Prostate cancer treatment methods

Abstract

The present disclosure relates to a method for treating prostate-specific membrane antigen (PSMA)-positive advanced metastatic castration-resistant prostate cancer (mCRPC) by administering a therapeutically effective amount of a PSMA-conjugated radioligand therapy (RLT) agent, preferably [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetane), to taxane-naive patients who have progressed after receiving a second-generation ARPI.

Description

[Technical Field]

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 386040, filed December 5, 2022, U.S. Application No. 18 / 448609, filed August 11, 2023, and U.S. Provisional Application No. 63 / 592377, filed October 23, 2023, the contents of all three applications being incorporated herein by reference.

[0002] Description The present disclosure relates to a method for treating prostate-specific membrane antigen (PSMA)-positive advanced metastatic castration-resistant prostate cancer (mCRPC) by administering a therapeutically effective amount of a PSMA-conjugated radioligand therapy (RLT) agent, preferably [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetane), to taxane-naive patients who have progressed after receiving a second-generation ARPI. [Background technology]

[0003] prostate cancer Prostate cancer is the second leading cause of cancer deaths among men in the United States and the third leading cause of cancer-related deaths among men in Europe (Malvezzi et al., 2019, Siegel et al., 2017). In 2012, an estimated 1.1 million men were diagnosed with prostate cancer worldwide, resulting in 307,000 deaths. Due to widespread use of prostate-specific antigen (PSA) testing, nearly 70% of diagnosed cases occur in developed regions, although mortality rates worldwide show only minor variation driven by metastatic and, often, castration-resistant disease (Bray et al., 2012).

[0004] More effective treatments are urgently needed 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). As participants reach the mCRPC stage, expected overall survival decreases, as seen in a randomized phase 3 trial of cabozantinib versus prednisone in men with mCRPC previously treated with docetaxel and abiraterone acetate and / or enzalutamide, with a median overall survival of 9.8 months in the prednisone control arm (Smith et al., 2016). Additionally, there are significant comorbidities associated with mCRPC. Approximately 90% of participants with mCRPC will develop bone metastases (Kirby et al., 2011), and 49% of these will develop significant bone metastases within two years (Saad et al., 2004). As a result, common symptoms include bone pain, bone marrow failure, fatigue, or complications such as fractures and spinal cord compression. Such cases usually require radiation or bone surgery, which can significantly impair physical, emotional, and functional well-being (Weinfurt et al., 2005). These participants are highly symptomatic and at risk for serious oncological complications. The symptoms of metastatic soft tissue and visceral disease, general weakness, and bone marrow damage pose considerable challenges in clinical practice.

[0005] Four main drug classes have been approved to extend survival in participants with mCRPC. These include ARDT (e.g., abiraterone and enzalutamide), taxanes (docetaxel and cabazitaxel), immunotherapy (sipuleucel-T), and bone-targeted radiopharmaceuticals (radium-223 dichloride). With advances in prostate cancer treatment, some of these life-prolonging therapies (ARDT and docetaxel) are increasingly being used in earlier stages of disease (e.g., metastatic hormone-sensitive prostate cancer and non-metastatic prostate cancer). This further increases the unmet medical need in mCRPC. Several mechanisms contribute to the development of treatment resistance in participants who have previously received ARDT therapy (Attard et al., 2009). Participants who modified their ARDT had a rPFS of 3.6 to 15 months and an OS of 11 to 23 months (de Bono et al., 2020, de Wit et al., 2019, Komura et al., 2019). Meanwhile, many participants who did not receive chemotherapy did so primarily due to pre-existing medical conditions or related toxicities (Harris et al., 2011, Engel Nitz et al., 2011, Lissbrant et al., 2013, Zielinski et al., 2014). Sipuleucel-T is most commonly used for mild, asymptomatic oligodendroglioma, while radium-223 is used to treat male patients with bone-only disease. PARP inhibitors are an emerging drug class in mCRPC, but their use is limited to the 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) trials].

[0006] Prostate-specific membrane antigen Prostate-specific membrane antigen (PSMA), also known as folate hydrolase or glutamate carboxypeptidase II, is a transmembrane protein. While PSMA is highly overexpressed in nearly all prostate cancers, its expression is restricted and several hundred-fold reduced in some normal tissues, such as duodenal mucosa, proximal renal tubules, and salivary glands (Bostwick et al., 1998, Ghosh et al., 2004), (Mannweiler et al., 2009). Furthermore, PSMA overexpression correlates with aggressive, high-grade, metastatic, and androgen-independent disease (Ross et al., 2003). Differential expression of PSMA from tumor to nontumor tissues has led to numerous targeting strategies, including both disease localization using radioimaging and therapeutic intervention, and thus may be an attractive target for men with mCRPC.

[0007] In addition to its expression pattern, PSMA functionality also plays an equally important role in its value as a tumor-specific targeting mechanism. Specifically, binding of high-affinity ligands to PSMA, such as the targeting moiety of 177Lu-PSMA-617, leads to endocytosis-mediated internalization, resulting in persistent retention of the ligand-bound radioactive cargo within cancer cells (Rajasekaran et al., 2003). This functional feature of PSMA is not limited to antibody-based targeting strategies but also enables the development of low-molecular-weight targeted radiopharmaceuticals with favorable pharmacokinetic and tumor-penetrating properties (Haberkorn et al., 2016).

[0008] Both PSMA-targeted selective expression and ligand-based uptake result in reduced background uptake and off-target toxicity, and increased radioactivity localized at the tumor site.

[0009] Mechanism of action of 177Lu-PSMA-617 The novel PSMA-targeting radioligand therapeutic, 177Lu-PSMA-617, consists of the PSMA-binding ligand glutamic acid-urea-lysine and a DOTA-chelator, linked via a naphthyl- and cyclohexyl-containing linker. 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 uniquely developed for both prostate cancer imaging and radioligand therapy and can be radiolabeled with gallium-68 (68Ga), lutetium-177 (177Lu), indium-111, copper-64, scandium-44, actinium-225, or yttrium-90.

[0010] 177Lu, the radioactive cargo delivered by PSMA-617, possesses physical properties that make it a suitable radionuclide for the treatment of mCRPC. 177Lu is a medium-energy P-emitting radionuclide (490 keV) with a maximum energy of 0.5 MeV and a maximum tissue penetration of less than 2 mm. 177Lu's short P-range, in contrast to the long P-range of 90Y, favors irradiation of small tumors (Emmett et al., 2017). The short path length also directs energy into the tumor rather than surrounding normal tissue, yet is sufficient to generate bystander and crossfire effects within the tumor lesion. 177Lu has a relatively long physical half-life of 6.6 days, which, combined with the intratumoral retention of 177Lu-PSMA-617, reduces the number of required administrations. It is these physical properties and the benefits of PSMA targeting that enable effective delivery of 177Lu activity to prostate cancer cells.

[0011] 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer The novel therapeutic agent 177Lu-PSMA-617 was developed by the German Cancer Research Center, Deutsches Krebsforschungszentrum (DKFZ), in collaboration with Heidelberg University Hospital, for the treatment of participants with metastatic prostate cancer (Hillier et al., 2009, Kratochwil et al., 2015, Kulkarni et al., 2018c).

[0012] 177Lu-PSMA-617 demonstrated PSMA binding affinity and compound internalization, prolonged tumor uptake, rapid renal clearance, and a high tumor-to-background ratio, and has progressed into clinical development at a German investigational site.

[0013] Data evaluation based on compassionate use according to the regulations of the German Medicines Act, AMG §13 2b, Clinical Trial Notification (Australia), and other countries where expanded access programs are implemented in accordance with national regulations, reports a favorable safety profile and promising results regarding PSA response rates of systemic radioligand therapy with 177Lu-PSMA-617 in participants with mCRPC.

[0014] Dosimetry data suggest that 177Lu-PSMA-617 targets PSMA-expressing tissues, including the salivary glands, kidneys, small intestine, and large intestine. The highest radiation exposure occurs in the salivary glands. However, in prospective studies, xerostomia appears to be low-grade and was observed in approximately 87% of treated participants. Renal clearance of 177Lu-PSMA-617 occurs rapidly. To date, nephrotoxicity has not been significant in any safety series. There have been no reports of grade 3 / 4 nephrotoxicity in the literature. Exposure to normal bone marrow tissue is expectedly low, as this tissue does not express PSMA and plasma clearance is normal.

[0015] There was some evidence of reversible hematological toxicity after 177Lu-PSMA-617 administration, manifested as leukopenia and thrombocytopenia, ranging from 0 to 40% and 4 to 67%, respectively.

[0016] The first published clinical series of 177Lu-PSMA-617 consisted of 10 participants treated between November 2013 and January 2014 (Ahmadzadehfar et al., 2015) with a dose of 5.6 GBq / 150 mCi (4.1–6.1 GBq / 110–165 mCi). PSA declines of >50% were observed in 50% of participants, increasing to 60% after two cycles of 6 GBq / 160 mCi (4.1–7.1 GBq / 110–190 mCi). With two or more doses of 6 GBq / 160 mCi, the level of PSA declines >50% (most commonly used to assess tumor response in these studies) has been remarkably consistent across several clinical series. Hofman published the first prospective, open-label, single-arm, non-randomized phase 2 trial of 177Lu-PSMA-617 in 50 participants with metastatic castration-resistant prostate cancer, administered at 4-8 GBq / 110-220 mCi every 6 weeks for up to four cycles (Hofman et al., 2018, Hofman et al., 2019). The primary endpoints of this trial were to evaluate both safety and efficacy, as measured by PSA response, bone pain score, quality of life measures, radiographic response, and survival.

[0017] Of the screened participants, 70% were identified as PSMA-positive on PET imaging and were eligible for treatment. Participants had been exposed to at least one taxane chemotherapy regimen and either abiraterone or enzalutamide for mCRPC. In this heavily pretreated population with few alternative treatment options, 64% of participants treated with 177Lu-PSMA-617 achieved a PSA response, with at least a 50% PSA decline, and 44% achieved a PSA decline of 80% or more. Among the 27 participants with measurable disease, the objective response rate (OBR) 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). Treatment with 177Lu-PSMA-617 was well tolerated. These safety and efficacy data were also associated with significant improvements in quality of life scores and reductions in pain scores.

[0018] More recently, Hofman published the first randomized, prospective, open-label, phase II study comparing 177Lu-PSMA-617 with cabazitaxel in 200 patients with metastatic castration-resistant prostate cancer who had progressed on docetaxel. Participants received up to six cycles of 177Lu-PSMA-617 (Hofman 2020). The primary endpoint was PSA response, defined as a PSA decline of 50% or more from baseline. Secondary endpoints included PSA progression-free survival, overall survival, and quality of life.

[0019] This first randomized trial demonstrated that significantly more patients receiving 177Lu-PSMA-617 (66%) achieved a PSA decline of 50% or greater compared with those receiving cabazitaxel (37%) (P<0.0001).

[0020] In summary, over 40 compassionate use publications and prospective phase 2 clinical trial data document the use of 177Lu-PSMA-617 in participants previously exposed to approved agents. In the post-taxane and post-androgen axis inhibitor settings, 177Lu-PSMA-617 demonstrated a well-established, predictable, and well-tolerated safety profile. Clinical series have shown that the most common adverse events (primarily grade 1–2) associated with 177Lu-PSMA-617 treatment are dry mouth, nausea, vomiting, diarrhea, constipation, fatigue, anemia, thrombocytopenia, and neutropenia. The incidence of grade 3 / 4 toxicities in these series was very low and primarily limited to reversible hematologic events. Efficacy has been demonstrated across multiple clinically important endpoints, including PSA response, RECIST soft tissue response, progression-free survival (PFS), OS, pain, and quality of life. A standard dosing and schedule has yet to be developed.

[0021] The VISION trial (NCT03511664) is a phase III study evaluating the best standard of care, with or without 177Lu-PSMA-617, in men with metastatic castration-resistant prostate cancer who have previously been treated with at least one androgen receptor pathway inhibitor and one or two taxane-based regimens and have a PSMA-positive gallium (68Ga) gozetotide ([68Ga]Ga-PSMA-11) positron emission tomography (PET) scan. The VISION trial was designed as a registrational trial of 177Lu-PSMA-617, with radiographic progression-free survival or overall survival as the primary endpoint. Key secondary endpoints included objective response, disease control, and time to symptomatic skeletal events.

[0022] The combination of 177Lu-PSMA-617 and standard of care significantly prolonged imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29–0.57; P < 0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52–0.74; P < 0.001) compared with standard of care (Sartor et al., 2021). All key secondary endpoints favored 177Lu-PSMA-617. Among 248 patients with measurable target lesions according to RECIST version 1.1 by independent central review at baseline, 17 of 184 (9.2%) patients in the 177Lu-PSMA-617 group had a complete response, compared with none of 64 in the control group. Partial responses were observed in 77 (41.8%) patients in the 177Lu-PSMA-617 group and 2 (3%) patients in the control group.

[0023] Treatment with 177Lu-PSMA-617 was associated with a low incidence of adverse events leading to dose reduction, interruption, or discontinuation. As of January 27, 2021, 734 patients who had received at least one randomized treatment were included in the safety analysis. Of these, 519 (98.1%) and 170 (82.9%) patients reported treatment-related adverse events (TEAEs) in the 177Lu-PSMA-617 and control groups, respectively. 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 there was no adverse impact on quality of life. The most common treatment-related adverse events (TEAEs) reported in ≥12% of patients who received at least one dose of study therapy in the 177Lu-PSMA-617 and control groups, respectively, 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%), and 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%) (Sartor et al. 2021).

[0024] Furthermore, the combination of 177Lu-PSMA-617 and SOC prolonged the time to deterioration of health-related quality of life (HRQoL) and pain, and delayed the time to first symptomatic skeletal event compared with standard of care alone in adult patients with advanced mCRPC (K. Fizazi et al., 2021).

[0025] Despite the success of 177Lu-PSMA-617 in the VISION trail, i.e., in the post-taxane setting, it is necessary to determine whether 177Lu-PSMA-617 administered at a dose of 7.4 GBq (200 mCi) ± 10% for up to six cycles improves radiographic progression-free survival (rPFS) or death compared with a treatment change from androgen receptor-directed therapy (ARDT) in participants with metastatic castration-resistant prostate cancer (mCRPC) who have been previously treated with other ARDT regimens but have not been exposed to a taxane-containing regimen in the CRPC or mHSPC setting, and whether data from such trials support an expanded indication for 177Lu-PSMA-617 as a treatment in pre-taxane mCRPC.

[0026] The majority of patients diagnosed with CRPC already have metastatic disease at the time of diagnosis,4 and the 5-year survival rate for patients with metastatic prostate cancer is approximately 3 in 10. Despite recent advances, outcomes for patients who progress after standard-of-care second-generation ARPIs remain poor, and new targeted treatment options are urgently needed to improve long-term outcomes. Summary of the Invention

[0027] This disclosure is based on the finding that the pivotal Phase 3 PSMAfore trial with Pruvict (International Nonproprietary Name: lutetium (177Lu) bipibotide tetraxetan), a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy, met its primary endpoint. Pruvict demonstrated a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) following androgen receptor pathway inhibitor (ARPI) treatment compared with a change in ARPI in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). No unexpected safety findings were observed with PSMAfore. The data are consistent with the established safety profile of Pruvict.

[0028] This marks the second positive result from a Phase 3 study of Pulvict, following the VISION trial, which showed a statistically significant reduction in the risk of death in patients with PSMA-positive mCRPC receiving Pulvict in combination with standard of care after receiving ARPI and taxane-based chemotherapy. The PSMAfore results continue to support the important role of Pulvict in the treatment of men with prostate cancer.

[0029] This disclosure provides interim Phase I and Phase III data for PSMAfore.

[0030] Based on the data disclosed herein, Pulvict represents the first PSMA-targeted radioligand therapy to demonstrate significant and clinically meaningful benefit for patients with this type of prostate cancer who have not received taxane-based chemotherapy.

[0031] Again, Pulvict is the first PSMA-targeted radioligand therapy to demonstrate clinical benefit in patients with mCRPC who have not received taxane-based chemotherapy, addressing an important unmet need.

[0032] The present disclosure provides methods of treatment in the following aspects:

[0033] A method for treating prostate-specific membrane antigen (PSMA)-positive [particularly: advanced] metastatic castration-resistant prostate cancer (mCRPC), comprising administering a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof, to a patient in need thereof, wherein the patient has been previously treated with (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), with the proviso that the patient has not been treated with taxane-based chemotherapy (i.e., the patient is taxane-naive).

[0034] Preferably, the radioligand therapeutic agent is [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetane). [Brief explanation of the drawings]

[0035] [Figure 1] FIG. 1 shows the PSMAfore clinical trial design. [Figure 2-1] Figure 2A shows Kaplan-Meier plots of radiographic progression-free survival (rPFS) based on independent central review (full analysis set, early DCO date). The numbers of subjects still at risk at 0, 2, 4, 6, 8, 10, 12, and 14 months after randomization were as follows: [177Lu]Lu-PSMA-617: 233, 180, 119, 65, 36, 14, 2, and 0, respectively; ARDT: 234, 161, 84, 39, 24, 6, 0, and 0, respectively. This indicates that 177Lu-PSMA-617 significantly extended rPFS relative to the change in ARPI. Figure 2B shows Kaplan-Meier plots of radiographic progression-free survival (rPFS) based on independent central review (full analysis set, early DCO date). The numbers of subjects still at risk at 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22 months after randomization were as follows: [177Lu]Lu-PSMA-617: 234, 216, 174, 150, 125, 82, 64, 45, 20, 10, 2, and 0, respectively; ARDT: 234, 197, 126, 79, 65, 36, 21, 12, 8, 4, 1, and 0, respectively. This indicates that 177Lu-PSMA-617 significantly extended rPFS relative to the change in ARPI. [Figure 2-2] (As mentioned above.) [Figure 3-1] Figure 3A shows a forest plot of hazard ratios and 95% confidence intervals for radiographic progression-free survival based on independent central review from sensitivity analyses (full analysis set) at early and late data cutoffs (DCO). From top to bottom, hazard ratios are associated with and based on the following events: [Table 1] Hazard ratios for [177Lu]Lu-PSMA-617 and ARDT obtained from stratified Cox PH models. 'a': COVID-19 related deaths are censored at the last adequate tumor assessment before death. 'b': COVID-19 related deaths are censored at the date of death. Stratification factors from IRT data: history of ARDT use in CRPC vs. HSPC; asymptomatic or mildly symptomatic (BPI-SF Short Pain Inventory (BPI-SF) questionnaire item 3 score 0-3) vs. symptomatic (BPI-SF questionnaire item 3 score >3). *Except for investigator assessment, all other analyses were based on BICR. Figure 3B shows a forest plot of hazard ratios and 95% confidence intervals for radiographic progression-free survival based on independent central review from the sensitivity analysis (full analysis set) at early and late data cutoffs (DCO). From top to bottom, the hazard ratios are associated with and based on the following events: [Table 2] Hazard ratios for [177Lu]Lu-PSMA-617 and ARDT obtained from stratified Cox PH models. 'a': COVID-19 related deaths are censored at the last adequate tumor assessment before death. 'b': COVID-19 related deaths are censored at the date of death. Stratification factors from IRT data: history of ARDT use in CRPC vs. HSPC; asymptomatic or mildly symptomatic (BPI-SF Short Pain Inventory (BPI-SF) questionnaire item 3 score 0-3) vs. symptomatic (BPI-SF questionnaire item 3 score >3). *Except for investigator assessment, all other analyses were based on BICR. [Figure 3-2] (As mentioned above.) [Figure 4]Kaplan-Meier plot of overall survival (OS) at 0, 2, 4, 6, 8, 10, 12, 14, and 16 months after randomization - number of controls still at risk at intermediate stage (full analysis set): [177Lu]Lu-PSMA-617: 233, 192, 157, 120, 68, 37, 14, 2, 0; ARDT: 234, 196, 155, 117, 76, 44, 11, 3, 0. [Figure 5] Figure 1 shows crossover-adjusted intention-to-treat (ITT) OS analysis. Interim OS analysis (DCO: June 2023). Pre-specified primary crossover-adjusted analysis HR: 0.80 (95% CI: 0.48, 1.33). Median, months (95% CI): 19.25 (16.95, NE) vs. 19.55 (14.95, NE). Number of events: 69 (29.5%) vs. 36 (15.4%). Pre-specified supplemental unadjusted (ITT) analysis HR: 1.16 (95% CI: 0.48, 1.33). CI: 0.83, 1.64). Median, months (95% CI): 19.25 (16.95, NE) vs. 19.71 (17.81, NE). Number of events: 69 (29.5%) vs. 65 (27.8%). Median OS follow-up, months (range): 12.72 (0.82, 23.00) vs. 13.08 (1.54, 22.64). Three patients died before receiving 177Lu-PSMA-617. ARPI: androgen receptor pathway inhibitor; CI: confidence interval; DCO: data cutoff; HR: hazard ratio; ITT: intention-to-treat analysis; NE: not estimable; OS: overall survival; PSMA: prostate-specific membrane antigen. [Figure 6] Figure 1: In evaluable patients, PSA responses were more frequent with 177Lu-PSMA-617 and ARPI changes (waterfall plot of highest percent change from baseline in PSA). Interim OS analysis (DCO: June 2023). (a) Patients with baseline and post-baseline PSA values. ARPI: androgen receptor pathway inhibitor; DCO: data cutoff; HR: hazard ratio; OS: overall survival; PSA: prostate-specific antigen; PSMA: prostate-specific membrane antigen. [Figure 7](a) Figure 1. Higher ORR and longer DOR were observed with 177Lu-PSMA-617 compared with a change in ARPI in evaluable patients. Interim OS analysis (DCO: June 2023). Soft tissue ORR (95% CI): 41.9% (32.3, 51.9) vs. 12.6% (6.9, 20.6). Median soft tissue DOR (in patients with a complete or partial response), months (95% CI): 17.1 (11.6, NE), n=44 vs. 10.1 (4.6, NE), n=13. (a) RECIST analysis population. ARPI: androgen receptor pathway inhibitor; CI: confidence interval; DCO: data cutoff; 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. [Figure 8] (a) 177Lu-PSMA-617 demonstrated higher ORR and longer DOR compared with ARPI modification in patients with measurable disease at baseline. Interim OS analysis (DCO: June 2023) ORR in soft tissue (95% CI): 50.7% (38.6, 62.8) vs. 14.9% (7.7, 25.0). Median DOR in soft tissue (in patients with a complete or partial response), months (95% CI): 13.63 (11.56, NE), n=36 vs. 10.05 (4.63, NE), n=11. (a) RECIST analysis population. ARPI: androgen receptor pathway inhibitor, CI: confidence interval, DCO: data cutoff, 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 [Figure 9-1] Figure 9A shows that the time to deterioration in composite (a) health-related quality of life and pain measures was longer with 177Lu-PSMA-617 compared with ARPI change. Interim OS analysis (DCO: June 2023) 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) vs. 4.27 (3.48, 4.53). [ka] FIG. 9B shows that the time to deterioration in composite (a) health-related quality of life and pain measures was longer with 177Lu-PSMA-617 compared with change in ARPI. Interim OS analysis (DCO: June 2023) 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) vs. 3.71 (3.09, 4.37) (a) Composite of score worsening, clinical disease progression, and death. ARPI: androgen receptor pathway inhibitor, BPI-SF: Brief Pain Inventory (short form), CI: confidence interval, DCO: data cutoff, FACT-P: Functional Assessment of Cancer Therapy-Prostate, HR: hazard ratio, OS: overall survival, PSMA: prostate-specific membrane antigen. [ka] [Figure 9-2] (As mentioned above.) DETAILED DESCRIPTION OF THE INVENTION

[0036] The present disclosure is further described and exemplified below.

[0037] Embodiment The therapeutic methods of the present disclosure are provided in particular as the following embodiments:

[0038] 1. A method for treating prostate-specific membrane antigen (PSMA)-positive [especially: advanced] metastatic castration-resistant prostate cancer (mCRPC), 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, co-crystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof; wherein the patient has been previously treated with [especially: 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), provided that the patient has not been treated with taxane-based chemotherapy (ie, is a taxane-naive patient).

[0039] Instead of embodiment 1, the present disclosure can also be formulated as the following embodiments:

[0040] 1a. A method for treating prostate-specific membrane antigen (PSMA)-positive [especially: advanced] metastatic castration-resistant prostate cancer (mCRPC), 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, co-crystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof, A method of treatment in which the patient has progressed after administration of a second generation ARPI (preferably only once) but has not been previously treated with taxane-based chemotherapy.

[0041] 1b. A method for treating prostate-specific membrane antigen (PSMA)-positive [particularly: advanced] metastatic castration-resistant prostate cancer (mCRPC), comprising administering to a taxane-naive patient who has progressed after [preferably: only one] treatment with a second-generation ARPI a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof.

[0042] 2. A method of treatment according to any one of the preceding embodiments, wherein said treatment reduces the risk of radiographic progression or death from prostate cancer by at least 40% / preferably 50% / more preferably 55% / even more preferably 57%, 58%, or 59% compared to continuing or substituting previously used or different ARDT / ARPI / ARAT treatment (corresponding to hazard ratios of 60% / 50% / 45% / 42%, respectively).

[0043] 3. A method of treatment according to any one of embodiments 1-2, wherein said treatment is characterized in that less than 40% / preferably less than 35% / more preferably less than 30% / even more preferably less than 25% / even more preferably less than 24% of the respective patient population show radiographic progression within approximately the first 7 months of treatment.

[0044] 4. A method of treatment according to any one of embodiments 1 to 3, wherein said treatment is characterized by an increase in radiographic progression-free survival (rPFS) in months of at least 40% / preferably 50% / more preferably 60% / even more preferably 65% ​​ / even more preferably 66% compared to continuing or substituting a previously used or different ARDT / ARPI / ARAT treatment.

[0045] 5. A method of treatment according to any one of embodiments 1 to 4, characterized in that the treatment results in at least a 15% / preferably a 20% / more preferably a 25% / even more preferably a 28% reduction in grade 3 or higher adverse events (AEs) compared to a previously used or different continuing or alternative ARDT / ARPI / ARAT treatment.

[0046] 6. A method of treatment according to any one of embodiments 1 to 5, characterized in that said treatment results in at least a 15% / preferably a 20% / more preferably a 25% reduction in grade 3 or higher serious adverse events (AEs) compared to continuing or substituting a previously used or different ARDT / ARPI / ARAT treatment.

[0047] 7. RLT agents contain at least two components: (1) a radionuclide component; (2) a ligand component, The radionuclide component (1) (a) preferably comprising at least one radionuclide selected from the group consisting of alpha particle-emitting radionuclides, beta negative electron-emitting radionuclides, and Auger electron-emitting radionuclides, more preferably a beta negative electron-emitting radionuclide; The ligand component (2) is (b) at least one PSMA-binding moiety; (c) at least one chelating agent for chelating a radionuclide or a salt containing a radionuclide, or a prosthetic group residue resulting from a radiohalogenation reaction; (d) optionally, at least one linker connecting the PSMA binding site (b) and the chelator or prosthetic group moiety (c), preferably said linker being a chemical moiety or a covalent bond; (e) A method of treatment according to any one of embodiments 1 to 6, optionally comprising at least one additional moiety that alters the systemic circulation time, tumor uptake, and / or biodistribution of the RLT agent, preferably said altering moiety consisting of oxyethylene units, e.g., oligo- or polyoxyethylene -(-CH2-CH2-O-)n-, where n=2 to 100, or an albumin binding site (e.g., Evans blue, 4-(p-iodophenyl)butyric acid, 4-(p-methylphenyl)butyric acid, ibuprofen).

[0048] 8. The method of embodiment 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.

[0049] 9. A method of treatment according to any one of embodiments 7 to 8, wherein the radionuclide is a beta-negative electron-emitting radionuclide having a half-life of about 2 days to about 10 days, preferably about 5 days to about 10 days, more preferably about 6 days to about 8 days, and even more preferably about 6 days or about 7 days, and the beta-negative electron maximum energy 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.

[0050] 10. The method of any one of embodiments 7 to 9, wherein the radionuclide is a beta-negative electron-emitting radionuclide with an absorbed electron energy fraction per decay of 100 to 300 keV / decay, 120 to 250 keV / decay, or about 150 keV / decay (e.g., 147 keV for Lu-177) to about 200 keV / decay (e.g., 196 keV / decay for Tb-161).

[0051] 11. The ligand is 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-7 11. The method of any one of embodiments 7 to 10, wherein the therapeutic agent is selected from the group consisting of PSMA-617, PSMA I&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, PSMA CM, or mcl-alb-M-PSMA, preferably PSMA-617, PSMA I&T, and PSMA-R2.

[0052] 12. The method of any one of embodiments 7-11, wherein the PSMA-binding moiety comprises at least two amino acids linked via a urea group or a 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.

[0053] 13. The radioligand therapeutic agent is selected from the group consisting of [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetan), [177Lu]Lu-EB-PSMA-617 (Evans Blue-modified [177Lu]Lu-PSMA-617), and [177Lu]Lu-PSMA I&T (lutetium (177Lu) zadavotide glaxetan), [161Tb]Tb-PSMA-617 (terbium (161Tb) bipibotide tetraxetan), [161Tb]Tb-EB-PSMA-617 (Evans Blue-modified [161Tb]Tb-PSMA-617), and [161Tb]Tb-PSMA The method of any one of embodiments 7 to 12, wherein the I&T is (Terbium (161Tb)zadabotidegraxetan), preferably [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetan), or [161Tb]Tb-PSMA-617 (terbium (161Tb) bipibotide tetraxetan), more preferably [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetan).

[0054] 14. A method of treatment according to any one of embodiments 7 to 13, wherein the PSMA binding site is glutamic acid-urea-lysine (GUL) and the linker consists of residues of (2-naphthyl)-L-alanine and trans-4-aminomethyl-cyclohexanecarboxylic acid, or the linker consists of residues of optionally substituted phenyl-alanine and / or optionally substituted tyrosine, preferably phenyl-alanine and substituted tyrosine, more preferably phenyl-alanine and iodo-substituted tyrosine, even more preferably D-phenyl-alanine and iodo-substituted D-tyrosine.

[0055] 15. A method of treatment according to any one of embodiments 1 to 14, wherein the radioligand therapeutic agent is administered 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, once every about 5 to about 10 weeks, preferably about 6 to about 8 weeks, more preferably 6 (±1) weeks (i.e., 1 cycle), for a maximum of about 4 to about 6 cycles, preferably about 6 cycles.

[0056] 16. The method of treatment of any one of embodiments 1-15, wherein the radioligand therapy is administered at a dose of 7.4 (±10%) GBq once every 6 (±1) weeks (i.e., 1 cycle), for up to 6 cycles.

[0057] 17. The PSMA positivity rate of mCRPC is determined by positron emission tomography (PET) using a PSMA-binding radioligand diagnostic or imaging agent, and the radioligand imaging agent is: (1) a radionuclide component; (2) a ligand component, The radionuclide component (1) (a) comprises at least one positron-emitting radionuclide; The ligand component (2) is (b) at least one PSMA-binding moiety; (c) at least one chelating agent for chelating a radionuclide or a salt containing a radionuclide, or a prosthetic group residue resulting from a radiohalogenation reaction; (d) optionally, at least one linker connecting the PSMA binding site (b) and the chelator or prosthetic group moiety (c), preferably said linker being a chemical moiety or a covalent bond;

[0058] 18. The method of treatment of embodiment 17, wherein the radionuclide is selected from the group consisting of F-18, Ga-67, Ga-68, and Cu-64.

[0059] 19. The method of any one of embodiments 17-18, wherein the ligand component is PSMA-11 (gozetotide), DCPyL (when labeled with 18F, available as PYLARIFY, International Nonproprietary Name: 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, PSMA I&T.

[0060] Further embodiments of the present disclosure are provided below.

[0061] 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 from prostate cancer in a patient in need thereof, comprising: the method comprises administering to the patient a therapeutically effective amount of a carrier-free (nca) lutetium-177 (177Lu)-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, conformer, or tautomer thereof; The prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC), The method, wherein the patient has been previously treated with androgen receptor directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis targeted therapy (ARAT), and the patient has not been previously treated with taxane-based chemotherapy, or if the patient has been previously treated with taxane-based chemotherapy, at least 12 months have passed since the completion (i.e., last dose) of the chemotherapy.

[0062] E2. The (treatment) method of any one of the preceding embodiments, wherein said treatment is characterized by at least a 40% / preferably a 50% / more preferably a 55% / even more preferably a 57% / 58% / 59% reduction in the risk of radiographic progression or death from prostate cancer (corresponding to a Hazard Ratio (HR) of 60% / 50% / 45% / 43% / 42% / 41% or less, respectively) compared to continuing or substituting ARDT / ARPI / ARAT treatment with previously used or a different ARDT / ARPI / ARAT, respectively.

[0063] E3. The (treatment) method of any one of the preceding embodiments, wherein said treatment is characterized in that less than 40% / preferably less than 35% / more preferably less than 30% / even more preferably less than 25% / even more preferably less than 24% of patients in the respective patient population show radiographic progression within about the first 7, 8, 9, 10, 11, 12 months of treatment.

[0064] E3.1 A method of treatment according to any one of the preceding embodiments, wherein said treatment is characterized by an increase in radiographic progression-free survival (rPFS) in months of at least 40% / preferably 50% / more preferably 60% / even more preferably 65% ​​ / even more preferably 66% compared to continuing or substituting a previously used or different ARDT / ARPI / ARAT treatment.

[0065] Alternatively, in certain embodiments, the methods of the present disclosure are formulated as follows:

[0066] E3.a A method of reducing radiographic progression of prostate cancer in a patient in need thereof, particularly within the first 7, 8, 9, 10, 11, 12 months of initiating the method, compared to continuing or alternative treatment with a previously used or different ARDT / ARPI / ARAT therapy, comprising: the method comprises administering to the patient a therapeutically effective amount of a carrier-free (nca) lutetium-177 (177Lu)-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, conformer, or tautomer thereof; The prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC), The patient has been previously treated with androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis-targeted therapy (ARAT), and the patient has not been previously treated with taxane-based chemotherapy, or if the patient has been previously treated with taxane-based chemotherapy, at least 12 months have passed since the completion of the chemotherapy (i.e., the last dose).

[0067] In certain embodiments, the reduction in radiographic progression is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0068] E4. The method of any one of the preceding embodiments, wherein said treatment is characterized by treatment-related adverse events of grade 3 or higher occurring in less than 25% of patients in the respective patient population.

[0069] E4.1 The (treatment) method according to any one of the preceding embodiments, wherein said treatment is characterized by at least a 15% / preferably a 20% / more preferably a 25% / even more preferably a 28% reduction in Grade 3 or higher adverse events (AEs) compared to a previously used or different ARDT / ARPI / ARAT continuation or alternative treatment.

[0070] Alternatively, in certain embodiments, the methods of the present disclosure are formulated as follows:

[0071] E4.a A method for reducing the incidence of Grade 3 or higher adverse events (AEs) in patients requiring treatment for prostate cancer compared to continuing or substituting a previously used or different ARDT / ARPI / ARAT therapy, comprising: the method comprises administering to the patient a therapeutically effective amount of a carrier-free (nca) lutetium-177 (177Lu)-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, conformer, or tautomer thereof; The prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC), The patient has been previously treated with androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis-targeted therapy (ARAT), and the patient has not been previously treated with taxane-based chemotherapy, or if the patient has been previously treated with taxane-based chemotherapy, at least 12 months have passed since the completion of the chemotherapy (i.e., the last dose).

[0072] In certain embodiments, the reduction in the rate of incidence of grade 3 or higher adverse events (AEs) is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0073] E5. The (treatment) method of any one of the preceding embodiments, wherein said treatment is characterized by treatment-related serious adverse events of Grade 3 or greater occurring in less than 15% of patients in the respective patient population.

[0074] E5.1 The (treatment) method according to any one of the preceding embodiments, wherein said treatment results in at least a 15% / preferably a 20% / more preferably a 25% reduction in Grade 3 or higher serious adverse events (AEs) compared to continuing or substituting a previously used or different ARDT / ARPI / ARAT treatment.

[0075] E5.a A method for reducing the incidence of Grade 3 or higher adverse events (AEs) in patients requiring treatment for prostate cancer compared to continuing or substituting a previously used or different ARDT / ARPI / ARAT therapy, comprising: the method comprises administering to the patient a therapeutically effective amount of a carrier-free (nca) lutetium-177 (177Lu)-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, conformer, or tautomer thereof; The prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC), The patient has been previously treated with androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis-targeted therapy (ARAT), and the patient has not been previously treated with taxane-based chemotherapy, or if the patient has been previously treated with taxane-based chemotherapy, at least 12 months have passed since the completion of the chemotherapy (i.e., the last dose).

[0076] In certain embodiments, the reduction in the rate of incidence of Grade 3 or higher serious adverse events (AEs) is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0077] E6. The (treatment) method of any one of the preceding embodiments, wherein said treatment is safer and better tolerated compared to continuation or substitution of ARDT / ARPI / ARAT treatment with previously used or a different ARDT / ARPI / ARAT, respectively.

[0078] E7. The (treatment) method of any one of the preceding embodiments, wherein said treatment results in at least a 15% reduction in Grade 3 or higher adverse events (AEs) compared to continuing or substituting previously used ARDT / ARPI / ARAT treatment with, respectively, a different ARDT / ARPI / ARAT.

[0079] E8. The (treatment) method of any one of the preceding embodiments, wherein said treatment is characterized by at least a 15% reduction in Grade 3 or higher serious adverse events (AEs) compared to continuing or substituting previously used ARDT / ARPI / ARAT treatment with a different ARDT / ARPI / ARAT, respectively.

[0080] E9. The (treatment) method of any one of the preceding embodiments, wherein the radioligand therapeutic agent is administered 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, once every 5 to 10 weeks, preferably 6 to 8 weeks, more preferably 6 (±1) weeks (i.e., 1 cycle) for a maximum of 4 to 6 cycles, preferably 6 cycles.

[0081] E10. The (treatment) method of any one of the preceding embodiments, wherein the radioligand therapy is administered at a dose of 7.4 (±10%) GBq once every 6 (±1) weeks (i.e., 1 cycle), for up to 6 cycles.

[0082] E11. A method for extending radiographic progression-free survival (rPFS) in a patient in need of prostate cancer treatment and / or for delaying the initiation of chemotherapy and / or for replacing chemotherapy in a patient in need of prostate cancer treatment, comprising: the method comprises 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, co-crystal, crystalline form, amorphous form, stereoisomer, conformer, or tautomer thereof; The prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC), The patient has been previously treated with androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis-targeted therapy (ARAT), with the proviso that the patient has not been previously treated with taxane-based chemotherapy less than 12 months prior.

[0083] E12. The (treatment) method of any one of the preceding embodiments, wherein said treatment results in at least a 40% increase in radiographic progression-free survival (rPFS) in months compared to continuing or substituting ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0084] E13. The (treatment) method of any one of the preceding embodiments, wherein said treatment is characterized by treatment-related adverse events of grade 3 or higher occurring in less than 25% of patients in the respective patient population.

[0085] E14. The (treatment) method of any one of the preceding embodiments, wherein said treatment is characterized by treatment-related serious adverse events of grade 3 or higher occurring in less than 15% of patients in the respective patient population.

[0086] E15. The (treatment) method of any one of the preceding embodiments, wherein said treatment is safer and better tolerated compared to continuation or substitution of ARDT / ARPI / ARAT treatment with previously used or a different ARDT / ARPI / ARAT, respectively.

[0087] E16. The (treatment) method of any one of the preceding embodiments, wherein said treatment results in at least a 15% reduction in grade 3 or higher adverse events (AEs) compared to continuing or substituting previously used ARDT / ARPI / ARAT treatment with, respectively, a different ARDT / ARPI / ARAT.

[0088] E17. The (treatment) method of any one of the preceding embodiments, wherein said treatment is characterized by at least a 15% reduction in Grade 3 or higher serious adverse events (AEs) compared to continuing or substituting previously used ARDT / ARPI / ARAT treatment with a different ARDT / ARPI / ARAT, respectively.

[0089] E18. The (treatment) method of any one of the preceding embodiments, wherein the radioligand therapeutic agent is administered 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, once every 5 to 10 weeks, preferably every 6 to 8 weeks, more preferably every 6 (±1) weeks (i.e., 1 cycle) for a maximum of 4 to 6 cycles, preferably 6 cycles.

[0090] E19. The (treatment) method of any one of the preceding embodiments, wherein the radioligand therapy is administered at a dose of 7.4 (±10%) GBq once every 6 (±1) weeks (i.e., 1 cycle), up to a maximum of 6 cycles.

[0091] E20.nca177Lu-labeled PSMA-binding RLT agent, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformer, or tautomer thereof, comprising the components: (1) NCA quality beta-negative electron-emitting radionuclide 177Lu, (2) a ligand component, The ligand component (2) is (a) at least one PSMA binding moiety; (b) at least one chelator moiety suitable for chelating a radionuclide; (c) at least one linker moiety connecting the PSMA binding moiety (a) and the chelator moiety (b); and (d) optionally at least one additional moiety that alters the systemic circulation time, tumor uptake, and / or biodistribution of the RLT agent, preferably said altering moiety comprises oxyethylene units, e.g., oligo- or polyoxyethylene-(-CH2-CH2-O-)n-, n=2 to 100, or is an albumin binding moiety (e.g., Evans blue, 4-(p-iodophenyl)butyric acid, 4-(p-methylphenyl)butyric acid, ibuprofen), said altering moiety preferably covalently attached to linker component (c).

[0092] E21. The (treatment) method of any one of the preceding embodiments, wherein the PSMA-binding moiety (a) comprises at least two amino acids linked via a urea group or a 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.

[0093] E22. The (therapeutic) method of any one of the preceding embodiments, wherein the linker (c), which comprises a functional group connecting the linker to the PSMA binding site, e.g., an amide bond connecting a lysine of the binding site to the linker, comprises at least one hydrophobic side chain, e.g., a side chain comprising an aromatic unit, e.g., an optionally substituted phenyl, an optionally substituted benzyl, or an optionally substituted naphthyl.

[0094] E23. The (therapeutic) method according to any one of the preceding 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 phenyl-alanine and / or optionally substituted tyrosine, preferably phenyl-alanine and subsubstituted tyrosine, more preferably phenyl-alanine and iodo-substituted tyrosine, even more preferably D-phenyl-alanine and iodo-substituted D-tyrosine.

[0095] E24. The (treatment) method of any one of the preceding embodiments, wherein the ligand is selected from the group consisting of PSMA-617 (bipibotide tetraxetan), PSMA I&T (zadabotide glaxetan), 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 the group consisting of PSMA-617, PSMA I&T, and PSMA-R2.

[0096] E25. The (treatment) method of any one of the preceding embodiments, wherein the RLT agent is selected from the group consisting of [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetan), [177Lu]Lu-EB-PSMA-617 (Evans blue modified [177Lu]Lu-PSMA-617), and [177Lu]Lu-PSMA I&T (lutetium (177Lu) zadabotide glaxetan).

[0097] E26. PSMA positivity of mCRPC is determined by positron emission tomography (PET) using a PSMA-binding radioligand diagnostic or imaging (RLI) agent, wherein said radioligand imaging agent is (1) a radionuclide component; (2) a ligand component, The radionuclide component (1) (a) containing at least one positron-emitting nuclide; The ligand component (2) is (b) at least one PSMA-binding moiety; (c) at least one chelating agent for chelating a radionuclide or a salt containing a radionuclide, or a prosthetic group residue resulting from a radiohalogenation reaction; (d) optionally, at least one linker connecting the PSMA binding site (b) and the chelator or prosthetic group moiety (c), preferably said linker being a chemical moiety or a covalent bond.

[0098] E27. The (treatment) method of any one of the preceding embodiments, wherein said radionuclide is selected from the group consisting of F-18, Ga-67, Ga-68, and Cu-64.

[0099] E28. The (treatment) method of any one of the preceding 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-7 I&T.

[0100] E29. The method of any one of the preceding embodiments, wherein the RLI agent is selected from the group consisting of [68Ga]Ga-PSMA-11 (gallium (68Ga) gozetotide (available from Novartis or Advanced Accelerator applications as LOCAMETZ or from Telix as ILLUCCIX), 18F-DCPyL (piflufolastat (18F) (available from Lantheus as PYLARIFY or from Curium as PYLCLARI)), 18F-PSMA-1007 (available from ABX as RADELIUM), 18F-CTT1057 (bidofolastat (18F)), 18F / natGa-rhPSMA-7.3 (flotufolastat (18F) (available from Blue Earth as POSLUMA)), [68Ga]Ga-PSMA-R2, and [64Cu]Cu-PSMA-R2.

[0101] Additional embodiments of the present disclosure are as follows:

[0102] e1. A method for reducing the risk of radiographic progression of or death from prostate cancer in a patient in need thereof, comprising: the method comprises administering to the patient a therapeutically effective amount of a carrier-free (nca) lutetium-177 (177Lu)-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, conformer, or tautomer thereof; The prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC), The patient has been previously treated with androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis-targeted therapy (ARAT), and the patient has not been previously treated with taxane-based chemotherapy, or if the patient has been previously treated with taxane-based chemotherapy, at least 12 months have passed since the completion of the chemotherapy (i.e., the last dose).

[0103] e2. A method of treatment according to any preceding embodiment, wherein said treatment reduces the risk of radiographic progression or death from prostate cancer by at least 50%, corresponding to a hazard ratio (HR) of 50% or less, compared to continuing or substituting ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0104] e3. The method of any one of the preceding two embodiments, wherein said treatment is characterized by less than 25% of the respective patient population showing radiographic progression within the first about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 months of treatment.

[0105] e4. A method for extending radiographic progression-free survival (rPFS) in a patient requiring treatment for prostate cancer, comprising: the method comprises administering to the patient a therapeutically effective amount of a carrier-free (nca) lutetium-177 (177Lu)-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, conformer, or tautomer thereof; The prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC), The patient has been previously treated with androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis-targeted therapy (ARAT), and the patient has not been previously treated with taxane-based chemotherapy, or if the patient has been previously treated with taxane-based chemotherapy, at least 12 months have passed since the completion of the chemotherapy (i.e., the last dose).

[0106] e5. A method of treatment according to any preceding embodiment, wherein said treatment results in at least a 40% increase in radiographic progression-free survival (rPFS) in months compared to continuing or substituting ARDT / ARPI / ARAT treatment with previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, respectively.

[0107] e6. A method for extending overall survival (OS) in a patient in need of prostate cancer treatment, comprising: the method comprises administering to the patient a therapeutically effective amount of a carrier-free (nca) lutetium-177 (177Lu)-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, conformer, or tautomer thereof; The prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC), The patient has been previously treated with androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis-targeted therapy (ARAT), and the patient has not been previously treated with taxane-based chemotherapy, or if the patient has been previously treated with taxane-based chemotherapy, at least 12 months have passed since the completion of the chemotherapy (i.e., the last dose).

[0108] e7. The method of treatment of the preceding embodiments, wherein said treatment reduces the risk of death by a hazard ratio of less than 1, about 0.95 or less, about 0.9 or less, about 0.85 or less, about 0.8 or less, about 0.75 or less, about 0.7 or less, about 0.65 or less, about 0.6 or less, about 0.55 or less, or about 0.5 or less, wherein said risk is calculated relative to patients continuing to receive ARDT / ARPI / ARAT treatment with the previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, or patients receiving ARDT / ARPI / ARAT treatment with an alternative ARDT / ARPI / ARAT, respectively.

[0109] e8. A method for increasing overall response rate (ORR) (i.e., complete response (CR) and partial response (PR)) in soft tissue in a patient in need of prostate cancer treatment, comprising: the method comprises administering to the patient a therapeutically effective amount of a carrier-free (nca) lutetium-177 (177Lu)-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, conformer, or tautomer thereof; The prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC), The patient has been previously treated with androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis-targeted therapy (ARAT), and the patient has not been previously treated with taxane-based chemotherapy, or if the patient has been previously treated with taxane-based chemotherapy, at least 12 months have passed since the completion of the chemotherapy (i.e., the last dose).

[0110] e9. The method of treatment of the preceding embodiments, wherein the 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 the previously used ARDT / ARPI / ARAT or continuation or substitution of ARDT / ARPI / ARAT treatment with a different ARDT / ARPI / ARAT, respectively.

[0111] e10. The method of treatment of any one of the preceding two embodiments, wherein the complete response (CR) rate in soft tissue is increased by at least 100% (1-fold increase), 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 the previously used ARDT / ARPI / ARAT or continuation or substitution of ARDT / ARPI / ARAT treatment with a different ARDT / ARPI / ARAT, respectively.

[0112] Overall survival (OS) refers to the length of time a patient is alive, and may include death from any cause, regardless of breast cancer recurrence or metastasis. OS can be defined as the time from the first date (e.g., the date cancer treatment began or ended) to the date of death from any cause.

[0113] e11. A method for improving the health-related quality of life (HRQoL) (e.g., as determined by Functional Assessment of Cancer Therapy-Prostate (FACT-P)) of a patient requiring prostate cancer treatment, comprising: the method comprises administering to the patient a therapeutically effective amount of a carrier-free (nca) lutetium-177 (177Lu)-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, conformer, or tautomer thereof; The prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC), The patient has been previously treated with androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis-targeted therapy (ARAT), and the patient has not been previously treated with taxane-based chemotherapy, or if the patient has been previously treated with taxane-based chemotherapy, at least 12 months have passed since the completion of the chemotherapy (i.e., the last dose).

[0114] e12. A method of treatment of any preceding embodiment, wherein the time to deterioration in composite HRQoL is about 50% longer, about 60% longer, or about 70% longer compared to continuing or substituting ARDT / ARPI / ARAT treatment with the previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, respectively.

[0115] e13. A method of treatment of any one of the preceding two embodiments, wherein the risk of worsening composite HRQoL 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 continuing or replacing ARDT / ARPI / ARAT treatment with the previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, respectively.

[0116] e14. A method for increasing PSA responsiveness in a patient in need of prostate cancer treatment, the method comprises administering to the patient a therapeutically effective amount of a carrier-free (nca) lutetium-177 (177Lu)-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, conformer, or tautomer thereof; The prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC), The patient has been previously treated with androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis-targeted therapy (ARAT), and the patient has not been previously treated with taxane-based chemotherapy, or if the patient has been previously treated with taxane-based chemotherapy, at least 12 months have passed since the completion of the chemotherapy (i.e., the last dose).

[0117] e15. A method of treatment according to the preceding embodiment, wherein the confirmed PSA reduction of at least 50% is about 100%, or at least 150%, compared to continuing or substituting ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0118] e16. A method for delaying the time to symptomatic skeletal events (SSE) in a patient requiring prostate cancer treatment, comprising: the method comprises administering to the patient a therapeutically effective amount of a carrier-free (nca) lutetium-177 (177Lu)-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, conformer, or tautomer thereof; The prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC), The patient has been previously treated with androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis-targeted therapy (ARAT), and the patient has not been previously treated with taxane-based chemotherapy, or if the patient has been previously treated with taxane-based chemotherapy, at least 12 months have passed since the completion of the chemotherapy (i.e., the last dose).

[0119] e17. A method of treatment as described in the preceding embodiment, wherein the delay in time to SSE is about 50% longer, about 60% longer, about 70% longer, about 80% longer, or about 90% longer compared to continuing or substituting ARDT / ARPI / ARAT treatment with a previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, respectively.

[0120] e18. A method for reducing the risk of symptomatic skeletal events (SSE) in a patient requiring prostate cancer treatment, comprising: the method comprises administering to the patient a therapeutically effective amount of a carrier-free (nca) lutetium-177 (177Lu)-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, conformer, or tautomer thereof; The prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC), The patient has been previously treated with androgen receptor-directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis-targeted therapy (ARAT), and the patient has not been previously treated with taxane-based chemotherapy, or if the patient has been previously treated with taxane-based chemotherapy, at least 12 months have passed since the completion of the chemotherapy (i.e., the last dose).

[0121] e19. The method of treatment of any preceding embodiment, wherein the risk is reduced by at least about 50%, about 55%, about 60%, about 65%, or about 70% compared to continuing or substituting ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0122] e20. The method of treatment of any one of the preceding embodiments, wherein said treatment is safer and better tolerated compared to continuation or substitution of ARDT / ARPI / ARAT treatment with a previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, respectively.

[0123] e21. A method of treatment according to any one of the preceding embodiments, wherein said treatment is characterized by treatment-related adverse events of grade 3 or higher occurring in less than 25% of patients in the respective patient population.

[0124] e22. A method of treatment according to any one of the preceding embodiments, wherein said treatment is characterized by treatment-related serious adverse events of grade 3 or higher occurring in less than 15% of patients in the respective patient population.

[0125] e23. The method of any one of the preceding embodiments, wherein the radioligand therapeutic is administered at a dose of about 6 to about 8 GBq once every 6 to 8 weeks (i.e., 1 cycle), for a maximum of 4 to 6 cycles.

[0126] e24. The method of any one of the preceding embodiments, wherein the radioligand therapy is administered at a dose of 7.4 (±10%) GBq once every 6 (±1) weeks (i.e., 1 cycle), for up to 6 cycles.

[0127] e25.nca177Lu-labeled PSMA-binding RLT agent, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformer, or tautomer thereof, comprising the components: (1) NCA quality beta-negative electron-emitting radionuclide 177Lu, (2) a ligand component, The ligand component (2) is (a) at least one PSMA binding moiety; (b) at least one chelator moiety suitable for chelating a radionuclide; (c) at least one linker moiety connecting the PSMA binding moiety (a) and the chelator moiety (b).

[0128] e26. A method of treatment according to any one of the preceding embodiments, wherein the PSMA-binding moiety (a) comprises the amino acids glutamic acid and lysine linked via a urea group, e.g., glutamic acid-urea-lysine (GUL), the chelating moiety (b) comprises a residue of DOTA or a residue of DOTAGA, and the linker (c) (including the functional group connecting the linker to the PSMA-binding site, e.g., an amide bond connecting the lysine of the binding site to the linker) comprises at least one hydrophobic side chain selected from the group consisting of optionally substituted phenyl, optionally substituted benzyl, or optionally substituted naphthyl.

[0129] e27. The method of any one of the preceding embodiments, wherein the RLT agent is selected from the group consisting of [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetan), [177Lu]Lu-PSMA I&T (lutetium (177Lu) zadabotide glaxetan), and [177Lu]Lu-PSMA-R2.

[0130] e28. A method of treatment according to any one of the preceding embodiments, wherein the RLT agent is selected from the group consisting of [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetan), and [177Lu]Lu-PSMA I&T (lutetium (177Lu) zadabotide glaxetan).

[0131] e29. The method of treatment of any one of the preceding embodiments, wherein the RLT agent is [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetane).

[0132] e30. The method of any one of the preceding embodiments, wherein PSMA positivity of the mCRPC is determined by positron emission tomography (PET) using a PSMA-binding radioligand diagnostic or imaging (RLI) agent, said radioligand imaging being selected from the group consisting of [68Ga]Ga-PSMA-11 (gallium (68Ga) gozetotide), 18F-DCPyL (piflufolastat (18F)), 18F-PSMA-1007, 18F-CTT1057 (bidofolastat (18F)), 18F / natGa-rhPSMA-7.3 (flotufolastat (18F)), [68Ga]Ga-PSMA-R2, and [64Cu]Cu-PSMA-R2.

[0133] More generally, the following are provided for embodiments throughout this disclosure:

[0134] In some embodiments, the method of treatment is a method of reducing the risk of radiographic progression of or death from prostate cancer in a patient in need thereof.

[0135] In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a carrier-free (nca) lutetium-177 (177Lu)-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, conformer, or tautomer thereof.

[0136] In some embodiments, the prostate cancer is prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC).

[0137] In some embodiments, the patient has been previously treated with androgen receptor directed therapy (ARDT), androgen receptor pathway inhibition (ARPI), or androgen receptor axis targeted therapy (ARAT).

[0138] In some embodiments, the patient has not been previously treated with taxane-based chemotherapy.

[0139] In some embodiments, the patient has not previously been treated with taxane-based chemotherapy, or if previously exposed to a taxane, at least 12 months have passed since completion of said chemotherapy (i.e., administration of the last dose).

[0140] In some embodiments, the treatment methods are characterized by a reduction in the risk of prostate cancer radiographic progression or death of 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 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, or 30% or less, respectively, compared to continuing or substituting ARDT / ARPI / ARAT treatment with the previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT.

[0141] In some embodiments, the treatment methods are characterized in that less than 25% of the patients in each patient population demonstrate radiographic progression within about the first 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months of treatment.

[0142] In some embodiments, the treatment methods are characterized in that less than 24% of the patients in each patient population demonstrate radiographic progression within about the first 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months of treatment.

[0143] In some embodiments, the treatment methods are characterized in that less than 23% of the patients in each patient population demonstrate radiographic progression within about the first 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months of treatment.

[0144] In some embodiments, the treatment methods are characterized in that less than 22% of the patients in each patient population demonstrate radiographic progression within about the first 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months of treatment.

[0145] In some embodiments, the treatment methods are characterized in that less than 21% of the patients in each patient population demonstrate radiographic progression within about the first 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months of treatment.

[0146] In some embodiments, the treatment methods are characterized in that less than 20% of the patients in each patient population demonstrate radiographic progression within about the first 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months of treatment.

[0147] In some embodiments, the treatment methods are characterized in that less than 19% of the patients in each patient population exhibit radiographic progression within about the first 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months of treatment.

[0148] In some embodiments, the treatment methods are characterized in that less than 18% of the patients in each patient population exhibit radiographic progression within about the first 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months of treatment.

[0149] In some embodiments, the treatment methods are characterized in that less than 17% of the patients in each patient population demonstrate radiographic progression within about the first 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months of treatment.

[0150] In some embodiments, the treatment methods are characterized in that less than 16% of patients in each patient population demonstrate radiographic progression within about the first 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months of treatment.

[0151] In some embodiments, the treatment methods are characterized in that less than 15% of the patients in each patient population demonstrate radiographic progression within about the first 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months of treatment.

[0152] In some embodiments, the treatment methods are characterized in that less than 10% of the patients in each patient population demonstrate radiographic progression within about the first 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months of treatment.

[0153] In some embodiments, the treatment methods are characterized in that less than 5% of the patients in each patient population exhibit radiographic progression within about the first 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months of treatment.

[0154] In some embodiments, the method of treatment is a method of extending radiographic progression-free survival (rPFS) in a patient in need of prostate cancer treatment.

[0155] In some embodiments, the treatment method is characterized by an increase in radiographic progression-free survival (rPFS) in months of at least 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 70%, 80%, 90%, 100%, 150%, or 200% compared to continuing or substituting ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT.

[0156] In some embodiments, the method of treatment is a method of increasing overall survival (OS) in a patient in need of prostate cancer treatment.

[0157] In some embodiments, the treatment method reduces the risk of death corresponding to a hazard ratio of less than 1, about 0.95 or less, about 0.9 or less, about 0.85 or less, about 0.8 or less, about 0.75 or less, about 0.7 or less, about 0.65 or less, about 0.6 or less, about 0.55 or less, or about 0.5 or less, where the risk is calculated relative to patients continuing to receive ARDT / ARPI / ARAT treatment with a previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, or patients receiving an alternative ARDT / ARPI / ARAT treatment, respectively.

[0158] In some embodiments, the method of treatment is a method of increasing the overall response rate (ORR) (i.e., complete response (CR) and partial response (PR)) in soft tissue in patients in need of prostate cancer treatment.

[0159] In some embodiments, in the method of treatment, the 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 continuing or substituting ARDT / ARPI / ARAT treatment with the previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, respectively.

[0160] In some embodiments, the complete response (CR) rate in soft tissue is increased by at least 100% (1-fold increase), 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 continuing or substituting ARDT / ARPI / ARAT treatment with the previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, respectively.

[0161] In some embodiments, overall survival (OS) may relate to the length of time a patient survives, which may include death from any cause, regardless of whether breast cancer recurs or spreads.

[0162] OS can be defined as the time from the first date (eg, the date cancer treatment began or ended) to the date of death from any cause.

[0163] In some embodiments, the method of treatment is a method of improving the health-related quality of life (HRQoL) (e.g., as determined by the Functional Assessment of Cancer Therapy-Prostate (FACT-P)) of a patient in need of prostate cancer treatment.

[0164] In some embodiments, the method of treatment described in the preceding embodiments, wherein the time to deterioration of composite HRQoL is about 50% longer, about 60% longer, or about 70% longer than when continuing or substituting ARDT / ARPI / ARAT treatment with the previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, respectively.

[0165] In some embodiments, the risk of deterioration in composite HRQoL 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 who continue or substitute ARDT / ARPI / ARAT treatment with the previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, respectively.

[0166] In some embodiments, the method of treatment is a method of increasing PSA responsiveness in a patient in need of prostate cancer treatment.

[0167] In some embodiments, the PSA response is a confirmed PSA decrease of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or at least 200%, respectively, compared to continuing or substituting ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT.

[0168] In some embodiments, the method of treatment is a method of delaying the time to symptomatic skeletal event (SSE) in a patient in need of prostate cancer treatment.

[0169] In some embodiments, the delay in time to SSE is about 50% longer, about 60% longer, about 70% longer, about 80% longer, or about 90% longer compared to continuing or substituting ARDT / ARPI / ARAT treatment with the previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, respectively.

[0170] In some embodiments, the method of treatment is a method of reducing the risk of symptomatic skeletal events (SSEs) in a patient in need of prostate cancer treatment.

[0171] In some embodiments, the risk of SSE is reduced by at least about 50%, about 55%, about 60%, about 65%, or about 70% compared to continuing or substituting ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0172] In some embodiments, the method of treatment is a safer and better tolerated treatment compared to continued or alternative ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0173] In some embodiments, the treatment is characterized by treatment-related grade 3 or higher adverse events occurring in less than 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 10%, or 5% of patients in the respective patient population.

[0174] In some embodiments, the treatment is characterized by treatment-related serious adverse events of grade 3 or higher occurring in less than 15%, less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, or less than 5% of patients in the respective patient population.

[0175] In some embodiments, the radioligand therapy is administered at a dose of about 6 to about 8 GBq once every 6 to 8 weeks (ie, 1 cycle), for up to 4 to 6 cycles.

[0176] In some embodiments, the radioligand therapy is administered at a dose of 7.4 (±10%) GBq once every 6 (±1) weeks (ie, 1 cycle) for up to 6 cycles.

[0177] In some embodiments, the nca177Lu labeled PSMA-binding RLT agent, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformer, or tautomer thereof, comprises one or more of the following components: (1) NCA quality beta-negative electron-emitting radionuclide 177Lu; (2) a ligand component, The ligand component (2) is (a) at least one PSMA binding moiety; (b) at least one chelator moiety suitable for chelating a radionuclide; (c) at least one linker moiety connecting the PSMA binding moiety (a) and the chelator moiety (b).

[0178] In some embodiments, the PSMA-binding moiety (a) comprises the amino acids glutamic acid and lysine linked through a urea group, e.g., glutamic acid-urea-lysine (GUL); the chelating moiety (b) comprises a residue of DOTA or a residue of DOTAGA; and 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.

[0179] In some embodiments, the PSMA-binding moiety (a) comprises the amino acids glutamic acid and lysine linked through a urea group, e.g., glutamic acid-urea-lysine (GUL); the chelating moiety (b) comprises a residue of DOTA or a residue of DOTAGA; and the linker (c) (including the functional group connecting the linker to the PSMA-binding site, e.g., an amide bond connecting the lysine of the binding site to the linker) is comprised of at least one hydrophobic side chain selected from the group consisting of optionally substituted phenyl, optionally substituted benzyl, or optionally substituted naphthyl.

[0180] In some embodiments, the RLT agent is selected from the group consisting of [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetan), [177Lu]Lu-PSMA I&T (lutetium (177Lu) zadabotide glaxetan), and [177Lu]Lu-PSMA-R2.

[0181] In some embodiments, the RLT agent is selected from the group consisting of [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetan) and [177Lu]Lu-PSMA I&T (lutetium (177Lu) zadabotide glaxetan).

[0182] In some embodiments, the RLT agent is [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetane).

[0183] 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 agent is [Ga]Ga-PSMA-11 (gallium (Ga) gozetotide), F-DCPyL (piflufolastat (F)), F-PSMA-1007, F-CTT1057 (bidoflufolastat (F)), F / natGa-rhPSMA-7.3 (flotufolastat (F)), [Ga]Ga-PSMA-R2, and [Cu]Cu-PSMA-R2.

[0184] The present disclosure provides methods of treating patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) whose cancer has progressed on or after administration of a second-generation ARPI with a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof.

[0185] So far, these patients have received taxene-based chemotherapy.

[0186] However, the clinical data reported herein indicate that radioligand therapy may be a safer and / or more effective treatment for treating ongoing prostate cancer.

[0187] In various embodiments, the methods of treatment described herein are also characterized by providing 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, or at least 3-fold higher rORR (radiographic overall response rate) compared to continuation or substitution of ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0188] In various embodiments, the methods of treatment described herein are also characterized by providing a higher rDCR (radiographic disease control rate), at least 20%, 30%, 40%, 50%, or higher, compared to continuing or substituting ARDT / ARPI / ARAT treatment with a previously used or different ARDT / ARPI / ARAT, respectively.

[0189] In various embodiments, the methods of treatment as described herein are also characterized by providing at least a three-fold higher rORR (radiographic overall response rate) compared to the previously used ARDT / ARPI / ARAT or continuation or substitution of ARDT / ARPI / ARAT treatment with a different ARDT / ARPI / ARAT, respectively.

[0190] In an embodiment of the present disclosure, the ligand may be selected from the group consisting of PSMA-617 (bipibotide tetraxetan), PSMA I&T (zadabotide glaxetan), 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-7 I&T, EB-PSMA-617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93, and RPS-074, and is 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.

[0191] In embodiments of the disclosure, the ligand is 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-7 I&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, PSMA CM, or mcl-alb-M-PSMA.

[0192] 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.

[0193] In embodiments of the present disclosure, the 177Lu radionuclide is either "carrier-added" in quality (ca 177Lu, e.g., produced by 176Lu (neutrons, gamma rays) 177Lu in a direct production route, and therefore also containing 177mLu), or "carrier-free" in quality (nca 177Lu, e.g., produced by 176Yb (neutrons, gamma rays) 177Yb beta-minus decay 177Lu in an indirect reactor production route, and essentially free of 177mLu). In a preferred embodiment, the radionuclide 177Lu is of nca quality.

[0194] Generally, "labeled," particularly in expressions such as "lutetium-177 (177Lu) labeled prostate-specific membrane antigen (PSMA)-binding radioligand therapy (RLT) agent," means that the radionuclide is complexed or chelated to a chelating moiety of the RLT agent, such as a DOTA or DOTAGA chelator.

[0195] In certain embodiments, the prostate-specific membrane antigen (PSMA)-positive (+) metastatic castration-resistant prostate cancer (mCRPC) is PSMA+ mCRPC that progresses after a first ARDT (e.g., cancer progresses under or after treatment with a second-generation ARDT such as abiraterone, enzalutamide, darolutamide, and apalutamide).

[0196] The above embodiments are formulated as method of treatment claims, which may also be formulated into other second medical uses, such as exemplified below, where [drug] is an RLT agent (alone or in combination with other agents), [indication] is mCRPC as defined in the above embodiments, and [characteristics] are characterizing characteristics as mentioned in the above embodiments:

[0197] The present invention provides a [drug] or a pharmaceutically acceptable salt thereof for use in the treatment of an [indication], characterized by [characteristics].

[0198] Alternatively, the invention provides a method for the treatment of [indication] in a human patient in need of such treatment, comprising administering an effective amount of [agent] or any pharmaceutically acceptable salt thereof, said treatment being characterized in [characteristics].

[0199] As a further alternative, the present invention provides the use of [agent] or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of [indication], characterized by [characteristics].

[0200] As a further alternative, the present invention provides the use of [agent] or a pharmaceutically acceptable salt thereof for the treatment of [indication], characterized by [characteristics].

[0201] As a further alternative, the present invention provides a medicament for the treatment of [indication] comprising [drug] or a pharmaceutically acceptable salt thereof, characterized by [characteristics].

[0202] In some embodiments of the present disclosure, the treatment, agent, medicine, or use thereof is for patients who have not previously been treated with taxane-based chemotherapy (i.e., taxane-naive patients). Preferably, the patient has not previously received taxane-based chemotherapy. In some embodiments, the patient has previously been treated with taxane-based chemotherapy, but in the case of previous taxane exposure, at least 12 months have passed since completion of the chemotherapy (i.e., administration of the last dose).

[0203] In some embodiments, the patient has not been previously treated with 223Ra therapy.

[0204] definition "About" in reference to a value means ±25%, preferably ±20%, more preferably ±15%, even more preferably ±10%, and even more preferably ±5%. "About" in reference to a week or cycle means ±2, preferably ±1.

[0205] In this disclosure and its embodiments, the terms radionuclide and radioisotope are interchangeable. Where technically meaningful, the terms radiometal and radiohalogen may also be used alternatively.

[0206] As used herein, instead of referring to a radionuclide in the form, for example, 177Lu or Lu-177 or lutetium-177, the form 177Lu is used alternatively. Thus, throughout this disclosure, when a mass number, e.g., 177, is not a superscript (e.g., 177Lu), it is nevertheless meant to refer to 177Lu as a superscript.

[0207] PSMA-617 or bipibotide tetraxetane refers to Pulvict's "cold" ligand (a ligand containing no radioactive nuclide), i.e., International Nonproprietary Name: lutetium (177Lu) bipibotide tetraxetane, and can be represented by the following formula (I): [ka]

[0208] PSMA I&T (zadabotide glaxetan) refers to the "cold" ligand (radionuclide-free ligand) of [177Lu]Lu-PSMA I&T (International Nonproprietary Name: Lutetium (177Lu) Zadabotide Glaxetan), which is commercially available from ABX GmbH, Radeberg, Germany, and may be represented by formula (II): [ka]

[0209] Drug substances, formulations, and methods for manufacturing formulations for clinical use of this RLT agent are described in U.S. Pat. Nos. 11,129,912 B1 and 11,491,246 B2, and WO 2002 / 013610. The glutamic acid / glutamic acid residues of 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 in which the L-configuration is in excess or the D-configuration is in abundance).

[0210] PSMA-R2 may be represented by formula (III), preferably with the glutamic acid and lysine adjacent to the urea in the L-configuration: [ka]

[0211] Any radionuclide, e.g., a radiometal such as 177Lu, can be complexed with a DOTA or DOTAGA residue, the latter acting as a chelator for the radiometal, resulting in a 177Lu-labeled RLT agent.

[0212] [68Ga]Ga-PSMA-11 (international non-proprietary name: gallium (68Ga) gozetotide, drug name: LOCAMETZ, ILLUCCIX) can be represented by formula (IV). [ka]

[0213] 18F-DCFPyL (international non-proprietary name: piflufolastat (18F), drug name: PYLARIFY, PYLCLARI) can be represented by formula (V). [ka]

[0214] 18F( / natGa)-rhPSMA-7.3 (international non-proprietary name: flotufolastat (18F), drug name: POSLUMA) can be represented by formula (VI). [ka]

[0215] Regarding taxenes and taxane-based chemotherapy: Taxanes are a class of diterpenes, generally consisting of a taxadiene core. Paclitaxel (Taxol) and docetaxel (Taxotere) are widely used chemotherapy drugs. Cabazitaxel is FDA-approved for the treatment of hormone-refractory prostate cancer.

[0216] Hormonal therapy may include androgen-targeted therapy such as finasteride, dutasteride, bicalutamide, apalutamide, abiraterone, enzalutamide, or a combination thereof. Taxane-based chemotherapy may include docetaxel or cabazitaxel, or a combination thereof. Other cancer therapeutic agents used in the context of the present disclosure may include abiraterone, orteronel, galeterone, ceviteronar, apalutamide, enzalutamide, or a combination thereof. Additional cancer therapeutic agents used in the context of the present disclosure may include palifosfamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafenib, or a combination thereof.

[0217] No carrier added (NCA, nca, nca): A radioisotope formulation essentially free of stable isotopes of the element. Methods for producing nca 177Lu are known, for example, from 176Yb via 177Yb, e.g., 176Yb(n,γ)177Yb, which then undergoes beta-minus decay to 177Lu (sometimes referred to as the "indirect" reactor production route). This method involves a radiochemical separation step to separate the desired nca 177Lu from the Yb isotope. No carrier added is sometimes also referred to as carrier-free.

[0218] The following response types and response rates are used herein:

[0219] [Table 3]

[0220] In the embodiments herein, features in brackets (...) or [...] refer to optional features or features that can be included, and therefore to subtypes of the respective embodiment.

[0221] References All publications, patents, and patent applications mentioned in this specification 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. (2019) A Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer (TheraP) p. / / clinicaltrials.gov / ct2 / history / NCT03392428. (Accessed 19-SEP-2020) (2020) ICH-E2D Guidelines p. / / database.ich.org / sites / default / files / E2D-R1_ConceptPaper_Final_2020_0115.pdf. Abeshouse A, Ahn J, Akbani R, et al (2015) The Molecular Taxonomy of Primary Prostate Cancer. Cell 1011-25. 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Zhao SG, Chang SL, Spratt DE, et al (2016) Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis. Lancet Oncol. 1612-1620. Zielinski RR, Azad AA, Chi KN, et al (2014) Population-based impact on overall survival after the introduction of docetaxel as standard therapy for metastatic castration resistant prostate cancer. 8(7-8): E520-3. de Bono J, Mateo J, Fizazi K, et al (2020) Olaparib for Metastatic Castration-Resistant Prostate Cancer 382:2091-102. de Wit R, de Bono J, Sternberg CN, et al (2019) Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer 2506-2518. 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 Nucl Med 446-451. [Example]

[0222] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0223] Example 1: Clinical trials The Phase 3 clinical trial, entitled "177Lu-PSMA-617 vs. Androgen Receptor-directed Therapy in Treatment of Progressive Metastatic Castrate-Resistant Prostate Cancer (PSMAfore)," is listed on ClinicalTrials.gov under the following identification code: NCT04689828 (the entire disclosure of which is accessible as of the filing date is incorporated herein by reference).

[0224] This test is also described as: PSMAfore: A Phase III, Open-Label, Multicenter, Randomized Trial, CAAA617B12302, Comparing 177Lu-PSMA-617 with Modified Androgen Receptor-Directed Therapy in the Treatment of Taxane-Naive Men with Advanced Metastatic Castration-Resistant Prostate Cancer.

[0225] Study design: See Figure 1.

[0226] Clinical Protocol:

[0227] [Table 4]

[0228] Table 5

[0229] Table 6

[0230] Table 7

[0231] Table 8

[0232] Table 9

[0233] Table 10

[0234] Table 11

[0235] Table 12

[0236] Table 13

[0237] Table 14

[0238] [Table 15]

[0239] [Table 16]

[0240] Rationale: Study design rationale The objective of this study was to determine whether 177Lu-PSMA-617 administered at a dose of 7.4 GBq (200 mCi) ± 10% for six cycles improves rPFS compared with a change in ARDT in participants with mCRPC who have not previously been treated with a taxane-containing regimen in the CRPC or HSPC setting, a key endpoint in mCRPC and recognized in PCWG3 and several other clinical trials.

[0241] Survival follow-up will continue after radiographic progression. A key secondary objective is to assess whether 177Lu-PSMA-617 improves overall survival (OS) compared with participants in the ARDT treatment-switching arm.

[0242] Eligible participants will be randomized to one of two treatment arms. Randomization will be stratified to avoid treatment selection bias. Treatment will be open-label. Once rPFS is confirmed by BICR, participants randomized to the ARDT arm will transition to receiving 177Lu-PSMA-617.

[0243] Preliminary clinical evidence suggests that 177Lu-PSMA-617 may demonstrate clinical benefit in men with mCRPC, improving rPFS and OS compared with modified ARDT. Data from this study complement data from the VISION trial of 177Lu-PSMA-617 for the treatment of taxane-naïve mCRPC.

[0244] Rationale for background therapy selection Supportive care is permitted in both treatment arms and includes treatments available to eligible participants according to best institutional practice in the treatment of mCRPC, including ADT, to maintain serum testosterone levels and to manage overall disease symptoms as determined by the treating physician.

[0245] Investigational drugs, biologics, immunotherapy, cytotoxic chemotherapy, other systemic radioisotopes (e.g., radium-223), poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors, and half-body radiation therapy should not be administered before radiographic progression as assessed by blinded central review (primary endpoint). ARDT should not be used in combination with 177Lu-PSMA-617.

[0246] Rationale for dose / regimen and duration of treatment The basic principle of 177Lu-PSMA-617 radioligand therapy is the systemic delivery of low-dose-rate radiation specifically to multiple PSMA-positive prostate cancer lesions while sparing normal tissue. To date, 12 dosimetry studies have been conducted in 158 participants. Results are consistent across studies, demonstrating radiation exposure that correlates well with the expected rapid clearance of the small molecule and the restricted distribution pattern of the PSMA-targeted radionuclide. The primary sites of non-tumor uptake are the salivary glands, lacrimal glands, and kidneys, with elimination mechanisms contributing to renal exposure, with approximately 50% of the injected dose being eliminated within 48 hours (Kratochwil et al., 2016). PSMA-negative tissues, such as the bone marrow, are transiently exposed to 177Lu-PSMA-617 during circulation, but this exposure is minimized by rapid elimination.

[0247] 177Lu-PSMA-617 has been well tolerated based on clinical experience documented in more than 53 publications summarizing safety and efficacy information from more than 1,280 participants.

[0248] Across these studies, doses ranged from 1.1 to 12.0 GBq, and the administration schedule typically consisted of one to nine cycles every 4–12 weeks. While the 2016 German Society of Nuclear Medicine recommended 6.0 GBq every 8 weeks for three cycles, the majority of these studies used a regimen of 6 GBq every 8 weeks for four cycles. However, efficacy and safety information from prospective phase 2 trials suggested that a dose of 4.0–8.9 (mean 7.5) GBq every 6 weeks for four cycles was well tolerated and effective (Violet et al., 2020). Currently, clinical series have reported the safe administration of 177Lu-PSMA-617 for four or more cycles as a means of maximizing participant benefit (Brauer 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).

[0249] In the phase II TheraP trial (ANZUP protocol 1603, NCT03392428), 200 Australian men with mCRPC were randomized (1:1) to receive either 177Lu-PSMA-617 or cabazitaxel. The starting dose of 177Lu-PSMA-617 was 8.5 GBq, which was reduced by 0.5 GBq per cycle (8.5, 8, 7.5, 7, 6.5, and 6) every 6 weeks for a maximum of 6 cycles. This corresponds to a cumulative dose of 43.5 GBq, similar to that in the proposed trial.

[0250] A clinical safety review and detailed analysis of radiation exposure support the dose and frequency of administration of 177Lu-PSMA-617 intended in this clinical trial.

[0251] Rationale for choice of comparator (comparator / placebo) or combination drug Four main drug classes have been approved to extend survival in participants with mCRPC. These include ARDT (e.g., abiraterone and enzalutamide), taxanes (docetaxel and cabazitaxel), immunotherapy (sipuleucel-T), and bone-targeted radiopharmaceuticals (radium-223 dichloride). With advances in prostate cancer treatment, some of these life-prolonging therapies (ARDT and docetaxel) are increasingly being used in earlier stages of disease (e.g., metastatic hormone-sensitive prostate cancer and non-metastatic prostate cancer). This further increases the unmet medical need in mCRPC. Several mechanisms contribute to the development of treatment resistance in participants who have previously received ARDT therapy (Attard et al., 2009). Participants who switched ARDT treatment had a rPFS of 3.6 to 15 months and an OS of 11 to 23 months (de Bono et al., 2020, de Wit et al., 2019, Komura et al., 2019). Meanwhile, many participants who do not receive chemotherapy do so primarily due to pre-existing medical conditions or associated toxicities (Engel Nitz et al., 2011, Harris et al., 2011, Lissbrant et al., 2013, Zielinski et al., 2014). Sipuleucel-T is most commonly used for mild, asymptomatic oligodendroglioma, while radium-223 is used to treat male patients with bone-only disease. PARP inhibitors are an emerging drug class in mCRPC, but their use is limited to the 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 trials].

[0252] ARDTs such as abiraterone and enzalutamide have demonstrated efficacy and are approved for the treatment of mCRPC in taxane-naive participants, making them appropriate comparators for this study.

[0253] investigational drug The second-generation ARDTs abiraterone, enzalutamide, darolutamide, and apalutamide (all four drugs are known as rINNs) are commercially available as registered medicines.

[0254] The radioligand imaging agent 68Ga-PSMA-11 (rINN: gallium (68Ga) gozetotide) is commercially available as a kit for labeling with Ga-68 under the product names ILLUCCIX and LOCAMETZ.

[0255] The radioligand therapeutic agent 177Lu-PSMA-617 (rINN: lutetium (177Lu) bipibotide tetraxetane) is commercially available under the product name Pruvict.

[0256] The contents of all these drug product inserts (prescribing information, summary of product characteristics) are incorporated herein by reference.

[0257] result Summary of results

[0258] [Table 17]

[0259] The CAAA617B12302 trial (PSMAfore trial) is a randomized, phase III, open-label, active-controlled, international, multicenter trial comparing the safety and efficacy of [177Lu]Lu-PSMA-617 with modifications to androgen receptor-directed therapy (ARDT) in participants with PSMA-positive mCRPC previously treated with ARDT in whom delaying taxane-based chemotherapy was deemed appropriate.

[0260] Below, we describe the first interpretable results (FIR) of the primary endpoint, rPFS, and the first interim analysis results of the key secondary endpoint, OS. The data cutoff for analysis was October 2, 2022. The primary efficacy and safety results are presented without clinical interpretation.

[0261] A total of 467 subjects were included in the analysis and randomized 1:1 to receive [177Lu]Lu-PSMA-617 (n=233) or ARDT (n=234) treatment, stratified by prior use of ARDT in the setting of castration-resistant prostate cancer (CRPC) versus hormone-sensitive prostate cancer (HSPC), and by baseline symptoms based on the BPI-SF questionnaire (asymptomatic or mildly symptomatic versus symptomatic).

[0262] The study duration (from randomization to data cutoff) was 7.26 months in the [177Lu]Lu-PSMA-617 group and 7.28 months in the ARDT group.

[0263] The median follow-up period for rPFS was 3.6 months (from randomization to BICR censoring or rPFS event). The minimum-maximum rPFS follow-up period ranged from 0 to 12.3 months.

[0264] In the [177Lu]Lu-PSMA-617 treatment group, 121 patients (51.9%) and in the ARDT treatment group, 93 patients (39.7%) were discontinued as "event-free continuing" before the median study period for each group.

[0265] The median follow-up period for OS was 6.08 months (from randomization to date of death or last contact), with a minimum-maximum follow-up period ranging from 0.6 to 14.9 months.

[0266] At the time of data cutoff, a total of 52 patients (22.2%) had crossed over from the ARDT treatment group to the [177Lu]Lu-PSMA-617 treatment group.

[0267] Treatment groups were well balanced in terms of demographics and baseline characteristics.

[0268] Treatment discontinuation was reported in 25.8% of patients in the [177Lu]Lu-PSMA-617 group and 47% in the ARDT group. The main reasons for treatment discontinuation ([177Lu]Lu-PSMA-617 vs. ARDT) were progressive disease (14.6% vs. 32.9%), physician's decision (6.0% vs. 9%), and adverse events (3.9% vs. 3.0%).

[0269] The median (min-max) duration of exposure to study treatment was 4.25 months (0.3-10.3 months) in the [177Lu]Lu-PSMA-617 group and 3.9 months (0.0-13.3 months) in the ARDT group (pre-crossover, from start of treatment to last treatment according to the data cutoff date). The median exposure duration was 4.2 months (0.0-12.4 months) in the abiraterone group, 3.55 months (0.0-13.3 months) in the enzalutamide group, and 2.8 months (0.4-9.6 months) in the crossover [177Lu]Lu-PSMA-617 group.

[0270] The median relative dose intensity (min-max) was 97.6 GBq (59.2-103.1) in the randomized [177Lu]Lu-PSMA-617 group and 100% (25.0-100) in the ARDT group. The median relative dose intensity (min-max) was 100% (53.9-100) in the abiraterone group, 100% (25.0-100) in the enzalutamide group, and 98.0 GBq (57.4-101.6) in the crossover [177Lu]Lu-PSMA-617 group.

[0271] This study met its primary objective: the primary endpoint of radiographic progression-free survival (rPFS), based on blinded independent central review according to PCWG3 criteria, demonstrated an estimated 58% risk reduction in the [177Lu]Lu-PSMA-617 arm (n=233) compared with the ARDT arm (n=234), a statistically significant difference between the treatment arms (stratified log-rank test p=0.00000003, one-sided) (hazard ratio: 0.42, 95% CI: (0.31-0.58)). Sixty-one events occurred in the [177Lu]Lu-PSMA-617 arm (26.2%) compared with 106 events in the ARDT arm (45.3%). Median rPFS (95% CI) was 9.3 months (6.77, NE) and 5.59 months (4.11, 5.98), respectively.

[0272] Overall survival (OS), a key secondary endpoint, was poor but not detrimental. The first interim analysis of OS reported in this FIR was based on 40 of 297 events / deaths (13.5%) included.

[0273] Median OS was not reached in either group. Estimated OS probability at 6 months was 94.4% (89.4, 97.1) in the [177Lu]Lu-PSMA-617 group and 94.4% (89.7, 96.9) in the ARDT group.

[0274] The following adverse events (AEs) were reported in the [177Lu]Lu-PSMA-617 and ARDT (before crossover) treatment groups, respectively: Any AE: Any 89.4% vs 85.3% Grade 3 or higher AEs: 23.5% vs 32.8% Treatment-related: 6.6% vs 10.3% Serious AEs: 15.5% vs 18.5% Treatment-related: 2.2% vs. 0.4% AEs leading to discontinuation: 4.0% vs 3.0% Treatment-related: 1.8% vs. 1.7% AEs leading to dose adjustment: 2.2% vs 11.2%. AEs leading to treatment interruption: 7.1% vs 12.1%. AEs requiring additional treatment: 53.5% vs 62.1%.

[0275] The most common adverse events (>10% in either group) in the [177Lu]Lu-PSMA-617 treatment group vs. the ARDT treatment group were dry mouth (44.7% vs. 1.7%), nausea (25.2% vs. 8.2%), asthenia (23.9% vs. 24.6%), fatigue (18.1% vs. 22.0%), anemia (16.8% vs. 11.2%), constipation (15.5% vs. 9.5%), decreased appetite (12.8% vs. 12.1%), diarrhea (12.4% vs. 6.9%), arthralgia (11.5% vs. 16.8%), COVID-19 (11.1% vs. 8.6%), and back pain (7.1% vs. 10.8%).

[0276] The most common serious adverse events in the [177Lu]Lu-PSMA-617 and ARDT treatment groups were urinary tract infections (1.8% vs 0.9%), respectively.

[0277] In the [177Lu]Lu-PSMA-617 and ARDT groups, 18 (8%) and 20 (8.6%) subjects who received at least one dose of study treatment died during the study. The primary cause of death during the study was study indications, with 4.4% (10 deaths) in the [177Lu]Lu-PSMA-617 group and 7.3% (17 deaths) in the ARDT group. Two subjects randomized to the [177Lu]Lu-PSMA-617 group died before the start of study treatment.

[0278] Four patients (1.8%) and seven patients (3.0%) died during treatment in the [177Lu]Lu-PSMA-617 and ARDT groups, respectively. The main cause of death during treatment was study indications, with 0% vs. 1.7% in the [177Lu]Lu-PSMA-617 and ARDT groups, respectively.

[0279] Additional Information Radiographic progression-free survival (rPFS) based on independent central review according to PCWG3 criteria was the primary endpoint, and overall survival (OS) was the key secondary endpoint of the study. The statistical design of the study dictated that the primary analysis of rPFS had to reach statistical significance for the study to be declared positive.

[0280] The primary analysis of rPFS and the first interim analysis of OS were performed using all patients randomized before the data cutoff date of October 2, 2022, with a one-sided alpha of 2.5%. One randomized and treated patient was excluded from the full analysis set due to failure to provide due-diligence informed consent (INCL1APD).

[0281] OS will be tested hierarchically based on a three-group sequential design using the Lan DeMets (O'Brien Flemming) alpha expenditure function. A final OS analysis was not planned at the time of the rPFS interim analysis reported in this FIR.

[0282] Following a protocol-defined hierarchical testing strategy, OS was tested once rPFS was statistically significant. The one-sided α level required for significance in OS at this first interim analysis (<0.000000001012) was calculated from a prespecified α-expense function and the number of events observed at the time of the rPFS analysis.

[0283] At the time of the first interim OS analysis, the OS result was based on 13.5% (40 / 297 deaths).

[0284] A second interim analysis of OS will be performed after additional follow-up when approximately 75% of the target number of deaths / events (223 / 297) has occurred. If OS is not statistically significant at the second interim analysis, a final analysis will be performed when approximately 297 deaths have been recorded.

[0285] Responding to the target Patient Care (Full Analysis Set)

[0286] Table 18

[0287] Demographic and other baseline characteristics Demographics and baseline characteristics (full analysis set)

[0288] Table 19

[0289] Subject exposure Duration of exposure to study treatment (safety set)

[0290] Table 20

[0291] Dose of study treatment received (safety set)

[0292] Table 21

[0293] Dosage of [177Lu]Lu-PSMA-617 (Lu-PSMA-617 safety set)

[0294] Table 22

[0295] Summary of the period from randomization to cut-off date (full analysis set)

[0296] Table 23

[0297] Efficacy Results Primary efficacy outcome Analysis of radiographic progression-free survival based on independent central review using stratified log-rank test and Cox regression model (full analysis set)

[0298] [Table 24]

[0299] Forest plot of hazard ratios and 95% confidence intervals for radiographic progression-free survival based on independent central review with sensitivity analysis (full analysis set)

[0300] See Figures 3A and 3B.

[0301] This indicates that the rPFS results were consistent across all preplanned sensitivity analyses and different subgroups.

[0302] Key secondary efficacy endpoints Interim analysis of overall survival using stratified log-rank test and Cox regression model (full analysis set)

[0303] [Table 25]

[0304] Safety Results Adverse events Adverse Event Summary (Safety Set)

[0305] [Table 26]

[0306] Adverse events by preferred term (incidence of 10% or more in any treatment group) (safety set)

[0307] [Table 27]

[0308] Serious adverse events by preferred term (incidence of at least 1% in any treatment group) (safety set)

[0309] [Table 28]

[0310] Overview of Safety Topics of Interest (Safety Set)

[0311] [Table 29]

[0312] The number of myelosuppressive and nephrotoxic events observed to date is surprisingly low for a radioligand therapy.

[0313] Deaths during treatment: by system organ class and preferred term (safety set)

[0314] [Table 30]

[0315] Update results See Figures 2B and 3B.

[0316] [Table 31]

[0317] [Table 32]

[0318] At the time of primary rPFS analysis (DCO on October 2, 2022): The trial was ongoing. The trial duration (from randomization to data cutoff) was 7.26 months in the [177Lu]Lu-PSMA-617 group and 7.28 months in the ARDT group. The median follow-up period for rPFS was 3.38 months (from randomization to BICR censoring or rPFS event). The minimum-maximum rPFS follow-up period ranged from 0.03 to 12.62 months. 125 participants (53.6%) in the [177Lu]Lu-PSMA-617 group and 97 participants (41.5%) in the ARDT group were censored as "ongoing without event" before the median study duration for each group.

[0319] At second interim analysis (DCO June 21, 2023): The trial was ongoing. The trial duration (from randomization to data cutoff) was 15.87 months in the [177Lu]Lu-PSMA-617 group and 15.89 months in the ARDT group. The median follow-up period for rPFS was 5.98 months (from randomization to BICR censoring or rPFS event). The minimum-maximum rPFS follow-up period ranged from 0.03 to 20.30 months. 76 participants (32.5%) in the [177Lu]Lu-PSMA-617 group and 29 participants (12.4%) in the ARDT group were censored as "ongoing without rPFS event" before the median study duration for each group.

[0320] A total of 123 participants (123 / 234 (52.6%) of all ARDT participants or 123 / 168 (73.2%) of ARDT participants with radiographic progression) crossed over from the ARDT treatment group to the [177Lu]Lu-PSMA-617 treatment group after notification of radiographic progression by BICR.

[0321] Treatment groups were well balanced in terms of demographics and baseline characteristics.

[0322] Treatment discontinuation was reported in 41.0% of participants in the [177Lu]Lu-PSMA-617 group and 82.5% in the ARDT group. The main reasons for treatment discontinuation ([177Lu]Lu-PSMA-617 vs. ARDT) were disease progression (21.8% vs. 62.4%), physician's decision (10.7% vs. 12.4%), and adverse events (5.6% vs. 5.1%).

[0323] The median duration of exposure to study treatment (min-max) was 8.41 months (0.36-11.63) in the [177Lu]Lu-PSMA-617 group and 6.52 months (0.03-20.99) in the ARDT group (before crossover, from treatment initiation to last dose of study drug, data cutoff date June 21, 2023). The median duration of exposure was 6.36 months (0.69-20.99) in participants who received abiraterone, 6.59 months (0.03-20.99) in participants who received enzalutamide, and 4.67 months (0.49-11.04) in participants randomized to ARDT who crossed over to the [177Lu]Lu-PSMA-617 group (hereafter referred to as [177Lu]Lu-PSMA-617 crossover participants).

[0324] The median relative dose intensity (min-max) was 97.6% (78.5-102.9) in the randomized [177Lu]Lu-PSMA-617 group and 100% (51.6-100) in the ARDT group. The median relative dose intensity (min-max) was 100% (53.9-100) in participants receiving abiraterone, 100% (51.6-100) in participants receiving enzalutamide, and 97.5% (76.0-105.4) in [177Lu]Lu-PSMA-617 crossover participants.

[0325] The study met its primary objective: the primary endpoint of radiographic progression-free survival (rPFS), based on blinded independent central review according to PCWG3-modified RECIST 1.1 criteria (using a DCO date of October 2, 2022), demonstrated an estimated 59% risk reduction in the [177Lu]Lu-PSMA-617 arm (n=233) compared with the ARDT arm (n=234), a statistically significant difference between treatment arms (stratified log-rank test, p<0.0001, one-sided) (hazard ratio: 0.41, 95% CI: 0.29-0.56). Sixty events occurred in the [177Lu]Lu-PSMA-617 arm (25.8%) and 106 events occurred in the ARDT arm (45.3%). 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 rPFS probability (95% CI) at 6 months was 69.0% (60.7, 75.9) in the [177Lu]Lu-PSMA-617 treatment group and 40.6% (32.1, 48.8) in the ARDT treatment group.

[0326] The rPFS results were consistent across all preplanned sensitivity analyses and across demographic and prognostic subgroups.

[0327] An updated exploratory analysis of rPFS, based on the DCO date of June 21, 2023, showed an estimated 57% risk reduction in the [177Lu]Lu-PSMA-617 arm (n=234) compared with the ARDT arm (n=234) (HR: 0.43, 95% CI: (0.33 0.54)). 115 events occurred in the [177Lu]Lu-PSMA-617 arm (49.1%) and 168 events occurred in the ARDT arm (71.8%). Median rPFS (95% CI) was 12.02 months (9.30, 14.42) and 5.59 months (4.17, 5.95), respectively (see table below).

[0328] [Table 33]

[0329] See also Figure 3B.

[0330] Based on BICR, the best overall radiological response rate was achieved, taking into account soft tissue and bone disease (Recist analysis set - participants with measurable disease at baseline)

[0331] [Table 34]

[0332] Response is based on soft tissue assessment and progression of bone lesions.

[0333] CR and PR best overall response were confirmed by repeat assessment at least 4 weeks after the response criteria were first met. CR also included participants with residual but non-progressing bone disease.

[0334] Results: [177Lu]Lu-PSMA-617 exhibits at least a three-fold higher rORR compared to ARDT and a higher rDCR compared to ARDT.

[0335] As can be seen in the table below, 177Lu-PSMA-617 delayed the time to SSE vs. ARPI change.

[0336] [Table 35]

[0337] Key secondary endpoint: Crossover-adjusted, intention-to-treat OS analysis Pre-specified first-order crossover-corrected analysis HR: 0.80 (95% CI: 0.48, 1.33) Median, months (95% CI): 19.25 (16.95, NE) vs 19.55 (14.95, NE) Number of events: 69 (29.5%), average: 36 (15.4%)

[0338] Pre-specified supplemental unadjusted (ITT) analyses HR: 1.16 (95% CI: 0.83, 1.64) Median, months (95% CI): 19.25(16.95,NE)vs19.71(17.81,NE) Number of events: 69 (29.5%) vs. 65 (27.8%)

[0339] Median OS follow-up, months (range): 12.72 (0.82, 23.00) vs 13.08 (1.54, 22.64)

[0340] aThree patients died before receiving 177Lu-PSMA-617. ARPI: androgen receptor pathway inhibitor, CI: confidence interval, DCO: data cutoff, HR: hazard ratio, ITT: intention-to-treat analysis, NE: not estimable, OS: overall survival, PSMA: prostate-specific membrane antigen, interim OS analysis (DCO: June 2023).

[0341] Regarding key secondary endpoints: The prespecified primary analysis method for OS was rank-preserving structural failure time (RPSFT) to adjust for crossover: Rank-preserving structural failure time 1.2 A model-based method for adjusting crossover in clinical trials has been recognized. Adjusted survival for patients randomized to the ARPI change arm who crossed over to the 177Lu-PSMA-617 arm -Assuming that each patient's disease progresses towards death at their own speed (accelerated failure time model) Assume that 177Lu-PSMA-617 slows / speeds this rate by the same factor (X) regardless of whether 177Lu-PSMA-617 is administered at randomization or crossover. - Use a grid search to find the value of X that balances survival times between treatment groups For all patients who received 177Lu-PSMA-617, the observed survival time was multiplied by X to obtain the adjusted survival time. - Use a re-censoring algorithm to maintain the assumption of independent random censoring required for unbiased estimation The observed survival time in the 177Lu-PSMA-617 treatment group was compared with the adjusted survival time in the ARPI-modified group, and the treatment effect was estimated as if there had been no crossover.

[0342] 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 2018;38:509-19

[0343] safety The following adverse events (AEs) were reported in the [177Lu]Lu-PSMA-617 treatment group and the ARDT (before crossover) treatment group, respectively (Table 6-1): Any AE: 98.2% vs 96.1% Grade 3 or higher AEs: 34.4% vs 43.5% Treatment-related: 11.0% vs 12.5% Serious AE: 20.3% vs 28.0% Treatment-related: 3.1% vs. 2.2% AEs leading to discontinuation: 5.7% vs 5.2% Treatment-related: 3.1% vs. 2.6% AEs leading to dose adjustment: 3.5% vs 15.1%. AEs leading to treatment interruption: 11.9% vs 16.8%. AEs requiring additional treatment: 71.4% vs 78.0%.

[0344] The most common adverse events (>10% in either treatment group) by PT (preferred term) in the [177Lu]Lu-PSMA-617 vs. ARDT groups were dry mouth (57.3% vs. 2.2%), asthenia (31.7% vs. 28.9%), nausea (31.3% vs. 12.1%), anemia (24.2% vs. 16.8%), fatigue (22.9% vs. 25.4%), and constipation (22.0% vs. 13.4%), decreased appetite (21.1% vs 18.1%), joint pain (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).

[0345] Summary Adverse Events, Safety Set

[0346] [Table 36]

[0347] Adverse events by preferred term (incidence of 10% or more in any treatment group) (safety set)

[0348] [Table 37]

[0349] Serious adverse events by preferred term (incidence of at least 1% in any treatment group) (safety set)

[0350] [Table 38]

[0351] The incidence of grade ≥3 AEs, serious AEs, and AEs leading to dose adjustments was lower with 177Lu-PSMA-617 when comparing 177Lu-PSMA-617 with a change in ARPI, as can be seen in the table below.

[0352] [Table 39]

[0353] As can be seen in the table below, AEs occurred in 10% or more of patients in both treatment groups.

[0354] [Table 40]

[0355] In summary, 177Lu-PSMA-617 extended rPFS relative to changes in ARPI in taxane-naive patients with mCRPC, with a favorable safety and tolerability profile. 177Lu-PSMA-617 significantly extended rPFS against ARPI changes. ·

[0356] As of the second interim OS analysis: There was a trend toward a longer OS after crossover adjustment, but no longer unadjusted OS The crossover rate was high 45.1% of the target death toll died - OS data collection is in progress PSA response, ORR, and DOR were favorable to 177Lu-PSMA-617 Time to deterioration in health-related quality of life and pain indicators favored 177Lu-PSMA-617 177Lu-PSMA-617 had a favorable safety profile and was well tolerated

Claims

1. 1. A method of reducing the risk of radiographic progression of or death from prostate cancer in a patient in need thereof, comprising: the method comprises administering to the patient a therapeutically effective amount of a no-carrier-added (n.c.a.) lutetium-177 (177Lu) labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) drug, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformer, or tautomer thereof; the prostate cancer is prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC); The patient has been previously treated with androgen receptor directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis targeted therapy (ARAT), with the proviso that the patient has not been previously treated with taxane-based chemotherapy.

2. 2. The method of claim 1, wherein the treatment reduces the risk of radiographic progression or death from prostate cancer by at least 50%, corresponding to a hazard ratio (HR) of 50% or less, compared to continuing or substituting ARDT / ARPI / ARAT treatment with the previously used or different ARDT / ARPI / ARAT, respectively.

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

4. 1. A method of extending the radiographic progression-free survival (rPFS) of a patient in need of treatment for prostate cancer, comprising: the method comprises administering to the patient a therapeutically effective amount of a no-carrier-added (n.c.a.) lutetium-177 (177Lu) labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) drug, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformer, or tautomer thereof; the prostate cancer is prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC); The patient has been previously treated with androgen receptor directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis targeted therapy (ARAT), with the proviso that the patient has not been previously treated with taxane-based chemotherapy.

5. 5. The method of claim 4, wherein the treatment results in at least a 40% increase in radiographic progression-free survival (rPFS) in months compared to continuing or substituting ARDT / ARPI / ARAT treatment with the previously used or different ARDT / ARPI / ARAT, respectively.

6. 1. A method of extending overall survival (OS) in a patient in need of treatment for prostate cancer, comprising: the method comprises administering to the patient a therapeutically effective amount of a no-carrier-added (n.c.a.) lutetium-177 (177Lu) labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) drug, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformer, or tautomer thereof; the prostate cancer is prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC); The patient has been previously treated with androgen receptor directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis targeted therapy (ARAT), with the proviso that the patient has not previously been treated with taxane-based chemotherapy.

7. 7. The method of claim 6, wherein the treatment reduces the risk of death by a hazard ratio of less than 1, about 0.95 or less, about 0.9 or less, about 0.85 or less, about 0.8 or less, about 0.75 or less, about 0.7 or less, about 0.65 or less, about 0.6 or less, about 0.55 or less, or about 0.5 or less, wherein the risk is calculated relative to a patient continuing to receive ARDT / ARPI / ARAT treatment with the previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, or a patient receiving ARDT / ARPI / ARAT treatment with an alternative ARDT / ARPI / ARAT, respectively.

8. 1. A method for increasing overall response rate (ORR) (i.e., complete response (CR) and partial response (PR)) in soft tissue in a patient in need of prostate cancer treatment, comprising: the method comprises administering to the patient a therapeutically effective amount of a no-carrier-added (n.c.a.) lutetium-177 (177Lu) labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) drug, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformer, or tautomer thereof; the prostate cancer is prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC); The patient has been previously treated with androgen receptor directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis targeted therapy (ARAT), with the proviso that the patient has not previously been treated with taxane-based chemotherapy.

9. 9. The method of claim 8, wherein the 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 continuing or substituting the previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT treatment, respectively.

10. 10. The method of treatment of any one of claims 8-9, wherein the complete response (CR) rate in soft tissue is increased by at least 100% (1-fold increase), 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 continuing or substituting the ARDT / ARPI / ARAT treatment with the previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, respectively.

11. 1. A method for improving health-related quality of life (HRQoL) (e.g., as determined by the Functional Assessment of Cancer Therapy-Prostate (FACT-P)) in a patient in need of prostate cancer treatment, comprising: the method comprises administering to the patient a therapeutically effective amount of a no-carrier-added (n.c.a.) lutetium-177 (177Lu) labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) drug, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformer, or tautomer thereof; the prostate cancer is prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC); The patient has been previously treated with androgen receptor directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis targeted therapy (ARAT), with the proviso that the patient has not previously been treated with taxane-based chemotherapy.

12. 12. The method of claim 11, wherein the time to deterioration in composite HRQoL is about 50% longer, about 60% longer, or about 70% longer compared to continuing or substituting the previously used ARDT / ARPI / ARAT treatment with a different ARDT / ARPI / ARAT, respectively.

13. 13. The method of treatment of any one of claims 11-12, wherein the risk of deterioration in composite HRQoL, when calculated relative to patients continuing or substituting ARDT / ARPI / ARAT treatment with the previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, respectively, 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. 1. A method for increasing PSA responsiveness in a patient in need of treatment for prostate cancer, comprising: the method comprises administering to the patient a therapeutically effective amount of a no-carrier-added (n.c.a.) lutetium-177 (177Lu) labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) drug, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformer, or tautomer thereof; the prostate cancer is prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC); The patient has been previously treated with androgen receptor directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis targeted therapy (ARAT), with the proviso that the patient has not previously been treated with taxane-based chemotherapy.

15. 15. The method of treatment of claim 14, wherein the confirmed PSA reduction of at least 50% is about 100%, or at least 150%, compared to continuing or substituting ARDT / ARPI / ARAT therapy with the previously used or different ARDT / ARPI / ARAT, respectively.

16. 1. A method of delaying the time to a symptomatic skeletal event (SSE) in a patient in need of prostate cancer treatment, comprising: the method comprises administering to the patient a therapeutically effective amount of a no-carrier-added (n.c.a.) lutetium-177 (177Lu) labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) drug, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformer, or tautomer thereof; the prostate cancer is prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC); The patient has been previously treated with androgen receptor directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis targeted therapy (ARAT), with the proviso that the patient has not previously been treated with taxane-based chemotherapy.

17. 17. The method of claim 16, wherein the delay in time to SSE is about 50% longer, about 60% longer, about 70% longer, about 80% longer, or about 90% longer compared to continuing or substituting ARDT / ARPI / ARAT therapy with the previously used ARDT / ARPI / ARAT or a different ARDT / ARPI / ARAT, respectively.

18. 1. A method for reducing the risk of symptomatic skeletal events (SSEs) in a patient in need of prostate cancer treatment, comprising: the method comprises administering to the patient a therapeutically effective amount of a no-carrier-added (n.c.a.) lutetium-177 (177Lu) labeled prostate-specific membrane antigen (PSMA) binding radioligand therapy (RLT) drug, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformer, or tautomer thereof; the prostate cancer is prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC); The patient has been previously treated with androgen receptor directed therapy (ARDT), androgen receptor pathway inhibitor therapy (ARPI), or androgen receptor axis targeted therapy (ARAT), with the proviso that the patient has not previously been treated with taxane-based chemotherapy.

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

20. 20. The method of treatment of any one of claims 1 to 19, wherein said treatment is safer and better tolerated compared to continuing or substituting ARDT / ARPI / ARAT treatment with said previously used or different ARDT / ARPI / ARAT, respectively.

21. The method of treatment according to any one of claims 1 to 20, characterized in that the treatment-related adverse events of grade 3 or higher occur in less than 25% of patients in the respective patient population.

22. The method of treatment according to any one of claims 1 to 21, characterized in that the treatment-related serious adverse events of grade 3 or higher occur in less than 15% of patients in the respective patient population.

23. 23. The method of any one of claims 1 to 22, wherein the radioligand therapy is administered at a dose of about 6 to about 8 GBq once every 6 to 8 weeks (i.e., 1 cycle) for a maximum of 4 to 6 cycles.

24. 24. The method of treatment of any one of claims 1 to 23, wherein the radioligand therapy is administered at a dose of 7.4 (±10%) GBq once every 6 (±1) weeks (i.e., 1 cycle) for up to 6 cycles.

25. The n.c.a. 177Lu-labeled PSMA-binding RLT agent, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, conformer, or tautomer thereof, comprising the components: (1) the beta-negative electron-emitting radionuclide 177Lu of n.c.a. quality; (2) a ligand component; The ligand component (2) is (a) at least one PSMA binding moiety; (b) at least one chelator moiety suitable for chelating said radionuclide; 25. The method of any one of claims 1 to 24, comprising (c) at least one linker moiety connecting the PSMA binding moiety (a) and the chelator component (b).

26. 26. The method of treatment of any one of claims 1 to 25, wherein the PSMA-binding moiety (a) comprises the amino acids glutamic acid and lysine linked through a urea group, e.g., glutamic acid-urea-lysine (GUL), the chelating moiety (b) comprises a residue of DOTA or a residue of DOTAGA, and 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. 27. The method of any one of claims 1 to 26, wherein the RLT agent is selected from the group consisting of [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetan), [177Lu]Lu-PSMA I&T (lutetium (177Lu) zadabotide glaxetan), and [177Lu]Lu-PSMA-R2.

28. 28. The method of any one of claims 1 to 27, wherein the RLT agent is selected from the group consisting of [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetan), and [177Lu]Lu-PSMA I&T (lutetium (177Lu) zadabotide glaxetan).

29. 29. The method of treatment of any one of claims 1 to 28, wherein the RLT agent is [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipibotide tetraxetane).

30. 30. The method of any one of claims 1-29, wherein the PSMA positivity of the mCRPC is determined by positron emission tomography (PET) using a PSMA-binding radioligand diagnostic or imaging (RLI) agent, and the radioligand imaging is selected from the group consisting of [68Ga]Ga-PSMA-11 (gallium (68Ga) gozetotide), 18F-DCPyL (piflufolastat (18F)), 18F-PSMA-1007, 18F-CTT1057 (bidofolastat (18F)), 18F / natGa-rhPSMA-7.3 (flotufolastat (18F)), [68Ga]Ga-PSMA-R2, and [64Cu]Cu-PSMA-R2.

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