Methods of treating prostate cancer

Abstract

The present disclosure relates to a method of treating prostate specific membrane antigen (PSMA) positive oligometastatic prostate cancer (OMPC) that progresses after decisive treatment of a primary tumor thereof, the method comprising administering a therapeutically effective amount of a PSMA binding radioligand therapeutic (RLT) agent, preferably [177Lu] Lu-PSMA-617 (lutetium (177Lu) vepivopeptide Tailaracetam). Furthermore, the disclosure relates to radioligand therapy for early stage prostate cancer patients to control recurrent tumor progression to fatal metastatic disease while maintaining quality of life by delaying treatment with androgen deprivation therapy (ADT).

Description

Technical Field

[0001] This disclosure relates to a method for treating prostate-specific membrane antigen (PSMA)-positive oligometastatic prostate cancer (OMPC) that has progressed after definitive treatment of its primary tumor, the method comprising administering a therapeutically effective amount of a PSMA-bound radioligand therapy (RLT) agent, preferably [ 177 Lu]Lu-PSMA-617 (Lutene) 177 Lu) Vipivotetide (Teraracetam). Furthermore, this disclosure relates to radioligand therapy for patients with early-stage prostate cancer to control the progression of recurrent tumors to fatal metastatic disease, while maintaining quality of life by delaying androgen deprivation therapy (ADT). Background Technology

[0002] It is estimated that 1.4 million new cases of prostate cancer (PC) and 375,000 cancer deaths worldwide will be attributed to PC in 2020 (Sung et al. 2021). PC incidence has changed over the past few decades due to increased detection rates of asymptomatic disease resulting from widespread prostate-specific antigen (PSA) testing (Siegel et al. 2017). Thorough local treatments such as radical prostatectomy (RP) or radiotherapy (XRT) are standard local therapies (Fakhrejahani et al. 2017).

[0003] Following failure of local therapy, elevated PSA levels (defined as biochemical relapse [BCR]) may occur, and a subset of patients may also experience limited recurrent disease, characterized by a limited number of distant sites of dissemination. Most commonly, specific cutoff values ​​are used to identify the number of distant sites involved in OMPC patients. There is currently no clear consensus on these cutoff values. In 25 retrospective studies including >1 cases, 10 (40%) used a definition of ≤5 metastases, 3 (12%) used ≤4 metastases, and 12 (48%) used ≤3 metastases to define patients with limited metastases. Ongoing prospective studies have adopted similar approaches to define limited metastases, using cutoff values ​​of ≤5, ≤4, and ≤3 metastases (Fodor et al. 2017, Foster et al. 2019).

[0004] While OMPC has traditionally been defined as a disease detected by conventional imaging (CT / MRI and bone scan), it has become possible to reclassify a subset of patients with BCR (defined by PSA progression in the absence of evidence of metastatic disease according to conventional imaging (CI)) as OMPC using more sensitive imaging modalities, such as PSMA-based positron emission tomography (PSMA-PET). Due to advancements in detection technology, most OMPC detected by CI can now be reclassified as multimetastatic disease (National Comprehensive Cancer Network, NCCN Guidelines Prostate Cancer V.1.2023).

[0005] Although the prevalence of CI-based OMPC has been reported in the literature, the incidence of PSMA-based OMPC with negative CI results remains unclear. In a study of 199 patients with BCR who were lesion-free according to CI and underwent PSMA-HBED PET / CT imaging, 148 patients (74%) showed PSMA-positive lesions, of which 113 patients (57%) were defined as oligometastatic with 3 or fewer metastases (McCarthy et al., 2019).

[0006] PC is an androgen-sensitive cancer. ADT has been a mainstay of treatment for metastatic PC since the 1940s. However, ADT is non-curative for metastatic PC and is associated with significant toxicity with prolonged exposure. The impact of ADT on survival is unclear, and data suggest that the benefit of immediate initiation of ADT compared to delayed initiation is questionable (Patrikidou et al. 2021). Furthermore, the initiation of ADT marks the beginning of castration-sensitive disease and foreshadows the eventual development of castration-resistant PC (Harris et al. 2009, Armandari et al. 2014, Sweeney et al. 2015, Rao et al. 2019). ADT has numerous adverse effects on metabolism, cardiovascular health, sexuality, cognitive health, and body composition; these effects are amplified with prolonged exposure (Sountoulides, Rountos 2013). The natural course of small metastatic PC (i.e., OMPC) is typically slow-progressing; therefore, delaying ADT may be reasonable for appropriately selected asymptomatic patients (Rao et al. 2019, Juan et al. 2022). In such cases, metastasis-directed therapy (MDT), particularly SBRT targeting metastatic lesions, may be effective and may have the potential to avoid or delay toxicities associated with systemic therapies such as ADT (Schweizer et al. 2013, Ost et al. 2015). The benefits of SBRT as an MDT in PC have recently been validated in two prospective randomized phase II studies (Ost et al. 2018, Ost et al. 2020, Phillips et al. 2020). Considering these results, SBRT targeting metastatic lesions is the standard of care for OMPC, where progression-free survival is the goal (NCCN Prostate Cancer Guidelines V.1.2023). The guidelines of the European Association of Urology (EAU), the European Association of Nuclear Medicine (EANM), the European Society of Radiation Therapy and Oncology (ESTRO), the European Society of Urogenital Radiology (ESUR), the International Society of Uropathology (ISUP), and the International Society for Geriatric Oncology (SIOG) also recommend MDT for M1 patients in clinical trial settings or in well-designed prospective cohort studies (Mottet et al. 2022). Recently, the Delphi Consensus of the European Society for Radiation Oncology-Radiation Oncology Practice Advisory Committee (ESTRO-ACROP) endorsed metastasis-guided radiotherapy (MRT) for patients diagnosed with up to five lymph node, bone, or visceral metastases in all disease settings (Zillli et al. 2022). Despite high local control rates, MDT alone (surgery or SBRT) offers limited control of distant metastases and is unlikely to be a curative treatment. In the STOMP trial, 61% of patients receiving MDT were observed to receive ADT due to multimetastatic progression, with 30% of MDT patients progressing to multimetastatic disease within the first year (Ost et al. 2018).Furthermore, early MDT in limited recurrent prostate cancer does not shorten the time from ADT initiation to castration resistance (Triggiani et al. 2021). Although few OMPC patients may achieve complete remission after SBRT, most men with limited metastatic disease do not achieve complete PSA remission after SBRT, indicating the presence of undetectable residual micrometastases. Macroscopic disease consolidation can simply reset the timeline to detectable metastases, while micrometastatic disease may continue to grow uncontrollably until it grows large enough to be clinically actionable (Phillips et al. 2020). The pattern of failure analysis suggests that while control of irradiated lesions is very high, most patients relapse and develop new, previously undetectable metastases due to untreated micrometastases (Soldatov et al. 2019). Therefore, even patients who achieve complete remission after SBRT may still benefit from additional therapies that potentially target micrometastases. Thus, the need for treatment options in early-stage patients remains unmet to control the progression of recurrent tumors to lethal metastases while maintaining quality of life by delaying ADT.

[0007] RLT

[0008] One of the molecular targets of RLT is prostate-specific membrane antigen (PSMA). PSMA is an ideal PC target because:

[0009] Its expression in "normal" tissues is limited.

[0010] • It is expressed in 60%–74% of BCR patients (McCarthy et al. 2019, Artigas et al. 2021).

[0011] It is highly expressed on the cell membrane of tumor cells.

[0012] • It functions as an internalized cell surface receptor (Silver et al. 1997, Liu et al. 1998).

[0013] The two PSMA-targeted PET imaging agents gallium used in this study ( 68 Ga) Gozetide and Piflufositol ( 18 F) has been approved for clinical use in the United States for prostate cancer (see Locametz). ® and Pilarify ® For more details, please refer to local prescription information. (Gallium) 68 Ga) locametz has also been approved for clinical use in Europe (see Locametz for more details). ® (Local prescription information).

[0014] Lu (177 Lu) Vipivoxytide Taracetam (also known as [ 177 Lu]Lu-PSMA-617 or 177 Lu-PSMA-617 (hereinafter referred to as AAA617) is a novel radioligand therapy that, based on results from the VISION trial (NCT03511664), has been approved in the United States, Canada, the United Kingdom, and the European Union for the treatment of adult patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have received androgen receptor pathway inhibition and taxane-based chemotherapy. In this randomized phase III study, AAA617 plus standard of care (SoC) significantly prolonged radiographic progression-free survival (median 8.7 months vs. 3.4 months; hazard ratio for progression or death 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P < 0.001) and overall survival (median, 15.3 months vs. 11.3 months; hazard ratio for death 0.62; 95% CI, 0.52 to 0.74; P < 0.001) compared to SoC alone (Sartor et al. 2021). Lu ( 177 The efficacy of lutetium (L) vepivotide tairacetam is also supported by another randomized study, which compared lutetium (L) vepivotide tairacetam with lutetium (L) vepivotide tairacetam. 177 Lu) Vepivotine, terazosin, and cabazitaxel, among which lutetium ( 177 Lu) The vepivotide-taracetam treatment group showed promising efficacy results (Hofman et al. 2021). Furthermore, two ongoing phase III studies are examining AAA617 in early-stage therapy lines for mPC patients: PSMAfore (NCT04689828) and PSMAddition (NCT04720157). Similarly, AAA617 treatment demonstrated a statistically and clinically significant improvement in radiographic progression-free survival (rPFS) in PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) patients receiving androgen receptor pathway inhibitor (ARPI) therapy compared to ARPI alterations (PSMAfore, NCT04689828). Additionally, an ongoing phase III study is examining AAA617 in metastatic hormone-sensitive prostate cancer (PSMAddition, NCT04720157).

[0015] Based on the results of the VISION and PSMAfore studies, the use of AAA617 after SBRT may delay further metastatic progression and the time to ADT initiation, thus benefiting OMPC patients. Summary of the Invention

[0016] This disclosure provides:

[0017] Methods of delayed castration [or: delayed initiation of hormone castration therapy; or: maintenance of quality of life by delaying androgen deprivation therapy (ADT); or: time to hormone therapy (TTHT), defined as the time from the initiation of said method to androgen deprivation therapy (ADT)] and / or disease recurrence [or: prolonged metastasis-free survival (MFS) by conventional imaging; or: prolonged metastasis-free survival (MFS), defined as the time from randomization to the first detectable distant metastases of bone or soft tissue on radiographic imaging by conventional imaging (i.e., CT / MRI and bone scan) (as assessed by BIRC using RECIST 1.1) or death from any cause, whichever occurs first; or: control of recurrent tumors in adult male patients with prostate-specific membrane antigen (PSMA) positive (+) oligometastatic prostate cancer (OMPC) from progression to fatal metastatic disease], wherein the method comprises the following steps:

[0018] (1) Stereotactic body radiotherapy (SBRT) was applied to the patients [or: the decisive treatment for their primary tumors];

[0019] (2) Administer to the patient a therapeutically effective amount of the PSMA-binding radioligand therapy (RLT) agent lutetium ( 177 Lu) Vipivopeptide-Teracillin ([ 177 Lu]Lu-PSMA-617 (also referred to herein as AAA617), or its pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer, or tautomer.

[0020] In the embodiments disclosed herein, the term "1" st (First) and "2" nd "(Second) indicates the order in which these steps are performed."

[0021] In the embodiments disclosed herein, SBRT is applied as a single part or a multi-part scheme (e.g., in two or three parts).

[0022] In a preferred embodiment of this disclosure, the RLT agent is administered at least one week after the completion of the final SBRT portion. In a preferred embodiment, RLT agent treatment begins 7 to 21 days after the final SBRT portion.

[0023] In some embodiments disclosed herein, OMPC is OMPC with 1-5 metastatic lesions that is detected by PSMA positron emission tomography (PET) using a radioligand imaging (RLI) agent containing a positron-emitting radionuclide, but is negative for M1 disease by conventional imaging (CI) [excluding: distant metastatic disease that is positive on conventional imaging (i.e., mHSPC)] [in short: oligometastatic prostate cancer (OMPC) according to PSMA PET, M1 negative according to CI].

[0024] In some embodiments disclosed herein, the positron-emitting radionuclides may be selected from the group consisting of: 11 C 13 N、 15 O、 18 F, 64 Cu、 68 Ga、 82 Rb、 83 Sr、 89 Zr, and 124 I. Preferred selection is based on the following groups: 18 F, 64 Cu and 68 Ga.

[0025] In some embodiments of this disclosure, the RLI agent is selected from gallium (GaN). 68 Ga) Gozetotide 68 Ga]Ga-PSMA-11]、 64 Cu-SAR-bisPSMA, 64 Cu-PSMA I&T [Copper ( 64 [Zadavotideguraxetan], piflufolastat (Cu) 18 F)[ 18 F-DCFPyL], flutufolastat (F-DCFPyL) 18 F)[ 18 F-rhPSMA-7.3], vidoflufolastat ( 18 F)[ 18 F-CTT1057] 18 F-PSMA-1007 18 F-JK-PSMA-7 and 18 The group consisting of F-FC303 preferably contains free gallium (GaN). 68 Ga) Gozetide and Piflufositol ( 18 The group consisting of F).

[0026] In some embodiments of this disclosure, CI is based on computed tomography (CT) / magnetic resonance imaging (MRI) and / or bone scans.

[0027] In some embodiments disclosed herein, 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, every 5 to 10 weeks, preferably 6 to 8 weeks, more preferably 6 (± 1) weeks (i.e., 1 cycle), for up to 3 or 4 cycles, preferably 3 to 4 cycles, more preferably 4 cycles [or: planned 4 cycles].

[0028] In a preferred embodiment of this disclosure, the radioligand therapeutic agent is administered at a dose of 7.4 (± 10%) GBq every 6 (± 1) weeks (i.e., 1 cycle) for 4 cycles. Attached Figure Description

[0029] Figure 1 The design of the PSMA-DC (PSMA-Delayed Castration) clinical trial is shown. Detailed Implementation

[0030] The contents of this disclosure are described and illustrated in more detail below. Example

[0031] The specific methods for processing the content disclosed herein are provided in the following examples:

[0032] 1.1 A method for delaying castration in an adult male patient with prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic prostate cancer (OMPC), wherein the method comprises the following steps:

[0033] (1) Stereotactic body radiotherapy (SBRT) is administered to the patient.

[0034] (2) Administer a therapeutically effective dose of PSMA-binding radioligand therapy (RLT) to the patient.

[0035] 1.2 A method for delaying disease relapse in adult male patients with PSMA+ OMPC, wherein the method includes the following steps:

[0036] (First) SBRT is applied to the patient;

[0037] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0038] 1.3 A method for delaying the initiation of hormone castration therapy in adult male patients with PSMA+ OMPC, wherein the method includes the following steps:

[0039] (First) SBRT is applied to the patient;

[0040] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0041] 1.4 A method for maintaining the quality of life of adult male patients with PSMA+ OMPC through delayed androgen deprivation therapy (ADT), wherein the method includes the following steps:

[0042] (First) SBRT is applied to the patient;

[0043] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0044] 1.5 A method for extending the time to hormone therapy (TTHT) in adult male patients with PSMA+ OMPC, TTHT being defined, for example, as the time from the start of the method to the commencement of androgen deprivation therapy (ADT), wherein the method comprises the following steps:

[0045] (First) SBRT is applied to the patient;

[0046] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0047] 1.6 A method for prolonging metastasis-free survival (MFS) via conventional imaging in adult male patients with PSMA+ OMPC, wherein the method includes the following steps:

[0048] (First) SBRT is applied to the patient;

[0049] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0050] 1.7 A method for prolonging metastasis-free survival (MFS) in adult male patients with PSMA+ OMPC, wherein MFS is defined, for example, from the start of the method to the first detectable distant metastases of bone or soft tissue on radiographic imaging by conventional imaging (i.e., CT / MRI and bone scan) (as assessed by BIRC using RECIST 1.1) or death from any cause, whichever occurs first, wherein the method comprises the following steps:

[0051] (First) SBRT is applied to the patient;

[0052] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0053] 1.8 A method for controlling the progression of recurrent tumors to lethal metastatic disease in adult male patients with PSMA+ OMPC, wherein the method comprises the following steps:

[0054] (First) SBRT is applied to the patient;

[0055] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0056] 1.9 A method for prolonging metastasis-free survival (MFS) in adult male patients with PSMA+ OMPC, wherein MFS is defined, for example, from the start of the method to the first detectable distant metastases of bone or soft tissue on radiographic imaging by routine imaging (i.e., CT / MRI and bone scan) (as assessed by the investigator using RECIST 1.1) or death from any cause, whichever occurs first, wherein the method comprises the following steps:

[0057] (First) SBRT is applied to the patient;

[0058] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0059] 1.10 A method for prolonging the time to prostate-specific antigen (PSA) progression (TTPSAP) in adult male patients with PSMA+ OMPC, wherein TTPSAP is defined, for example, as the time from the start of the method to the first PSA progression 1 [wherein the first PSA progression 1 can be defined as a PSA rise confirmed by repeated measurements at least 3 weeks later, and the rise is at least greater than 25% and above the nadir or baseline ≥ 2 ng / mL, whichever is lower], wherein the method comprises the following steps:

[0060] (First) SBRT is applied to the patient;

[0061] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0062] 1.11 A method for prolonging radiographic progression-free survival (rPFS) in adult male patients with PSMA+ OMPC, rPFS being defined, for example, as the time from the start of this method to the first confirmed radiographic progression of disease or death from any cause by routine imaging (i.e., CT / MRI and bone scan) using RECIST 1.1, whichever occurs first [wherein the rPFS may be analyzed according to BIRC and investigator assessment, respectively], wherein the method comprises the following steps:

[0063] (First) SBRT is applied to the patient;

[0064] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0065] 1.12 A method for extending the time to the next therapy (local or systemic) in adult male patients with PSMA+ OMPC, wherein the time to the next therapy (local or systemic) is defined, for example, as the time from the start of this therapy to the initiation of the next therapy line (local or systemic) [wherein the next therapy line is defined as the first new (local or systemic) antitumor therapy initiated after discontinuation of study treatment, regardless of the reason for the end of treatment (EOT)], wherein the method comprises the following steps:

[0066] (First) SBRT is applied to the patient;

[0067] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0068] 1.13 A method for prolonging 24-month PSA PFS (≥ 0.5 ng / mL) in adult male patients with PSMA+ OMPC, wherein 24-month PSA PFS is defined, for example, as PSA PFS at 24 months [where PSA PFS is defined as the time from the date of randomization to the date of first recorded PSA progression 2 or death from any cause (whichever occurs first), and PSA progression 2 is defined as a PSA concentration confirmed by repeated measurements at least 3 weeks later that is ≥ 0.5 ng / mL above the lowest point (or baseline, if lower)], wherein the method comprises the following steps:

[0069] (First) SBRT is applied to the patient;

[0070] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0071] 1.14 A method for prolonging the time to symptomatic progression in adult male patients with PSMA+ OMPC, wherein the time to symptomatic progression is defined, for example, from the start of the method to the time of deterioration of Eastern Cooperative Oncology Group (ECOG) performance status (PS), clinical progression as assessed by investigators, escalation of cancer-related pain, and worsening of disease-related symptoms (all leading to the initiation of new systemic anticancer therapy), or to the time of clinically significant symptoms due to local or regional tumor progression (leading to surgery or radiation therapy), wherein the method comprises the following steps:

[0072] (First) SBRT is applied to the patient;

[0073] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0074] 1.15 A method for improving the quality of life of adult male patients with PSMA+ OMPC, wherein the quality of life is assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, wherein the method comprises the following steps:

[0075] (First) SBRT is applied to the patient;

[0076] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0077] FACT-P assesses symptoms / problems associated with prostate cancer and its treatment. It is a combination of the FACT-G General and the Prostate Cancer Subscale (PCS). The FACT-G General is a 27-item measure of quality of life (QoL), providing a total score and subscale scores: physical (0-28), functional (0-28), social (0-28), and affective (0-24). The total score ranges from 1 to 108, with higher scores indicating better total and subscale scores. The PCS is a 12-item prostate cancer subscale that inquires about prostate cancer-specific symptoms and problems (range 0-48, with higher scores being better). The FACT-P total score is the sum of the scores from all five subscales of the FACT-P questionnaire, ranging from 0 to 156. Higher scores indicate better functional status and quality of life.

[0078] 1.16 A method for alleviating pain in adult male patients with PSMA+ OMPC, wherein the pain is assessed using the Brief Pain Scale-Short Form (BPI-SF) questionnaire, wherein the method comprises the following steps:

[0079] (First) SBRT is applied to the patient;

[0080] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0081] The Pain Intensive Pain Assessment Questionnaire (BPI-SF) is a publicly available pain assessment tool that includes 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 a participant's daily functioning. The pain severity score is the average of BPI-SF questions 3, 4, 5, and 6 (questions asking about the degree of pain, ranging from 0 [no pain] to 10 [the level of pain you can imagine]). Progression in pain severity is defined as an increase in score of 30% or more from baseline without a decrease in analgesic use.

[0082] 1.17 A method for improving health-related quality of life in adult male patients with PSMA+ OMPC, wherein the health-related quality of life is assessed using the EuroQol-5 Domain 5-Level Scale (EQ-5D-5L), wherein the method comprises the following steps:

[0083] (First) SBRT is applied to the patient;

[0084] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0085] The EQ-5D-5L is a standardized participant-completed questionnaire used to measure health-related quality of life and converts scores into index values ​​or utility scores. The EQ-5D-5L consists of two components: a health status overview and an optional visual analog scale (VAS). The EQ-5D health status overview comprises five dimensions: mobility, self-care ability, daily activities, pain / discomfort, and anxiety / depression. Each dimension has five levels: 1 = no problem, 2 = minor problem, 3 = moderate problem, 4 = severe problem, and 5 = extreme problem. Higher scores indicate a higher level of problem in each of the five dimensions.

[0086] 1.18 A method for extending the time to first symptomatic skeletal event (TTSSE) in adult male patients with PSMA+ OMPC, TTSSE being defined, for example, as the date the method begins until the date of the first new symptomatic pathological fracture, spinal cord compression, tumor-related orthopedic surgical intervention, the need for radiation therapy to relieve bone pain, or death from any cause (whichever occurs first), wherein the method comprises the following steps:

[0087] (First) SBRT is applied to the patient;

[0088] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0089] 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, wherein the method comprises the following steps:

[0090] (First) SBRT is applied to the patient;

[0091] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0092] The distribution of adverse events can be monitored by analyzing the frequency of treatment-associated adverse events (TEAEs), serious adverse events (TESAEs), and deaths caused by AEs, based on relevant clinical and laboratory safety parameters.

[0093] 1.20 A method for prolonging overall survival (OS) in adult male patients with PSMA+ OMPC, wherein OS is defined, for example, as the time from the start date of the method to the date of death from any cause, wherein the method comprises the following steps:

[0094] (First) SBRT is applied to the patient;

[0095] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0096] In the embodiments disclosed herein, stereotactic total body radiotherapy (SBRT) may also be referred to as the definitive treatment for the patient's primary tumor.

[0097] In the embodiments disclosed herein, the PSMA-binding radioligand therapy (RLT) agent may be a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer, or tautomer of the RLT agent.

[0098] In embodiments disclosed herein, the terms “patient” (singular) and “patient” (plural) may be used interchangeably.

[0099] In the embodiments disclosed herein, particularly in the embodiments described above (from 1.1 to 1.20), compared to a method that includes step 1 (SBRT) but does not include step 2 (RLT), or compared to a method consisting of (only) SBRT, 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 a reduction of at least 95%, even more preferably at least 100%.

[0100] In the embodiments disclosed herein, particularly in the embodiments described above (from 1.1 to 1.20), compared to a method that includes step 1 (SBRT) but does not include step 2 (RLT), or compared to a method consisting of (only) SBRT, the extension or 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%, even more preferably at least 500%.

[0101] Based on the methods described in Independent Embodiments 1.1 to 1.20, other embodiments of this disclosure can be formed by combining features of any one of the methods with features of any one or more of the other methods.

[0102] For example, the methods of Examples 1.1 and 1.3 form the following further embodiments:

[0103] A method for delaying castration and delaying the initiation of hormone castration therapy in adult male patients with prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic prostate cancer (OMPC), wherein the method includes the following steps:

[0104] (1) Stereotactic body radiotherapy (SBRT) is administered to the patient.

[0105] (2) Administer a therapeutically effective dose of PSMA-binding radioligand therapy (RLT) to the patient.

[0106] Another example is a combination of the methods in Examples 1.5 and 1.7:

[0107] A method for extending the time to hormone therapy (TTHT) in adult male patients with PSMA+ OMPC. and Methods for prolonging metastasis-free survival (MFS), where TTHT is defined, for example, as the time from the start of the method to androgen deprivation therapy (ADT), and MFS is defined, for example, as the time from the start of the method to the first detectable distant metastases to bone or soft tissue on radiographic imaging by conventional imaging (i.e., CT / MRI and bone scan) (as assessed by BIRC using RECIST 1.1) or death from any cause (whichever occurs first), wherein the method comprises the following steps:

[0108] (First) SBRT is applied to the patient;

[0109] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0110] Another example is a combination of the methods in embodiments 1.5, 1.7, and 1.20:

[0111] A study on prolonging time to hormone therapy (TTHT) and extending metastasis-free survival (MFS) in adult male patients with PSMA+ OMPC. and Methods for prolonging overall survival (OS), such as TTHT defined as the time from the start of the method to androgen deprivation therapy (ADT), and MFS defined as the time from the start of the method to the first detectable distant metastases of bone or soft tissue on radiographic imaging by conventional imaging (i.e., CT / MRI and bone scan, as assessed by BIRC using RECIST 1.1) or death from any cause (whichever occurs first), OS is defined as the time from the date the method begins to the date of death from any cause, wherein the method includes the following steps:

[0112] (First) SBRT is applied to the patient;

[0113] (2) Administer a therapeutically effective amount of the PSMA-bound RLT agent to the patient.

[0114] These are just a few examples of possible combinations of embodiments 1.1 to 1.19. Any other combinations are disclosed herein as further embodiments.

[0115] This disclosure further provides the following examples:

[0116] 2.1 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0117] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0118] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0119] The treatment described therein is characterized by a castration 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 SBRT alone.

[0120] 2.2 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0121] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0122] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0123] The treatment described therein is characterized by a delay in disease recurrence 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.

[0124] 2.3 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0125] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0126] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0127] The treatment described therein is characterized by a delay in the occurrence of hormone castration 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% compared to the application of SBRT alone.

[0128] 2.4 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0129] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0130] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0131] The treatment described therein is characterized by maintaining quality of life by delaying androgen deprivation therapy (ADT) treatment 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% compared to SBRT alone.

[0132] 2.5 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA), comprising the following steps:

[0133] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0134] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0135] The treatment described therein is characterized by a time to hormone therapy (TTHT) (e.g., defined as the time from the start of the method to the commencement of androgen deprivation therapy (ADT)) that is extended 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% compared to the application of SBRT alone.

[0136] 2.6 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0137] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0138] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0139] The treatment described therein is characterized by a metastasis-free survival (MFS) 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% as measured by conventional imaging, compared to SBRT alone.

[0140] 2.7 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0141] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0142] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0143] The treatment described therein is characterized by a metastasis-free survival (MFS) 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% compared to SBRT alone. MFS is defined, for example, as the time from the start of the method to the first detectable distant metastasis to bone or soft tissue on radiographic imaging by conventional imaging (i.e., CT / MRI and bone scan) (as assessed by BIRC using RECIST 1.1 mortality) or death from any cause, whichever occurs first.

[0144] 2.8 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA), comprising the following steps:

[0145] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0146] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0147] The treatment described therein 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 controlling the progression of recurrent tumors to fatal metastatic disease compared with SBRT alone.

[0148] 2.9 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA), comprising the following steps:

[0149] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0150] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0151] The treatment described therein is characterized by a metastasis-free survival (MFS) 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% compared to SBRT alone. MFS is defined, for example, as the time from the start of the method to the first detectable distant metastasis of bone or soft tissue on radiographic imaging by conventional imaging (i.e., CT / MRI and bone scan, as assessed by the investigator using RECIST 1.1) or death from any cause, whichever occurs first.

[0152] 2.10 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA), comprising the following steps:

[0153] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0154] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0155] The treatment described therein is characterized by a time to prostate-specific antigen (PSA) progression (TTPSAP) that is prolonged 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% compared to SBRT alone. TTPSAP is defined, for example, as the time from the start of the method to the first PSA progression 1 [wherein the first PSA progression 1 can be defined as a PSA rise confirmed by repeated measurements after at least 3 weeks, and the rise is at least greater than 25% and above the lowest point or baseline ≥ 2 ng / mL, whichever is lower].

[0156] 2.11 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0157] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0158] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0159] The treatment described therein is characterized by a radiographic progression-free survival (rPFS) 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% compared to SBRT alone. rPFS is defined, for example, as the time from the start of the treatment to the first confirmed radiographic progression of disease or death from any cause by routine imaging (i.e., CT / MRI and bone scan) using RECIST 1.1, whichever occurs first [wherein the rPFS may be analyzed according to BIRC and researcher assessments, respectively].

[0160] 2.12 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0161] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0162] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0163] The treatment described therein 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% to the next therapy (local or systemic) compared to SBRT alone. The time to the next therapy (local or systemic) is defined, for example, as the time from the start of the treatment to the initiation of the next therapy line (local or systemic) [wherein the next therapy line is defined as the first new (local or systemic) antitumor therapy initiated after the discontinuation of the study treatment, regardless of the reason for the end of treatment (EOT).]

[0164] 2.13 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0165] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0166] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0167] The treatment described therein is characterized by a 24-month PSA PFS (≥ 0.5 ng / mL) 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% compared to SBRT alone. 24-month PSA PFS is defined, for example, as PSA PFS at 24 months [where PSA PFS is defined as the time from the date of randomization to the date of the first recorded PSA progression 2 or death from any cause (whichever occurs first), and PSA progression 2 is defined as a PSA concentration confirmed by repeated measurements at least 3 weeks above the lowest point (or baseline, if lower) by ≥ 0.5 ng / mL].

[0168] 2.14 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0169] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0170] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0171] The treatment described therein is characterized by a time to symptomatic progression that is extended 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% compared to SBRT alone. The time to symptomatic progression is defined, for example, from the start of the method to a deterioration in Eastern Cooperative Oncology Group (ECOG) performance status (PS), clinical progression as assessed by researchers, escalation of cancer-related pain, and worsening of disease-related symptoms (all leading to the initiation of new systemic anticancer therapy), or to the appearance of clinically significant symptoms due to local or regional tumor progression (leading to surgery or radiation therapy).

[0172] 2.15 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0173] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0174] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0175] The treatment described therein is characterized by a quality of life 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% compared to SBRT alone, as assessed by the Functional Assessment of Cancer Therapy-P-Prostate Questionnaire.

[0176] FACT-P assesses symptoms / problems associated with prostate cancer and its treatment. It is a combination of the FACT-G General and the Prostate Cancer Subscale (PCS). The FACT-G General is a 27-item measure of quality of life (QoL), providing a total score and subscale scores: physical (0-28), functional (0-28), social (0-28), and affective (0-24). The total score ranges from 1 to 108, with higher scores indicating better total and subscale scores. The PCS is a 12-item prostate cancer subscale that inquires about prostate cancer-specific symptoms and problems (range 0-48, with higher scores being better). The FACT-P total score is the sum of the scores from all five subscales of the FACT-P questionnaire, ranging from 0 to 156. Higher scores indicate better functional status and quality of life.

[0177] 2.16 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0178] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0179] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0180] The treatment described therein is characterized by a reduction in pain of at least 50%, 60%, 70%, 80%, 90%, or 100% compared to the application of SBRT alone, as assessed by the Brief Pain Scale-Short Form (BPI-SF) questionnaire.

[0181] The Pain Intensive Pain Assessment Questionnaire (BPI-SF) is a publicly available pain assessment tool that includes 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 a participant's daily functioning. The pain severity score is the average of BPI-SF questions 3, 4, 5, and 6 (questions asking about the degree of pain, ranging from 0 [no pain] to 10 [the level of pain you can imagine]). Progression in pain severity is defined as an increase in score of 30% or more from baseline without a decrease in analgesic use.

[0182] 2.17 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0183] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0184] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0185] The treatment described therein is characterized by an improvement in health-related quality of life 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% as assessed by the EuroQol 5 Domains 5 Levels Scale (EQ-5D-5L) compared to SBRT alone.

[0186] The EQ-5D-5L is a standardized participant-completed questionnaire used to measure health-related quality of life and converts scores into index values ​​or utility scores. The EQ-5D-5L consists of two components: a health status overview and an optional visual analog scale (VAS). The EQ-5D health status overview comprises five dimensions: mobility, self-care ability, daily activities, pain / discomfort, and anxiety / depression. Each dimension has five levels: 1 = no problem, 2 = minor problem, 3 = moderate problem, 4 = severe problem, and 5 = extreme problem. Higher scores indicate a higher level of problem in each of the five dimensions.

[0187] 2.18 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0188] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0189] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0190] The treatment described therein is characterized by a time to first symptomatic skeletal event (TTSSE) that is prolonged 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% compared to SBRT alone. TTSSE is defined, for example, as the date of the start of the method to the date of the first new symptomatic pathological fracture, spinal cord compression, tumor-related orthopedic surgical intervention, the need for radiation therapy to relieve bone pain, or death from any cause (whichever occurs first).

[0191] 2.19 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0192] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0193] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0194] The treatment is characterized by a reduction in the incidence and / or severity of adverse events (AEs) and / or serious adverse events (SAEs) by at least 50%, 60%, 70%, 80%, 90%, or 100% compared to the application of SBRT alone.

[0195] The distribution of adverse events can be monitored by analyzing the frequency of treatment-associated adverse events (TEAEs), serious adverse events (TESAEs), and deaths caused by AEs, based on relevant clinical and laboratory safety parameters.

[0196] 2.20 A method for treating oligometastatic castration-resistant prostate cancer (OMPC) that is positive for prostate-specific membrane antigen (PSMA) (+), comprising the following steps:

[0197] (1) Administer stereotactic body radiotherapy (SBRT) to patients in need, and

[0198] (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT) agent or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer thereof;

[0199] The treatment described therein is characterized by an overall survival (OS) 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% compared to SBRT alone, where OS is defined, for example, as the time from the start of the method to the date of death from any cause.

[0200] In the embodiments herein, the term "compared to the application of SBRT alone" may also be referred to as "compared to a treatment method consisting of (only) SBRT".

[0201] Based on the methods described in Independent Embodiments 2.1 to 2.20, other embodiments of this disclosure can be formed by combining features of any one of the methods with any one or more features of the other methods.

[0202] In the embodiments disclosed herein, the RLT agent may include at least two components:

[0203] (1) Radioactive nuclide components; and

[0204] (2) Ligand components;

[0205] The radionuclide component (1) comprises:

[0206] (a) at least one radionuclide, preferably selected from the group consisting of: alpha particle emitting radionuclides, beta-electron emitting radionuclides, and Auger electron emitting radionuclides, more preferably beta-electron emitting radionuclides; and

[0207] The ligand component (2) comprises:

[0208] (b) At least one PSMA binding portion;

[0209] (c) Optionally at least one chelating agent for chelating the radionuclide or a salt containing the radionuclide, or a prosthetic residue from a radiohalogenation reaction.

[0210] (d) Optionally at least one linker connecting the PSMA binding portion (b) to the chelating agent or cofactor component (c), preferably the linker being a chemical portion or a covalent bond;

[0211] (e) Optionally at least one additional portion that alters the systemic circulation time, tumor uptake, and / or biodistribution of the RLT agent, preferably said altered portion comprising an oxyethylene unit, such as oligo or polyoxyethylene-(-CH2-CH2-O-)n-, n = 2 – 100, or an albumin-binding portion (e.g., Evans blue, 4-(p-iodophenyl)butyric acid, 4-(p-methylphenyl)butyric acid, ibuprofen).

[0212] In the embodiments disclosed herein, the radionuclides 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, preferably from the group consisting of: Lu-177 and Tb-161.

[0213] In the embodiments disclosed herein, the radionuclide preferably has a half-life of about 2 to about 10 days, more preferably about 5 to about 10 days, more preferably about 6 to about 8 days, and even more preferably about 6 or about 7 days; and the maximum energy of the β-electron is about 0.3 to about 1.0 MeV, preferably about 0.5 to about 0.8 MeV, more preferably about 0.5, 0.6, 0.7 or 0.8 MeV, and even more preferably about 0.5 or about 0.6 MeV.

[0214] In the embodiments disclosed herein, the radionuclides are preferably β-electron emitting radionuclides with an absorption electron energy fraction / decay of 100 to 300 keV / decay, 120 to 250 keV / decay, about 150 keV / decay (e.g., for Lu-177: 147 keV) to about 200 keV / decay (e.g., for Tb-161: 196 keV / decay).

[0215] In the embodiments disclosed herein, the ligand may be selected from 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, EB-PSMA 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, pelgifatamab, NG001, ADVC001, RPS-072 and RPS-074, preferably the group consisting of PSMA-617, PSMA I&T and PSMA-R2.

[0216] In embodiments of the present invention, the PSMA binding portion may contain at least two amino acids linked by urea or phosphoramide groups, preferably glutamic acid-urea-lysine (GUL), or antibodies or fragments thereof, such as TLX591, J591, roxopertuzumab, IAB2M, GCP-05, 1H8H5, SP29, or FOLH1.

[0217] In the embodiments disclosed herein, the radioligand therapeutic agent may be selected from the group consisting of: [177Lu]Lu-PSMA-617 (lutetium (177Lu) vepivotide talracetam), [177Lu]Lu-EB-PSMA-617 (Evans blue modified [177Lu]Lu-PSMA-617), [177Lu]Lu-PSMA I&T (lutetium (177Lu) zadavotide gulracetam), [161Tb]Tb-PSMA-617 (terbium (161Tb) vepivotide talracetam), [161Tb]Tb-EB-PSMA-617 (Evans blue modified [161Tb]Tb-PSMA-617), and [161Tb]Tb-PSMA I&T (terbium (161Tb) zadavote gracilitan), preferably [177Lu]Lu-PSMA-617 (lutetium (177Lu) verpivotide gracilitan) or [161Tb]Tb-PSMA-617 (terbium (161Tb) verpivotide gracilitan), more preferably [177Lu]Lu-PSMA-617 (lutetium (177Lu) verpivotide gracilitan).

[0218] In the embodiments disclosed herein, the PSMA-binding moiety is glutamic acid-urea-lysine (GUL), and the linker comprises residues of (2-naphthyl)-L-alanine and trans-4-aminomethyl-cyclohexanecarboxylic acid, or the linker may comprise residues of optionally substituted phenylalanine and / or optionally substituted tyrosine, preferably phenylalanine and substituted tyrosine, more preferably phenylalanine and iodine-substituted tyrosine, and even more preferably D-phenylalanine and iodine-substituted D-tyrosine.

[0219] In the embodiments disclosed herein, the radioligand therapeutic agent is administered once every about 5 to about 10 weeks, preferably about 6 to about 8 GBq, more preferably about 6.5 to about 7.8 GBq, more preferably 7.4 (± 10%) GBq, for up to about 4 to about 6 cycles, preferably about 4 cycles, at a dose of about 6 to about 8 weeks, more preferably 6 (± 1) weeks (i.e., 1 cycle).

[0220] In the embodiments disclosed herein, PSMA positivity of OMPC is determined by positron emission tomography (PET) using PSMA combined with a radioligand diagnostic or imaging agent, wherein the radioligand imaging agent comprises:

[0221] (1) Diagnostic radionuclide components; and

[0222] (2) Ligand components;

[0223] The radionuclide component (1) comprises:

[0224] (a) at least one positron-emitting radionuclide; and

[0225] The ligand component (2) comprises:

[0226] (b) At least one PSMA binding portion;

[0227] (c) Optionally at least one chelating agent for chelating the radionuclide or a salt containing the radionuclide, or a prosthetic residue from a radiohalogenation reaction.

[0228] (d) Optionally at least one linker connecting the PSMA binding portion (b) to the chelating agent / cofactor component (c), preferably the linker being a chemical portion or a covalent bond.

[0229] In the embodiments disclosed herein, the diagnostic radionuclide is selected from the group consisting of: F-18, Ga-67, Ga-68, and Cu-64.

[0230] In the embodiments disclosed herein, the ligand component may be selected from the group consisting of: PSMA-11 (Gozetin), DCPyL (if labeled with 18F, it may be PYLARIFY, INN:pyrflufosstat F-18, also simply referred to as PyL), 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.

[0231] Form of medical use

[0232] The above embodiments are formulated as treatment method claims. They can also be formulated as other forms of second medical use, such as those shown below, where the medicament is an RLT agent (alone or in combination with other agents), the indication is OMPC as specified in the above embodiments, and the features are those mentioned in the above embodiments:

[0233] The present invention provides a [medicine] or any pharmaceutically acceptable salt thereof for treating [the indication], characterized by [features].

[0234] Alternatively, the present invention provides a method for treating a patient requiring treatment for an indication, the method comprising administering an effective amount of the drug or any pharmaceutically acceptable salt thereof, wherein the treatment is characterized by the following features.

[0235] As a further alternative, the present invention provides the use of [the drug] or any pharmaceutically acceptable salt thereof in the preparation of a drug for treating [the indication], characterized by [features].

[0236] As a further alternative, the present invention provides the use of [the drug] or any pharmaceutically acceptable salt thereof for the treatment of [the indication], characterized by [features].

[0237] As a further alternative, the present invention provides a medicament for treating [the indication], comprising [the drug] or any pharmaceutically acceptable salt thereof, characterized by [the following features].

[0238] Patient criteria

[0239] In some embodiments of this disclosure, one or more patients may, or in other embodiments must, suffer from biochemical relapse following definitive treatment of the prostate via RP (alone or in combination with postoperative radiation to the prostate bed / pelvic lymph nodes) or XRT (prostate alone or prostate with seminal vesicles and / or pelvic lymph nodes) and / or brachytherapy prior to randomization. Biochemical relapse is defined as: a minimum PSA of +2 ng / mL after XRT (if the participant received radiation therapy to the entire prostate) and PSA > 0.2 ng / mL rising after RP (with or without postoperative RT).

[0240] In some embodiments of this disclosure, one or more patients may, or in other embodiments must, have OMPC with ≤ 5 PSMA-positive metastatic lesions at the time of screening PSMA PET / CT scans (using gallium (68Ga) gozepeptide or pivofosstat (18F)), as visually assessed using the methodology proposed by BIRC in Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) (Eiber et al. 2018). Metastatic lesions may include regional / pelvic lymph nodes (N1), distant lymph nodes (M1a), bone (M1b), lungs, and other viscera (M1c) (excluding the liver and brain using AJCC 8 classification). When counting the number of oligometastatic lesions, each lesion is counted as a distinct metastatic lesion regardless of its anatomical location (e.g., one pelvic and one extrapelvic lymph node may be counted as two metastatic lesions).

[0241] In some embodiments of this disclosure, the patient may, or must, have the following conditions:

[0242] According to the AJCC8 classification at the time of screening, at least one PSMA-positive lesion should be a distant metastasis (M1). For AJCC M staging, PSMA PET information should be used.

[0243] In some embodiments of this disclosure, one or more patients may, or in other embodiments must, have negative routine imaging for M1 disease at the time of screening.

[0244] Notice:

[0245] • For patients who refuse in the embodiments of this disclosure, CI-positive M1 lesions should be clearly defined on CI scans, i.e., likely not attributable to findings that are thought to represent something other than a tumor (e.g., degenerative or post-traumatic changes or Paget's disease in bone lesions).

[0246] • Prior knowledge of a positive PSMA PET scan should not affect the radiologist's (reader's) determination of a positive CI scan. This may involve two different readers: one for PSMA PET and one for CI. The reader will not be able to see the PSMA PET scan results while reading the CI scan. After reading the PSMA PET scan, the reader should not modify their assessment of the CI scan (e.g., changing a previously ambiguous lesion in the CI to a definitive one). Similarly, a positive biopsy should not affect the reader's assessment of a positive CI scan. More details on the reading paradigm will be provided in the imaging protocol.

[0247] • An MRI used for a radiotherapy plan may show M1 disease, but this will not exclude a participant from the study if the lesion is negative based on a baseline CT or bone scan.

[0248] • Patients with pelvic disease (N1) seen on routine imaging are included in the examples if the local diffusion is below the common iliac artery bifurcation (as defined in AJCC 8 for local disease).

[0249] • Regardless of whether PSMA PET is positive, the examples do not exclude distal lymph node disease (M1a) visible in each CI with a short axis less than 10 mm.

[0250] In some embodiments of this disclosure, the patient may, or must, have the following conditions:

[0251] All metastatic lesions identified during screening should be eligible for SBRT.

[0252] In some embodiments of this disclosure, the patient may, or must, have the following conditions:

[0253] If a patient has previously undergone SBRT for OMPC, disease progression (e.g., new PSMA PET lesions) may / must be demonstrated prior to randomization. Previously treated lesions may / must remain stable on baseline imaging scans and will not be counted in the 1-5 lesions required for this study. Patients whose previously treated lesions were identified as M1 by bone scan or CT prior to the previous SBRT are excluded in this study.

[0254] Screening confirms primary tumor control: If local recurrence is suspected, MRI is required to rule it out. Patients with MRI or PET-positive local lesions require biopsy to rule out local progression. These patients with local recurrence (with biopsy-proven local disease or with MRI or PET-positive local lesions without biopsy) may be included in the examples after salvage therapy for the local disease. Note: The examples cover patients who previously received pelvic RT (salvage pelvic RT) for local recurrence after RP.

[0255] In some embodiments of this disclosure, one or more patients must have < 10 months of PSADT at screening or in other embodiments [PSADT will be calculated using a linear regression model of PSA and the normal logarithm of time (Pound et al. 1999)].

[0256] In some embodiments of this disclosure, patients may or must have a non-castrated testosterone level >100 ng / dL at the time of screening, or in other embodiments.

[0257] In some embodiments of this disclosure, one or more patients may not have, or in other embodiments must not have, de novo OMPC at the start of treatment.

[0258] In some embodiments of this disclosure, one or more patients may not have, or in other embodiments must not have, received any prior therapy consisting of any of the following groups:

[0259] a. ADT, including bilateral orchiectomy

[0260] • If the last dose of ADT (or ADT+ARPI) was taken 12 months prior to the start of treatment, the example covers patients who received XRT or RP and completed adjuvant ADT (or ADT+androgen receptor pathway inhibitor (ARPI)) before relapse.

[0261] • Patients who discontinue ADT due to disease progression are excluded from the examples (i.e., CRPC patients).

[0262] b. Other hormone therapies. For example...

[0263] • Use estrogen, 5-alpha reductase inhibitors (finasteride, dutasteride), and other steroid synthesis inhibitors (aminoglutamine).

[0264] • First-generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone acetate).

[0265] • Second-generation antiandrogens (e.g., enzalutamide, apalutamide, and dalostamide), or

[0266] • CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone, ketoconazole) [allowing short-term ketoconazole treatment (< 28 days)],

[0267] c. Radiopharmaceuticals (e.g., Strontium-89, PSMA-targeted radioligand therapy)

[0268] d. Immunotherapy (e.g., sipuleucel-T).

[0269] e. Chemotherapy, unless administered in an adjuvant / neoadjuvant setting completed within > 12 months prior to randomization, or

[0270] f. Any other investigational or systemic drugs used for metastatic diseases.

[0271] In some embodiments of this disclosure, one or more patients may or must not receive radiotherapy, external beam radiation therapy (EBRT), or brachytherapy within 28 days prior to randomization.

[0272] In some embodiments of this disclosure, one or more patients may not, or in other embodiments must not, receive concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, hormone therapy, PARP inhibitors, biotherapy, or any investigational therapy.

[0273] definition

[0274] In terms of value, “about” means ± 25%, preferably ± 20%, more preferably ± 15%, even more preferably ± 10%, even more preferably ± 5%.

[0275] In terms of weeks or periods, “approximately” means ±2, preferably ±1.

[0276] PSMA-617 or Vipivote teraracetam refers to the “cold” ligand (the ligand without a radionuclide) of PLUVICTO, namely INN: lutetium (177Lu) vepivotide teraracetam.

[0277] PSMA I&T (Zadavotetrazetan) refers to the “cold” ligand (non-radioactive ligand) of [177Lu]Lu-PSMA I&T (INN: lutetium (177Lu)zadavotetrazetan), and is commercially available from ABX, Radberg, Germany. Methods for producing clinically applicable pharmaceutical products using this RLT agent are described in US 11,129,912 B1 and US 11,491,246 B2.

[0278] Hormone therapy: This includes any androgen-directed therapy, such as finasteride, dutasteride, bicalutamide, apalutamide, abiraterone, or enzalutamide, or taxane-based chemotherapy (docetaxel or cabazitaxel).

[0279] PSMA+: Prostate cancer (including its metastases) is a heterogeneous cancer. Not all cancer cells may be PSMA+, but only a portion, or a portion of cells may show only low or poor 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%, even more preferably at least about 90% of prostate cancer cells (including metastatic cells) express PSMA at a considerable level / to a considerable extent / in a considerable amount.

[0280] OMPC: PCs with ≤ 5 PSMA-positive metastatic lesions on PSMA PET / CT scans (using gallium (68Ga) gozepeptide or pivofosstat (18F)), as visually assessed using the methodology proposed in BIRC’s Standardized Assessment of Molecular Imaging for Prostate Cancer (PROMISE) (Eiber et al. 2018). Metastatic lesions may include regional / pelvic lymph nodes (N1), distant lymph nodes (M1a), bone (M1b), lungs, and other viscera (M1c) (excluding the liver and brain using AJCC 8 classification). When counting oligometastatic lesions, each lesion is counted as a distinct metastatic lesion regardless of its anatomical location (e.g., one pelvic and one extrapelvic lymph node will be counted as two metastatic lesions). References

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[0360] The disclosure will be described in more detail and with more specific examples below, but these examples are not intended to limit the disclosure.

[0361] Reference Example 1 Early clinical trials

[0362] Title

[0363] lutetium-177-PSMA-617 (Bullseye, also known as Bullseye-2) in oligometastatic hormone-sensitive prostate cancer

[0364] Background

[0365] [ 177 Lu-PSMA-617 radioligand therapy (RLT) is a novel treatment for patients with metastatic castration-resistant prostate cancer. Previously, we showed that... 177 Lu-PSMA-617 has been shown to produce encouraging results and minimal toxicity in patients with oligometastatic hormone-sensitive prostate cancer (mHSPC) expressing PSMA (CCR, 2021). [Usage] 177 Lu-PSMA-617 RLT can delay androgen deprivation therapy (ADT), thereby delaying ADT-related toxicities. We hereby report interim results from a randomized trial analysis using [ 177 Lu]Lu-PSMA-617 RLT compared to the time without ADT for delayed ADT (current standard care; SoC).

[0366] Methods

[0367] This is an ongoing international, multicenter, open-label, randomized phase 2 trial (NCT04443062). 58 patients will be randomized in a 1:1 ratio. Eligibility includes rapidly progressing HSPC following topical treatment (PSA doubling time <6 months), and according to […]. 18F]PSMA-PET / CT showed a maximum of 5 metastases. Patients can receive 2+2 cycles of 7.4 GBq [ 177 Lu]Lu-PSMA-617. The primary outcome is progression-free survival (i.e., time without ADT). Disease progression (PD) is defined as a 100% increase in PSA after ADT initiation and randomization, or radiographic or clinical progression. Secondary outcomes are PSA response and toxicity after CTCAE v5.0.

[0368] Results

[0369] To date (April 3, 2023), 42 patients have been enrolled. Their median PSA at enrollment was 4.5 ng / mL (range: 1.3–38). During a median follow-up of 6 months (range 1–20 months), SoC and [ 177 In the Lu-PSMA-617 group, 77% (17 / 22) and 10% (2 / 20) respectively met the definition of progression-free survival (PD). The median PD survival in the SoC group was 4 months, while [ 177 The Lu-PSMA-617 group did not reach this level (HR 0.03; 95% CI 0.004 to 0.227; p < 0.001). The most common treatment-related adverse events were grade 1 dry mouth (70%), grade 1 fatigue (61%), grade 1 nausea (35%), and grade 1 myelotoxicity (30%). All of these treatment-related adverse events were transient. Grade ≥ 2 adverse events were observed in less than 10% of patients. One patient experienced grade 3 dry eye and grade 2 dry mouth. The SoC group compared to [ 177 The median percentage change in PSA in the Lu]Lu-PSMA-617 group was +114% and -91%, respectively. Currently, 55% (11 / 20) of the treated patients have experienced a PSA reduction of more than 90%, with five patients achieving complete biochemical remission. Some patients also showed CR on PSMA PET.

[0370] Conclusions

[0371] [ 177 Lu-PSMA-617 RLT has shown promising efficacy in patients with oligometastatic HSPC to delay ADT with minimal and mostly transient side effects. Following surgery and external beam radiation therapy, [ 177 Lu-PSMA-617 may become a third treatment option for patients with oligometastatic hormone-sensitive prostate cancer, aiming to prolong the ADT-free interval. Final results from this trial are pending.

[0372] Example 1: Key clinical trial (brief description)

[0373] An open-label study compared lutetium (177Lu) vepivotide taracetam with observations in PSMA-positive OMPCs. (PSMA-DC)

[0374] Purpose

[0375] The aim of this study was to evaluate the efficacy and safety of lutetium (177Lu) vepivotide taracetam (AAA617) in participants with oligometastatic prostate cancer (OMPC) that had progressed after decisive therapy for the primary tumor. Data from this study will provide evidence for AAA617 treatment in patients with early-stage prostate cancer to control recurrent tumor progression to lethal metastatic disease while maintaining quality of life by delaying androgen deprivation therapy (ADT).

[0376]

[0377]

[0378] Further study of details

[0379] Key outcome measures:

[0380] • Blinded Independent Review Committee (BIRC) assesses metastasis-free survival (MFS) [Timeframe: from the date of randomization until the first radiologically detectable evidence of distant bone or soft tissue metastasis or death from any cause (whichever comes first), with an assessment period of up to approximately 30 months].

[0381] Metastasis-free survival (MFS) assessed by the Blinded Independent Review Committee (BIRC) is defined as the time from randomization to the first detectable distant metastasis to bone or soft tissue on radiographic imaging by routine imaging (i.e., CT / MRI and bone scan) (as assessed by the BIRC using RECIST 1.1) or death from any cause (whichever occurs first).

[0382] Participants who were alive without distant metastasis at the data cutoff or lost follow-up at the time of analysis will undergo MFS review at their last adequate radiographic evaluation. Clinical deterioration without objective radiographic evidence will not be considered documented distant metastasis.

[0383] Secondary outcome measure:

[0384] • Key secondary endpoint: Time to hormone therapy (TTHT) [Time range: from randomization date to androgen deprivation therapy (ADT) date, assessment up to approximately 74 months]

[0385] The time to hormone therapy (TTHT) is defined as the time from randomization to androgen deprivation therapy (ADT). The type of hormone therapy will be determined by the researchers themselves.

[0386] • Researchers assessed metastasis-free survival (MFS) [timeframe: from the date of randomization until the first radiographically detectable evidence of distant bone or soft tissue metastasis or death from any cause (whichever comes first), with an assessment period of approximately 74 months].

[0387] Researcher-assessed metastasis-free survival (MFS) is defined as the time from randomization to the first detectable distant metastases in bone or soft tissue on radiographic imaging via routine imaging (i.e., CT / MRI and bone scan) (as assessed by researchers using RECIST 1.1) or death from any cause, whichever occurs first.

[0388] • Time to Prostate-Specific Antigen (PSA) Progression (TTPSAP) [Time range: from randomization date to the date of first PSA progression, assessment time up to approximately 74 months]

[0389] Time to prostate-specific antigen (PSA) progression (TTPSAP) is defined as the time from randomization to first PSA progression 1. First PSA progression 1 is defined as a PSA increase confirmed by repeated measurements at least 3 weeks later, which is at least 25% higher than the lowest point or baseline (whichever is lower) and ≥ 2 ng / mL.

[0390] • Radiological progression-free survival (rPFS) [Time range: from the date of randomization until the date of radiological progression or death from any cause (whichever comes first), with an assessment period of up to approximately 74 months]

[0391] Radiographic progression-free survival (rPFS) is defined as the time from randomization to the first confirmed radiographic progression of disease or death from any cause via routine imaging (i.e., CT / MRI and bone scan) using RECIST 1.1, whichever occurs first. rPFS will be analyzed separately based on BIRC and investigator assessments.

[0392] • Time to the next line of therapy (local or systemic) [Time range: from the randomization date until the start of the next line of therapy (local or systemic), with an evaluation period of up to approximately 74 months]

[0393] The time to the next therapy (local or systemic) is defined as the time from randomization to the start of the next therapy line (local or systemic). The next therapy line is defined as the first new (local or systemic) antitumor therapy started after the study treatment was discontinued (regardless of the reason for treatment end (EOT)).

[0394] • 24-month PSA PFS [Time range: from the randomization date until the date of first recorded PSA progression 2 or death from any cause (whichever comes first), with an assessment period of approximately 74 months]

[0395] 24-month PSA PFS (≥ 0.5 ng / mL) is defined as PSA PFS at 24 months. PSA PFS is defined as the time from the randomization date up to the date of first recorded PSA progression 2 or death from any cause, whichever comes first. PSA progression 2 is defined as a PSA concentration ≥ 0.5 ng / mL confirmed by repeated measurements at least 3 weeks later to be above the lowest point (or baseline, if lower).

[0396] • Time to symptomatic progression [Time range: from randomization date until Eastern Cooperative Oncology Group (ECOG) performance status (PS) deterioration, assessment period up to approximately 74 months]

[0397] The time to symptomatic progression is defined as the time from randomization to deterioration of performance status (PS) in the Eastern Cooperative Oncology Group (ECOG), clinical progression as assessed by researchers, escalation of cancer-related pain, and worsening of disease-related symptoms (all leading to the initiation of new systemic anticancer therapies), or the time to the appearance of clinically significant symptoms due to local or regional tumor progression (leading to surgery or radiation therapy).

[0398] • Functional Assessment of Cancer Therapy – Prostate (FACT-P) Questionnaire [Time range: from randomization date to 42-day safety follow-up, assessment period up to approximately 74 months]

[0399] FACT-P assesses symptoms / problems associated with prostate cancer and its treatment. It is a combination of the FACT-G General and the Prostate Cancer Subscale (PCS). The FACT-G General is a 27-item measure of quality of life (QoL), providing a total score and subscale scores: physical (0-28), functional (0-28), social (0-28), and affective (0-24). The total score ranges from 1 to 108, with higher scores indicating better total and subscale scores. The PCS is a 12-item prostate cancer subscale that inquires about prostate cancer-specific symptoms and problems (range 0-48, with higher scores being better). The FACT-P total score is the sum of the scores from all five subscales of the FACT-P questionnaire, ranging from 0 to 156. Higher scores indicate better functional status and quality of life.

[0400] • Brief Pain Inventory – Short Form (BPI-SF) Questionnaire [Time range: from randomization date to 42-day safety follow-up, assessment period up to approximately 74 months]

[0401] The Pain Intensive Pain Assessment Questionnaire (BPI-SF) is a publicly available pain assessment tool that includes 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 a participant's daily functioning. The pain severity score is the average of BPI-SF questions 3, 4, 5, and 6 (questions asking about the degree of pain, ranging from 0 [no pain] to 10 [the level of pain you can imagine]). Progression in pain severity is defined as an increase in score of 30% or more from baseline without a decrease in analgesic use.

[0402] • EuroQol 5-Domain 5-Level Quality of Life Scale (EQ-5D-5L) [Time range: from randomization date to 42-day safety follow-up, assessment period up to approximately 74 months]

[0403] The EQ-5D-5L is a standardized participant-completed questionnaire used to measure health-related quality of life and converts scores into index values ​​or utility scores. The EQ-5D-5L consists of two components: a health status overview and an optional visual analog scale (VAS). The EQ-5D health status overview comprises five dimensions: mobility, self-care ability, daily activities, pain / discomfort, and anxiety / depression. Each dimension has five levels: 1 = no problem, 2 = minor problem, 3 = moderate problem, 4 = severe problem, and 5 = extreme problem. Higher scores indicate a higher level of problem in each of the five dimensions.

[0404] • Time to first symptomatic skeletal event (TTSE) [Time range: from randomization date to end of treatment (EOT) or death (whichever occurs first), assessment period up to approximately 74 months]

[0405] The time to SSE (TTSSE) is defined as the date of randomization to the date of the first new symptomatic pathological fracture, spinal cord compression, tumor-related orthopedic surgical intervention, the need for radiation therapy to relieve bone pain, or death from any cause (whichever occurs first).

[0406] • Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) [Time range: from randomization date to 42-day safety follow-up, assessment period up to approximately 74 months]

[0407] The distribution of adverse events will be determined by monitoring relevant clinical and laboratory safety parameters through analysis of the frequency of treatment-associated adverse events (TEAEs), serious adverse events (TESAEs), and deaths caused by AEs.

[0408] • Dosage modifications and intensity of AAA617 [Time range: from randomization date to end of treatment (EOT), assessment period up to approximately 30 months]

[0409] Descriptive statistics will be used to evaluate and summarize the dose modifications (dose interruptions and reductions) and dose intensities of AAA617.

[0410] • Overall survival (OS) [Time range: from the randomization date to the date of death from any cause, with an assessment period of up to approximately 74 months]

[0411] Overall survival (OS) was defined as the time from the randomization date to death from any cause. The OS of participants who were still alive or lost to follow-up at the end of the study was reviewed on the date of their last contact.

[0412] Expected enrollment: 450

[0413]

[0414] Detailed description:

[0415] All participants will be eligible for assessment and will undergo baseline disease assessment, including forced gallium (68Ga) gozetide (also known as [68Ga]Ga-PSMA-11) or pivofosstat (18F) (also known as [18F]DCFPyL) PET / CT scans and routine imaging (i.e. CT / MRI and bone scans).

[0416] Pyrflufosstat (18F) PET / CT scans will be performed in approved countries.

[0417] After randomization and before starting AAA617 treatment or observation, all metastatic prostate cancer (PC) lesions will undergo stereotactic total body radiation therapy (SBRT).

[0418] • The SBRT procedure lasts approximately 3 weeks.

[0419] • For participants randomized to the study group (AAA617), treatment will last for up to 4 cycles of AAA617. For participants randomized to the control group (observation group), treatment will end at the last part of SBRT administration.

[0420] • Visits were scheduled for weeks 1 and 3 of each of the four cycles, and then every 16 weeks thereafter (for both groups) until the first disease progression event (RECIST 1.1).

[0421] • The study lasted approximately 6.5 years.

[0422] • For participants in the observation group, after the start of ADT, if distant metastatic radiological progression (MFS event) is detected by routine imaging and confirmed by BIRC, crossover to AAA617 is permitted.

[0423] After treatment, participants who were randomized to the study group or crossed over from the control group will undergo long-term safety assessments every 32 weeks until the end of this study, and will participate in a follow-up study after the completion of this study, starting with the first dose of AAA617, for a total of 10 years. All participants will be followed up for survival.

[0424] qualified

[0425]

[0426] standard

[0427] Inclusion criteria:

[0428] 1. A signed informed consent form must be provided before participating in the research.

[0429] 2. Participants must be adults aged 18 or older at the time of informed consent.

[0430] 3. During screening, the ECOG fitness level is 0 or 1.

[0431] 4. Researchers determined during screening that participants' life expectancy must be ≥ 24 months.

[0432] 5. Histologically confirmed prostate cancer prior to randomization

[0433] 6. Participants must have biochemical relapse following definitive treatment of the prostate via RP (alone or with postoperative radiation to the prostate bed / pelvic lymph nodes) or XRT (prostate alone or prostate with seminal vesicles and / or pelvic lymph nodes) and / or brachytherapy prior to randomization. Biochemical relapse is defined as: a minimum PSA of +2 ng / mL after XRT (if the participant received radiation therapy to the entire prostate) and PSA > 0.2 ng / mL rising after RP (with or without postoperative RT).

[0434] 7. Participants must meet the following criteria: OMPC with ≤ 5 PSMA-positive metastatic lesions at the time of screening PSMA PET / CT scans (using gallium (68Ga) gozepeptide or pivofosstat (18F)), as visually assessed using the methodology proposed by BIRC in the Prostate Cancer Molecular Imaging Standardized Assessment (PROMISE) (Eiber et al. 2018); see Section 8.1 and the Imaging Manual for more details. Metastatic lesions may include regional / pelvic lymph nodes (N1), distant lymph nodes (M1a), bone (M1b), lungs, and other viscera (M1c) (except for the liver and brain using AJCC 8 classification). When counting oligometastatic lesions, each lesion is counted as a distinct metastatic lesion regardless of its anatomical location (e.g., one pelvic and one extrapelvic lymph node will be counted as two metastatic lesions).

[0435] 8. Based on the AJCC8 classification at screening, at least one PSMA-positive lesion should be a distant metastasis (M1). PSMA PET information should be used for AJCCM staging.

[0436] 9. Participants must have negative routine imaging results for M1 disease at the time of screening. Note:

[0437] • For ineligible participants, CI-positive M1 lesions should be clearly defined on CI scans, i.e., not attributable to findings that are thought to represent something other than a tumor (e.g., degenerative or post-traumatic changes or Paget's disease in bone lesions).

[0438] • Prior knowledge of a positive PSMA PET scan should not affect the radiologist's (reader's) determination of a positive CI scan. Two separate readers will be involved: one for the PSMA PET scan and one for the CI scan. The reader will not see the PSMA PET scan results while reviewing the CI scan. After reviewing the PSMA PET scan, the reader should not modify their assessment of the CI scan (e.g., changing a previously ambiguous lesion in the CI to a definitive one). Similarly, a positive biopsy should not affect the reader's assessment of a positive CI scan. More details on the reading paradigm will be provided in the imaging protocol.

[0439] • An MRI used for a radiotherapy plan may show M1 disease, but this will not exclude a participant from the study if the lesion is negative based on a baseline CT or bone scan.

[0440] • Patients with pelvic disease (N1) seen on routine imaging are permitted if the local spread is below the common iliac artery bifurcation (as defined in AJCC 8 for localized disease).

[0441] • Regardless of whether PSMA PET is positive, distal lymph node disease (M1a) with a short axis less than 10 mm can not be ruled out in each CI.

[0442] 10. All metastatic lesions identified during screening should be suitable for SBRT.

[0443] 11. If a patient has previously undergone SBRT for OMPC, disease progression (e.g., new PSMA PET lesions) must be demonstrated prior to randomization. Previously treated lesions must remain stable on baseline imaging scans and will not be counted in the required 1–5 lesions for this study. Participants are ineligible if the previously treated lesion was identified as M1 by bone scan or CT prior to the previous SBRT.

[0444] 12. Screening confirmation of primary tumor control: If local recurrence is suspected, MRI is required to rule it out. Patients with MRI or PET-positive local lesions require biopsy to rule out local progression. These patients with local recurrence (with biopsy-proven local disease or with MRI or PET-positive local lesions without biopsy) may be eligible for the study after salvage therapy for the local disease. Note: Patients who previously received pelvic RT (salvage pelvic RT) for local recurrence after RP are allowed to participate in the study.

[0445] 13. PSADT < 10 months at screening [PSADT will be calculated using a linear regression model of PSA and the normal logarithm of time (Pound et al. 1999)]

[0446] 14. At screening, non-castrated testosterone levels > 100 ng / dL

[0447] 15. Participants who are infected with human immunodeficiency virus (HIV) at screening and during the study period, and who are in good health and have a low risk of acquired immunodeficiency syndrome (AIDS)-related outcomes, may participate in this trial.

[0448] 16. Subjects must have adequate organ function, including the following laboratory values ​​at the time of screening:

[0449] Bone marrow reserve

[0450] • ANC ≥1.5 x 10⁹ / L

[0451] • Platelet count ≥ 100 x 10⁹ / L

[0452] • Hemoglobin ≥ 9 g / dL

[0453] liver

[0454] • Total bilirubin (TBIL) ≤ 2 x institutional upper limit of normal (ULN). For participants known to have Gilbert's syndrome, ≤ 3 x ULN is permitted.

[0455] • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3.0 x ULN.

[0456] • Albumin ≥ 2.5 g / dL

[0457] kidney

[0458] • eGFR ≥ 60 mL / min / 1.73 m2, using the Modified Diet for Kidney Disease (MDRD) equation.

[0459] Exclusion criteria:

[0460] 1. Use participants with de novo OMPC during screening.

[0461] 2. Concurrent bladder outflow tract obstruction or urinary incontinence that is difficult to manage at the time of screening. Note: Participants with bladder outflow tract obstruction or urinary incontinence are permitted to participate, as these can be managed and controlled with existing best practices in care (including pads, drainage).

[0462] 3. Previous treatments:

[0463] a. ADT, including bilateral orchiectomy

[0464] • Patients who received XRT or RP and completed adjuvant ADT (or ADT + androgen receptor pathway inhibitor (ARPI)) before relapse are eligible to participate if their last dose of ADT (or ADT + androgen receptor pathway inhibitor (ARPI) was taken 12 months prior to self-randomization.

[0465] • Participants who are not allowed to stop ADT due to disease progression (i.e., CRPC participants).

[0466] b. Other hormone therapies. For example...

[0467] • Use estrogen, 5-alpha reductase inhibitors (finasteride, dutasteride), and other steroid synthesis inhibitors (aminoglutamine).

[0468] • First-generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone acetate).

[0469] • Second-generation antiandrogens (e.g., enzalutamide, apalutamide, and dalolutamide)

[0470] • CYP17 inhibitors (e.g., abiraterone acetate, oterolone, galetabolone, ketoconazole). Short-term ketoconazole treatment (< 28 days) is permitted.

[0471] c. Radiopharmaceuticals (e.g., Strontium-89, PSMA-targeted radioligand therapy)

[0472] d. Immunotherapy (e.g., sipuleucel-T)

[0473] e. Chemotherapy, unless administered in an adjuvant / neoadjuvant setting completed within > 12 months prior to randomization.

[0474] f. Any other investigational or systemic drugs used for metastatic diseases.

[0475] 4. Herbal and non-herbal products that may lower PSA levels within 28 days prior to randomization (i.e., saw palmetto, pomegranate juice).

[0476] 5. Other investigational drugs were used within 28 days prior to the day of randomization.

[0477] 6. Patients who received radiotherapy, external beam radiotherapy (EBRT), or brachytherapy within 28 days prior to randomization.

[0478] 7. Systemic (oral / intravenous / intramuscular (IM)) corticosteroids within 28 days prior to randomization. Note: Short-term (≤ 4 weeks) use of corticosteroids is permitted during the study period if clinically indicated.

[0479] 8. Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, hormone therapy (see ADT initiation guidelines in Section 6.8.2), PARP inhibitors, biotherapy, or investigational therapy.

[0480] 9. Known hypersensitivity to any investigational treatment or excipient, or to drugs in similar chemical classes.

[0481] 10. The sole purpose of blood transfusions during the screening process is to qualify participants for inclusion in the study.

[0482] 11. Participants diagnosed at screening with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a history of adequately treated malignancies and who have been disease-free / treatment-free for more than 3 years are eligible, such as participants with adequately treated non-melanoma skin cancer and superficial bladder cancer.

[0483] 12. Concurrent serious (as determined by the researcher) medical conditions, including but not limited to uncontrolled infection, known active hepatitis B or C, or other significant comorbidities that the researcher believes would impair research participation or collaboration. Participants with documented active COVID-19 infection (of any severity) at the time of informed consent may only be included if they have fully recovered (in accordance with local guidelines).

[0484] 13. A history of abnormal ECG or current diagnosis indicates a significant safety risk to participants in the study, such as:

[0485] • Accompanied by clinically significant arrhythmias, such as sustained ventricular tachycardia, and clinically significant second- or third-degree AV block without a pacemaker.

[0486] • A known family history of familial long QT syndrome or torsion point

[0487] • Resting heart rate (physical examination or 12-lead ECG) < 60 bpm

[0488] 14. History of physical or mental illness / symptoms that may interfere with research objectives and assessment.

[0489] 15. Any situation that prevents the arm from being raised.

[0490] 16. Sexually active men are unwilling to use condoms during intercourse.

[0491] More information

[0492]

[0493] Keywords:

[0494]

[0495] Other related MeSH terms:

[0496]

[0497] Example 2: pivotal clinical trials

[0498] Title

[0499] An international, prospective, open-label, multicenter, randomized phase III study comparing lutetium (L) 177 Lu) Vepivotide tyraciltan (AAA617) and observation to delay castration or disease recurrence in adult male patients with prostate-specific membrane antigen (PSMA) positive oligometastatic prostate cancer (OMPC);

[0500] In short:

[0501] PSMA-DC: An open-label study comparing lutetium ( 177 Lu) Vipivoxytide Taracetam (also known as [ 177 Lu]Lu-PSMA-617 or 177Observational results of Lu-PSMA-617 (hereinafter referred to as AAA617) and PSMA-positive OMPC.

[0502] Study rationale

[0503] The aim of this study was to evaluate the efficacy and safety of lutetium AAA617 in participants with oligometastatic prostate cancer (OMPC) that had progressed after decisive therapy for the primary tumor. Data from this study will provide evidence for AAA617 treatment of delayed castration, a highly unmet need in this population.

[0504] Benefit / risk assessment

[0505] Various retrospective and prospective studies, including randomized trials, have provided evidence of significant clinical benefit in patients with mCRPC treated with AAA617 (see the AAA617 Investigator's Handbook). Such benefits are expected to extend to the OMPC population.

[0506] Dosimetry studies have confirmed that AAA617 targets PSMA-expressing prostate cancer cells and some normal tissues expressing PSMA (Delker et al. 2016). From the VISION sub-study, on average, the organ receiving the largest absorbed dose was the lacrimal gland at 2.1 Gy / GBq (standard deviation = 0.47), followed by the salivary gland at 0.63 Gy / GBq (standard deviation = 0.36). For a complete six-cycle cumulative administration of 44.4 GBq, the estimated absorbed doses for the lacrimal and salivary glands were 92 Gy (standard deviation = 21) and 28 Gy (standard deviation = 16), respectively. The absorbed dose received by the red bone marrow was 0.035 Gy / GBq (standard deviation = 0.020), with an estimated absorbed dose of 1.5 Gy (standard deviation = 0.90) calculated for a complete six-cycle administration. On average, the kidneys received 0.43 (standard deviation = 0.16) Gy / GBq for a cumulative administration of 44.4 GBq over six complete cycles, resulting in an estimated absorbed dose of 19 (standard deviation = 7.3) Gy for the kidneys.

[0507] AAA617 (Lutetium) 177The safety profile of AAA617 (Vipivotide / Taracetam) includes fatigue, dry mouth, bone marrow suppression (including anemia, thrombocytopenia, lymphopenia, and leukopenia), nausea, vomiting, and renal adverse reactions. All of these adverse events can be attributed to the mechanism of action of AAA617 or are related to aggressive anticancer therapy. Symptomatic hematologic toxicity may occur, but is uncommon. Potential risks may include radiation toxicity effects (e.g., increased risk of carcinogenesis, risk of infertility), late nephrotoxicity, and bleeding events. The safety of AAA617 used with SOCs containing ADT and ARPI has been well characterized in a randomized controlled trial using the same dosing regimen proposed in this study (Sartor et al. 2021).

[0508] Overall, safety data shows that the safety of AAA617 is tolerable and manageable.

[0509] 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.

[0510] During and after AAA617 treatment, radiation exposure to participants, healthcare workers, and family contacts should be minimized in accordance with institutional good radiation safety practices, patient management procedures, and instructions for participants to take subsequent radiation protection measures at home.

[0511] The safety profile of SBRT as a multidisciplinary treatment (MDT) in OMPC has been well characterized in various studies, with no difference between single-part and multi-part administration. Grade 3 or higher acute or any late toxicity is extremely rare (Kalinauskaite et al. 2020). This study standardized the SBRT dosing regimen (see SBRT manual). To avoid any potential overlapping toxicities, AAA617 should be administered at least one week after the completion of the last SBRT part.

[0512] Supportive care is permissible to minimize some risks and should be optimized throughout the study participation. Other treatments for managing PC (not explicitly excluded from the study) should be used according to routine clinical practice and at the investigator's discretion. These may include, but are not limited to, optimal pain control, hydration, and blood transfusions.

[0513] This protocol includes appropriate eligibility criteria and dosing modification and discontinuation rules for AAA617 for toxicity management. By adhering to eligibility criteria and study procedures, and through close clinical monitoring, the risk to participants in this trial can be minimized. This study incorporates routine safety monitoring and periodic safety assessments to identify and report any potential safety issues. Furthermore, to monitor for long-term toxicity, all participants receiving AAA617 during the trial will be monitored for adverse events of concern until death, loss of follow-up, or up to 10 years (whichever occurs first in a post-marketing study).

[0514] Locametz (used for the preparation of injectable gallium) 68 The Ga(gazetide) kit has shown good safety, with mild reactions such as fatigue, nausea, constipation, and vomiting occurring in approximately 1% of patients. Overall, gallium (Ga(gazetide)) has good safety. 68 The risks-benefit profile of Ga (Gozerin imaging agent) is more favorable than anticipated.

[0515] Pylarify® (pyrflufosstat F 18 injection for intravenous use) has demonstrated a favorable safety profile with a mild spectrum of adverse events (AEs) including headache (2%), taste disturbance (2%), and fatigue (1%). More detailed information can be found on the Pylarify® US label. Overall, the risk-benefit profile of Pylarify® imaging agents is more favorable than anticipated.

[0516] Objectives, endpoints, and measures

[0517] Table of objectives and related endpoints

[0518]

[0519]

[0520]

[0521] Primary measure

[0522] This assessment is an accurate description of the treatment effect and reflects strategies for addressing events that occur during the trial that could affect the interpretation of the trial results (e.g., premature discontinuation of treatment).

[0523] The main clinical question of concern is: for adult male participants with lesions treated with SBRT, how does the efficacy of AAA617-based MFS in OMPC treatment compare to observation, regardless of whether study treatment was discontinued, additional SBRT was performed, or a new anti-tumor therapy was started?

[0524] The main metrics are described by the following attributes:

[0525] 1. Group: OMPC participants defined by inclusion / exclusion criteria

[0526] 2. Variables and / or endpoints: MFS is defined as the time from randomization to the first detectable distant metastasis of bone or soft tissue on radiographic imaging via conventional imaging (i.e., CT / MRI and bone scan) (as assessed by BIRC using RECIST 1.1) or death from any cause, whichever occurs first.

[0527] 3. Treatment of Interest: The study drug is AAA617. The control group is observational only. SBRT will be administered to both groups after randomization and before the start of the study treatment / observation.

[0528] 4. Concurrent events:

[0529] • AAA617 suspended for any reason

[0530] • Apply additional SBRT before assessing MFS events via routine imaging (after the final part of the originally planned SBRT).

[0531] • Initiate new anti-tumor therapies, including ADT, before routine imaging assessment of MFS events.

[0532] 5. The pooled measure is the hazard ratio (HR) of MFS between the two treatment groups and the 95% confidence interval, estimated using a Cox proportional hazards model stratified by randomization factor. The primary comparison will be performed using the log-rank test stratified by randomization factor.

[0533] Secondary measures

[0534] Key secondary clinical questions of concern (hypothesis): In the absence of crossover and regardless of whether AAA617 was discontinued, additional SBRT was performed, or a new antitumor therapy was started, how did the treatment effect of AAA617-based TTHT in OMPC compare to observation in adult male participants with lesions treated with SBRT?

[0535] The reason for estimating the critical secondary is that it will capture the effects of the investigational drug and other drugs, including SBRT, while taking into account cross-effects.

[0536] Key secondary factors are described by the following attributes:

[0537] 1. Group: OMPC participants defined by inclusion / exclusion criteria

[0538] 2. Variable / or endpoint: TTHT is defined as the time from randomization to the start of castration therapy (ADT).

[0539] 3. Treatment of Interest: The study drug is AAA617. The control group is observational. SBRT will be administered to both groups after randomization and before the start of the study treatment / observation.

[0540] 4. Concurrent events:

[0541] • AAA617 suspended for any reason

[0542] • Administer additional SBRT before starting ADT (after the last part of the originally planned SBRT).

[0543] • Initiate new anti-tumor therapy before starting ADT.

[0544] • Participants in the observation group were cross-referenced to AAA617

[0545] The summative measures were the TTHT HR between the two treatment groups and the 95% confidence interval (CI) in the target population, estimated using a Cox proportional hazards model stratified by randomization. The primary comparisons will be performed using a log-rank test stratified by randomization.

[0546] Study design

[0547] Overall design

[0548] This international, prospective, open-label, multicenter, randomized phase III study will recruit adult male participants for OMPC. Approximately 450 eligible participants will be randomized in a 2:1 ratio to one of the two treatment groups:

[0549] • Research Group: AAA617

[0550] • Control group: Observation

[0551] All participants will receive SBRT treatment for all metastatic lesions before starting AAA617 or observation.

[0552] The primary objective of this study was to compare observations following AAA617 and SBRT, and to assess MFS in adult OMPC participants as defined by PSMAPET imaging using conventional imaging.

[0553] Screening

[0554] Participants must sign an informed consent form (ICF) before undergoing any study-specific screening assessment. All screening procedures must be completed within 28 days prior to randomization. Participants must register for screening in the Interactive Response Technology (IRT) system and must complete all procedures, prioritizing laboratory and imaging assessments to allow time for results.

[0555] During the screening process, all participants will be assessed for eligibility and will undergo baseline disease evaluation, including mandatory gallium (CGL). 68 Ga) Gozetide or Piflufosstat ( 18 F) PET / CT scan (where it is locally approved and commercially available) and CI scan. All participants meeting all eligibility criteria will be randomized.

[0556] After all the necessary screening procedures are completed and participants' eligibility is verified, participants will be randomized through the IRT system.

[0557] Randomization

[0558] Once all eligibility criteria are met, randomization should be performed within a 28-day screening period. Participants will be randomized in a 2:1 ratio to receive AAA617 or observation only.

[0559] Randomization will be stratified based on the following three factors:

[0560] 1. PSADT: > 6 months vs. ≤ 6 months

[0561] 2. According to gallium ( 68 Ga) Gozetide or Pyrflufosstat ( 18 F) Number of PSMA-positive lesions on PET / CT (based on central readings): 1-3 compared to 4-5

[0562] 3. Location of metastatic disease: According to AJCC 8 classification, distant lymph nodes (M1a) compared to bone (M1b) compared to other distant tissues (including internal organs) (M1c).

[0563] Treatment / observation period

[0564] All participants will receive SBRT targeting all metastatic lesions before initiating AAA617 or beginning observation. The first part of SBRT must be administered within 14 days of randomization. The SBRT procedure has been standardized in this study to avoid variability between different sites (see SBRT manual). End of Treatment 1 (EOT1) will be performed on the day the last SBRT part is administered after SBRT is completed.

[0565] For participants randomized to the study group, AAA617 treatment must begin 7 to 21 days after the final part of the SBRT. Due to unforeseen scheduling delays, C1D1 (i.e., the first dose day of AAA617) may be delayed by up to 3 days. AAA617 is administered at a dose of 7.4 GBq (± 10%) every 6 weeks (± 1 week) for up to 4 cycles.

[0566] Participants in the randomized control group will seek C1D1 consultation 7 to 21 days after administration of the last part of SBRT.

[0567] All participants in both groups will have a site visit on the first day of each cycle (C#W1). A mandatory safety call will be made in week 3 of each cycle (C#W3) to ensure participant safety; optional site study safety visits may also be made at the same time (C#W3) at the researchers' discretion. Unplanned safety visits may be permitted during treatment if deemed necessary at the researchers' discretion.

[0568] For participants in the study group, EOT2 will be performed 42 days (+7 days) after the last dose of AAA617. For participants in the control group, EOT2 will be performed at their week 24 visit.

[0569] Efficacy was assessed every 16 weeks from randomization. At each efficacy assessment, all participants were monitored for efficacy via CT (or MRI, if CT was not tolerated) and whole-body bone scans.

[0570] The primary endpoint of MFS will be assessed by BIRC using routine radiographic images (i.e., CT / MRI and bone scans) provided by the attending physician.

[0571] Crossover period

[0572] If eligible, participants randomized to the control group who have experienced distant metastatic radiographic progression (MFS) events in CI, as confirmed by BIRC and have initiated ADT, will be allowed to crossover to receive AAA617 at the investigator's discretion. After a maximum of 4 doses of AAA617, participants will receive EOT3. During the crossover period, AAA617 will be administered at the same dose / timetable as the participants initially randomized to receive AAA617 as described above.

[0573] Post-treatment follow-up (safety, efficacy)

[0574] 42-day safety follow-up visit

[0575] Following discontinuation of AAA617, all participants (including crossover participants) will undergo a 42-day (+7-day) safety follow-up following the last dose of AAA617 to ensure safety. Note: Safety follow-up will be conducted at EOT2 (or EOT3 for crossover participants).

[0576] Participants in the control group will also be followed up on safety at their week 24 visit.

[0577] Long-term safety follow-up

[0578] After safety follow-up visits (EOT2 / EOT3 visits), participants randomized to the study / crossover group will be followed up every 32 weeks for safety assessment until the end of the study.

[0579] Participants who have received AAA617 and continue to be followed up after the sponsor completes the study will be required to participate in a separate long-term safety study (CAAA617A12402) lasting up to 10 years.

[0580] For control group participants without crossover, long-term safety follow-up is not required. After EOT2, safety monitoring of control group participants will depend on the researchers' preferences based on local clinical practice.

[0581] Efficacy follow-up

[0582] Participants who, after EOT2 in both the study and control groups, or after discontinuation of SBRT or AAA617, do not have distant metastases recorded on routine imaging confirmed by BIRC, will subsequently continue to undergo efficacy assessments every 16 weeks from randomization until distant metastases are confirmed by BIRC on routine imaging, or other discontinuation criteria are met, or if the total number of protocol-defined MFS events that triggered the initial analysis has occurred, whichever occurred first. Furthermore, participants will be followed up on ADT initiation in the study until the protocol-defined TTHT event count has occurred.

[0583] Survival follow-up

[0584] Following discontinuation of study treatment and completion of the applicable follow-up period, participants' status will be collected every 90 days (by telephone) as part of survival follow-up. Every effort should be made to adhere to the survival follow-up schedule and ensure that participant survival status is collected. Survival follow-up will continue until the end of the study and the transition to a long-term safety rolling study.

[0585] Scientific rationale for study design

[0586] AAA617 is effective against PSMA-positive metastatic prostate cancer (Sartor et al. 2021). Several studies have confirmed the presence of PSMA-PET-positive lesions in biochemically recurrent disease settings (McCarthy et al. 2019. Artigas et al. 2021), and therefore, using AAA617 to target PSMA-expressing lesions in early prostate cancer to delay progression or delay other systemic therapies is an effective approach.

[0587] To assess the efficacy of AAA617 in this population, approximately 450 participants with baseline PSMA-positive PET / CT and negative M1 CI were randomized to the study. The randomization ratio for AAA617 compared to the observation-only group was 2:1.

[0588] Randomization will be stratified based on the following factors:

[0589] 1. PSADT: > 6 months vs. ≤ 6 months

[0590] Short PSADT has been associated with a shortened time to metastasis and death in men with post-RP BCR and is therefore expected to have prognostic significance (Pound et al. 1999).

[0591] 2. Based on the number of PSMA-positive lesions on PSMA PET / CT (based on local readings): 1-3 compared to 4-5

[0592] Multiple studies have shown that the number of metastatic sites is associated with survival (Rao et al. 2019).

[0593] 3. Location of metastatic disease: According to AJCC 8 classification, distant lymph nodes (M1a) compared to bone (M1b) compared to other distant tissues (including internal organs) (M1c).

[0594] The location of metastatic disease is a prognostic factor in prostate cancer. A surveillance, epidemiology, and end-outcome (SEER) – Medicare analysis of 3,857 patients found a median overall survival (OS) of 43 months for lymph node metastases only, 24 months for bone metastases only, 16 months for visceral metastases only, and 14 months for both bone and visceral metastases (Gandaglia et al. 2015).

[0595] Stratification by PSADT, number of transfers, and location will support an analytical framework for pre-specified subgroup analyses to avoid intergroup imbalances of factors known to influence primary and key secondary study outcomes.

[0596] PSMA PET scans will be used to select participants for this study. While conventional imaging has been used to define OMPC in the past, many participants may have metastatic disease earlier than it appears in CI. Meta-analyses have confirmed that after PSMA PET, more patients receive targeted RT and surgical resection, while the proportion receiving systemic therapy is reduced by more than 50%, primarily due to fewer patients receiving androgen deprivation therapy (ADT) and fewer patients subsequently undergoing observation (Müller et al. 2019).

[0597] While PSMA-based PET imaging is useful for participant selection, advancements in imaging (CI) are still considered the starting point for classifying metastatic hormone-sensitive prostate cancer (mHSPC). Therefore, CI will be used to establish the primary endpoint of metastatic survival (MFS). Furthermore, the prognostic significance of PSMA-based PET imaging in efficacy assessment is not yet fully understood.

[0598] MFS has been demonstrated as a robust surrogate endpoint for OS in localized prostate cancer and BCR settings (Schweizer et al. 2013, Xie et al. 2017). Considering the long-term expected OS of this population, choosing MFS as an endpoint compared to OS can significantly shorten the study duration without compromising the interpretability of clinical benefit. MFS is a validated study endpoint accepted by various regulatory agencies for evaluating clinical efficacy in similar but castration-resistant settings. MFS is also the primary endpoint of the ongoing Phase III ATLAS registration trial, which uses apalutamide to treat high-risk localized disease patients similar to the population in this study (NCT02531516). Furthermore, a large body of comparative MFS data exists in this population (Paller et al. 2013) to determine the risk / benefit of AAA617 treatment in this population.

[0599] Rationale for AAA617 dose

[0600] In this study, AAA617 was administered at a dose of 7.4 GBq (± 10%) every 6 weeks (± 1 week) for up to 4 cycles. AAA617 at a dose of 7.4 GBq (± 10%) every 6 weeks for up to 6 cycles is a well-established treatment regimen and was approved for metastatic prostate cancer based on the Phase III VISION study (Sartor et al. 2021). In the VISION study, the actual number of administration cycles was 4.5 (mean) and 5 (median). Overall, the treatment regimen was safe, tolerable, and effective.

[0601] In typical metastatic PC trials, AAA617 treatment is administered as six injections every six weeks, including in a hormone-sensitive setting evaluated in the ongoing PSMAddition (NCT04720157) study. (lutetium) 177Clinical experience with vepivotide taracetam (L) is documented in over 60 publications summarizing safety and / or efficacy information from over 1900 participants (see AAA617 Investigator's Handbook, version 7.0). In these series, the dosage range is 1.1–12.0 GBq, and administration is typically followed by 1–9 cycles every 4–12 weeks. Most publications use a 4-cycle regimen of 6 GBq. It is unclear whether fewer than 4 doses are effective, particularly for patients with metastatic lesions detected by PSMA PET in this study. Although a 6-dose regimen is currently approved in the US for the treatment of metastatic disease, based on the VISION study, the low-volume disease cohort treated in this proposed study justifies a lower exposure.

[0602] Furthermore, dosimetry studies supported administration of 7.4 GBq (± 10%) of AAA617 every 6 weeks for up to 6 cycles. Particularly for organs considered at risk of radiation exposure due to exposure levels, such as the salivary glands, lacrimal glands, kidneys, and bone marrow, the radiation exposure in the VISION sub-study (N = 29), which tested the same dose every 6 weeks but at a higher dose than the 4 doses recommended in this study, was considered acceptable for this population and consistent with the ranges published in the literature (AAA617 Investigator's Handbook). For a complete six-cycle cumulative administration of 44.4 GBq, the estimated absorbed doses for the lacrimal glands, salivary glands, red bone marrow, and kidneys were calculated to be 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 was an estimated glomerular filtration rate (eGFR) ≥ 60 mL / min / 1.73 m², therefore only patients with normal or mild renal impairment were included. According to the VISION sub-study, for patients with mild renal impairment, the estimated renal absorbed dose after 4 cycles was 16.4 Gy (range: 11.2 - 19.8), which is well below the safety threshold. Therefore, a dose of 7.4 GBq (±10%) is supported, every 6 weeks (± 1 week) for up to 4 cycles.

[0603] The clinical results of the VISION study also confirmed that organ-related adverse events (AEs) are generally of low to moderate severity, tolerable and reversible, and do not translate into clinical significance.

[0604] The potential increased toxicity of AAA617 in low-volume disease compared to high-volume disease due to the "tumor pooling" effect has been debated in the literature for some time. However, recent data suggest that the tumor pooling effect in similar populations (mHSPCs) is not as worrying as initially thought. In a study of in-treatment dose determination of AAA617 in patients with small-volume hormone-sensitive metastatic prostate cancer, no threshold radiation dose was reached in organs at risk, while the tumor absorbed a high dose, including minimal metastases detected by PET imaging (Gafita et al. 2022, Peters et al. 2022). Overall, patients without detectable metastases or with very low-volume disease are less likely to face greater risk of non-target toxicity compared to patients with high-volume disease.

[0605] In this study, all participants will receive SBRT prior to initiating AAA617. Given the conformal nature of the SBRT treatment plan and the very low lesion volume in this patient population, it is expected that the SBRT plan will be significantly lower than partial volume tolerance in most cases, and as mentioned above, the dose to the whole organ from four cycles of AAA617 will be lower than whole organ tolerance. Regarding the concurrent administration of six doses of AAA617 for radiotherapy, data from the VISION study are encouraging, and data from case reports also suggest that concurrent administration of AAA617 for external beam radiotherapy is tolerable (Wei et al., 2017). Furthermore, an ongoing clinical trial (NCT05079698) is testing the concurrent administration of AAA617 and SBRT.

[0606] For these reasons, the administration of AAA617 at a dose of 7.4 GBq (± 10%) every 6 weeks, for a maximum of 4 doses, was deemed 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.

[0607] Rationale for selection of SBRT treatment

[0608] In both groups, participants will undergo SBRT on all metastatic lesions before starting AAA617 (study group) or entering observation (control group). While there are no specific treatment guidelines for OMPC patients with M1 disease-negative CI as defined by PSMA PET, various guidelines suggest that observation after SBRT is suitable for OMPC patients who strongly desire to postpone the initiation of ADT. For OMPC patients (as defined by CI), the standard of care recommended by NCCN (NCCN Prostate Cancer Guidelines V.1.2023) is metastasis-directed therapy (MDT) via SBRT followed by observation or ADT, with the aim of delaying progression. Current German guidelines state that MDT can be used to postpone ADT and tumor progression (Rogowski et al. 2022). Similarly, the EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines for prostate cancer also recommend close observation of patients with recurrent oligometastatic disease who strongly desire to postpone the initiation of ADT (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 settings (Zillli et al. 2022). Furthermore, OMPC patients who have progressed with previous SBRT may still be eligible for additional SBRT if there is a medical indication and no urgent need for systemic therapy. Following radiographic progression, further SBRT has been performed in other OMPC studies, with a second SBRT course being a treatment option in nearly 50% of patients with progression (Kalinauskaite et al. 2020), and repeat SBRT has proven beneficial (Decaestecker et al. 2014, Kwon et al. 2022).

[0609] Rationale for selection of control drug (comparator / placebo)

[0610] For the control group, observation is the appropriate standard of care for this group.

[0611] Study population

[0612] The study population consisted of approximately 450 adult male participants with recurrent OMPC, defined as those with 1–5 PSMA-positive metastatic lesions detected by PSMA-only PET and negative M1 lesions detected by conventional imaging.

[0613] Inclusion criteria

[0614] Participants eligible for inclusion in this study must meet all of the following criteria:

[0615] 1. A signed informed consent form must be provided before participating in the research.

[0616] 2. Participants must be adults aged 18 or older at the time of informed consent.

[0617] 3. During screening, the ECOG fitness level is 0 or 1.

[0618] 4. Researchers determined that participants' life expectancy must be ≥ 24 months during screening.

[0619] 5. Histologically confirmed prostate cancer prior to randomization

[0620] 6. Participants must have biochemical relapse following definitive treatment of the prostate via RP (alone or with postoperative radiation to the prostate bed / pelvic lymph nodes) or XRT (prostate alone or prostate with seminal vesicles and / or pelvic lymph nodes) and / or brachytherapy prior to randomization. Biochemical relapse is defined as: a minimum PSA of +2 ng / mL after XRT (if the participant received radiation therapy to the entire prostate) and PSA > 0.2 ng / mL rising after RP (with or without postoperative RT).

[0621] 7. Participants must meet the following criteria: OMPC with ≤ 5 PSMA-positive metastatic lesions at the time of screening PSMA PET / CT scan (using gallium ( 68 Ga) Gozetide or Piflufosstat ( 18 F), such as visual assessment using the methodology presented in the BIRC Standardized Assessment of Molecular Imaging for Prostate Cancer (PROMISE) (Eiber et al. 2018); for more details, please refer to the Imaging Manual. Metastatic lesions may include regional / pelvic lymph nodes (N1), distant lymph nodes (M1a), bone (M1b), lungs and other viscera (M1c) (except for the liver and brain using AJCC 8 classification). When calculating the number of oligometastatic lesions, each lesion is counted as a distinct metastatic lesion regardless of its anatomical location (e.g., one pelvic and one extrapelvic lymph node will be counted as two metastatic lesions).

[0622] 8. Based on the AJCC8 classification at screening, at least one PSMA-positive lesion should be a distant metastasis (M1). PSMA PET information should be used for AJCCM staging.

[0623] 9. Participants must have negative routine imaging results for M1 disease at the time of screening. Note:

[0624] • For ineligible participants, CI-positive M1 lesions should be clearly defined on CI scans, i.e., not attributable to findings that are thought to represent something other than a tumor (e.g., degenerative or post-traumatic changes or Paget's disease in bone lesions).

[0625] • Prior knowledge of a positive PSMA PET scan should not affect the radiologist's (reader's) determination of a positive CI scan. Two separate readers will be involved: one for PSMA PET and one for CI. The reader will not see the PSMA PET scan results while reviewing the CI scan. After reviewing the PSMA PET scan, the reader should not modify their assessment of the CI scan (e.g., changing a previously ambiguous lesion in the CI to a definitive one). Similarly, a positive biopsy should not affect the reader's assessment of a positive CI scan. More details on the reading paradigm will be provided in the imaging protocol.

[0626] • An MRI used for radiotherapy planning may show M1 disease, but this will not exclude participants from the study if the lesion is negative based on a baseline CT or bone scan.

[0627] • Patients with pelvic disease (N1) seen on routine imaging are permitted if the local spread is below the common iliac artery bifurcation (as defined by AJCC 8 for localized disease).

[0628] • Regardless of whether PSMA PET is positive, distal lymph node disease (M1a) with a short axis less than 10 mm can not be ruled out in each CI.

[0629] 10. All metastatic lesions identified during screening should be suitable for SBRT.

[0630] 11. If a patient has previously undergone SBRT for OMPC, disease progression (e.g., new PSMA PET lesions) must be demonstrated prior to randomization. Previously treated lesions must remain stable on baseline imaging scans and will not be counted in the required 1–5 lesions for this study. Participants are ineligible if the previously treated lesion was identified as M1 by bone scan or CT prior to the previous SBRT.

[0631] 12. Screening Confirmation of Primary Tumor Control: If local recurrence is suspected, MRI is required to rule it out. Patients with MRI or PET-positive local lesions require biopsy to rule out local progression. These patients with local recurrence (with biopsy-proven local disease or with MRI or PET-positive local lesions without biopsy) may be eligible for the study after salvage therapy for the local disease. Note: Patients who previously received pelvic RT (salvage pelvic RT) for local recurrence after RP are allowed to participate in the study.

[0632] 13. PSADT < 10 months at screening [PSADT will be calculated using a linear regression model of PSA and the normal logarithm of time (Pound et al. 1999)]

[0633] 14. At screening, non-castrated testosterone levels > 100 ng / dL

[0634] 15. Participants who are infected with human immunodeficiency virus (HIV) at screening and during the study period, and who are in good health and have a low risk of acquired immunodeficiency syndrome (AIDS)-related outcomes, may participate in this trial.

[0635] 16. Subjects must have adequate organ function, including the following laboratory values ​​at the time of screening:

[0636] Bone marrow reserve

[0637] •ANC ≥1.5 x 10 9 / L

[0638] • Platelet count ≥ 100 x 10 9 / L

[0639] • Hemoglobin ≥ 9 g / dL

[0640] liver

[0641] • Total bilirubin (TBIL) ≤ 2 x institutional upper limit of normal (ULN). For participants known to have Gilbert's syndrome, ≤ 3 x ULN is permitted.

[0642] • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3.0 x ULN.

[0643] • Albumin ≥ 2.5 g / dL

[0644] kidney

[0645] • eGFR ≥ 60 mL / min / 1.73 m2, using the Modified Nephrological Diet (MDRD) equation.

[0646] Exclusion criteria

[0647] Participants who meet any of the following criteria are not eligible for inclusion in this study:

[0648] 1. Use participants with de novo OMPC during screening.

[0649] 2. Concurrent bladder outflow tract obstruction or urinary incontinence that is difficult to manage at the time of screening. Note: Participants with bladder outflow tract obstruction or urinary incontinence are permitted to participate, as these can be managed and controlled with existing best practices in care (including pads, drainage).

[0650] 3. Previous treatments:

[0651] a.ADT, including bilateral orchiectomy

[0652] • Patients who received XRT or RP and completed adjuvant ADT (or ADT + androgen receptor pathway inhibitor (ARPI)) before relapse are eligible to participate if their last dose of ADT (or ADT + androgen receptor pathway inhibitor (ARPI) was taken 12 months prior to self-randomization.

[0653] • Participants who are not allowed to stop ADT due to disease progression (i.e., CRPC participants)

[0654] b. Other hormone therapies. For example...

[0655] • Use estrogen, 5-alpha reductase inhibitors (finasteride, dutasteride), and other steroid synthesis inhibitors (aminoglutamine).

[0656] • First-generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone acetate).

[0657] • Second-generation antiandrogens (e.g., enzalutamide, apalutamide, and dalolutamide)

[0658] • CYP17 inhibitors (e.g., abiraterone acetate, oterolone, galetabolone, ketoconazole). Short-term ketoconazole treatment (< 28 days) is permitted.

[0659] c. Radiopharmaceuticals (e.g., Strontium-89, PSMA-targeted radioligand therapy)

[0660] d. Immunotherapy (e.g., sipuleucel-T)

[0661] e. Chemotherapy, unless administered in an adjuvant / neoadjuvant setting completed within > 12 months prior to randomization.

[0662] f. Any other investigational or systemic drugs used for metastatic diseases.

[0663] 4. Herbal and non-herbal products that may lower PSA levels within 28 days prior to randomization (i.e., saw palmetto, pomegranate juice).

[0664] 5. Other investigational drugs were used within 28 days prior to the day of randomization.

[0665] 6. Received radiotherapy, external beam radiotherapy (EBRT), or brachytherapy within 28 days prior to randomization.

[0666] 7. Systemic (oral / intravenous / intramuscular (IM)) corticosteroids within 28 days prior to randomization. Note: Short-term (≤ 4 weeks) use of corticosteroids is permitted during the study period if clinically indicated.

[0667] 8. Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, hormone therapy, PARP inhibitors, biotherapy, or investigational therapy

[0668] 9. Known hypersensitivity to any investigational treatment or excipient or to drugs in similar chemical classes.

[0669] 10. The sole purpose of blood transfusions during the screening process is to qualify participants for inclusion in the study.

[0670] 11. Participants diagnosed at screening with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a history of adequately treated malignancies and who have been disease-free / treatment-free for more than 3 years are eligible, such as participants with adequately treated non-melanoma skin cancer and superficial bladder cancer.

[0671] 12. Concurrent serious (as determined by the researcher) medical conditions, including but not limited to uncontrolled infection, known active hepatitis B or C, or other significant comorbidities that the researcher believes would impair research participation or collaboration. Participants with documented active COVID-19 infection (of any severity) at the time of informed consent may only be included if they have fully recovered (in accordance with local guidelines).

[0672] 13. An abnormal ECG history or current diagnosis indicates a significant safety risk for participants in the study, such as:

[0673] • Accompanied by clinically significant arrhythmias, such as sustained ventricular tachycardia, and clinically significant second- or third-degree AV block without a pacemaker.

[0674] • Family history of long QT syndrome or a known family history of torsades de pointes ventricular tachycardia

[0675] • Resting heart rate (physical examination or 12-lead ECG) < 60 bpm

[0676] 14. History of physical or mental illness / symptoms that may interfere with research objectives and assessment.

[0677] 15. Any situation that prevents the arm from being raised.

[0678] Study treatment

[0679] Participants randomized to either group will undergo SBRT on all metastatic lesions after randomization and before initiating study treatment or observation. In this study, the term "study treatment" refers to radioligand therapy compound AAA617 and radioligand imaging compound gallium (…). 68 Ga) Gozetide and Pyrflufosstat ( 18 F) and SBRT.

[0680] The research drug is AAA617, and the radioligand imaging compound gallium ( 68 Ga) Gozetide and Pyrflufosstat ( 18 F (which was used as a PET / CT imaging agent during the screening process). There were no comparative drugs in this trial; participants randomized to the control group (observation group) will not receive any treatment after administration of the final part of SBRT.

[0681] The treatment methods studied are listed in the table below.

[0682] Table: Study Treatment

[0683]

[0684] gallium( 68 Ga) Gozetide will be administered in a single intravenous (iv) dose of approximately 150 MBq (4 mCi). The dose administered should not be less than 111 MBq (3 mCi) or more than 259 MBq (7 mCi).

[0685] Gallium ( 68 Baseline imaging assessments for Ga) Gozetin must be performed using only the methods provided by the sponsor for ( 68 The PSMA-11 kit for the radiopharmaceutical preparation of Ga (ga) gozepeptide or ready-to-use gallium (Ga) radiopharmaceuticals provided by the central radiopharmacy can be used. 68 The Ga) Gozetide radiopharmaceutical injection solution was administered.

[0686] Pyrflufosstat ( 18 F) Radioligand imaging compounds can be used for baseline imaging assessment in countries where they are approved, commercialized, and supplied locally. Pyrflufosstat ( 18 F) It should be used according to its packaging insert.

[0687] No other PSMA-targeting radiopharmaceuticals may be used for imaging, whether in screening for PSMA positivity or during treatment / efficacy follow-up.

[0688] Study participants randomized to the investigational drug will receive a dose of 7.4 GBq (200 mCi) ± 10% of AAA617, administered every 6 weeks (1 cycle), for a planned total of 4 cycles.

[0689] In this study, SBRT will be applied locally to treat PC lesions after randomization and before initiating AAA617 treatment or observation.

[0690] The research site will be responsible for procuring SBRT. The site should follow local practices and guidelines regarding SBRT prescribing, administration, follow-up, and toxicity management; however, to ensure standardization of SBRT during the study, a separate SBRT manual and specific instructions will be provided to the site, and the study must follow them. The following general practices must be ensured:

[0691] • CT and / or PET / CT or PET / MRI simulations will be performed using a radiation therapy fixation device (such as the Alpha Cradle). If the target is expected to move with breathing, 4D CT should be used during the simulation.

[0692] • The CT components of the PSMA PET CT will be registered to the CT simulation using rigid or deformable registration, based on institutional protocols and / or the clinical judgment of the researchers. At least one radiation oncologist or radiologist / nuclear medicine physician will review and confirm accurate registration.

[0693] • The total tumor volume (GTV) will be depicted on continuous axial computed tomography images, and the planned target volume (PTV) will be expanded to the institutional standard for SBRT, typically 5 mm. The attending radiation oncologist may decide at their discretion whether a larger or smaller PTV volume is permissible. If a 4D CT is performed, respiratory motion must be taken into account in the PTV.

[0694] • For lesions (including bone lesions) that are not clearly visible on simulated CT, diagnostic MRI should be performed and, where necessary, fused with the simulated CT to aid in delineating the target volume and identifying key structures (e.g., the spinal cord). Visualization of the target on MRI will not disqualify a participant from attending the study. More details on demarcation will be available in the SBRT manual.

[0695] • Clinical target volume (CTV) is usually equal to gross volume (GTV). However, given the uncertainty of locating tumor margins on small lesions that are not clearly visible on simulated CT, radiation oncologists may add CTV boundaries as appropriate.

[0696] • The contours of adjacent normal structures (including but not limited to the heart, esophagus, aorta, spinal cord, kidneys, rectum, intestines, liver, and stomach) within 5 cm of the PTV will be delineated to quantify the dose delivered to these structures.

[0697] • An SBRT treatment plan will be generated. The dosage will be specified according to the minimum isodose line covering the PTV.

[0698] • Dosage and fractionation depend on the size and location of the lesion and the limitations imposed by surrounding normal tissue. More detailed information and requirements regarding dosing schedules and fractionation will be provided in the SBRT manual.

[0699] • Image-guided delivery of SBRT will be used within three weeks of the initial treatment plan.

[0700] • Considering participant comfort and resource limitations at treatment sites, we will make every effort to consolidate all SBRT treatments into 3 weeks.

[0701] • Patients with identified pelvic lesions and with or without para-aortic involvement may receive standard fractionation therapy to comprehensively treat pelvic lymph nodes and provide additional doses to the affected lymph nodes. However, at least one metastatic lesion must be eligible for SBRT.

[0702] •AAA617 will be administered 7 to 21 days after the final SBRT is completed.

[0703] • If administered during the study, additional SBRT should also be administered following the guidelines above.

[0704] Once all eligibility criteria are confirmed, participants will be randomized in a 2:1 ratio to one of the following two treatment groups:

[0705] Research Group: AAA617

[0706] Control group: Observation (waiting for further observation)

[0707] SBRT must be administered to all metastatic lesions before AAA617 treatment can begin. A response to SBRT (e.g., a decrease in PSA) is not a prerequisite for initiating AAA617 or observation. Participants who prematurely discontinue SBRT on all lesions or all planned portions due to toxicity may begin AAA617 treatment (if enrolled in the study group) or observation (if enrolled in the control group) at the investigator's discretion. The decision to discontinue SBRT in the event of toxicity is made by the investigator based on local practice.

[0708] Participants randomized to either group will undergo SBRT for all metastatic lesions. The duration of SBRT is expected to be completed within 3 weeks. The duration of AAA617 treatment is expected to be approximately 24 weeks.

[0709] Treatment after disease progression

[0710] Progression occurred during SBRT treatment:

[0711] If distant metastases are assessed by BIRC using standard imaging (i.e., CT / MRI and bone scan), both groups of participants should discontinue further SBRT and receive any other treatments as determined by the investigators and in accordance with local regulations, and proceed to the appropriate follow-up period.

[0712] Progression occurred during AAA617 treatment:

[0713] Once distant metastases are detected by BIRC using standard imaging (i.e., CT / MRI and bone scan), participants in the study group should discontinue AAA617 treatment and receive any other therapies as determined by the investigators and in accordance with local regulations, and enter an appropriate follow-up period. AAA617 treatment may continue for up to four cycles if the investigators determine that the participant still benefits from continuing AAA617 treatment. Continuing AAA617 is permitted if the participant meets all of the following criteria:

[0714] • Evidence of clinical benefit evaluated by researchers

[0715] • No rapid radiological or clinical progression

[0716] • Tolerant to AAA617

[0717] • It should not jeopardize key interventions for the treatment / prevention of serious complications, or prevent participants from receiving adequate care.

[0718] • Participants' physical condition is stable

[0719] • No new anti-tumor treatment has been started.

[0720] After completing up to four cycles of AAA617, researchers will decide on the next line of treatment.

[0721] Progress occurred during the observation period:

[0722] Once radiographic progression (i.e., distant metastasis) occurs according to CI, as assessed by BIRC and initiated by ADT, participants randomized to the control group will be allowed to cross over to AAA617 (if eligible) or receive any subsequent therapy at the investigator’s discretion.

[0723] Other progress events during SBRT or AAA617:

[0724] Participants with local progression only (e.g., new or progressive regional pathological lymph nodes, N1), PSMA-only PET progression (if performed outside the protocol), or PSA progression will continue to complete SBRT in both groups (unless medically necessary) and 4 doses of AAA617 in the study group until distant metastatic progression in CI is assessed by BIRC or other discontinuation criteria are met.

[0725] In addition to radiographically confirmed distant metastatic progression (MFS events) by BIRC and initiating ADT, the following eligibility criteria for randomization to the control group must be confirmed before crossover to AAA617:

[0726] • Participants with central nervous system (CNS) metastases must be neurologically stable.

[0727] • Participants' ECOG PS must be between 0 and 2.

[0728] • Participants must adhere to contraception guidelines.

[0729] • Participants must have sufficient organ function, including the following laboratory values ​​prior to starting the cycle using AAA617 at crossover:

[0730] •eGFR ≥ 60 mL / min / 1.73m 2 (Using the MDRD equation)

[0731] • Total bilirubin (TBIL) ≤ 2 x ULN (upper limit of normal), ≤ 3 x ULN is permitted for participants with known Gilbert's syndrome.

[0732] • Participants with liver metastases had ALT or AST ≤ 3.0 x ULN or ≤ 5.0 x ULN.

[0733] •ANC ≥ 1.5 x 10 9 / L

[0734] • Platelet count ≥ 100 x 10 9 / L

[0735] • Hemoglobin ≥ 9 g / dL

[0736] • Progression events confirmed by BIRC other than distant metastatic radiological progression (i.e., MFS events according to CI) (e.g., local progression, clinical progression, PSMA-only PET progression) will not meet the crossover criteria.

[0737] • At least one PSMA-positive PET lesion should be present.

[0738] • If researchers determine that a participant develops any serious or unstable medical condition during the study that would prevent them from participating in the crossover phase, the participant should not crossover with AAA617 treatment.

[0739] • Participants who begin a new anti-tumor therapy during treatment or post-treatment follow-up will not be eligible for crossover.

[0740] After crossover, researchers can decide for themselves whether to allow ARPIs to be added to the ADT. Crossover participants are not allowed to receive other anti-tumor therapies (e.g., concurrent cytotoxic chemotherapy, immunotherapy, PARP inhibitors, biotherapy, or investigational therapy).

[0741] Crossover participants will receive AAA617 at the same dose and schedule as those initially randomized to the study group. Crossover participants must register with the IRT after investigators confirm their eligibility and must order AAA617 within 28 days of BIRC confirmation of radiographic distant metastasis progression. Participants should begin treatment immediately upon receipt of AAA617 by the site.

[0742] Participants selected from the control group to undergo crossover to AAA617 therapy must follow the study assessment according to the appointment schedule. Efficacy assessments (radiological imaging, RECIST 1.1 assessment, first SSE, first symptomatic progression), biomarkers, and testosterone levels will not be collected during the crossover period, and these participants should be followed up in accordance with local clinical practice.

[0743] After a maximum of 4 doses of AAA617, participants must discontinue AAA617 and undergo an EOT3 visit (42-day safety FU visit), and then proceed to post-treatment follow-up as directed for evaluation.

[0744] Efficacy assessment

[0745] MFS and rPFS

[0746] The assessment of MFS and rPFS will include radiographic evaluation of bone disease by whole-body radionuclide scanning (technetium-99m-labeled diphosphate) and radiographic evaluation of soft tissue disease by CT scan (or MRI, if CT is contraindicated). Tumor evaluation by positron emission tomography (PET), ultrasound, or chest X-ray may not replace CT or MRI scans, but the CT portion of PET / CT may substitute for dedicated CT if the diagnostic quality of CT is similar to that of CT without PET (including CT with intravenous contrast agents). The same imaging methods should be used throughout the study, and the frequency of imaging evaluations should be the same for both treatment groups.

[0747] The central review of the scans will be conducted blinded. Further details of the central review process will be described in the BIRC section.

[0748] MFS

[0749] MFS events are defined as the appearance of a new CI-positive distant metastasis (M1) or the progression of an existing PSMA-only PET-positive M1 lesion to a CI-positive M1 lesion (according to the AJCC 8 M classification). Radiographic confirmation of disease progression will be based on RECIST 1.1 criteria (Eisenhauer et al. 2009) and assessed by BIRC as follows.

[0750] • Metastasis to non-bone tissue is defined as new distant pathological lymph nodes (M1a) or other pathological lesions (M1c). Progression in the soft tissue below the bifurcation of the common iliac artery is considered localized regional progression, therefore new or progressive regional pathological lymph nodes (N1) are not defined as metastases.

[0751] • Radiographic progression of bone disease is defined as the presence of one or more metastatic lesions on a bone scan. Evaluation of bone disease will be performed using a whole-body technetium-99m-labeled bisphosphonate bone scan. When a solitary bone lesion is found on a bone scan, confirmation using a secondary imaging modality (plain film, CT, or MRI) is required. For confirmatory imaging, the date of metastasis should be the date of initial identification of the metastasis. The presence of two or more metastatic lesions on a bone scan may not require confirmation using a secondary imaging modality.

[0752] rPFS

[0753] • Radiological progression-free survival (rPFS) will be based on RECIST 1.1.

[0754] • Localized progression: Localized progression includes the progression of any existing positive localized lesions in the iliac artery and N1 disease below the common iliac bifurcation, or the appearance of one or more new localized lesions in the iliac artery. For participants with unmeasurable disease only observed on CT or MRI scans, definite progression (representing a change in overall disease status) will be considered as progression.

[0755] • rPFS will be derived by: acquiring all distant metastasis events determined based on the MFS endpoint, adding all local radiographic progression events assessed according to RECIST, and selecting the first event to occur if both types of radiographic progression are observed.

[0756] Advances seen in imaging modalities other than conventional imaging (such as PSMA PET / CT imaging) will not be considered for MFS or rPFS.

[0757] Imaging data will be centrally collected and quality-checked by the Imaging Contract Research Organization (CRO). The results of the central assessment will serve as the primary method for analyzing study endpoints. Evaluations by local researchers will be used for treatment decisions.

[0758] Detailed information regarding the collection and transmission of additional information required for BIRC imaging assessment will be described in the imaging manual provided by the designated CRO.

[0759] All study imaging (including any unplanned imaging studies) should be submitted to the designated imaging CRO for quality control and central review. Information regarding previous interventions (e.g., radiotherapy), pre-existing radiological findings mimicking metastatic disease at baseline / screening, and previous interventions should be transmitted to the imaging CRO along with baseline images via a baseline clinical form for review by independent radiologists. The site must ensure that the data entered in the form is consistent with the data entered in the clinical database.

[0760] BIRC will not evaluate subsequent images collected from participants who were cross-referenced to AAA617 based on the researchers' judgment.

[0761] Table: Imaging Evaluation Collection Plan

[0762]

[0763] If a participant is known to have contraindications to intravenous (iv) contrast agents for CT or if such contraindications develop during the trial, non-contrast CT of the chest (MRI is not recommended due to respiratory artifacts; however, MRI may be performed instead if CT is not feasible according to local regulations) should be performed, along with contrast-enhanced MRI of the abdomen and pelvis (if possible).

[0764] Baseline imaging assessment

[0765] Imaging assessments will be performed at screening / baseline within 28 days prior to randomization. Any imaging assessments completed during regular participant check-ups within 28 days prior to randomization (including before signing the primary study ICF) will be considered baseline images for this study. Any imaging assessments obtained after randomization will not be considered baseline images.

[0766] If the screening bone scan shows lesions suggesting metastatic disease but not definitively, the participant will be eligible.

[0767] Note that this protocol allows participants with localized lesions (N1 lesions below the bifurcation of the common iliac artery) visible on routine imaging (i.e., CT or MRI) at baseline to be eligible for the study. These lesions may be measurable or non-measurable according to RECIST 1.1 and can be selected for rPFS regardless of prior radiotherapy.

[0768] Post-baseline imaging assessment

[0769] The imaging assessment described in the table above should be performed using the same imaging modality as the baseline.

[0770] Imaging assessments should be performed every 16 weeks (± 7 days) after randomization until BIRC confirms distant metastasis, death, withdrawal of consent / objection to use of data / biosamples, loss of follow-up, or participant / guardian decision in the CI. Imaging assessments should be scheduled using the randomization date and should be adhered to regardless of whether AAA617 treatment is temporarily discontinued or an unplanned assessment is performed.

[0771] For participants who have not experienced radiographic progression in their CI as confirmed by BIRC, or for participants in the study group who discontinued treatment for reasons other than recorded radiographic metastatic progression, death, loss of follow-up, or withdrawal of consent (if applicable), tumor assessment must be performed every 16 weeks from randomization until distant metastasis, death, withdrawal of consent / objection to use of data / biosamples, loss of follow-up, or participant / guardian decision is made in the CI as confirmed by BIRC.

[0772] If necessary, researchers may conduct additional imaging assessments at any time during the study. Additional imaging assessments should follow the imaging guidelines specified in the protocol and be documented in the eCRF and submitted to the BIRC. Clinically suspected disease progression at any time requires prompt physical examination and imaging assessment, rather than waiting for the next scheduled imaging assessment.

[0773] Every lesion measured at baseline must be measured using the same method (the same imaging method), and, where possible, by the same local radiologist / physician throughout the study, to ensure consistency in the comparison. If an imaging assessment deviated from the schedule due to suspected progression, subsequent imaging assessments should be performed according to the original imaging schedule.

[0774] Time points for locally determined progression

[0775] All participants identified by local researchers as having disease progression (new distant metastases; MFS events) require expedited central review by BIRC. Rapid image transfer to the Imaging CRO can be accomplished electronically, such as via the internet. In all cases, the Imaging CRO's procedures will ensure that the central reviewer is unaware of the results of the local assessment and the expedited nature of the review. Researchers seeking expedited review must indicate this request to the Imaging CRO using a designated form or other means. Imaging will undergo expedited central review (within 5 business days of receiving the images from the Imaging CRO, and after all applicable questions have been resolved), and the results of the central review will be communicated to the site.

[0776] If the central review determines that an MFS event has occurred, proceed as described in this document.

[0777] If the central review does not identify an MFS event, the participant should continue to receive all 4 doses of AAA617 unless there is a medical need (i.e., rapid disease progression or clinical deterioration) requiring an immediate change in therapy.

[0778] If another anti-tumor treatment has already begun, participants will continue imaging according to the protocol until a central review determines an MFS event.

[0779] The imaging supplier will ensure that the central reviewers involved are unaware of the expedited status of the reading.

[0780] Time points without locally determined progression

[0781] All imaging time points without locally definitive progress (transfers) will be read continuously and non-urgently, in accordance with the detailed specifications in the imaging manual provided by the designated imaging CRO and independent review charter. The results of these reads will not be communicated to the site.

[0782] Symptomatic skeletal events

[0783] The time to the first SSE will be defined as the time of the first new SSE or death from any cause, whichever occurs first. A symptomatic skeletal event (SSE) will be defined by the occurrence of any of the following (whichever occurs earlier):

[0784] • Symptomatic pathological fractures.

[0785] • Spinal cord compression.

[0786] • Tumor-related orthopedic surgical intervention.

[0787] • Radiation therapy is needed to relieve bone pain.

[0788] Symptomatic progression

[0789] The time to symptomatic progression will measure the time from randomization to recording in the CRF (whichever occurs earlier):

[0790] • Symptomatic skeletal events (SSEs) occur.

[0791] • If pain progresses or disease-related symptoms worsen, a new systemic anticancer therapy needs to be started.

[0792] • Significant clinical symptoms may arise due to local tumor progression, requiring surgical intervention or radiation therapy.

[0793] PSA progression

[0794] PSA progression time is defined as the time from randomization to the first PSA progression. PSA progression 1 is defined as the date on which a PSA increase of ≥25% and an absolute increase of 2 ng / mL or more from the lowest point or baseline is recorded and confirmed by a second consecutive value obtained 3 weeks or more later. Elevations in PSA within the first 12 weeks are ignored if there is no other evidence of disease progression (adapted from the Prostate Cancer Working Group (PCWG3) guidelines). If no decline relative to baseline is recorded, PSA progression is defined as a 25% increase relative to baseline and an absolute increase of 2 ng / mL or more after 12 weeks of treatment.

[0795] PSA Progress 2 is defined as a PSA concentration confirmed by repeated measurements at least 3 weeks later to be ≥ 0.5 ng / mL above the lowest point (or baseline, if lower).

[0796] Next therapy (local or systemic)

[0797] The time to the next line of therapy is defined as the time from randomization to the start of the next line of cancer therapy (local or systemic). Local therapy may include additional given SBRT (i.e., after initial SBRT for all metastatic lesions) or any other MDT (e.g., surgery). The next line of therapy will be recorded in the CRF and used in this analysis.

[0798] PSA and testosterone levels

[0799] The central laboratory will measure PSA and serum testosterone levels throughout the study according to the activity schedule. PSA values ​​will be available to study sites or participants. Regardless of PSA values, AAA617 administration should continue until radiological progression occurs and the investigator determines that continuing AAA617 is not beneficial. If PSA elevation occurs throughout the study without BIRC-confirmed radiological progression (MFS event), it is strongly advised against using it as a criterion for initiating new systemic anti-tumor therapies (including ADT).

[0800] Appropriateness of efficacy assessment

[0801] The aforementioned efficacy measures are standard in clinical studies involving patients with OMPC (Ost et al. 2018, Ost et al. 2020, Phillips et al. 2020). The proposed MFS endpoint has previously been used in registration studies in similar but castration-resistant settings (Smith et al. 2018, Fizazi et al. 2019, Sternberg et al. 2020). Furthermore, elements of the specific nmCRPC guidance for MFS and rPFS proposed by the US FDA (FDA 2021) have been incorporated into the definitions of these endpoints. In addition, an agreement has been reached with the FDA, and consultation with the Scientific Advisory Working Group (SAWP) on the proposed endpoints / definitions has been obtained. These assessments also conform to the PCWG3 guidelines.

[0802] Safety assessment

[0803] Safety assessments are detailed in the activity schedule, specifying when each assessment will be performed. For crossover participants in the control group, safety assessments must be performed up to 10 years after the first dose of AAA617 (in this study and in separate follow-up studies).

[0804] For detailed information on AE collection and reporting, please refer to the relevant section of this article.

[0805] The ECOG Performance Status Scale will be used as described in the table below.

[0806] ECOG physical fitness status

[0807]

[0808] Physical examination

[0809] A complete physical examination will include a general appearance, skin, neck (including the thyroid gland), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, limbs, blood vessels, and nervous system. If based on medical history and / or symptom indications, an examination of the rectum, external genitalia, breasts, and / or pelvis will also be performed.

[0810] Height (cm) and weight (in indoor clothing but without shoes, accurate to the nearest 0.1 kg) will be measured.

[0811] Researchers should pay particular attention to clinical signs associated with a previous serious illness.

[0812] All medical examination information must be included in the research center's source files. Clinically relevant findings existing prior to informed consent must be documented in the appropriate CRF (Clinical Review File) used to collect the medical history. Significant findings meeting the definition of an adverse event after informed consent has been obtained must be documented as adverse events.

[0813] Vital signs

[0814] Vital signs include blood pressure (preferably in a supine position when collecting ECG), respiratory rate, pulse measurement, and body temperature. Vital signs will be monitored according to the activity schedule.

[0815] Electrocardiogram

[0816] ECGs will be collected and evaluated locally. Interpretation of the recordings must be provided by a qualified physician and documented in writing on the appropriate CRF. Each ECG recording should be labeled with the study number, the participant's initials (where permitted by regulations), the participant number, and the date, and should be kept in the source files at the study site. Clinically significant abnormalities present at screening should be reported on the appropriate CRF. Clinically significant findings must be discussed with the trial sponsor before recruiting participants for the study. New or worsening clinically significant findings that occur after informed consent must be documented as adverse events.

[0817] Single local 12-lead ECGs were collected at baseline and at the first visit of week 1 of cycle 1 for both groups. For the study group and the crossover group, ECGs should be collected prior to AAA617 administration during week 1 of cycle 1.

[0818] An electrocardiogram (ECG) must be recorded after resting supine for 10 minutes to ensure baseline stability. The preferred order for collecting cardiovascular data during the study visit is to collect the ECG first, followed by vital signs and blood samples.

[0819] Clinical decision-making must use the Fridericia QT correction formula (QTcF). If the ECG machine does not automatically calculate the QTcF, researchers must calculate it themselves.

[0820] The original ECG on non-thermal paper or a certified copy on properly signed thermal paper must be archived at the research site.

[0821] Researchers may repeat additional, unplanned safety ECGs at any time during the study, as directed by clinical instructions. For any ECG involving participant safety concerns, two additional 12-lead ECGs must be performed to confirm the safety outcome. ECG safety monitoring or review procedures (at the study site) should be established for clinically significant ECG results at baseline, both before and during the study.

[0822] Clinically significant abnormalities must be documented on the CRF as medical history / current medical condition or adverse event (where appropriate).

[0823] Clinical safety laboratory tests

[0824] The local laboratory will be used for hematological / coagulation, chemistry, and urinalysis (safety monitoring) analysis, according to the assessment schedule and the separately outlined collection plans. The local laboratory will also be used to analyze urine collections for dosimetry (Germany only). The central laboratory will be used for PSA and testosterone analysis.

[0825] An abnormal laboratory value or test result can constitute an adverse event only if it meets at least one of the following criteria: 1) it induces clinical signs or symptoms, 2) it is considered clinically significant, or 3) it requires concomitant therapy or procedure.

[0826] Clinically significant abnormal laboratory values ​​or test results should be identified by reviewing values ​​outside the normal / clinically noteworthy range, self-screening, or significant changes from the last visit.

[0827] If there is a medical indication, researchers may decide to conduct unplanned laboratory assessments (local or central) at any time during the study period. Further results of unplanned laboratory assessments should be recorded in the appropriate unplanned visit eCRF.

[0828] At any point during the study, any clinically relevant abnormal laboratory parameters requiring intervention with the study treatment (e.g., dosage modification and / or interruption of study treatment resulting in clinical symptoms or signs, or the need for treatment intervention), regardless of whether specifically required by the protocol, will be recorded on the AE eCRF page. Laboratory data will be summarized 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 medical condition.

[0829] Clinical chemistry and hematology / coagulation tests will be performed according to the appointment schedule. Please see the table below for details regarding the biochemistry / hematology team. Even if the investigational drug is rejected, a biochemistry / hematology evaluation should be performed on the actually scheduled date.

[0830] If applicable, it should be in gallium ( 68 Ga) Gozetide or Pyrflufosstat ( 18 F) Perform clinical chemistry / hematology / coagulation tests before and before AAA617 administration.

[0831] More frequent chemical / hematological / coagulation tests may be performed if medically necessary. If eGFR based on serum creatinine decreases, a renal ultrasound may be recommended at the researcher's discretion. Additional results of unplanned chemical / hematological / coagulation laboratory assessments should be recorded on the eCRF as unplanned visits.

[0832] Urine analysis strip measurements will be performed according to the table below and the evaluation schedule. Any significant findings on the strips will be evaluated under a microscope.

[0833] Table: Laboratory Assessment

[0834]

[0835] Clinical outcome assessment (COA)

[0836] Patient-reported outcomes (PRO)

[0837] PRO is a measurement based on reports from study participants about their health status, and does not require interpretation of these reports by a medical leader or any other person. Symptoms or other unobservable concepts known only to the participant (such as pain severity or fatigue) can only be assessed using the PRO assessment scale.

[0838] All PRO data will be collected on the clinic's electronic devices (except during survival follow-up, when PRO data will be collected on the participants' own electronic devices). The portal can also be used in case of tablet malfunction.

[0839] Before any clinical assessment, participants must be given one or more PRO assessment scales to complete at their scheduled appointment. Any participant's refusal to complete all or any part of the PRO measurements should be recorded in the study data capture system and should not be captured as protocol bias. Protocol bias treatment may be modified if required by the study protocol.

[0840] Participant questionnaires should be completed in the language most familiar to the participants.

[0841] Participants should be given sufficient space and time to complete one or more PRO assessment scales.

[0842] Site staff should check the completeness of one or more PRO assessment scales and require participants to complete any missing responses. Responses stored electronically in the database will be considered the source files.

[0843] Before conducting any clinical research examination, researchers must review and evaluate one or more completed assessment scales to identify responses that may indicate potential adverse events (AEs) or subacute acute exacerbations (SAEs). This evaluation should be documented in the study source record. If an AE or SAE is confirmed, researchers should not encourage participants to change the answers they reported in the completed questionnaires. Researchers must follow the reporting instructions in the study protocol.

[0844] The PRO assessment scales used in this study will be FACT-P, BPI-SF, and EQ-5D-5L, which will be described further below.

[0845] PRO assessments will be conducted on the study and control groups at screening, week 1 of each cycle, at EOT2 / week 24 visit, and every 16 weeks during efficacy follow-up. Participants who terminate early due to disease progression, loss of follow-up, or withdrawal of consent will continue PRO assessments at the same time points as radiological assessments during efficacy follow-up. Participants who enter long-term safety follow-up after a MFS event (study group participants) will undergo PRO assessments every 32 weeks. For control group participants who do not enter long-term safety follow-up (non-crossover participants), PRO assessments will continue at three additional time points during survival follow-up. PRO data can be collected remotely via a portal or by participants using their own devices during this survival follow-up study.

[0846] FACT-P

[0847] The FACT-P questionnaire will also be used as part of this study to specifically assess HRQoL in prostate cancer participants. FACT-P consists of two parts: the Cancer Therapy Functional Assessment-General (FACT-G) questionnaire contains 27 questions, and the Prostate Cancer Subscale (PCS) contains an additional 12 questions. The FACT-G questionnaire is one of the most widely used assessments of the impact of cancer / treatment on: physical, social-familial, emotional, and functional health (Cella et al. 1993). The PCS is specifically designed to measure prostate cancer-specific issues. Each item in both FACT-G and the PCS is scored on a Likert scale from 0 to 4, and the scores are then combined to produce subscale scores for each domain, as well as a total score, where higher scores represent higher function / fewer prostate-specific issues. The FACT system has many advantages:

[0848] The questionnaire was designed to reflect the most relevant specific questions about diseases and treatments among the target population.

[0849] The FACT-P measurement has been validated in the target population and is available in multiple translations / languages ​​(Cella et al. 1993, Esper et al. 1997).

[0850] The FACT-P measurement is designed for self-administered responses, but can also be completed via interview if / as needed (Webster et al. 2003).

[0851] Full details (including references) of the FACT-P questionnaire are available on the FACIT website: / / facit.org / FACITOrg / Questionnaires.

[0852] Brief Pain Inventory-Short Form (BPI-SF)

[0853] The BPI-SF is a 9-item self-administered questionnaire used to assess the severity of pain in participants and its impact on their daily functioning. Participants are asked to rate their most severe, minimum, average, and current pain intensity, list current treatments and related relief, and rate the degree to which pain interferes with general activities, mood, walking ability, work performance, relationships with others, sleep, and enjoyment of life on a 10-point scale. Originally developed to assess cancer pain, the BPI has now proven to be an appropriate measure of pain caused by a variety of clinical conditions. The BPI-SF has become a standard of care used in clinical trials. The recall period for the BPI-SF is the past 24 hours plus the current pain (now), and the estimated time to complete the BPI is 5 minutes.

[0854] Pain score: Pain will be assessed using the BPI-SF. The BPI-SF will be used as part of this study to assess the severity of pain (most severe pain and average pain) and the impact of pain on daily functioning (pain interference). For complete details on the BPI-SF, its validation, and clinical applications, please refer to the Brief Pain Inventory User Guide (Cleeland 2009).

[0855] EQ-5D-5L

[0856] As part of this study, the EQ-5D-5L questionnaire will also be used to assess HRQoL.

[0857] The EQ-5D is an international, validated, standardized, and universal questionnaire used to describe and assess HRQoL (Rabin, de Charro 2001). Developed by the EuroQol Group, the EQ-5D was designed to provide a simple and universal measure of health for clinical and economic assessments (EuroQoL Group 1990).

[0858] The tool generates a preference-based health status utility score (EQ-5D utility index) and an overall health status score based on the Visual Analogue Scale (EQ-5D VAS).

[0859] The EQ-5D is designed for self-reflection and is well-suited for use in clinics and face-to-face interviews. The EQ-5D has been widely tested and used in the general population for calculating health utility, conducting cost-benefit analyses, and submitting data to health technology assessment agencies (Herdman et al., 2011). The recall period for the EQ-5D-5L is "today," with an estimated completion time of several minutes.

[0860] The questionnaire includes instructions for respondents. The latest version of the EQ-5D is the EQ-5D-5L, which was developed to improve the tool's sensitivity and reduce the ceiling effect.

[0861] The number of dimensions (activity, self-care, daily activities, pain / discomfort, anxiety / depression) remains unchanged, but the new version includes five severity levels in each existing dimension instead of three (EuroQoL 2015). Full details (including references) of the EQ-5D-5L questionnaire are available on the EQ-5D website: / / euroqol.org / eq-5d-instruments / eq-5d-51-about.

[0862] Other assessments (dose determination)

[0863] Dosimetry will be performed on all participants receiving AAA617 (including those in the crossover group) in specific countries. Dosimetry will be evaluated in organs and tumors. Other countries may also require this if local regulations mandate it.

[0864] Additional SPECT / CT imaging and whole-body planar scintillation scans (for local assessment only) may be performed as required by local laws for dose measurement assessment.

[0865] Dosimetry assessments will be conducted for the study group and the crossover group according to the following schedule.

[0866] • Cycle 1 (C1W1 visit): Whole-body plane and SPECT / CT will be performed 1-2 hours, 18-26 hours, 48 ​​hours (+ / - 12 hours) and 168 hours (+ / - 12 hours) after the AAA617 infusion.

[0867] • Cycle 3 (C3W1 visit): Whole-body planar imaging and SPECT / CT will be performed 1-2 hours and 48 hours (+ / - 12 hours) after the AAA617 infusion.

[0868] • Collect urine at the first week of the first cycle after AAA617 administration, i.e., between the start of infusion and the start of the first image (1-2 hours after infusion).

[0869] Population dosimetry models can be used to derive estimates of the absorbed dose of tumors in OMPC patients and their variability, and to explore individual factors (i.e., weight, renal function, lesion type, number of metastases) that may explain the dose variability among individuals in this population.

[0870] Adverse events (AEs), serious adverse events (SAEs), and other safety reports

[0871] AEs will be reported by the participant (or, where appropriate, by a caregiver, agent, or legally authorized representative of the participant).

[0872] Researchers and any qualified designated personnel are responsible for detecting, documenting, and recording events that meet the definition of AE or SAE, and for following up on all serious AEs.

[0873] Adverse events

[0874] An adverse event (AE) is any unfortunate medical event (e.g., any adverse or unexpected sign [including abnormal laboratory findings], symptom, or illness) that occurs in a clinical study participant after providing written informed consent to participate in the study. Therefore, an AE may or may not be temporally or causally related to the use of the drug (investigation) product.

[0875] During each visit during the study period, adverse events must be sought through non-directive questioning of participants. Adverse events may also be detected when they are voluntarily reported by participants during visits, between visits, or through physical examination, laboratory testing, or other assessments. Patient-reported outcomes are considered additional assessments for detecting adverse events.

[0876] Adverse events must be recorded under the relevant signs, symptoms, or diagnoses, with the following information (if possible):

[0877] 1. Adverse events will be assessed and graded according to the Common Terminology Standard for Adverse Events (CTCAE) version 5.0, or, if a CTCAE grading system is not available, according to severity. Grades 1 to 5 will be used to describe the severity of the adverse event. If a CTCAE grading system is not available for the adverse event, the severity levels of mild, moderate, severe, life-threatening, and fatal caused by the AE will be used, corresponding to grades 1 through 5 respectively. Information regarding any deaths (related to or unrelated to the adverse event) will also be collected through a death form.

[0878] 2. Its relationship to the investigational treatment and other investigational treatments. If the event is due to lack of efficacy or progression of the underlying disease (i.e., progression of the investigational indication), the assessment of causality will generally be 'not doubtful'. The basic principle of this guideline is that the symptoms of lack of efficacy or progression of the underlying disease are not caused by the investigational drug, although they occur at the time of administration of the investigational drug, and / or both lack of efficacy and progression of the underlying disease can only be meaningfully evaluated on an analytical cohort basis (rather than on a single participant).

[0879] 3. Its duration (start and end dates or continued existence) and outcome must be reported.

[0880] 4. Whether it constitutes an SAE and which severity criteria it meets.

[0881] 5. Measures taken for research and treatment.

[0882] All adverse events must be treated appropriately. Treatment may include one or more of the following:

[0883] • No change in dosage

[0884] • Dosage reduction

[0885] • Medication interruption / permanent discontinuation

[0886] 6. Its ending

[0887] • Not recovered / not subsided

[0888] • Recovering / Regressing

[0889] • Recovered / Disappeared

[0890] • Recovered / subsided but with lingering effects

[0891] •fatal

[0892] •Unknown (UNK)

[0893] If an event worsens, it should be reported a second time in the CRF, noting the start date of the toxicological deterioration. Only for Level 3 and 4 adverse events, if improvement to a lower level is determined, a new entry for the event should be reported in the CRF, noting the start date of the improvement from Level 3 or 4.

[0894] Pre-existing conditions should be recorded in the participant's medical history at the time of obtaining informed consent.

[0895] Adverse events (including laboratory abnormalities that constitute AEs) should be described using diagnoses rather than individual underlying signs and symptoms whenever possible.

[0896] Adverse event monitoring should continue for at least 42 days after the last dose of AAA617.

[0897] Following safety follow-up visits (EOT2 / EOT3 follow-up visits), participants randomized to the study group / crossover group will be followed up every 32 weeks for safety assessment until the end of the study, after which they will be proposed to join a separate long-term safety study (CAAA617A12402). This long-term follow-up study will continue for up to 10 years from the first dose of AAA617. During the long-term safety follow-up period, selected adverse events related to AAA617, namely xerostomia, dry eye, myelosuppression, nephrotoxicity, and secondary primary malignancies and their outcomes, will be documented in the case report form and reported.

[0898] The selected AAA617-related adverse events will be followed up until the event or its sequelae or abnormal test results subside or stabilize at a level acceptable to the researchers.

[0899] For non-randomized participants, AE monitoring will continue until gallium is applied ( 68 3 days (inclusive) after Ga) Gozepeptide.

[0900] For all adverse events (AEs), sufficient information will be obtained to fully determine the outcome of the event and assess the causal relationship between the AE and the investigational treatment.

[0901] Once an adverse event is detected, it must be followed up until it subsides or until it is determined to be non-recoverable / non-subdued (e.g., continuing at the end of the study), and any changes in severity, the suspected relationship to the intervention required to treat it, and the outcome must be assessed at each visit (or more frequently if necessary).

[0902] If the progression of a malignant tumor (including fatal outcomes) is documented using appropriate methods (e.g., according to RECIST criteria for solid tumors), it should not be reported as a serious adverse event unless the researcher believes that the progression of the malignant tumor is related to the investigational treatment.

[0903] Adverse events that are separated from the progression of malignancy (such as deep vein thrombosis during progression or hemoptysis at the same time as the discovery of disease progression) will be reported in accordance with the standard guidelines for the proper attribution of the relationship between the event and the drug.

[0904] Information on adverse drug reactions to investigational drugs can be found in the Investigator's Handbook (IB) and appropriate documents from the SBRT, such as institutional guidelines.

[0905] An abnormal laboratory value or test result can constitute an adverse event only if it meets at least one of the following criteria:

[0906] • They induce clinical signs or symptoms

[0907] • They are considered clinically significant

[0908] •They need treatment

[0909] Clinically significant abnormal laboratory values ​​or test results must be identified by reviewing values ​​that are outside the normal / clinically noteworthy range, significant changes from baseline or the previous visit, or values ​​that are considered atypical for participants with an underlying disease.

[0910] Serious adverse events

[0911] SAE is defined as any adverse event [occurrence (or worsening of any pre-existing condition)] that meets any of the following criteria for an undesirable sign, symptom, or medical condition:

[0912] •fatal

[0913] • Life-threatening

[0914] In the context of SAE, life-threatening refers to a reaction in which the participant is at risk of death; it does not mention a reaction that, if more severe (see the International Committee for Standardization (ICH-E2D) guidelines), could lead to death.

[0915] • Leading to persistent or obvious disability / incapacity

[0916] • Constitutes congenital abnormalities / birth defects, fetal death, or congenital abnormalities or birth defects.

[0917] • Hospitalization or extension of the existing hospital stay is required, unless the hospitalization is for:

[0918] • Indications for routine treatment or monitoring studies, unrelated to any worsening of the condition.

[0919] • Selective or pre-planned treatment for a pre-existing condition that is unrelated to the indication in the study and has not worsened since the informed consent was signed.

[0920] • In the absence of any deterioration in the participant's general condition, social causes and temporary care

[0921] • For events that do not meet any of the above SAE definitions and do not result in hospitalization, treatment should be provided on an emergency outpatient basis.

[0922] • Medically significant events, for example, events defined as harmful to participants or potentially requiring medical or surgical intervention to prevent one of the outcomes listed above.

[0923] In determining whether other situations should be considered serious reactions—such as significant medical events that may not be immediately life-threatening or result in death or hospitalization, but may endanger the participant or may require intervention to prevent one of the other outcomes listed above—medical and scientific judgment should be made. Such events should be considered “medically significant.” Examples of such events are intensive treatment in the emergency room or at home for anaphylactic bronchospasm, blood dysregulation, or seizures that do not lead to hospitalization or the development of drug dependence or abuse (see ICH-E2D guidelines).

[0924] If other severity criteria are not met, and the malignancy is not a disease progression for the research indication, all new malignancies will be assessed as “medically significant” for severity.

[0925] All reports of intentional misuse and abuse of the product are also considered serious adverse events, regardless of whether a clinical event occurred.

[0926] Any suspected transmission of infectious agent drugs is also considered a serious adverse reaction.

[0927] During this long-term safety follow-up, all serious adverse events related to AAA617, including dry mouth, dry eye, myelosuppression, nephrotoxicity, and secondary primary malignancy, will be documented and reported in the case report form.

[0928] SAE reporting

[0929] To ensure participant safety, every SAE occurring after the participant provides informed consent but before EOT2 / EOT3, regardless of causality, must be reported immediately to the trial sponsor's safety department without undue delay, but no later than 24 hours after becoming aware of the event (Note: if more stringent, local regulations regarding reporting timelines apply). Detailed instructions on the submission process and requirements will be available in the folder provided to researchers at each site. Collect information on all SAEs and record them on the Serious Adverse Event Reporting Form (eSAE, with a paper copy); all applicable sections of the form must be completed to provide a clinically comprehensive report.

[0930] Any SAE that occurs between the time a participant provides informed consent and the time when the participant is deemed to have failed the screening must be reported to the sponsor.

[0931] All follow-up information for SAEs, including information on complications, progression of the initial SAE, and recurrence, must be reported immediately as follow-up information for the original episode, without undue delay, but no later than 24 hours after the researcher receives the follow-up information (Note: if more stringent, local regulations regarding reporting timelines shall prevail). SAEs occurring at different time intervals or deemed completely unrelated to previously reported events must be reported separately as new events.

[0932] If an SAE is not previously documented in the investigator's handbook or packaging instructions (new occurrence) and is believed to be related to the investigational treatment, colleagues in the Chief Medical Office and the Patient Safety (CMO & PS) department may urgently require the investigator to provide further information in order to report to health authorities.

[0933] Suspected unintended serious adverse events (SUSARs) will be collected and reported to the competent authorities and relevant ethics committees in accordance with EU Clinical Trials Regulation 536 / 2014 or the national regulatory requirements of the participating countries.

[0934] Any SAE, including but not limited to xerostomia, dry eye, myelosuppression, nephrotoxicity, and secondary primary malignancy, as well as non-serious AEs of xerostomia, dry eye, myelosuppression, nephrotoxicity, and secondary primary malignancy that occur within 42 days following the last administration of AAA617, should be reported if the investigator suspects a causal relationship with AAA617, unless otherwise required by local laws / regulations.

Claims

1. A method for delaying castration and / or disease recurrence in adult male patients with prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic prostate cancer (OMPC), wherein the method comprises the following steps: (1) Administer stereotactic body radiotherapy (SBRT) to the patient, and (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT), such as lutetium ( 177 Lu) Vipivopeptide-Teracillin ([ 177 Lu]Lu-PSMA-617), or its pharmaceutically acceptable salt, solvate, hydrate, eutectic, crystalline form, amorphous form, stereoisomer or tautomer.

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

3. The method of claim 2, wherein the positron-emitting radionuclide is selected from the group consisting of: 18 F, 64 Cu and 68 Ga.

4. The method of claim 2, wherein the RLI agent is selected from gallium ( 68 Ga) Goze peptide [[ 68 Ga]Ga-PSMA-11]、 64 Cu-SAR-bisPSMA, 64 Cu-PSMA I&T [Copper ( 64 [Cu] Zadavotine gulasitam, pivofostine ( 18 F)[ 18 F-DCFPyL], Flutifexat ( 18 F)[ 18 F-rhPSMA-7.3], veflufosstatin ( 18 F)[ 18 F-CTT1057] 18 The group consisting of F-PSMA-1007 is preferably selected from gallium free ( 68 Ga) Gozetide and Piflufositol ( 18 The group consisting of F).

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

6. The method of claim 1, wherein the RLT agent is administered at a dose of about 6 GBq to about 8 GBq, preferably about 6.5 GBq 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., 1 cycle), for up to 3 or 4 cycles, preferably 3 to 4 cycles, more preferably 4 cycles.

7. The treatment method of claim 1, wherein the radioligand therapeutic agent is administered at a dose of 7.4 (± 10%) GBq once every 6 (± 1) weeks (i.e., 1 cycle) for 4 cycles.

8. A method for delaying castration and / or disease recurrence in adult male patients with prostate-specific membrane antigen (PSMA)-positive (+) oligometastatic prostate cancer (OMPC), wherein the method comprises the following steps: (1) Administer stereotactic body radiotherapy (SBRT) to the patient, and (2) Administer to the patient a therapeutically effective amount of a PSMA-binding radioligand therapy (RLT), such as lutetium ( 177 Lu) Vipivopeptide-Teracillin ([ 177 Lu]Lu-PSMA-617), or its pharmaceutically acceptable salts, solvates, hydrates, eutectics, crystalline forms, amorphous forms, stereoisomers or tautomers; The OMPC mentioned above is an OMPC with 1-5 metastatic lesions that are detected by PSMA positron emission tomography (PET) using a radioligand imaging (RLI) agent containing a positron-emitting radionuclide, but are negative for M1 disease by conventional imaging (CI). The positron-emitting radionuclide mentioned above is gallium (GaN). 68 Ga) Gozetide or Pyrflufosstat ( 18 F); The CI mentioned therein is based on computed tomography (CT) / magnetic resonance imaging (MRI) and / or bone scans; and The radioligand therapy agent is administered at a dose of 7.4 (± 10%) GBq every 6 (± 1) weeks (i.e., 1 cycle) for 4 cycles.

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