of Compound 1* with either 21.8 MBq161Tb-PSMA-I&T (FIG4A) or 30 or 60 MBq177Lu-PSMA-617 (FIG4C and FIG4D respectively) reduced tumor growth compared to treatment with vehicle or single agents alone. Treatment with 43.7 MBq161Tb-PSMA-I&T alone reduced tumor growth (FIG 4B) compared to vehicle or monotherapy with Compound 1*. Moreover, the combination of 43.7 MBq161Tb-PSMA-I&T with Compound 1* led to a greater reduction in tumor growth after study day 15 compared to treatment with161Tb-PSMA-I&T alone (FIG 4B).

[0220] Some of the mice treated with161Tb-PSMA-I&T or177Lu-PSMA-617 alone reached the endpoint of tumor volume >1500 mm3after study day 15 (i.e., the day on which most mice in the vehicle group and Compound 1 * monotherapy treatment group reached a tumor volume of>1500 mm3) and several mice treated with Compound 1* in combination with161Tb-PSMA- I&T or177LU-PSMA-617 did not exhibit a tumor volume > 1500 mm3until on or after study day 20. Individual tumor volumes are shown in Figure 5. Based on these individual tumor data, the number of days-until-endpoint was calculated for each mouse (i.e., the number of days from treatment start to reaching a tumor volume of >1500 mm3) (FIG 6). Tumors of mice treated with a combination of161Tb-PSMA-I&T or177Lu-PSMA-617 and Compound 1* reached the endpoint significantly later than mice treated with vehicle, Compoundl*,161Tb- PSMA-I&T or177LU-PSMA-617 alone (p<0.05). Attorney Ref: P6973PC00 41

[0221] EXAMPLE 3: CO-ADMINISTRATION OF225AC-PSMA OR212PB-PSMA AND COMPOUND 1* (PQR309; BIMIRALISIB) OR COMPOUND 2 IN NUDE MICE BEARING 22RV1 TUMORS

[0222] The purpose of this study will be to evaluate and compare the anti-tumor efficacy of225AC-PSMA- and212Pb-PSMA-targeting radioligand therapy (RLT; e.g., PSMA-617 or PSMA-I&T), as single treatment and in combination with dual PI3K / mTOR inhibitors (such as Compound 1* (PQR309; bimiralisib) or Compound 2 in mice (e.g., female NMRI nude mice) bearing subcutaneous human prostate carcinoma (established with cell lines such as 22Rvl, LNCaP, or PC3-PIP).

[0223] Mice (e.g., 8-week-old female NMRI nude mice) will be implanted with cells (e.g., 3x10622Rvl cells in PBS:Matrigel (1:1)) by subcutaneous injection (e.g., using a 27G needle and a total injection volume of 100 pL, e.g., at the flank above the right limb). A sufficient number of mice per treatment group will be implanted (e.g., 8 mice per group plus extra mice as described in Example 2). When subcutaneous tumors reach a certain volume (e.g., 100, 150, or 200 mm3), the mice will be randomized based on tumor size and body weight to ensure similar average and variation of the groups. Mice will be distributed to the treatment and control groups (e.g., 8 mice per group).

[0224] In a first experiment, sub-optimal doses of225Ac-PSMA- and212Pb-PSMA-targeting RLT will be determined by treating tumor-bearing mice with different target doses (e.g., 50, 75, 150, 200, and 300 kBq).225Ac-PSMA- and212Pb-PSMA-targeting RLT or vehicle will be administered once by IV. In parallel, sub-optimal doses of dual PI3K / mTOR inhibitors (such as Compound 1 * or Compound 2) will be determined by treating tumor-bearing mice with different target doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg). The dual PI3K / mTOR inhibitors will be administered (e.g., by IP injection) multiple times (e.g., daily, every 2ndday, or every 3rdday). Mice will be checked daily and adverse clinical reactions will be noted. Animal body weight and tumor size will be assessed twice a week. Animals will be euthanized (e.g., by cervical dislocation) at the end of the experiment or upon reaching humane endpoints (e.g., as listed above in Table 4). Tumor size will be measured by caliper (e.g., 2x every week and on the day of stratification). The tumor volume will be estimated with a formula such as: 0.52(length x width2). Tumor volumes over time (i.e., study days) will be displayed and used to estimate sub-optimal treatment doses for each agent. A sub-optimal dose of225Ac-PSMA- and212Pb-PSMA-targeting RLT and dual PI3K / mTOR inhibitors (such as Compound 1* or Compound 2) is defined as a dose which is not capable of inhibiting or only capable of Attorney Ref: P6973PC00 42 moderately inhibiting tumor growth (e.g., a dose leading to an inhibition of 10, 20, 30, 40, 50, or 60% compared to vehicle).

[0225] In a second experiment, sub-optimal doses of225Ac-PSMA- and212Pb-PSMA-targeting RLT will be combined with sub-optimal doses of dual PI3K / mT0R inhibitors (such as Compound 1* or Compound 2).225Ac-PSMA- and212Pb-PSMA-targeting RLT or vehicle will be administered once by IV. Dual PI3K / mTOR inhibitors will be administered (e.g., by IP injections) multiple times (e.g., daily, every 2ndday, or every 3rdday). Mice will be checked and tumor volumes will be measured and analyzed (e.g., as described in Example 2). Additive or synergistic effects of225Ac-PSMA- and212Pb-PSMA-targeting RLT with dual PI3K / mTOR inhibitors (such as Compound 1 * or Compound 2) will be calculated using methods described in the art, such as SynergyFinder

[0226] (https: / / synergyfinder.fimm.fi / synergy / 20241025144228237071 / ).

[0227] EXAMPLE 4: TREATMENT OF PSMA-I&T OR PSMA-617 RADIOLIGAND THERAPIES IN CWR22 OR CWR22RV1 HUMAN PROSTATE CANCER CELLS

[0228] Prostate cancer cells (e.g., CWR22 or CWR22Rvl cells) were cultured according to standard procedures (using growth medium: RPMI-1640 ATCC modified supplemented with 10% (v / v) FBS, 2 mM L-glutamine, and 1% (v / v) Pen / Strep; growth at 37 °C with 5 % CO2) and harvested when cells were between 50-70 % confluent.

[0229] To determine the efficacy of PSMA-I&T and PSMA-617 RLTs in CWR22 or CWR22Rvl (hereafter referred to as 22Rvl) cells, a survival assay was performed as described as follows: Different doses (0, 2.5, 5, 10, 20, and 40 MBq / mL) of PSMA-targeting RLT (PSMA-I&T or PSMA-617 labeled with177Lu or161Tb) were added to tubes containing cells in medium (CWR22 or 22Rvl cells) and then incubated under constant agitation at 37 °C with 5 % CO2 for 4 hours. After incubation, the cells were washed twice with PBS and cells were seeded in opaque-walled clear bottom 96-well plate (9000 cells per well). Triplicates (3 wells) were seeded for each treatment. Cells were incubated at 37 °C with 5 % CO2 for 7 days. After incubation, a CellTiter-Glo viability assay was performed as per manufacturer’s instructions. The plates were placed on a shaker to induce cell lysis and incubated at room temperature to stabilize the signal. Luminescence was measured on a Spectramax i3x multi-mode microplate reader and the dose-response curve was determined by non-linear regression analysis in GraphPad Prism, including calculation of the IC50.

[0230] A plot of percent survival of 22Rvl and CWR22 cells as a function of PSMA-targeting RLT (PSMA-I&T or PSMA-617 labeled with177Lu or161Tb) is shown in FIG 7 and FIG 8, Attorney Ref: P6973PC00 43 respectively, and the ICsos are given in Table 5, below.

[0231] Table 5: ICsos of177Lu-PSMA-I&T.161Tb-PSMA-I&T. and161Tb-PSMA-617 in 22Ryl and

[0232] CWR22 Cells (MBq / mL)

[0233] 177LU-PSMA-I&T,161Tb-PSMA-I&T, and161Tb-PSMA-617 dose-dependently inhibited survival of 22Rvl and CWR22 cells (FIG 7 and FIG 8). The ICsos of PSMA-617 and PSMA-I&T labeled with161Tb were comparable and lower than the IC50 of PSMA-I&T labeled with177Lu in both 22Rvl and CWR22 cells.

[0234] EXAMPLE 5: TREATMENT OF PSMA-I&T OR PSMA-617 RADIOLIGAND THERAPIES IN MICE BEARING CWR22 OR CWR22RV1 TUMORS

[0235] Prostate cancer cells (e.g., CWR22 or CWR22Rvl cells) are cultured according to standard procedures (such as using growth medium: RPMI-1640 ATCC modified supplemented with 10% (v / v) FBS, 2 mM L-glutamine, and 1% (v / v) Pen / Strep; growth at 37 °C with 5 % CO2) and harvested when cells are between 50-70 % confluent.

[0236] For anti-tumor activities of PSMA-I&T and PSMA-617 RLTs in CWR22- or CWR22Rvl -derived xenografts, an in vivo tumor growth and survival experiment will be performed as follows: Adult (e.g., 8-week-old) immunodeficient mice (e.g., NMRI nude or BRGSF mice) are implanted with cells (e.g., 3x106CWR22Rvl or CWR22 cells, e.g., in PBS:Matrigel (1: 1)) or CWR22 tumor fragments by subcutaneous injection using a needle (e.g., 27G needle and a total injection volume of 100 pL) at the flank (e.g., above the right limb). Start of treatment is defined as study day 0 and corresponds to the day when tumors have reached a defined size (e.g., 100, 150, or 200 mm3). On day -1, the mice are randomized based on tumor size and body weight to ensure similar average and variation of the groups. Mice are distributed to treatment and control groups (e.g., 8 mice per group). Radioligands (e.g., PSMA-I&T or PSMA-617 labeled with, e.g.,177Lu,161Tb,212Pb, or225Ac) are intravenously (IV) administered at the lateral tail vein (e.g., with an injection volume of 100- Attorney Ref: P6973PC00 44

[0237] 200 pL) once or repeatedly (e.g., every week, every two weeks, every 4 weeks) at defined target doses (e.g., 75, 150, or 300 kBq for225Ac and212Pb and 30, 60, or 90 MBq for177Lu and161Tb). Control mice are IV administered with vehicle once or repeatedly at the same frequency as the radioligand therapy treatments. All injections are performed at the same dosing volume (e.g., 5 mL / kg). Mice are checked daily and adverse clinical reactions are noted. Animal body weight and tumor size are assessed twice a week. Animals are euthanized (e.g., by cervical dislocation) at the end of the experiment or upon reaching humane endpoints (such as tumor volume of 1500 mm3). Tumor volumes (in mm3) and survival are plotted against time (in days) for the different treatment groups and statistical analyses (e.g., relative tumor volumes or survival probabilities in the different treatment groups) are performed using GraphPad Prism.

Claims

Attorney Ref: P6973PC00 45CLAIMS1. A compound for use in a method of treating a prostate cancer in a subject, wherein said compound is a PSMA-targeted radiopharmaceutical.

2. The compound for use of claim 1, wherein said PSMA-targeted radiopharmaceutical is selected from PSMA I&T.

3. The compound for use of claim 1, wherein said PSMA-targeted radiopharmaceutical is selected from PSMA-617.

4. The compound for use of any of the preceding claims, wherein said PSMA-targeted radiopharmaceutical is chelated to a radionuclide.

5. The compound for use of any of the preceding claims, wherein said PSMA-targeted radiopharmaceutical is chelated to a radionuclide selected from the group consisting of 161Tb and177Lu, preferably161Tb.

6. The compound for use according to any of the preceding claims, wherein said prostate cancer is high-risk localized prostate cancer.

7. The compound for use according to any of the preceding claims, wherein said prostate cancer is a very high-risk localized prostate cancer.

8. The compound for use of any the preceding claims, wherein said prostate cancer is high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA I&T, PSMA-11, PSMA-617, PSMA-62, and PSMA-R2, wherein said PSMA-targeted radiopharmaceutical is chelated to a radionuclide selected from the group consisting of161Tb,177Lu,212Pb, and225Ac.

9. The compound for use of any the preceding claims, wherein said prostate cancer is high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA I&T and PSMA-617, wherein saidAttorney Ref: P6973PC00 46PSMA-targeted radiopharmaceutical is chelated to161Tb or177Lu.

10. The compound for use of any the preceding claims, wherein said prostate cancer is high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb or177Lu, preferably161Tb.

11. The compound for use of any the preceding claims, wherein said prostate cancer is high-risk localized prostate cancer; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb or177Lu, preferably177Lu.

12. The compound for use of any the preceding claims, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) but has not previously been subject to radical prostatectomy.

13. The compound for use of any the preceding claims, wherein said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection.

14. The compound for use of any the preceding claims, wherein said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has not previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA-617, wherein said PSMA-617 is chelated to161Tb.

15. The compound for use of any the preceding claims, wherein said prostate cancer is very high-risk localized prostate cancer, wherein said very high-risk localized prostate cancer is treatment-naive very high-risk localized prostate cancer that is eligible for radical prostatectomy (RPE) with extended pelvic lymph node dissection but has notAttorney Ref: P6973PC00 47 previously been subject to radical prostatectomy (RPE) with extended pelvic lymph node dissection; and said PSMA-targeted radiopharmaceutical is PSMA I&T, wherein said PSMA I&T is chelated to161Tb.

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