Methods of treating prostate cancer

Abstract

The present disclosure relates to a method of treating prostate specific membrane antigen (PSMA) positive progressive metastatic castration resistant prostate cancer (mCRPC) by administering a therapeutically effective amount of a PSMA binding radioligand therapy (RLT) agent, preferably [177Lu] Lu-PSMA-617 (lutetium (177Lu) vevovortitide Tailaracetam), to a taxane primarily treated patient whose disease progresses after receiving a second generation ARPI.

Description

[0001] This application claims the priority and benefit of U.S. Provisional Application No. 63 / 386,040, filed on December 5, 2022, U.S. Application No. 18 / 448,609, filed on August 11, 2023, and U.S. Provisional Application No. 63 / 592,377, filed on October 23, 2023. The contents of all three applications are hereby incorporated by reference in their entirety.

[0002] Description TECHNICAL FIELD

[0003] This disclosure relates to methods for treating prostate-specific membrane antigen (PSMA)-positive progressive metastatic castration-resistant prostate cancer (mCRPC) by administering a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, preferably 177 Lu]Lu-PSMA-617 (lutetium ([[]Lu) vipivotide tetraxetan)) to taxane-naive patients who have progressed after receiving second-generation ARPIs. 177 Lu) BACKGROUND OF THE INVENTION

[0004] Prostate Cancer

[0005] Prostate cancer is the second leading cause of cancer death in the United States (US) and the third leading cause of cancer-related death in men in Europe (Malvezzi et al. 2019; Siegel et al. 2017). In 2012, an estimated 1.1 million men were diagnosed with prostate cancer globally, and 307,000 died from the disease. Due to the use of prostate-specific antigen (PSA) testing, nearly 70% of diagnosed cases occur in more developed regions, but the global mortality rate is only slightly different, which is driven by metastatic and usually castration-resistant disease (Bray et al. 2012).

[0006] There is an urgent need for more effective treatments to improve outcomes for participants with metastatic castration-resistant prostate cancer (mCRPC). The median age at diagnosis of mCRPC is 70 years (Flaig et al. 2016). Once participants reach the mCRPC stage, their expected overall survival is low, as seen in the randomized phase 3 study of cabozantinib compared with prednisone, which was conducted in mCRPC men who had previously received docetaxel, abiraterone acetate, and / or enzalutamide; the median overall survival in the prednisone control group was 9.8 months (Smith et al. 2016). In addition, mCRPC is associated with significant comorbidities. Approximately 90% of mCRPC participants develop bone metastases (Kirby et al. 2011), and 49% of these individuals experience serious skeletal events within 2 years (Saad et al. 2004). As a result, common presentations include bone pain, marrow failure, fatigue, or complications such as fractures and spinal cord compression. These presentations often require radiation or bone surgery, which can severely compromise physical, emotional, and functional health (Weinfurt et al. 2005). These participants may experience severe symptoms and be at risk of serious oncologic complications. Clinically, there can be considerable challenges due to symptoms of metastatic soft tissue and visceral disease, general debility, and marrow impairment.

[0007] Four major drug classes have been approved for the treatment to prolong survival in mCRPC participants. These include ARDT (i.e., abiraterone and enzalutamide), taxanes (docetaxel and cabazitaxel), immunotherapy (sipuleucel-T), and bone-seeking radiopharmaceuticals (radium-223 dichloride). As the field of prostate cancer treatment has evolved, some of these life-prolonging therapies (ARDT and docetaxel) are increasingly being used in earlier stages (e.g., metastatic hormone-sensitive prostate cancer and non-metastatic prostate cancer). This has led to a greater unmet medical need in mCRPC. Among participants previously treated with ARDT, several mechanisms have been associated with the development of treatment resistance (Attard et al. 2009). The range of rPFS for participants who switched to ARDT was 3.6 to 15 months, and the range of OS was 11 to 23 months (de Bono et al. 2020, de Wit et al. 2019, Komura et al. 2019). On the other hand, many participants do not receive chemotherapy mainly because of pre-existing medical conditions or related toxic effects. (Harris et al. 2011; EngelNitz et al. 2011; Lissbrant et al. 2013; Zielinski et al. 2014). Sipuleucel-T is most suitable for small-volume disease that is mildly asymptomatic; radium-223 is used to treat men with only bone disease. PARP inhibitors are an emerging drug class in mCRPC, but their use is limited to a subgroup of mCRPC participants with homologous recombination repair gene mutations [PROfound (de Bono et al. 2020, Hussain et al. 2019) and TRITON2 (Abida et al. 2019) studies].

[0008] Prostate-specific membrane antigen

[0009] Prostate-specific membrane antigen (PSMA) is a transmembrane protein also known as folate hydrolase or glutamate carboxypeptidase II. PSMA is highly overexpressed in almost all prostate cancers but is expressed at limited levels and hundreds of times lower in some normal tissues (such as the duodenal mucosa, proximal renal tubules, and salivary glands) (Bostwick et al. 1998, Ghosh et al. 2004), (Mannweiler et al. 2009). In addition, PSMA overexpression is also associated with advanced, high-grade, metastatic, androgen-independent disease (Ross et al. 2003). The differential expression of PSMA from tumor tissue to non-tumor tissue has spawned many targeting strategies, involving the use of radioactive imaging for disease localization and therapeutic intervention, and thus may be an attractive target for men with mCRPC.

[0010] In addition to the expression pattern, the function of PSMA also plays an equally important role in its value as a tumor-specific targeting mechanism. Specifically, the binding of high-affinity ligands to PSMA (such as the targeting moiety in 177Lu-PSMA-617) leads to internalization through endocytosis and persistent retention of the ligand and its conjugated radioactive cargo within cancer cells (Rajasekaran et al. 2003). This functional feature of PSMA allows the development of low-molecular-weight targeted radiopharmaceuticals with favorable pharmacokinetic and tumor penetration properties, rather than being limited to antibody-based targeting strategies (Haberkorn et al. 2016).

[0011] The result of selective expression and ligand-based uptake when using PSMA as a target is a reduction in background uptake and off-target toxicity, as well as an increase in the amount of radioactivity located at the tumor site.

[0012] Mechanism of action of 177Lu-PSMA-617

[0013] The novel PSMA-targeted radiopharmaceutical 177Lu-PSMA-617 consists of a PSMA-binding ligand, glutamate-urea-lysine, and a DOTA chelator, which are linked by a linker containing a naphthyl and a cyclohexyl group. By design, 177Lu-PSMA-617 exhibits high PSMA-binding affinity and internalization, prolonged tumor retention, and rapid renal clearance (Benesova et al. 2015). PSMA-617 was specifically developed for the imaging and radiopharmaceutical therapy of prostate cancer and can be radiolabeled with gallium 68 (68Ga), lutetium 177 (177Lu), indium 111, copper 64, scandium 44, actinium 225, or yttrium 90.

[0014] 177Lu is the radioactive cargo delivered by PSMA-617, and its physical properties make it a suitable radionuclide for the treatment of mCRPC. 177Lu is a medium-energy β emitter (490 keV) with a maximum energy of 0.5 MeV and a maximum tissue penetration of <2 mm. Compared with the longer β range of 90Y, the shorter β range of 177Lu can better irradiate small tumors (Emmett et al. 2017). The shorter path length can also direct the energy into the tumor rather than the surrounding normal tissues, while the path length is still sufficient to produce bystander and cross-fire effects within the tumor lesion. The relatively long physical half-life of 177Lu, which is 6.6 days, in combination with the intratumoral retention of 177Lu-PSMA-617, can reduce the necessary dosing frequency. It is these physical properties and the advantages of PSMA targeting that enable 177Lu to deliver effective activity to prostate cancer cells.

[0015] 177Lu-PSMA-617 for the treatment of metastatic castration-resistant prostate cancer

[0016] The novel therapeutic agent 177Lu-PSMA-617 was developed in cooperation between the Deutsches Krebsforschungszentrum (DKFZ) and the University Hospital Heidelberg for use in participants with metastatic prostate cancer (Hillier et al. 2009, Kratochwil et al. 2015, Kulkarni et al. 2018c).

[0017] 177Lu-PSMA-617 has PSMA binding affinity and compound internalization, prolonged tumor uptake, rapid renal clearance, and a high tumor-to-background ratio and has entered clinical development at the German research center.

[0018] Based on data evaluation of compassionate use, favorable safety and promising results of PSA response rates of systemic radioligand therapy with 177Lu-PSMA-617 in mCRPC participants have been reported according to the German Medicines Act, AMG §13 2b, the Clinical Trials Notification (Australia) Regulations, and other countries / regions where an expanded access program has been established based on local regulations.

[0019] Dosimetry data indicate that 177Lu-PSMA-617 targets tissues expressing PSMA, which may include the salivary glands, kidneys, and small and large intestines. The salivary glands have the highest exposure; however, in prospective studies, xerostomia presented as low grade and had an incidence of approximately 87% in treated participants. 177Lu-PSMA-617 is rapidly cleared from the kidneys. To date, no significant renal toxicity has been found in any safety series. There are no reports of grade 3 / 4 renal toxicity in the literature. Exposure of normal bone marrow tissue is expected to be low because it does not express PSMA and corresponds to normal plasma clearance.

[0020] There is some evidence of reversible hematological toxicity after 177Lu-PSMA-617 treatment, manifested as leukopenia and thrombocytopenia, with incidences of 0% to 40% and 4% to 67% respectively.

[0021] The first published 177Lu-PSMA-617 clinical series consisted of 10 participants (Ahmadzadehfar et al. 2015), who were treated between November 2013 and January 2014 at 5.6 GBq / 150 mCi (4.1–6.1 GBq / 110–165 mCi). PSA decline >50% was seen in 50% of participants, increasing to 60% after 2 cycles of 6 GBq / 160 mCi (4.1–7.1 GBq / 110–190 mCi). When doses of approximately 6 GBq / 160 mCi or more were given in 2 or more fractions, PSA decline levels >50% (most commonly used in these studies to assess tumor response) remained significantly consistent across multiple clinical series. Hofman presented the first prospective open-label, single-arm, non-randomized phase 2 study of 177Lu-PSMA-617, which was conducted in 50 participants with metastatic castration-resistant prostate cancer and administered up to 4 cycles of 4–8 GBq / 110–220 mCi every 6 weeks (Hofman et al. 2018, Hofman et al. 2019). The primary endpoints of this study were to assess safety and efficacy, measured by PSA response, bone pain score, quality-of-life measurements, imaging response, and survival.

[0022] Among screened participants, 70% were identified as PSMA-positive by PET imaging and were eligible for treatment. Participants had received at least 1 taxane chemotherapy as well as abiraterone or enzalutamide in the mCRPC setting. In this heavily pre-treated participant population with few alternative treatment options, 64% of participants in the 177Lu-PSMA-617 group demonstrated a PSA response defined as a PSA decline of at least 50%, and 44% had a PSA decline of 80% or more. Among 27 participants with measurable disease, the objective response rate for measurable disease as defined by RECIST criteria was 56% (complete response [CR] and partial response [PR]). Median overall survival was 13.3 months (95% confidence interval [CI] 10.5–18.0). The 177Lu-PSMA-617 therapy was well tolerated. These safety and efficacy data also translated into significant improvements in quality-of-life scores and a reduction in pain scores.

[0023] More recently, Hofman presented the first randomized prospective open-label phase II study of 177Lu-PSMA-617 compared to cabazitaxel, which was conducted in 200 participants with docetaxel-progressive metastatic castration-resistant prostate cancer who received up to 6 cycles of 177Lu-PSMA-617 administration (Hofman 2020). The primary endpoint was PSA response, defined as a ≥50% decrease in PSA from baseline. Secondary endpoints included PSA progression-free survival, overall survival, and quality of life.

[0024] The first-ever randomized study shows that a significantly greater proportion of patients (66%) who received 177Lu-PSMA-617 had a PSA decline of >=50% compared with cabazitaxel (37%) (P<0.0001).

[0025] In summary, more than 40 compassionate use publications and prospective phase 2 clinical trial data have described the use of 177Lu-PSMA-617 in participants exposed to approved agents. In the post-taxane, post-androgen axis inhibitor setting, 177Lu-PSMA-617 has demonstrated a favorable, predictable, and well-tolerated safety profile. Clinical series have shown that the most common side effects of 177Lu-PSMA-617 treatment (mostly grade 1-2) are dry mouth, nausea, vomiting, diarrhea, constipation, fatigue, anemia, thrombocytopenia, and neutropenia. The incidence of grade 3 / 4 toxicities in this series is very low and is mainly limited to reversible hematologic events. Efficacy has been demonstrated at multiple clinically meaningful endpoints, including PSA response, soft tissue lesion regression as measured by RECIST, progression-free survival (PFS), OS, pain, and quality of life. Standard dosing and schedules have not been established.

[0026] VISION (NCT 03511664) is a phase III trial evaluating best practice standards with or without 177Lu-PSMA-617 in men with metastatic castration-resistant prostate cancer who have been previously treated with at least one androgen receptor pathway inhibitor and one or two taxane regimens and have had a PSMA-positive gallium (68Ga) PSMA-11 positron emission tomography. VISION is designed as a registration trial for 177Lu-PSMA-617 with alternative primary endpoints of radiographic progression-free survival or overall survival. Key secondary endpoints are objective response, disease control, and time to symptomatic skeletal events.

[0027] Compared with standard care, 177Lu-PSMA-617 plus standard care significantly prolonged imaging-based progression-free survival (median, 8.7 months vs 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P < 0.001) and overall survival (median, 15.3 months vs 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P < 0.001) (Sartor et al. 2021). All key secondary endpoints favored 177Lu-PSMA-617. At baseline with independent central review according to RECIST version 1.1, among 248 patients with measurable target lesions, 17 (9.2%) of 184 patients in the 177Lu-PSMA-617 group had a complete response, while none of the 64 patients in the control group had a complete response. 77 patients (41.8%) in the 177Lu-PSMA-617 group had a partial response, and 2 patients (3%) in the control group had a partial response.

[0028] The incidence of adverse events with 177Lu-PSMA-617 treatment was low, and these adverse events led to dose reduction, interruption, or discontinuation. As of January 27, 2021, 734 patients who received at least one dose of randomized treatment were included in the safety analysis. Among them, 519 patients (98.1%) in the 177Lu-PSMA-617 group and 170 patients (82.9%) in the control group reported treatment-emergent adverse events (TEAEs). The incidence of grade 3 or higher adverse events was higher in the 177Lu-PSMA-617 group than in the control group (52.7% vs 38.0%), but quality of life was not adversely affected. The most common treatment-emergent adverse events (TEAEs) reported in ≥12% of patients who received at least 1 dose of study therapy were fatigue (43.1% vs 22.9%), dry mouth (38.8% vs 0.5%), nausea (35.3% vs 16.6%), anemia (31.8% vs 13.2%), back pain (23.4% vs 14.6%), arthralgia (22.3% vs 12.7%), decreased appetite (21.2% vs 14.6%), constipation (20.2% vs 11.2%), diarrhea (18.9% vs 2.9%), vomiting (18.9% vs 6.3%), thrombocytopenia (17.2% vs 4.4%), lymphopenia (14.2% vs 3.9%), and leukopenia (12.5% vs 2.0%) in the 177Lu-PSMA-617 group and the control group, respectively (Sartor et al. 2021)

[0029] In addition, compared to standard care alone, 177Lu-PSMA-617 plus SOC delayed the time to deterioration of health-related quality of life (HRQoL) and pain, and the time to first symptomatic skeletal event in adult patients with advanced mCRPC (K. Fizazi et al. 2021).

[0030] Although 177Lu-PSMA-617 was successful in the VISION trial (i.e., in the post-taxane setting), it remains to be determined whether administering up to 6 cycles of 177Lu-PSMA-617 at a dose of 7.4 GBq (200 mCi) + / - 10% in participants with metastatic castration-resistant prostate cancer (mCRPC) who have previously received another ARDT treatment but have not been exposed to a taxane-containing regimen in the CRPC or mHSPC setting improves radiographic progression-free survival (rPFS) or death compared to a treatment change with androgen receptor-directed therapy (ARDT), and whether data from such clinical studies support label expansion of 177Lu-PSMA-617 prior to taxane use as a treatment for mCRPC.

[0031] The vast majority of patients diagnosed with CRPC have metastases at diagnosis4, and the chance of a patient with metastatic prostate cancer surviving 5 years is approximately three in ten. Despite recent advances, the outcomes for patients who progress after second-generation ARPI standard of care remain poor, and there is an urgent need for new targeted treatment options to help improve long-term outcomes. SUMMARY OF THE INVENTION

[0032] This disclosure is based on the following: The pivotal Phase III PSMAfore study of the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy Pluvicto (INN: lutetium (177Lu) vipivotide tetraxetan) reached its primary endpoint. Pluvicto demonstrated a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) compared to a treatment change with androgen receptor pathway inhibitors (ARPI). No unexpected safety findings were observed in PSMAfore; the data were consistent with the already established safety profile of Pluvicto.

[0033] This is the second positive readout for Pluvicto in a Phase III trial following the VISION study, in which the risk of death was statistically significantly reduced in PSMA-positive mCRPC patients who received Pluvicto plus standard of care after ARPI and taxane-based chemotherapy. The PSMAfore results continue to support the important role of Pluvicto in treating patients with prostate cancer.

[0034] This disclosure provides the first and interim Phase III data for PSMAfore.

[0035] Based on the data in this disclosure, Pluvicto became the first PSMA-targeted radioligand therapy to demonstrate significant and clinically meaningful benefits for such prostate cancer patients who have not received taxane-based chemotherapy.

[0036] Pluvicto again became the first PSMA-targeted radioligand therapy to demonstrate clinical benefit for mCRPC patients prior to receiving taxane-based chemotherapy, addressing a major unmet need.

[0037] This disclosure provides methods of treatment in the following aspects:

[0038] A method of treating prostate-specific membrane antigen (PSMA)-positive [particularly: progressive] metastatic castration-resistant prostate cancer (mCRPC), the method comprising administering to a patient in need thereof a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0039] wherein the patient has previously received (particularly: second-generation) androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI) or androgen receptor axis-targeted therapy (ARAT) [e.g., abiraterone, enzalutamide, darolutamide or apalutamide];

[0040] provided that the patient has not previously been treated with taxane-based chemotherapy [i.e., the patient is taxane-naïve].

[0041] Preferably, the radioligand therapy agent is [177Lu]Lu-PSMA-617 (lutetium (177Lu) vipivotide tetraxetan). BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 Shows the design of the PSMAfore clinical trial.

[0043] Figure 2A Shows the radiographic progression-free survival Kaplan-Meier plot (full analysis set, early DCO data) based on independent central review, the number of subjects at risk at randomization 0, 2, 4, 6, 8, 10, 12, 14 months 177For 177Lu-PSMA-617, it is: 233, 180, 119, 65, 36, 14, 2, 0; and for ARDT, it is: 234, 161, 84, 39, 24, 6, 0, 0.

[0044] This indicates that 177Lu-PSMA-617 significantly prolonged rPFS as compared with ARPI.

[0045] Figure 2B The Kaplan-Meier plot of radiological progression-free survival based on independent central review (full analysis set, late DCO data) shows the number of subjects at risk at 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 months after randomization for 177 For 177Lu-PSMA-617, it is: 234, 216, 174, 150, 125, 82, 64, 45, 20, 10, 2, 0; and for ARDT, it is: 234, 197, 126, 79, 65, 36, 21, 12, 8, 4, 1, 0.

[0046] This indicates that 177Lu-PSMA-617 significantly prolonged rPFS as compared with ARPI.

[0047] Figure 3A The forest plot of the hazard ratio for radiological progression-free survival with a 95% confidence interval is shown, based on independent central review of sensitivity analysis (full analysis set) at the early and late data cut-off (DCO).

[0048] From top to bottom, the hazard ratio is associated with the following values and is based on the following events:

[0049]

[0050] The hazard ratio of [177Lu]Lu-PSMA-617 compared with ARDT obtained from the stratified Cox PH model.

[0051] ‘a’: COVID-19 related death was reviewed at the last adequate tumor assessment before death.

[0052] ‘b’: COVID-19 related death was reviewed on the date of death.

[0053] Stratification factors for IRT data: previous use of ARDT in CRPC compared with HSPC; asymptomatic or mild symptoms (Brief Pain Inventory Short Form (BPI-SF) questionnaire item 3 score of 0 - 3 compared with symptomatic (BPI-SF questionnaire item 3 score > 3).

[0054] *All other analyses, except for the investigator assessment, were based on BICR.

[0055] Figure 3B Figure 4 shows a forest plot of the hazard ratios for radiographic progression-free survival with 95% confidence intervals, based on independent central review of sensitivity analyses (full analysis set) at the early and late data cut-offs (DCO).

[0056] From top to bottom, the hazard ratios are associated with the following values and are based on the following events:

[0057]

[0058] Hazard ratio of [177Lu]Lu-PSMA-617 compared to ARDT obtained from a stratified Cox PH model.

[0059] ‘a’: COVID-19 related deaths were reviewed at the last adequate tumor assessment before death.

[0060] ‘b’: COVID-19 related deaths were reviewed on the date of death.

[0061] Stratification factors for IRT data: previous use of ARDT in CRPC compared to HSPC; asymptomatic or mild symptoms (Brief Pain Inventory Short Form (BPI-SF) questionnaire item 3 score of 0 - 3 compared to symptomatic (BPI-SF questionnaire item 3 score > 3).

[0062] *All other analyses, except for the investigator assessment, were based on BICR.

[0063] Figure 4 Figure 5 shows the Kaplan-Meier plot for overall survival - interim (full analysis set), the number of subjects at risk after randomization at 0, 2, 4, 6, 8, 10, 12, 14, 16 months for 177 For [177Lu]Lu-PSMA-617 were: 233, 192, 157, 120, 68, 37, 14, 2, 0; and for ARDT were: 234, 196, 155, 117, 76, 44, 11, 3, 0.

[0064] Figure 5 Figure 6 shows the OS analysis for crossover and adjusted by ITT

[0065] Interim OS analysis (DCO: June 2023)

[0066] Pre-specified primary crossover-adjusted analysis

[0067] HR: 0.80 (95% CI: 0.48, 1.33)

[0068] Median, months (95% CI):

[0069] 19.25 (16.95, NE) vs 19.55 (14.95, NE)

[0070] Number of events 69 (29.5%) a vs 36 (15.4%)

[0071] Pre-specified supplementary unadjusted (ITT) analysis

[0072] HR: 1.16 (95% CI: 0.83, 1.64)

[0073] Median, months (95% CI):

[0074] 19.25 (16.95, NE) vs 19.71 (17.81, NE)

[0075] Number of events 69 (29.5%) vs 65 (27.8%)

[0076] Median OS follow-up time, months (range):

[0077] 12.72 (0.82, 23.00) vs 13.08 (1.54, 22.64)

[0078] Three patients died before receiving 177Lu-PSMA-617. ARPI, androgen receptor pathway inhibitor; CI, confidence interval; DCO, data cut-off; HR, hazard ratio; ITT, intention-to-treat; NE, not estimable; OS, overall survival; PSMA, prostate-specific membrane antigen.

[0079] Figure 6 Shown is a waterfall plot of the best percent change from baseline in PSA demonstrating more frequent PSA responses in the 177Lu-PSMA-617 setting compared to ARPI changes in evaluable patients

[0080] Interim OS analysis (DCO: June 2023)

[0081] (a) Patients with baseline and post-baseline PSA values. ARPI, androgen receptor pathway inhibitor; DCO, data cut-off; HR, hazard ratio; OS, overall survival; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen

[0082] Figure 7 Shown is a higher ORR and longer DOR in the 177Lu-PSMA-617 setting compared to ARPI changes in evaluable patients (a)

[0083] Intermediate OS Analysis (DCO: June 2023)

[0084] ORR (95% CI) in soft tissue: 41.9% (32.3, 51.9) vs 12.6% (6.9, 20.6)

[0085] Median DOR (patients with complete or partial response) in soft tissue, months (95% CI): 17.1 (11.6, NE), n = 44 vs 10.1 (4.6, NE), n = 13

[0086] (a) RECIST analysis set. ARPI, androgen receptor pathway inhibitor; CI, confidence interval; DCO, data cut-off date; DOR, duration of response; HR, hazard ratio; NE, not estimable; ORR, overall response rate; OS, overall survival; PSMA, prostate-specific membrane antigen; RECIST, Response Evaluation Criteria in Solid Tumors

[0087] Figure 8 Showed higher ORR and longer DOR in the case of 177Lu-PSMA-617 compared with ARPI change in patients with measurable disease at baseline (a)

[0088] Intermediate OS Analysis (DCO: June 2023)

[0089] ORR (95% CI) in soft tissue: 50.7% (38.6, 62.8) vs 14.9% (7.7, 25.0)

[0090] Median DOR (patients with complete or partial response) in soft tissue, months (95% CI): 13.63 (11.56, NE), n = 36 vs 10.05 (4.63, NE), n = 11

[0091] (a) RECIST analysis set. ARPI, androgen receptor pathway inhibitor; CI, confidence interval; DCO, data cut-off date; DOR, duration of response; HR, hazard ratio; NE, not estimable; ORR, overall response rate; OS, overall survival; PSMA, prostate-specific membrane antigen; RECIST, Response Evaluation Criteria in Solid Tumors

[0092] Figure 9A and 9B showed longer time to deterioration in combined (a) health-related quality of life and pain measurement in the case of 177Lu-PSMA-617 compared with ARPI change

[0093] Intermediate OS Analysis (DCO: June 2023)

[0094] Figure 9A: FACT-P total score, HR: 0.59 (95% CI: 0.47, 0.72), median time to deterioration, (a) months (95% CI)(a): 7.46 (6.08, 8.51) compared to 4.27 (3.48, 4.53)

[0095]

[0096] Figure 9B : BPI-SF pain intensity scale, HR: 0.69 (95% CI: 0.56, 0.85), median time to deterioration, (a) months (95% CI): 5.03 (4.40, 6.87) compared to 3.71 (3.09, 4.37)

[0097] (a) Composite of deterioration score, clinical disease progression, or death. ARPI, androgen receptor pathway inhibitor; BPI-SF, Brief Pain Inventory-Short Form; CI, confidence interval; DCO, data cut-off; FACT-P, Functional Assessment of Cancer Therapy-Prostate; HR, hazard ratio; OS, overall survival; PSMA, prostate-specific membrane antigen

[0098] Detailed implementation mode

[0099] The present disclosure is described and illustrated in more detail below.

[0100] Example

[0101] The treatment methods of the present disclosure are specifically provided as the following examples:

[0102] 1. A method for treating prostate-specific membrane antigen (PSMA)-positive [especially: progressive] metastatic castration-resistant prostate cancer (mCRPC), the method comprising administering to a patient in need thereof a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0103] wherein the patient has previously received [especially: second-generation] androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI) or androgen receptor axis-targeted therapy (ARAT) [such as abiraterone, enzalutamide, darolutamide or apalutamide];

[0104] provided that the patient has not previously been treated with taxane-based chemotherapy [i.e., taxane-naïve patients].

[0105] As an alternative to Example 1, the present disclosure can be expressed as the following example:

[0106] 1a. A method for treating prostate-specific membrane antigen (PSMA)-positive [especially: progressive] metastatic castration-resistant prostate cancer (mCRPC), the method comprising administering to a patient in need thereof a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0107] wherein the patient has progressed [preferably: only once] after receiving a second-generation ARPI, but has not previously received taxane-based chemotherapy.

[0108] 1b. A method for treating prostate-specific membrane antigen (PSMA)-positive [especially: progressive] metastatic castration-resistant prostate cancer (mCRPC), the method comprising administering to a taxane-naive patient who has progressed [preferably: only once] after receiving a second-generation ARPI a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer or tautomer thereof.

[0109] 2. The treatment method according to any one of the foregoing embodiments, wherein the treatment is characterized in that, compared with continuous or alternating treatment with a previously used or different ARDT / ARPI / ARAT, the risk of radiographic progression or death of prostate cancer is reduced by at least 40% / preferably 50% / more preferably 55% / even more preferably 57%, 58% or 59% (corresponding to hazard ratios of 60% / 50% / 45% / 42% respectively).

[0110] 3. The treatment method according to any one of the foregoing embodiments, wherein the treatment is characterized in that less than 40% / preferably 35% / more preferably 30% / even more preferably 25% / even more preferably 24% of the patients in the corresponding patient population show radiographic progression within the first approximately 7 months after the start of treatment.

[0111] 4. The treatment method according to any one of the foregoing embodiments, wherein the treatment is characterized in that, compared with continuous or alternating treatment with a previously used or different ARDT / ARPI / ARAT, the radiographic progression-free survival (rPFS) in months is increased by at least 40% / preferably 50% / more preferably 60% / even more preferably 65 / even more preferably 66%.

[0112] 5. The treatment method according to any one of the foregoing embodiments, wherein the treatment is characterized in that compared with continuous or alternating treatment with a previously used or different ARDT / ARPI / ARAT, the ≥ grade 3 adverse events (AE) are reduced by at least 15% / preferably 20% / more preferably 25% / even more preferably 28%.

[0113] 6. The treatment method according to any one of the foregoing embodiments, wherein the treatment is characterized in that compared with continuous or alternating treatment with a previously used or different ARDT / ARPI / ARAT, the ≥ grade 3 serious adverse events (AE) are reduced by at least 15% / preferably 20% / more preferably 25%.

[0114] 7. The treatment method according to any one of the foregoing embodiments, wherein the RLT agent comprises at least two components:

[0115] (1) A radionuclide component; and

[0116] (2) A ligand component;

[0117] Wherein the radionuclide component (1) comprises:

[0118] (a) At least one radionuclide, preferably selected from the group consisting of: alpha particle-emitting radionuclides, beta-negative electron-emitting radionuclides, and Auger electron-emitting radionuclides, more preferably beta-negative electron-emitting radionuclides; and

[0119] Wherein, the ligand component (2) comprises:

[0120] (b) At least one PSMA-binding moiety;

[0121] (c) Optionally at least one chelating agent for chelating the radionuclide or a salt containing the radionuclide, or a prosthetic residue from a radiohalogenation reaction;

[0122] (d) Optionally at least one linker connecting the PSMA-binding moiety (b) to the chelating agent or prosthetic component (c), preferably the linker is a chemical moiety or a covalent bond;

[0123] (e) Optionally at least one additional moiety that modifies the systemic circulation time, tumor uptake, and / or biodistribution of the RLT agent, preferably the modifying moiety comprises an oxyethylene unit, such as oligomeric or polymeric oxyethylene -(-CH2-CH2-O-)n-, n = 2-100, or is an albumin-binding moiety (such as Evans blue, 4-(p-iodophenyl)butyric acid, 4-(p-methylphenyl)butyric acid, ibuprofen).

[0124] 8. The treatment method according to Example 7, wherein the radionuclide is selected from the group consisting of: Lu-177, Tb-161, I-131, Tc-99m, Y-90, Sc-47, Cu-67, Re-188, Pb-212, Bi-213, Ac-255, and Th-227, preferably selected from the group consisting of: Lu-177 and Tb-161.

[0125] 9. The treatment method according to any one of Examples 7 to 8, wherein the radionuclide is a β-emitting radionuclide with a half-life of about 2 to about 10 days, preferably about 5 to about 10 days, more preferably about 6 to about 8 days, and even more preferably about 6 or about 7 days; and the maximum energy of the β-particles is about 0.3 to about 1.0 MeV, preferably about 0.5 to about 0.8 MeV, more preferably about 0.5, 0.6, 0.7, or 0.8 MeV, and even more preferably about 0.5 or about 0.6 MeV.

[0126] 10. The treatment method according to any one of Examples 7 to 9, wherein the radionuclide is a β-emitting radionuclide with an absorbed electron energy fraction / decay of 100 to 300 keV / decay, 120 to 250 keV / decay, about 150 keV / decay (e.g., for Lu-177: 147 keV) to about 200 keV / decay (e.g., for Tb-161: 196 keV / decay).

[0127] 11. The treatment method according to any one of Examples 7 to 10, wherein the ligand is selected from the group consisting of: PSMA-617, PSMAI&T, PSMA-R2, MIP-1095, MIP-1545, MIP-1555, MIP-1557, MIP-1558, CTT1403, FC705, BAY-2315497, TLX592, PSMA-TCC, rhPSMA, rhPSMA-7, rhPSMA-7.3, rhPSMA-10.1, Ludotadipep, PNT2001, PNT2002, PSMA-7I&T, EB-PSMA-617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93, RPS-074, RPS-072, NG001, ADVC00, PMI-21, HTK03121, IBU DAB PSMA, PSMACM, or mcl-alb-M-PSMA, preferably selected from the group consisting of: PSMA-617, PSMAI&T, and PSMA-R2.

[0128] 12. The treatment method according to any one of Examples 7 to 11, wherein the PSMA-binding moiety comprises at least two amino acids linked by a urea or phosphoramide group, preferably glutamic acid-urea-lysine (GUL), or an antibody or fragment thereof, such as TLX591, J591, rosopatamab, IAB2M, GCP-05, 1H8H5, SP29 or FOLH1.

[0129] 13. The treatment method according to any one of Examples 7 to 12, wherein the radiopharmaceutical agent is selected from the group consisting of: [177Lu]Lu-PSMA-617 (lutetium (177Lu) vipivotide tetraxetan), [177Lu]Lu-EB-PSMA-617 (Evans blue-modified [177Lu]Lu-PSMA-617) and [177Lu]Lu-PSMA I&T (lutetium (177Lu) zedavaptide curaxin), [161Tb]Tb-PSMA-617 (terbium (161Tb) vipivotide tetraxetan), [161Tb]Tb-EB-PSMA-617 (Evans blue-modified [161Tb]Tb-PSMA-617), and [161Tb]Tb-PSMA I&T (terbium (161Tb) zedavaptide curaxin), preferably [177Lu]Lu-PSMA-617 (lutetium (177Lu) vipivotide tetraxetan) or [161Tb]Tb-PSMA-617 (terbium (161Tb) vipivotide tetraxetan), more preferably [177Lu]Lu-PSMA-617 (lutetium (177Lu) vipivotide tetraxetan).

[0130] 14. The treatment method according to any one of Examples 7 to 13, wherein the PSMA-binding moiety is glutamic acid-urea-lysine (GUL) and the linker comprises residues of (2-naphthyl)-L-alanine and trans-4-aminomethyl-cyclohexanecarboxylic acid or the linker comprises residues of optionally substituted phenylalanine and / or optionally substituted tyrosine, preferably phenylalanine and substituted tyrosine, more preferably phenylalanine and iodine-substituted tyrosine, even more preferably D-phenylalanine and iodine-substituted D-tyrosine.

[0131] 15. The treatment method according to any one of the foregoing examples, wherein the radiopharmaceutical agent is administered once every about 5 to about 10 weeks, preferably about 6 to about 8 weeks, more preferably 6 (±1) weeks (i.e., 1 cycle) at a dose of about 6 to about 8 GBq, preferably about 6.5 to about 7.8 GBq, more preferably 7.4 (±10%) GBq, for up to about 4 to about 6 cycles, preferably about 6 cycles.

[0132] 16. The treatment method according to any one of the foregoing embodiments, wherein the radiopharmaceutical agent is administered once every 6 (±1) weeks (i.e., one cycle) at a dose of 7.4 (±10%) GBq for up to 6 cycles.

[0133] 17. The treatment method according to any one of the foregoing embodiments, wherein the PSMA positivity of the mCRPC is determined by positron emission tomography (PET) using a PSMA-binding radiodiagnostic agent or imaging agent, wherein the radiopharmaceutical imaging agent comprises:

[0134] (1) A radionuclide component; and

[0135] (2) A ligand component;

[0136] Wherein the radionuclide component (1) comprises:

[0137] (a) At least one positron-emitting radionuclide; and

[0138] Wherein, the ligand component (2) comprises:

[0139] (b) At least one PSMA-binding moiety;

[0140] (c) Optionally at least one chelating agent for chelating the radionuclide or a salt containing the radionuclide, or a prosthetic residue from a radiohalogenation reaction;

[0141] (d) Optionally at least one linker connecting the PSMA-binding moiety (b) to the chelating agent / prosthetic component (c), preferably the linker is a chemical moiety or a covalent bond.

[0142] 18. The treatment method according to embodiment 17, wherein the radionuclide is selected from the group consisting of F-18, Ga-67, Ga-68 and Cu-64.

[0143] 19. The treatment method according to any one of embodiments 17 to 18, wherein the ligand component is selected from the group consisting of: PSMA-11 (gozetotide), DCPyL (if labeled with 18F, can be used as PYLARIFY, INN: piflufolastat F-18, also abbreviated as PyL), MIP-1404, rhPSMA 07, PSMA-1007, THP-PSMA, iPSMA, P16-093, PSMA-93, rhPSMA, rhPSMA-7, rhPSMA-7.3, PSMA-7 and PSMAI&T.

[0144] Further embodiments of the present disclosure are provided below

[0145] E1. A method of reducing the risk of prostate cancer progression, particularly radiographic progression, clinical progression, and / or PSA progression, particularly radiographic progression or death, in a patient in need thereof;

[0146] The method comprises administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) agent, n.c.a. (no carrier added), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer, or tautomer thereof;

[0147] wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC);

[0148] wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI), or androgen receptor axis targeting therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy, or in the case of previous taxane exposure, at least 12 months have elapsed since the completion of said chemotherapy (i.e., the last dose was administered).

[0149] E2. The (treatment) method according to any one of the preceding embodiments, wherein the treatment is characterized in that the risk of radiographic progression or death of the prostate cancer is reduced by at least 40% / preferably 50% / more preferably 55% / even more preferably 57% / 58% / 59% [corresponding to a hazard ratio (HR) of not more than 60% / 50% / 45% / 43% / 42% / 41% respectively] compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT.

[0150] E3. The (treatment) method according to any one of the preceding embodiments, wherein the treatment is characterized in that less than 40% / preferably 35% / more preferably 30% / even more preferably 25% / even more preferably 24% of the patients in the respective patient population show radiographic progression within the first approximately 7, 8, 9, 10, 11, 12 months after the start of treatment.

[0151] E3.1 The (treatment) method according to any one of the preceding embodiments, wherein the treatment is characterized in that the radiographic progression-free survival (rPFS) in months is increased by at least 40% / preferably 50% / more preferably 60% / even more preferably 65 / even more preferably 66% compared to continuous or alternating treatment with a previously used or different ARDT / ARPI / ARAT.

[0152] Alternatively, in certain embodiments, the methods of the present disclosure are formed in the following manner:

[0153] E3.a A method for reducing the rate of radiographic progression of prostate cancer in patients in need thereof, compared to continuous or alternating treatment with a previously used or different ARDT / ARPI / ARAT, particularly within the first 7, 8, 9, 10, 11, or 12 months after the start of the method,

[0154] The method comprising administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA)-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformational isomer, or tautomer thereof, without added carrier (n.c.a.);

[0155] wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC);

[0156] wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI), or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy, or, in the case of previous taxane exposure, at least 12 months have elapsed since the completion of the chemotherapy (i.e., the last dose administration).

[0157] In certain embodiments, the rate of radiographic progression is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0158] E4. A (treatment) method as described in any of the preceding embodiments, wherein the treatment is characterized in that treatment-related ≥ grade 3 adverse events occur in less than 25% of the patients in the corresponding patient population.

[0159] E4.1 A (treatment) method as described in any of the preceding embodiments, wherein the treatment is characterized in that ≥ grade 3 adverse events (AE) are reduced by at least 15% / preferably 20% / more preferably 25% / even more preferably 28%, compared to continuous or alternating treatment with a previously used or different ARDT / ARPI / ARAT.

[0160] Alternatively, in certain embodiments, the methods of the present disclosure are formed in the following manner:

[0161] E4.a A method for reducing the incidence rate of ≥ grade 3 adverse events (AE) in patients in need of prostate cancer treatment, compared to continuous or alternating treatment with a previously used or different ARDT / ARPI / ARAT,

[0162] The method comprises administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu) labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof;

[0163] wherein the prostate cancer is prostate-specific membrane antigen (PSMA) positive (+) metastatic castration-resistant prostate cancer (mCRPC);

[0164] wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI) or androgen receptor axis targeting therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy, or in the case of previous taxane exposure, at least 12 months have elapsed since the completion of said chemotherapy (i.e., the last dose administration).

[0165] In certain embodiments, the incidence rate of said ≥ grade 3 adverse events (AE) is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0166] E5. The (treatment) method according to any one of the preceding embodiments, wherein the treatment is characterized in that treatment-related ≥ grade 3 Severe adverse events occur in less than 15% of the patients in the corresponding patient population.

[0167] E5.1 The (treatment) method according to any one of the preceding embodiments, wherein the treatment is characterized in that the ≥ grade 3 serious adverse events (AE) are reduced by at least 15% / preferably 20% / more preferably 25%, compared to continuous or alternating treatment with a previously used or different ARDT / ARPI / ARAT.

[0168] E5.a A method for reducing the incidence rate of ≥ grade 3 adverse events (AE) in patients in need of prostate cancer treatment, compared to continuous or alternating treatment with a previously used or different ARDT / ARPI / ARAT,

[0169] The method comprises administering to the patient a therapeutically effective amount of a lutetium-177 ( 177A prostate-specific membrane antigen (PSMA)-binding radioligand therapy (RLT) agent labeled with Lu), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof;

[0170] wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC);

[0171] wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI) or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy, or in the case of previous taxane exposure, at least 12 months have elapsed since the completion of said chemotherapy (i.e., the last dose administration).

[0172] In certain embodiments, the incidence of ≥ grade 3 serious adverse events (AEs) is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0173] E6. The (treatment) method according to any one of the preceding embodiments, wherein the treatment is safer and more tolerable compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0174] E7. The (treatment) method according to any one of the preceding embodiments, wherein the treatment is characterized in that the ≥ grade 3 adverse events (AEs) are reduced by at least 15% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0175] E8. The (treatment) method according to any one of the preceding embodiments, wherein the treatment is characterized in that the ≥ grade 3 serious adverse events (AEs) are reduced by at least 15% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0176] E9. The (treatment) method according to any one of the preceding embodiments, wherein the radioligand therapy agent is administered once every 5 to 10 weeks, preferably 6 to 8 weeks, more preferably 6 (±1) weeks (i.e., 1 cycle) at a dose of about 6 to about 8 GBq, preferably about 6.5 to about 7.8 GBq, more preferably 7.4 (±10%) GBq, for up to 4 to 6 cycles, preferably 6 cycles.

[0177] E10. The (treatment) method as described in any one of the foregoing embodiments, wherein the radioligand therapeutic agent is administered once every 6 (±1) weeks (i.e., one cycle) at a dose of 7.4 (±10%) GBq for up to 6 cycles.

[0178] E11. A Prolong the radiographic progression-free survival (rPFS) period in patients requiring prostate cancer treatment method for delaying the initiation of chemotherapy in patients in need of prostate cancer treatment and / or a method for substituting chemotherapy for patients in need of prostate cancer treatment;

[0179] The method includes administering to the patient a therapeutically effective amount of a prostate-specific membrane antigen (PSMA)-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof;

[0180] wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC);

[0181] wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI) or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not received taxane-based chemotherapy less than 12 months prior.

[0182] E12. The (treatment) method as described in any one of the foregoing embodiments, wherein the treatment is characterized in that the radiographic progression-free survival (rPFS) period in months is increased by at least 40% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT.

[0183] E13. The (treatment) method as described in any one of the foregoing embodiments, wherein the treatment is characterized in that treatment-related ≥ grade 3 adverse events occur in less than 25% of the patients in the corresponding patient population.

[0184] E14. The (treatment) method as described in any one of the foregoing embodiments, wherein the treatment is characterized in that treatment-related ≥ grade 3 Severe adverse events occur in less than 15% of the patients in the corresponding patient population.

[0185] E15. The (treatment) method as described in any one of the foregoing embodiments, wherein the treatment is safer and more tolerable compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT.

[0186] E16. The (treatment) method according to any one of the foregoing embodiments, wherein the treatment is characterized in that the ≥ grade 3 adverse events (AE) are reduced by at least 15% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0187] E17. The (treatment) method according to any one of the foregoing embodiments, wherein the treatment is characterized in that the ≥ grade 3 serious adverse events (AE) are reduced by at least 15% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0188] E18. The (treatment) method according to any one of the foregoing embodiments, wherein the radiopharmaceutical agent is administered once every 5 to 10 weeks, preferably 6 to 8 weeks, more preferably 6 (±1) weeks (i.e., 1 cycle) at a dose of about 6 to about 8 GBq, preferably about 6.5 to about 7.8 GBq, more preferably 7.4 (±10%) GBq, for up to 4 to 6 cycles, preferably 6 cycles.

[0189] E19. The (treatment) method according to any one of the foregoing embodiments, wherein the radiopharmaceutical agent is administered once every 6 (±1) weeks (i.e., 1 cycle) at a dose of 7.4 (±10%) GBq, for up to 6 cycles.

[0190] E20. The (treatment) method according to any one of the foregoing embodiments, wherein n.c.a. 177 The Lu-labeled PSMA-binding RLT agent or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof comprises the following components:

[0191] (1) A β-emitting radionuclide in n.c.a. mass 177 Lu;

[0192] (2) A ligand component;

[0193] Wherein, the ligand component (2) comprises:

[0194] (a) At least one PSMA-binding moiety;

[0195] (b) At least one chelating agent moiety suitable for chelating the radionuclide;

[0196] (c) At least one linker moiety connecting the PSMA-binding moiety (a) to the chelating agent component (b);

[0197] (d) Optionally, at least one additional moiety that modifies the systemic circulation time, tumor uptake, and / or biodistribution of the RLT agent, preferably the modifying moiety comprises oxyethylene units, such as oligomeric or polymeric oxyethylene -(-CH2-CH2-O-)n-, where n = 2 - 100, or is an albumin-binding moiety (such as Evans blue, 4-(p-iodophenyl)butyric acid, 4-(p-methylphenyl)butyric acid, ibuprofen), and the modifying moiety is preferably covalently linked to the linker component (c).

[0198] E21. The (therapeutic) method of any one of the foregoing embodiments, wherein the PSMA-binding moiety (a) comprises at least two amino acids linked by a urea or phosphoramide group, preferably glutamic acid-urea-lysine (GUL), or an antibody or fragment thereof, such as TLX591, J591, rosopatamab, IAB2M, GCP-05, 1H8H5, SP29, or FOLHl.

[0199] E22. The (therapeutic) method as described in any one of the foregoing embodiments, wherein the linker (c) that includes a functional group for binding to the PSMA-binding moiety, for example, the amide bond that links the lysine of the binding moiety to the linker, comprises at least one hydrophobic side chain, such as a side chain containing an aromatic unit, such as an optionally substituted phenyl, an optionally substituted benzyl, or an optionally substituted naphthyl.

[0200] E23. The (therapeutic) method of any one of the foregoing embodiments, wherein the linker (c) comprises residues of (2-naphthyl)-L-alanine and trans-4-aminomethyl-cyclohexanecarboxylic acid or the linker comprises residues of optionally substituted phenylalanine and / or optionally substituted tyrosine, preferably phenylalanine and substituted tyrosine, more preferably phenylalanine and iodine-substituted tyrosine, even more preferably D-phenylalanine and iodine-substituted D-tyrosine.

[0201] E24. The (therapeutic) method as described in any one of the foregoing embodiments, wherein the ligand is selected from the group consisting of: PSMA-617 (vipivotide tetraxetan), PSMA I&T (zadavotide curaxetan), PSMA-R2, rhPSMA-7.3, rhPSMA-10.1, EB-PSMA-617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93, CTT1403, and RPS-074, preferably selected from PSMA-617, PSMA I&T, and PSMA-R2.

[0202] E25. The (therapeutic) method as described in any one of the foregoing embodiments, wherein the RLT agent is selected from the group consisting of: 177 Lu]Lu-PSMA-617 (lutetium (177 Lu) Vipivotide Tetraxetan), 177 Lu] Lu-EB-PSMA-617 (Evans Blue 177 Lu] Lu-PSMA-617) and 177 Lu] Lu-PSMA I&T (Lutetium ([ 177 Lu) Zadivotide Gualaxo).

[0203] E26. The (treatment) method according to any one of the foregoing embodiments, wherein the PSMA positivity of the mCRPC is determined by positron emission tomography (PET) using a PSMA-binding radioligand diagnostic or imaging (RLI) agent, wherein the radioligand imaging agent comprises:

[0204] (1) a radionuclide component; and

[0205] (2) a ligand component;

[0206] wherein the radionuclide component (1) comprises:

[0207] (a) at least one positron-emitting radionuclide; and

[0208] wherein the ligand component (2) comprises:

[0209] (b) at least one PSMA-binding moiety;

[0210] (c) optionally at least one chelating agent for chelating the radionuclide or a salt containing the radionuclide, or a prosthetic group residue from a radiohalogenation reaction;

[0211] (d) optionally at least one linker connecting the PSMA-binding moiety (b) to the chelating agent / prosthetic group component (c), preferably the linker is a chemical moiety or a covalent bond.

[0212] E27. The (treatment) method according to any one of the foregoing embodiments, wherein the radionuclide is selected from the group consisting of F-18, Ga-67, Ga-68 and Cu-64.

[0213] E28. The (treatment) method according to any one of the foregoing embodiments, wherein the ligand component is selected from the group consisting of: PSMA-11, DCPyL, PyL, MIP-1404, rhPSMA 07, PSMA-1007, THP-PSMA, iPSMA, P16-093, PSMA-93, rhPSMA, rhPSMA-7, rhPSMA-7.3 and PSMA-7I&T.

[0214] E29. The (treatment) method according to any one of the foregoing embodiments, wherein the RLI agent is selected from the group consisting of: 68 Ga]Ga-PSMA-11 (gallium ( 68 Ga) gozetide, available as LOCAMETZ from Novartis or Advanced Accelerator Applications, or available as ILLUCCIX from Telix), 18 F-DCPyL (piflufolastat ( 18 F), available as PYLARIFY from Lantheus or available as PYLCLARI from Curium), 18 F-PSMA-1007 (available as RADELIUM from ABX), 18 F-CTT1057 (vidoflufolastat ( 18 F)), 18 F / nat Ga-rhPSMA-7.3 (flotufolastat ( 18 F), available as POSLUMA from Blue Earth), 68 Ga]Ga-PSMA-R2 and 64 Cu]Cu-PSMA-R2.

[0215] Further embodiments of the present disclosure are as follows:

[0216] e1. A method of reducing the risk of radiographic progression or death of prostate cancer in a patient in need thereof;

[0217] The method comprises administering to the patient a therapeutically effective amount of an lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA)-binding radioligand therapy (RLT) agent without added carrier (n.c.a.), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof;

[0218] wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC);

[0219] wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI), or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy, or, in the case of previous taxane exposure, at least 12 months have elapsed since the completion of such chemotherapy (i.e., the last dose administration).

[0220] e2. The treatment method as described in the previous embodiment, wherein the treatment is characterized in that the risk of radiographic progression or death of the prostate cancer is reduced by at least 50% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, corresponding to a hazard ratio (HR) of no more than 50%.

[0221] e3. The treatment method as described in any one of the previous two embodiments, wherein the treatment is characterized in that within the first approximately 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months from the start of treatment, radiographic progression occurs in less than 25% of the corresponding patient population.

[0222] e4. A method for prolonging the radiographic progression-free survival (rPFS) period of a patient in need of prostate cancer treatment;

[0223] The method comprises administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA)-binding radiopharmaceutical therapy (RLT) agent without added carrier (n.c.a.), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer, or tautomer thereof;

[0224] wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC);

[0225] wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI), or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy, or, in the case of previous taxane exposure, at least 12 months have elapsed since the completion of such chemotherapy (i.e., the last dose administration).

[0226] e5. The treatment method as described in the previous embodiment, wherein the treatment is characterized in that the time in months of radiological progression-free survival (rPFS) is increased by at least 40% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0227] e6. A method for increasing the overall survival (OS) of a patient in need of prostate cancer treatment;

[0228] The method comprises administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu) labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) agent without added carrier (n.c.a.), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof;

[0229] wherein the prostate cancer is prostate-specific membrane antigen (PSMA) positive (+) metastatic castration-resistant prostate cancer (mCRPC);

[0230] wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI) or androgen receptor axis targeting therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy, or in the case of previous taxane exposure, at least 12 months have elapsed since the completion of said chemotherapy (i.e., the last dose was administered).

[0231] e7. The treatment method as described in the previous embodiment, wherein when calculating the risk of death corresponding to a hazard ratio of less than 1, about 0.95 or lower, about 0.9 or lower, about 0.85 or lower, about 0.8 or lower, about 0.75 or lower, about 0.7 or lower, about 0.65 or lower, about 0.6 or lower, about 0.55 or lower or 0.5 or lower, respectively, relative to patients receiving continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, the treatment reduces said risk.

[0232] e8. A method for increasing the overall response rate (ORR) (i.e., complete response (CR) and partial response (PR)) in soft tissues of a patient in need of prostate cancer treatment;

[0233] The method comprises administering to the patient a therapeutically effective amount of a lutetium-177 ( 177A lutetium-177 ([ 177 Lu])-labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof;

[0234] wherein the prostate cancer is prostate-specific membrane antigen (PSMA) positive (+) metastatic castration-resistant prostate cancer (mCRPC);

[0235] wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI) or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy, or in the case of previous taxane exposure, at least 12 months have elapsed since the completion of said chemotherapy (i.e., the last dose administration).

[0236] e9. The method of treatment as described in the previous example, wherein the objective response rate (ORR) in soft tissue is increased by at least 100%, at least 150%, at least 200%, at least 250% or at least 300% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0237] e10. The method of treatment as described in any one of the previous two examples, wherein the complete response (CR) rate in soft tissue is increased by at least 100% (doubled), at least 150%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450% or at least 500% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0238] Overall survival (OS) can be related to the length of time a patient survives, which can include death from any cause, whether or not breast cancer recurs or spreads. OS can be defined as the time from a first date (e.g., the date cancer treatment starts or alternatively the date cancer treatment ends) to the date of death from any cause.

[0239] e11. A method of improving the health-related quality of life (HRQoL) (e.g., determined by Functional Assessment of Cancer Therapy - Prostate (FACT-P)) of a patient in need of prostate cancer treatment;

[0240] The method comprises administering to the patient a therapeutically effective amount of lutetium-177 ([ 177 Lu]) without added carrier (n.c.a.) 177A lutetium-177 (

[0241] wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC);

[0242] wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI), or androgen receptor axis targeting therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy, or, in the case of previous taxane exposure, at least 12 months have elapsed since the completion of said chemotherapy (i.e., the last dose administration).

[0243] e12. The treatment method according to the previous embodiment, wherein the time to overall HRQoL deterioration is increased by about 50%, about 60%, or about 70% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0244] e13. The treatment method according to any one of the previous two embodiments, wherein the risk of overall HRQoL deterioration is reduced by at least 25%, at least 30%, at least 35%, or at least 40% (corresponding to an HR of up to 0.75, up to 0.70, up to 0.65, or up to 0.60) when calculated relative to patients receiving continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0245] e14. A method of increasing PSA response in a patient in need of prostate cancer treatment;

[0246] The method comprises administering to the patient a therapeutically effective amount of a non-carrier-added (n.c.a.) lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA)-binding radiopharmaceutical therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer, or tautomer thereof;

[0247] wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC);

[0248] wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI), or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy, or, in the case of prior taxane exposure, at least 12 months have elapsed since the completion of such chemotherapy (i.e., the last dose administration).

[0249] e15. The method of treatment as described in the previous embodiment, wherein the demonstrated at least 50% PSA reduction is about 100% or at least 150% as compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0250] e16. A method of delaying the time to symptomatic skeletal events (SSE) in a patient in need of prostate cancer treatment;

[0251] the method comprising administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA)-binding radiopharmaceutical therapy (RLT) agent without added carrier (n.c.a.), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer, or tautomer thereof;

[0252] wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC);

[0253] wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI), or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy, or, in the case of prior taxane exposure, at least 12 months have elapsed since the completion of such chemotherapy (i.e., the last dose administration).

[0254] e17. The method of treatment as described in the previous embodiment, the delay in time to SSE is lengthened by about 50%, lengthened by about 60%, lengthened by about 70%, lengthened by about 80%, lengthened by about 90% as compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0255] e18. A method of reducing the risk of symptomatic skeletal events (SSE) in a patient in need of prostate cancer treatment;

[0256] the method comprising administering to the patient a therapeutically effective amount of a lutetium-177 ( 177A prostate-specific membrane antigen (PSMA)-binding radioligand therapy (RLT) agent labeled with Lu), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof;

[0257] wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC);

[0258] wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI) or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy, or in the case of previous taxane exposure, at least 12 months have elapsed since the completion of said chemotherapy (i.e., the last dose administration).

[0259] e19. The treatment method as described in the previous embodiment, compared with continuous or alternating ARDT / ARPI / ARAT treatment with previously used or different ARDT / ARPI / ARAT, the risk is reduced by at least about 50%, about 55%, about 60%, about 65% or about 70%.

[0260] e20. The treatment method as described in any one of the foregoing embodiments, wherein the treatment is safer and more tolerable compared with continuous or alternating ARDT / ARPI / ARAT treatment with previously used or different ARDT / ARPI / ARAT, respectively.

[0261] e21. The treatment method as described in any one of the foregoing embodiments, wherein the treatment is characterized in that treatment-related ≥ grade 3 adverse events occur in less than 25% of the patients in the corresponding patient population.

[0262] e22. The treatment method as described in any one of the foregoing embodiments, wherein the treatment is characterized in that treatment-related ≥ grade 3 serious adverse events occur in less than 15% of the patients in the corresponding patient population.

[0263] e23. The treatment method as described in any one of the foregoing embodiments, wherein the radioligand therapy agent is administered once every 6 to 8 weeks (i.e., 1 cycle) at a dose of about 6 to about 8 GBq for up to 4 to 6 cycles.

[0264] e24. The treatment method as described in any one of the foregoing embodiments, wherein the radioligand therapy agent is administered once every 6 (±1) weeks (i.e., 1 cycle) at a dose of 7.4 (±10%) GBq for up to 6 cycles.

[0265] e25. The treatment method according to any one of the foregoing embodiments, wherein n.c.a. 177 The Lu-labeled PSMA-binding RLT agent or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof comprises the following components:

[0266] (1) A β - minus electron emitting radionuclide in n.c.a. mass 177 Lu;

[0267] (2) A ligand component;

[0268] Wherein, the ligand component (2) comprises:

[0269] (a) At least one PSMA-binding moiety;

[0270] (b) At least one chelating agent moiety suitable for chelating the radionuclide; and

[0271] (c) At least one linker moiety connecting the PSMA-binding moiety (a) and the chelating agent component (b).

[0272] e26. The treatment method according to any one of the foregoing embodiments, wherein the PSMA-binding moiety (a) comprises the amino acids glutamate and lysine linked by a urea group, such as glutamate-urea-lysine (GUL); wherein the chelating agent moiety (b) comprises a DOTA residue or a DOTAGA residue; and wherein the linker (c) (including the functional group that binds the linker to the PSMA-binding moiety, for example, the amide bond that links the lysine of the binding moiety to the linker) comprises at least one hydrophobic side chain selected from the group consisting of an optionally substituted phenyl, an optionally substituted benzyl, or an optionally substituted naphthyl.

[0273] e27. The treatment method according to any one of the foregoing embodiments, wherein the RLT agent is selected from the group consisting of: 177 Lu]Lu-PSMA-617 (lutetium ( 177 Lu) vipivotide tetraxetan), 177 Lu]Lu-PSMAI&T (lutetium ( 177 Lu) zadavotide curaclam) and 177 Lu]Lu-PSMA-R2.

[0274] e28. The treatment method according to any one of the foregoing embodiments, wherein the RLT agent is selected from the group consisting of: 177 Lu]Lu-PSMA-617 (lutetium ( 177 Lu) vipivotide tetraxetan) and 177Lu-Lutetium-PSMA I&T (Lutetium 177 Lu) Zadaxin Piracetam).

[0275] e29. The treatment method according to any one of the foregoing embodiments, wherein the RLT agent is 177 Lu-Lutetium-PSMA-617 (Lutetium 177 Lu) Vipivotide Tetraxetan).

[0276] e30. The treatment method according to any one of the foregoing embodiments, wherein the PSMA positivity of the mCRPC is determined by positron emission tomography (PET) using a PSMA-binding radioligand diagnostic or imaging (RLI) agent, wherein the radioligand imaging is selected from the group consisting of: 68 Ga-Gallium-PSMA-11 (Gallium 68 Ga) Gozetide), 18 F-DCPyL (Piflufolastat 18 F)), 18 F-PSMA-1007, 18 F-CTT1057 (Vesiflufolastat 18 F)), 18 F / nat Ga-rhPSMA-7.3 (Rotufolastat 18 F)), 68 Ga-Gallium-PSMA-R2 and 64 Cu-Copper-PSMA-R2.

[0277] More generally, for the embodiments throughout this disclosure, the following is provided:

[0278] In some embodiments, the treatment method is a method of reducing the risk of radiographic progression or death of prostate cancer in a patient in need thereof.

[0279] In some embodiments, the treatment method comprises administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu) labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) agent without added carrier (n.c.a.), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof.

[0280] In some embodiments, the prostate cancer is prostate-specific membrane antigen (PSMA) positive (+) metastatic castration-resistant prostate cancer (mCRPC).

[0281] In some embodiments, the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI), or androgen receptor axis-targeted therapy (ARAT).

[0282] In some embodiments, the patient has not previously been treated with taxane-based chemotherapy.

[0283] In some embodiments, the patient has not previously been treated with taxane-based chemotherapy, or in the case of prior taxane exposure, at least 12 months have elapsed since the completion of said chemotherapy (i.e., the last dose administration).

[0284] In some embodiments, the treatment method is characterized in that, compared with continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, the risk of radiographic progression or death of prostate cancer is reduced by at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69% or 70%, corresponding to a hazard ratio (HR) of no more than 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31% or 30%.

[0285] In some embodiments, the treatment method is characterized in that within the first approximately 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 months from the start of treatment, less than 25% of the patients in the corresponding patient population experience radiographic progression.

[0286] In some embodiments, the treatment method is characterized in that within the first approximately 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 months from the start of treatment, less than 24% of the patients in the corresponding patient population experience radiographic progression.

[0287] In some embodiments, the treatment method is characterized in that within the first approximately 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months from the start of treatment, less than 23% of the patients in the corresponding patient population exhibit radiographic progression.

[0288] In some embodiments, the treatment method is characterized in that within the first approximately 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months from the start of treatment, less than 22% of the patients in the corresponding patient population exhibit radiographic progression.

[0289] In some embodiments, the treatment method is characterized in that within the first approximately 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months from the start of treatment, less than 21% of the patients in the corresponding patient population exhibit radiographic progression.

[0290] In some embodiments, the treatment method is characterized in that within the first approximately 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months from the start of treatment, less than 20% of the patients in the corresponding patient population exhibit radiographic progression.

[0291] In some embodiments, the treatment method is characterized in that within the first approximately 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months from the start of treatment, less than 19% of the patients in the corresponding patient population exhibit radiographic progression.

[0292] In some embodiments, the treatment method is characterized in that within the first approximately 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months from the start of treatment, less than 18% of the patients in the corresponding patient population exhibit radiographic progression.

[0293] In some embodiments, the treatment method is characterized in that within about the first 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months or 24 months from the start of treatment, less than 17% of the patients in the corresponding patient population exhibit radiographic progression.

[0294] In some embodiments, the treatment method is characterized in that within about the first 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months or 24 months from the start of treatment, less than 16% of the patients in the corresponding patient population exhibit radiographic progression.

[0295] In some embodiments, the treatment method is characterized in that within about the first 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months or 24 months from the start of treatment, less than 15% of the patients in the corresponding patient population exhibit radiographic progression.

[0296] In some embodiments, the treatment method is characterized in that within about the first 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months or 24 months from the start of treatment, less than 10% of the patients in the corresponding patient population exhibit radiographic progression.

[0297] In some embodiments, the treatment method is characterized in that within about the first 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months or 24 months from the start of treatment, less than 5% of the patients in the corresponding patient population exhibit radiographic progression.

[0298] In some embodiments, the treatment method is a method for prolonging the radiographic progression-free survival (rPFS) period of patients in need of prostate cancer treatment.

[0299] In some embodiments, compared to continuous or alternating ARDT / ARPI / ARAT treatment with previously used or different ARDT / ARPI / ARAT, the treatment method is characterized by an increase in the time in months of radiographic progression-free survival (rPFS) of at least 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 70%, 80%, 90%, 100%, 150% or 200%.

[0300] In some embodiments, the treatment method is a method of increasing overall survival (OS) in patients in need of prostate cancer treatment.

[0301] In some embodiments, when calculating the risk of death corresponding to a hazard ratio of less than 1, about 0.95 or lower, about 0.9 or lower, about 0.85 or lower, about 0.8 or lower, about 0.75 or lower, about 0.7 or lower, about 0.65 or lower, about 0.6 or lower, about 0.55 or lower or 0.5 or lower, respectively, relative to patients receiving continuous or alternating ARDT / ARPI / ARAT treatment with previously used or different ARDT / ARPI / ARAT, the treatment method reduces this risk.

[0302] In some embodiments, the treatment method is a method of increasing the overall response rate (ORR) (i.e., complete response (CR) and partial response (PR)) in soft tissues of patients in need of prostate cancer treatment.

[0303] In some embodiments, in the treatment method, compared to continuous or alternating ARDT / ARPI / ARAT treatment with previously used or different ARDT / ARPI / ARAT, the ORR in soft tissues increases by at least 100%, at least 150%, at least 200%, at least 250% or at least 300%.

[0304] In some embodiments, compared to continuous or alternating ARDT / ARPI / ARAT treatment with previously used or different ARDT / ARPI / ARAT, the complete response (CR) rate in soft tissues increases by at least 100% (doubled), at least 150%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450% or at least 500%.

[0305] In some embodiments, overall survival (OS) can be related to the length of time a patient survives, which can include death from any cause, regardless of whether breast cancer recurs or spreads.

[0306] The OS can be defined as the time from a first date (e.g., the date of initiation of cancer treatment or alternatively the date of completion of cancer treatment) to the date of death from any cause.

[0307] In some embodiments, the treatment method is a method of improving the health-related quality of life (HRQoL) of a patient in need of prostate cancer treatment (e.g., as determined by the Functional Assessment of Cancer Therapy - Prostate (FACT-P)).

[0308] In some embodiments, the treatment method as described in the previous embodiment, wherein the time to overall HRQoL deterioration is increased by about 50%, increased by about 60%, or increased by about 70% as compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0309] In some embodiments, when calculating the risk of overall HRQoL deterioration relative to patients receiving continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively, the risk is reduced by at least 25%, at least 30%, at least 35%, or at least 40% (corresponding to an HR of up to 0.75, up to 0.70, up to 0.65, or up to 0.60).

[0310] In some embodiments, the treatment method is a method of increasing the PSA response of a patient in need of prostate cancer treatment.

[0311] In some embodiments, the PSA response is a confirmed PSA reduction of at least 50% which is about at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or at least 200% as compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0312] In some embodiments, the treatment method is a method of delaying the time to symptomatic skeletal events (SSE) in a patient in need of prostate cancer treatment.

[0313] In some embodiments, the delay in the time to SSE is increased by about 50%, increased by about 60%, increased by about 70%, increased by about 80%, increased by about 90% as compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0314] In some embodiments, the treatment method is a method of reducing the risk of symptomatic skeletal events (SSE) in a patient in need of prostate cancer treatment.

[0315] In some embodiments, the SSE risk is reduced by at least about 50%, about 55%, about 60%, about 65% or about 70% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0316] In some embodiments, the treatment method is safer and more tolerable compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0317] In some embodiments, the treatment is characterized in that less than 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 10% or 5% of the corresponding patient population experiences treatment-related grade ≥3 adverse events.

[0318] In some embodiments, the treatment is characterized in that less than 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6% or 5% of the corresponding patient population experiences treatment-related grade ≥3 serious adverse events.

[0319] In some embodiments, the radioligand therapeutic agent is administered once every 6 to 8 weeks (i.e., 1 cycle) at a dose of about 6 to about 8 GBq, for up to 4 to 6 cycles.

[0320] In some embodiments, the radioligand therapeutic agent is administered once every 6 (±1) weeks (i.e., 1 cycle) at a dose of 7.4 (±10%) GBq, for up to 6 cycles.

[0321] In some embodiments, n.c.a. 177 An n.c.a. Lu-labeled PSMA-binding RLT agent or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof comprises the following components:

[0322] (1) A β-emitting radionuclide in n.c.a. mass 177 Lu;

[0323] (2) A ligand component;

[0324] Wherein, the ligand component (2) comprises:

[0325] (a) At least one PSMA-binding moiety;

[0326] (b) At least one chelating agent moiety suitable for chelating the radionuclide; and

[0327] (c) At least one linker moiety connecting the PSMA-binding moiety (a) to the chelator component (b).

[0328] In some embodiments, the PSMA-binding moiety (a) comprises the amino acids glutamic acid and lysine linked by a urea group, such as glutamic acid-urea-lysine (GUL); wherein the chelator moiety (b) comprises a DOTA residue or a DOTAGA residue; and wherein the linker (c) comprises at least one hydrophobic side chain selected from the group consisting of an optionally substituted phenyl, an optionally substituted benzyl, or an optionally substituted naphthyl.

[0329] In some embodiments, the PSMA-binding moiety (a) comprises the amino acids glutamic acid and lysine linked by a urea group, such as glutamic acid-urea-lysine (GUL); wherein the chelator moiety (b) comprises a DOTA residue or a DOTAGA residue; and wherein the linker (c) includes a functional group that binds the linker to the PSMA-binding moiety, for example, an amide bond that links the lysine of the binding moiety to the linker, and comprises at least one hydrophobic side chain selected from the group consisting of an optionally substituted phenyl, an optionally substituted benzyl, or an optionally substituted naphthyl.

[0330] In some embodiments, the RLT agent is selected from the group consisting of: 177 Lu]Lu-PSMA-617 (lutetium ( 177 Lu) vipivotide tetraxetan), 177 Lu]Lu-PSMA I&T (lutetium ( 177 Lu) zedevostide curaxil), and 177 Lu]Lu-PSMA-R2.

[0331] In some embodiments, the RLT agent is selected from the group consisting of: 177 Lu]Lu-PSMA-617 (lutetium ( 177 Lu) vipivotide tetraxetan) and 177 Lu]Lu-PSMA I&T (lutetium ( 177 Lu) zedevostide curaxil).

[0332] In some embodiments, the RLT agent is 177 Lu]Lu-PSMA-617 (lutetium ( 177 Lu) vipivotide tetraxetan).

[0333] In some embodiments, PSMA positivity in mCRPC is determined by positron emission tomography (PET) using a PSMA-binding radioligand diagnostic or imaging (RLI) agent, wherein the radioligand imaging is selected from the group consisting of: 68Ga]Ga-PSMA-11 (Gallium( 68 Ga) PSMA-11), 18 F-DCPyL (Fluciclovine( 18 F)), 18 F-PSMA-1007, 18 F-CTT1057 (Vesiforine( 18 F)), 18 F / nat Ga-rhPSMA-7.3 (Lotuforine( 18 F)), 68 Ga]Ga-PSMA-R2 and 64 Cu]Cu-PSMA-R2.

[0334] The present disclosure provides a method for treating a patient suffering from prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) with a therapeutically effective amount of a PSMA-binding radiopharmaceutical therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer or tautomer thereof, wherein the cancer of the patient is progressing after receiving or having received a second-generation ARPI.

[0335] So far, these patients have received taxane-based chemotherapy.

[0336] However, the clinical data reported herein indicate that radiopharmaceutical therapy may be a safer and / or more effective treatment for prostate cancer that is still progressing.

[0337] The treatment methods described in various embodiments herein are further characterized in that they provide a higher, at least 50% higher, at least 75% higher, at least 100% higher, at least 150% higher, at least 200% higher, at least 2-fold higher, at least 3-fold higher radiographic overall response rate (rORR) compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0338] The treatment methods described in various embodiments herein are further characterized in that they provide a higher, at least 20% higher, 30% higher, 40% higher, 50% higher radiographic disease control rate (rDCR) compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0339] The features of the treatment methods described in the various embodiments herein are further characterized in that they provide at least three times higher rORR (radiographic overall response rate) compared to continuous or alternating ARDT / ARPI / ARAT treatments with previously used or different ARDT / ARPI / ARATs, respectively.

[0340] In embodiments of the present disclosure, the ligand can be selected from the group consisting of: PSMA-617 (vipivotide tetraxetan), PSMA I&T (zadavotide curaxetan), PSMA-R2, MIP-1095, MIP-1545, MIP, MIP-1555, MIP-1557, MIP-1558, CTT1403, FC705, BAY-2315497, TLX592, PSMA-TCC, rhPSMA, rhPSMA-7, rhPSMA-7.3, PSMA-7I&T, EB-PSMA-617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93, and RPS-074, preferably selected from the group consisting of: PSMA-617, PSMA I&T, and PSMA-R2, more preferably PSMA-617 or PSMA I&T, and most preferably PSMA-617.

[0341] In embodiments of the present disclosure, the ligand can be selected from the group consisting of: PSMA-617, PSMA I&T, PSMA-R2, MIP-1095, MIP-1545, MIP-1555, MIP-1557, MIP-1558, CTT1403, FC705, BAY-2315497, TLX592, PSMA-TCC, rhPSMA, rhPSMA-7, rhPSMA-7.3, rhPSMA-10.1, Ludotadipep, PNT2001, PNT2002, PSMA-7I&T, EB-PSMA-617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93, RPS-074, RPS-072, NG001, ADVC00, PMI-21, HTK03121, IBU DAB PSMA, PSMACM, or mcl-alb-M-PSMA.

[0342] In embodiments of the present disclosure, the radionuclide may be selected from the group consisting of: Lu-177, Tb-161, I-131, Tc-99m, Y-90, Sc-47, Cu-67, Re-188, Pb-212, Bi-213, Ac-255, and Th-227, preferably selected from the group consisting of: Lu-177 and Tb-161, and most preferably Lu-177.

[0343] In embodiments of the present disclosure, the 177Lu radionuclide may have the mass of "carrier-added" (c.a. 177Lu, e.g., produced by a direct production route, 176Lu(neutron,γ)177Lu, and thus also including 177mLu), or have the mass of "carrier-free" or "no-carrier" (n.c.a. 177Lu, e.g., produced by an indirect reactor production route, 176Yb(neutron,γ)177Ybβ-negative decay 177Lu, substantially free of 177mLu). In a preferred embodiment, the radionuclide 177Lu has the mass of n.c.a.

[0344] Generally and particularly in the phrase "lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA)-binding radioligand therapy (RLT) agent", "labeled" means that the radionuclide is complexed or chelated to the chelator moiety of the RLT agent, such as a DOTA or DOTAGA chelator.

[0345] In certain embodiments, prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC) is progressive or progressive PSMA + mCRPC after the first ARDT (e.g., the cancer progresses during or after treatment with the following drugs: second-generation ARDT, such as abiraterone, enzalutamide, darolutamide, and apalutamide).

[0346] The above embodiments are presented as treatment method claims. They can equally be presented in other forms of second medical use, such as as follows, where the drug is the RLT agent (alone or in combination with other agents), the indication is mCRPC as specified in the above embodiments, and the features are those mentioned in the above embodiments:

[0347] The present invention provides [drug] for treating [indication] or any pharmaceutically acceptable salt thereof, characterized in that [features].

[0348] Alternatively, the present invention provides a method of treating [indication] in a human patient in need thereof, the method comprising administering an effective amount of [drug] or any pharmaceutically acceptable salt thereof, wherein the treatment is characterized in that [features].

[0349] As a further alternative, the present invention provides the use of [drug] or any pharmaceutically acceptable salt thereof in the preparation of a medicament for treating [indication], characterized in that [feature].

[0350] As a further alternative, the present invention provides the use of [drug] or any pharmaceutically acceptable salt thereof for treating [indication], characterized in that [feature].

[0351] As a further alternative, the present invention provides a medicament for treating [indication], comprising [drug] or any pharmaceutically acceptable salt thereof, characterized in that [feature].

[0352] In some embodiments of the present disclosure, the therapy, drug, medicament or use thereof is for patients who have not previously received taxane-based chemotherapy [i.e., taxane-naïve patients]. Preferably, the patient has not previously received taxane-based chemotherapy. In some embodiments, the patient may have received taxane-based chemotherapy in the past, but in the case of previous taxane exposure, at least 12 months have passed since the completion of the chemotherapy (i.e., the last dose administration).

[0353] In some embodiments, the patient has also not been treated with 223 Ra therapy.

[0354] Definitions

[0355] In terms of values, "about" means ±25%, preferably ±20%, more preferably ±15%, even more preferably ±10%, and even more preferably ±5%.

[0356] In terms of weeks or cycles, "about" means ±2, preferably ±1.

[0357] The terms radionuclide and radioisotope may be used interchangeably in the present disclosure and its embodiments. Where technically meaningful, the terms radioactive metal and radioactive halogen may also be used as alternatives.

[0358] Not indicating the radionuclide in the form of, for example 177 Lu or Lu-177 or lutetium-177, the form 177Lu is used as an alternative herein. Thus, regardless of the mass number, for example 177, there is no superscript (e.g., 177Lu) throughout the disclosure, yet it is intended to refer to the superscript version 177 Lu.

[0359] PSMA-617 or vipivotide tetraxetan refers to the "cold" ligand (ligand without radionuclide) of PLUVICTO (i.e., INN: lutetium (177Lu) vipivotide tetraxetan) and can be represented by formula (I):

[0360]

[0361] PSMA I&T (zadavaptan aceglutamide) refers to the "cold" ligand (ligand without radionuclide) of [177Lu]Lu-PSMA I&T (INN: lutetium (177Lu) zadavaptan aceglutamide), and is commercially available from ABX GmbH, Radeberg, Germany, and can be represented by formula (II).

[0362]

[0363] The drug substances, products, and methods for producing pharmaceuticals using such RLT agents are described in US11,129,912B1, US11,491,246B2, and WO 2002 / 013610. The glutamate / glutamine residues in PSMA I&T can be in the L- or D-configuration, or a mixture of both (e.g., a racemic mixture, or an optically enriched mixture with an excess of the L-configuration or an excess of the D-configuration).

[0364] PSMA-R2 can be represented by formula (III), preferably, the glutamate and lysine in the L-configuration adjacent to the urea:

[0365]

[0366] Any radionuclide, such as a radioactive metal, such as 177Lu, can be complexed with a DOTA or DOTAGA residue, which acts as a chelator for the radioactive metal. This will then produce a 177Lu-labeled RLT agent.

[0367] [68Ga]Ga-PSMA-11 (INN: gallium (68Ga) gozetotide, drug name: LOCAMETZ, ILLUCCIX) can be represented by formula (IV).

[0368]

[0369] 18F-DCFPyL (INN: florofosfamide (18F), drug name; PYLARIFY, PYLCLARI) can be represented by formula (V).

[0370]

[0371] 18F( / natGa)-rhPSMA-7.3 (INN: rotifosfamide (18F), drug name: POSLUMA) can be represented by formula (VI).

[0372]

[0373] Regarding taxane- and taxol-based chemotherapy:

[0374] Taxanes are diterpenes that generally contain a taxadiene core. Paclitaxel (Taxol) and docetaxel (Taxotere) are widely used as chemotherapeutic agents. Cabazitaxel is approved by the FDA for the treatment of hormone-refractory prostate cancer.

[0375] Hormone therapy can include any androgen-directed therapy such as finasteride, dutasteride, bicalutamide, apalutamide, abiraterone, enzalutamide, or combinations thereof.

[0376] Taxane-based chemotherapy can include docetaxel or cabazitaxel or combinations thereof.

[0377] Other cancer drugs used in the context of the present disclosure can include abiraterone, orteronel, galeterone, seviteronal, apalutamide, enzalutamide, or combinations thereof.

[0378] Additional cancer drugs used in the context of the present disclosure can include palifosfamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribuline, docetaxel, cyclophosphamide, doxorubicin, regorafenib, or combinations thereof.

[0379] No carrier added (NCA, nca, n.c.a.): A preparation of a radioisotope that is substantially free of the stable isotope of the element in question. n.c.a. 177 The production of Lu is known and can be obtained, for example, from 176 Yb via 177 Yb, e.g., 176Yb(n,γ)177Yb, which undergoes β− decay to 177Lu (sometimes referred to as the “indirect” reactor production route). The method includes a radiochemical separation step to isolate the desired n.c.a. 177Lu from the Yb isotopes. No carrier added is sometimes also referred to as carrier-free.

[0380] The following types of remission and remission rates are used herein:

[0381]

[0382] In the examples herein, features in parentheses (…) or [… ] refer to features that can be omitted or can be included and thus refer to subtypes of the respective embodiments.

[0383] References

[0384] All publications, patents, and patent applications mentioned in this text are incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

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[0480] de Bono J, Mateo J, Fizazi K, et al (2020) Olaparib for Metastatic Castration - Resistant Prostate Cancer 382:2091 - 102.

[0481] de Wit R, de Bono J, Sternberg CN, et al (2019) Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer 2506 - 2518.

[0482] van Kalmthout L, Braat A, Lam M, et al (2019) First Experience With 177Lu-PSMA-617 Therapy for Advanced Prostate Cancer in the Netherlands. Clin NuclMed 446-451.

[0483] Example

[0484] In the following, the present invention will be described in more detail and specifically with reference to examples, but these examples are not intended to limit the present invention.

[0485] Example 1:

[0486] Clinical trial

[0487] The title is " 177 Clinical Phase 3 trial of 177Lu-PSMA-617 compared to androgen receptor-directed therapy for progressive metastatic castration-resistant prostate cancer (PSMAfore)" is described on ClinicalTrials.gov, identifier: NCT04689828 (the entire disclosure of the web page accessible at the filing date is incorporated herein by reference).

[0488] This trial is also described as:

[0489] PSMAfore: A Phase III, open-label, multi-center, randomized study comparing 177 177Lu-PSMA-617 with androgen receptor-directed therapy alteration, CAAA617B12302.

[0490] Study design:

[0491] See Figure 1 .

[0492] Clinical protocol:

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508] Basic principle:

[0509] Basic principle of the study design

[0510] The aim of this study was to determine whether administering 6 cycles of 177Lu-PSMA-617 at a dose of 7.4 GBq (200 mCi) + / - 10% improves rPFS compared with ARDT changes in mCRPC participants who had previously received alternative ARDT treatment and were not exposed to taxane-containing regimens, in the setting of CRPC or HSPC. rPFS is an important endpoint for mCRPC recognized by PCWG3 and several other trials conducted in this setting.

[0511] After radiographic progression, survival will be followed up. The key secondary objective is to assess whether 177Lu-PSMA-617 improves overall survival (OS) compared with participants treated with altered ARDT.

[0512] Eligible participants will be randomized to one of two treatment groups. Randomization will be stratified to avoid bias in treatment selection. Treatment will be open-label. After BICR confirmation of rPFS, participants randomized to the ARDT group will be allowed to cross over to receive 177Lu-PSMA-617.

[0513] Preliminary clinical evidence suggests that 177Lu-PSMA-617 may show clinical benefit in men with mCRPC, improving rPFS and OS compared with altered ARDT. The data from this study will complement the data from the VISION study of 177Lu-PSMA-617 as a treatment for mCRPC before the use of taxanes.

[0514] Rationale for Selecting Background Therapy

[0515] Permit supportive care in both arms, including care provided to eligible participants according to the best institutional practices for mCRPC treatment, including ADT. This is permitted to maintain serum testosterone levels and manage overall disease symptoms at the discretion of the treating physician.

[0516] Study agents, biologics, immunotherapies, cytotoxic chemotherapy, other systemic radioisotopes (e.g., radium 223), poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors, or hemibody radiotherapy treatments must not be administered prior to radiographic progression being assessed by blinded central review (primary endpoint). ARDT must not be administered concurrently with 177Lu-PSMA-617.

[0517] Rationale for Dose / Regimen and Treatment Duration

[0518] The rationale for 177Lu-PSMA-617 radioligand therapy is to deliver low-dose-rate radiation systemically to multiple PSMA-positive prostate cancer lesions while sparing normal tissues. To date, 12 dosimetry studies have been conducted on 158 participants. The results of all studies have been consistent and have demonstrated that exposure is closely related to the expected rapid clearance of the small molecule and the limited distribution pattern of the PSMA-targeted radionuclide. The major sites of non-tumor uptake are the salivary glands, lacrimal glands, and kidneys, and the excretion mechanism results in renal exposure, with approximately 50% of the injected dose being cleared within 48 hours (Kratochwil et al., 2016). PSMA-negative tissues (such as bone marrow) are transiently exposed to 177Lu-PSMA-617 during circulation, but this exposure is minimized due to its rapid elimination.

[0519] Based on clinical experience documented in over 53 publications (which summarize safety and / or efficacy information from more than 1280 participants), 177Lu-PSMA-617 has good tolerance.

[0520] In these studies, the dose range was 1.1 - 12.0 GBq, and the regimens generally followed an administration schedule of 1 - 9 cycles every 4 to 12 weeks. Although the German Society of Nuclear Medicine recommended a dose of 6.0 GBq every 8 weeks for 3 cycles in 2016, most publications used a regimen of 6 GBq every 8 weeks for 4 cycles. However, efficacy and safety information from a prospective phase 2 study indicated good tolerance and effectiveness with a dose of 4.0 - 8.9 (mean 7.5) GBq every 6 weeks for 4 cycles (Violet et al. 2020). Clinical series now show reports of safe administration of 177Lu-PSMA-617 for more than 4 cycles as a means to maximize participant benefit ( et al. 2017, Kessel K et al. 2019, Kulkarni et al. 2018a, Kulkarni et al. 2018b, Kulkarni et al. 2018c, Maffey Steffan et al. 2020, Rahbar et al. 2018, Yadav et al. 2020, Yordanova et al. 2017, van Kalmthout et al. 2019).

[0521] In the Phase II TheraP study (ANZUP protocol 1603, NCT03392428), 200 Australian men with mCRPC were randomly assigned (1:1) to receive 177Lu-PSMA-617 or cabazitaxel. The starting dose of 177Lu-PSMA-617 was 8.5 GBq, with a reduction of 0.5 GBq per cycle, i.e., 8.5, 8, 7.5, 7, 6.5, 6, given every 6 weeks for up to 6 cycles. This corresponds to a cumulative dose of 43.5 GBq, similar to the dose in this proposed study.

[0522] Detailed analysis of clinical safety reviews and radiation exposure supports the expected dose and frequency of 177Lu-PSMA-617 administration in this clinical trial.

[0523] Rationale for the choice of control drug (comparator / placebo) or combination drug

[0524] Four major drug classes have been approved for treating to extend survival in mCRPC participants. These include ARDT (i.e., abiraterone and enzalutamide), taxanes (docetaxel and cabazitaxel), immunotherapy (sipuleucel-T), and bone-targeted radiopharmaceuticals (radium-223 dichloride). As the field of prostate cancer treatment has evolved, some of these life-extending therapies (ARDT and docetaxel) are increasingly being used in earlier stages (e.g., metastatic hormone-sensitive prostate cancer and non-metastatic prostate cancer). This has created a greater unmet medical need in mCRPC. In participants previously treated with ARDT therapy, several mechanisms have been associated with the development of treatment resistance (Attard et al., 2009). The range of rPFS in participants who changed ARDT treatment was 3.6 to 15 months, and the range of OS was 11 to 23 months (de Bono et al. 2020, deWit et al. 2019, Komura et al. 2019). On the other hand, many participants do not receive chemotherapy mainly due to pre-existing medical conditions or related toxic effects. (Engel Nitz et al., 2011; Harris et al., 2011; Lissbrant et al., 2013; Zielinski et al., 2014). Sipuleucel-T is most suitable for mild asymptomatic small-volume disease; radium-223 is used to treat men with only bone disease. PARP inhibitors are an emerging drug class in mCRPC, but their use is limited to a subgroup of mCRPC participants with homologous recombination repair gene mutations [PROfound (de Bono et al. 2020, Hussain et al. 2019) and TRITON2 (Abida et al. 2019) ESMO 2019 studies].

[0525] ARDT such as abiraterone and enzalutamide have shown efficacy and are approved for treating mCRPC in participants who have not previously received taxane-based chemotherapy and are the relevant comparators in this study.

[0526] Investigational drug

[0527] The second-generation ARDT abiraterone, enzalutamide, darolutamide, and apalutamide (all four drug names are rINNs) have been marketed as registered medicines.

[0528] Radioligand imaging agents 68 Ga-PSMA-11 (rINN: gallium ( 68 Ga) gozetotide is commercially available as a kit for labeling with Ga-68 under the drug brand names ILLUCCIX and LOCAMETZ.

[0529] Radioligand therapeutic agents177 Lu-PSMA-617 (rINN: lutetium (177Lu) vipivotide tetraxetan) is commercially available under the medicinal brand name PLUVICTO.

[0530] The content of the medicinal product labels (prescription information, summary of product characteristics) for all of these medicinal products is incorporated herein by reference.

[0531] Results

[0532] Summary of results

[0533]

[0534]

[0535]

[0536] # The first interim analysis of OS reported in this FIR was based on 40 (13.5%) of the 297 targeted events / deaths. Based on the results from the pre-specified α-spending function used in the three-group sequential design, the target one-sided P-value for the statistically significant log-rank test at the first interim analysis was almost zero (P < 0.000000001012).

[0537] *NE: Not estimable / not reached.

[0538] Study CAAA617B12302 (PSMAfore) is a randomized, phase III, open-label, active-controlled, global multi-center study that compared the safety and efficacy of [177Lu]Lu-PSMA-617 with androgen receptor-directed therapy (ARDT) in PSMA-positive mCRPC participants who had previously received ARDT (in which case, delaying taxane-based chemotherapy was considered appropriate).

[0539] The first interpretable results (FIR) of the primary endpoint analysis of rPFS are described below, including the results of the first interim analysis of the key secondary endpoint OS. The data cut-off date for the analysis was October 2, 2022. The key efficacy and safety results presented do not have any clinical interpretation.

[0540] A total of 467 subjects included in the analysis were randomized in a 1:1 ratio to the [177Lu]Lu-PSMA-617 group (n = 233) or the ARDT group (n = 234) and were stratified according to the following: prior ARDT use in the setting of castration-resistant prostate cancer (CRPC) compared to hormone-sensitive prostate cancer (HSPC), and symptomatology based on the baseline BPI-SF questionnaire (asymptomatic or mild symptoms compared to symptomatic).

[0541] The study is ongoing. The median study duration (from randomization to data cut-off) for the [177Lu]Lu-PSMA-617 arm was 7.26 months, compared to 7.28 months for the ARDT arm.

[0542] The median follow-up for rPFS was 3.6 months (from randomization to review or rPFS event according to BICR). The shortest-longest rPFS follow-up was 0 - 12.3 months.

[0543] Prior to the median study duration in each arm, a total of 121 (51.9%) patients in the [177Lu]Lu-PSMA-617 arm were censored as "continuously event-free", compared to 93 (39.7%) patients in the ARDT arm.

[0544] The median follow-up for OS was 6.08 months (from randomization to death or last contact date). The shortest-longest follow-up was 0.6 - 14.9 months.

[0545] As of data cut-off, a total of 52 patients (22.2%) crossed from the ARDT arm to the [177Lu]Lu-PSMA-617 arm.

[0546] The treatment groups were balanced with respect to demographics and baseline characteristics.

[0547] It was reported that 25.8% of the subjects in the [177Lu]Lu-PSMA-617 arm discontinued treatment, and 47% of the subjects in the ARDT arm discontinued treatment. The main reasons for treatment discontinuation ([177Lu]Lu-PSMA-617 vs ARDT) were disease progression (14.6% vs 32.9%), physician decision (6.0% vs 9%), and adverse events (3.9% vs 3.0%).

[0548] The median (minimum-maximum) duration of exposure to study treatment in the [177Lu]Lu-PSMA-617 arm was 4.25 months (0.3 - 10.3), and in the ARDT arm was 3.9 months (0.0 - 13.3) (as of data cut-off, prior to crossover and from treatment initiation to last treatment). The median duration of exposure to abiraterone was 4.2 months (0.0 - 12.4), to enzalutamide was 3.55 months (0.0 - 13.3), and to crossover [177Lu]Lu-PSMA-617 subjects was 2.8 months (0.4 - 9.6).

[0549] The median (minimum-maximum) relative dose intensity of the randomized [177Lu]Lu-PSMA-617 group was 97.6 GBq (59.2-103.1), and that of the ARDT group was 100% (25.0-100). The median relative dose intensity (minimum-maximum) of abiraterone was 100% (53.9-100), that of enzalutamide was 100% (25.0-100), and that of the crossover [177Lu]Lu-PSMA-617 subjects was 98.0 GBq (57.4-101.6).

[0550] The study achieved its primary objective: based on the PCWG3 criteria, the primary endpoint of radiographic progression-free survival (rPFS) based on blinded independent central review was statistically significant between treatment groups (stratified log-rank test p = 0.00000003, one-sided), and the estimated risk reduction in the [177Lu]Lu-PSMA-617 group (n = 233) was 58%, which was compared to

[0551] the ARDT group (n = 234) (hazard ratio: 0.42, 95% CI: (0.31 0.58)). There were 61 events (26.2%) in the [177Lu]Lu-PSMA-617 group and 106 events (45.3%) in the ARDT group. The median rPFS (95% CI) was 9.3 months (6.77, NE) and 5.59 months (4.11, 5.98), respectively.

[0552] The key secondary endpoint of overall survival (OS) was not yet mature but did not show any impairment. The first interim analysis of OS reported in this FIR was based on 40 (13.5%) of the target 297 events / deaths.

[0553] The median OS was not reached in any group. The estimated 6-month OS probability was 94.4% (89.4, 97.1) for [177Lu]Lu-PSMA-617 and 94.4% (89.7, 96.9) for the ARDT group, respectively.

[0554] The following adverse events (AEs) were reported in the [177Lu]Lu-PSMA-617 group and the ARDT (pre-crossover) group, respectively:

[0555] Any AE: 89.4% compared to 85.3%

[0556] ≥Grade 3 AE: 23.5% compared to 32.8%

[0557] Treatment-related: 6.6% compared to 10.3%

[0558] Serious AE: 15.5% compared to 18.5%

[0559] Treatment-related: 2.2% compared to 0.4%

[0560] AEs leading to discontinuation: 4.0% compared to 3.0%

[0561] Treatment-related: 1.8% compared to 1.7%

[0562] AEs leading to dose adjustment were 2.2% compared to 11.2%

[0563] AEs leading to dose interruption were 7.1% compared to 12.1%

[0564] AEs requiring additional therapy were 53.5% compared to 62.1%

[0565] The most common adverse events in the [177Lu]Lu-PSMA-617 group compared to the ARDT group (in any group > 10%) were dry mouth (44.7% compared to 1.7%), nausea (25.2% compared to 8.2%), asthenia (23.9% compared to 24.6%), fatigue (18.1% compared to 22.0%), anemia (16.8% compared to 11.2%), constipation (15.5% compared to 9.5%), decreased appetite (12.8% compared to 12.1%), diarrhea (12.4% compared to 6.9%), arthralgia (11.5% compared to 16.8%), COVID-19 (11.1% compared to 8.6%) and back pain (7.1% compared to 10.8%).

[0566] The most common serious adverse events in the [177Lu]Lu-PSMA-617 group and the ARDT group were urinary tract infections (1.8% compared to 0.9%) respectively.

[0567] In the [177Lu]Lu-PSMA-617 group and the ARDT group, a total of 18 (8%) and 20 (8.6%) subjects who received at least one dose of the study treatment died during the study respectively. The main cause of death during the study was the study indication, 4.4% (10 deaths) in the [177Lu]Lu-PSMA-617 group compared to 7.3% (17 deaths) in the ARDT group. Two subjects randomized to the [177Lu]Lu-PSMA-617 group died before starting the study treatment.

[0568] In the [177Lu]Lu-PSMA-617 group and the ARDT group, a total of 4 (1.8%) and 7 (3.0%) subjects died during treatment respectively. The main cause of death during treatment was the study indication, 0% and 1.7% in the [177Lu]Lu-PSMA-617 group and the ARDT group respectively.

[0569] Additional information

[0570] Radiographic progression-free survival (rPFS) based on the PCWG3 criteria with independent central review was the primary endpoint, and overall survival (OS) was the key secondary endpoint of the study. The statistical design of the study was such that for the study to be declared positive, it needed to achieve statistical significance in the primary analysis of rPFS.

[0571] The primary analysis of rPFS and the first interim analysis of OS were conducted using a one-sided α level of 2.5% for all patients randomized on or before the data cut-off date of October 2, 2022. One patient randomized and treated was excluded from the full analysis set due to lack of informed consent obtained in accordance with due process (INCL1A PD).

[0572] Stratified testing for OS was performed based on a three-group sequential design using the Lan DeMets (O’Brien Flemming) α spending function. The final OS analysis was not planned at the time of the interim rPFS analysis reported in this FIR.

[0573] In accordance with the stratified testing strategy defined in the study protocol, OS was tested once rPFS was statistically significant. The one-sided α level required for a significant OS difference in the first interim analysis (<0.000000001012) was calculated based on the pre-specified α spending function and the number of events observed at the time of the rPFS analysis.

[0574] The results for OS at the time of the first interim OS analysis were based on 13.5% (40 / 297 deaths).

[0575] A second interim OS analysis was planned after additional follow-up when approximately 75% (223 / 297) of the target deaths / events had occurred. If OS was not statistically significant in the second interim analysis, a final analysis was planned at the time of recording approximately 297 deaths.

[0576] Subject disposition

[0577] Patient Disposition (Full Analysis Set)

[0578]

[0579] Demographics and other baseline characteristics Demographics and Baseline Characteristics (Full Analysis Set)

[0580]

[0581]

[0582] Subject exposure

[0583] Duration of exposure to study treatment (safety set)

[0584]

[0585]

[0586] Dose of study treatment received (safety set)

[0587]

[0588]

[0589] Dose of [177Lu]Lu-PSMA-617 received (Lu-PSMA-617 safety set)

[0590]

[0591]

[0592] Summary of duration between randomization and cutoff date (full analysis set)

[0593]

[0594]

[0595] Efficacy results

[0596] Primary efficacy results

[0597] Analysis of radiographic progression-free survival using stratified log-rank test and Cox regression model, based on independent central review (full analysis set)

[0598]

[0599]

[0600] Forest plot of hazard ratio with 95% confidence interval

[0601] Radiographic progression-free survival based on sensitivity analysis independent central review (full analysis set)

[0602] See Figure 3A and 3B

[0603] This indicates that the rPFS results were consistent across all pre-planned sensitivity analyses and different subgroups.

[0604] Key secondary efficacy IA results

[0605] Perform a mid-term analysis of overall survival using the stratified log-rank test and Cox regression model (full analysis set)

[0606]

[0607] Safety results

[0608] Adverse events Overview of adverse events (safety set)

[0609]

[0610]

[0611] Adverse events according to preferred terms (incidence in any group at least 10%) (safety set)

[0612]

[0613]

[0614] Serious Serious adverse events according to preferred terms (incidence in any group at least 1%) (safety set)

[0615]

[0616] Purpose Overview of safety topics (safety set)

[0617]

[0618] The number of myelosuppression and nephrotoxicity events observed so far with radioligand therapy has been unexpectedly low.

[0619] Deaths during treatment according to system organ class and preferred terms (safety set)

[0620]

[0621] See the result update in Figure 2B and 3B .

[0622]

[0623]

[0624]

[0625] *Data provided in this document is based on the latest data from the central vendor, using the original primary analysis data cut-off date of October 2, 2022 and the second mid-term OS analysis data cut-off date of June 21, 2023.

[0626] DCO = Data Cut-off Date; RPSFT = Rank Preserving Structural Failure Time; NE: Not Evaluable / Not Reached.

[0627] At the time of the primary rPFS analysis (DCO on October 2, 2022):

[0628] The study was ongoing. The study duration (from randomization to data cut-off) for the [177Lu]Lu-PSMA-617 group was 7.26 months, compared to 7.28 months for the ARDT group.

[0629] The median follow-up for rPFS was 3.38 months (from randomization to review or rPFS event according to BICR). The shortest-longest rPFS follow-up was 0.03 - 12.62 months. Before the median study duration in each group, a total of 125 (53.6%) participants in the [177Lu]Lu-PSMA-617 group compared to 97 (41.5%) participants in the ARDT group were censored as "continuously event-free".

[0630] At the time of the second interim analysis (DCO on June 21, 2023):

[0631] The study was ongoing. The study duration (from randomization to data cut-off) for the [177Lu]Lu-PSMA-617 group was 15.87 months, compared to 15.89 months for the ARDT group.

[0632] The median follow-up for rPFS was 5.98 months (from randomization to review or rPFS event according to BICR). The shortest-longest rPFS follow-up was 0.03 - 20.30 months. Before the median study duration in each group, a total of 76 (32.5%) participants in the [177Lu]Lu-PSMA-617 group compared to 29 (12.4%) participants in the ARDT group were censored as "continuously rPFS event-free".

[0633] A total of 123 participants (123 / 234 (52.6%) of all ARDT participants) or 123 / 168 (73.2%) of ARDT participants with confirmed radiographic progression had crossed over from the ARDT group to the [177Lu]Lu-PSMA-617 group after confirmation of radiographic progression according to BICR notification.

[0634] The treatment groups were balanced in terms of demographics and baseline characteristics.

[0635] It was reported that 41.0% of the subjects in the [177Lu]Lu-PSMA-617 group discontinued treatment, and 82.5% of the participants in the ARDT group discontinued treatment. The main reasons for treatment discontinuation ([177Lu]Lu-PSMA-617 vs. ARDT) were disease progression (21.8% vs. 62.4%), physician decision (10.7% vs. 12.4%), and adverse events (5.6% vs. 5.1%).

[0636] The median (minimum-maximum) duration of exposure to study treatment in the [177Lu]Lu-PSMA-617 group was 8.41 months (0.36 - 11.63), and in the ARDT group was 6.52 months (0.03 - 20.99) (as of the data cut-off date of June 21, 2023, before crossover treatment and from treatment initiation to the last administration of study treatment). The median duration of exposure for participants receiving abiraterone was 6.36 months (0.69 - 20.99), for those receiving enzalutamide was 6.59 months (0.03 - 20.99), and for participants randomized to the ARDT group who crossed over to [177Lu]Lu-PSMA-617 (hereinafter referred to as [177Lu]Lu-PSMA-617 crossover participants) was 4.67 months (0.49 - 11.04).

[0637] The median (minimum-maximum) relative dose intensity in the randomized [177Lu]Lu-PSMA-617 group was 97.6 (78.5 - 102.9), and in the ARDT group was 100% (51.6 - 100). The median (minimum-maximum) relative dose intensity for participants receiving abiraterone was 100% (53.9 - 100), for those receiving enzalutamide was 100% (51.6 - 100), and for [177Lu]Lu-PSMA-617 crossover participants was 97.5% (76.0 - 105.4).

[0638] The study met its primary objective: based on the modified RECIST 1.1 criteria of PCWG3 (using the DCO date of October 2, 2022), the primary endpoint of radiological progression-free survival (rPFS) based on blinded independent central review was statistically significant between treatment groups (stratified log-rank test p < 0.0001, one-sided). The estimated risk reduction in the [177Lu]Lu-PSMA-617 group (n = 233) was 59%, compared to the ARDT group (n = 234) (hazard ratio: 0.41, 95% CI: (0.29 0.56)). There were 60 events (25.8%) in the [177Lu]Lu-PSMA-617 group and 106 events (45.3%) in the ARDT group. The median rPFS (95% CI) was 9.30 months (6.77, NE) and 5.55 months (4.04, 5.95) respectively (Table 5-1a). The estimated probability of rPFS at 6 months in the [177Lu]Lu-PSMA-617 group (95% CI) was 69.0% (60.7, 75.9), compared to 40.6% (32.1, 48.8) in the ARDT group.

[0639] The rPFS results were consistent across all pre-planned sensitivity analyses and demographic and prognostic subgroups.

[0640] Based on the DCO date of June 21, 2023, an updated analysis of rPFS was conducted as an exploratory analysis, showing that the estimated risk reduction in the [177Lu]Lu-PSMA-617 group (n = 234) was 57%, compared to the ARDT group (n = 234) (HR: 0.43, 95% CI: (0.33 0.54)). There were 115 events (49.1%) in the [177Lu]Lu-PSMA-617 group and 168 events (71.8%) in the ARDT group. The median rPFS (95% CI) was 12.02 months (9.30, 14.42) and 5.59 months (4.17, 5.95) respectively (see table below).

[0641]

[0642]

[0643]

[0644] See also Figure 3B .

[0645] Best overall radiological response for soft tissue and bone disease based on BICR (Recist analysis set - participants with measurable disease at baseline)

[0646]

[0647] Alleviation is based on soft tissue assessment and bone lesion progression.

[0648] The best overall response of CR and PR was confirmed by repeated assessments conducted no less than 4 weeks after initially meeting the response criteria.

[0649] CR may include participants with residual but non-progressive bone disease.

[0650] Results: [177Lu]Lu-PSMA-617 showed an rORR at least three times higher compared to ARDT, as well as a higher rDCR compared to ARDT

[0651] Compared to ARPI alteration, 177Lu-PSMA-617 delayed the time to SSE, as shown in the following table.

[0652]

[0653] ARPI, androgen receptor pathway inhibitor; CI, confidence interval; DCO, data cut-off date; HR, hazard ratio; NE, not estimable; OS, overall survival; PSMA, prostate-specific membrane antigen; SSE, symptomatic skeletal event; Median OS analysis, DCO: June 2023.

[0654] Key secondary endpoint: OS analysis for crossover and ITT-adjusted

[0655] Pre-specified primary crossover-adjusted analysis

[0656] HR: 0.80 (95% CI: 0.48, 1.33)

[0657] Median, months (95% CI):

[0658] 19.25 (16.95, NE) compared to 19.55 (14.95, NE)

[0659] Number of events 69 (29.5%) a Compared to 36 (15.4%)

[0660] Pre-specified supplementary unadjusted (ITT) analysis

[0661] HR: 1.16 (95% CI: 0.83, 1.64)

[0662] Median, months (95% CI):

[0663] 19.25 (16.95, NE) compared to 19.71 (17.81, NE)

[0664] The number of events was 69 (29.5%) compared to 65 (27.8%)

[0665] Median OS follow-up time, months (range):

[0666] 12.72 (0.82, 23.00) compared to 13.08 (1.54, 22.64)

[0667] a Three patients died before receiving 177 Lu-PSMA-617. ARPI, androgen receptor pathway inhibitor; CI, confidence interval; DCO, data cut-off date; HR, hazard ratio; ITT, intention-to-treat; NE, not estimable; OS, overall survival; PSMA, prostate-specific membrane antigen, interim OS analysis (DCO: June 2023).

[0668] Regarding the key secondary endpoints:

[0669] The pre-specified primary analysis method for OS was the rank-preserving structural failure time (RPSFT) to adjust for crossovers:

[0670] Rank-preserving structural failure time 1,2

[0671] ■ A recognized model-based method to adjust for crossovers in clinical trials

[0672] ■ Adjust the survival of patients randomized to ARPI changes and crossed over to 177 Lu-PSMA-617

[0673] ■ Assume that each patient progresses from disease to death at their own rate (accelerated failure time model)

[0674] ■ Assume 177 Lu-PSMA-617 slows down / speeds up that rate by the same factor (X), regardless of 177 whether Lu-PSMA-617 is given at randomization or at crossover

[0675] - Use grid search to find the value of X that balances survival times between groups

[0676] ■ Multiply the observed survival times by X to obtain the adjusted survival times for all patients receiving 177 Lu-PSMA-617

[0677] - Use a re-review algorithm to maintain the assumption of independent random censorship required for unbiased estimation

[0678] ■ The 177The survival times observed in the Lu-PSMA-617 group were compared with the adjusted survival times in the ARPI change group to estimate the treatment effect as if no crossover had occurred

[0679] ARPI, androgen receptor pathway inhibitor; OS, overall survival; PSMA, prostate-specific membrane antigen; RPSFT, rank-preserving structural failure time. 1. Morden JP et al. BMC 2011; 11; 4. 2. Ouwens M et al. Med Decis Mak [Medical Decision Making] 2018; 38: 509-19

[0680] Safety

[0681] The following adverse events (AEs) were reported in the [177Lu]Lu-PSMA-617 group and the ARDT (before crossover) group, respectively (Table 6-1):

[0682] Any AE: 98.2% vs 96.1%

[0683] ≥ Grade 3 AE: 34.4% vs 43.5%

[0684] Treatment-related: 11.0% vs 12.5%

[0685] Serious AE: 20.3% vs 28.0%

[0686] Treatment-related: 3.1% vs 2.2%

[0687] AE leading to discontinuation: 5.7% vs 5.2%

[0688] Treatment-related: 3.1% vs 2.6%

[0689] AE leading to dose adjustment was 3.5% vs 15.1%

[0690] AE leading to dose interruption was 11.9% vs 16.8%

[0691] AE requiring additional therapy was 71.4% vs 78.0%

[0692] In the [177Lu]Lu-PSMA-617 group, the most common adverse events according to preferred terms (PT) in the ARDT group (incidence > 10% in any group) were dry mouth (57.3% vs 2.2%), fatigue (31.7% vs 28.9%), nausea (31.3% vs 12.1%), anemia (24.2% vs 16.8%), tiredness (22.9% vs 25.4%), constipation (22.0% vs 13.4%), decreased appetite (21.1% vs 18.1%), arthralgia (18.9% vs 20.7%), COVID-19 (16.3% vs 11.2%), diarrhea (16.3% vs 8.6%), back pain (12.3% vs 16.4%), vomiting (11.5% vs 4.7%), peripheral edema (8.4% vs 11.2%), and weight loss (6.6% vs 12.1%) (Table 6-2).

[0693] Overview of adverse events, safety set

[0694]

[0695]

[0696] Adverse events according to preferred terms (incidence in any group of at least 10%) (safety set)

[0697]

[0698]

[0699] Serious adverse events according to preferred terms (incidence in any group of at least 1%) (safety set)

[0700]

[0701] As shown in the table below, compared with ARPI changes, the incidences of ≥ grade 3 AEs, serious AEs, and AEs leading to dose adjustment were lower in the case of 177Lu-PSMA-617.

[0702]

[0703] AE, adverse event; ARPI, androgen receptor pathway inhibitor; DCO, data cut-off date; OS, overall survival; PSMA, prostate-specific membrane antigen; SAE, serious adverse event. Interim OS analysis (DCO: June 2023).

[0704] As shown in the table below, AEs occurred in ≥ 10% of patients in any group

[0705]

[0706]

[0707] AE, adverse event; ARPI, androgen receptor pathway inhibitor; DCO, data cut-off date; OS, overall survival; PSMA, prostate-specific membrane antigen, interim OS analysis (DCO: June 2023).

[0708] In summary, compared with ARPI alteration, 177Lu-PSMA-617 prolonged rPFS and had good safety and tolerability in taxane-naïve mCRPC patients.

[0709] ■ Compared with ARPI alteration, 177 177Lu-PSMA-617 significantly prolonged rPFS

[0710] ■

[0711] At the second interim OS analysis:

[0712] ■ Cross-adjusted OS trended longer, but not unadjusted OS

[0713] ■ The crossover rate was high

[0714] ■ 45.1% of the target number of deaths had been reached

[0715] - OS data collection is ongoing

[0716] ■ PSA response, ORR, and DOR favored 177 177Lu-PSMA-617

[0717] ■ Time to deterioration of health-related quality of life and pain measurements favored 177 177Lu-PSMA-617

[0718] ■ 177 177Lu-PSMA-617 had good safety and was well tolerated

Claims

1. A method for reducing the risk of radiographic progression or death in a patient in need thereof; The method comprises administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) agent, n.c.a., or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof; wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC); wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI), or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy.

2. The treatment method according to claim 1, wherein the treatment is characterized in that the risk of radiographic progression or death of the prostate cancer is reduced by at least 50%, corresponding to a hazard ratio (HR) of no more than 50%, as compared with continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

3. The treatment method according to any one of claims 1 to 2, wherein the treatment is characterized in that within about 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months from the start of treatment, less than 25% of the patients in the corresponding patient population experience radiographic progression.

4. A method for prolonging the radiographic progression-free survival (rPFS) period in a patient in need of prostate cancer treatment; The method comprises administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) agent, n.c.a. (without added carrier), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer, or tautomer thereof; wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC); wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI), or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy.

5. The treatment method according to claim 4, wherein the treatment is characterized in that the time in months of the radiographic progression-free survival (rPFS) period is increased by at least 40% as compared with continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

6. A method for increasing the overall survival (OS) in a patient in need of prostate cancer treatment; The method includes administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof, without added carrier (n.c.a.); wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC); wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI), or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy.

7. The treatment method according to claim 6, wherein when calculating the risk of death corresponding to a hazard ratio of less than 1, about 0.95 or lower, about 0.9 or lower, about 0.85 or lower, about 0.8 or lower, about 0.75 or lower, about 0.7 or lower, about 0.65 or lower, about 0.6 or lower, about 0.55 or lower, or 0.5 or lower, respectively, relative to patients receiving continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, the treatment reduces the risk.

8. A method of increasing the overall response rate (ORR) (i.e., complete response (CR) and partial response (PR)) in soft tissues of patients in need of prostate cancer treatment; The method comprises administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) agent, n.c.a. (i.e., without added carrier), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof; wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC); wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI), or androgen receptor axis-targeted therapy (ARAT) treatment; provided that the patient has not previously been treated with taxane-based chemotherapy.

9. The treatment method according to claim 8, wherein the ORR in the soft tissues is increased by at least 100%, at least 150%, at least 200%, at least 250%, or at least 300% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

10. The treatment method according to any one of claims 8 to 9, wherein the complete response (CR) rate in the soft tissues is increased by at least 100% (doubled), at least 150%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, or at least 500% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

11. A method of improving the health-related quality of life (HRQoL) (e.g., determined by Functional Assessment of Cancer Therapy - Prostate (FACT-P)) of patients in need of prostate cancer treatment; The method includes administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) agent without added carrier (n.c.a.), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer, or tautomer thereof; wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC); wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI), or androgen receptor axis-targeted therapy (ARAT) treatment; provided that the patient has not previously been treated with taxane-based chemotherapy.

12. The treatment method according to claim 11, wherein the time to overall HRQoL deterioration is prolonged by about 50%, about 60%, or about 70% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

13. The treatment method according to any one of claims 11 to 12, wherein when calculating the risk of progression to a composite HRQoL deterioration relative to patients receiving continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, the risk is reduced by at least 25%, at least 30%, at least 35% or at least 40% (corresponding to an HR of up to 0.75, up to 0.70, up to 0.65 or up to 0.60).

14. A method of increasing PSA response in a patient in need of prostate cancer treatment; The method includes administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) agent without added carrier (n.c.a.), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof; wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC); wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI) or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy.

15. The treatment method according to claim 14, wherein the demonstrated PSA reduction of at least 50% is about 100% or at least 150% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

16. A method of delaying the time to symptomatic skeletal events (SSE) in a patient in need of prostate cancer treatment; The method comprises administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) agent without added carrier (n.c.a.), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof; wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC); wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI) or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy.

17. The treatment method according to claim 16, wherein the delay in the time to SSE is prolonged by about 50%, about 60%, about 70%, about 80% or about 90% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

18. A method of reducing the risk of symptomatic skeletal events (SSE) in a patient in need of prostate cancer treatment; The method comprises administering to the patient a therapeutically effective amount of a lutetium-177 ( 177 Lu)-labeled prostate-specific membrane antigen (PSMA) binding radiopharmaceutical therapy (RLT) agent without added carrier (n.c.a.), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof; wherein the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC); wherein the patient has previously received androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibition (ARPI) or androgen receptor axis-targeted therapy (ARAT); provided that the patient has not previously been treated with taxane-based chemotherapy.

19. The treatment method according to claim 18, wherein the risk is reduced by at least about 50%, about 55%, about 60%, about 65% or about 70% compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

20. The treatment method according to any one of the preceding claims, wherein the treatment is safer and more tolerable compared to continuous or alternating ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

21. The treatment method according to any one of the preceding claims, wherein the treatment is characterized in that treatment-related ≥ grade 3 adverse events occur in less than 25% of the patients in the corresponding patient population.

22. The treatment method according to any one of the preceding claims, wherein the treatment is characterized in that treatment-related ≥ grade 3 serious adverse events occur in less than 15% of the patients in the corresponding patient population.

23. The treatment method according to any one of the preceding claims, wherein the radioligand therapeutic agent is administered once every 6 to 8 weeks (i.e., 1 cycle) at a dose of about 6 to about 8 GBq for up to 4 to 6 cycles.

24. The treatment method according to any one of the preceding claims, wherein the radioligand therapeutic agent is administered once every 6 (±1) weeks (i.e., 1 cycle) at a dose of 7.4 (±10%) GBq for up to 6 cycles.

25. The treatment method according to any one of the preceding claims, wherein the n.c.a. 177 The Lu-labeled PSMA-binding RLT agent or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformational isomer or tautomer thereof comprises the following components: (1)β-minus electron-emitting radionuclide of n.c.a. quality 177 Lu; (2) Ligand component; Among them, The ligand component (2) comprises: (a) at least one PSMA-binding moiety; (b) at least one chelator moiety suitable for chelating the radionuclide; and (c) at least one linker moiety connecting the PSMA-binding moiety (a) to the chelator component (b).

26. The treatment method according to any one of the preceding claims, wherein the PSMA-binding moiety (a) comprises the amino acids glutamic acid and lysine linked by a urea group, such as glutamic acid-urea-lysine (GUL); wherein the chelator moiety (b) comprises a DOTA residue or a DOTAGA residue; and wherein the linker (c) comprises at least one hydrophobic side chain selected from the group consisting of: Optionally substituted phenyl, optionally substituted benzyl or optionally substituted naphthyl.

27. The treatment method according to any one of the preceding claims, wherein the RLT agent is selected from the group consisting of: 177 Lu]Lu-PSMA-617 (lutetium ( 177 Lu) vipivotide tetraxetan), 177 Lu]Lu-PSMA I&T (lutetium ( 177 Lu) zedevotide gacyclidine), and 177 Lu]Lu-PSMA-R2.

28. The treatment method according to any one of the preceding claims, wherein the RLT agent is selected from the group consisting of: 177 Lu]Lu-PSMA-617 (lutetium ( 177 Lu) vapreotide teracurum) and 177 Lu]Lu-PSMA I&T (lutetium ( 177 Lu) zaldavarotide guracil).

29. The treatment method according to any one of the preceding claims, wherein the RLT agent is 177 Lu]Lu-PSMA-617 (lutetium ( 177 Lu) vapreotide teracetyl).

30. The treatment method according to any one of the preceding claims, wherein the PSMA positivity of the mCRPC is determined by positron emission tomography (PET) using a PSMA-binding radioligand diagnostic or imaging (RLI) agent, wherein the radioligand imaging is selected from the group consisting of: 68 Ga]Ga-PSMA-11 (gallium ( 68 Ga) gozetide), 18 F-DCPyL (fluciclovine ( 18 F)), 18 F-PSMA-1007, 18 F-CTT1057 (vodeciclovine ( 18 F)), 18 F / nat Ga-rhPSMA-7.3 (rotatodine ( 18 F)), 68 Ga]Ga-PSMA-R2 and 64 Cu]Cu-PSMA-R2.

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