TW202228794A - Methods for treating prostate cancer - Google Patents

Abstract

The disclosure provides methods comprising administering a therapeutic agent to a plurality of individuals having prostate cancer; performing prostate-specific membrane antigen-positron emission tomography (PSMA-PET) on the individuals and producing results thereof; analyzing said results; and determining intervals over which the individuals exhibit metastatic progression of said prostate cancer. Such methods have a broad range of uses including, e.g., predicting the outcomes and survival for patients having prostate cancer.

Description

Methods for treating prostate cancer

Disclosed herein are, among other things, methods for monitoring the progression of prostate cancer.

Prostate cancer is currently the fifth leading cause of cancer death in men worldwide, with 1 million patients diagnosed each year and a mortality burden exceeding 300,000 deaths.

Approximately 25% to 35% of patients with localized adenocarcinoma of the prostate treated with radical prostatectomy will recur in the form of elevated serum prostate-specific antigen (PSA) without overt metastatic disease, which This is called biochemical recurrence (which can progress to metastasis). Short PSA doubling time (PSADT) is an integral part of patients with metastasis (detected by conventional ^99m Tc bone scan and computed tomography), prostate cancer-specific mortality, and biochemical recurrence (BCR) One of the main predictors of mortality. PSADT is a mathematical determination of the length of time (in months) required for a given patient's PSA level to double. Risk stratification of patients based on PSADT has changed from study to study; a recent systematic review and meta-analysis investigated the effect of BCR on endpoints and concluded that patients who experienced BCR were at risk of developing metastatic, prostate cancer-specific, and an increased risk of overall mortality. Thus, high risk BCR patients are a discrete cohort of prostate cancer patients with a high unmet medical need for improved management and treatment outcomes.

Apalutamide is a next-generation non-steroidal androgen receptor inhibitor for prostate cancer treatment. Apalutamide is currently approved in several countries for the treatment of non-metastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer.

Positron emission tomography with radiolabeled prostate-specific membrane antigen (PSMA-PET) is an emerging imaging modality for assessing the burden of prostate cancer. PSMA-PET is more sensitive than conventional angiography (eg, ^99m Tc-bone scan and computed tomography/magnetic resonance imaging scan) and is the preferred imaging modality recommended for low levels of PSA in patients with biochemical recurrence. Different ⁶⁸ Ga and ¹⁸ F radiolabeled PET tracers show similar performance, even in the absence of comparative data.

The use of PSMA-PET in routine practice to detect local, distant, and recurrent prostate cancer is profoundly impacting patient management. However, data from prospective trials on the effect of PSMA-PET angiography on tumor outcome have not been obtained. Recent PET/CT studies of BCR patients have shown that, for scan-positive patients, approximately 65% to 75% of these recurrences are located in the pelvis and may be rescued with whole-pelvic radiotherapy. More than half of the patients had a limited number of lesions.

However, methods are needed to better manage patient outcomes and survival.

The present disclosure pertains to, for example, methods comprising, consisting of, and/or consisting essentially of: administering a therapeutic agent to a plurality of individuals having prostate cancer; administering to the individuals a prostate-specific membrane antigen Positron emission tomography (PSMA-PET), and generate its results; analyze the results; and determine the interval at which the individuals exhibited metastatic progression of the prostate cancer.

0.2ng/mL後，所有評估必須遵循表C的活動排程中之排程，無論隨後的PSA水平如何；及(iii)當達到主要終點的192個事件時，所有參與者的研究將結束，無論參與者遵循的活動排程為何。 [Fig. 1] is a flow chart of Example 1. [Fig. The diamond shape in the flowchart represents the decision time point at which the active schedule to switch to is determined. CT/MRI ^and99mTc bone scans at screening will be assessed by BICR and locally during post-PSMA-PET progression. See eg Table D. Circumstances not shown in the flowchart include (i) PSMA-PET assessment for all subjects at Week 26 (Month 6) regardless of PSA level; if BICR informs PSMA-PET progression, participants move to Form D activity schedule in; (ii) first PSA reading after end of treatment

After 0.2ng/mL, all assessments must follow the schedule in the activity schedule in Table C, regardless of subsequent PSA levels; and (iii) the study will end for all participants, regardless of participation, when 192 events of the primary endpoint are reached What is the schedule of activities that people follow.

It should be appreciated that certain features of the invention that are, for clarity, described herein in the context of different embodiments, may also be provided in combination in a single embodiment. That is, unless expressly incompatible or specifically excluded, each individual embodiment is considered combinable with any other embodiment(s) and that combination is considered another embodiment. Conversely, various features of the invention, which are presented for brevity in the context of a single embodiment, may also be provided separately or in any subcombination. Finally, although an embodiment may be described as part of a series of steps or part of a general structure, each step may itself be considered a separate embodiment that can be combined with others.

The study described herein introduced the primary endpoint of PSMA-PET metastatic progression-free survival (ppMPFS), which assesses the progression of new or existing metastases. The endpoint for PSMA-PET response at the end of Week 26 will use criteria modified from the PERCIST criteria. The introduction of PSMA-PET endpoints in clinical trials will be useful to inform decision-making based on PSMA-PET assessments in routine clinical practice. Prospective assessment of participants by PSMA-PET, whole-body (WB)-MRI, ^99m Tc-bone/CT scans will provide valuable information that is currently lacking in clinical trial data.

some terms

As used herein, the term "cancer" means an abnormal growth of cells that tends to proliferate in an uncontrolled manner and, in some cases, metastasize (spread). The term "prostate cancer" as used herein means histologically or cytologically proven adenocarcinoma of the prostate. Adenocarcinomas can be acinar or ductal. In some aspects, the adenocarcinoma is acinar. In some aspects, the adenocarcinoma is ductal. In some embodiments, the prostate cancer is localized prostate cancer, wherein the cancer is found only in the prostate. In other embodiments, the prostate cancer is distant prostate cancer, wherein the cancer has spread outside the prostate.

In further embodiments, the cancer has metastasized. As used herein, the term "metastasis" refers to the spread of cancer from an initial or primary site to a different or secondary site in the body. In some aspects, the cancer has spread within the prostate. In other aspects, the cancer is distant metastases, ie, in which the cancer continues to spread outside the prostate. Cancer can spread to other areas of the body, including but not limited to bones, lungs, liver, brain, lymph nodes, or a combination thereof. Typically, prostate cancer spreads to the hip of the individual. In certain embodiments, an individual treated according to the methods described herein has prostate cancer metastasis that begins after treatment. In other embodiments, the individual treated according to the methods described herein has prostate cancer metastases that were present prior to treatment. In a further embodiment, the prostate cancer is recurrent prostate cancer, ie, the cancer is found after treatment and after a period of time when the cancer cannot be detected. Recurrent prostate cancer can return to where it started (ie, a local recurrence) or elsewhere in the body. In further embodiments, the individual has adenocarcinoma of the prostate and has a PSADT of about 12 months or less, a Gleason score of about 8 or higher, and less than about 0.1 after pelvic radiography One or more of the prostate specific antigens in ng/mL. In other In the embodiment, the prostate cancer is castration resistant prostate cancer (CRPC).

Prostate cancer can also be grouped or staged using categories known in the art. Thus, the prostate cancer can be stage I, II, IIA, IIB, IIC, III, IIIA, IIIB, IIIC, IV, IVA, or IVB. In some embodiments, the prostate cancer is stage I, ie, slow growing cancer, no tumor can be felt, tumor involves half or less of one side of the prostate, low PSA levels, well-differentiated cancer cells, or a combination thereof. In other embodiments, the prostate cancer is stage II, ie, the tumor is found only in the prostate, the PSA level is moderate or low, the tumor is small but may have an increased risk of growth and spread, or a combination thereof. In further embodiments, the prostate cancer is stage IIA, i.e. (i) no tumor can be felt, tumor involves half or less of one side of the prostate, moderate PSA levels, well-differentiated cancer cells, or a combination thereof; or (ii) Larger tumors confined to the prostate with well-differentiated cancer cells. In yet other embodiments, the prostate cancer is stage IIB, i.e. the tumor is found only within the prostate, the tumor is large enough to be felt during a digital rectal exam (DRE), the PSA level is moderate, the cancer cells are moderately differentiated , or a combination thereof. In still further embodiments, the prostate cancer is stage IIC, ie, the tumor is found only within the prostate, the tumor is large enough to be felt during DRE, the PSA level is moderate, the cancer cells are moderately or poorly differentiated, or a combination thereof. In other embodiments, the prostate cancer is stage III, ie, the PSA level is high, the tumor is growing, the cancer is high grade, or a combination thereof. In further embodiments, the prostate cancer is stage IIIA, ie, the cancer has spread beyond the outer layers of the prostate into nearby tissues, the cancer has spread to the seminal vesicles, the PSA level is high, or a combination thereof. In still other embodiments, the prostate cancer is stage IIIB, ie, the tumor has grown outside the prostate, the tumor has invaded nearby structures (such as the bladder or rectum), or a combination thereof. In yet a further embodiment, the prostate cancer is stage IIIC, ie, the cancer cells of the entire tumor are poorly differentiated. In other embodiments, the prostate cancer is stage IV, ie the cancer has spread beyond the prostate. In a further embodiment, the prostate cancer is stage IVA, ie the cancer has spread to regional lymph nodes. In yet other embodiments, the prostate cancer is stage IVB, ie, the cancer has spread to distant lymph nodes, other parts of the body, or to the bone.

As used herein, the terms "co-administration," "concomitant administration," or the like encompass, and are intended to include, administration of a selected therapeutic agent to one or more individuals The agents are therapeutic regimens administered by the same or different routes of administration or at the same or different times. For example, a therapeutic agent can be administered before, after, or concurrently with another therapeutic agent.

The term "treat/treatment" refers to the treatment of one or more individuals suffering from a pathological condition, and refers to the reduction or amelioration of such conditions and/or symptoms associated therewith. It will be understood that, although not excluded, treatment of a pathological condition does not require complete elimination of the condition or symptoms associated therewith. Unless otherwise indicated, the term "treating" refers to all of the stated effects, but in other embodiments, the term may refer to any of the stated effects, or to exclude at least one of the effects.

The term "progression-free survival" is based on RECIST v1.1 and is defined as follows: For individuals with at least one measurable lesion, disease progression is defined as at least a 20% increase in the sum of the diameters of the target lesions, which is Reference is made to the smallest sum in the study (if the baseline sum is the smallest in the study, this includes the baseline sum). In addition to a relative increase of about 20%, the sum must also show an absolute increase of at least 5mm. In addition, the appearance of one or more new lesions is also considered progression. For individuals with only unmeasurable disease observed on CT or MRI scans, definite progression (as represented by a change in overall disease status) or the appearance of one or more new lesions was considered progression. For new bone lesions detected on a bone scan, a second imaging modality, such as CT or MRI, must be performed to confirm progression. In some embodiments, administration of a therapeutically effective amount of apalutamide provides improved anti-tumor activity as measured by progression-free survival.

The term "overall survival" was defined as the time from randomization to the date of death (from any cause). Survival data for surviving individuals at the time of analysis were limited to the date on which they were last known to be alive. In addition, for individuals with no post-baseline information, data were limited to the date of randomization; for individuals who lost follow-up or withdrew consent, data were limited to the date they were last known to be alive. In some embodiments, administration of a therapeutically effective amount of an anti-androgen provides improved anti-tumor activity as measured by overall survival.

"Randomization" when referring to a clinical trial refers to the time when an individual is confirmed eligible for a clinical trial and assigned to a treatment group.

The terms "subject," "patient," "human," and "individual" are used interchangeably.

The conjunctions "comprising", "consisting essentially of", and "consisting" are intended to mean their generally accepted meanings in patent language; that is , (i) "comprising" is synonymous with "including" or "containing", is inclusive or open-ended, and does not exclude additional, unrecited elements or method steps; (ii) "represented by "consists of" excludes any element, step, or ingredient not specified in the scope of the claim; and (iii) "consisting essentially of" limits the scope of the scope of the claim to the specified materials or steps, and does not materially affect the present disclosure of the basic and novel feature(s). More specifically, the basic and novel characteristics relate to the ability of the method to provide at least one of the benefits described herein, including, but not limited to, providing information about the survival of male human populations relative to the comparative male human population survival capabilities described elsewhere herein. The capacity of the information of the capacity.

Embodiments described with the phrase "comprising" (or its equivalent) also provide embodiments described independently with "consisting of" and "consisting essentially of."

When numerical systems are expressed as approximations, by use of the descriptor "about," it will be apparent that the particular numerical value forms another embodiment. In general, use of the term "about" indicates approximations that may vary depending upon the desired properties sought to be obtained by disclosing the subject matter, and will be interpreted in the particular context in which the term is used based on its function in the text. Those of ordinary skill in the art will be able to interpret this as a matter of routine. In some cases, the number of significant digits used for a particular value may be a non-limiting method of determining the degree of the word "about." In other cases, gradients used in a series of values can be used to determine the intended range within which each value can be used for the term "about." When present, all ranges are included and combinable. That is, reference to a value stated in a range includes every value within that range. If not indicated otherwise, the term "about" means a ±10% variance of the relevant value, but additional embodiments include where the variance can be ±5%, ±15%, ±20%, ±25%, or ±50% %By.

It should be appreciated that certain features of the invention, which are, for clarity, described herein in the context of different embodiments, may also be provided in combination in a single embodiment. That is, unless expressly incompatible or specifically excluded, each individual embodiment is considered combinable with any other embodiment(s) and that combination is considered another embodiment. Conversely, various features of the invention, which are presented for brevity in the context of a single embodiment, may also be provided separately or in any subcombination. Finally, while an embodiment may be described as part of a series of steps or part of a general structure, each such step is itself considered a separate embodiment that can be combined with the other.

When a list is presented, unless stated otherwise, it should be understood that each individual element of the list and each combination of the list is a separate embodiment. For example, a list of embodiments presented as "A, B, or C" would be read to include the embodiments "A", "B", "C", "A or B", "A or C", "B" or C", or "A, B, or C".

The present invention may be more readily understood by reference to the following description in conjunction with the accompanying drawings and examples, all of which form a part of this disclosure. It is to be understood that this invention is not limited to the particular products, methods, conditions, or parameters described or shown herein, and that the language used herein is intended to describe specific embodiments by way of example only and is not intended to limit any claimed invention. Likewise, unless specifically stated otherwise, any description of a possible mechanism or mode of action or reason for improvement is for illustration only, and the invention is not limited to the validity of any such suggested mechanism or mode of action or reason for improvement sex or inaccuracy. Throughout this text, it is recognized that such descriptions refer to various compounds, compositions, and methods of using such compounds and compositions. That is, when the present disclosure describes or claims features or embodiments related to compositions or methods of using compositions, it should be understood that such descriptions or claims are intended to extend such features or embodiments to each instance (ie, compositions). and methods of use).

method

The methods described herein provide clinical endpoints that can be used to analyze treatment of individuals and groups of individuals (ie, individuals in clinical trials). In contrast to common endpoints used during clinical trials in individuals with prostate cancer, the endpoints described herein allow for a faster overall determination that a given treatment protocol is successful. As such, the methods allow for modification, discontinuation, or establishment of treatment protocols, thereby increasing patient survival.

These methods can also be used to predict the effectiveness of therapeutic agents in treating prostate cancer by preventing prostate cancer metastasis (preventing further metastasis), slowing prostate cancer metastasis, and/or increasing survival in one or more individuals. In some embodiments, the methods can be used to predict the effectiveness of a therapeutic agent in the treatment of prostate cancer. In further embodiments, the methods can be used to predict the effectiveness of a therapeutic agent in slowing prostate cancer metastasis. In yet other embodiments, the methods can be used to predict the effectiveness of a therapeutic agent in increasing the survival rate of one or more individuals.

In some cases, the endpoint analyzed in these methods includes "progressive free survival". In some embodiments, progression-free survival is PSMA-PET metastatic progression-free survival (ppMPFS). As used herein, ppMPFS is the time from randomization to the scan date for metastatic progression (as analyzed by PSMA-PET) or death from any cause. In some embodiments, ppMPFS is the time from randomization to the scan date of metastatic progression, as analyzed by PSMA-PET. In other embodiments, ppMPFS is the time from randomization to death from any cause.

The methods comprise administering a therapeutic agent to a plurality of individuals having prostate cancer. As used herein, the term "plurality of individuals" refers to a number of individuals that provide statistically reliable results. In some embodiments, the plurality of systems are two or more. In other embodiments, the plurality of systems is about 10, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1000, or more. In further embodiments, the plurality of systems is 50 or more. In still other embodiments, the plurality of systems is 100 or more. In yet further embodiments, the plurality of individuals is 150 or more. In other embodiments, the plurality of systems is 200 or more. However, one of ordinary skill in the art can easily determine, depending on the specific clinical trial and its phase (ie, a Phase 1, Phase 2, Phase 3, or Phase 4 clinical trial) that producing statistically significant results will How many individuals are needed.

As used herein, Phase 1, Phase 2, and Phase 3 refer to the phases of clinical trials filed under 21 USC 312.21 for an investigational new drug (IND). Pursuant to this section, an IND may be submitted for one or more phases of the study. The clinical studies of the IND are divided into three sequential (but overlapping) phases. The three phases of the study are as follows:

(a) Phase 1 includes the initial introduction of the investigational drug into humans. Phase 1 trials are generally closely monitored and can be conducted in patients or normal volunteer subjects. These trials are designed to determine the metabolic and pharmacological effects of the drug in humans, the side effects associated with increasing doses, and, where possible, to obtain early evidence of efficacy. During Phase 1, sufficient information on the pharmacokinetics and pharmacological effects of the drug should be obtained to allow the design of a well-controlled, scientifically valid Phase 2 study. The total number of subjects and patients included in the Phase 1 trial varied with study medication, but generally ranged from 20 to 80. (2) Phase 1 trials also include studies of drug metabolism, structure-activity relationships, and mechanisms of action in humans, and studies where investigational drugs are used as research tools to explore biological phenomena or disease processes.

(b) Phase 2 involves conducting controlled clinical trials to evaluate the effectiveness of the drug for a specific indication or indications in patients with the disease or condition under investigation, and to determine common short-term side effects and risks associated with the drug. Phase 2 clinical trials are generally well-controlled, closely monitored, and conducted in relatively small numbers of patients, usually involving no more than a few hundred subjects.

(c) Phase 3 is a controlled or uncontrolled expansion trial. They are performed after preliminary evidence of the drug's effectiveness has been obtained, and are intended to collect additional information on efficacy and safety necessary to assess the drug's overall benefit-risk relationship and to provide adequate physician labeling Base. Phase 3 trials typically involve hundreds to thousands of subjects, and the results of such trials are often the basis for marketing authorization and registration.

Phase 4 studies covered by 21 CFR 312.85 are postmarketing studies. In conjunction with obtaining marketing approval, the FDA may request a Phase 4 study to describe additional information about the drug's risks, benefits, and optimal use. Such studies may include, but are not limited to, studies of different inputs than those used in the Phase 2 study. Dosing or scheduling, using the drug in other patient groups or other disease stages, or using the drug over an extended period of time.

Such methods include the use of prostate-specific membrane antigen positron emission tomography (PSMA-PET). PSMA-PET is performed on the individual, resulting in results. One of ordinary skill in the art will readily be able to utilize analytical techniques, knowledge, and instrumentation to perform PSMA-PET and produce the results used herein.

Next, the results produced by PSMA-PET were analyzed. Those with ordinary knowledge in the art can easily analyze the PSMA-PET results using the analysis techniques and knowledge in the art. In general, baseline PSMA-PET scans are obtained for each individual, optionally at randomization, and for comparison with subsequent PSMA-PET scans for the purpose of monitoring cancer metastasis. In some embodiments, the PSMA-PET analysis shows lesions that are not present in the baseline PSMA-PET scan. In other embodiments, the PSMA-PET analysis shows the same lesions present in the baseline PSMA-PET scan. In further embodiments, PSMA-PET analysis shows PSMA-PET positive distant lesions. In yet other embodiments, the PSMA-PET analysis shows PSMA-PET positive loco-regional lesions. In still further embodiments, the presence of at least one new PSMA-PET positive distant lesion compared to a baseline scan indicates metastatic progression of the cancer. In other embodiments, the presence of at least one new PSMA-PET positive locoregional lesion compared to the baseline scan indicates locoregional progression of the cancer.

PSMA-PET results allow those of ordinary skill in the art to provide information and/or data regarding the progression of prostate cancer. In some embodiments, the results allow one of ordinary skill in the art to determine the interval at which an individual exhibits metastatic progression of prostate cancer. As used herein, the term "interval" refers to the period during which prostate cancer metastasizes in an individual or group of individuals. In some aspects, the interval is determined for a single individual. In other aspects, for multiple individuals (ie, a group of individuals) Judgment interval. In some embodiments, the interval is based on weekly increments. In other embodiments, the interval is based on monthly increments. In further embodiments, the interval is based on annual increments. In certain aspects, the interval is a monthly increment, such as at least one month. In other aspects, the interval is in monthly increments, such as about 3 months, about 6 months, about 9 months, or about 12 months. In further aspects, the interval is in monthly increments, such as greater than or equal to about 3 months. In yet other aspects, the interval is in monthly increments, such as about 3 to about 12 months, about 3 to about 6 months, or about 6 to about 12 months.

Once the interval has been established, further action can be taken. In some embodiments, the administration of the therapeutic agent can be varied. In further embodiments, the analysis of test results may be altered. In yet other embodiments, the determination of the interval at which an individual exhibits metastatic progression of prostate cancer can be altered.

In some embodiments, the methods include altering the administration of the therapeutic agent. Accordingly, the amount or frequency of administration of the therapeutic agent can be varied. In some aspects, the daily dose of the therapeutic agent is increased. In other aspects, the daily amount per dose of the therapeutic agent is reduced. In a further aspect, the administration of the therapeutic agent is temporarily or permanently discontinued. In yet other aspects, the frequency of administration of the therapeutic agent is increased, ie, the therapeutic agent is administered more frequently. In still further aspects, the frequency of administration of the therapeutic agent is reduced, ie, the therapeutic agent is administered less frequently.

In other aspects, the use of PSMA-PET is discontinued. In some aspects, PSMA-PET is discontinued when a representative percentage of individuals exhibit an interval of a predetermined length of PSMA-PET-free metastatic progression survival. As used herein, the term "representative percentage" refers to the percentage of individuals in which survival is systematically significant. Similarly, as used herein, "predetermined length" refers to the period, ie, the length of time, in which prostate cancer has statistically significant limited or no metastatic progression. Representative percentages and predetermined lengths can be calculated by statistical analysis techniques of ordinary skill in the art and well-recognized.

In addition to administering a therapeutic agent, the methods described herein can also include administering radiation therapy to an individual. Radiation therapy may be administered to the individual prior to initiating the method, as part of the method, or after the method. Radiation therapy may also be administered to the individual as a result of the PSMA-PET analysis. In such embodiments, the PSMA-PET analysis provides information for changing one or more parameters of radiation therapy when administered to a single individual.

In some embodiments, PSMA-PET may guide those of ordinary skill in the art to adjust the radiation field or radiation frequency of radiation therapy. The above may be performed if the results of PSMA-PET indicate metastasis of prostate cancer, or if the results indicate no change. In some aspects, the radiation field of the radiation therapy is adjusted. In other aspects, the radiation frequency of radiation therapy is adjusted, ie, increased or decreased. In a further aspect, if the results of PSMA-PET indicate metastasis of prostate cancer, the radiation field for pelvic radiation therapy is adjusted. Several radiation therapy techniques are available to treat individuals with prostate cancer, particularly metastatic prostate cancer. In some embodiments, the radiation therapy is pelvic radiation therapy. In other embodiments, the radiation therapy is rescue radiation therapy, such as rescue radiation therapy to the entire pelvis. In a further embodiment, the radiation therapy is stereotaxic body radiation therapy.

The methods described herein can include the use of one or more additional diagnostic techniques. Additional techniques can be incorporated into the method to assist in determining the extent of metastasis, the likely survival of the individual, the need to discontinue administration of the therapeutic agent or any second therapeutic agent, the need for continued administration of the therapeutic agent or any second therapeutic agent, the need for increased treatment dose of the therapeutic agent or any second therapeutic agent, need to reduce the dose of the therapeutic agent or any second therapeutic agent, etc. In some embodiments, the additional diagnostic technique is whole body MRI, ^or99mTc -bone/CT, or both. In other embodiments, the additional diagnostic technique is whole body MRI. In a further embodiment, the additional diagnostic technique ^is99mTc -Bone/CT. In yet other embodiments, the methods include the use of whole body MRI ^and99mTc -bone/CT as additional diagnostic techniques.

therapeutic agent

In some embodiments, the therapeutic agent is an anti-androgen. As used herein, the term "anti-androgen" refers to a group of hormone receptor inhibitor or antagonist compounds that prevent or inhibit the biological effects of androgens on normally responsive tissues in the body. In some embodiments, the anti-androgens are small molecules. In some embodiments, the antiandrogen is an AR antagonist. In some embodiments, the anti-androgens are full AR antagonists. The terms "AR antagonist" or "AR inhibitor" are used interchangeably herein and refer to an agent that inhibits or reduces at least one activity of an AR polypeptide. Exemplary AR activities include, but are not limited to, coactivator binding, DNA binding, ligand binding, or nuclear translocation.

A "full antagonist" refers to an antagonist that substantially completely inhibits the activity of an AR polypeptide at effective concentrations. "Partial antagonist" refers to an antagonist capable of partially inhibiting the activity of an AR polypeptide, but which is not a complete antagonist even at the highest concentrations. "Essentially completely" means at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or greater Inhibits the activity of AR polypeptides.

Exemplary anti-androgens include 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxy-6-sulfanyl-5,7-diazaspiro[ 3.4] Oct-5-yl]-2-fluoro-N-methylbenzamide (also known as apalutamide, ARN-509, or JNJ-56021927; CAS No. 956104-40-8); 4- (3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxy-2-thioimidazolidin-1-yl)-2-fluoro -N-methylbenzamide (also known as MDV3100 or enzalutamide; CAS number: 915087-33-1) and 4-[7-(4-cyano-3-trifluoromethyl) Phenyl)-8-oxy-6-sulfanyl-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (RD162; CAS No. 915087-27-3). In some embodiments, second-generation anti-androgens Binds to the AR polypeptide at or near the ligand binding site of the AR polypeptide. Thus, in some embodiments, the therapeutic agent used in the methods is apalutamide.

In some embodiments, anti-androgens contemplated in the methods described herein inhibit AR nuclear transfer (such as darolutamide), binding of DNA to androgen-responsive elements, and recruitment of co-activators. In other embodiments, the anti-androgens contemplated in the methods described herein do not exhibit agonist activity in AR-overexpressing prostate cancer cells.

Apalutamide is a next-generation anti-androgen that directly binds to the ligand-binding domain of AR, thereby preventing nuclear translocation, AR binding to DNA, and AR target gene regulation, thereby inhibiting tumor growth and promoting apoptosis. Apalutamide binds AR with greater affinity than bicalutamide and is in non-castration hormone-sensitive and bicalutamide-resistant human prostate cancer xenotransplantation Induces partial or complete tumor regression in an explant model. Apalutamide lacks some of the agonist activity of bicalutamide seen in the context of AR overexpression.

Darolutamide (N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5 -(1-Hydroxyethyl)-1H-pyrazol-3-carboxamide; BAY1841788 or ODM-201) is an AR antagonist that includes two diastereomers, ORM-16497 and ORM-16555. It is active against known AR mutants that confer other anti-androgen resistance. Darulutamide binds to AR with high affinity and prevents subsequent androgen-induced AR nuclear translocation and transcription of AR gene targets.

In general, the amount of therapeutic agent will vary depending on the particular therapeutic agent selected and other factors such as, but not limited to, the condition and severity of the disease or disorder, and characteristics of humans (eg, body weight), and the amount of any second therapeutic agent.

For example, when apalutamide is the therapeutic agent, the amount used may range from 10 mg to 1000 mg per day. In some embodiments, apalutamide is administered orally to a human at a dose of about 30 mg per day to about 1200 mg per day. In other embodiments, apalutamide is administered orally to a human at a dose of about 30 mg per day to about 600 mg per day. In some embodiments, apalutamide is administered orally to a human at about 30 mg per day, about 60 mg per day, about 90 mg per day, about 120 mg per day, about 160 mg per day, about 180 mg per day, about 240 mg per day, about 300 mg, about 390 mg per day, about 480 mg per day, about 600 mg per day, about 780 mg per day, about 960 mg per day, or about 1200 mg per day.

The dose of the therapeutic agent can also be formulated to achieve a certain daily dose. For example, the dose of apalutamide may have the following ranges: 30 to 40 mg/day, 40 to 50 mg/day, 50 to 60 mg/day, 60 to 70 mg/day, 70 to 80 mg/day, 80 to 90 mg/day, 90 to 100 mg/day, 100 to 120 mg/day, 120 to 140 mg/day, 140 to 160 mg/day, 160 to 180 mg/day, 180 to 200 mg/day, 200 to 220 mg/day, 220 to 240 mg/day, 240 to 240 mg/day 260mg/day, 260 to 280mg/day, 280 to 300mg/day, 300 to 320mg/day, 320 to 340mg/day, 340 to 360mg/day, 360 to 380mg/day, 380 to 400mg/day, 400 to 420mg/day day, 420 to 440 mg/day, 440 to 460 mg/day, 460 to 480 mg/day, or any range defined by two or more of these values, or any individual value recited in such ranges. In other embodiments, the dose of apalutamide may have the following ranges: 0.3 to 0.4 mg/kg/day, 0.4 to 0.5 mg/kg/day, 0.5 to 0.6 mg/kg/day, 0.6 to 0.7 mg/day kg/day, 0.7 to 0.8 mg/kg/day, 0.8 to 0.9 mg/kg/day, 0.9 to 1 mg/kg/day, 1 to 1.2 mg/kg/day, 1.2 to 1.4 mg/kg/day, 1.4 to 1.4 mg/kg/day 1.6 mg/kg/day, 1.6 to 1.8 mg/kg/day, 1.8 to 2 mg/kg/day, 2 to 2.2 mg/kg/day, 2.2 to 2.4 mg/kg/day, 2.4 to 2.6 mg/kg/day , 2.6 to 2.8 mg/kg/day, 2.8 to 3.0 mg/kg/day, 3.0 to 3.2 mg/kg/day, 3.2 to 3.4 mg/kg/day, 3.4 to 3.6 mg/kg/day, 3.6 to 3.8 mg /kg/day, 3.8 to 4.0 mg/kg/day, 4.0 to 4.2 mg/kg/day, 4.2 to 4.4 mg/kg/day, 4.4 to 4.6 mg/kg/day, 4.6 to 4.8 mg/kg/day, or any range delimited by two or more of these equivalent values, or any individual value recited in such range.

In a further embodiment, apalutamide is administered orally to a male human at a dose of about 30 mg per day to about 480 mg per day. In still further embodiments, apalutamide is administered orally to a male human at a dose of about 180 mg per day to about 480 mg per day. In certain embodiments, apalutamide is administered orally to a male human at the following doses: (a) about 30 mg per day; (b) about 60 mg per day; (c) about 90 mg per day mg; (d) about 120 mg per day; or (d) about 240 mg per day. In some embodiments, apalutamide is administered orally to a male human at a dose of about 240 mg per day.

In certain embodiments where improvement in the state of the human disease or condition is not observed, the daily dose of the therapeutic agent can be increased. In some embodiments, the once-daily dosing schedule is changed to a twice-daily dosing schedule. In a further embodiment, a three-daily dosing schedule is employed to increase the amount of therapeutic agent.

The individual may have received at least one prior therapy for the treatment of cancer. In some embodiments, the prior therapy for treating cancer is bicalutamine, flutamide, or nilutamide. In other embodiments, the male human is treatment naïve.

The therapeutic agent can be administered in combination with androgen deprivation therapy (ADT). In some embodiments, the therapeutic agent is administered in combination with a second therapeutic agent. In other embodiments, the second therapeutic agent is a gonadotropin-releasing hormone agonist or antagonist. GnRH agonists or antagonists may include leuprolide, buserelin, naferelin, histrelin, goserelin, Deslorelin, degarelix, ozarelix, ABT-620 (elagolix), TAK-385 (relugolix), EP -100, KLH-2109, or triptorelin. In other embodiments, the second therapeutic agent is a luteinizing hormone-releasing hormone (LHRH) antagonist. Examples of LHRH agonists include goserelin, goserelin acetate, histaminerelin acetate, leuprolide, leuprolide acetate, triptorelin pamoate, or triptorelin acetate , or a combination thereof.

A physician may prescribe a second therapeutic agent based on instructions, recommendations, and practice. In some embodiments, the second therapeutic agent is leuprolide. In other embodiments, the second therapeutic agent is buserelin. In a further embodiment, the second therapeutic agent is nafarelin. In yet other embodiments, the second set of therapeutic agents aminerelin. In still further embodiments, the second therapeutic agent is histaminerelin acetate. In other embodiments, the second therapeutic agent is goserelin. In other embodiments, the second therapeutic agent is desirelin. In further embodiments, the second therapeutic agent is degarelix. In still other embodiments, the second therapeutic agent is Ozarelix. In yet further embodiments, the second therapeutic agent is Ozarelix. In other embodiments, the second therapeutic agent is ABT-620 (Elagoli). In a further embodiment, the second therapeutic agent is TAK-385 (Rilagolix). In yet other embodiments, the second therapeutic agent is EP-100. In still further embodiments, the second therapeutic agent is KLH-2109. In other embodiments, the second therapeutic agent is triptorelin.

Additional diagnostic steps

Additional diagnostic techniques may be performed to assist in treating an individual. In some embodiments, the methods further comprise determining the level of prostate specific antigen (PSA) in the individual. Techniques are known to those of ordinary skill in the art and include blood tests in which serum PSA is measured.

Once obtained, PSA is used to determine how often PSMA-PET is performed. In some embodiments, PSMA-PET is performed every about 6 months after the first PSMA-PET if the individual's prostate specific antigen line is about 0.2 ng/mL or higher. In other embodiments, the PSMA-PET is performed every about 12 months after the first PSMA-PET if the individual's prostate specific antigen is less than about 0.2 ng/mL. In a further embodiment, if the subject's PSA is less than about 0.2 ng/mL, the subject's PSA level is assessed every about 3 months after the individual's PSA is first determined.

Routes of Administration and Pharmaceutical Compositions

The therapeutic agents described herein are administered in any suitable manner or in a suitable formulation. Suitable routes of administration for therapeutic agents include, but are not limited to, oral and parenteral (eg, intravenous, subcutaneous, intramuscular). All formulations are in dosages suitable for administration to humans. An overview of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L. , Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), such disclosures are incorporated herein by reference.

Trials investigating safety also seek to identify any possible adverse effects that may result from drug exposure. Efficacy is typically measured by determining whether the active pharmaceutical ingredient demonstrates a health benefit superior to a placebo or other intervention when tested in an appropriate setting, such as a well-controlled clinical trial.

Unless otherwise specified, the terms "effective amount" or "therapeutically effective amount" as used herein refers to the amount of Dosage of anti-androgens.

The term "acceptable" as used herein in relation to a formulation, composition or ingredient means that the beneficial effect of the formulation, composition or ingredient on the overall health of the male human being treated substantially exceeds any of its beneficial effects, if any. harmful effects.

In some embodiments, the therapeutic agent is present in a solid dosage form. In certain embodiments, the therapeutic agent is formulated as a lozenge. In some embodiments, the therapeutic agent is present in a solid oral dosage form. In some embodiments, the therapeutic agent is formulated as an oral dosage form, an oral unit dosage form, or a solid dosage form (eg, a capsule, lozenge, or pill). For example, in some embodiments, the therapeutic agent is formulated as a lozenge. Solid oral dosage forms containing the therapeutic agent may be as disclosed in WO2014113260 and CN104857157 (each of which is incorporated herein by reference) as a soft gel capsule or as disclosed in WO2016090098, WO2016090101, WO2016090105, and WO2014043208 (each of which is incorporated by reference herein) incorporated herein) as disclosed in available in lozenges. Techniques suitable for preparing the solid oral dosage forms of the present invention are described in Chapter 89 in Remington's Pharmaceutical Sciences, 18th edition, edited by AR. Gennaro, 1990 and in Remington-The Science, and Practice of Pharmacy, 21st edition, 2005 Chapter 45.

In certain embodiments, the therapeutic agent is presented in a solid unit dosage form, and the solid unit dosage form is suitable for oral administration. For example, a unit dosage form may contain about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, or 240 mg of apalutamide, or an amount within the range defined by either of these values.

To prepare the pharmaceutical compositions of the present invention, the active pharmaceutical ingredients are intimately mixed with pharmaceutical carriers according to conventional pharmaceutical compounding techniques, wherein the carriers can be in a wide variety of forms depending on the intended administration (eg, oral or parenteral). ) in the form of preparations. Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

In solid oral formulations such as, for example, dry powders for reconstitution or inhalation, granules, capsules, caplets, gelcaps, pills, and lozenges (each including immediate release, timed release, and sustained release formulations)), suitable carriers and additives include, but are not limited to, diluents, granulating agents, lubricants, binders, glidants, disintegrants, and the like. Because of their ease of administration, lozenges and capsules are the most advantageous oral dosage unit forms in which solid pharmaceutical carriers are obviously employed. If desired, lozenges may be sugar-coated, gelatin-coated, film-coated, or enteric-coated by standard techniques.

Preferably, these compositions are in unit dosage forms such as lozenges, pills, capsules, dry powders for reconstitution or inhalation, granules, lozenges, sterile solutions or suspensions, metered aerosols. Gel or liquid sprays, drops, or suppositories for administration by oral, intranasal, sublingual, intraocular, transdermal, rectal, vaginal, dry powder inhaler, or other means of inhalation or insufflation.

These formulations are prepared by conventional formulation techniques. To prepare solid pharmaceutical compositions such as lozenges, the principal active ingredient is mixed with a pharmaceutical carrier, eg, conventional tableting ingredients, such as diluents, binders, sticking agents, disintegrants, lubricants, antiseptics Adhesives and Glidants. Suitable diluents include, but are not limited to, starch (ie, corn, wheat, or potato starch, which may be hydrolyzed), lactose (granulated, spray-dried, or anhydrous), sucrose, sucrose-based diluents (powdered sugar; sucrose plus About 7 to 10 weight percent invert sugar; sucrose plus about 3 weight percent modified dextrin; sucrose plus invert sugar, about 4 weight percent invert sugar, about 0.1 to 0.2 weight percent cornstarch and magnesium stearate), right Spinose, inositol, mannitol, sorbitol, microcrystalline cellulose (ie AVICEL microcrystalline cellulose, available from FMC Corp.), dicalcium phosphate, calcium sulfate dihydrate, calcium lactate trihydrate, and the like By. Suitable binders and sticking agents include, but are not limited to, acacia, guar, tragacanth, sucrose, gelatin, glucose, starch, and cellulosic (ie, methylcellulose, sodium carboxymethylcellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and the like), water-soluble or dispersible binders (i.e. alginic acid and its salts, magnesium aluminum silicate, hydroxyethyl cellulose [ ie TYLOSE, available from Hoechst Celanese], polyethylene glycol, polysaccharide acid, bentonite, polyvinylpyrrolidone, polymethacrylate, and pregelatinized starch), and the like. Suitable disintegrants include, but are not limited to, starch (corn, potato, etc.), sodium carboxymethyl starch, pregelatinized starch, clays (magnesium aluminum silicate), celluloses (such as croscarmellose sodium and microfiber). crystalline cellulose), alginate, pregelatinized starch (ie, corn starch, etc.), gums (ie, agar, guar, locust bean, karaya, pectin, and tragacanth), cross-linked polyvinylpyrrole pyridone, and the like. Suitable lubricants and anti-adherents include, but are not limited to, Stearates (Magnesium, Calcium, and Sodium), Stearic Acid, Talc, Stearowet, Boric Acid, Sodium Chloride, DL-Leucine, Carbowax 4000, Carbowax 6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate, and the like. Suitable glidants include, but are not limited to, talc, cornstarch, silica (available as CAB-O-SIL silica, SYLOID silica available from W.R. Grace/Davison, and commercially available from Degussa AEROSIL Silica), and the like. Sweetening and flavoring agents can be added to the chewable solid dosage form to improve the palatability of the oral dosage form. In addition, colorants and coatings can be added or applied to the solid dosage form to facilitate drug identification or for aesthetic purposes. These carrier systems are formulated with the pharmaceutically active agent to provide a precise, appropriate pharmaceutically active agent with a therapeutic release profile.

Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, starch, cellulose, and derivatives thereof (eg, ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose cellulose, hydroxypropyl methylcellulose), polyvinylpyrrolidone, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pregelatinized starch, and mixtures thereof.

Binders or fillers in pharmaceutical compositions are generally present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

Disintegrants can be used in the compositions to provide lozenges that disintegrate when exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate on storage, whereas those containing too little may not disintegrate at the desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant should be used neither too much nor too little to adversely alter the release of the active ingredient to form a solid oral dosage form. The amount of disintegrant used will vary with the type of formulation, as will be apparent to those of ordinary skill in the art. A typical pharmaceutical composition contains from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant. Disintegrants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, croscarmellose sodium, croscarmellose, Vidone, sodium carboxymethyl starch, potato or tapioca starch, pregelatinized starch, other starches, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, polyethylene glycols, other glycols, hard Fatty acid, sodium lauryl sulfate, sodium stearyl fumarate, talc, hydrogenated vegetable oils (such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate , ethyl oleate, ethyl laurate, agar, and mixtures thereof. Lubricants are generally used in an amount less than about 1 weight percent of the pharmaceutical composition or dosage form into which they are to be incorporated.

The compressed tablet formulation may optionally be film coated to provide color, light protection, and/or taste masking. Tablets may also be coated to modulate the onset and/or rate of release in the gastrointestinal tract to optimize or maximize the biological exposure of one or more subjects to the API.

Hard capsule formulations can be produced by filling a blend or granules of the therapeutic agent into a shell consisting of, for example, gelatin or hydroxypropyl methylcellulose. Softgel capsule formulations can also be produced.

Pharmaceutical compositions intended for oral use can be prepared from solid dispersion formulations and the above-described materials blended according to the methods described herein and other methods known in the art for the manufacture of pharmaceutical compositions. The compositions may further contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives to provide pharmaceutically aesthetically pleasing and palatable formulations.

Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Such excipients can be, for example, inert diluents, granulating agents, and disintegrating agents, binders, glidants, lubricants, and antioxidants, such as propyl gallate, butylhydroxymethoxybenzene, and dihydroxymethoxybenzene Butylated Hydroxytoluene. Tablets may be uncoated or they may be film coated to modify their appearance or may be coated with a functional coating to delay disintegration and gastrointestinal absorption, and thereby provide sustained action over a longer period of time.

Compositions for oral use may also be presented in capsules, such as hard gelatin, in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or starch, or in soft gelatin capsules, in which the active ingredient is mixed with Liquid or semi-solid blends such as peanut oil, liquid paraffin, fractionated glycerides, surfactants, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. In certain embodiments of the present invention, the pharmaceutical compositions of the present invention comprise diluent systems, disintegrants, salts, lubricants, glidants, and film coatings at concentrations from about 3% w/w to about 58% w/w, from about 4% w/w to about 20% w/w, from about 4% w/w to about 20% w/w, from about 0.5% w/w to about 4% w/ w, from about 0% w/w to about 2% w/w, and from about 1% w/w to about 5% w/w, or from about 18% w/w to about 40% w/w, respectively , from about 7% w/w to about 15% w/w, from about 7% w/w to about 18% w/w, from about 1.0% w/w to about 3.0%, from about 0.1% w/w to about 1.0% w/w, and from about 2.0% w/w to about 4.0% w/w. In certain embodiments, solid dispersion formulations are admixed with diluents, one or more disintegrants, lubricants, and glidants. Exemplary blend compositions or oral dosage forms include mannitol, microcrystalline cellulose, croscarmellose sodium, sodium chloride, gum silicate, sodium stearyl fumarate, and magnesium stearate .

The disintegrant may be present at a concentration of from about 4% w/w to about 20% w/w or from about 7% w/w to about 15% w/w. Salt may also be present, which may be sodium chloride, potassium chloride, or a combination thereof. The combination of salt and disintegrant is present at a concentration of from about 5% w/w to about 35% w/w of the final pharmaceutical composition.

In certain embodiments, the inactive ingredients of the core tablet include: colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose acetate succinate, magnesium stearate, microcrystalline cellulose , and silicified microcrystalline cellulose. In other embodiments, the tablet surface is treated with a film coating consisting of the following excipients: black iron oxide, yellow iron oxide, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide

In other embodiments, a single unit dose of a pharmaceutical composition comprises, consists of, or consists essentially of a therapeutic agent, such as apalutamide. In some embodiments, multiple doses of a single unit dose pharmaceutical composition, eg, 4 multiple or individual unit dosage forms, are administered to humans, the single unit dose pharmaceutical composition comprising, consisting of, or consisting essentially of Composition: A therapeutic agent such as apalutamide.

All oral formulations are suitable for this method of administration.

Use of Approved Drugs

The methods provided herein can comprise administering a drug product, such as apalutamide, in the amount stated on the drug label of the approved drug product. In some embodiments, the approved drug product comprising apalutamide is an ANDA drug product or a supplemental new drug application drug product. In certain embodiments, the method is clinically proven safe.

The term "drug product" or "approved drug product" refers to an active pharmaceutical ingredient that has been approved by a governmental authority (such as the U.S. Food and Drug Administration or similar authority in other countries) Products approved for marketing for at least one indication.

The term "Reference Listed Drug (RLD)" is a new generic drug with which it is compared to show that they are biologically equivalent. 21 CFR 314.3(b)). It is also a marketing authorisation that has been issued by an EU Member State or the Commission based on a complete application file (i.e. submission of quality, preclinical, and clinical data under Article 8(3), 10a, 10b, or 10c of Directive 2001/83/EC) certified drugs, and the generic name/mixed drug is the reference drug for which bioequivalence is usually demonstrated by submitting appropriate bioavailability studies when applying for marketing authorization.

In the U.S., companies seeking marketing approval for scientific name equivalents must reference the RLD in their abbreviated new drug application (ANDA). For example, ANDA applicants rely on the FDA's review of previously approved drugs (ie, RLDs) are found to be safe and effective, and must demonstrate, among other things, that the proposed generic drug is identical in some respects to the RLD. Specifically, with limited exceptions, a drug product for which an ANDA is submitted must, among other things, have the same active ingredient(s), conditions of use, route of administration, dosage form, strength, and (with certain permitted) difference) label. An RLD is a registered drug product, and an ANDA applicant must show that the proposed ANDA drug product is identical with other features such as active ingredient(s), dosage form, route of administration, strength, labeling, and conditions of use. In the electronic version of the Orange Book, there is a column for RLD and a column for reference standards. In the printed Orange Book, RLDs and reference standards are represented by specific symbols. For an ANDA based on a petition for applicability of approval (appellant ANDA), the reference drug is usually the listed drug referenced in the petition for applicability of approval.

A reference standard is a drug product selected by the FDA that an applicant seeking ANDA approval must use to conduct in vivo bioequivalence studies required for approval. FDA typically selects a single reference standard that ANDA applicants must use in in vivo bioequivalence testing. Generally, FDA will select a reference drug product as a reference standard. However, in some cases (eg, when the reference product has been discontinued and FDA has determined that it was not discontinued for safety or efficacy reasons, and FDA selected ANDA as the reference standard), the reference product may differ from the reference standard.

FDA identifies prescription drugs, OTC drugs, and comparator drugs on the Discontinued Drug List. A registered drug product identified as a comparator product represents a drug product upon which the applicant may seek ANDA approval. FDA intends to periodically update comparator products identified on the prescription drug, OTC drug, and discontinued drug lists as needed.

FDA also recognizes reference standards on the Prescription Drug and OTC Drug Lists. The listed drug product identified as the reference standard represents FDA's best judgement at the time as an appropriate comparator for the purpose of conducting any in vivo bioequivalence studies required for approval.

In some instances where FDA has not designated a registered drug as a comparator, the registered drug may not be subject to generic competition. If FDA has not designated a comparator product for a drug that the applicant intends to copy, a potential applicant may request FDA to designate a comparator product for that drug.

FDA can choose new reference standards on its own initiative, and doing so will help ensure that applications for generic drugs can be submitted and evaluated, such as when the reference drug currently selected as the reference standard has been discontinued for reasons other than safety and efficacy. case.

In Europe, the applicant identifies the reference medicinal product (product name, strength, dosage form, MAH, first license, member state) synonymous with the RLD as follows /community):

1. Medicines that are or have been licensed by the EEA, which are used as a basis to demonstrate that the data protection period as defined in the EU medical regulations has expired. This reference drug product, and the scientific name/mixed drug product, identified for the purpose of calculating the expiry of the data protection period, may be of different strengths, dosage forms, routes of administration or presentation.

2. Drugs whose application documents are cross-referenced in the scientific name/mixed application (product name, strength, dosage form, MAH, marketing license number). This reference medicinal product may be licensed under a separate process and under a different name from the reference medicinal product identified for the purpose of calculating the expiry of the data protection period. The product information for this reference medicinal product will in principle serve as the basis for the product information claimed for the generic/mixed medicinal product.

3. Drug product (product name, strength, dosage form, MAH, source Member State) used in the bioequivalence study (if applicable). Different simplified approval pathways for drugs under the FD&C Act - The simplified approval pathways are described in sections 505(j) and 505(b)(2) of the FD&C Act (21 U.S.C. 355(j) and 21 U.S.C. 355(b)(2), respectively) ).

According to FDA (https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM579751.pdf), the contents of which are incorporated herein by reference), NDAs and ANDAs can be divided into the following four categories:

(1) A "separate NDA" is an application filed under section 505(b)(1) of the FD&C Act and approved under section 505(c) that contains an application made or commissioned by the applicant or the applicant has the right to reference or use Complete safety and efficacy investigation report.

(2) A 505(b)(2) application is an NDA filed under section 505(b)(1) of the FD&C Act and approved under section 505(c) that contains a complete safety and efficacy investigation report, However, at least some of the information required for approval comes from research not conducted or commissioned by the applicant and the applicant has not been granted the right to reference or use the research.

(3) An ANDA is an application for a generic version of a previously approved drug that is filed and approved pursuant to Section 505(j) of the FD&C Act. The ANDA relies on the FDA's finding that a previously approved drug product, the comparator product (RLD), is safe and effective. The ANDA must generally contain information showing that the proposed scientific name product is: (a) identical to the RLD with respect to active ingredient(s), conditions of use, route of administration, dosage form, strength, and labelling (with some permissible differences), and (b) Bioequivalent to RLD. If testing is required to demonstrate the safety and efficacy of the proposed product, the ANDA cannot be applied for.

(4) A petition ANDA is a type of ANDA for a drug product whose dosage form, route of administration, strength, or active ingredient (products with more than one active ingredient) is different from the RLD, and FDA responds in accordance with 505(j) of the FD&C Act )(2)(C) (applicability petition), determining that the proposed drug does not require research to demonstrate safety and efficacy.

The scientific premise behind the Hatch-Waxman amendment is that ANDA drugs approved under Section 505(j) of the FD&C Act are considered therapeutic equivalents for their RLD. A product classified as a therapeutic equivalent can be substituted and it is fully expected that the substituted product, when administered to a patient under the conditions indicated on the label, will produce the same clinical effect and safety profile as the prescription product. Relative to ANDAs, 505(b)(2) applications allow greater flexibility in proposing product features. A 505(b)(2) application will not necessarily be rated as the therapeutic equivalent of the listed drug to which it is referenced at the time of approval.

The phrase "therapeutically equivalent to a reference listed drug" means that the drug is the scientific equivalent of the reference drug, i.e., the pharmaceutical equivalent, and is therefore assessed by the FDA as the AB therapeutic equivalent of the reference drug, in which the actual or Potential bioequivalence issues have been addressed by appropriate in vivo and/or in vitro evidence supporting bioequivalence.

"Pharmaceutical equivalents" means a drug product in the same dosage form and route(s) of administration containing the same amount of the same active pharmaceutical ingredient as a reference drug product.

FDA classifies these products as therapeutically equivalent when they meet the following general criteria: (1) they are approved as safe and effective; (2) they are pharmaceutical equivalents because they (a) are in the same dosage form and administered The routes contain the same active pharmaceutical ingredient in the same amount, and (b) meet pharmacopoeial or other applicable standards for strength, quality, purity, and identification; (3) they are biologically equivalent, wherein (a) they do not appear to have known or potential bioequivalence issues and they meet acceptable in vitro standards, or (b) if they exhibit such known or potential issues, they have been shown to meet appropriate bioequivalence standards; (4) They are properly labeled; and (5) they are manufactured in compliance with current Good Manufacturing Practice regulations

The term "bioequivalent" or "bioequivalence" refers to the difference between a pharmaceutical equivalent or pharmaceutical substitute when administered under similar conditions at the same molar dose in a properly designed study. The rate and extent to which the active ingredient or active moiety becomes available at the site of drug action There are no significant differences. Section 505(j)(8)(B) of the FD&C Act describes the set of conditions under which test and reference products should be considered biologically equivalent: whether a single dose or multiple doses, when treated at the same molar dose When the ingredients are administered under similar experimental conditions, the rate and extent of absorption of the [test] drug and the [control] drug do not show significant differences; or, regardless of single dose or multiple doses, when administered in the same molar When doses of therapeutic ingredients are administered under similar experimental conditions, the extent of absorption of the [test] drug does not show a significant difference from that of the [control] drug, whereas the difference in the rate of drug absorption from the [control] drug is intentional and reflects In its proposed label, long-term use is not critical to achieving effective body drug concentrations, and the drug is deemed not medically significant.

If these above methods are not applicable (eg, the drug product is not intended to be absorbed through the bloodstream), it may be appropriate to demonstrate bioequivalence using other scientifically valid in vivo or in vitro testing modalities.

For example, bioequivalence can sometimes be demonstrated using in vitro bioequivalence criteria, especially when the in vitro testing has been correlated with in vivo bioavailability data in humans. In other cases, bioequivalence can sometimes be demonstrated through comparative clinical trials or pharmacodynamic trials.

Also provided herein is a medicinal product comprising a clinically proven safe and clinically proven amount of apalutamide, wherein the medicinal product is packaged and wherein the package includes a label that identifies apalutamide as a regulated approved chemical entity.

As used herein, unless otherwise stated, the term "safe" means, when used in the manner of the present invention, without undue adverse side effects (such as toxicity, irritation, or allergic reactions), and with reasonable benefit / risk ratio. Similarly, unless otherwise stated, the phrase "effective" means that when administered in a therapeutically effective dose, the therapeutic efficacy of a treatment in an individual suffering from prostate cancer has been demonstrated. In certain embodiments, the methods described herein are safe. In other embodiments, the methods described herein are effective. In further embodiments, the methods described herein are safe and Effective. In yet other embodiments, a therapeutically effective amount of apalutamide is safe. In still further embodiments, a therapeutically effective amount of apalutamide is effective. In other embodiments, a therapeutically effective amount of apalutamide is safe and effective.

As used herein, unless otherwise stated, the term "clinically proven" (used alone or to modify the terms "safe" and/or "effective") means that evidence has been Evidence from a clinical trial of the Agency's approved standards or a similar study for EMEA marketing authorization. Evidence can be provided, for example, by clinical trials as described in Example 1.

As used herein, unless otherwise stated, the term "clinically proven effective" means that the efficacy of a treatment has been shown to be statistically significant by a clinical trial, ie, at an alpha level of less than 0.05, the clinical trial The results cannot be due to chance, or the clinical efficacy results are sufficient to meet FDA approval criteria or similar studies for EMEA marketing authorization. Evidence can be provided, for example, by clinical trials as described in Example 1.

As used herein, unless otherwise stated, the term "clinically proven safe" means that the safety of a treatment has been demonstrated by clinical trials by analysis of trial data and results, which determine that the treatment does not have undue adverse side effects and is commensurate with statistically significant clinical benefits (eg, efficacy) from similar studies sufficient to meet FDA approval criteria or marketing authorization in Europe, the Middle East, and Africa (EMEA). Evidence can be provided, for example, by clinical trials as described in Example 1.

Abbreviations and terms

Example 1.

0.2ng/mL的參與者每6個月一次，PSA<0.2ng/mL的參與者每12 個月一次)。此PSA臨限係基於BCR前列腺癌患者中之PSA升高與PSMA-PET陽性率的相關分析。當參與者有PSMA-PET轉移性進展時，其在研究期間記錄的造影歷史(PSMA-PET、CT/MRI、及WB-MRI)將提供給主治醫師，以協助在規程之外的後續治療決策。接著，可起始PET引導之以轉移為導向的治療作為下一線治療。 In this study, early detection of metastatic progression will be identified by frequent PSMA-PET assessment (PSA

every 6 months for participants with 0.2 ng/mL and every 12 months for participants with PSA < 0.2 ng/mL). This PSA threshold was based on a correlation analysis of elevated PSA and PSMA-PET positivity in BCR prostate cancer patients. When participants have metastatic progression on PSMA-PET, their angiographic history (PSMA-PET, CT/MRI, and WB-MRI) recorded during the study period will be provided to the attending physician to assist in out-of-protocol follow-up treatment decisions . Next, PET-guided metastasis-directed therapy can be initiated as the next line of therapy.

These treatment modalities (rescue radiation therapy plus a luteinizing hormone-releasing hormone agonist [LHRHa] plus apalutamide) are administered simultaneously with different well-known mechanisms of action in high-risk patients with BCR who relapse after RP , an additive effect between these treatment modalities can be expected, which may lead to a related delay in metastasis.

A. Goal and destination

(i) Interventional groups:

Main objective: To determine whether the addition of apalutamide to RT+LHRHa delayed metastatic progression as assessed by PSMA-PET or death compared to RT+LHRHa alone.

Primary endpoint: PSMA-PET metastatic progression-free survival (ppMPFS): defined as the time from randomization to the (scan) date of PSMA-PET metastatic progression (as judged by BICR) or death from any cause. PSMA-PET metastatic progression was defined as the appearance of at least 1 new PSMA-PET-positive distant lesion compared to the previous scan.

Secondary purpose:

• To determine whether the addition of apalutamide to RT+LHRHa provided superior efficacy in other efficacy endpoints compared to RT+LHRHa alone.

• To characterize the safety profile of treatment with RT+LHRHa plus apalutamide.

secondary endpoint

• Time to PSA progression: defined as the time from randomization to the date on which PSA progression was first recorded. PSA progression was defined as a PSA concentration above a nadir of 0.5 ng/mL confirmed by repeated measurements after at least 3 weeks.

PSA response rate: defined as the proportion of participants with a 50%, 90%, or undetectable reduction in PSA from baseline. PSA level at the end of week 26

• Time to PSMA-PET locoregional progression (as determined by BICR): defined as the time from randomization to the date of the first occurrence of PSMA-PET locoregional progression. The criterion for locoregional progression on PSMA-PET was the presence of at least one new PSMA-PET-positive locoregional lesion compared to the previous scan.

The Molecular Imaging-Tumor Node Metastasis (miTNM) classification will be used to report and localize PSMA-PET-positive lesions. PSMA-PET scans will be assessed by BICR.

●Overall survival and prostate cancer-specific survival: defined as the time from randomization to death from any cause and death from prostate cancer, respectively.

●Adverse events and serious adverse events.

explore purpose

• To assess response to study treatment as assessed by PSMA-PET at the end of Week 26.

• To assess the effect of study treatment on quality of life, anxiety symptoms in participants with elevated PSA, and anxiety and depressive symptoms in participants with metastatic progression diagnosed by PSMA-PET.

• To assess whether the addition of apalutamide to RT+LHRHa delayed the initiation of subsequent systemic therapy.

• To assess the effect of study treatment on disease progression by WB-MRI.

• To assess possible associations between PSMA-PET metastatic progression status and metastases detected by conventional angiography.

Explore the end

30%；在所有其他病灶中，SUV沒有增加

30%；無(多個)新病灶；(c)疾病穩定(stable disease,SD)：不是CR、PR、或疾病進展(progressive disease,PD)；(d)疾病進展：任何病灶中之SUV增加

30%或

1個新病灶 • PSMA-PET response at the end of Week 26 (as judged by BICR, modified from PERCIST criteria). The categories of PSMA-PET responses compared to previous PSMA-PET include (a) complete reaction (CR): no pathological uptake on PSMA-PET scan; no new lesion(s); (b) partial response ( partial response, PR): reduction in the highest SUV in target lesions

30%; no increase in SUV in all other lesions

30%; no new lesion(s); (c) stable disease (SD): not CR, PR, or progressive disease (PD); (d) progressive disease: increased SUV in any lesion

30% or

1 new lesion

• Patient reported results include (a) MAX-PC; (b) PHQ-9; (c) FACT-P.

• Time to start next systemic therapy: defined as the time from randomization to the start date of systemic therapy for prostate cancer after metastatic progression as determined by PSMA-PET.

• WB-MRI response at the end of Week 26 (end of apalutamide treatment) (for the WB-MRI sub-study): Determined by BICR, modified from MET-RADS-P guidelines.

• Association between findings by imaging techniques: assessed by comparing screening, end of week 26, and lesions detected by WB-MRI and PSMA-PET at the last scan in the study.

• Proportion of patients with metastatic progression determined by conventional angiography after progression on PSMA-PET.

(ii) Observational cohorts:

Target:

● To describe the natural history, management, and outcomes of PSMA-PET-negative patients within routine clinical practice.

● To compare baseline characteristics of PET-PSMA-positive and PET-PSMA-negative patients.

Endpoints: Time from screening to PSMA-PET positivity, time to PSA progression, time to treatment, moderator-assessed progression-free survival and overall survival (where data allow).

B. Research Design

(i) Overview of study design

12個月或病理格里森分數

8)之經組織學證實患有前列腺腺癌的患者之研究。參與者在RP後將達到無法偵測的PSA水平(PSA<0.1ng/mL)，但將出現PSA再發(任何PSA上升)。 This line is for those with high-risk features (PSADT at screening

12-month or pathological Gleason score

8) A study of patients with histologically confirmed prostate adenocarcinoma. Participants will reach undetectable PSA levels (PSA < 0.1 ng/mL) after RP, but will experience PSA relapse (any rise in PSA).

At screening, participants will undergo eligibility assessments including PSMA-PET scan and conventional angiography ( ^99m Tc-bone scan and CT/MRI scan); participants must have no evidence of metastasis on conventional angiography. The study consisted of interventional cohorts and observational cohorts.

The interventional cohort is a randomized, controlled, open-label, parallel group, multicenter, international study of radiation therapy + luteinizing hormone-releasing hormone agonist (RT + LHRHa) plus apalutamide versus RT + LHRHa alone. Eligible participants in this cohort had no evidence of metastasis on conventional angiography, but had at least one locoregional lesion on PSMA-PET scan (with or without distant , metastatic lesions in other parts). For this study, "radiotherapy (RT)" was defined as prostatic bed plus pelvic lymph node rescue external beam radiation therapy, with or without optional SBRT.

Patients without evidence of any lesions on PSMA-PET scans will be referred to an observational cohort to describe the management and outcomes of high-risk BCR PSMA-PET-negative patients in routine clinical practice.

An exploratory sub-study will also assess response based on WB-MRI and compare progression by WB-MRI versus PSMA-PET in the interventional cohort.

The final analysis of the primary endpoint will be event-driven and will be performed when 192 events have occurred; an interim analysis is planned to be performed when approximately 96 events have been reached.

The study will end when the primary endpoint of 192 events is reached. The study has a planned duration of approximately 7 years, with an expected receipt period of approximately 24 months.

(ii) Interventional cohort: The interventional cohort was divided into 3 stages: treatment stage, late stage of treatment, and late stage of exploratory PSMA-PET progression. Primary assessments during the study included PSMA-PET scan, WB-MRI (for substudy), PSA and testosterone levels, and patient-reported outcome (PRO).

Treatment Period and Research Interventions:

During a treatment period of approximately 26 weeks (approximately 6 months) duration, the ITT population of approximately 412 PSMA-PET positive participants will be randomized (1:1) to either RT+LHRHa or RT+LHRHa plus Apa Lutamide group and will receive the following treatments:

3個轉移之參與者，有或沒有可選的SBRT)。 (a) Radiation therapy: For this study, radiation therapy was defined as prostate bed plus pelvic lymph node rescue external beam radiation therapy (for patients with

3 transfer participants, with or without optional SBRT).

Whole pelvic rescue radiation therapy: Participants in both groups will receive prostate bed plus pelvic lymph node rescue external beam radiation therapy with a total recommended total dose of approximately 70 Gy for the prostate bed and approximately 70 Gy for the pelvic lymph nodes 45 to 50 Gy. Treatment must be initiated within 4 weeks of randomization.

3個遠處病灶之參與者可接受(可選的)SBRT：(i)SBRT之使用是可選的，但必須在隨機分組之前做出使用SBRT的決定。(ii)治療必須在隨機分組後4週內起始，且其後應嚴格遵守SBRT之使用。(iii)SBRT之建議總劑量為30Gy。 Stereotactic body radiation therapy: in both groups, PSMA-PET with

Participants with 3 distant lesions received (optional) SBRT: (i) The use of SBRT is optional, but the decision to use SBRT must be made prior to randomization. (ii) Treatment must be initiated within 4 weeks after randomization, and the use of SBRT should be strictly adhered to thereafter. (iii) The recommended total dose of SBRT is 30 Gy.

(b) Luteinizing hormone-releasing hormone agonists: Participants in both groups will receive 6 months of LHRHa therapy (eg, leuprolide, goserelin, triptorelin acetate) on Day 1 and The 3-month depot was administered at the end of Week 12, or the 6-month depot was administered on Day 1. Treatment must be initiated within 3 days of randomization.

(c) Apalutamide: Participants in the RT+LHRHa plus apalutamide group will receive 240 mg (4 x 60 mg) of apalutamide starting on day 1. Apalutamide will be administered as a film-coated tablet to be swallowed whole (or mixed) once daily with a meal or on an empty stomach for a total of 180 days (approximately 26 weeks). Treatment must be initiated within 3 days of randomization.

6個月或>6個月)、及(iii)計劃使用SBRT(是或否)。 At randomization, participants will be stratified based on (i) location of PSMA-PET-positive lesions (distant [outside the pelvis]: yes or no), (ii) PSADT (

6 months or >6 months), and (iii) plan to use SBRT (yes or no).

Late stage of treatment and late stage of PSMA-PET progression:

0.2ng/mL觸發PSMA-PET頻率增加至每6個月一次)。 Following the treatment period, participants will be prospectively evaluated late in the treatment period until PSMA-PET-positive metastatic progression. During the later period of treatment, total serum PSA levels will be assessed every 3 months, and the results will determine the frequency of PSMA-PET scans during this period (PSA<0.2ng/mL, the frequency of PSMA-PET is maintained annually, and the frequency of PSA

0.2ng/mL triggers an increase in PSMA-PET frequency to every 6 months).

At the time of PSMA-PET metastatic progression, participants will transition to the late stage of PSMA-PET progression (which is the exploratory phase of the study). During this period, if the respective conventional scan was negative for metastatic progression, conventional angiography will be performed at the time of progression determined by PSMA-PET and up to 2 times thereafter at 6-month intervals. Subsequent treatment of prostate cancer (eg, surgery, radiation therapy, systemic therapy), conventional angiography within clinical practice, and survival status will be recorded until the end of the study.

(ii) Observational cohorts:

In the observational cohort, eligible participants who were negative for PSMA-PET and therefore could not be randomized to the interventional cohort, will be observed until a time point in the interventional cohort when the number of events required for analysis of the primary endpoint is reached in the interventional cohort. During this period, data collected in the course of routine clinical practice will include clinical assessments, assessments of disease progression, details of therapy administered at the study center per standard of care, and survival status.

The objectives of the observational group are:

● To describe the natural history, management, and outcomes of PSMA-PET-negative patients within routine clinical practice.

● To compare baseline characteristics of PET-PSMA-positive and PET-PSMA-negative patients.

standard constrain:

1. Male, over 18 years of age (or the legal age of consent in the country in which the study is conducted);

2. Histologically confirmed adenocarcinoma of the prostate.

3. Previously treated with radical prostatectomy and lymph node dissection, and the first postoperative PSA measurement between weeks 6 and 13 was <0.1 ng/mL.

4. Any pathological stage at initial diagnosis: pTany, pNany, M0 (on CT/MRI and ^99m Tc bone scan).

8，或(ii)從BCR開始之使用至少3個連續值

0.1ng/mL進行篩選時PSADT

12個月，其係使用Memorial Sloan Kettering Cancer Center線上計算器評估。 5. Biochemically recurring prostate cancer after RP has a high risk of developing metastasis, defined as (i) pathological Gleason score at diagnosis or surgery

8, or (ii) use at least 3 consecutive values starting from BCR

PSADT at 0.1ng/mL for screening

At 12 months, it was assessed using the Memorial Sloan Kettering Cancer Center online calculator.

6. PSMA-PET must be performed at screening. PSMA-PET-positive patients with at least one locoregional (pelvic) lesion with or without distant (extrapelvic) lesions at screening, as determined by BICR, will be eligible for randomization to any of the interventional cohorts One group. After randomization, the trial host will be blinded to the location of the PSMA-PET lesions. Patients who are PSMA-PET negative for any prostate cancer lesion at screening (ie, no locoregional lesions and no distant lesions) will be eligible for inclusion in the observational cohort, as determined by BICR.

7. No evidence of metastasis on screening CT/MRI, ^99m Tc whole body bone scan of chest/abdomen/pelvis. Participants with a single skeletal lesion on a ^99m Tc whole-body bone scan should have confirmatory angiography by CT or MRI; patients should be excluded from the study if a confirmatory scan confirms a bone lesion. Conventional imaging ( ^99m Tc bone scan and CT/MRI) from screening will be sent to BICR to confirm metastatic disease prior to randomization.

8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) grade 0 or 1.

2.5 x正常值上限(ULN)及總膽紅素

1.5×ULN。在患有Gilbert氏症候群的參與者中，若總膽紅素>1.5×ULN，則測量直接及 間接膽紅素(若直接膽紅素

1.5×ULN，則參與者符合此資格標準)；(ii)血清肌酸酐<1.8mg/dL；(iii)血小板

75,000/μL，在隨機分組前1個月內沒有輸血及/或生長因子；及(iv)血紅素

10.0g/dL(6.21mmol/L)，在隨機分組前1個月內沒有輸血及/或生長因子。 9. Adequate organ function defined by the following criteria: (i) Aspartate transaminase (AST) and alanine transaminase (ALT)

2.5 x upper limit of normal (ULN) and total bilirubin

1.5×ULN. In participants with Gilbert's syndrome, if total bilirubin >1.5 x ULN, direct and indirect bilirubin (if direct bilirubin

1.5×ULN, the participant meets this eligibility criteria); (ii) Serum creatinine <1.8 mg/dL; (iii) Platelets

75,000/μL without blood transfusion and/or growth factors within 1 month prior to randomization; and (iv) heme

10.0 g/dL (6.21 mmol/L), no blood transfusion and/or growth factors within 1 month before randomization.

10. Able to swallow study drug lozenges whole or mix with applesauce as directed.

11. Participants who engage in sexual activity with women of childbearing potential must use condoms and another highly effective method of contraception during the treatment period and within 3 months after the last dose of study intervention.

12. Participants must agree not to donate sperm for reproductive purposes during the treatment period and for a minimum of 3 months after receiving the last dose of study intervention.

13. Receive osteoprotective agents suitable for the treatment of osteoporosis (eg, denosumab [Prolia ^® ], zoledronic acid [Reclast ^® ]) at doses and dosing schedules suitable for the treatment of osteoporosis. Participants on a course of bone loss prevention therapy must be on a stable dose for at least 4 weeks before randomization.

Exclusion criteria:

1. History of pelvic radiation therapy for malignant disease.

2. Previous treatment of prostate cancer with ADT.

3. Previous BCR treatment for prostate cancer.

4. Use of CYP17 inhibitors (such as oral ketoconazole, orteronel, abiraterone acetate, galeterone) or any AR antagonist (including Bica) Lutamide, Flutamide, Nilutamide, Apalutamide, En Zalutamide, or darolutamide) and any other drugs that may reduce androgen levels (eg, estrogen, progesterone, amilutamide, etc.) prior treatment, including bilateral testiectomy.

5. Pathological findings consistent with small cell or neuroendocrine carcinoma of the prostate.

6. Any of the following within 6 months prior to the first dose of study intervention: severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (such as pulmonary embolism, including transient cerebrovascular accident of cerebral ischemic attack), or clinically significant ventricular arrhythmia, or New York Heart Association class II to IV heart disease; uncomplicated deep vein thrombosis is not considered to be excluded

4週使用5α-還原酶抑制劑。 7. Before randomization

A 5α-reductase inhibitor was used for 4 weeks.

4週使用試驗藥。 8. Before randomization

The test drug was used for 4 weeks.

9. Not applicable; standard number omitted from erroneous initial procedure.

10. Previous prostate cancer chemotherapy.

11. Active malignant disease other than the disease under investigation (ie, progression within the past 24 months or need for a change in treatment). The only allowed exceptions are:

●Non-muscle invasive bladder cancer.

●Skin cancer (not melanoma or melanoma) treated within the past 24 months is considered completely cured.

• Breast cancer: History of lobular carcinoma in situ or ductal carcinoma in situ, or localized breast cancer that has been adequately treated and considered to have a very low risk of recurrence.

●Malignant disease considered cured with minimal risk of recurrence.

12. Included immunocompromised virus-positive participants with 1 or more of the following:

Not receiving high-potency antiretroviral therapy

Changes in antiretroviral therapy within 6 months of screening

receiving antiretroviral therapy that may interfere with study intervention

● CD4 count <350 at screening

AIDS-defined opportunistic infection within 6 months of initiation of screening

13. Chronic, active, or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to abnormal liver function.

1年有先前的中風、短暫性腦缺血發作、或失去意識；腦部動靜脈畸形；或顱內腫塊，諸如造成水腫或腫塊效應之神經鞘瘤及腦膜瘤)。 14. History of the following: epilepsy or any condition that can predispose to epilepsy (including but not limited to prior to randomization

1 year prior stroke, transient ischemic attack, or loss of consciousness; brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas causing edema or mass effect).

15. Treatment with a drug known to lower the epilepsy threshold within 4 weeks prior to randomization.

16. Known or suspected contraindications or hypersensitivity reactions to apalutamide, LHRH agonists, or any component of the formulation.

17. Any condition not in the best interests of the participant.

0.2ng/mL-表D)之治療後期之兩個不同排程中的相關程序。篩選時PSMA-PET陰性參與者將加入觀察性群組。 The activity schedules in Tables A through D show the relevant procedures in each phase of the interventional cohort (Treatment - Table A, Post-Treatment - Table B, and PSMA-PET Post-Progress - Table C) and based on PSA levels ( PSA level <0.2ng/mL or PSA level

0.2 ng/mL - Table D) Relevant procedures in two different schedules at the end of treatment. PSMA-PET negative participants at screening will be enrolled in the observational cohort.

^a 訪視可在最後一劑研究介入的30天內進行。所有評估應盡可能接近最後一劑研究藥物執行。參與者可接受3個月長效製劑或6個月長效製劑。^b對於已完成180天全身性治療的參與者及在排定第26週結束訪視之30天內中止全身性治療的參與者而言，第26週結束訪視將係治療結束訪視。^c訪視可在最後一劑研究介入的30天內進行。所有評估應盡可能接近最後一劑研究藥物執行。自基線至第5個月的任何時間都可進行提前中止訪視。第26週結束訪視及程序應如計劃進行；將此視為治療結束訪視。^d在提前退出研究的情況下，應執行針對第26週結束訪視列出的所有研究程序。將此視為研究結束訪視。在最後一劑研究介入後收集不良事件至多30天。^e必須報告嚴重不良事件，包括在最後一劑研究介入後30天內自發性報告的事件。被認為與研究介入相關之在最後研究介入投予後30天後發生的嚴重不良事件將在發現或通知事件後24小時內收集及報告並記錄。^f血紅素、血小板計數、及白血球計數。^g在第一PSA結果高於最低點>0.5ng/mL後至少3週執行PSA測量，以評估PSA進展。針對在第26週結束時PSA<0.2ng/mL或

0.2ng/mL且無PSMA-PET轉移性進展的參與者。^h針對此研究，放射療法係定義為前列腺床加骨盆淋巴結救援性體外射線 放射療法(針對在篩選時具有

3個藉由PSMA-PET判定之遠處病灶之參與者，有或沒有可選的SBRT)。ⁱALP、AST、ALT、TSH(若TSH>ULN-T3、T4；直接)。總膽紅素(若>1.5ULN：直接及間接)、HDL-C(空腹)、LDL-C(空腹)、三酸甘油酯(空腹)、葡萄糖(空腹)、鉀。^j在各時間點測量之血壓及心率。^k在隨機分組前大約8週內執行的PSMA-PET掃描可用於由BICR評估資格。^l無論PSA水平如何，所有參與者將在第6個月進行PSMA-PET評估。^m針對由BICR判定的在第26週結束時具有PSMA-PET轉移性進展的參與者。針對無轉移性進展的參與者，後續評估將藉由其PSA水平判定。針對各個別參與者，研究期間所有PSMA-PET掃描應使用相同的PET示蹤劑。ⁿ胸部、腹部、及骨盆

^aVisits may be conducted within 30 days of the last dose of study intervention. All assessments should be performed as close as possible to the last dose of study drug. Participants received either a 3-month long-acting formulation or a 6-month long-acting formulation. ^bFor participants who have completed 180 days of systemic therapy and those who discontinue systemic therapy within 30 days of the scheduled end of Week 26 visit, the end of week 26 visit will be the end of treatment visit. ^cVisits may be conducted within 30 days of the last dose of study intervention. All assessments should be performed as close as possible to the last dose of study drug. Early discontinuation visits can be made at any time from baseline to month 5. The End of Week 26 visit and procedure should proceed as planned; this is considered the end of treatment visit. ^d In the event of early withdrawal from the study, all study procedures listed for the end of week 26 visit should be performed. Consider this an end-of-study visit. Adverse events were collected up to 30 days after the last dose of study intervention. ^eSerious adverse events must be reported, including spontaneously reported events within 30 days of the last dose of study intervention. Serious adverse events that occurred after 30 days after the administration of the last study intervention and were considered related to the study intervention will be collected and reported and recorded within 24 hours of the event being discovered or notified. ^fHemoglobin , platelet count, and white blood cell count. ^g Perform PSA measurements at least 3 weeks after the first PSA result is >0.5 ng/mL above nadir to assess PSA progression. For PSA <0.2ng/mL at the end of Week 26 or

Participants with 0.2 ng/mL and no metastatic progression on PSMA-PET. ^h For this study, radiation therapy was defined as prostate bed plus pelvic lymph node rescue external beam radiation therapy (for patients with

3 participants with distant lesions by PSMA-PET, with or without optional SBRT). ⁱ ALP, AST, ALT, TSH (if TSH>ULN-T3, T4; direct). Total bilirubin (if >1.5ULN: direct and indirect), HDL-C (fasting), LDL-C (fasting), triglycerides (fasting), glucose (fasting), potassium. ^jMeasured blood pressure and heart rate at each time point. ^kPSMA -PET scans performed approximately 8 weeks before randomization may be used to assess eligibility by BICR. ^l All participants will undergo PSMA-PET assessment at month 6 regardless of PSA level. ^mFor participants with metastatic progression on PSMA-PET at the end of Week 26 as judged by BICR. For participants without metastatic progression, follow-up assessments will be determined by their PSA levels. For each individual participant, the same PET tracer should be used for all PSMA-PET scans during the study. ⁿ Chest, abdomen, and pelvis

^a總血清PSA。^b針對各個別參與者，研究期間所有PSMA-PET掃描應使用相同的PET示蹤劑。針對由BICR判定的具有PSMA-PET轉移性進展的參與者。習知造影(^99mTc-骨掃描、CT/MRI掃描)必須在PSMA-PET轉移性進展之BICR判定時執行。^c針對無PSMA-PET轉移性進展的參與者。^d被認為與研究介入相關之在最後研究介入投予後30天發後發生的嚴重不良事件。

^aTotal serum PSA. ^b The same PET tracer should be used for all PSMA-PET scans during the study for each individual participant. For participants with metastatic progression on PSMA-PET as judged by BICR. Conventional angiography ( ^99m Tc-bone scan, CT/MRI scan) must be performed at the time of BICR determination of metastatic progression on PSMA-PET. ^c For participants without metastatic progression on PSMA-PET. ^d Serious adverse events that occurred after 30 days after the last study intervention administered and were considered related to the study intervention.

^a總血清PSA。在第一個

0.2ng/mL讀數之後，所有評估必須遵循目前的排程，無論隨後的PSA水平如何。在第一PSA結果高於最低點>0.5ng/mL後至少3週執行PSA測量，以評估PSA進展。^b針對無PSMA-PET轉移性進展的參與者。^c被認為與研究介入相關之在最後研究介入投予後30天發後發生的嚴重不良事件。

^aTotal serum PSA. in the first

After the 0.2 ng/mL reading, all assessments must follow the current schedule, regardless of subsequent PSA levels. PSA measurements were performed at least 3 weeks after the first PSA result was >0.5 ng/mL above nadir to assess PSA progression. ^b For participants without metastatic progression on PSMA-PET. ^c Serious adverse events that occurred after 30 days after administration of the last study intervention that were considered related to the study intervention.

^a在PSMA-PET進展後6個月，僅在PSMA-PET轉移性進展時藉由習知造影(99mTc-骨掃描及/或CT/MRI掃描)未發現轉移的情況下執行。在PSMA-PET進展後12個月，僅在PSMA-PET轉移性進展後6個月藉由習知造影未發現轉移的情況下執行。^b在PSMA-PET進展後6個月，僅在PSMA-PET轉移性進展時藉由習知造影(99mTc-骨掃描及/或CT/MRI掃描)未發現轉移的情況下執行。在PSMA-PET進展後12個月，僅在PSMA-PET轉移性進展後6個月藉由習知造影未發現轉移的情況下執行。^c僅針對WB-MRI子研究中的參與者。^d在PSMA-PET轉移性進展後12個月期間藉由習知造影未發現轉移的情況下，按照常規臨床實務執行習知造影評估(^99mTc-骨掃描及/或CT/MRI掃描)直至研究結束。^e被認為與研究介入相關之在最後研究介入投予後30天發後發生的嚴重不良事件。

^a Performed at 6 months after PSMA-PET progression, only if no metastases were detected by conventional angiography (99mTc-bone scan and/or CT/MRI scan) at the time of PSMA-PET metastatic progression. 12 months after PSMA-PET progression, performed only if no metastases were detected by conventional angiography 6 months after PSMA-PET metastatic progression. ^b Performed 6 months after PSMA-PET progression, only if no metastases were detected by conventional angiography (99mTc-bone scan and/or CT/MRI scan) at the time of PSMA-PET metastatic progression. 12 months after PSMA-PET progression, performed only if no metastases were detected by conventional angiography 6 months after PSMA-PET metastatic progression. ^c For participants in the WB-MRI substudy only. ^dIn the absence of metastases by conventional angiography during the 12-month period after metastatic progression on PSMA-PET, perform conventional angiographic assessment ( ^99m Tc-bone scan and/or CT/MRI scan) as per routine clinical practice until study Finish. ^e Serious adverse events that occurred after 30 days after the administration of the last study intervention that were considered related to the study intervention.

b.將觀察患者直到在介入性群組中達到大約192個ppMPFS事件的時間點。c.公共記錄可用以記錄死亡及獲得存活狀態。d.僅在參與者接受乙酸阿比特龍+強體松(prednisone)或阿帕魯胺的情況下需要收集安全性數據。

b. Patients will be observed until a time point of approximately 192 ppMPFS events is reached in the interventional cohort. c. Public records can be used to record death and obtain survival status. d. Safety data will only be collected if the participant is receiving abiraterone acetate + prednisone or apalutamide.

C. Research intervention

(i) Radiation therapy

(a) Whole pelvic rescue radiotherapy

1cm的分段式技術(Step-and-Shoot-Technique)、滑動式技術(Sliding-Window-Technique)、或體積調控弧形療法(Volumetric Modulated Arc Therapy,VMAT)而執行。允許使用螺旋刀(Tomotherapy)及MRI引導的放射療法系統(MRIdian^®、Elekta Unity^®)。將最佳化所有治療計劃，使得滿足靶體積及危急器官體積的所有劑量要求。在整個治療計劃中應仔細檢查劑量不均勻性，因為相較於習知體外放射療法，IMRT達到的目標區域之劑量不均勻性增加。 Radiation therapy must be initiated within 4 weeks of randomization. A preferred treatment technique is intensity modulated radiotherapy (IMRT). This technique can be achieved by using a multi-leaf collimator

1cm segmented technology (Step-and-Shoot-Technique), sliding technology (Sliding-Window-Technique), or volume control arc therapy (Volumetric Modulated Arc Therapy, VMAT) to perform. Helical knife (Tomotherapy) and MRI-guided radiation therapy systems (MRIdian ^® , Elekta Unity ^® ) are permitted. All treatment plans will be optimized so that all dose requirements for the target volume and the volume of the organ at risk are met. Dose inhomogeneity should be carefully examined throughout the treatment plan because of increased dose inhomogeneity to the target area reached with IMRT compared to conventional external radiation therapy.

The recommended total dose of radiation therapy for the prostate bed is approximately 70 Gy, and the recommended total dose of radiation therapy for the pelvic lymph nodes is approximately 45 to 50 Gy, with the recommended dose schedule as follows:

●The recommended schedule for the prostate bed is 25×2Gy+16-20Gy, 28×2Gy+12-16Gy, or 23×2Gy+20-24Gy.

●For pelvic lymph nodes, the recommended schedule is 25×1.8Gy (45Gy), 28×1.8Gy (50.4Gy), or 23×2Gy (46Gy).

(b) Stereotactic body radiation therapy

3個遠處病灶)的參與者之額外治療選項。 Based on the clinical judgment of the research center, stereotaxic body radiation therapy has oligometastatic lesions on PSMA-PET (

Additional treatment options for participants with 3 distant lesions).

The decision to use SBRT must be made prior to randomization. Treatment must be initiated within 4 weeks of randomization. The recommended total dose for SBRT is 30 Gy delivered in 3 fractions. Treatment will be prescribed for the perimeter of the target.

Treatment should be set up with reproducible positioning and validated. All patients should undergo planned CT simulations. Treatment can be delivered using static beams or rotational therapy. All treatment plans will be optimized so that all dose requirements for the target volume and the volume of the organ at risk are met.

Any imaging required to perform the SBRT procedure can be considered procedural imaging and should not be confused with the initial imaging used to confirm eligibility at screening.

(ii) Treatment with LHRHa

Treatment must be initiated within 3 days of randomization. Only LHRH agonists are allowed; LHRH antagonists are not allowed. In both study arms, LHRHa (eg, leuprolide, goserelin, triptorelin acetate) will be administered as a 3-month depot on Day 1 and at the end of Week 12, or on 1 day as a 6 month depot.

(iii) Treatment with apalutamide

Treatment must be initiated within 3 days of randomization. Treatment with apalutamide 240 mg will be provided for 180 days (approximately 26 weeks) from the first administration of LHRHa (day 1). Apalutamide is administered orally on a continuous once-daily dosing schedule. The therapeutic dose is 240 mg once daily (4 x 60 mg lozenges). Participants should take their doses at the same time each day. Apalutamide can be taken with a meal or on an empty stomach. Each lozenge should be swallowed whole or mixed with applesauce (as directed). In the event of a missed daily dose of apalutamide, participants should take their normal dose as soon as possible that day and resume their normal schedule the next day. Participants should not take additional lozenges to make up for a missed dose.

(iv) Treatment of localized pelvic progression during follow-up

Radiation therapy and surgical procedures (eg, urethral and ureteral stenting) to treat localized pelvic progression as determined by BICR were permitted after the treatment period; participants who received these therapies could continue the study. Systemic therapy for prostate cancer was not permitted for these participants.

(v) Dose adjustment of apalutamide

Apalutamide dose reductions are described in Table 1. The apalutamide dose can be reduced as follows: the first dose level is reduced to 180 mg/day; the second dose level is reduced to 120 mg/day. If further dose reduction is required, apalutamide should be discontinued.

Dose reductions for study intervention-related toxicity should generally not be re-escalated; however, re-escalation back to previous dose levels is permissible.

D. Research Evaluation and Procedures

Frequency and timing of efficacy, safety, and other measurements in PSMA-PET positive participants (ie, the interventional cohort) are presented in Tables A through D for Screening and Treatment, Post-treatment, and PSMA-PET Activities are scheduled at a later stage of progress.

All PRO assessments should be completed prior to any other tests, procedures, or other consultations to prevent influencing participants' perceptions. If multiple assessments are scheduled at the same time point, it is recommended that the procedures be performed in the following order: vital signs, blood draw. If desired, other measurements may be taken earlier than the specified time points. See Tables 2 to 4.

The approximate blood volume (no more than 200 mL) drawn from each participant in this study was within the range considered acceptable for donation. Repeated or unscheduled visit samples may be taken for safety reasons or sample technical issues.

Participants who meet all of the study's inclusion/exclusion criteria and who are PSMA-PET negative and known angiography negative at screening will be proposed for consecutive inclusion in the observational cohort and will not be randomized in the study.

修改自Eiber M,Herrmann,Calais J,et al.Prostate Cancer Molecular Imaging Standardized Evaluation(PROMISE)：Proposed miTNM Classification for the Interpretation of PSMA-Ligand PET/CT.J Nucl Med.2018 Mar；59(3)：469-478，其以引用方式併入本文中。

Modified from Eiber M, Herrmann, Calais J, et al. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE): Proposed miTNM Classification for the Interpretation of PSMA-Ligand PET/CT. J Nucl Med. 2018 Mar;59(3):469 -478, which is incorporated herein by reference.

Data will be evaluated using eg RECIST and PERCIST. See (i) RECIST: Eisenhauer et al. "New response evaluation criteria in solid tumours: Revised RECIST guideline (Version 1.1)" Eur. J. Cancer. 2009;45:228-247 Sections 3 and 4 and appendix I; and (ii) PERCIST: Kim et al., “Comparison of the morphologic criteria (RECIST) and metabolic criteria (EORTC and PERCIST) in tumor response assessments: a pooled analysis” Korean J. Intern. Med. 2019; 34 ( 3): 608-617 and Wahl et al. "From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors" J.Nucl.Med.2009;50 Suppl 1:122S-50S, all incorporated by reference in this article

(i) Proposed modalities of rescue radiotherapy

Treatment by Intensity Modulated Radiation Therapy (IMRT) or rotational techniques such as Tomotherapy ^® , RapidArc ^® , VMAT is highly recommended. Dosimetry obtained only by reverse treatment planning was considered IMRT for this study. Image-guided radiotherapy (IGRT) is recommended. Dose distributions were obtained in 3-dimensional mode with calculated dose volume histograms to allow evaluation of treatment plans against predefined dose limits.

Participant Preparation/Data Acquisition

Participants should have a jejunum and a half full bladder for planned CT. Daily use of glycerin suppositories may be helpful in cases where participants are constipated and have difficulty emptying the rectum. The jejunum was provided by using a rectal enema ± 60 minutes before the scheduled CT. After emptying the rectum and bladder, participants were asked to drink 500 to 750 mL of water and perform a planned CT 40 minutes later. Participants repeated the bladder filling procedure throughout the course of treatment and, at the discretion of the attending physician, advised participants to check their bladder capacity by urinating in a measuring cup after each treatment fraction. This feedback to participants may improve their bladder filling reproducibility.

The supine position is the preferred participant position during treatment. The use of fixed molds to ensure improved positioning reproducibility is at the discretion of the center. Knee support and foot immobilization provide pelvic stability and are recommended but not mandatory.

The treatment plan must be CT based and have a flat bed surface. The CT scan should start at least from the lower part of the second lumbar vertebra (L2) to ensure that the most proximal slice of the PTV is delineated. The lower border of the CT scan should extend to the lower part of the ischial tuberosity. Additional CT images were obtained beyond these scan limits, with slice thicknesses of 0.5 cm extending 10 cm beyond the head and tail of the PTV (to allow for non-coplanar treatment and calculation of scattered radiation dose contributions). For SBRT treatment, the CT scan of the treatment plan should extend at least 10 cm above and below the treatment field boundary.

3mm。 ●Slice thickness: 3mm according to institutional standards. We recommend choosing a CTV-PTV boundary larger than the planned CT slice thickness. For extra-pelvic SBRT, the thickness of CT slices should be

3mm.

●Contrast agent: i.v. or oral imaging agent is not mandatory. If a contrast agent is used, tissue density correction must be applied during the planning process.

- Gating: Not recommended because the expected movement of the target volume caused by breathing is small. May be recommended in cases where bone metastases are located in the thoracic area.

●Image alignment: In addition to planned CT, MRI or PET angiography can provide useful information for target volume delineation of the prostate and seminal vesicles. Image co-alignment presents many pitfalls due to different body positions associated with planned CT, different bladder and rectal filling states and subsequent deformation of the prostate, and possible MRI image artifacts that can hinder accurate prostate-to-prostate matching.

• Delineation using co-alignment (MRI or PET) is at the discretion of the physician.

treatment plan

1cm的分段式技術、滑動式技術、或VMAT而執行。允許使用螺旋刀及MRI引導的放射療法系統(MRIdian^®、Elekta Unity^®)。 A preferred treatment technique is intensity modulated radiotherapy (IMRT). This technique can be achieved by using MLC

1 cm segmented technique, sliding technique, or VMAT. Helical knives and MRI-guided radiation therapy systems (MRIdian ^® , Elekta Unity ^® ) are permitted.

All treatment plans will be optimized so that all dose requirements for the target volume and the volume of the organ at risk are met. Dose inhomogeneity should be carefully examined throughout the treatment plan because of increased dose inhomogeneity to the target area reached with IMRT compared to conventional external radiation therapy.

Treatment verification should use CBCT (Cone Beam Computed Tomography), or portal imaging, or digital reconstruction radiography compared to oblique radiography. The use of film for field verification is not allowed due to low accuracy. The frequency of photofield image processing verification is defined in accordance with institutional policy, but is at least weekly.

Correction of deviations is performed in accordance with institutional policy. Inclusion of the total treatment validation dose (KV contrast, MV contrast, or CBCT) in the treatment plan is optional. Institutions should record daily treatment verification doses during treatment in accordance with radiation protection regulations.

(iii) Rescue radiotherapy

Gross tumor volume: Local tumor volume (GTV) pb (macroscopic local recurrence) can be defined in the prostate bed if visualized during staging studies with the help of PET and MRI studies.

clinical target volume

●Clinical target volume (CTV)_pelvis: including the prostate bed and local regional lymphatic vessels, up to the L4/L5 space or the upper border of the sacrum (L5/S1). The locoregional lymphatics were defined as arterial and venous vessels, encompassing a margin of 7 mm to ensure coverage of the lymphatics, carefully "carve out" the bowel, bladder, bone, and muscle. To sum up, for primary radiotherapy without surgery, the pelvic lymph nodes to be irradiated include: distal common iliac (starting from the L4/L5 space), presacral lymph nodes (S1 to S3), external iliac lymph nodes. , internal iliac lymph nodes, and obturator lymph nodes. The volume begins at the L4/L5 gap and ends at the superior pubic border. Detailed instructions can be found in the RTOG Guidelines, published by Lawton et al or online at https://www.rtog.org/CoreLab/ContouringAtlases/ProstatePelvicLymphNodes.aspx

• CTV_PB: includes the prostate bed as defined by any published consensus guidelines, such as the European Organization for Research and Treatment of Cancer or RTOG.

• If the presence of seminal vesicles or their remnants is identified on CT or MRI, they will receive the full dose. Immediate periprostatic bed clips should receive full dose.

In general, the following limits are recommended (derived from RTOG guidelines):

• Inferior: The CTV will extend 8 to 12 mm below the vesicourethral anastomosis (VUA) and up to just above the pubic symphysis (at least in the most anterior part of the bladder). Using axial CT angiography, the VUA can usually be seen in the retropubic region as a slice below the lowest urine-containing image (the bladder must be moderately full). Magnetic resonance angiography uses a high-intensity urine signal on T2 images to define this landmark more clearly. If visualization of the VUA is problematic due to image quality or clip artefacts, the lower limit of the CTV can be extended to just above the level of the ball of the penis.

• Lateral: The CTV will extend from the medial edge of one obturator internus muscle to the other.

- Anterior: CTV will include the entire bladder neck up to above the pubic symphysis, where a gradual reduction off of the anterior bladder is performed.

●Above: Above the pubic symphysis, the CTV should include at least 2 cm behind the bladder, and the area between the bladder and rectum, up to the anterior wall of the rectum. The CTV should extend upward to cover the seminal vesicle bed and any clips in the seminal vesicle remnants (if present), and should extend at least 2 cm above the pubic symphysis.

● Posterior: The CTV is defined by the most anterior part of the anorectum. Based on angiographic information prior to prostatectomy, CTV may increase (rather than decrease) beyond these limits.

The magnitude of the planning target volume (PTV) CTV-PTV margin depends on the validation of settings to ensure minimum dose coverage

The PTV_pelvis must include the entire CTV_pelvis plus a minimum 5mm 3D margin. The PTV_PB must include the entire CTV_PB plus a 10mm 3D margin, except for the posterior 8 to 10mm margin of the center without Image-Guided Radiation Therapy (IGRT). For centers with appreciable IGRT implementations, a minimum 5mm edge in all directions is allowed.

Dose prescription, specification, and reporting will be performed in accordance with the International Commission on Radiation Units and Measurements (ICRU) report83. Dose inhomogeneity often occurs after treatment planning and optimization using IMRT. Therefore, the dosage strength of the prescribed dose will be expressed as the target average dose. The following dose values should be recorded: Prescribed dose, minimum and maximum point dose in PTV, target mean dose, dose to 98% of target volume (in %), dose to 2% of target volume (in %) ). See Table 5.

Dose limitation according to the protocol: Any PTV: 98% of PTV is covered by 95% isodose, and less than 2% of PTV is higher than 107% isodose. See Table 6.

Guidelines for Proposed Stereotactic Body Radiation Therapy Methods (modified from https://www.ncbi.nlm.nihh.gov/pmc/articles/PMC7201684/)

Patients with vertebral or paravertebral metastases require magnetic resonance imaging, although MRI may be limited to the involved segment, including at least (several) involved vertebral bodies plus the lower 2 vertebral bodies, if applicable.

Dosage prescription: A total dose of 30 Gy (80% of the maximum dose) will be delivered in 3 fractions, and the fractions will be separated by >48h and <96h. Treatment will be prescribed for the periphery targeted to cover the PTV (80% of the dose (=30 Gy) should cover 90% of the planned target volume (PTV)). Violation of dose limits for peripheral critical organs In such cases, the prescription will be modified accordingly. Alternatively, for bone metastases, a single fraction of 20 Gy was also permitted to be prescribed peripherally at 80% of the maximum dose covering 90% of the PTV.

Fixed: Treatment will use reproducible positioning settings and be validated for all patients in this study using an online protocol. Depending on the manner in which the SABR is delivered by the individual institution, fixation may include custom fixation devices such as thermoplastic shells or vacuum bags. Some centers do not use fixtures and have demonstrated a high degree of accuracy; this was acceptable in this study.

Angiography/Location/Alignment: All patients will undergo planned CT simulations. 4D CT will be used for tumors in the lung, liver, or adrenal glands. Axial CT images will be obtained over the entire region of interest. For centers using a stereotaxic radiosurgery platform, immediate tumor tracking and orthogonal imaging systems are allowed.

4D-CT Procedures: For patients undergoing 4D-CT, the physicist will review the 4D-CT images and will perform the following quality assurance procedures indicated on the 4D-CT template designed for SABR:

i. Make sure all end-inspiratory (0%) labels are present and in the correct position to ensure image integrity.

i. If the quality of the 4D-CT image is not sufficient (as judged by the physicist), standard 3D-CT will be performed on either rapid spiral CT or unlabeled mean CT.

iii. Perform movement measurements in all 3 directions:

1) If the movement is less than or equal to 7mm and high quality images are present, treatment planning can be performed on unlabeled mean CT with 50% or 60% phase (end-expiration) and 0% phase fused to it; this will define IGTV.

2) If the movement in either direction is greater than 7mm, then respiratory modulation radiotherapy can be considered. In this case, the treatment plan will be performed on a subset of mean CT data sets (usually denoted 30% to 60% mean CT or 40% to 70% mean CT) generated by the physicist; This is the mean CT within the intended regulatory interval. Therefore, the GTV delineated on this scan will incorporate residual movement at the desired modulation interval. The 0% phase will also be fused with this dataset. PTV used for planning will include GTV plus margin delineated on subset-averaged CT for microscopic extension (at physician's discretion) and setting uncertainty. GTV_0% should also be delineated and combined with the GTV delineated on the subset-averaged CT to define the additional volume labeled IGTV_CBCT. This contour can only be used for image alignment with CBCT.

Volume Definition:

For all lesions, GTV will be defined as tumor visible on CT and/or MRI contrast ± PET that is more accurate on SBRT procedure. No extra margin is added for microscopic spread of disease (ie CTV=GTV). For bone lesions, a CTV of 3 to 5 mm is allowed. For vertebral lesions, an anatomical approach is recommended but not mandatory according to the International Spinal consortium guidelines (Cox 2012).

A PTV margin of 2 to 5 mm will be added, depending on disease site, fixation, and mechanism setting Accuracy: 2 to 3 mm margin for spinal stereotaxic treatment, 0 to 2 mm for brain tumors, and 5 mm for other sites .

Targets should be named based on the organ involved and numbered from head to tail. For example, in a patient with 3 bone lesions, there would be: GTV_bone_1, GTV_bone_2, and GTV_bone_3 and corresponding PTV_bone_1, PTV_bone_2_, and PTV _bone_3, represents the lesion from top to bottom.

For spinal lesions, pre-treatment MRI is required to assess the extent of the disease and the location of the spinal cord. This must be fused with the planned CT scan. The planned critical organ volume of 2 mm will be added to the spinal cord (planning organ-at-risk volume, PRV) expansion, and dose limitations of the spinal cord apply to this PRV. Alternatively, a dural sac can be used as a PRV. For radiosurgery platforms, a PRV margin of 1 mm is allowed for the spinal cord.

critical organ dose

OAR doses should not be exceeded except in the case of chest wall/ribs. In cases where PTV coverage cannot be achieved without exceeding the OAR dose, PTV coverage will be compromised, but should not be less than 3 x 7 Gy. OARs of all contiguous tissues within 5 cm of the PTV must be contoured (partial organ contours allowed); for organs with parallel tissues within 5 cm of the PTV (liver, lung, etc.), the entire organ needs to be contoured. This should test each PTV by creating a 5cm extension to check which OARs are in that extension.

Treatment can be delivered using static beams (3D conformal radiation therapy or intensity modulation) or rotational therapy (VMA or helical knife).

Dosage limits (except chest wall/ribs) must not be exceeded. See Table 7. If the dose limit cannot be achieved because the target overlaps with the organ at risk, target coverage should be compromised to meet the limit. In cases where target coverage or dose must be reduced, the priority for dose coverage is GTV (eg, try to cover as much GTV as possible with the prescribed dose). All such dose reductions or target coverage compromises must be approved by the local PI prior to treatment. For vertebral tumors, note that spinal cord restrictions apply to PRV (see above).

For all targets, the dose should be prescribed as a 60 to 90% isodose around the PTV, and all hot spots should fall within the GTV. 95% of the PTV should be covered by the prescribed dose and 99% of the PTV should be covered by 90% of the prescribed dose.

Dose must be corrected for tissue inhomogeneity. Several non-overlapping 6/10 MV beams (about 7 to 11 beams) or 1 to 2 VMAT arcs should be used, possibly in combination with some non-coplanar beams. Non-coplanar beams can be used to reduce isodose volumes by 50%. The number of isocenters is at the discretion of the attending physician, physicist, and dosimetrist. Generally, if the metastases are sufficiently separated, different isocenters can be used to treat the metastases. The scheduling and sequence of treatment of each metastasis is at the discretion of the individual physician. All SABRs must be completed within 2 weeks.

The parameters in Table 7 are based on AAPM TG 101, SABR-COMET, SC-24 tests, etc. If no structures are listed, limits can be calculated using a linear quadratic formula from the dose of QUANTEC received, using an alpha-beta ratio of 3 (except for neural structures: alpha-beta is 2) for late effects. See eg Benedict et al., AAPM TG101, Med. Phys 37(9), 2010 (NB: max pt=0.035cc); Palma et al., SABR-COMET Trial, Palma et al, v.1.9, Apr 2015; RTOG 0915, http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?id=en study=0915; Forquer et al., Radiother. Onc., 93:408-413, 2009; Karlsson et al., IJROBP, 87(3):590-595, 2013; Dunlap et al., IJROBP 76(3) : 796-801, 2010; Andolino et al., IJROBP 80(3): 692-697, 2011; Baker, IJROBP, 85(1): 190-195, 2013; Matsuo et al., IJROBP, 83(4) : e545-549, 2012; Bongers et al., Radiother. Onc., 109: 95-99, 2013 (VU EMC TO 2013); Sahgal et al., IJROBP, 82(1): 107-116, 2012; Sahgal , NCIC CTG Protocol #SC.24.Feb 2, 2017; Sahgal, IJROBP, 85(2): 341-7, 2013 (Table 5; use 5% risk according to Sahgal); BCCA Liver Protocol 2011; Velec, et al, IJROBP (2017), doi: 10.1016/j.ijrobp.2017.01.221; Grimm, et al., JACMP (2011), 12(2) 267; Hiniker, et al., Sem.Radiat.Oncol.26(2) , 97-104, 2016. DOI: (10.1016/j.semradonc.2015.11.008); Rashid, et al., Sem.Radiati.Oncol.26(2) 105-111, 2016. DOI: (10.1016/j. semradonc.2015.11.004); Kimsey et al., Sem.Radiat.Oncol.26(2), 129-134, 2016. DOI: (10.1016/j.semradonc.2015.11.003); Xue et al, Sem.Radiat .Oncol.26(2), 135-139, 2016. DOI: (10.1016/j.semradonc.2015.11.001); Nuyttens et al., Sem.Radiat.Oncol.26(2), 120-128, 2016. DOI: (10.1016/j.semradonc.2015.11.006); Goldsmith et al., Sem.Radiat.Oncol.26(2), 149-156, 2016. DOI: (10.1016/j.semradonc.2015.12.002); and LaCouture et al., Sem.Radiat.Oncol.26(2), 157- 164, 2016. DOI: (10.1016/j.semradonc.2015.11.009), all of which are incorporated herein by reference in their entirety.

E. Statistical Analysis

All statistical analyses will be done by or under the authorization of the research sponsor. A general description of the statistical methods used to analyze efficacy and safety data is outlined below. Specific details will be provided in the Statistical Analysis Project.

(i) Interventional cohorts

The hypothesis of the interventional cohort of this study is that the addition of apalutamide to RT+LHRHa provides superior efficacy in terms of ppMPFS. In this study, all participants showed PSMA-PET-positive lesions at randomization. Based on this, it was hypothesized that the median time to distant disease by PSMA-PET would be 5 years for high-risk BCR participants who were PSMA-PET positive and treated with salvage radiation therapy and ADT.

A group sequential design with 2 stages (interim analysis and final analysis) has been chosen. Statistical assumptions for the calculation are: test force = 80%, alpha = 5%, two-tailed, O'Brien-Fleming alpha consumption. The clinical hypothesis was that the median ppMPFS for the control group (RT+LHRHa) would be 60 months (5 years) and the experimental group (RT+LHRHa plus apalutamide) would be 90 months (7.5 years), respectively, resulting in HR =0.667. Assume a 2% dropout rate every 12 months.

Based on the above considerations, approximately 412 participants are expected to generate approximately 192 events in the interventional cohort, assuming an accumulation time of approximately 24 months and a follow-up time of 60 months. is expected to be approximately 200 patients were enrolled in an observational cohort. For analytical purposes, the cohort system in Table 8 is defined for the interventional cohort.

Efficacy Analysis: Continuous/numeric variables will be summarized using number of participants (n), mean, standard deviation, median, minimum, and maximum. Categorical variables will be aggregated by n and percentage. For categorical data, the Cochran-Mantel-Haenszel test can also be applied if appropriate. Efficacy analyses will be performed on the ITT population. The Kaplan-Meier method will be used to assess the time-to-event endpoint and the log-rank test will be used to compare treatment groups. Cox proportional hazards models will be used to obtain HRs and associated CIs. Participants who did not have an event at the time of analysis will be limited to the last known date for which the participant does not have a documented record of the corresponding event. Detailed limit rules will be provided in SAP.

Analysis of the primary endpoint:

6個月或>6個月)、或及計劃使用SBRT(是否)。HR及對應的CI將使用藉由分層因子分層的Cox比例風險模型評估。 The primary efficacy analysis will be event-driven and will be performed when 192 events have occurred, which are expected to occur approximately 84 months after randomization of the first participant. The distribution of ppMPFS will be assessed using the Kaplan-Meier method. Median ppMPFS and corresponding CIs will be reported as Kaplan-Meier curves. Comparison of ppMPFS between the 2 treatment groups will be based on the log-rank test stratified by the randomization stratification factor location of PSMA-PET positive lesion(s): (distant [outside pelvis]; yes or no ), PSADT (

6 months or >6 months), or and planning to use SBRT (whether or not). HR and corresponding CIs will be estimated using Cox proportional hazards models stratified by stratification factors.

Interim Analysis: For this study, a cluster-sequential design with 2 phases (interim and final analysis) has been chosen. The interim analysis will be performed when approximately 96 events are reached, which is expected to occur approximately 41 months after the randomization of the first participant. The interim analysis will have a = 0.0052 (21.0% test power) and the final analysis will have a = 0.0448, two-tailed, O'Brien-Fleming alpha consumption.

Security Analysis: A security analysis will be performed on the Security Analysis Group. Safety parameters to be assessed were the incidence, intensity, and type of AEs, vital sign measurements, ECOG performance scale, and clinical laboratory results. The reasons for study intervention exposure and study treatment discontinuation were tabulated.

Adverse Events: Treatment-emergent AEs (ie, events that occurred or worsened at or after the first dose of study intervention and up to 30 days after the last dose of study intervention) will be included in the analysis. Adverse events were aggregated by system organ class and preferred term. SAE and death will be provided in the list. All AEs leading to discontinuation of study intervention and dose adjustment will also be listed and tabulated in preferred terms. Participants with multiple events will be counted only once for the maximum severity of study intervention for each preferred team, system organ class, and overall.

3的參與者之數目及百分比。將提供在研究期間毒性等級自基線至參與者所經歷之最差等級的偏移。 Clinical Laboratory Tests: Aggregate laboratory data by type of laboratory test. For continuous measurements, descriptive statistics will be calculated for each laboratory analyte at baseline and for observations and changes from baseline at each scheduled time point. A list of participants with any laboratory results outside the reference range will be provided. A list of participants with any apparently abnormal laboratory results will also be provided. The number and percentage of participants with outliers will be summarized. The parameter NCI-CTCAE toxicity class will be aggregated

3 Number and percentage of participants. The shift in toxicity grade from baseline to the worst grade experienced by the participant during the study period will be provided.

Vital Signs: Vital signs (blood pressure [systolic and diastolic] and heart rate) will be assessed at baseline and, in the case of clinically significant abnormalities, will be recorded in the medical history. During the treatment period, clinically significant abnormalities in vital signs will be recorded as AEs.

Patient-Reported Outcomes: PRO data (total scale scores and subscales) will be descriptively summarized by intervention and study visit. Where applicable, individual item scores will be aggregated. Details of the analysis will be included in the statistical analysis plan.

Exploratory Analysis: The exploratory analysis will include participant and disease characteristics of all screened participants at baseline in both PSMA-PET-positive and PSMA-PET-negative patients.

(ii) Observational cohorts:

The data collected at screening will be analyzed. Baseline parameters and patient history can be used to identify participant characteristics that may influence treatment selection and outcomes. The results of the angiographic assessments were tabulated. Prostate cancer treatments (surgery, radiation therapy, drugs) are tabulated, including type, duration, and reason for discontinuation.

The following parameters will be derived and analyzed as data collected allows: time from screening to PSMA-PET positivity, time to PSA progression, time to treatment, moderator-assessed PFS and OS.

A descriptive summary will be reported. Continuous/numeric variables will be summarized using number of patients (n), mean, standard deviation, median, minimum, maximum, and 95% CI. Categorical variables will be aggregated by n and percentage. Time-to-event variables will be analyzed using standard survival analysis methods, including Kaplan-Meier multiplied limit survival curves. Median time to event with 2-sided 95% CI will be assessed.

Aggregate laboratory data by type of laboratory test. Descriptive statistics will be calculated for each laboratory analyte at screening, and for observed values and changes from screening to follow-up measurements. A list of patients with any laboratory results outside the reference range will be provided. The number and percentage of patients with outliers will be summarized.

AEs will be summarized by system organ class, preferred term, and toxicity class. Serious adverse events and deaths will also be aggregated.

The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes that may be suggested to those of ordinary skill in the art are included within the spirit and scope of the present application and the scope of the appended claims .

Claims (30)

A method that includes: ‧Administering a therapeutic agent to a plurality of individuals with prostate cancer; Performing prostate-specific membrane antigen positron emission tomography (PSMA-PET) scans on these individuals and producing their results; ‧Analyze the results; and • Determining the interval at which the individuals exhibited metastatic progression of the prostate cancer. The method of claim 1, comprising altering the administration of the therapeutic agent or discontinuing the PSMA-PET when a representative percentage of the individuals exhibit an interval of a predetermined length of PSMA-PET-free metastatic progression survival at least one of the implementation. The method of any of the preceding claims, wherein the interval is greater than or equal to about 3 months, such as about 3 to about 12 months, about 3 to about 6 months, or about 6 to about 12 months. The method of any of the preceding claims, wherein the altering comprises increasing or decreasing the dose of the therapeutic agent. The method of any of the preceding claims, wherein the altering comprises ceasing administration of the therapeutic agent. The method of any of the preceding claims, comprising ceasing execution of the PSMA-PET. The method of any one of the preceding claims, wherein the therapeutic agent is apalutamide. The method of any of the preceding claims, further comprising administering a second therapeutic agent. The method of claim 8, wherein the second therapeutic agent is a luteinizing hormone-releasing hormone agonist. The method of claim 9, wherein the luteinizing hormone-releasing hormone agonist is leuprolide, goserelin, or triptorelin acetate, or a combination thereof . The method of any of the preceding claims, comprising administering radiation therapy to the individuals. The method of claim 11, wherein the radiation therapy is pelvic radiation therapy. The method of claim 12, wherein the radiation therapy is rescue radiation therapy to the entire pelvis. The method of claim 12 or 13, wherein the radiation field for the pelvic radiation therapy is adjusted if the PSMA-PET results indicate metastasis of the prostate cancer. The method of claim 11, wherein the radiation therapy is stereotaxic body radiation therapy. The method of any one of the preceding claims, wherein the prostate cancer is localized prostate cancer, distant prostate cancer, recurrent prostate cancer, or a combination thereof. The method of any one of the preceding claims, wherein the prostate cancer metastasis is new or existing. The method of any of the preceding claims, wherein the prostate cancer metastases to the individual's hip. The method of any of the preceding claims, further comprising performing a second diagnostic technique. The method of claim 19, wherein the second diagnostic technique is one or both of whole body MRI ^or99mTc -bone/CT. The method of any one of the preceding claims, wherein the intervals comprise at least one month. The method of claim 21, wherein the intervals comprise about 3 months, about 6 months, about 9 months, or about 12 months. The method of any of the preceding claims, further comprising determining the level of prostate specific antigen in the individuals. The method of any one of the preceding claims, wherein if the prostate-specific antigen line of the individuals is about 0.2 ng/mL or higher, after performing the first prostate-specific membrane antigen positron emission tomography scan Prostate-specific membrane antigen positron emission tomography scans were performed approximately every 6 months. The method of any one of claims 1 to 23, wherein if the prostate specific antigen of the individuals is less than 0.2 ng/mL, every approx. Prostate-specific membrane antigen positron emission tomography was performed at 12 months. The method of any one of claims 1-23, wherein if the prostate-specific antigen of the individuals is less than about 0.2 ng/mL, each time the prostate-specific antigen of the individuals is determined for the first time The individuals were assessed for prostate specific antigen levels at approximately 3 months. The method of any one of the preceding claims, wherein the appearance of at least one new prostate-specific membrane antigen positron emission tomography-positive distant lesion compared to a baseline scan is indicative of metastatic progression of the cancer. The method of any one of claims 1 to 26, wherein the appearance of at least one new prostate-specific membrane antigen positron emission tomography-positive locoregional lesion compared to a baseline scan indicates locoregional progression of the cancer. The method of any one of the preceding claims, wherein prior to initiation of treatment, the individuals have adenocarcinoma of the prostate and have a PSADT of about 12 months or less, a Gleason of about 8 or more Gleason score, and one or more of less than about 0.1 ng/mL of prostate specific antigen after pelvic radiography. A method that includes: ‧Administering a therapeutic agent to an individual suffering from prostate cancer; ‧Prostate-Specific Membrane Antigen Positron Emission Tomography (PSMA-PET) was performed on the individual and its results were generated; ‧Analyze the results; and • Determine the interval at which the individual exhibits metastatic progression of the prostate cancer.

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