How to treat prostate cancer

Abstract

This disclosure relates to a method for treating prostate-specific membrane antigen (PSMA)-positive oligometastatic prostate cancer (OMPC) that has progressed after curative treatment for the primary tumor, comprising a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, preferably [ 177 Lu]Lu-PSMA-617(Lutetium( 177 The present disclosure relates to a method comprising administering (Lu) bipivotide tetraxetan. Furthermore, the present disclosure relates to radioligand therapy for early prostate cancer patients to control the progression of recurrent tumors to lethal metastatic disease while maintaining quality of life by delaying treatment with androgen deprivation therapy (ADT).

Description

Technical Field

[0001] The present disclosure relates to a method of treating prostate-specific membrane antigen (PSMA)-positive oligometastatic prostate cancer (OMPC) that has progressed after radical therapy for primary tumors, comprising administering a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, preferably 177 Lu]Lu-PSMA-617 (lutetium ( 177 Lu) bipyramidotetraoxetan). Further, the present disclosure relates to radioligand therapy for early-stage prostate cancer patients to control the progression of recurrent tumors to life-threatening metastatic diseases while maintaining quality of life by delaying treatment with androgen deprivation therapy (ADT).

Background Art

[0002] In 2020, an estimated 1.4 million new cases of prostate cancer (PC) and 375,000 cancer deaths worldwide were attributable to PC (Sung et al 2021). The PC incidence has changed over the past few decades due to increased detection of asymptomatic disease as a result of widespread prostate-specific antigen (PSA) testing (Siegel et al 2017). Radical local therapies such as radical prostatectomy (RP) or radiotherapy (XRT) are standard local treatments (Fakhrejahani et al 2017).

[0003] Following failure of topical therapy presented by elevated PSA levels (defined as biochemical relapse [BCR]), a subset of patients may also present with oligo-recurrent disease characterized by limited sites of distant dissemination. Most commonly, patients with OMPC are identified using specific cutoffs regarding the number of distant sites involved. There is no clear consensus on these cutoffs. Of 25 retrospective studies including more than one case, 10 (40%) used a definition of 5 or fewer metastases, 3 (12%) used a definition of 4 or fewer metastases, and 12 (48%) used a definition of 3 or fewer metastases to define patients with oligo-metastases. Ongoing prospective studies are taking similar approaches to defining oligo-metastases using cutoffs of 5 or fewer, 4 or fewer, and 3 or fewer metastases (Fodor et al 2017, Foster et al 2019).

[0004] Traditionally, OMPC has been defined by disease detected by conventional imaging (CT / MRI and bone scans). However, using more sensitive imaging modalities such as PSMA-based positron emission tomography (PSMA-PET), it is now possible to reclassify a subset of patients with BCR if OMPC is defined as PSA progression without evidence of metastatic disease on conventional imaging (CI). Due to this advance in detection technology, most OMPCs detected by CI may be reclassified as multiple metastatic diseases (National Comprehensive Cancer Network, NCCN Guidelines Prostate Cancer V.1.2023).

[0005] While the prevalence of OMPC based on CI has been reported in the literature, the incidence of OMPC based on PSMA-PET in patients with negative CI findings remains unknown. In a study of 199 BCR patients without CI-based lesions who underwent PSMA-HBED PET / CT imaging, 148 patients (74%) showed PSMA-positive lesions, and 113 patients (57%) had oligometastases defined as having three or fewer metastases (McCarthy et al 2019).

[0006] PC is an androgen-sensitive cancer. ADT has been the backbone of treatment for metastatic PC since the 1940s. However, ADT for metastatic PC is non-curative and carries significant toxicity with long-term exposure. The impact of ADT on survival is unclear, and data suggest a questionable benefit of immediate ADT initiation compared to delayed initiation (Patrikidou et al 2021). Furthermore, initiation of ADT indicates the onset of gonadectomy-sensitive disease and is a precursor to the eventual development of gonadectomy-resistant PC (Harris et al 2009, Armandari et al 2014, Sweeney et al 2015, Rao et al 2019). ADT is associated with numerous adverse effects on metabolism, cardiovascular health, sexual function, cognitive health, and body composition, and these effects are amplified with long-term exposure (Sountoulides, Roundos 2013). The natural history of small-scale metastatic PC (i.e., OMPC) is often slow-acting; therefore, delaying ADT in appropriately selected asymptomatic patients may be appropriate (Rao et al 2019, Juan et al 2022). In such situations, metastasis-targeted therapy (MDT), particularly SBRT for metastatic lesions, may be effective and may avoid or delay the toxicity associated with the use of systemic therapies such as ADT (Schweizer et al 2013, Ost et al 2015). The merits of SBRT as MDT in PC have recently been validated in two prospective randomized phase II trials (Ost et al 2018, Ost et al 2020, Phillips et al 2020). Considering these results, SBRT for metastatic lesions is the standard of care in OMPC where progression-free survival is the goal (NCCN Guidelines Prostate Cancer V.1.2023).MDT for M1 patients in clinical trials or well-designed prospective cohort studies is also suggested in the guidelines of the European Association of Urology (EAU), European Association of Nuclear Medicine (EANM), European Society for Radiotherapy and Oncology (ESTRO), European Society of Urogenital Radiology (ESUR), International Society of Urological Pathology (ISUP), and International Society of Geriatric Oncology (SIOG) (Mottet et al 2022). More recently, the European Society for Radiation and Oncology - Advisory Committee on Radiation Oncology Practice (ESTRO-ACROP) Delphi consensus supports metastasis-targeted radiotherapy for patients diagnosed with up to five lymph node, bone, or visceral metastases in any disease context (Zilli et al 2022). Despite excellent local control rates, MDT (surgery or SBRT) alone provides moderate control of distant metastases and is unlikely to be a curative treatment. In the STOMP trial, 61% of patients who received MDT transitioned to ADT due to multiple metastatic progression, and 30% of MDT patients progressed to multiple metastatic disease within one year (Ost et al 2018). In addition, prior MDT in oligometastatic prostate cancer does not shorten the time from the start of ADT to gonadectomy resistance (Triggiani et al 2021). A small number of OMPC patients may achieve a complete response after SBRT, but most men with oligometastatic disease do not experience a complete PSA response after SBRT, suggesting that residual micrometastases are present but undetectable.Macroscopic disease fixation can only reset the time to detectable metastasis, and microscopic metastatic disease may continue to grow unchecked until it reaches a clinically viable size (Phillips et al 2020). Failure analysis patterns show that while radiation-induced lesions are highly controlled, most patients recur with new, previously undetectable metastases arising from untreated microscopic metastatic disease (Soldatov et al 2019). Therefore, even patients who achieve complete response after SBRT may still benefit from additional therapies that may target microscopic metastatic disease. Thus, there is an unmet need for early-stage treatment options to control the progression of recurrent tumors to lethal metastatic disease while maintaining quality of life by delaying treatment with ADT.

[0007] RLT One molecular target of RLT is prostate-specific membrane antigen (PSMA). PSMA is an ideal PC target for the following reasons: • Expression is limited in "normal" tissues. • It is expressed in 60-74% of BCR patients (McCarthy et al 2019, Artigas et al 2021). • Highly expressed on the plasma membrane of tumor cells, • It functions as an internalized cell surface receptor (Silver et al 1997, Liu et al 1998).

[0008] The two PSMA-targeted PET contrast agents used in this study are gallium ( 68 Ga) Gozetotide and Pifluforastat ( 18 F) is approved for clinical use in the United States for prostate cancer (for further details, please refer to the local prescribing information for Locametz® and Pilarify®). Gallium ( 68(Ga) Gozetotide is also approved for clinical use in Europe (see local prescribing information for Locametz® for further details).

[0009] Lutetium ( 177 Lu) bixibotride tetraxetan ( 177 Lu] Lu-PSMA-617 or 177 also known as Lu-PSMA-617 and hereinafter referred to as AAA617) is a novel radioligand therapy based on the results of the VISION trial (NCT03511664) and is approved in the United States, Canada, the United Kingdom, and the EU for the treatment of adult patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) treated with androgen receptor pathway inhibition and taxane-based chemotherapy. In this randomized phase III trial, AAA617 and standard of care (SoC) significantly prolonged the imaging-based progression-free survival (median, 8.7 months vs 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 - 0.57; P < 0.001) and overall survival (median, 15.3 months vs 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52 - 0.74; P < 0.001) when compared to SoC alone (Sartor et al 2021). The efficacy of lutetium ( 177 Lu) bixibotride tetraxetan has also been shown in a comparison of lutetium ( 177 Lu) bixibotride tetraxetan and cabazitaxel with lutetium ( 177This is further supported by another randomized trial comparing the bipivotide tetraxetan treatment group for favorable efficacy outcomes (Hofman et al 2021). In addition, there are two ongoing Phase III trials testing AAA617 in an earlier treatment line for patients with mPC: PSMAfore (NCT04689828) and PSMAddition (NCT04720157). Similarly, AAA617 treatment showed a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) after androgen receptor pathway inhibitor (ARPI) therapy in patients with PSMA-positive metastatic gonadectomy-resistant prostate cancer (mCRPC) compared to a change in ARPI (PSMAfore, NCT04689828). In addition, an ongoing Phase III trial is testing AAA617 in metastatic hormone-sensitive prostate cancer (PSMAddition, NCT04720157).

[0010] Based on findings from the VISION and PSMAfore trials, treatment with AAA617 after SBRT may benefit OMPC patients by delaying further metastatic progression and the time to ADT initiation. [Overview of the project]

[0011] This disclosure provides the following: A method for delaying gonadectomy in adult male patients with prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic prostate cancer (OMPC) [or: a method for delaying the initiation of hormonal gonadectomy; or a method for maintaining quality of life by delaying treatment with androgen deprivation therapy (ADT); or a method for extending the time to hormonal therapy (TTHT) as defined as the time from the initiation of the said method to androgen deprivation therapy (ADT)] and / or a method for delaying disease recurrence [or: a method for extending metastasis-free survival (MFS) as determined by conventional imaging; or: a method for extending metastasis-free survival (MFS) as defined as the time from randomization to the first evidence of bone or soft tissue distant metastasis detectable by radiographic imaging (i.e., CT / MRI and bone scan) as assessed by BIRC using RECIST 1.1, or death for any reason (whichever occurs first); or a method for controlling the progression of a recurrent tumor to a fatal metastatic disease], (1) Apply stereotactic radiotherapy (SBRT) [or: curative treatment of the primary tumor] to the patient; (2) The patient is given a therapeutically effective amount of lutetium, which is a PSMA-binding radioligand therapy (RLT) drug. 177 Lu) Bipivotide Tetraxetane ([ 177 Administering Lu]Lu-PSMA-617 (also referred to herein as AAA617) or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, crystalline forms, amorphous forms, stereoisomers, or tautomers. A method that includes this.

[0012] In embodiments of this disclosure, "the first (1 st )" (first) and "2 nd The term "second" indicates the order in which these steps are performed.

[0013] In embodiments of this disclosure, SBRT is administered in a single-fraction or split-fraction regimen (e.g., two or three irradiations).

[0014] In preferred embodiments of this disclosure, the RLT drug is administered at least one week after the completion of the final SBRT fraction. In preferred embodiments, RLT drug treatment is initiated 7 to 21 days after the final SBRT fraction.

[0015] In certain embodiments of this disclosure, OMPC is an OMPC having 1 to 5 metastatic lesions detected by PSMA positron emission tomography (PET) using a radioligand contrast agent containing a positron-emitting nuclide, but negative for M1 disease by conventional imaging (CI) [except: conventional imaging-positive distant metastatic disease (i.e., mHSPC)] [briefly: oligometastatic prostate cancer (OMPC) by PSMA PET, M1 negative by CI].

[0016] In certain embodiments of this disclosure, the positron-emitting nuclide is: 11 C, 13 N, 15 O, 18 F, 64 Cu, 68 Ga, 82 Rb, 83 SR, 89 Zr, and 124 A selection may be made from the group consisting of I, preferably, 18 F, 64 Cu, and 68 It can be selected from the group consisting of Ga.

[0017] In certain embodiments of this disclosure, the RLI agent is gallium ( 68 Ga) Gozetotide[[ 68 Ga]Ga-PSMA-11], 64 Cu-SAR-bisPSMA, 64 Cu-PSMA I&T [Copper ( 64 Cu) Zadabotide glaxetan, Pifluforastat ( 18 F)[ 18 F-DCFPyL], Flotsflustat ( 18 F)[ 18 F-rhPSMA-7.3], Vidofluhorastat ( 18 F)[ 18F-CTT1057] 18 F-PSMA-1007, 18 F-JK-PSMA-7, and 18 Selected from the group consisting of F-FC303, preferably gallium ( 68 Ga) Gozetotide and Pifluforastat ( 18 Selected from the group consisting of F).

[0018] In certain embodiments of this disclosure, the CI is based on computed tomography (CT) / magnetic resonance imaging (MRI) and / or bone scans.

[0019] In certain embodiments of the present disclosure, the RLT 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 once every 6 to 8 weeks, more preferably once every 6 (±1) weeks (i.e., one cycle), for a maximum of 3 to 4 cycles, preferably 3 to 4 cycles, more preferably 4 cycles [or over a planned 4 cycles].

[0020] In a preferred embodiment of the present disclosure, the radioligand therapeutic agent is administered at a dose of 7.4 (±10%) GBq once every 6 (±1) weeks (i.e., one cycle) for four cycles. [Brief explanation of the drawing]

[0021] [Figure 1] This document outlines the design of the PSMA-DC (PSMA-delayed gonadal resection) clinical trial. [Modes for carrying out the invention]

[0022] The following provides further details and examples of this disclosure.

[0023] Embodiment The treatment method described herein is provided in the following embodiments.

[0024] 1.1 A method for delaying gonadectomy in adult male patients with prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic prostate cancer (OMPC), (1) The step of applying stereotactic radiotherapy (SBRT) to the patient; (2) The step of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) drug. A method that includes this.

[0025] 1.2 A method for delaying disease recurrence in adult male patients with PSMA+OMPC, (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0026] 1.3 A method for delaying the initiation of hormonal gonadal resection therapy in adult male patients with PSMA+OMPC, (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0027] 1.4 A method for maintaining quality of life in adult male patients with PSMA+OMPC by delaying treatment with androgen deprivation therapy (ADT), (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0028] 1.5 A method for extending the time to hormone therapy (TTHT) in adult male patients with PSMA+OMPC (this time is defined, for example, as the time from the start of the method to androgen deprivation therapy (ADT)), (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0029] 1.6 A method for extending metastasis-free survival (MFS) in adult male patients with PSMA+OMPC using conventional imaging tests, (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0030] 1.7 A method for extending metastasis-free survival (MFS) in adult male patients with PSMA+OMPC (MFS is defined, for example, as the time from the start of this method to the first evidence of bone or soft tissue distant metastasis detectable by conventional imaging tests (i.e., CT / MRI and bone scans) as assessed by BIRC using RECIST 1.1, or death for any other reason (whichever occurs first)), (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0031] 1.8 A method for controlling the progression of recurrent tumors to lethal metastatic disease in adult male patients with PSMA+OMPC, (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0032] 1.9 A method for extending metastasis-free survival (MFS) in adult male patients with PSMA+OMPC (MFS is defined, for example, as the time from the start of this method to the first evidence of bone or soft tissue distant metastasis detectable by conventional imaging (i.e., CT / MRI and bone scan) as assessed by a principal investigator using RECIST 1.1, or death for any reason (whichever occurs first)), (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0033] 1.10 A method for extending the time to prostate-specific antigen (PSA) progression (TTPSAP) in adult male patients with PSMA+OMPC (this time is defined, for example, as the time from the start of this method to the first PSA progression 1 [wherein the first PSA progression 1 may be defined as an increase in PSA confirmed by repeated measurements at least 3 weeks later, and above 25% of the lowest point or baseline (whichever is lower) and above 2 ng / mL]), (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0034] 1.11 A method for extending radiographic progression-free survival (rPFS) in adult male patients with PSMA+OMPC (where rPFS is defined, for example, as the time from the start of this method to the first radiographic record of progressive disease confirmed by conventional imaging studies using RECIST 1.1 (i.e., CT / MRI and bone scan) or death for any reason (whichever occurs first). [Therefore, rPFS may be analyzed based on assessments by BIRC and the principal investigator, respectively]), (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0035] 1.12 A method for extending the time to the next treatment (local or systemic) in adult male patients with PSMA+OMPC (this time is defined, for example, as the time from the start of this method to the start of the next treatment line (local or systemic) [wherein the next treatment line is defined as the first new (local or systemic) antitumor therapy initiated after discontinuation of the study treatment, regardless of the reason for end of treatment (EOT)]), (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0036] 1.13 A method for extending 24-month PFS in adult male patients with PSMA+OMPC, specifically PFS (≥0.5 ng / mL) (for example, defined as PSA PFS at 24 months [wherein PSA PFS is defined as the time from the randomization date to the first recorded day of PSA progression 2 or death for any reason (whichever occurs first), and PSA progression 2 is defined as a PSA concentration exceeding the lowest point (or baseline, if lower) of ≥0.5 ng / mL, as confirmed by repeated measurements at least 3 weeks later], (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0037] 1.14 Methods for extending the time to symptomatic progression in adult male patients with PSMA+OMPC (this time is defined, for example, as the time from the initiation of this method to the deterioration of Eastern Cooperative Oncology Group (ECOG) performance status (PS) as assessed by the principal investigator as clinical progression, such as an increase in cancer-related pain and / or worsening of disease-related symptoms (both leading to the initiation of new systemic anticancer therapy), or the time to the onset of clinically significant symptoms resulting from local or regional tumor progression leading to surgery or radiotherapy), (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0038] 1.15 A method for improving the quality of life in adult male patients with PSMA+OMPC as assessed by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0039] FACT-P assesses symptoms / problems associated with prostate cancer and its treatment. It is a combination of FACT-General and the Prostate Cancer Subscale (PCS). FACT-General (FACT-G) is a 27-item quality of life (QoL) scale providing a total score and subscale scores: physical (0-28), functional (0-28), social (0-28), and emotional well-being (0-24). The total score range is 1-108, with higher scores indicating better overall and subscale well-being. The PCS is a 12-item prostate cancer subscale (range 0-48, higher scores indicating better overall and subscale well-being) that asks about symptoms and problems specific to prostate cancer. The FACT-P total score is the sum of all five subscale scores from the FACT-P questionnaire, ranging from 0-156. Higher scores indicate a better degree of functioning and a better quality of life.

[0040] 1.16 A method for reducing pain in adult male patients with PSMA+OMPC as assessed by the Brief Pain Inventory-Short Form (BPI-SF) questionnaire, (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0041] The BPI-SF is a publicly available tool for assessing pain, including severity and interference scores. The BPI-SF is an 11-item self-report questionnaire designed to assess the severity of pain and its impact on daily functioning in participants. The pain severity score is the mean of BPI-SF questions 3, 4, 5, and 6 (these questions ask about the degree of pain, ranked from 0 [no pain] to 10 [the worst pain imaginable]). Progression in pain severity is defined as a score increase of 30% or more from baseline without a decrease in analgesic use.

[0042] 1.17 A method for improving health-related quality of life in adult male patients with PSMA+OMPC, as assessed by the European Quality of Life (EuroQol)-5Domain 5Level scale (EQ-5D-5L), (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0043] The EQ-5D-5L is a standardized participant-completed questionnaire that measures health-related quality of life and converts the score into an index value or utility score. The EQ-5D-5L consists of two components: a health status profile and an optional visual analog scale (VAS). The EQ-5D health status profile consists of the following five aspects: mobility, self-care, usual activity, pain / discomfort, and anxiety / depression. Each aspect has the following five levels: 1=no problem, 2=mild problem, 3=moderate problem, 4=severe problem, and 5=extreme problem. A higher score indicates a higher level of problem across each of the five aspects.

[0044] 1.18 A method for extending the time to the first symptomatic skeletal event (TTSSE) in adult male patients with PSMA+OMPC (TTSSE is defined, for example, from the start date of the method to the date of the first new symptomatic pathological fracture, spinal cord compression, tumor-related orthopedic surgical intervention, request for radiotherapy to relieve bone pain, or death for any reason (whichever occurs first)), (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0045] 1.19 A method for reducing the incidence and / or severity of adverse events (AEs) and / or serious adverse events (SAEs) in adult male patients with PSMA+OMPC, (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0046] Adverse events can be classified through the analysis of the frequency of adverse events (TEAEs), serious adverse events (TESAEs), and deaths caused by AEs, based on monitoring of relevant clinical and laboratory safety parameters.

[0047] 1.20 A method for extending overall survival (OS) in adult male patients with PSMA+OMPC (where OS is defined, for example, as the time from the start of this method to the date of death due to any cause), (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0048] In embodiments of this disclosure, stereotactic radiotherapy (SBRT) may also be referred to as curative therapy for the patient's primary tumor.

[0049] In embodiments of the present disclosure, the PSMA-binding radioligand therapeutic (RLT) agent may be a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline, amorphous, stereoisomer, or tautomer of the RLT agent.

[0050] In the embodiments of this disclosure, the terms “patient” (singular) and “patients” (plural) are interchangeable.

[0051] In embodiments of the present disclosure, particularly in the embodiments described above (1.1 to 1.20), the extension, improvement, or reduction may be at least 25%, preferably at least 30%, more preferably at least 35%, even more preferably at least 40%, even more preferably at least 45%, even more preferably at least 50%, even more preferably at least 55%, even more preferably at least 60%, even more preferably at least 65%, even more preferably at least 70%, even more preferably at least 75%, even more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, and even more preferably at least 100%, compared to a method that includes the first step (SBRT) but does not include the second step (RLT); or even more preferably at least 50%, even more preferably at least 55%, even more preferably at least 60%, even more preferably at least 65%, even more preferably at least 70%, even more preferably at least 75%, even more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, and even more preferably at least 100%.

[0052] In embodiments of the present disclosure, particularly in the embodiments described above (1.1 to 1.20), the extension, improvement may be at least 110%, preferably at least 120%, more preferably at least 130%, even more preferably at least 140%, even more preferably at least 150%, even more preferably at least 160%, even more preferably at least 170%, even more preferably at least 180%, even more preferably at least 190%, even more preferably at least 200%, even more preferably at least 250%, even more preferably at least 300%, even more preferably at least 350%, even more preferably at least 400%, even more preferably at least 450%, and even more preferably at least 500%, compared to a method that includes the first step (SBRT) but does not include the second step (RLT); or even more preferably at least SBRT alone.

[0053] Further embodiments of the present disclosure may be formed by combining any one feature of the methods described as independent embodiments 1.1 to 1.20 with any one or more features of the other methods.

[0054] For example, the following further embodiments are formed from the methods of embodiments 1.1 to 1.3: A method for delaying gonadectomy and the initiation of hormonal gonadectomy therapy in adult male patients with prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic prostate cancer (OMPC), (1) The step of applying stereotactic radiotherapy (SBRT) to the patient; (2) The step of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) drug. A method that includes this.

[0055] Another example is a combination of the methods of Embodiments 1.5 to 1.7: A method for extending the time to hormone therapy (TTHT) in adult male patients with PSMA+OMPC (this time is defined, for example, as the time from the start of the method to androgen deprivation therapy (ADT)), and a method for extending metastasis-free survival (MFS) (this MFS is defined, for example, as the time from the start of the method to the first evidence of bone or soft tissue distant metastasis detectable by conventional imaging tests (i.e., CT / MRI and bone scans) as assessed by BIRC using RECIST 1.1, or death for any reason (whichever occurs first)), (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0056] Another example is a combination of the methods of Embodiments 1.5, 1.7, and 1.20: A method for extending the time to hormone therapy (TTHT) in adult male patients with PSMA+OMPC (this time is defined, for example, as the time from the start of the method to androgen deprivation therapy (ADT)), and a method for extending metastasis-free survival (MFS) (this MFS is defined, for example, as the time from the start of the method to the first evidence of bone or soft tissue distant metastasis detectable by conventional imaging tests (i.e., CT / MRI and bone scan) as assessed by BIRC using RECIST 1.1, or death for any reason (whichever occurs first)), and a method for extending overall survival (OS) (this OS is defined, for example, as the time from the start of the method to the date of death for any reason), (1) The step of applying SBRT to the patient; (2) The step of administering a therapeutically effective amount of PSMA-binding RLT drug to the patient. A method that includes this.

[0057] These are just a few examples of possible combinations of Embodiments 1.1 to 1.19. Any other combinations are disclosed as further embodiments therewith.

[0058] This disclosure further provides the following embodiments: 2.1 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned procedure is characterized by a delay of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% compared to the application of SBRT alone. method.

[0059] 2.2 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned treatment is characterized by a delay of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% of disease recurrence compared to the application of SBRT alone. method.

[0060] 2.3 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned procedure is characterized by a delay of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% in the initiation of hormonal gonadal therapy compared to the application of SBRT alone. method.

[0061] 2.4 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned treatment is characterized by maintaining quality of life with a delay of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% compared to treatment with androgen deprivation therapy (ADT), compared to the application of SBRT alone. method.

[0062] 2.5 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The treatment is characterized by an extension of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% of the time to hormone therapy (TTHT) (for example, defined as the time from the start of the method to androgen deprivation therapy (ADT)) compared to the application of SBRT alone. method.

[0063] 2.6 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned treatment is characterized by an extension of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% of the metastasis-free survival (MFS) as determined by conventional imaging, compared to the application of SBRT alone. method.

[0064] 2.7 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned treatment is characterized by an extension of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% of metastasis-free survival (MFS) (defined, for example, as the time from the initiation of this method to the first evidence of bone or soft tissue distant metastasis detectable by conventional imaging tests (i.e., CT / MRI and bone scans) as assessed by BIRC using RECIST 1.1, or death for any other reason (whichever occurs first)) compared to the application of SBRT alone. method.

[0065] 2.8 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The treatment is characterized by at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% improvement in controlling the progression of recurrent tumors to lethal metastatic disease, compared to the application of SBRT alone. method.

[0066] 2.9 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned treatment is characterized by an extension of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% of metastasis-free survival (MFS) (defined, for example, as the time from the initiation of this method to the first evidence of bone or soft tissue distant metastasis detectable by radiographic imaging (i.e., CT / MRI and bone scan) as assessed by a principal investigator using RECIST 1.1, or death for any other reason (whichever occurs first)) compared to the application of SBRT alone. method.

[0067] 2.10 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The treatment is characterized by an extension of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% of the time to prostate-specific antigen (PSA) progression (TTPSAP) compared to the application of SBRT alone (for example, defined as the time from the start of this method to the first PSA progression 1 [wherein the first PSA progression 1 may be defined as an increase in PSA confirmed by repeated measurements at least 3 weeks later, and above 25% above the lowest point or baseline (whichever is lower) and above 2 ng / mL]). method.

[0068] 2.11 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned treatment is characterized by an extension of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% of radiographic progression-free survival (rPFS) compared to the application of SBRT alone (for example, the time from the initiation of this method to the first radiographic recording of progressive disease or death for any reason confirmed by conventional imaging tests using RECIST 1.1 (i.e., CT / MRI and bone scans) [so rPFS can be analyzed based on assessments by BIRC and the principal investigator, respectively]). method.

[0069] 2.12 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned procedure is characterized by an extension of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% of the time to the next treatment (local or systemic) compared to the application of SBRT alone (for example, defined as the time from the start of this method to the start of the next line of treatment (local or systemic) [wherein the next line of treatment is defined as the first new (local or systemic) antitumor therapy initiated after discontinuation of the study treatment, regardless of the reason for end of treatment (EOT)]). method.

[0070] 2.13 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned treatment is characterized by an extension of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% of 24-month PFS (PFS ≥ 0.5 ng / mL) compared to SBRT alone. [For example, PFS is defined as PSA PFS at 24 months [wherein PSA PFS is defined as the time from the randomization date to the first recorded day of PSA progression 2 or the day of death for any reason (whichever occurs first), and PSA progression 2 is defined as a PSA concentration exceeding the lowest point (or lower baseline, if lower) of ≥ 0.5 ng / mL, as confirmed by repeated measurements at least 3 weeks later]. method.

[0071] 2.14 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned treatment is characterized by an extension of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% of the time to symptomatic progression (e.g., time from initiation of this method to deterioration of Eastern Cooperative Oncology Group (ECOG) performance status (PS) as assessed by the principal investigator as clinical progression, such as increasing cancer-related pain and worsening disease-related symptoms, both of which lead to the initiation of new systemic anticancer therapy, or time to the onset of clinically significant symptoms resulting from local or regional tumor progression leading to surgery or radiotherapy) compared to the application of SBRT alone. method.

[0072] 2.15 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned treatment is characterized by an improvement of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% in quality of life as assessed by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, compared to the application of SBRT alone. method.

[0073] FACT-P assesses symptoms / problems associated with prostate cancer and its treatment. It is a combination of FACT-General and the Prostate Cancer Subscale (PCS). FACT-General (FACT-G) is a 27-item quality of life (QoL) scale providing a total score and subscale scores: physical (0-28), functional (0-28), social (0-28), and emotional well-being (0-24). The total score range is 1-108, with higher scores indicating better overall and subscale well-being. The PCS is a 12-item prostate cancer subscale (range 0-48, higher scores indicating better overall and subscale well-being) that asks about symptoms and problems specific to prostate cancer. The FACT-P total score is the sum of all five subscale scores from the FACT-P questionnaire, ranging from 0-156. Higher scores indicate a better degree of functioning and a better quality of life.

[0074] 2.16 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned treatment is characterized by a reduction of at least 50%, 60%, 70%, 80%, 90%, or 100% of pain as assessed by the Brief Pain Inventory-Short Form (BPI-SF) questionnaire, compared to the application of SBRT alone. method.

[0075] The BPI-SF is a publicly available tool for assessing pain, including severity and interference scores. The BPI-SF is an 11-item self-report questionnaire designed to assess the severity of pain and its impact on daily functioning in participants. The pain severity score is the mean of BPI-SF questions 3, 4, 5, and 6 (these questions ask about the degree of pain, ranked from 0 [no pain] to 10 [the worst pain imaginable]). Progression in pain severity is defined as a score increase of 30% or more from baseline without a decrease in analgesic use.

[0076] 2.17 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned treatment is characterized by an improvement of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% in health-related quality of life as assessed by the European Quality of Life (EuroQol)-5 Domain 5 Level Scale (EQ-5D-5L), compared to the application of SBRT alone. method.

[0077] The EQ-5D-5L is a standardized participant-completed questionnaire that measures health-related quality of life and converts the score into an index value or utility score. The EQ-5D-5L consists of two components: a health status profile and an optional visual analog scale (VAS). The EQ-5D health status profile consists of the following five aspects: mobility, self-care, usual activity, pain / discomfort, and anxiety / depression. Each aspect has the following five levels: 1=no problem, 2=mild problem, 3=moderate problem, 4=severe problem, and 5=extreme problem. A higher score indicates a higher level of problem across each of the five aspects.

[0078] 2.18 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The treatment is characterized by an extension of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% of the time to the first symptomatic skeletal event (TTSSE) (defined, for example, from the start date of the method to the date of the first new symptomatic pathological fracture, spinal cord compression, tumor-related orthopedic surgical intervention, request for radiotherapy to alleviate bone pain, or death for any reason (whichever occurs first)) compared to the application of SBRT alone. method.

[0079] 2.19 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The aforementioned treatment is characterized by a reduction of at least 50%, 60%, 70%, 80%, 90%, or 100% in the incidence and / or severity of adverse events (AEs) and / or serious adverse events (SAEs) compared to the application of SBRT alone. method.

[0080] Adverse events can be classified through the analysis of the frequency of adverse events (TEAEs), serious adverse events (TESAEs), and deaths caused by AEs, based on monitoring of relevant clinical and laboratory safety parameters.

[0081] 2.20 A method for treating prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic gonadectomy-resistant prostate cancer (OMPC), (1) The process of applying stereotactic radiotherapy (SBRT) to patients who require it, and (2) The process of administering to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Includes, The treatment is characterized by an extension of at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% of overall survival (OS) (defined, for example, as the time from the start of this method to the date of death due to any cause) compared to the application of SBRT alone. method.

[0082] In embodiments of this specification, the term “compared to the application of SBRT alone” may also be referred to as “compared to a treatment method consisting of SBRT (alone).”

[0083] Further embodiments of the present disclosure may be formed by combining any one feature of the methods described as independent embodiments 2.1 to 2.20 with any one or more features of the other methods.

[0084] In embodiments of this disclosure, the RLT drug comprises at least two components: (1) Radioactive nuclide components; and (2) Ligand components May include, The aforementioned radioactive nuclide component (1) is, (a) At least one radioactive nuclide preferably selected from the group consisting of alpha particle emitting nuclides, beta-negative electron emitting nuclides, and Auger electron emitting nuclides, and more preferably selected from beta-negative electron emitting nuclides. Includes, The ligand component (2) includes the following: (b) at least one PSMA binding portion; (c) Optionally, at least one chelating agent for chelating a radionuclide or a salt containing such radionuclide, or a prosthetic group residue derived from a radiohalogenation reaction; (d) Optionally, at least one linker connecting the PSMA binding component (b) to the chelating agent or prosthetic group component (c), preferably the linker being a chemical moiety or a covalent bond; (e) Optionally, at least one additional portion that modifies the systemic circulation time, tumor uptake, and / or biodistribution of the RLT agent, preferably the modifying portion comprising an oxyethylene unit, for example, an oligo or polyoxyethylene-(-CH2-CH2-O-)n-(n=2~100), or an albumin-binding portion (e.g., Evans blue, 4-(p-iodophenyl)butyrate, 4-(p-methylphenyl)butyrate, ibuprofen).

[0085] In embodiments of this disclosure, the radionuclide may be selected from the group consisting of Lu-177, Tb-161, Er-169, I-131, Tc-99m, Y-90, Sc-47, Cu-67, Re-188, Pb-212, Bi-213, Ac-255, and Th-227, and preferably from the group consisting of Lu-177 and Tb-161.

[0086] In embodiments of the present disclosure, the radionuclide is preferably a beta-negative electron-emitting nuclide having a half-life of about 2 to about 10 days, preferably about 5 to about 10 days, more preferably about 6 to about 8 days, and even more preferably about 6 or about 7 days; and a beta-negative electron maximum energy of 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.

[0087] In embodiments of the present disclosure, the radioactive nuclide is preferably a beta-negative electron-emitting nuclide having an absorption rate of electron energy per decay of 100-300 keV / decay, 120-250 keV / decay, about 150 keV / decay (e.g., 147 keV for Lu-177) to about 200 keV / decay (e.g., 196 keV / decay for Tb-161).

[0088] In embodiments of this disclosure, ligands include PSMA-617, PSMA I&T, PSMA-R2, MIP-1095, MIP-1545, MIP-1555, MIP-1557, MIP-1558, CTT1403, FC705, BAY-2315497, BAY-2315487, TLX591, TLX592, PSMA-TCC, rhPSMA, rhPSMA-7, rhPSMA-7.3, rhPSMA-10.1, Ludotadipep, PNT2001, PNT2002, PSMA-7, and EB-PSMA. The following may be selected from the group consisting of -617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93, PSMA-62, PSMA-1, SAR-bis-PSMA, ITM-22, ITM-24D, PMI-21, DOTA-h11B6, FPI-1434, pergifatamab, NG001, ADVC001, RPS-072, and RPS-074, and preferably from the group consisting of PSMA-617, PSMA I&T, and PSMA-R2.

[0089] In embodiments of this disclosure, the PSMA binding moiety may comprise at least two amino acids connected via a urea or phosphoramide group, preferably glutamic acid-urea-lysine (GUL), or may comprise an antibody or a fragment thereof, for example, TLX591, J591, rosopatamab, IAB2M, GCP-05, 1H8H5, SP29, or FOLHl.

[0090] In embodiments of this disclosure, the radioligand therapeutic agents are [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipivotide 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) bipivotide tetraxetan), [161Tb]Tb-EB-PSMA-617 (Evans Blue modified [161Tb]Tb-PSMA-617), and [161Tb]Tb-PSMA It may be selected from the group consisting of I&T (terbium (161Tb) zadabotide tetraxetan), preferably from the group consisting of [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipivotide tetraxetan) or [161Tb]Tb-PSMA-617 (terbium (161Tb) bipivotide tetraxetan), more preferably [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipivotide tetraxetan).

[0091] In embodiments of this disclosure, the PSMA binding moiety is glutamic acid-urea-lysine (GUL), and the linker comprises (2-naphthyl)-L-alanine and trans-4-aminomethyl-cyclohexanecarboxylic acid residues, or the linker may comprise optionally substituted phenylalanine and / or optionally substituted tyrosine residues, preferably comprising phenylalanine and subsubstituted tyrosine residues, more preferably comprising phenylalanine and iodine-substituted tyrosine residues, and even more preferably comprising D-phenylalanine and iodine-substituted D-tyrosine residues.

[0092] In embodiments of the present disclosure, the radioligand therapeutic agent is administered in 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 about 10 weeks, preferably once every 6 to about 8 weeks, more preferably once every 6 (±1) weeks (i.e., one cycle), for a maximum of about 4 to about 6 cycles, preferably for about 4 cycles.

[0093] In embodiments of this disclosure, PSMA positivity of OMPC is determined by positron emission tomography (PET) using a PSMA-binding radioligand diagnostic agent or contrast agent, wherein the radioligand contrast agent is (1) Components of radionuclides used for diagnostic purposes; and (2) Ligand components The radioactive nuclide component (1) is (a) at least one positron-emitting nuclide Includes, The ligand component (2) includes the following: (b) at least one PSMA binding portion; (c) optionally, at least one chelating agent for chelating a radionuclide or a salt containing such radionuclide, or a prosthetic group residue derived from a radiohalogenation reaction; (d) Optionally, at least one linker connecting the PSMA binding component (b) and the chelating agent / prosthetic group component (c), preferably the linker being a chemical moiety or a covalent bond.

[0094] In embodiments of this disclosure, the diagnostic radionuclide is selected from the group consisting of F-18, Ga-67, Ga-68, and Cu-64.

[0095] In embodiments of the present disclosure, the ligand component may be selected from the group consisting of PSMA-11 (gozetotide), DCPyL (available as PYLARIFY when labeled with 18F, international generic name: pifluforastat F-18, also known as PyL for short), MIP-1404, rhPSMA 07, PSMA-1007, THP-PSMA, iPSMA, P16-093, PSMA-93, rhPSMA, rhPSMA-7, rhPSMA-7.3, PSMA-7, and PSMA I&T.

[0096] Forms of medical use The above embodiments are summarized as claims for a treatment method. These can similarly be summarized as other second forms of medical use, for example, as illustrated below, in which [drug] is an RLT agent (alone or in combination with other drugs), [indication] is an OMPC as defined in the above embodiments, and [features] are features characterized as mentioned in the above embodiments.

[0097] The present invention provides a [drug] or any pharmaceutically acceptable salt thereof, characterized by this [feature], for use in the treatment of [indications].

[0098] Alternatively, the present invention provides a method for treating a [condition] in a human patient in need, comprising administering an effective amount of [drug] or any pharmaceutically acceptable salt thereof, wherein the treatment is characterized by this [feature].

[0099] As a further alternative, the present invention provides the use of a [drug] or any pharmaceutically acceptable salt thereof for the preparation of a drug for the treatment of an [indication] characterized by this [feature].

[0100] As a further alternative, the present invention provides the use of a [drug] or any pharmaceutically acceptable salt thereof for the treatment of an [indication] characterized by this [feature].

[0101] As a further alternative, the present invention provides a pharmaceutical product for the treatment of an indication, comprising a drug or any pharmaceutically acceptable salt thereof, characterized by this feature.

[0102] Patient details In certain embodiments of this disclosure, patients may have, or must have, biochemical recurrent disease after radical treatment of the prostate by RP (alone or with postoperative radiation to the prostatic bed / pelvic lymph nodes), XRT (prostate alone or prostate with seminal vesicles and / or pelvic lymph nodes), and / or brachytherapy prior to randomization. Biochemical recurrent disease is defined as: lowest point PSA +2 ng / mL after XRT (if the participant received radiotherapy to the intact prostate), and PSA >0.2 ng / mL, and elevation after RP (with or without postoperative RT).

[0103] In certain embodiments of this disclosure, a patient may have, or must have in other embodiments, five or fewer PSMA-positive metastatic lesions at the time of a screening PSMA PET / CT scan (using either gallium (68Ga) gozetotide or pifulforastat (18F)) as visually assessed by BIRC based on the methodology proposed in Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) (Eiber et al 2018). Metastatic lesions may include local / pelvic lymph nodes (N1), distant lymph nodes (M1a), bone (M1b), lungs, and other viscera (M1c) excluding the liver and brain as classified using AJCC 8. For counting the number of oligometastatic lesions, each lesion is counted as a separate metastasis regardless of its anatomical location (for example, one intrapelvic lymph node and one extrapelvic lymph node may be counted as two metastatic lesions).

[0104] In certain embodiments of this disclosure, the patient may have, or must have, the following conditions: During screening, at least one PSMA-positive lesion should be metastatic (M1) according to the AJCC 8-stage classification. PSMA PET information should be used for the AJCC M-stage classification.

[0105] In certain embodiments of this disclosure, the patient may be negative for conventional imaging tests for M1 disease at the time of screening, or in other embodiments, must be negative.

[0106] Note: With respect to patients excluded from embodiments of this disclosure, CI-positive M1 lesions should be evident on CI scans, i.e., not resulting from findings that are potentially indicative of something other than a tumor (e.g., degeneration or post-traumatic changes in bone lesions or Paget's disease). Prior knowledge of PSMA PET positivity should not influence the radiologist's (reader's) determination of CI positivity. Two different readers may be included (one for PSMA PET scans and one for CIs), and readers are blinded to the PSMA PET scan results while reading the CI scan. Readers should not change their evaluation of the CI scan after reading the PSMA PET scan (e.g., changing a lesion previously identified as unclear in the CI to clear). Similarly, biopsy positivity should not influence the reader's evaluation of CI positivity. Further details of the reading paradigm are described in the imaging charter. • MRI for radiotherapy planning may show M1 disease, but this does not mean that participants should be excluded from the study if the lesion is considered negative on each baseline CT or bone scan. Patients suffering from pelvic disorders (N1) as detected by conventional imaging tests are included in the embodiments (according to the AJCC 8 definition of local disorders) if the local extent is below the common bowel bifurcation. Distant lymph node disease (M1a) that is visible for each CI and has a short axis of less than 10 mm is not excluded from the embodiments, regardless of whether it is PSMA PET positive.

[0107] In certain embodiments of this disclosure, the patient may have, or must have, the following conditions: All metastatic lesions detected during screening should be suitable for SBRT.

[0108] In certain embodiments of this disclosure, the patient may have, or must have, the following conditions: If a patient has already received SBRT for OMPC, progressive disease may / must be demonstrated before randomization (e.g., a new PSMA PET lesion). Previously treated lesions may / must be stable on baseline imaging scans and will not be counted towards the 1-5 lesions required in this trial. If a previously treated lesion was evident with respect to M1 by bone scan or CT prior to the previous SBRT, the patient will be rejected in the embodiment.

[0109] Confirmation of controlled primary tumor at screening: If local recurrence is suspected, MRI is required to rule out local recurrence. Patients with MRI or PET-positive local lesions require biopsy to rule out local progression. These patients with local recurrence (either with local disease confirmed by biopsy or with MRI or PET-positive local lesions without biopsy) may be included in the post-salvage therapy for local disease embodiment. Note: Patients who have already received pelvic RT (pelvic salvage RT) at the time of local recurrence after RP are included in the embodiment.

[0110] In certain embodiments of this disclosure, a patient may have a PSADT of less than 10 months at screening, or in other embodiments, must have a PSADT of less than 10 months [PSADT is calculated using a linear regression model of the natural logarithm of PSA and time (Pound et al 1999)].

[0111] In certain embodiments of this disclosure, a patient may have a non-gonadectomy testosterone level greater than 100 ng / dL at the time of screening, or in other embodiments, must have a non-gonadectomy testosterone level greater than 100 ng / dL.

[0112] In certain embodiments of this disclosure, the patient may not have a new OMPS at the start of the treatment method, or in other embodiments, must not have one.

[0113] In certain embodiments of this disclosure, the patient may not have received prior treatment with any one of the following, or in other embodiments, must not have received any: a. ADT including bilateral orchiectomy Patients who have received XRT or RP prior to relapse and have completed adjuvant ADT (or ADT + androgen receptor pathway inhibitor (ARPI)) are included in the embodiments if the final dose of ADT (or ADT + ARPI) was 12 months prior to the initiation of the treatment method. Patients who discontinue ADT due to disease progression are excluded from this embodiment (i.e., CRPC patients). b. Other hormone therapies, for example • Use of estrogen, 5-α-reductase inhibitors (finasteride, dutasteride), and other steroid production inhibitors (aminoglutetoamides) • First-generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone), • Second-generation antiandrogens (e.g., enzalutamide, apalutamide, and darolutamide), or • CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone, ketoconazole) [Short-term ketoconazole treatment (less than 28 days) is acceptable]. c. Radiopharmaceuticals (e.g., strontium-89, PSMA-targeted radioligand therapy), d. Immunotherapy (e.g., Ciproisel-T), e. Chemotherapy administered in an adjuvant / neoadjuvant setting completed more than 12 months before randomization, or f. Any other investigational drug or systemic drug for metastatic disease.

[0114] In certain embodiments of this disclosure, patients may not have received radiotherapy, external beam radiotherapy (EBRT), and brachytherapy within 28 days prior to randomization, or in other embodiments, they must not have received them.

[0115] In certain embodiments of this disclosure, the patient may not be receiving, or in other embodiments may not be receiving, concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, hormone therapy, PARP inhibitors, biological therapy, or any investigational therapy.

[0116] definition The term "approximately" in relation to a value means ±25%, preferably ±20%, more preferably ±15%, even more preferably ±10%, and even more preferably ±5%. In relation to weeks or cycles, "approximately" means ±2, preferably ±1.

[0117] PSMA-617, or bipivotide tetraxetan, refers to the "cold" ligand (a ligand that does not contain a radionuclide) of Pulvicto, i.e., the internationally recognized generic name: lutetium (177Lu) bipivotide tetraxetan.

[0118] PSMA I&T (zadavotidoglaxetan) refers to the "cold" ligand (a ligand that does not contain a radionuclide) of [177Lu]Lu-PSMA I&T (international generic name: lutetium (177Lu) zadavotidoglaxetan), and is marketed by ABX, Radeberg, Germany. Methods for manufacturing drug products for clinical use using this RLT drug are described in U.S. Patent No. 11,129,912B1 and U.S. Patent No. 11,491,246B2.

[0119] Hormone therapy: including any androgen-targeted treatment (e.g., finasteride, dutasteride, bicalutamide, apalutamide, abiraterone, or enzalutamide), or taxane-based chemotherapy (docetaxel or cabazitaxel).

[0120] PSMA+: Prostate cancer (including its metastases) is a heterogeneous cancer. Not all cancer cells are PSMA+; only some may be PSMA+, or some cells may exhibit low or insufficient levels of PSMA expression. In some embodiments, PSMA+ means that at least about 10%, preferably at least about 20%, more preferably at least about 30%, even more preferably at least about 40%, even more preferably at least about 50%, even more preferably at least about 60%, even more preferably at least about 70%, even more preferably at least about 80%, and even more preferably at least about 90% of prostate cancer cells (including metastatic cells) express PSMA at a substantial level / to a substantial degree / to a substantial amount.

[0121] OMPC: Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) (Eiber et al 2018) is defined as a patient with five or fewer PSMA-positive metastatic lesions as visually evaluated by BIRC during a screening PSMA PET / CT scan (using either gallium (68Ga) gozetotide or pifluforastat (18F)). Metastatic lesions may include local / pelvic lymph nodes (N1), distant lymph nodes (M1a), bone (M1b), lungs, and other viscera (M1c) excluding the liver and brain, as classified using AJCC 8. When counting the number of oligometastatic lesions, each lesion is counted as a separate metastasis regardless of its anatomical location (for example, one intrapelvic lymph node and one extrapelvic lymph node may be counted as two metastatic lesions).

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[0123] The present disclosure will now be described in more detail, specifically with reference to examples, but the examples are not intended to limit the present disclosure.

[0124] Reference Example 1: Early Clinical Trial title Lutetium-177-PSMA-617 (also known as Bullseye or Bullseye-2) in oligometastatic hormone-sensitive prostate cancer

[0125] background [ 177 Lu]Lu-PSMA-617 radioligand therapy (RLT) is a novel treatment for patients with metastatic gonadectomy-resistant prostate cancer. Previously, the inventors [ 177[Lu]Lu-PSMA-617 has been shown to be potentially effective and minimally toxic in patients with oligometastatic hormone-sensitive prostate cancer (mHSPC) expressing PSMA (CCR, 2021). 177 Lu]Lu-PSMA-617 RLT may delay androgen deprivation therapy (ADT), thereby delaying ADT-related toxicity. In accordance with this specification, the inventors [ 177 We report the interim results of a randomized trial analyzing time without ADT using Lu]Lu-PSMA-617 RLT versus prolonged ADT (current standard of care; SoC).

[0126] method This is an ongoing international, multicenter, open-label, randomized phase 2 trial (NCT04443062). 58 patients will be randomized in a 1:1 ratio. Eligibility is [ 18 F]PSMA-PET / CT shows up to 5 metastases in rapidly progressive HSPC after local treatment (PSA doubling time less than 6 months). The patient received 2+2 cycles of 7.4 GBq[ 177 Patients may receive Lu]Lu-PSMA-617. The primary outcome is progression-free survival (i.e., ADT-free time). Progressive disease (PD) is defined as initiation of ADT, a 100% increase in PSA after randomization, or radiological or clinical progression. Secondary outcomes are PSA response and toxicity according to CTCAE v5.0.

[0127] result To date (April 3, 2023), 42 patients have been included. The median PSA level at the time of ingestion was 4.5 ng / mL (range 1.3-38). During the median 6-month follow-up period (range 1-20 months), SoC and [ 177 77% (17 / 22 cases) and 10% (2 / 20 cases) of the Lu-PSMA-617 arms reached the definition of PD. The median progression-free survival was 4 months for the SoC arm, compared to [ 177The Lu]Lu-PSMA-617 arm did not reach this level (HR 0.03; 95% CI 0.004~0.227; p<0.001). The most common procedure-related adverse events were grade 1 xerostomia (70%), grade 1 fatigue (61%), grade 1 nausea (35%), and grade 1 myelotoxicity (30%). All of these procedure-related adverse events were transient. Grade 2 or higher adverse events were observed in 10% of patients. One patient developed grade 3 xeropthalmia and grade 2 xerostomia. The median percentage change in PSA was SoC vs. [ 177 The results for each of the Lu]Lu-PSMA-617 arms were +114% versus -91%. Currently, 55% (11 / 20 patients) of the treated patients have shown a PSA reduction of over 90%, and 5 patients have a complete biochemical response. Some patients also showed complete response (CR) on PSMA PET.

[0128] conclusion [ 177 Lu]Lu-PSMA-617 RLT shows promising efficacy in delaying ADT with minimal and mostly transient side effects in patients with oligometastatic HSPC. Following surgery and external beam radiotherapy, 177 Lu]Lu-PSMA-617 may be a third metastasis-targeted treatment option for extending the ADT-free interval in patients with oligometastatic hormone-sensitive prostate cancer. The final results of this trial are awaited.

[0129] Example 1: Main Clinical Trial (Brief Description) An open-label study comparing lutetium (177Lu) bipivotide tetraxetan with observations in PSMA-positive OMPCs. (PSMA-DC)

[0130] the purpose The purpose of this study is to evaluate the efficacy and safety of lutetium (177Lu) bipivotide tetraxetan (AAA617) in participants with oligometastatic prostate cancer (OMPC) progression after curative treatment of the primary tumor. The data obtained from this study will provide evidence that treatment with AAA617 in patients with early-stage prostate cancer controls the progression of recurrent tumors to fatal metastatic disease while maintaining quality of life by delaying treatment with androgen deprivation therapy (ADT).

[0131] [Table 1]

[0132] Trial type: Intervention Test design. Main objective: Treatment. Test phase: Phase 3 Intervention trial model: parallel Shielding: No shielding Assignment: Randomization Official Title: An international, prospective, open-label, multicenter, randomized phase III trial comparing lutetium (177Lu) bipivotide tetraxetan (AAA617) with observation to delay gonadectomy or disease recurrence in adult male patients with prostate-specific membrane antigen (PSMA)-positive oligometastatic prostate cancer (OMPC).

[0133] Further test details Primary outcome criteria: • Metastasis-free survival (MFS) as assessed by the Blinded Independent Review Committee (BIRC) [Time frame: Up to approximately 30 months from the randomization date to the first evidence of radiographically detectable bone or soft tissue distant metastasis, or death for any other reason (whichever occurs first)]. Metastasis-free survival (MFS), as assessed by the Blinded Independent Review Committee (BIRC), is defined as the time from randomization to the first evidence of bone or soft tissue distant metastasis detectable by conventional imaging (i.e., CT / MRI and bone scans) as assessed by the BIRC using RECIST 1.1, or death for any other reason (whichever occurs first). Participants who are alive and without distant metastases at the time of analysis data cutoff, or who are unable to be followed up at the time of analysis, will have their MFS terminated at the last sufficient radiographic evaluation. Clinical deterioration without objective radiographic evidence will not be considered recorded distant metastases.

[0134] Secondary outcome criteria: • Primary secondary endpoint: Time to hormone therapy (TTHT) [Time frame: Evaluation over up to approximately 74 months from randomization date to androgen deprivation therapy (ADT)] The time to hormone therapy (TTHT) is defined as the time from randomization to androgen deprivation therapy (ADT). The type of hormone therapy is at the discretion of the principal investigator. • Metastasis-free survival (MFS) as assessed by the principal investigator [Time frame: Assessment over a maximum of approximately 74 months from the randomization date to the first evidence of radiographically detectable bone or soft tissue distant metastasis, or death for any reason (whichever occurs first)]. Metastasis-free survival (MFS), as assessed by the investigator, is defined as the time from randomization to the first evidence of bone or soft tissue distant metastasis detectable by conventional imaging (i.e., CT / MRI and bone scan) as assessed by the investigator using RECIST 1.1, or death for any other reason (whichever occurs first). • Time to progression of prostate-specific antigen (PSA) (TTPSAP) [Time frame: Evaluation over up to approximately 74 months from the randomization date to the first PSA progression] The time to prostate-specific antigen (PSA) progression (TTPSAP) is defined as the time from randomization to the first PSA progression 1. The first PSA progression 1 is defined as an increase in PSA confirmed by repeated measurements at least 3 weeks later, and at least 25% above the lowest point or baseline (whichever is lower) and above 2 ng / mL. • Progression-free survival (rPFS) on radiographs [Time frame: Evaluation over a maximum of approximately 74 months from the randomization date to the date of radiographed progression or death for any reason (whichever occurs first)] Radiographic progression-free survival (rPFS) is defined as the time from randomization to the first recorded instance of progressive disease on radiographically confirmed images using conventional imaging techniques (i.e., CT / MRI and bone scans) or death for any other reason (whichever occurs first). rPFS is analyzed based on BIRC and investigator assessments, respectively. • Time to the next treatment (local or systemic) [Time frame: Evaluation period of up to approximately 74 months from the randomization date to the start of the next treatment line (local or systemic)] The time to the next treatment (local or systemic) is defined as the time from randomization to the initiation of the next treatment line (local or systemic). The next treatment line is defined as the first new (local or systemic) antitumor therapy initiated after discontinuation of the study treatment, regardless of the reason for end-of-treatment (EOT). • 24-month PFS (PFS) [Time frame: Evaluation for up to approximately 74 months from the randomization date to the first recorded day of PSA progression 2 or the date of death for any reason (whichever occurs first)] PFS (PFS ≥0.5 ng / mL) at 24 months is defined as PSA PFS at 24 months. PSA PFS is defined as the time from the randomization date to the first recorded day of PSA progression 2 or death for any reason (whichever occurs first). PSA progression 2 is defined as a PSA concentration exceeding the lowest point (or baseline, if lower) of ≥0.5 ng / mL, confirmed by repeated measurements at least 3 weeks later. • Time to symptomatic progression [Time frame: Evaluation over up to approximately 74 months from randomization date until deterioration of Eastern Cooperative Oncology Group (ECOG) performance status (PS)] Time to symptomatic progression is defined as the time from randomization to a deterioration in Eastern Cooperative Oncology Group (ECOG) performance status (PS) assessed by the principal investigator as clinical progression, specifically an increase in cancer-related pain and / or worsening of disease-related symptoms (both leading to the initiation of new systemic anticancer therapy), or to the onset of clinically significant symptoms resulting from localized or regional tumor progression leading to surgery or radiotherapy. • Functional Assessment of Cancer Therapy-Prostate (FACT-P) Questionnaire [Timeframe: Up to approximately 74 months of evaluation from the randomization date to the 42-day safety follow-up] FACT-P assesses symptoms / problems associated with prostate cancer and its treatment. It is a combination of FACT-General and the Prostate Cancer Subscale (PCS). FACT-General (FACT-G) is a 27-item quality of life (QoL) scale providing a total score and subscale scores: physical (0-28), functional (0-28), social (0-28), and emotional well-being (0-24). The total score range is 1-108, with higher scores indicating better overall and subscale well-being. The PCS is a 12-item prostate cancer subscale (range 0-48, higher scores indicating better overall and subscale well-being) that asks about symptoms and problems specific to prostate cancer. The FACT-P total score is the sum of all five subscale scores from the FACT-P questionnaire, ranging from 0-156. Higher scores indicate a better degree of functioning and a better quality of life. • Brief Pain Inventory-Short Form (BPI-SF) questionnaire [Time frame: Evaluation for up to approximately 74 months, from the randomization date to the 42-day safety follow-up] The BPI-SF is a publicly available tool for assessing pain, including severity and interference scores. The BPI-SF is an 11-item self-report questionnaire designed to assess the severity of pain and its impact on daily functioning in participants. The pain severity score is the mean of BPI-SF questions 3, 4, 5, and 6 (these questions ask about the degree of pain, ranked from 0 [no pain] to 10 [the worst pain imaginable]). Progression in pain severity is defined as a score increase of 30% or more from baseline without a decrease in analgesic use. • European Quality of Life (EuroQol)-5 Domain 5-Level Scale (EQ-5D-5L) [Timeframe: Evaluation over up to approximately 74 months, from randomization date to 42-day safety follow-up] The EQ-5D-5L is a standardized participant-completed questionnaire that measures health-related quality of life and converts the score into an index value or utility score. The EQ-5D-5L consists of two components: a health status profile and an optional visual analog scale (VAS). The EQ-5D health status profile consists of the following five aspects: mobility, self-care, usual activity, pain / discomfort, and anxiety / depression. Each aspect has the following five levels: 1=no problem, 2=mild problem, 3=moderate problem, 4=severe problem, and 5=extreme problem. A higher score indicates a higher level of problem across each of the five aspects. • Time to first symptomatic skeletal event (TTSSE) [Time frame: Evaluation over a maximum of approximately 74 months from the randomization date until end of treatment (EOT) or death (whichever occurs first)] Time to SSE (TTSSE) is defined as the date of randomization to the date of the first new symptomatic pathological fracture, spinal compression, tumor-related orthopedic surgical intervention, request for radiation therapy to alleviate bone pain, or death for any reason (whichever occurs first). • Incidence and severity of adverse events (AEs) and / or serious adverse events (SAEs) [Time frame: Evaluation for up to approximately 74 months, from the randomization date to the 42-day safety follow-up] Adverse events are classified through the analysis of the frequency of adverse events (TEAEs), serious adverse events (TESAEs), and deaths caused by AEs that occur during procedures, based on monitoring of relevant clinical and laboratory safety parameters. • Dosage changes and intensity of AAA617 [Time frame: Evaluation for up to approximately 30 months from the randomization date to the end of treatment (EOT)] We will evaluate dose changes (dose interruption and reduction) and dose intensity for AAA617 and summarize the findings using descriptive statistics. • Overall survival (OS) [Time frame: Evaluation over a maximum of approximately 74 months, from the randomization date to the date of death for any reason] Overall survival (OS) is defined as the time from the randomization date to the date of death for any cause. For participants who are alive or unable to be followed up at the end of the study, the OS time is censored on the last contact date.

[0135] Estimated number of subscribers: 450

[0136] [Table 2]

[0137] Detailed explanation: All participants will be assessed for eligibility and undergo baseline disease assessment including mandatory gallium (68Ga) gozetotide (also known as [68Ga]Ga-PSMA-11) or pifluforastat (18F) (also known as [18F]DCFPyL) PET / CT scans, and conventional imaging studies (i.e., CT / MRI and bone scans).

[0138] Perform a pifluforastat (18F) PET / CT scan in a country where it is approved.

[0139] Stereotactic radiotherapy (SBRT) will be administered to all metastatic prostate cancer (PC) lesions after randomization and before initiation or observation of treatment with AAA617. The duration of the SBRT procedure is approximately 3 weeks. · For participants randomized to the treatment arm (AAA617), the treatment period is up to 4 cycles of AAA617. For participants randomized to the control arm (observation), the treatment period ends at the final fraction of SBRT administration. · The frequency of hospital visits is every 1st and 3rd week of each of the 4 cycles, and then every 16 weeks until the first event of disease progression (RECIST 1.1) (for both arms). · The study period is approximately 6.5 years. <00ooo883>· Crossover to AAA617 for participants in the observation arm with radiographic progression (MFS event) of distant metastases by conventional imaging confirmed by BIRC is permitted after the start of ADT.

[0140] After treatment, participants randomized to the treatment arm or crossed over from the control arm are followed every 32 weeks for long-term safety assessment until the end of this trial, and after the completion of this trial, they are enrolled in a rollover trial for a total period of 10 years from the first dose of AAA617. All participants are followed for survival.

[0141] Eligibility Eligible age for the trial: 18 years or older Eligible gender for the trial: Male

[0142] Criteria Inclusion criteria: 1. A signed informed consent must be obtained prior to participation in this trial. 2. Participants must be adults 18 years of age or older at the time of informed consent. 3. The ECOG performance status at screening is 0 or 1. <00ooo899>4. Participants must have a life expectancy of 24 months or more as determined by the principal investigator at the time of screening. Before randomization, prostate cancer must be histologically confirmed. 6. Participants must have a biochemically recurrent disease following radical treatment of the prostate with RP (alone or with postoperative radiation to the prostatic bed / pelvic lymph nodes), XRT (prostate alone or prostate with seminal vesicles and / or pelvic lymph nodes), and / or brachytherapy prior to randomization. Biochemical recurrence is defined as: lowest point PSA +2 ng / mL after XRT (if the participant received radiotherapy to the intact prostate), PSA >0.2 ng / mL, and elevation after RP (regardless of whether postoperative RT was performed). 7. Participants must have an OMPC with 5 or fewer PSMA-positive metastatic lesions at the time of screening PSMA PET / CT scan (using either gallium (68Ga) gozetotide or pifulforastat (18F)) as visually assessed by BIRC based on the methodology proposed in Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) (Eiber et al 2018); see Section 8.1 and the Imaging Manual for further details. Metastatic lesions may include local / pelvic lymph nodes (N1), distant lymph nodes (M1a), bone (M1b), lungs, and other viscera (M1c) excluding the liver and brain as classified using AJCC 8. When counting the number of oligometastatic lesions, each lesion is counted as a separate metastasis regardless of its anatomical location (e.g., one intrapelvic lymph node and one extrapelvic lymph node are counted as two metastatic lesions). 8. At the time of screening, at least one PSMA-positive lesion should be metastatic (M1) according to the AJCC 8 classification. PSMA PET information should be used for the AJCC M staging classification. 9. Participants must be negative on conventional imaging tests for M1 disease at the time of screening. Note: ·For ineligible participants, CI-positive M1 lesions should be evident on CI scans, i.e., potentially not due to findings that could represent something other than the tumor (e.g., degenerative or post-traumatic changes in bone lesions or Paget's disease). ·Prior knowledge of PSMA PET positivity should not influence the radiologist (reader) in the determination of CI positivity. Two different readers are included (one reader for the PSMA PET scan and one reader for CI), and the reader is blinded to the PSMA PET scan results during the reading of the CI scan. The reader should not change the evaluation of the CI scan after reading the PSMA PET scan (e.g., changing a lesion previously identified as equivocal on CI to definite). Similarly, biopsy positivity should not influence the reader in the evaluation of CI positivity. Further details of the reading paradigm are described in the imaging charter. ·MRI for radiation treatment planning may show M1 disease, but this does not exclude participants from the trial if the lesions are considered negative on baseline CT or bone scan per protocol. ·Participants with pelvic disease (N1) identified on conventional imaging are eligible if the local spread is below the inferior mesenteric bifurcation (by AJCC 8 definition of local disease). ·Remote lymph node disease (M1a) visible on CI and with a short axis less than 10 mm is not excluded regardless of PSMA PET positivity. 10. All metastatic lesions detected at screening should be suitable for SBRT 11. If a participant has already received SBRT for OMPC, progressive disease must be demonstrated (e.g., new PSMA PET lesions) prior to randomization. Lesions that have already been treated must be stable on baseline imaging scans and are not counted towards the 1 - 5 lesions required in this trial. If a previously treated lesion was evident for M1 on bone scan or CT prior to previous SBRT, the participant is ineligible. 12. Confirmation of controlled primary tumor at screening: If local recurrence is suspected, MRI is required to rule out local recurrence. Patients with MRI or PET-positive local lesions require biopsy to rule out local progression. These participants with local recurrence (either with local disease confirmed by biopsy or with MRI or PET-positive local lesions without biopsy) may be eligible for this study after salvage therapy for the local disease. Note: Participants who have already received pelvic RT (pelvic salvage RT) at the time of local recurrence after RP are permitted to participate in this study. 13. PSADT is less than 10 months at the time of screening [PSADT is calculated using a linear regression model of the natural logarithm of PSA and time (Pound et al 1999)]. 14. Non-gonadectomy testosterone levels are greater than 100 ng / dL at the time of screening. 15. Participants who are healthy and at low risk of acquired immunodeficiency syndrome (AIDS) related outcomes, and who are infected with human immunodeficiency virus (HIV) at the time of screening and during this study, may participate in this study. 16. Participants must have appropriate organ function, including the following clinical laboratory values, at the time of their screening visit: Bone marrow reserve: ANC ≥ 1.5 × 10⁹ / L ·Platelet≧100×109 / L • Hemoglobin ≥ 9 g / dL liver • Total bilirubin (TBIL) ≤ 2 × upper limit of normal (ULN) at the institution. For participants with known Gilbert's syndrome, ≤ 3 × ULN is acceptable. • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3.0 × ULN. Albumin ≥ 2.5 g / dL kidney • eGFR of 60 mL / min / 1.73m2 or higher using the Diet Modification Renal Disease (MDRD) formula.

[0143] Exclusion criteria: 1. Participants who have a new OMPC at the time of screening. 2. Presence of uncontrolled bladder outflow obstruction or urinary incontinence at the time of screening. Note: Participants with bladder outflow obstruction or urinary incontinence that is managed and controlled with the best available standard treatment (including pads and drainage) are permitted. 3. Prior treatment as follows: a. ADT including bilateral orchiectomy Participants who received XRT or RP before relapse and completed adjuvant ADT (or ADT + androgen receptor pathway inhibitor (ARPI)) are eligible to participate if their final dose of ADT (or ADT + ARPI) was 12 months prior to randomization. Patients who discontinue ADT due to disease progression are not permitted (i.e., CRPC participants). b. Other hormone therapies, for example • Use of estrogen, 5-α-reductase inhibitors (finasteride, dutasteride), and other steroid production inhibitors (aminoglutetoamides) • First-generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone). • Second-generation antiandrogens (e.g., enzalutamide, apalutamide, and darolutamide) • CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone, ketoconazole). Short-term ketoconazole treatment (less than 28 days) is acceptable. c. Radiopharmaceuticals (e.g., strontium-89, PSMA-targeted radioligand therapy) d. Immunotherapy (e.g., Ciproisel-T) e. Chemotherapy administered in an adjuvant / neoadjuvant setting completed more than 12 months before randomization. f. Any other investigational or systemic drug for metastatic disease 4. Herbal and non-herbal products (i.e., saw palmetto, pomegranate juice) that may lower PSA levels within 28 days prior to randomization. 5. Use of other investigational drugs within 28 days prior to the randomization date. 6. Radiotherapy, external beam radiotherapy (EBRT), and brachytherapy performed within 28 days prior to the randomization date. 7. Systemic (oral / intramuscular (IM)) corticosteroids administered within 28 days prior to randomization. Note: Short-term use of corticosteroids (up to 4 weeks) during this study is permitted if clinically necessary. 8. Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, hormone therapy (see ADT initiation guidance in Section 6.8.2), PARP inhibitors, biological therapy, or investigational drug therapy. 9. Known hypersensitivity to the test treatment or its excipients, or to drugs of a similar chemical classification. 10. Blood transfusion during screening procedures for the sole purpose of qualifying participants for study enrollment. 11. Diagnosis of other malignancies at the time of screening that are expected to alter life expectancy or interfere with disease assessment. However, participants with a history of well-treated malignancies and who have been disease-free for more than 3 years are just as eligible as participants with well-treated non-melanoma skin cancer and superficial bladder cancer. 12. Any concurrent, serious medical condition (as determined by the Principal Investigator) that would, in the opinion of the Principal Investigator, impair participation in or cooperation with the study, including but not limited to, uncontrolled infection, known active hepatitis B or C, or other serious comorbidities. Participants with a recorded active COVID-19 infection (of any disease severity grade) at the time of informed consent may be included only if they have fully recovered (in accordance with local guidance). 13. A history or current diagnosis of ECG abnormalities that pose a significant safety risk to participants in this study, such as those listed below: • Clinically significant cardiac arrhythmias, such as sustained ventricular tachycardia, and clinically significant second- or third-degree AV block without a pacemaker. • A history of familial long QT syndrome, or a known family history of torsades de pointe. • Resting heart rate less than 60 bpm (physical examination or 12-lead ECG) 14. History of somatic or mental diseases / conditions that may interfere with the objectives and evaluation of this trial 15. Any condition that interferes with arm elevation 16. Sexually active men who do not wish to use a condom during sexual intercourse

[0144] Further information Trial ID number: CAAA617D12302, 2022 - 502956 - 29 - 00 [Other identifier: EU CTIS registration]

[0145] Keywords: Lutetium (177Lu) bixibotide tetraxetan Oligometastatic prostate cancer (OMPC) Metastasis - free survival (MFS) Gallium (68Ga) dotatoc Piflufolastat (18F) Prostate - specific membrane antigen (PSMA) Delay of orchiectomy

[0146] Additional related MeSH terms: Oligometastatic prostate cancer (OMPC)

[0147] Example 2: Main clinical trial Title International, prospective, non - blinded, multi - center, randomized Phase III trial comparing lutetium ( 177 Lu) bixibotide tetraxetan (AAA617) with observation to delay orchiectomy and / or disease recurrence in adult male patients with prostate - specific membrane antigen (PSMA) - positive oligometastatic prostate cancer (OMPC);

[0148] Briefly stated: PSMA - DC: A non - blinded trial comparing lutetium ( 177 Lu) bixibotide tetraxetan ( 177 Lu]Lu - PSMA - 617 or 177 Lu - PSMA - 617, also known as AAA617 hereafter) with observation in PSMA - positive OMPC.

[0149] The rationale for the exam The purpose of this study is to evaluate the efficacy and safety of AAA617 in participants with oligometastatic prostate cancer (OMPC) that has progressed after curative therapy for the primary tumor. The data obtained from this study will provide evidence for the treatment of AAA617 in the case of delayed gonadectomy, which is a high unmet need in this population.

[0150] Benefit / Risk Assessment Various retrospective and prospective trials, including randomized controlled trials, provide evidence of significant clinical benefit in mCRPC patients treated with AAA617 (see AAA617 Investigator's Materials). Such benefit is expected to extend to the OMPC population.

[0151] Dosimetry studies have confirmed that AAA617 targets PSMA-expressing prostate cancer cells and some normal tissues that express PSMA (Delker et al 2016). From the VISION sub-study, the organ that received the highest average absorbed dose was the lacrimal gland at 2.1 (standard deviation = 0.47) gray (Gy) / GBq, followed by the salivary gland at 0.63 (standard deviation = 0.36) Gy / GBq. Over the entire 6 cycles of 44.4 GBq, the estimated absorbed doses calculated for the lacrimal and salivary glands were 92 (standard deviation = 21) Gy and 28 (standard deviation = 16) Gy, respectively. The red bone marrow was irradiated with an absorbed dose of 0.035 (standard deviation = 0.020) Gy / GBq, and the estimated absorbed dose calculated for the entire 6 cycles was 1.5 (standard deviation = 0.90) Gy. On average, the kidneys are irradiated with 0.43 (standard deviation = 0.16) Gy / GBq, resulting in an estimated absorbed dose to the kidneys of 19 (standard deviation = 7.3) Gy for a total of 6 cycles of 44.4 GBq administration.

[0152] AAA617 (Lutetium ( 177The safety profile of AAA617 (Lu) bipivotide tetraxetan includes fatigue, dry mouth, myelosuppression (including anemia, thrombocytopenia, lymphopenia, and leukopenia), nausea, vomiting, and renal side effects. All of these AEs may be attributable to the mechanism of action of AAA617 or may be associated with active anticancer treatment. Symptomatic hematological toxicity may occur but is uncommon. Potential risks include radiotoxicity (e.g., increased risk of carcinogenicity, risk of infertility), late-stage nephrotoxicity, and the effects of bleeding events. The safety of AAA617 administered with SOCs including ADT and ARPI has been well characterized in randomized controlled trials using the same dosing regimen as proposed in this study (Sartor et al 2021).

[0153] Overall, the safety data indicates an acceptable and manageable safety profile for AAA617.

[0154] AAA617 contributes to the patient's overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer.

[0155] Radiation exposure to participants, healthcare workers, and their families should be minimized during and after treatment with AAA617, in accordance with the facility's good radiation safety practices, patient management procedures, and instructions given to participants regarding follow-up radiation protection at home.

[0156] The safety profile of SBRT has been well-characterized in various studies when administered as MDT in OMPC, and there is no difference when administered as a single fraction or fraction regimen. Grade 3 or higher acute or any late toxicity is extremely rare (Kalinauskaite et al 2020). The SBRT dose regimen has been standardized for this study (see SBRT manual). To avoid any potential duplicate toxicity, AAA617 will be administered at least one week after completion of the last SBRT fraction.

[0157] Supportive care can minimize some of the risks and should be optimized throughout the trial. Other measures for managing PC (not specifically excluded as part of the trial) should follow routine clinical practice and be used at the discretion of the principal investigator. These may include, but are not limited to, optimal pain control, hydration, and blood transfusions.

[0158] Appropriate eligibility criteria for AAA617 for toxicity management, as well as rules for dose changes and discontinuation, are included in this protocol. Risks to participants in this study can be minimized through adherence to eligibility criteria and study procedures, as well as close clinical monitoring. This study incorporates routine safety monitoring and regularly scheduled safety assessments to identify and report any potential safety issues. In addition, to monitor long-term toxicity, the target AE will be monitored in post-marketing studies for all participants who receive AAA617 during this study until the first occurrence of death, loss of follow-up, or up to 10 years.

[0159] Locametz (Gallium for injection) 68 The gozetotide preparation kit (Ga) has shown a good safety profile, with approximately 1% of patients experiencing mild reactions such as fatigue, nausea, constipation, and vomiting. Overall, gallium ( 68 Ga) The risk / benefit ratio of gozetotide contrast agent is expected to be favorable.

[0160] Pylarify® (pifluforastat F18 injection, for intravenous use) exhibits a favorable safety profile with mild adverse event profiles including headache (2%), dysgeusia (2%), and fatigue (1%). Further details can be found on the Pylarify® US label. Overall, the risk / benefit ratio of Pylarify® contrast agents is expected to be favorable.

[0161] Objective, endpoint, and estimate

[0162] [Table 3]

[0163] [Table 4]

[0164] [Table 5]

[0165] Main estimates The estimation is an accurate description of the treatment effect and reflects strategies to address events that may occur during the trial that could affect the interpretation of the trial results (e.g., early discontinuation of the treatment).

[0166] The primary clinical question of the objective: What is the MFS-based treatment effect of AAA617 compared to observations with OMPC treatment in adult male participants with SBRT-treated lesions, regardless of discontinuation of the study treatment, administration of additional SBRT, or initiation of new anti-cancer therapy?

[0167] The main estimations are explained by the following attributes: 1. Group: Participants with OMPC as defined by the inclusion / exclusion criteria. 2. Variables / Endpoints: MFS is defined as the time from randomization to the first evidence of bone or soft tissue distant metastasis detectable by radiographic imaging (i.e., CT / MRI and bone scan) as assessed by BIRC using RECIST 1.1, or death for any other reason (whichever occurs first). 3. Target treatment: The investigational drug is AAA617. The control arm is observational only. SBRT will be administered in both arms after randomization and before the start of the study treatment / observation. 4. Intermediate events: • AAA617 interrupted for some reason • Additional SBRT administered before the MFS event assessed by conventional imaging (after the last fraction of the initially planned SBRT) • Initiation of new anti-cancer therapies such as ADT before an MFS event is assessed by conventional imaging tests. 5. The aggregated scale is the hazard ratio (HR) for MFS between two treatment arms, with a 95% confidence interval, estimated using a Cox proportional hazards model stratified by a randomization stratification factor. A primary comparison is performed using a log-rank test stratified by a randomization stratification factor.

[0168] Secondary estimation A key and secondary clinical question (hypothesis) of the objective: What is the TTHT-based treatment effect of AAA617 compared to observations with OMPC treatment in adult participants with SBRT-treated lesions who did not crossover, regardless of discontinuation of AAA617, administration of additional SBRT, or initiation of new anti-cancer therapy?

[0169] The basis for an important secondary estimation is to capture both the effect of the investigational drug and the effect of additional drugs such as SBRT, while taking into account the effects of crossover.

[0170] Important secondary estimations are explained by the following attributes: 1. Group: Participants with OMPC as defined by the inclusion / exclusion criteria. 2. Variable / Endpoint: TTHT is defined as the time from randomization to the initiation of gonadal therapy (ADT). 3. Target treatment: The investigational drug is AAA617. The control arm is observation. SBRT will be administered in both arms after randomization and before the start of the study treatment / observation. 4. Intermediate events: • AAA617 interrupted for some reason • Additional SBRT administered before the start of ADT (after the last fraction of the initially planned SBRT) • Initiation of new anti-cancer therapy before starting ADT • Crossover to AAA617 regarding participants in the observation arm

[0171] The aggregated measure is the TTHT HR between two treatment arms with 95% confidence intervals in the target population where no crossover occurred, estimated using a Cox proportional hazards model stratified by a randomization stratification factor. Primary comparisons are performed using a log-rank test stratified by a randomization stratification factor.

[0172] Test design Overall design This international, prospective, open-label, multicenter, randomized Phase III trial will enroll adult male participants with OMPC. Approximately 450 eligible participants will be randomized in a 2:1 ratio to one of the following two treatment arms: • Investigational drug arm: AAA617 • Control arm: Observation

[0173] All participants will be treated with SBRT for all metastatic lesions before the start of AAA617 or observation.

[0174] The primary objective of this study is to evaluate MFS by conventional imaging in adult participants with OMPC as defined by PSMA PET imaging, after administering AAA617 compared to observation after SBRT.

[0175] screening Participants must sign an Informed Consent Form (ICF) before any trial-specific screening assessment. All screening procedures must be completed within 28 days prior to randomization. Participants must be enrolled in an Interactive Response Technology (IRT) system for screening, and all procedures must be performed with priority given to laboratory and imaging assessments to allow sufficient time for results to be obtained.

[0176] During screening, all participants will be evaluated for eligibility, along with the mandatory gallium (CI scan). 68 Ga) Gozetotide or Pifluforastat ( 18 F) Perform baseline disease assessment including PET / CT scans (approved and commercially available locally). Randomize all participants who meet all eligibility criteria.

[0177] After completing all necessary screening procedures and verifying participant eligibility, participants will be randomized via the IRT system.

[0178] Randomization Randomization should be performed within a 28-day screening period after all eligibility criteria have been met. Participants will be randomized in a 2:1 ratio to receive either AAA617 or observation only.

[0179] Randomization is stratified according to the following three factors: 1. PSADT: Over 6 months vs. 6 months or less 2. Gallium ( 68 Ga) Gozetotide or Pifluforastat ( 18 F) Number of PSMA-positive lesions by PET / CT (based on central readout): 1-3 vs. 4-5 3. Location of metastatic disease: distant lymph nodes (M1a) vs. bone (M1b) vs. other distant tissues including internal organs according to the AJCC 8 classification (M1c).

[0180] Treatment / Observation Period All participants will be treated with SBRT for all metastatic lesions prior to the initiation of AAA617 or observation. The first fraction of SBRT must be administered within 14 days of randomization. The SBRT procedure has been standardized for this study to avoid site-to-site variability (see SBRT manual). After completion of SBRT, End of Treatment 1 (EOT1) will be performed on the day of the final SBRT fraction.

[0181] For participants randomized to a clinical trial arm, treatment with AAA617 must be initiated 7–21 days after the final fraction of SBRT. C1D1 (i.e., the day of the first dose of AAA617) may be delayed by up to an additional 3 days due to unforeseen scheduling delays. AAA617 will be administered at a dose of 7.4 GBq (±10%) once every 6 weeks (±1 week) for a maximum of 4 cycles.

[0182] Participants randomized to the control arm will make a C1D1 visit 7–21 days after receiving the final fraction of SBRT.

[0183] All participants in both arms will undergo a site visit on the first day of each cycle (C#W1). To ensure participant safety, a mandatory safety phone call will be made in the third week of each cycle (C#W3), and optional site safety visits may also be conducted at the same time (C#W3) at the discretion of the principal investigator. Unscheduled safety visits will be permitted within the treatment period if deemed necessary at the discretion of the principal investigator.

[0184] For participants in the clinical trial arm, EOT2 will be administered 42 days (+7 days) after the final dose of AAA617. For participants in the control arm, EOT2 will be administered at the 24-week visit.

[0185] Efficacy will be evaluated every 16 weeks from randomization. At each efficacy evaluation, all participants will be followed up for efficacy using CT (or MRI if CT is not permitted) and whole-body bone scans.

[0186] The primary endpoint of MFS will be evaluated by BIRC using conventional X-ray images (i.e., CT / MRI and bone scans) provided by the treating physician.

[0187] Crossover period If eligible, participants randomized to the control arm who have experienced a distant metastatic radiographic progression (MFS event) in CI, confirmed by BIRC and initiated ADT, may crossover to AAA617 at the discretion of the investigator. After up to four doses of AAA617, this participant will receive EOT3. During the crossover, AAA617 will be administered at the same dose / schedule as the participant who was initially randomized to receive AAA617 as described above.

[0188] Post-treatment follow-up (safety, effectiveness) 42-day safety follow-up visit After discontinuation of AAA617, all participants (including crossover participants) will be followed up for safety, and a safety follow-up visit will be scheduled for 42 days (+7 days) after the final dose of AAA617. Note: The safety follow-up visit will be at EOT2 (or EOT3 in the case of crossovers).

[0189] Participants in the control arm will also be followed up for safety, with a safety follow-up visit scheduled at week 24.

[0190] Long-term safety follow-up study After the safety follow-up visit (EOT2 / EOT3 visit), participants randomized to the clinical trial / crossover arm will be followed up every 32 weeks for safety assessment until the end of the study.

[0191] Participants who have received AAA617 and are still being followed up on this study when the sponsor terminates the trial will be required to participate in a separate long-term safety study (CAAA617A12402) for up to 10 years.

[0192] Long-term safety follow-up is not required for control arm participants who did not cross over. After EOT2, safety monitoring of control arm participants will be at the discretion of the principal investigator based on local clinical practice.

[0193] Effectiveness follow-up study Participants who have not recorded the appearance of distant metastases on conventional imaging confirmed by BIRC after EOT2 in both the investigational arm and the control arm, or after discontinuation of SBRT or AAA617, will continue to be followed up every 16 weeks from randomization for efficacy assessment until BIRC confirms the appearance of distant metastases on conventional imaging or other criteria for discontinuation are met, or until the primary analysis is initiated if the total number of MFS events defined in the protocol occurs (whichever occurs first). In addition, participants will be followed up in the trial for initiation of ADT until the number of TTHT events defined in the protocol occurs.

[0194] Survival tracking survey Following the discontinuation of the trial treatment and the completion of any applicable post-treatment follow-up periods, the status of participants will be collected every 90 days (by telephone) as part of the survival follow-up. All efforts should be made to ensure adherence to the survivor follow-up schedule and to guarantee the collection of participant survival data. Survival follow-up will be continued until the end of the trial and into the long-term safety rollover trial.

[0195] Scientific rationale for the experimental design AAA617 is effective in PSMA-positive metastatic prostate cancer (Sartor et al 2021). Several studies have confirmed the presence of PSMA PET-positive lesions in biochemically recurrent disease situations (McCarthy et al 2019, Artigas et al 2021). Therefore, targeting PSMA-expressing lesions with AAA617 in early-stage prostate cancer to delay progression or other systemic therapies is a sound approach.

[0196] To evaluate the efficacy of AAA617 in this population, approximately 450 participants with PSMA-positive disease on baseline PSMA PET / CT and CI-negative for M1 will be randomized to this study. Randomization will be performed in a 2:1 ratio between the AAA617 arm and the observation-only arm.

[0197] Randomization will be stratified according to the following factors: 1. PSADT: Over 6 months vs. 6 months or less Short PSADT is consistently associated with a shorter time to metastasis and death in men with BCR after RP, and is therefore expected to be prognostic (Pound et al 1999). 2. Number of PSMA-positive lesions by PSMA PET / CT (based on on-site readings): 1-3 vs. 4-5 The number of metastatic sites has been associated with survival in several studies (Rao et al 2019). 3. Location of metastatic disease: distant lymph nodes (M1a) vs. bone (M1b) vs. other distant tissues including internal organs according to the AJCC 8 classification (M1c).

[0198] The location of metastatic disease is a prognostic factor in prostate cancer. A Surveillance, Epidemiology, and End Results (SEER)-Medicare analysis of 3,857 patients revealed that the median OS was 43 months for lymph node-only metastasis, 24 months for bone-only metastasis, 16 months for visceral-only metastasis, and 14 months for bone-visceral metastasis (Gandaglia et al 2015).

[0199] Stratification by PSADT, along with the number and location of metastases, supports a pre-specified subgroup analysis framework to avoid imbalances between arms of factors known to influence primary and major secondary trial outcomes.

[0200] Participants in this study will be selected using PSMA PET scans. While conventional imaging has been used in the past to define OMPC, many participants may present with metastatic disease much earlier than is evident in CI. A meta-analysis confirmed that after PSMA PET, more patients receive targeted radiotherapy and surgical resection, but the proportion receiving systemic treatment is reduced by more than 50%, mainly due to fewer patients receiving androgen deprivation therapy (ADT), followed by a smaller number of patients receiving observation (Mueller et al 2019).

[0201] While PSMA PET-based imaging is useful for participant selection, progression of CI (continuous cytosis) is still considered the initiation of metastatic hormone-sensitive prostate cancer (mHSPC) classification. Therefore, CI is used to establish the primary endpoint of MFS. Furthermore, the prognostic significance of PSMA PET-based imaging in efficacy evaluation is still not fully understood.

[0202] MFS has been shown to be a strong surrogate endpoint for OS in localized prostate cancer and BCR situations (Schweizer et al 2013, Xie et al 2017). Considering the expected long-term OS in this population, selecting MFS as the endpoint may substantially shorten the study duration compared to the OS endpoint without compromising the interpretability of clinical benefit. MFS is a validated trial endpoint approved by various regulatory authorities for evaluating clinical efficacy in similar but gonadectomy-resistant situations. MFS is also the primary endpoint in the ongoing Phase III ATLAS enrollment trial with apalutamide in patients with high-risk localized disease (NCT02531516), similar to the population of this study. In addition, this population has a large amount of MFS data that can be compared to establish the risk / benefit of AAA617 treatment in this population (Paller et al 2013).

[0203] Rationale for the dosage of AAA617 In this study, AAA617 was administered at a dose of 7.4 GBq (±10%) once every 6 weeks (±1 week) for a maximum of 4 cycles. AAA617 at a dose of 7.4 GBq (±10%) once every 6 weeks for a maximum of 6 cycles is a well-established regimen approved for use in metastatic prostate cancer based on the Phase III VISION trial (Sartor et al 2021). In the VISION trial, the actual number of cycles administered was 4.5 (mean) and 5 (median). Overall, the treatment regimen was safe, tolerable, and effective.

[0204] In a typical metastatic PC trial, AAA617 treatment is administered in six doses every six weeks, including the hormone sensitivity status being evaluated in the ongoing PSMAddition (NCT04720157) trial. Lutetium ( 177 Clinical experience with bipivotide tetraxetan is documented in over 60 publications summarizing safety and / or efficacy information from more than 1900 participants (see AA617 Principal Investigator's Guide, Version 7.0). Throughout these series, doses ranged from 1.1 to 12.0 GBq, typically following a schedule of once every 4 to 12 weeks over 1 to 9 cycles. Most publications use a 4-cycle regimen of 6 GBq. It is unclear whether fewer than four doses are effective, particularly in patients with metastatic lesions detected by PSMA PET, as in this study. While a 6-dose regimen is currently approved in the US for metastatic disease, based on the VISION trial, the small disease population treated in this proposed trial justifies lower exposure.

[0205] In addition, dosimetry studies supported the administration of a 7.4 GBq (±10%) dose of AAA617 every six weeks for up to six cycles. Although the same dose was tested every six weeks, radiation exposure from the VISION side study (N=29), which was higher than the four doses proposed in this study, was considered acceptable for this population, particularly with respect to organs considered to be at risk of radiation due to exposure levels (e.g., salivary glands, lacrimal glands, kidneys, and bone marrow), and was consistent with the range published in the literature (AAA617 Investigator's Materials). For a total of six cycles of cumulative administration of 44.4 GBq, the estimated absorbed doses calculated for the lacrimal glands, salivary glands, red spinal cord, and kidneys were 92±21 Gy, 28±16 Gy, 1.5±0.90 Gy, and 19±7.3 Gy, respectively. One of the inclusion criteria for this study is an estimated glomerular filtration rate (eGFR) of ≥ 60 mL / min / 1.73m2; therefore, only patients with normal or mild renal impairment are included in this study. From the VISION side study, the estimated absorbed renal dose after 4 cycles in patients with mild renal impairment was 16.4 Gy (range: 11.2–19.8), which is well below the safety threshold, thus supporting a dose of 7.4 GBq (±10%) once every 6 weeks (±1 week) over a maximum of 4 cycles.

[0206] Clinical findings from the VISION trial also confirmed that AEs associated with these organs are generally of low to moderate severity, tolerable, reversible, and do not translate to clinical significance.

[0207] The potential for increased toxicity from AAA617 in low-volume versus high-volume disease due to the "tumor sink" effect has been debated in the literature for some time. However, recent data have shown that the tumor sink effect in similar populations (mHSPC) is less concerning than previously anticipated. In a study of intrathermal dosimetry of AAA617 in patients with low-volume hormone-sensitive metastatic prostate cancer, correlated with treatment outcomes, none of the organs at risk reached the threshold dose, but tumor absorbed doses were high, including minimal metastases detected by PET imaging (Gafita et al 2022, Peters et al 2022). Overall, patients with no detectable metastases or very low-volume disease are less likely to be at higher risk due to non-targeted toxicity compared to patients with high-volume disease.

[0208] In this trial, all participants will receive SBRT before initiating AAA617. Given the conformal nature of the SBRT treatment plan and the fact that this patient population has very small volume lesions, the SBRT plan is expected to be well below partial volume tolerance in most cases, and as described above, the whole-organ dose from four cycles of AAA617 is expected to be below whole-organ tolerance. Data from the VISION trial are promising regarding the co-administration of radiotherapy with six doses of AAA617, and data from case reports also indicate that co-administration of external beam radiotherapy with AAA617 is tolerable (Wei et al 2017). In addition, an ongoing clinical trial (NCT05079698) is testing the co-administration of AAA617 with SBRT.

[0209] For these reasons, AAA617 administered at a dose of 7.4 GBq (±10%) in a regimen of once every six weeks over a maximum of four doses is considered appropriate in this study. Overall, the clinical safety review and detailed analysis of radiation exposure support the intended dose and frequency of AAA617 administration in this clinical trial.

[0210] Rationale for selecting SBRT treatment In both arms, participants will receive SBRT for all metastatic lesions before initiating AAA617 (investigation arm) or enrolling in observation (control arm). While there are no specific treatment guidelines for patients with OMPC as defined by PSMA PET who are negative for M1 disease on CI, various guidelines suggest that observation following SBRT is appropriate for OMPC patients who strongly desire to delay the initiation of ADT. For OMPC patients (as defined by CI), metastasis-targeted therapy (MDT) with observation or ADT following SBRT is the standard treatment suggested by the NCCN (NCCN Guidelines for Prostate Cancer V.1.2023) when the intention is to slow progression. Current German guidelines state that MDT may be used to delay ADT and tumor progression (Rogowski et al 2022). Similarly, the EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines for prostate cancer also suggest careful observation in recurrent oligometastatic disease where delaying the initiation of ADT is strongly desired (Mottet et al 2022). The recent ESTRO-ACROP Delphi consensus supports metastasis-directed radiotherapy for patients diagnosed with up to five lymph node, bone, or visceral metastases in all disease situations (Zilli et al 2022). In addition, OMPC patients who have progressed on previous SBRT may still be eligible for further SBRT if medically necessary, and there is no guarantee of an urgent need for systemic therapy. Further SBRT has been performed in other OMPC trials after radiographic progression, and a second SBRT course is an elective in approximately 50% of patients with progression (Kalinauskaite et al 2020), demonstrating the benefit of repeated SBRT (Decaestecker et al 2014, Kwon et al 2022).

[0211] Rationale for selecting a comparator / placebo drug Regarding the control arm, observation is the appropriate standard of care in this population.

[0212] Test group The study population consisted of approximately 450 adult male participants with recurrent omnipotencephaly (OMPC) defined as having 1 to 5 PSMA-positive metastatic lesions detected solely by PSMA PET and being negative for M1 lesions on conventional imaging tests.

[0213] Inclusion criteria: Participants eligible for inclusion in this study must meet all of the following criteria: 1. Signed informed consent must be obtained prior to participation in this examination. 2. Participants must be adults aged 18 or older at the time of informed consent. 3. The ECOG performance status at the time of screening is 0 or 1. 4. Participants must have a life expectancy of 24 months or more, as determined by the principal investigator at the time of screening. 5. Prostate cancer has been histologically confirmed before randomization. 6. Participants must have a biochemically recurrent disease following radical treatment of the prostate with RP (alone or with postoperative radiation to the prostatic bed / pelvic lymph nodes), XRT (prostate alone or prostate with seminal vesicles and / or pelvic lymph nodes), and / or brachytherapy prior to randomization. Biochemical recurrence is defined as: lowest point PSA +2 ng / mL after XRT (if the participant received radiotherapy to the intact prostate), PSA >0.2 ng / mL, and elevation after RP (regardless of whether postoperative RT was performed). 7. Participants will be visually evaluated by BIRC based on the methodology proposed in Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) (Eiber et al 2018) and will undergo screening PSMA PET / CT scans (gallium 68 Ga) Gozetotide or Pifluforastat ( 18When using either F), the patient must have an OMPC with five or fewer PSMA-positive metastatic lesions; see the imaging manual for further details. Metastatic lesions may include local / pelvic lymph nodes (N1), distant lymph nodes (M1a), bone (M1b), lungs, and other viscera (M1c) excluding the liver and brain, as classified using AJCC 8. When counting the number of oligometastatic lesions, each lesion is counted as a separate metastasis regardless of its anatomical location (for example, one intrapelvic lymph node and one extrapelvic lymph node are counted as two metastatic lesions). 8. At the time of screening, at least one PSMA-positive lesion should be metastatic (M1) according to the AJCC 8 classification. PSMA PET information should be used for the AJCC M staging classification. 9. Participants must be negative on conventional imaging tests for M1 disease at the time of screening. Note: Regarding ineligible participants, CI-positive M1 lesions should be evident on CI scans, i.e., not resulting from findings that potentially indicate something other than a tumor (e.g., degeneration or post-traumatic changes in bone lesions or Paget's disease). Prior knowledge of PSMA PET positivity should not influence the radiologist's (reader's) determination of CI positivity. Two different readers are included (one for PSMA PET scans and one for CI scans), and the readers are blinded to the PSMA PET scan results while reading the CI scan. Readers should not change their evaluation of the CI scan after reading the PSMA PET scan (e.g., changing a lesion previously identified as unclear in the CI to clear). Similarly, biopsy positivity should not influence the reader's evaluation of CI positivity. Further details of the reading paradigm are described in the imaging charter. • MRI for radiotherapy planning may show M1 disease, but this does not mean that participants should be excluded from this study if the lesion is considered negative on each baseline CT or bone scan. Participants with pelvic disorders (N1) as detected by conventional imaging tests are permitted if the local extent is below the common bowel bifurcation (according to the AJCC 8 definition of local disorders). Distant lymph node disease (M1a) that is visible in each CI and has a short axis of less than 10 mm is not excluded regardless of whether it is PSMA PET positive. 10. All metastatic lesions detected during screening should be suitable for SBRT. 11. If a participant has already received SBRT for OMPC, progressive disease must be demonstrated before randomization (e.g., a new PSMA PET lesion). Previously treated lesions must be stable on baseline imaging scans and will not be counted towards the 1–5 lesions required for this study. Participants will not be eligible if previously treated lesions were evident in relation to M1 on bone scan or CT prior to the previous SBRT. 12. Confirmation of controlled primary tumor at screening: If local recurrence is suspected, MRI is required to rule out local recurrence. Patients with MRI or PET-positive local lesions require biopsy to rule out local progression. These participants with local recurrence (either with local disease confirmed by biopsy or with MRI or PET-positive local lesions without biopsy) may be eligible for this study after salvage therapy for the local disease. Note: Participants who have already received pelvic RT (pelvic salvage RT) at the time of local recurrence after RP are permitted to participate in this study. 13. PSADT is less than 10 months at the time of screening [PSADT is calculated using a linear regression model of the natural logarithm of PSA and time (Pound et al 1999)]. 14. Non-gonadectomy testosterone levels are greater than 100 ng / dL at the time of screening. 15. Participants who are healthy and at low risk of acquired immunodeficiency syndrome (AIDS) related outcomes, and who are infected with human immunodeficiency virus (HIV) at the time of screening and during the study, may participate in this study. 16. Participants must have appropriate organ function, including the following clinical laboratory values, at the time of their screening visit: Bone marrow reserve: ANC ≥ 1.5 × 10 9 / L Platelets ≥ 100 × 10 9 / L • Hemoglobin ≥ 9 g / dL liver • Total bilirubin (TBIL) ≤ 2 × upper limit of normal (ULN) at the institution. For participants with known Gilbert's syndrome, ≤ 3 × ULN is acceptable. • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3.0 × ULN. Albumin ≥ 2.5 g / dL kidney • The eGFR using the Dietary Modification-Resistant Diet (MDRD) formula is 60 mL / min / 1.73m2 or higher.

[0214] Exclusion criteria: Participants who meet any of the following criteria are not eligible for inclusion in this study. 1. Participants who have a new OMPC at the time of screening. 2. Presence of uncontrolled bladder outflow obstruction or urinary incontinence at the time of screening. Note: Participants with bladder outflow obstruction or urinary incontinence that is managed and controlled with the best available standard treatment (including pads and drainage) are permitted. 3. Prior treatment as follows: a. ADT including bilateral orchiectomy Participants who received XRT or RP before relapse and completed adjuvant ADT (or ADT + androgen receptor pathway inhibitor (ARPI)) are eligible to participate if their final dose of ADT (or ADT + ARPI) was 12 months prior to randomization. Patients who discontinue ADT due to disease progression are not permitted (i.e., CRPC participants). b. Other hormone therapies, for example • Use of estrogen, 5-α-reductase inhibitors (finasteride, dutasteride), and other steroid production inhibitors (aminoglutetoamides) • First-generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone), • Second-generation antiandrogens (e.g., enzalutamide, apalutamide, and darolutamide), CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone, ketoconazole) and short-term ketoconazole treatment (less than 28 days) are acceptable. c. Radiopharmaceuticals (e.g., strontium-89, PSMA-targeted radioligand therapy) d. Immunotherapy (e.g., Ciproisel-T) e. Chemotherapy administered in an adjuvant / neoadjuvant setting completed more than 12 months before randomization. f. Any other investigational or systemic drug for metastatic disease 4. Herbal and non-herbal products (i.e., saw palmetto, pomegranate juice) that may lower PSA levels within 28 days prior to randomization. 5. Use of other investigational drugs within 28 days prior to the randomization date. 6. Radiotherapy, external beam radiotherapy (EBRT), and brachytherapy performed within 28 days prior to the randomization date. 7. Systemic (oral / intramuscular (IM)) corticosteroids administered within 28 days prior to randomization. Note: Short-term use of corticosteroids (up to 4 weeks) during this study is permitted if clinically necessary. 8. Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, hormone therapy, PARP inhibitors, biological therapy, or investigational drug therapy. 9. Known hypersensitivity to the test treatment or its excipients, or to drugs of a similar chemical classification. 10. Blood transfusion during screening procedures for the sole purpose of qualifying participants for study enrollment. 11. Diagnosis of other malignancies at the time of screening that are expected to alter life expectancy or interfere with disease assessment. However, participants with a history of well-treated malignancies and who have been disease-free for more than 3 years are just as eligible as participants with well-treated non-melanoma skin cancer and superficial bladder cancer. 12. Any concurrent, serious medical condition (as determined by the Principal Investigator) that would, in the opinion of the Principal Investigator, impair participation in or cooperation with the study, including but not limited to, uncontrolled infection, known active hepatitis B or C, or other serious comorbidities. Participants with a recorded active COVID-19 infection (of any disease severity grade) at the time of informed consent may be included only if they have fully recovered (in accordance with local guidance). 13. A history or current diagnosis of ECG abnormalities that pose a significant safety risk to participants in this study, such as those listed below: • Clinically significant cardiac arrhythmias, such as sustained ventricular tachycardia, and clinically significant second- or third-degree AV block without a pacemaker. • A history of familial long QT syndrome, or a known family history of torsades de pointe. • Resting heart rate less than 60 bpm (physical examination or 12-lead ECG) 14. History of somatic or psychiatric disorders / conditions that may interfere with the purpose and evaluation of this study. 15. Any condition that prevents raising the arm

[0215] Test treatment Participants randomized to either arm will receive SBRT for all metastatic lesions after randomization and before the commencement of the study treatment or observation. In this study, the term “study treatment” refers to the radioligand therapeutic compound AAA617 and the radioligand imaging compound gallium ( 68 Ga) Gozetotide and Pifluforastat ( 18 F) refers to both SBRT and other related fields.

[0216] The investigational drug is AAA617, as well as gallium (a radioligand imaging compound used as a PET / CT contrast agent during screening). 68 Ga) Gozetotide and Pifluforastat ( 18 F) In this trial, there was no comparator drug; participants randomized to the control arm (observational) received no treatment after the final fraction of SBRT was administered.

[0217] The test procedures are listed in the table below.

[0218] [Table 6]

[0219] gallium( 68 Ga) Administer gozetotide as a single intravenous (iv) dose of approximately 150 MBq (4 mCi). The administered dose should not be less than 111 MBq (3 mCi) or greater than 259 MBq (7 mCi).

[0220] gallium( 68 Baseline imaging evaluation using Ga) gozetotide, gallium ( 68 Ga) The preparation of the radiopharmaceutical gozetotide may be carried out using only the PSMA-11 kit provided by the sponsor, or ready-to-use injectable gallium provided by Central Radio Pharmacy. 68 Ga) This procedure must be carried out using only gozetotide radiopharmaceutical solution.

[0221] Pifluforastat ( 18 F) Radioligand imaging compounds, once approved, marketed, and supplied locally, can be used for baseline imaging assessment in each country. Pifluforastat ( 18 F) should be used in accordance with its accompanying documentation.

[0222] No other PSMA-targeted radiopharmaceuticals should be used for imaging tests, either during screening to assess PSMA positivity or during the treatment / efficacy follow-up period.

[0223] Trial participants randomized to the investigational drug will receive a dose of 7.4 GBq (200 mCi) ± 10% of AAA617, administered once every 6 weeks (1 cycle) over a planned 4 cycles.

[0224] SBRT will be administered in this study for local treatment of PC lesions after randomization and before initiation or observation of treatment with AAA617.

[0225] The clinical trial site is responsible for procuring SBRT. While the site should adhere to local practices and guidelines regarding SBRT prescription, administration, follow-up, and toxicity control, a separate SBRT manual with specific instructions must be provided to and followed by the site to ensure standardization of SBRT within the trial. The following general practices must be ensured: CT and / or PET / CT or PET / MRI simulations should be performed using a radiotherapy fixation device (e.g., Alpha Cradle). 4D CT should be used during simulations when the target is expected to move with respiration. • The CT component of PSMA PET CT is enrolled in the CT simulation in either a rigid or deformable registry, according to the site protocol and / or the clinical discretion of the principal investigator. Verification of accurate enrollment is reviewed by at least one radiation oncologist or radiologist / nuclear medicine physician. Macroscopic tumor volume (GTV) depiction is performed on continuous axial computed tomography images, and the planned target volume (PTV) is enlarged to the facility standard for SBRT (typically 5 mm). Making the PTV volume larger or smaller is permissible at the discretion of the radiologic oncologist performing the procedure. If 4D CT is performed, respiratory motion must be taken into account for the PTV. For lesions that are not clearly visible on simulation CT, including bone lesions, diagnostic MRI should also be performed and, if necessary, fused with simulation CT to aid in the visualization of the target volume and the identification of important structures (e.g., spinal cord). Visualizing the target with MRI will not disqualify participants from this study. Further details on visualization are described in the SBRT manual. • The clinical target volume (CTV) is generally equal to the gross tissue volume (GTV). However, given the uncertainty in localizing tumor edges on small lesions that are not clearly visible on simulated CT, the radiologist performing the procedure may add a CTV margin at their discretion. • The PTV is within 5 cm and the contours of adjacent normal structures, including but not limited to the heart, esophagus, aorta, spinal cord, kidneys, rectum, intestines, liver, and stomach, are formed to quantify the dose irradiated to these structures. • Create an SBRT treatment plan. Prescribe doses based on the minimum isodose lines covering the PTV. • Dose and fractions depend on the size and location of the lesion, as well as the constraints of surrounding normal tissue. Further details and requirements regarding dose schedules and fractionation are described in the SBRT manual. • Implement SBRT using image guidance within 3 weeks of the initial treatment plan. • Every effort will be made to consolidate all SBRT procedures into a three-week period, taking into consideration participant comfort and resource constraints at the treatment site. Patients with pelvic disease, whether or not involving the para-aortic region, may receive conventional standard fractionated radiotherapy to deliver an additional dose to the affected nodal basin for comprehensive treatment. However, at least one metastatic lesion must be suitable for SBRT. AAA617 is administered 7 to 21 days after the completion of the final fraction of SBRT. • If administered during the trial, the above guidance should also be followed for any additional SBRT administered.

[0226] Once all eligibility criteria have been confirmed, participants will be randomized in a 2:1 ratio to one of the following two treatment arms: Investigational drug arm: AAA617 Control arm: Observation (follow-up)

[0227] SBRT must be administered to all metastatic lesions before initiating treatment with AAA617. A response to SBRT (e.g., PSA reduction) is not a requirement for initiating AAA617 or observation. Participants who prematurely discontinue SBRT for all lesions or all planned fractions due to toxicity may, at the discretion of the investigator, initiate treatment with AAA617 (if enrolled in the investigational arm) or initiate observation (if enrolled in the control arm). The decision to discontinue SBRT in the event of toxicity is left to the investigator based on local practice.

[0228] Participants randomized to one of the arms will receive SBRT for all metastatic lesions. The duration of SBRT is expected to be completed within 3 weeks. The duration of treatment with AAA617 is expected to be approximately 24 weeks.

[0229] Treatments that go beyond disease progression Progression that occurs during SBRT treatment: In the event of distant metastasis as assessed by BIRC using conventional imaging tests (i.e., CT / MRI and bone scans), participants in both arms should discontinue further SBRT, receive any other therapy as per the discretion of the principal investigator and local regulations, and enter an applicable follow-up period.

[0230] Progression that occurs during AAA617 treatment: If distant metastases are detected by BIRC using conventional imaging (i.e., CT / MRI and bone scans), participants in the clinical arm should discontinue AAA617 treatment, receive any other therapy as deemed appropriate and in accordance with the investigator's discretion and local regulations, and enter an applicable follow-up period. Treatment with AAA617 may be continued for up to four cycles if the investigator determines that the participant is still benefiting from continued treatment with AAA617. Continuation of AAA617 is permitted if the participant meets all of the following criteria: • Evidence of clinical benefit as assessed by the principal investigator. • No rapid radiological or clinical progression. • Resistance to AAA617 • Important interventions to treat or prevent serious complications should not be jeopardized, nor should they prevent participants from receiving appropriate care. • The participants' general condition is stable. • No new antitumor therapy has been initiated.

[0231] After completing up to four cycles of AAA617, the next treatment line will be determined by the principal investigator.

[0232] Progression occurring during observation: If radiological progression (i.e., distant metastasis) occurs as assessed by BIRC and as an initiation of ADT, participants randomized to the control arm may, if eligible, crossover to receive AAA617 or receive any subsequent therapy at the discretion of the investigator.

[0233] Other ongoing events during SBRT or AAA617: Participants with locally advanced disease (e.g., new or progressive local pathological lymph node, N1), progression based solely on PSMA PET (if performed outside the protocol), or progression based solely on PSA will continue to complete SBRT in both arms until distant metastatic progression is observed in CI as assessed by BIRC, or until other criteria for discontinuation are met (until medically justifiable), and will complete four doses of AAA617 in the study arm.

[0234] In addition to radiographically confirmed distant metastatic progression (MFS events) confirmed by the initiation of BIRC and ADT, the following eligibility criteria for participants randomized to the control arm must be confirmed before crossover to AAA617: • Participants with central nervous system (CNS) metastases must be neurologically stable. • Participants must have an ECOG PS score of 0-2. Participants must adhere to contraception guidelines. • Before initiating a cycle with AAA617 in a crossover, participants must have adequate organ function, including the following clinical laboratory values: • Using the MDRD equation, eGFR ≥ 60 mL / min / 1.73 m² 2 • Total bilirubin (TBIL) ≤ 2 × ULN (upper limit of normal), ≤ 3 × ULN is acceptable for participants with known Gilbert's syndrome. • ALT or AST ≤ 3.0 × ULN, or ≤ 5.0 × ULN for participants with liver metastases. ANC ≥ 1.5 × 10 9 / L Platelets ≥ 100 × 10 9 / L • Hemoglobin ≥ 9 g / dL • Progressive events other than distant metastatic progression on radiographs confirmed by BIRC (i.e., MFS events by CI) (e.g., local progression, clinical progression, progression on PSMA PET only) are not eligible for crossover. • At least one PSMA PET-positive lesion should be present. • If the principal investigator determines that a participant has any serious or unstable medical condition during the trial that would prevent them from participating in the crossover phase, the participant should not cross over to treatment with AAA617. • Participants who initiated new antitumor treatment during the treatment period or the post-treatment follow-up period are not eligible to cross over.

[0235] After crossover, the addition of ARPI to ADT is permitted at the discretion of the principal investigator. Participants undergoing crossover are permitted to receive other antitumor therapies (e.g., concurrent cytotoxic chemotherapy, immunotherapy, PARP inhibitors, biological therapies, or investigational therapies).

[0236] Crossover participants will initially receive AAA617 at the same dose and schedule as participants randomized to the initial investigational arm. Following confirmation of participant eligibility by the principal investigator, crossover participants must be enrolled in the Intra-Research Team (IRT) and order AAA617 within 28 days of confirmation of distant metastatic progression by radiographic examination by BIRC. Participants should begin receiving treatment as soon as AAA617 is available on-site.

[0237] Participants in the control arm who choose to cross over to AAA617 therapy must follow the trial evaluation schedule according to their visit schedule. Efficacy evaluations (radiography, RECIST 1.1 evaluation, first SSE, first symptomatic progression), biomarkers, and testosterone levels should not be collected during the crossover period, and these participants should be followed according to their local clinical practice.

[0238] After a maximum of four doses of AAA617, participants must discontinue AAA617, attend an EOT3 visit (42-day safety FU visit), and then proceed to post-treatment follow-up according to the indicated assessments.

[0239] Effectiveness evaluation MFS and rPFS The evaluation of MFS and rPFS includes radiographic evaluation of bone disease by whole-body radionuclide scanning (technetium-99m-labeled diphosphonate) and radiographic evaluation of soft tissue disease by CT scan (or MRI if CT is contraindicated). Positron emission tomography (PET) scans, or tumor evaluation by ultrasound or chest X-ray, may not be a substitute for CT or MRI scans, but the CT portion of a PET / CT can be used in place of a dedicated CT if the CT has the same diagnostic quality as a CT performed without PET, including the use of iv contrast. The same imaging methods should be used throughout the study, and the frequency of imaging evaluation should be the same in both treatment arms.

[0240] The central review of the scan will be conducted in a blind manner. Further details of the central review process are described in the BIRC charter.

[0241] MFS An MFS event is defined as the appearance of a new CI-positive distant metastasis (M1), or as the progression of an existing PSMA PET-positive M1 lesion to a CI-positive M1 lesion (according to the AJCC 8M classification). Radiographic confirmation of disease progression is evaluated by BIRC based on the RECIST 1.1 criteria (Eisenhauer et al 2009) as follows. Metastasis in non-bone tissue is defined as a new distant pathological lymph node (M1a) or other pathological lesion (M1c). Progression in the soft tissues below the common intestinal bifurcation is considered localized progression, and therefore, new or progressive local pathological lymph nodes (N1) are not defined as metastasis. • Radiographic progression of bone disease is defined as the appearance of one or more metastatic lesions on a bone scan. Bone disease is evaluated using a whole-body technetium-99m-labeled diphosphonate bone scan. If a solitary bone lesion is found on the bone scan, confirmation with a second imaging modality (plain radiograph, CT, or MRI) is required. When confirmatory imaging is performed, the date of metastasis should be the date the metastasis was first identified. The appearance of two or more metastatic lesions on a bone scan may not require confirmation with a second imaging modality.

[0242] rPFS • Progression-free survival (rPFS) based on radiographic data is determined according to RECIST 1.1. • Localized progression: Localized progression includes progression of any existing CI-positive localized lesions and N1 disease below the common bowel bifurcation, or the appearance of one or more new localized localized lesions in the CI. For participants in whom only disease unmeasurable by CT or MRI scans was observed, obvious progression (representing an overall change in disease status) is considered progression. rPFS is derived by collecting all distant metastasis events determined with respect to the MFS endpoint, adding radiographic progression events in all local regions according to RECIST assessment, and selecting what happens first when both types of radiographic progression are observed.

[0243] Progression observed in imaging modalities other than conventional imaging (e.g., PSMA PET / CT imaging) is not considered in MFS or rPFS.

[0244] Image examination data is centrally collected and quality-checked by a contract research organization (CRO). The results of central evaluation are used as the primary method for analyzing trial endpoints. Local investigator evaluations are used for decision-making regarding treatment.

[0245] Details regarding the collection and shipment of additional information necessary for BIRC-based image examination evaluation are described in the image examination manual provided by the designated CRO.

[0246] All test imaging studies (including any unscheduled imaging studies) should be submitted to a designated imaging CRO for quality control and central review. Information regarding previous interventions (e.g., radiotherapy), existing radiographic findings mimicking metastatic disease at baseline / screening, and information about previous interventions should be communicated to the imaging CRO via a baseline clinical form, along with baseline images, for review by an independent radiologist. The facility must ensure that the data entered on the form matches the data entered in the clinical database.

[0247] Subsequent images collected from participants who cross over to AAA617 at the discretion of the principal investigator will not be evaluated by BIRC.

[0248] [Table 7]

[0249] Baseline imaging evaluation Imaging assessments will be performed at screening / baseline within 28 days prior to randomization. Any imaging assessments already completed during the participant's routine follow-up examination within 28 days prior to randomization, including before signing the primary trial ICF, may be considered baseline images for this study. Any imaging assessments obtained after randomization may not be considered baseline images.

[0250] Participants are eligible if a screening bone scan shows lesions suggestive of metastatic disease, but are not clearly evident.

[0251] It should be noted that the protocol allows participants with localized lesions (N1 lesions below the common bowel bifurcation) that are visible on conventional imaging (i.e., CT or MRI) at baseline to be eligible to participate in the study. These lesions may or may not be measurable according to RECIST 1.1 and may be selected for rPFS independently of previous radiotherapy.

[0252] Post-baseline imaging evaluation The imaging assessments described in the table above should be performed using the same imaging modalities used at baseline.

[0253] Imaging assessments should be performed every 16 weeks (±7 days) after randomization until the appearance of distant metastases in CI confirmed by BIRC, death, withdrawal of consent / opposition to the use of data / biological samples, loss of follow-up, or participant / guardian decision. Imaging assessments should be scheduled using the randomization date and should be considered regardless of whether AAA617 procedures are temporarily withheld or unscheduled assessments are performed.

[0254] For participants who did not have radiographic progression as confirmed by BIRC-based CI, or, where applicable, for participants in a trial arm who discontinued treatment for reasons other than progression of metastases on recorded radiographs, death, loss of follow-up, or withdrawal of consent, tumor assessments must continue to be performed every 16 weeks from randomization until the appearance of distant metastases as confirmed by BIRC-based CI, death, withdrawal of consent / opposition to the use of data / biological samples, loss of follow-up, or participant / guardian decision.

[0255] If necessary, and at the discretion of the principal investigator, additional imaging evaluations may be performed at any point during the study if disease progression is suspected. Additional imaging evaluations should follow the imaging guidelines specified in the protocol and be recorded in the eCRF and submitted to the BIRC. Whenever disease progression is clinically suspected, physical examination and imaging evaluations should be performed promptly, rather than waiting for the next scheduled imaging evaluation.

[0256] Each lesion measured at baseline must be measured using the same method (any of the same imaging methods) and, where possible, by the same local radiologist / physician throughout the entire study, to ensure consistency in comparisons. If an off-schedule imaging evaluation is performed due to suspected progression, subsequent imaging evaluations should be performed according to the original imaging schedule.

[0257] The point at which the progress will be decided on-site All participants with disease progression (new distant metastasis; MFS event) as determined by the local principal investigator require expedited central review by BIRC. Rapid transmission of images to the imaging CRO can be achieved, for example, by electronically transferring images via the internet. In all cases, the process at the imaging CRO ensures that the central reviewer remains blinded to the results of the local assessment and the expedited nature of the review. The principal investigator requesting expedited review must submit this request to the imaging CRO using the designated form or alternative means. The imaging will undergo expedited central review (within 5 business days of receiving the images at the imaging CRO, once all relevant queries have been resolved), and the results of the central review will be communicated to the site.

[0258] If an MFS event is determined by the central review, the actions described herein must be taken accordingly.

[0259] If a central review does not determine an MFS event, all four doses of AAA617 should be continued in the participant unless there is a medical need for an immediate change in therapy (i.e., rapid progression or clinical deterioration).

[0260] Participants will continue to undergo imaging tests according to the protocol, even if another antitumor therapy is initiated, until a central review determines that an MFS event has occurred.

[0261] Image inspection suppliers ensure that the central review personnel involved are blinded to the speed of the readings.

[0262] At a point when no progress has been decided locally. All imaging time points where no progression (metastasis) is determined on-site are read on a continuous non-rapid basis, as detailed in the imaging manual provided by the designated imaging CRO and independent review charter. These readings are not communicated to the on-site staff.

[0263] Symptomatic skeletal events The time to the first SSE is defined as the time to the first new SSE or death from any cause (whichever occurs first). A symptomatic skeletal event (SSE) is defined by the occurrence of either of the following (whichever occurs first): ·Symptomatic pathological fractures. • Spinal cord compression. • Tumor-related orthopedic surgical interventions. • Request for radiation therapy to alleviate bone pain.

[0264] Symptomatic progression The time to symptomatic progression will be measured by the time from randomization to recording in the CRF for either of the following (whichever occurs earlier): • Occurrence of symptomatic skeletal events (SSEs). • Progression or worsening of disease-related pain requiring the initiation of new systemic anticancer therapy. • Development of clinically significant symptoms resulting from localized tumor progression requiring surgical intervention or radiotherapy.

[0265] PSA progress Time to PSA progression is defined as the time from randomization to the first PSA progression. PSA progression 1 is defined as the day when a ≥25% increase in PSA and an absolute increase of ≥2 ng / mL from the lowest point or baseline are recorded and confirmed by a second consecutive value obtained at least 3 weeks later. PSA increases within the first 12 weeks are ignored if there is no other evidence of disease progression (Source: Prostate Cancer Working Group (PCWG3) Guidance). If no decrease from baseline is recorded, PSA progression is defined as a 25% increase from baseline, along with an absolute increase of ≥2 ng / mL 12 weeks after treatment.

[0266] PSA progression 2 is defined as a PSA concentration exceeding the lowest point (or baseline, if lower) of 0.5 ng / mL or higher, as confirmed by repeated measurements at least 3 weeks later.

[0267] The following treatments (local or systemic) The time to the next treatment is defined as the time from randomization to the initiation of the next line of anticancer therapy (local or systemic). Local therapy may include any additional SBRT administered (i.e., after the initial SBRT for all metastatic lesions) or any other MDT, such as surgery. The next line of therapy is captured in the CRF and used for this analysis.

[0268] PSA and testosterone levels The central laboratory will measure PSA and serum testosterone levels throughout the trial according to the activity schedule. PSA levels will be made public to the study site or participants. Regardless of PSA levels, AAA617 administration should be continued until radiographic progression occurs and the principal investigator deems continued AAA617 administration unbeneficial. Throughout the trial, elevated PSA levels without evidence of radiographic progression (MFS event) confirmed by BIRC are not strongly recommended as a criterion for initiating new systemic antitumor therapy, including ADT.

[0269] Appropriateness of effectiveness evaluation The efficacy measures outlined above are standard for clinical trials involving patients with OMPC (Ost et al 2018, Ost et al 2020, Phillips et al 2020). The proposed MFS endpoint is similar to those previously used in registration trials but for setting gonadectomy resistance (Smith et al 2018, Fizazi et al 2019, Sternberg et al 2020). In addition, elements of the nmCRPC-specific guidelines proposed by the US FDA (FDA 2021) regarding MFS and rPFS are incorporated into the definitions of these endpoints. Furthermore, FDA agreement has been reached on the proposed endpoints / definitions, and consultations have been obtained with the Scientific Advice Working Party (SAWP). These evaluations are also consistent with the PCWG3 guidance.

[0270] Safety evaluation Safety assessments are outlined under the Schedule of Activities, detailing the timing of each assessment. For participants in the crossover control arm, safety assessments must be followed up for up to 10 years after the initial dose of AAA617 (in this study and in any other rollover study).

[0271] For further details regarding the collection and reporting of AEs, please refer to the corresponding sections of this specification.

[0272] Use the ECOG performance status scale as described in the table below.

[0273] [Table 8]

[0274] Physical examination A general physical examination includes the overall external appearance, skin, neck (including the thyroid), eyes, ears, nose, pharynx, lungs, heart, abdomen, back, lymph nodes, limbs, blood vessels, and nerves. If instructed based on medical history and / or symptoms, a rectal examination, external genital examination, mammography, and pelvic examination will be performed.

[0275] Measure height (in centimeters (cm)) and weight (to the nearest 0.1 kilograms (kg) while wearing indoor clothing (but without shoes)).

[0276] The principal investigator should pay particular attention to clinical signs associated with a history of serious illness.

[0277] All information regarding physical examinations must be included in the source documents available at the research facility. Clinically relevant findings existing before the signing of informed consent must be recorded in an appropriate CRF that captures the patient's medical history. Significant findings made after the signing of informed consent that meet the definition of an adverse event must be recorded as an adverse event.

[0278] Vital signs Vital signs include blood pressure (supine position is preferable if an ECG is taken), respiratory rate, pulse rate, and body temperature. Monitor vital signs according to the activity schedule.

[0279] electro-cardiogram ECGs are collected and evaluated on-site. Interpretation of trace maps must be performed by a qualified physician and recorded in the appropriate CRF. Each ECG trace map should be labeled with the study number, participant initials (if permitted by regulation), participant number, and date, and stored in the source documentation at the study site. Clinically significant abnormalities present at screening should be reported in the appropriate CRF. Clinically significant findings must be discussed with the study sponsor before enrolling participants in the study. New or worsening clinically significant findings that appear after informed consent must be recorded as adverse events.

[0280] For both arms, a single local lead 12 ECG will be collected at baseline and at the first visit of the first cycle. For the investigational arm and crossover arm, the ECG will be collected before AAA617 administration in week 1 of the first cycle.

[0281] To ensure a stable baseline, an electrocardiogram (ECG) should be recorded after a 10-minute rest period in the supine position. The preferred sequence for collecting cardiovascular data during a trial visit is to first collect the ECG, followed by vital signs and then blood sampling.

[0282] For clinical assessment, the Fridericia QT correction formula (QTcF) must be used. If QTcF is not automatically calculated by the ECG device, the principal investigator must calculate it.

[0283] The original ECG on non-thermal paper or a properly signed certified copy on thermal paper must be kept at the testing site.

[0284] If clinically necessary, additional unscheduled safety ECGs may be repeated at any point during the study at the discretion of the principal investigator. For any ECGs that raise safety concerns for the participant, two additional 12-lead ECGs must be performed to confirm safety findings. ECG safety monitoring or review processes should be performed (in-situ) for clinically significant ECG findings at baseline before administration of the study procedure and during the study.

[0285] Clinically significant abnormalities must be recorded in the CRF as either a medical history / current condition or an adverse event, as necessary.

[0286] Clinical Safety Clinical Tests Using local laboratories, blood / coagulation, chemistry, and urine tests (safety monitoring) will be analyzed according to the outlined evaluation schedules and sampling plans. Local laboratories will also be used for analyzing urine samples for dose measurement (Germany only). PSA and testosterone analyses will be performed using the central laboratory.

[0287] An abnormal clinical laboratory value or test result is considered an adverse event only if it meets at least one of the following criteria: 1) it induces a clinical sign or symptom, 2) it is considered clinically significant, or 3) it requires concomitant treatment or procedure.

[0288] Clinically significant abnormal laboratory values ​​or results should be identified through a review of previous visits, whether they fall outside the normal / clinically significant range, represent a significant change from screening, or indicate a clinically significant abnormality.

[0289] If medically necessary, unscheduled clinical laboratory evaluations (on-site or centrally) may be performed at any point during the trial at the discretion of the principal investigator. Additional results from unscheduled clinical laboratory evaluations should be recorded in an appropriate unscheduled visit eCRF.

[0290] At any point during the study, any abnormal laboratory parameters that are clinically relevant and require action in conjunction with the study procedure (e.g., requiring dose changes and / or discontinuation of the study procedure, leading to clinical symptoms or signs, or requiring therapeutic intervention) will be recorded on the AE eCRF page, regardless of whether they are specifically required by the protocol. A summary of the laboratory data will be compiled using the Common Terminology Criteria for Adverse Events (CTCAE) version 5. Clinically significant abnormalities at baseline must be recorded as part of the medical history / current condition.

[0291] Clinical chemistry and hematology / coagulation tests will be performed according to the visit schedule. Please refer to the table below for details on the biochemistry / hematology panel. Biochemistry / hematology should be evaluated on the actual scheduled date, even if the investigational drug is withheld.

[0292] Clinical chemistry / hematology / coagulation tests, gallium (where applicable) 68 Ga) Gozetotide or Pifluforastat ( 18 This should be done before administering F) and before administering AAA617.

[0293] If medically necessary, more frequent chemistry / hematology / coagulation tests may be performed. Renal ultrasonography is recommended at the discretion of the principal investigator if eGFR based on serum creatinine decreases. Additional results from unscheduled chemistry / hematology / coagulation clinical laboratory evaluations should be recorded in the eCRF as unscheduled visits.

[0294] Measurements will be performed using urine test strips according to the table below and the evaluation schedule. Any significant findings from the urine test strips will be followed up by microscopic evaluation.

[0295] [Table 9]

[0296] Clinical outcome assessment (COA) Patient-reported outcomes (PROs) PRO is a measure based on reports from study participants regarding their health status, and does not involve interpretation of participant reports by medical leaders or others. Symptoms or other unobservable concepts known only to the participant (e.g., pain severity or fatigue) can only be assessed using PRO measurements.

[0297] All PRO data will be collected using the clinic's electronic devices (except during the survival follow-up period, participants will collect PRO data using their own electronic devices). A web portal will also be available in case of tablet technical problems.

[0298] Participants must undergo PRO measurements to be completed during scheduled visits before any clinical evaluations are performed. If a participant refuses to complete all or any part of the PRO measurements, this should be documented in the study data collection system and should not be treated as a protocol deviation. The handling of protocol deviations may be modified as necessary for each study protocol.

[0299] Participant questionnaires should be completed in the language most familiar to the participant.

[0300] Participants should be given sufficient space and time to complete the PRO measurements.

[0301] On-site personnel should verify the PRO measurement for completeness and ask participants to complete any missing answers. Responses stored electronically in the database will be considered source files.

[0302] Completed measurements must be reviewed and evaluated by the principal investigator before any clinical trial examination for responses that may indicate a potential adverse event (AE) or adverse event (SAE). This evaluation should be documented in the original study record. If an AE or SAE is identified, the principal investigator should not encourage the participant to change the responses reported on the completed questionnaire. The principal investigator must follow the reporting instructions in the study protocol.

[0303] The PRO measurements used in this study are FACT-P, BPI-SF, and EQ-5D-5L, which are further explained below.

[0304] PRO measurements will be assessed for both the investigational arm and the control arm at screening, week 1 of each cycle, at the EOT2 / week 24 visit, and every 16 weeks during the efficacy follow-up. Participants who discontinue early for reasons other than disease progression, loss of follow-up, or withdrawal of consent will continue to have their PRO assessments at the same time as their radiographic assessments during the efficacy follow-up. Participants entering the long-term safety follow-up after an MFS event (investigational arm participants) will receive PRO assessments every 32 weeks. For control arm participants who do not enter the long-term safety follow-up (participants who did not cross over), PRO assessments will continue at three additional time points during the survival follow-up. During this survival follow-up trial period, PRO data may be collected remotely via a web portal or by participants using their own devices.

[0305] FACT-P The FACT-P questionnaire will also be completed as part of this study to specifically assess the HRQoL of prostate cancer participants. FACT-P consists of two parts: the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire (27 questions) and the Prostate Cancer Subscale (PCS) (12 additional questions). The FACT-G questionnaire is one of the most widely used assessments of the impact of cancer / treatment on: physical, social-family, emotional, and functional well-being (Cella et al 1993). The PCS is specifically designed to measure concerns specific to prostate cancer. Each item in both the FACT-G and PCS is rated on a Likert scale from 0 to 4, and then combined to generate subscale scores for each domain, as well as a total score where a higher score indicates greater functionality / fewer prostate-specific concerns. The FACT system offers several advantages, including:

[0306] The questionnaire is designed to reflect the most relevant disease and treatment-specific concerns within the target population.

[0307] FACT-P measurement has been validated in target populations and is available in multiple translations / languages ​​(Cella et al 1993, Esper et al 1997).

[0308] The FACT-P measurement is designed for self-reporting, but can also be completed through an interview format if necessary (Webster et al 2003).

[0309] Complete details regarding the FACT-P questionnaire, including references, are available on the FACIT website: / / facit.org / FACITOrg / Questionnaires.

[0310] Simplified Pain Inventory - Short Form (BPI-SF) The BPI-SF is a nine-item self-administered questionnaire used to assess the severity of a participant's pain and its impact on their daily functioning. Participants are asked to rate their worst, lowest, average, and current pain intensity, list current treatments and associated reliefs, and rate on a 10-point scale how much the pain interferes with general activity, mood, walking ability, normal work, relationships with others, sleep, and enjoyment of life. The BPI was originally developed to assess cancer pain and has been shown to be an appropriate measure of pain caused by a wide range of clinical conditions. The BPI-SF is the standard for use in clinical trials. The recall period for the BPI-SF is the past 24 hours and current pain (present), and the estimated time to complete the BPI is 5 minutes.

[0311] Pain Score: Pain is assessed using the BPI-SF. The BPI-SF is used as part of this study to assess pain severity (worst and mean pain) and the impact of pain on daily functioning (pain interference). Complete details on the BPI-SF, its validation, and clinical applications are available in the Brief Pain Inventory User Guide (Cleeland 2009).

[0312] EQ-5D-5L The EQ-5D-5L questionnaire is also completed as part of this examination to assess HRQoL.

[0313] The EQ-5D is an internationally validated, standardized, and common questionnaire for describing and assessing HRQoL (Rabin, de Charro 2001). The EQ-5D was developed by the EuroQoL Group to provide a simple and common measure of health status for clinical and economic assessment (The EuroQoL Group 1990).

[0314] This device generates a preference-based health utility score (EQ-5D Utility Index) and an overall health status score (EQ-5D VAS) based on a visual analog scale.

[0315] The EQ-5D is designed for self-contained responses and is ideally suited for use in clinics and face-to-face interviews. The EQ-5D has been widely tested and used in both general populations and is used to calculate health benefits for cost-benefit analyses presented to healthcare technology evaluation organizations (Herdman et al 2011). The recall period for the EQ-5D-5L is "today," and the estimated time to complete is several minutes.

[0316] Instructions for respondents are included in the questionnaire. The latest version of the EQ-5D is the EQ-5D-5L, which was developed to improve the instrument's sensitivity and reduce ceiling effects.

[0317] The number of perspectives (Motor activity, Self-care, Daily living activities, Pain / Discomfort, Anxiety / Depression) remains unchanged, but the new version includes five levels of severity for each of the existing perspectives instead of three (EuroQoL 2015). Complete details on the EQ-5D-5L questionnaire, including references, are available on the EQ-5D website:: / / euroqol.org / eq-5d-instruments / eq-5d-51-about.

[0318] Other evaluations (dose measurement) Dose measurements will be conducted in the specific country / region of all participants receiving AAA617 (including participants in the crossover arm). Dose measurements will be evaluated in organs and tumors. This may be required in other countries if required by local regulations.

[0319] Additional SPECT / CT imaging and whole-body planar scintigraphy (for on-site evaluation only) may be performed for dose measurement evaluation, in accordance with local legal requirements.

[0320] Dosimetry evaluations will be conducted for both the clinical trial arm and the crossover arm according to the following schedule. • Cycle 1 (C1W1 visit): Whole-body planar and SPECT / CT scans are performed 1-2 hours, 18-26 hours, 48 ​​hours (+ / - 12 hours), and 168 hours (+ / - 12 hours) after the completion of AAA617 injection. • Third cycle (C3W1 visit): Whole-body planar and SPECT / CT scans are performed 1-2 hours and 48 hours (+ / - 12 hours) after the completion of AAA617 injection. • A urine sample should be collected at the first week of the first cycle after AAA617 administration, between the start of the infusion and the start of the first imaging test (1-2 hours after the infusion).

[0321] Using a population dosimetry model, we can derive tumor absorbed dose estimates, along with their variability, and explore individual factors (i.e., body weight, renal function, lesion type, number of metastases) that may explain interpersonal variability in dosimetry within this population.

[0322] Adverse events (AEs), serious adverse events (SAEs), and other safety reports AEs are reported by the participant (or, where appropriate, by a caregiver, agent, or legally authorized representative of the participant).

[0323] The principal investigator and any qualified designated investigators are responsible for detecting, documenting, and recording any events that meet the definition of an AE or SAE, and for continuing to be responsible for the follow-up of all serious AEs.

[0324] Adverse events An adverse event (AE) is any undesirable medical occurrence (e.g., any undesirable and unintended sign [including abnormal clinical laboratory findings], symptom, or disease) in a clinical trial participant after providing written informed consent to participate in the trial. Therefore, an AE may or may not be temporally or causally related to the use of the drug (investigational drug).

[0325] The occurrence of adverse events must be investigated by non-directive questioning of participants at each visit during the study period. Adverse events may also be detected if participants spontaneously report them during or between visits, or through physical examination findings, laboratory findings, or other assessments. Patient-reported outcomes are considered another assessment for detecting adverse events.

[0326] Adverse events must be recorded under the signs, symptoms, or diagnoses associated with them, along with the following information (to the extent possible): 1. Adverse events are evaluated and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, or, if a CTCAE grading classification does not exist, according to the severity grades. Grades 1-5 are used to characterize the severity of adverse events. If a CTCAE grading classification does not exist for adverse events, the following severity levels corresponding to grades 1-5 are used: mild, moderate, severe, life-threatening, and death due to AE. Information on any deaths (whether or not related to an adverse event) is also collected through death forms. 2. Relationship between the study treatment and other investigational treatments. When an event is attributable to a lack of efficacy or progression of the underlying disease (i.e., progression of the study indication), the assessment of causality is usually "not suspect." The rationale for this guidance is that symptoms of a lack of efficacy or progression of the underlying disease, which occurred despite the administration of the investigational drug and / or both, can only be meaningfully assessed through cohort analysis, not through a single participant. 3. The period (start date and end date, or ongoing) and the outcome must be reported. 4. Does it constitute a SAE, and which severity criteria are met? 5. Actions taken regarding the experimental procedure.

[0327] All adverse events must be treated appropriately. Treatment may include one or more of the following: • Dosage will not be changed. • Dosage reduction • Discontinuation / permanent cessation of drug use 6. Outcome • Unresolved / Unresolved • Recovering / Resolving • Recovered / Resolved • Recovered from / resolved after-effects ·lethal ·Unknown (UNK)

[0328] If an event worsens, the event should be re-reported in the CFR, specifying the start date of the worsening toxicity. For Grade 3 and 4 adverse events only, if improvement to a lower grade is determined, a new entry for the event should be reported in the CFR, specifying the start date of the improvement from Grade 3 or Grade 4.

[0329] Conditions that already existed at the time of informed consent should be recorded in the participant's medical history.

[0330] Adverse events (including abnormal clinical laboratory values ​​that constitute AEs) should be explained using diagnoses whenever possible, rather than individual underlying signs and symptoms.

[0331] Adverse event monitoring should continue for at least 42 days after the final dose of AAA617.

[0332] Following safety follow-up visits (EOT2 / EOT3 visits), participants randomized to a clinical trial arm / crossover will be followed every 32 weeks for safety assessments until the end of this trial, and then invited to participate in a separate long-term safety trial (CAAA617A12402). This long-term follow-up trial will last up to 10 years from the initial dose of AAA617. During this long-term safety follow-up, selected adverse events associated with AAA617 (i.e., xerostomia, xerophthalmos, myelosuppression, nephrotoxicity, and secondary primary malignancies, and their outcomes) will be documented and reported in case report forms.

[0333] The selected adverse events (AEs) described above that are perceived to be associated with AAA617 will be followed until the event, its sequelae, or abnormal laboratory findings resolve or stabilize to a level acceptable to the principal investigator.

[0334] For non-randomized participants, AE monitoring was performed using gallium ( 68 Ga) Continue administration of gozetotide for up to 3 days after administration.

[0335] For all AEs, sufficient information is obtained to enable appropriate determination of the event outcome and evaluation of the causal relationship between the AE and the test treatment.

[0336] If an adverse event is detected, it must be followed up until it disappears or is determined not to have resolved (e.g., persisting at the end of the study), and the severity of the event, the suspected relationship with interventions required for treatment, and the outcome must be evaluated at each visit (or more frequently as necessary).

[0337] Progression of malignant tumors (including fatal outcomes) should not be reported as a serious adverse event unless the investigator determines that the progression of malignant tumors is related to the study procedure, provided that it is documented using appropriate methods (e.g., according to the RECIST criteria for solid tumors).

[0338] Adverse events that are separate from the progression of the malignant tumor (e.g., deep vein thrombosis at the time of progression, or hemoptysis occurring concurrently with the detection of disease progression) are reported with appropriate attributes regarding their association with the drug, in accordance with the standard guidelines used for such events.

[0339] Information regarding adverse drug reactions to the investigational drug can be found in the Principal Investigator's Information (IB) and appropriate documentation related to SBRT (e.g., site guidelines).

[0340] An abnormal clinical test result or test result is considered an adverse event only if at least one of the following criteria is met: • To induce clinical signs or symptoms • Considered clinically significant • Treatment is necessary

[0341] Clinically significant abnormal clinical laboratory values ​​or results must be identified through review of values ​​outside the normal / clinically noteworthy range, significant changes from baseline or previous visit, or values ​​considered atypical in participants with underlying medical conditions.

[0342] Serious adverse events A SAE is defined as any adverse event [the appearance (or worsening) of any pre-existing condition] that meets any one of the following criteria: ·lethal • Threatening life

[0343] In the context of SAEs, "life-threatening" refers to a response in which the participant was at risk of death at the time of the response, and not to a response that could have hypothetically caused death if it had been more severe (see the International Council for Harmonization (ICH-E2D) guidelines). • To cause permanent or serious disability / incapacity • Congenital abnormalities / congenital defects, fetal death, or constituting a congenital abnormality or congenital defect • Hospitalization is necessary for the purpose of hospitalizing a patient or extending an existing hospitalization, except in the following cases: • Routine treatment or monitoring of the indication under trial, not related to any worsening of the condition. • Elective or pre-planned treatment for pre-existing conditions unrelated to the indication under study and that have not worsened since the signing of informed consent. Social reasons and respite care when there is no worsening of the participant's overall condition. • Emergency outpatient-based management for events that do not meet any of the above definitions of SAE and do not result in hospitalization. • Defined as an event that is medically significant, for example, one that may endanger the patient or require medical or surgical intervention to prevent one of the outcomes listed above.

[0344] Medical and scientific judgment should be exercised in determining whether other situations (e.g., significant medical events) should be considered significant responses if they do not immediately threaten life or likely to result in death or hospitalization, but could endanger the participant or require intervention to prevent one of the other outcomes listed above. Such events should be considered “medically significant.” Examples of such events include hospitalization or intensive care in the emergency room or at home for allergic bronchospasm, blood abnormalities, or seizures that do not result in the development of addiction or abuse (see ICH-E2D guidelines).

[0345] If other severity criteria are not met and the malignant neoplasm is not a progression of a disease for which the study is indicated, all new malignant neoplasms are assessed as severe under "medically significant" conditions.

[0346] Regardless of whether a clinical event occurred, all reports of intentional misuse and abuse of the product will be considered serious adverse events.

[0347] If transmission via a drug containing an infectious agent is suspected, it is also considered a serious adverse reaction.

[0348] During this long-term safety follow-up, all serious adverse events associated with AAA617, including xerostomia, xerophthalmos, myelosuppression, nephrotoxicity, and secondary primary malignancies, will be recorded and reported in case report forms.

[0349] SAE report To ensure participant safety, all SAEs occurring between EOT2 / EOT3 after a participant has provided informed consent, regardless of causal relationship, must be reported immediately to the sponsor without undue delay, no later than 24 hours after the event is recognized (Note: In stricter cases, local regulations regarding reporting timelines take precedence). Detailed instructions regarding the submission process and requirements can be found in the Principal Investigator's folder provided to each site. Information on all SAEs must be collected and recorded in the Serious Adverse Event Report form (eSAE with paper backup); all relevant sections of this form must be completed to provide a clinically thorough report.

[0350] Any SAEs that occur between the time a participant provides informed consent and the time they are deemed to have failed the screening must be reported to the trial sponsor.

[0351] All follow-up information for a SAE, including information on complications, progression of the initial SAE, and recurrent episodes, must be reported positively as a follow-up to the original episode without excessive delay, no later than 24 hours after the principal investigator receives the follow-up information (Note: Local regulations regarding reporting timelines take precedence in stricter cases). SAEs occurring at different time intervals or considered completely unrelated to those previously reported must be reported separately as new events.

[0352] If a SAE has not been previously documented in the Principal Investigator's Materials or Package Insert (a new occurrence) and is thought to be related to a study procedure, the Chief Medical Office and the Patient Safety (CMO&PS) department may urgently request further information from the Principal Investigator for reporting to the health authorities.

[0353] In accordance with the EU Clinical Trials Regulation 536 / 2014 or the national regulatory requirements of participating countries, unexpected suspected serious adverse reactions (SUSARs) will be collected and reported to the competent authority and relevant ethics committee.

[0354] If the principal investigator suspects a causal relationship with AAA617, they should report any SAEs (Severely Affective Ecological Exposures) experienced within 42 days of the last dose of AAA617, unless otherwise specified by local laws / regulations. These SAEs include, but are not limited to, xerostomia, xerostomia, myelosuppression, nephrotoxicity, and secondary primary malignancies.

Claims

1. A method for delaying gonadectomy and / or disease recurrence in adult male patients with prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic prostate cancer (OMPC), (1) The step of applying stereotactic radiotherapy (SBRT) to the patient, and (2) The patient is given a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) drug, for example, lutetium ( １７７ Lu) Bibivotide Tetraxetane ([ １７７ A step of administering Lu]Lu-PSMA-617), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. A method that includes this.

2. The method according to claim 1, wherein the OMPC is an OMPC having 1 to 5 metastatic lesions that are detected by PSMA positron emission tomography (PET) using a radioligand contrast agent (RLI) containing a positron-emitting nuclide, but are negative for M1 disease by conventional imaging (CI).

3. The aforementioned positron-emitting nuclide, １８ F, ６４ Cu, and ６８ The method according to claim 2, selected from the group consisting of Ga.

4. The RLI agent is gallium ( ６８ Ga) gozetotide ６８ Ga]Ga-PSMA-11], ６４ Cu-SAR-bisPSMA, ６４ Cu-PSMA I&T [copper ( ６４ Cu) zadavitide glaxixtan], piflufostat ( １８ F) １８ F-DCFPyL], florotufostat ( １８ F) １８ F-rhPSMA-7.3], bidoflufostat ( １８ F) １８ F-CTT1057], １８ selected from the group consisting of F-PSMA-1007, preferably selected from the group consisting of gallium ( ６８ Ga) gozetotide and piflufostat ( １８ F), the method according to claim 2.

5. The method according to claim 2, wherein the CI is based on computed tomography (CT) / magnetic resonance imaging (MRI) and / or bone scanning.

6. The method according to claim 1, wherein the RLT agent is administered in 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 once every 6 to 8 weeks, more preferably once every 6 (±1) weeks (i.e., one cycle), for a maximum of 3 to 4 cycles, preferably over 3 to 4 cycles, more preferably over 4 cycles.

7. The treatment method according to claim 1, wherein the radioactive ligand therapeutic agent is administered at a dose of 7.4 (±10%) GBq once every 6 (±1) weeks (i.e., one cycle) for four cycles.

8. A method for delaying gonadectomy and / or disease recurrence in adult male patients with prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic prostate cancer (OMPC), (1) The step of applying stereotactic radiotherapy (SBRT) to the patient, and (2) The patient is given a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) drug, for example, lutetium ( １７７ Lu) Bibivotide Tetraxetane ([ １７７ A step of administering Lu]Lu-PSMA-617), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof. Including; The aforementioned OMPC is an OMPC having 1 to 5 metastatic lesions that are detected by PSMA positron emission tomography (PET) using a radioligand contrast agent (RLI) containing a positron-emitting nuclide, but are negative for M1 disease by conventional imaging (CI); The positron-emitting nuclide is gallium ( ６８ Ga) Gozetotide or Pifluforastat ( １８ F) is; The aforementioned CI is based on computed tomography (CT) / magnetic resonance imaging (MRI) and / or bone scans; The radioactive ligand therapeutic agent is administered at a dose of 7.4 (±10%) GBq once every 6 (±1) weeks (i.e., one cycle) for four cycles. method.

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