WO2023152611A1 - Apalutamide and relugolix for the treatment of prostate cancer - Google Patents

Abstract

Provided herein are methods for treating prostate cancer in a male human comprising administering apalutamide in combination with relugolix to a male human in need of such treatment.

Description

APALUTAMIDE AND RELUGOLIX FOR THE TREATMENT OF PROSTATE CANCER

TECHNICAL FIELD

Disclosed herein are methods for treating prostate cancer in a male human comprising administering apalutamide in combination with relugolix to a male human in need of such treatment.

BACKGROUND

Prostate cancer is the most common non-cutaneous malignancy in men and the second leading cause of death in men from cancer in the western world. Prostate cancer results from the uncontrolled growth of abnormal cells in the prostate gland. Once a prostate cancer tumor develops, androgens, such as testosterone, promote prostate cancer tumor growth. Not all prostate cancer is the same. It ranges from cancer confined to the prostate gland, i.e., localized, to cancer that has spread outside of the prostate to the lymph nodes, bones, or other parts of the body, i.e., metastatic. At its early stages, localized prostate cancer is often treated with local therapy including, for example, surgical removal of the prostate gland and radiotherapy. However, when local therapy fails to cure prostate cancer, as it does in up to a third of men, the disease progresses into incurable metastatic disease (i.e., disease in which the cancer has spread from one part of the body to other parts).

There is a need for therapies that improve patient outcomes, especially in patients with high-risk localized prostate cancer after radical prostatectomy. The disclosed methods are directed to these and other important needs.

SUMMARY

Described herein are methods for treating prostate cancer in a patient (preferably a male human) comprising administering apalutamide at a dose of about 30 mg per day to about 480 mg per day (preferably at a dose of about 60 mg per day to about 240 mg per day, administered in a single or divided dosage forms) in combination with relugolix to a male human in need of such treatment. In certain embodiments, administration of apalutamide in combination with relugolix results in maintenance of castrate levels of testosterone in said male human. In some embodiments, said male human received a radical prostatectomy prior to administration of apalutamide in combination with relugolix. In certain embodiments, said male human is a candidate for radical prostatectomy.

In further embodiments, said prostate cancer is localized prostate cancer (LPC). In further embodiments, said prostate cancer is high risk localized prostate cancer (HR-LPC) or localized prostate cancer at high risk for metastases. In certain embodiments, said male human does not have a history of the presence of soft tissue/bone metastasis or metastasis in distant lymph nodes. In still further embodiments, said male human has not had a bilateral orchiectomy.

In some embodiments, the apalutamide is administered daily to the male human. In certain embodiments, the apalutamide is administered orally to the male human. In further embodiments, the apalutamide is administered orally to the male human on a continuous daily dosing schedule. In still further embodiments, the apalutamide is administered orally to the male human at a dose in the range of from about 30 mg per day to about 480 mg per day, preferably at a dose in the range of from about 60 mg per day to about 240 mg per day (for example, at a dose of 60 mg per day, at a dose of 120 mg per day, at a dose of 180 mg per day or 240 mg per day). In some embodiments, the apalutamide is administered orally to the male human at a dose of about 240 mg per day. In certain embodiments, the apalutamide is administered orally to the male human at a dose of about 240 mg once daily, as a single dosage form or as multiple dosage forms (for example as two, three or four dosage forms taken together once a day). In certain embodiments, the apalutamide is administered orally to the male human at a dose of about 240 mg once daily, as a single dosage form or as four 60 mg dosage forms.

In some embodiments, the apalutamide is formulated as a solid dosage form. In certain embodiments, the apalutamide is formulated as a tablet. In some embodiments, the apalutamide is formulated as a solid dosage form comprising, consisting of, or consisting essentially of about 60 mg of apalutamide. In some embodiments, the apalutamide is formulated as a solid dosage form comprising, consisting of, or consisting essentially of about 240 mg of apalutamide.

In certain embodiments, the relugolix is administered daily to the male human. In some embodiments, the relugolix is administered orally to the male human.

In further embodiments, the relugolix is administered at a loading dose of about 360 mg followed by a daily dose of about 120 mg. In still further embodiments, the relugolix is administered at a loading dose of about 360 mg followed by a daily dose of about 120 mg for two weeks. In some embodiments, the relugolix is administered to the male human at a dose of about 120 mg/day for two weeks, followed by co-administration of relugolix and apalutamide. In some embodiments, the relugolix is administered to the male human at a dose of about 120 mg/day for two weeks, followed by co-administration of relugolix at a dose of about 120 mg/day and apalutamide at a dose of about 240 mg/day. In some embodiments, the relugolix is administered to the male human at a dose of about 120 mg/day for two weeks, followed by co-administration of relugolix at a dose of about 120 mg/day, and apalutamide at a dose of about 240 mg/day, wherein the relugolix and the apalutamide are administered on a continuous daily dosing schedule. In some embodiments, the relugolix is administered at a loading dose of about 360 mg, followed by administration of the relugolix at a daily dose of about 120 mg for two weeks, followed by co-administration of relugolix at a dose of about 120 mg/day and apalutamide at a dose of about 240 mg/day.

In some embodiments, the relugolix is formulated as a solid dosage form. In certain embodiments, the relugolix is formulated as a tablet.

In certain embodiments, administration of relugolix results in castrate levels of testosterone in said male human. In some embodiments, administration of apalutamide in combination with relugolix results in maintenance of castrate levels of testosterone in said male human. In further embodiments, the dose of relugolix is not adjusted following administration of apalutamide in combination with relugolix. In further embodiments, the maintenance of castrate levels of testosterone does not require an adjustment of the dose of relugolix, when the relugolix is administered in combination with apalutamide.

Also described herein are methods of achieving and / or maintaining castrate levels of testosterone in a male human with prostate cancer (preferably, localized prostate cancer, more preferably high risk localized prostate cancer), said method comprising administering apalutamide at a dose in the range of from about 30 mg per day to about 480 mg per day (for example, at a dose of about 60 mg per day, 90 mg per day, 120 mg per day or 240 mg per day) in combination with relugolix to said male human. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments may also be provided in combination in a single embodiment. That is, unless obviously incompatible or specifically excluded, each individual embodiment is deemed to be combinable with any other embodiment(s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. Finally, although an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself, combinable with others.

The transitional terms "comprising," "consisting essentially of," and "consisting" are intended to connote their generally in accepted meanings in the patent vernacular; that is, (i) "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps;

(ii) "consisting of excludes any element, step, or ingredient not specified in the claim; and

(iii) "consisting essentially of limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. More specifically, the basic and novel characteristics relates to the ability of the method to provide at least one of the benefits described herein, including but not limited to the ability to improve the survivability of the male human population relative to the survivability of the comparative male human population described elsewhere herein.

Embodiments described in terms of the phrase "comprising" (or its equivalents), also provide, as embodiments, those which are independently described in terms of "consisting of and "consisting essentially of."

When a value is expressed as an approximation by use of the descriptor “about,” it will be understood that the particular value forms another embodiment. In general, use of the term “about” indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word “about.” In other cases, the gradations used in a series of values may be used to determine the intended range available to the term “about” for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range.

If not otherwise specified, the term “about” signifies a variance of ±10% of the associated value, but additional embodiments include those where the variance may be ±5%, ±15%, ±20%, ±25%, or ±50%.

It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or specifically excluded, each individual embodiment is deemed to be combinable with any other embodiment(s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself, combinable with others.

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

The present invention may be understood more readily by reference to the following description taken in connection with the accompanying Drawing and Examples, all of which form a part of this disclosure. It is to be understood that this invention is not limited to the specific products, methods, conditions or parameters described or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of any claimed invention. Similarly, unless specifically otherwise stated, any description as to a possible mechanism or mode of action or reason for improvement is meant to be illustrative only, and the invention herein is not to be constrained by the correctness or incorrectness of any such suggested mechanism or mode of action or reason for improvement. Throughout this text, it is recognized that the descriptions refer to various compounds, compositions and methods of using said compounds and compositions. That is, where the disclosure describes or claims a feature or embodiment associated with a composition or a method of using a composition, it is appreciated that such a description or claim is intended to extend these features or embodiment to embodiments in each of these contexts (i.e., compositions and methods of using). The androgen receptor (AR) is a member of the steroid and nuclear receptor superfamily. Among this large family of proteins, only five vertebrate steroid receptors are known and include the androgen receptor, estrogen receptor, progesterone receptor, glucocorticoid receptor, and mineralocorticoid receptor. AR is a soluble protein that functions as an intracellular transcriptional factor. AR function is regulated by the binding of androgens, which initiates sequential conformational changes of the receptor that affect receptor-protein interactions and receptor-DNA interactions.

AR is mainly expressed in androgen target tissues, such as the prostate, skeletal muscle, liver, and central nervous system (CNS), with the highest expression level observed in the prostate, adrenal gland, and epididymis. AR can be activated by the binding of endogenous androgens, including testosterone and 5-dihydrotestosterone (5a-DHT).

The androgen receptor (AR), located on Xql 1-12, is a 110 kD nuclear receptor that, upon activation by androgens, mediates transcription of target genes that modulate growth and differentiation of prostate epithelial cells. Similar to the other steroid receptors, unbound AR is mainly located in the cytoplasm and associated with a complex of heat shock proteins (HSPs) through interactions with the ligand-binding domain. Upon agonist binding, AR goes through a series of conformational changes: the heat shock proteins dissociate from AR, and the transformed AR undergoes dimerization, phosphorylation, and translocation to the nucleus, which is mediated by the nuclear localization signal. Recruitment of other transcription co- regulators (including co-activators and co-repressors) and transcriptional machinery further ensures the transactivation of AR-regulated gene expression. All of these processes are initiated by the ligand-induced conformational changes in the ligand-binding domain.

AR signaling is crucial for the development and maintenance of male reproductive organs including the prostate gland, as genetic males harboring loss of function AR mutations and mice engineered with AR defects do not develop prostates or prostate cancer. This dependence of prostate cells on AR signaling continues even upon neoplastic transformation. Androgen depletion (such as using GnRH agonists) continues to be the mainstay of prostate cancer treatment. However, androgen depletion is usually effective for a limited duration and prostate cancer evolves to regain the ability to grow despite low levels of circulating androgens.

Castration resistant prostate cancer (CRPC) is a lethal phenotype and almost all of patients will die from prostate cancer. Interestingly, while a small minority of CRPC does bypass the requirement for AR signaling, the vast majority of CRPC, though frequently termed "androgen independent prostate cancer" or "hormone refractory prostate cancer," retains its lineage dependence on AR signaling.

Prostate cancer is the second most common cause of cancer death in men in the US, and approximately one in every six American men will be diagnosed with the disease during his lifetime. Treatment aimed at eradicating the tumor is unsuccessful in 30% of men, who develop recurrent disease that is usually manifest first as a rise in plasma prostate-specific antigen (PSA) followed by spread to distant sites. Given that prostate cancer cells depend on androgen receptor (AR) for their proliferation and survival, these men are treated with agents that block production of testosterone (e.g., GnRH agonists), alone or in combination with anti- androgens (e.g., bicalutamide), which antagonize the effect of any residual testosterone on AR. The approach is effective as evidenced by a drop in PSA and regression of visible tumor (if present) in some patients; however, this is followed by regrowth as a castration resistant prostate cancer (CRPC) to which most patients eventually succumb. Recent studies on the molecular basis of CRPC have demonstrated that CRPC continues to depend on AR signaling and that a key mechanism of acquired resistance is an elevated level of AR protein. AR targeting agents with activity in castration sensitive and castration resistant prostate cancer have great promise in treating this lethal disease.

The course of prostate cancer from diagnosis to death is best categorized as a series of clinical states based on the extent of disease, hormonal status, and absence or presence of detectable metastases: localized disease, rising levels of prostate-specific antigen (PSA) after radiation therapy or surgery with no detectable metastases, and clinical metastases in the noncastrate or castrate state. Although surgery, radiation, or a combination of both can be curative for patients with localized disease, a significant proportion of these patients have recurrent disease as evidenced by a rising level of PSA, which can lead to the development of metastases, especially in the high-risk group - a transition to the lethal phenotype of the disease.

Androgen depletion is the standard treatment with a generally predictable outcome: decline in PSA, a period of stability in which the tumor does not proliferate, followed by rising PSA and regrowth as castration-resistant disease. Molecular profiling studies of castration- resistance prostate cancers commonly show increased androgen receptor (AR) expression, which can occur through AR gene amplification or other mechanisms.

Anti-androgens are useful for the treatment of prostate cancer during its early stages. However, prostate cancer often advances to a castration resistant state in which the disease progresses in the presence of continued androgen ablation or anti-androgen therapy. Instances of antiandrogen withdrawal syndrome have also been reported after prolonged treatment with anti- androgens. Antiandrogen withdrawal syndrome is commonly observed clinically and is defined in terms of the tumor regression or symptomatic relief observed upon cessation of antiandrogen therapy. AR mutations that result in receptor promiscuity and the ability of these anti-androgens to exhibit agonist activity might at least partially account for this phenomenon. For example, hydroxyflutamide and bicalutamide act as AR agonists in T877A and W741L/W741C AR mutants, respectively.

In the setting of prostate cancer cells that were rendered castration resistant via overexpression of AR, it has been demonstrated that certain anti-androgen compounds, such as bicalutamide, have a mixed antagonist/agonist profile: 787- 90). This agonist activity helps to explain a clinical observation, called the anti-androgen withdrawal syndrome, whereby about 30% of men who progress on AR antagonists experience a decrease in serum PSA when therapy is discontinued.

Prostate Cancer Stages

In the early stages of prostate cancer, the cancer is localized to the prostate. In these early stages, treatment typically involves either surgical removal of the prostate or radiation therapy to the prostate or observation only with no active intervention therapy in some patients. In the early stages where the prostate cancer is localized and requires intervention, surgery or radiation therapy are curative by eradicating the cancerous cells. About 30% of the time these procedures fail, and the prostate cancer continues to progress, as typically evidenced by a rising PSA level. Men whose prostate cancer has progressed following these early treatment strategies are said to have advanced or recurrent prostate cancer.

Because prostate cancer cells depend on the androgen receptor (AR) for their proliferation and survival, men with advanced prostate cancer are treated with agents that block the production of testosterone (e.g., GnRH agonists), alone or in combination with antiandrogens (e.g., bicalutamide), which antagonize the effect of any residual testosterone on AR. These treatments reduce serum testosterone to castrate levels, which generally slows disease progression for a period of time. The approach is effective as evidenced by a drop in PSA and the regression of visible tumors in some patients. Eventually, however, this is followed by regrowth referred to as castration-resistant prostate cancer (CRPC), to which most patients eventually succumb. Castration-resistant prostate cancer (CRPC) is categorized as non-metastatic or metastatic, depending on whether or not the prostate cancer has metastasized to other parts of the body. In certain embodiments, the male human is characterized as having localized prostate cancer. In certain embodiments, the male human is characterized as having high risk localized prostate cancer. In certain embodiments, the male human is characterized as having high risk localized prostate cancer following radical prostatectomy. In certain embodiments, the male human is characterized as being at high risk for developing metastases after radical prostatectomy.

In some embodiments, the male human meets one or more of the following criteria:

• The male human is a candidate for radical prostatectomy (RP) or is post RP. (Preferably, the male human has exhibited a post RP prostate-specific antigen (PSA) of < 0.2 nanograms per milliliter (ng/mL)).

• The male human has histologically confirmed adenocarcinoma of the prostate and said adenocarcinoma of the prostate is categorized as high risk for recurrent prostate cancer.

In certain embodiments, high risk for recurrent prostate cancer post RP is defined based on PSA alone, or based on biopsy, or based on RP specimen as follows: PSA greater than or equal to (>) 20 ng/ml or; Gleason Score > 9 in any core on biopsy or; Gleason Score > 8 (4+4 or 5+3) in greater than (>) 80 percentage (%) of 2 cores on biopsy or; Gleason Score = 8 (4+4 or 5+3) in 1 core as long 5 or more other cores with minimum Gleason Score of 4+3 on biopsy. In certain embodiments, the determination of high risk may be based on pathology report of biopsy or equivalent criteria from radical prostatectomy.

In some embodiments, the male human meets one or more of the following criteria:

• The male human is a candidate for radical prostatectomy (RP) or is post RP. (Preferably, the male human has exhibited a post RP prostate-specific antigen (PSA) of < 0.2 nanograms per milliliter (ng/mL)).

• The male human has recovered from RP procedure and has had no worsening in cardiac risk in the peri -operative period per the clinical judgement of the investigator

• The male human has adequate organ function (hepatic, renal, hematologic and cerebral) as determined at the discretion of the treating physician

• The male human has an Eastern Cooperative oncology Group (ECOG) Performance Status Score of 0 or 1

• The male human has histologically confirmed adenocarcinoma of the prostate and said adenocarcinoma of the prostate is categorized as high risk for recurrent prostate cancer. Apalutamide

Apalutamide is an androgen receptor inhibitor that binds directly to the ligandbinding domain of AR, impairing nuclear translocation, AR binding to DNA and AR target gene modulation, thereby inhibiting tumor growth and promoting apoptosis. Apalutamide binds AR with greater affinity than bicalutamide and induces partial or complete tumor regression in non-castrate hormone-sensitive and bicalutamide -resistant human prostate cancer xenograft models. Apalutamide lacks the partial agonist activity seen with bicalutamide in the context of AR overexpression.

Apalutamide is also known as 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]oct-5- yl]-2-fhioro-N-methylbenzamide, or CAS No. 956104-40- 8. Apalutamide has the following chemical structure:

In certain embodiments, apalutamide is administered in a single dosage form or in divided dosage forms administered simultaneously (or over a short period of time) or at appropriate intervals. In certain embodiments, apalutamide is administered in a single dosage form. In certain embodiments, apalutamide is administered in divided dosage forms (for example, in two, three or four dosage forms, preferably in equally divided dosage forms, more preferably in four equally divided dosage forms) that are administered simultaneously (or over a short period of time) once a day.

In certain embodiments, apalutamide is administered in an amount in the range of from about 30 mg per day to about 480 mg per day. In certain embodiments, apalutamide is administered in an amount in the range of from about 60 mg per day to about 240 mg per day. In certain embodiments, apalutamide is administered in an amount of about 60 mg per day or about 90 mg per day or about 120 mg per day or about 180 mg per day or about 240 mg per day. In certain embodiments, apalutamide is administered in an amount of about 240 mg per day. In certain embodiments, apalutamide is administered once daily as a single or as divided dosage forms. In certain embodiments, apalutamide is administered in an amount of about 240 mg per day, once daily, as a single or as divided dosage forms. In certain embodiments, apalutamide is administered in an amount of about 240 mg per day, once daily as a single dosage form. In certain embodiments, apalutamide is administered in an amount of about 240 mg per day, once daily as two, three or four (preferably four) divided dosage forms (preferably equally divided dosage forms, more preferably as four 60 mg dosage forms).

As used herein, the term "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, co-activator binding, DNA binding, ligand binding, or nuclear translocation.

As used herein, the term "anti-androgen" carries its generally accepted meaning and may refer to a group of hormone receptor antagonist compounds that are capable of preventing or inhibiting the biologic effects of androgens on normally responsive tissues in the body. In some embodiments, an anti-androgen is a small molecule. In some embodiments, an anti-androgen is an AR antagonist. In some embodiments, an anti-androgen is an AR full antagonist. In some embodiments, an anti-androgen is a first- generation anti-androgen. In some embodiments, an anti-androgen is a second-generation anti-androgen.

Relugolix

Relugolix, also known as N-(4-{ l[(2,6-difhrorophenyl)methyl]-5- [(dimethylamino)methyl] -3 -(6-methoxypyridazin-3 -yl)-2,4-dioxo- l,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl}phenyl)-N’-methoxyurea, TAK-385 or ORGOVYX™, is a gonadotropin-releasing hormone (GnRH) receptor antagonist. The molecular weight is 623.63 Daltons and the molecular formula is C29H27F2N7O5S. Relugolix has the following chemical structure:

Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to pituitary GnRH receptors, thereby, reducing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and consequently testosterone.

One skilled in the art will readily recognize that recommended dosage amounts and regiments for known and / or marketed compounds such as relugolix may be determined by consulting appropriate references such as drug package inserts, FDA guidelines, the Physician’s Desk Reference, and the like.

Certain Terminology

The terms used herein carry their normally accepted meaning, but for avoidance of doubt, some of the definitions are provided herein. The term "cancer" as used herein refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread).

The term "prostate cancer" as used herein refers to histologically or cytologically confirmed adenocarcinoma of the prostate.

The term "androgen-deprivation therapy (ADT)" refers to the reduction of androgen levels in a prostate cancer patient to castrated levels of testosterone (< 50 ng/dL). Such treatments can include orchiectomy or the use of gonadotropin-releasing hormone agonists or antagonists. ADT includes surgical castration (orchiectomy) and/or the administration of luteinizing hormone-releasing hormone (“LHRH”)/gonadotropin-releasing hormone (GnRH) agonists or antagonists to a human. Bilateral orchiectomy refers to surgical castration of both testicles. Examples of GnRH agonist or antagonist is or comprises leuprolide, buserelin, naferelin, histrelin, goserelin, deslorelin, degarelix, ozarelix, ABT-620 (elagolix), TAK-385 (relugolix), EP-100, KLH-2109 or triptorelin. In certain embodiments, examples of GnRH agonists include goserelin acetate, histrelin acetate, leuprolide acetate, and triptorelin pamoate.

The term “radical prostatectomy” refers to surgical removal of the prostate gland. In certain cases, radical prostatectomy may further include surgical removal of surrounding tissues (for example, seminal vesicles) and / or nearby lymph nodes.

The term "locally advanced prostate cancer" refers to prostate cancer where all actively cancerous cells appear to be confined to the prostate and adjacent structures (e.g., seminal vesicle, bladder neck, and rectal wall).

The terms “high risk localized prostate cancer” or “localized prostate cancer at high risk for metastases” refer to histologically confirmed adenocarcinoma of the prostate, wherein the adenocarcinoma of the prostate is categorized as being of high risk for recurrence as defined by PSA greater than or equal to (>) 20 ng/ml, biopsy Gleason sum > 8 or clinical stage >T3a (see National Comprehensive Cancer Network (NCCN) guidelines, www.nccn.org). The determination of high risk may be based on pathology report of biopsy or equivalent criteria from radical prostatectomy.

In certain embodiments, the male human has histologically confirmed adenocarcinoma of the prostate, wherein the adenocarcinoma of the prostate is categorized by one or more of the following: PSA greater than or equal to (>) 20 ng/ml or; Gleason Score > 9 in any core on biopsy or; Gleason Score > 8 (4+4 or 5+3) in greater than (>) 80 percentage (%) of 2 cores on biopsy or; Gleason Score = 8 (4+4 or 5+3) in 1 core as long 5 or more other cores with minimum Gleason Score of 4+3 on biopsy. In some embodiments, high risk for development of metastases is defined as prostate specific antigen doubling time (PSADT) < 20 months, < 19 months, < 18 months, < 17 months, < 16 months, < 15 months, < 14 months, < 13 months, < 12 months, < 11 months, < 10 months, < 9 months, < 8 months, < 7 months, < 6 months, < 5 months, < 4 months, < 3 months, < 2 months, or < 1 month. In some embodiments, high risk for development of metastases is defined as prostate specific antigen doubling time (PSADT) <10 months. In some embodiments, high risk for development of metastases is defined as prostate specific antigen doubling time (PSADT) <6 months. In some embodiments, high risk for development of metastases is defined as prostate specific antigen doubling time (PSADT) <3 months. In some embodiments, high risk for development of metastases is defined as having a Gleason score >8 . In some embodiments, high risk for development of metastases is defined as having local -regional recurrence (e.g. primary tumor bed, bladder neck, anastomotic area, pelvic lymph nodes).

The term “castrate levels of testosterone” refer to measured blood levels of testosterone of <50 ng/dL.

For the avoidance of doubt, the terms “castration-sensitive prostate cancer” and “hormone -sensitive prostate cancer” are equivalent and are used interchangeably.

The terms "castration-sensitive prostate cancer" and “hormone -sensitive prostate cancer” refer to cancer that is responsive to ADT either as localized disease, biochemical relapse or in the metastatic setting.

The terms "metastatic castration-sensitive prostate cancer" and “metastatic hormonesensitive prostate cancer” refers to cancer that has spread (metastasized) to other areas of the body, e.g., the bone, lymph nodes or other parts of the body in a male, and that is responsive to ADT.

The terms "non-metastatic castration-sensitive prostate cancer" refers to cancer that has not spread (metastasized) from the prostate in a male, and that is responsive to ADT. In some embodiments, non-metastatic castration-sensitive prostate cancer is assessed with bone scan and computed tomography (CT) or magnetic resonance imaging (MRI) scans. [0089] The term "CRPC" as used herein refers to castration-resistant prostate cancer. CRPC is prostate cancer that continues to grow despite the suppression of male hormones that fuel the growth of prostate cancer cells.

The term "metastatic castration-resistant prostate cancer" refers to castration-resistant prostate cancer that has metastasized to other parts of the human body. Metastatic castration-sensitive prostate cancer (CSPC), refers to prostate cancerthat still responds to testosterone suppression therapy.

The term "NM-CRPC" as used herein refers to non-metastatic castration-resistant prostate cancer. In some embodiments, NM-CRPC is assessed with bone scan and computed tomography (CT) or magnetic resonance imaging (MRI) scans.

The term "chemotherapy naive metastatic castration-resistant prostate cancer" refers to metastatic castration-resistant prostate cancer that has not been previously treated with a chemotherapeutic agent.

The term "high risk NM-CRPC" refers to probability of a man with NM-CRPC developing metastases. In some embodiments, high risk for development of metastases is defined as prostate specific antigen doubling time (PSADT) < 20 months, < 19 months, <18 months, <17 months, <16 months, <15 months, <14 months, <13 months, <12 months, < 11 months, <10 months, <9 months, <8 months, <7 months, <6 months, <5 months, <4 months, <3 months, <2 months, or <1 month. In some embodiments, high risk for development of metastases is defined as prostate specific antigen doubling time (PSADT) <10 months. In some embodiments, high risk for development of metastases is defined as prostate specific antigen doubling time (PSADT) <6 months. In some embodiments, high risk for development of metastases is defined as prostate specific antigen doubling time (PSADT) <3 months. In some embodiments, high risk for development of metastases is defined as having local- regional recurrence (e.g. primary tumor bed, bladder neck, anastomotic area, pelvic lymph nodes).

The terms “administered in combination with” "co-administration" or the like, as used herein, encompass administration of the one or more selected therapeutic agents to a single patient (the male human), and are intended to include treatment regimens in which the agents are administered by the same or different route of administration, and/or at the same or different time (for example, concurrently, sequentially, consecutively or in any order and at any time points such that the administration provides the desired therapeutic effect).

In certain embodiments, the methods of the present invention are directed to cotherapy or combination therapy wherein relugolix and apalutamide are each administered once daily. In certain embodiments, the methods of the present invention are directed to cotherapy or combination therapy wherein relugolix and apalutamide are each administered once daily and at approximately the same time.

The term "pharmaceutical combination" as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g., apalutamide and a co-agent, are both administered to a patient simultaneously in the form of a single unit or single dosage form. The term "non-fixed combination" means that the active ingredients, e.g., apalutamide and a co-agent, are administered to a patient as separate units or separate dosage forms, either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides safe and effective levels of the two active ingredients in the body of the human male. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

The term "continuous daily dosing schedule" refers to the administration of a particular therapeutic agent without any drug holidays from the particular therapeutic agent. In some embodiments, a continuous daily dosing schedule of a particular therapeutic agent comprises administration of a particular therapeutic agent every day at roughly the same time each day.

The terms “treat”, “treating”, and "treatment" refer to the eradication, removal, modification, management, or control of a tumor or primary, regional, or metastatic cancer cells or tissue and the minimization or delay of the spread of cancer.

The term “randomization” as it refers to a clinical trial refers to the time when the patient is confirmed eligible for the clinical trial and gets assigned to a treatment arm.

The terms "kit" and "article of manufacture" are used as synonyms. The term "subject" and "patient" and "human" are used interchangeably.

Methods of Dosing and Treatment Regimens

Described herein are methods for treating prostate cancer (for example, localized prostate cancer or high risk localized prostate cancer) in a male human comprising, consisting of, or consisting essentially of administering apalutamide at a dose of about 30 mg per day to about 480 mg per day (preferably, at a dose in the range of from about 60 mg per day to about 240 mg per day, more preferably at a dose of about 60 mg per day, 90 mg per day, 120 mg per day or 240 mg per day) in combination with relugolix, to a male human in need of such treatment.

Also described herein are methods for treating prostate cancer (for example, localized prostate cancer or high risk localized prostate cancerjin a male human comprising, consisting of, or consisting essentially of administering apalutamide at a dose of about 30 mg per day to about 480 mg per day (preferably, at a dose in the range of from about 60 mg per day to about 240 mg per day, more preferably at a dose of about 60 mg per day, 90 mg per day, 120 mg per day or 240 mg per day) in combination with relugolix at an initial dose of 360 mg followed by a dose of about 120 mg per day, to a male human in need of such treatment.

Also described herein are methods of achieving castrate levels of testosterone in a male human with prostate cancer (for example, localized prostate cancer or high risk localized prostate cancer), said method comprising, consisting of, or consisting essentially of administering apalutamide at a dose of about 30 mg per day to about 480 mg per day (preferably, at a dose in the range of from about 60 mg per day to about 240 mg per day, more preferably at a dose of about 60 mg per day, 90 mg per day, 120 mg per day or 240 mg per day) in combination with relugolix, to said male human.

In the following disclosure, “methods of treating prostate cancer,” may alternatively be recited as “methods of treating a male human having prostate cancer.” For the sake of brevity, each possible alternative is not parsed out, but each are considered separately considered as if fully described.

In certain embodiments, administration of apalutamide in combination with relugolix results in maintenance of castrate levels of testosterone in said male human. In certain embodiments, said male human achieved castrate levels of testosterone following administration of relugolix monotherapy. In further embodiments, castrate levels of testosterone are maintained following administration of relugolix in combination with apalutamide following relugolix monotherapy. In certain embodiments, levels of testosterone are measured in ng/dL. In certain embodiments, castrate levels of testosterone refers to testosterone levels < 50 ng/dL.

In some embodiments, said male human received a radical prostatectomy prior to administration of apalutamide in combination with relugolix. In certain embodiments, said male human is a candidate for radical prostatectomy. In some embodiments, the male human has recovered from radical prostatectomy procedure and has had no worsening in cardiac risk in the peri-operative period.

In further embodiments, said prostate cancer is localized prostate cancer at high risk for metastases.

In some embodiments, the male human has adequate organ function (hepatic, renal, hematologic and cerebral) prior to treatment with apalutamide and relugolix.

In further embodiments, the male human has an Eastern Cooperative Oncology Group performance status (ECOG PS) grade of 0 or 1 . In certain embodiments, the male human is determined to have an ECOG PS grade of 0 or 1 at the time of initiation of treatment with apalutamide in combination with relugolix.

In certain embodiments, the male human has histologically confirmed adenocarcinoma of the prostate wherein the adenocarcinoma of the prostate is categorized as high risk for recurrence.

In certain embodiments, said patient does not have a history of the presence of soft tissue/bone metastasis or metastasis in distant lymph nodes. In certain embodiment, pelvic lymph nodes below the iliac bifurcation that are less than (<) 2 centimeter (cm) in diameter [short axis] either radiographically or pathologically are allowed.

In still further embodiments, said patient does not have bilateral orchiectomy.

In some embodiments, the male human did not receive an investigational intervention < 4 weeks before the planned first dose of study intervention.

In certain embodiments, the male human does not have a history of seizure or any condition that may predispose to seizure or treatment with drugs known to lower the seizure threshold within 4 weeks prior to starting treatment with apalutamide in combination with relugolix.

In one aspect, described herein are methods treating prostate cancer in a male human comprising, consisting of, or consisting essentially of administering apalutamide at a dose of about 30 mg per day to about 480 mg per day (preferably, at a dose in the range of from about 60 mg per day to about 240 mg per day, more preferably at a dose of about 60 mg per day, 90 mg per day, 120 mg per day or 240 mg per day) in combination with relugolix to a male human in need of such treatment, wherein the apalutamide is administered orally. In some embodiments, the apalutamide is administered daily. In some embodiments, the apalutamide is administered orally on a continuous daily dosage schedule. In some embodiments, the apalutamide is administered orally, once a day, in a single or equally divided (for example two, three or four equally divided) dosage forms, on a continuous daily dosage schedule.

In some embodiments, the apalutamide is administered daily to the male human. In certain embodiments, the apalutamide is administered orally to the male human. In further embodiments, the apalutamide is administered orally to the male human on a continuous daily dosing schedule. In still further embodiments, the apalutamide is administered orally to the male human at a dose of about 30 mg per day to about 480 mg per day (preferably, at a dose in the range of from about 60 mg per day to about 240 mg per day, more preferably at a dose of about 60 mg per day, 90 mg per day, 120 mg per day or 240 mg per day). In some embodiments, the apalutamide is administered orally to the male human at a dose of about 240 mg per day. In certain embodiments, the apalutamide is administered orally to the male human at a dose of about 240 mg as a single or as equally divided dosage forms (for example, 60 mg dosage forms, administered simultaneously once a day)\.

In one aspect, described herein are methods of treating prostate cancer in a male human comprising, consisting of, or consisting essentially of administering apalutamide at a dose of about 30 mg per day to about 480 mg per day (preferably, at a dose in the range of from about 60 mg per day to about 240 mg per day, more preferably at a dose of about 60 mg per day, 90 mg per day, 120 mg per day or 240 mg per day) in combination with relugolix to a male human in need of such treatment, wherein the relugolix is administered orally. In some embodiments, the relugolix is administered daily. In some embodiments, the relugolix is administered orally on a continuous daily dosage schedule.

In further embodiments, relugolix is administered at a loading dose of about 360 mg on day one of treatment. In further embodiments, relugolix is administered at a loading dose of about 360 mg on day one of treatment, followed by a dose of about 120 mg/day. In still further embodiments, relugolix is administered at a loading dose of about 360 mg on day one of treatment, followed by a dose of about 120 mg/day for two weeks. In some embodiments, administration of relugolix at about 120 mg/day for two weeks is followed by coadministration of apalutamide at a dose of about 240 mg/day. In still further embodiments, relugolix is administered at a loading dose of about 360 mg on day one of treatment, followed by a dose of about 120 mg/day for two weeks, followed by co-administration of relugolix at about 120 mg/day and apalutamide at a dose of about 240 mg/day.

In certain embodiments, administration of relugolix results in castrate levels of testosterone in said male human. In certain embodiments, the castrate levels of testosterone in said male human are < 50 ng/dL. In certain embodiments, the castrate levels of testosterone in said male human are < 1.72 nmol/L.

In some embodiments, administration of apalutamide in combination with relugolix results in maintenance of castrate levels of testosterone in said male human. In some embodiments, administration of apalutamide in combination with relugolix results in maintenance of testosterone levels below 50 ng/dL in said male human. In further embodiments, the dose of relugolix is not adjusted following administration of apalutamide in combination with relugolix. In further embodiments, the maintenance of castrate levels of testosterone (preferably below 50 ng/dL) does not require an adjustment in the dose of relugolix, when the relugolix is administered in combination with apalutamide. In general, doses of the apalutamide employed for treatment of the diseases or conditions described herein in humans are typically in the range of 10 mg to 1200 mg per day. In some embodiments, the apalutamide is administered orally to the human at a dose of about 30 mg per day to about 1200 mg per day. In some embodiments, the apalutamide is administered orally to the human at a dose of about 30 mg per day to about 600 mg per day. In some embodiments, the apalutamide is administered orally to the human at a dose of 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 per day, 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.

In certain embodiments, the doses of the apalutamide employed for treatment of the diseases or conditions described herein in humans may have a range of from 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 260 mg/day, 260 to 280 mg/day, 280 to 300 mg/day, 300 to 320 mg/day, 320 to 340 mg/day, 340 to 360 mg/day, 360 to 380 mg/day, 380 to 400 mg/day, 400 to 420 mg/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 ranges, or any individual value cited in these ranges.

In some embodiments, the doses of the apalutamide employed for treatment of the diseases or conditions described herein in humans may have a range of from 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/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 1.6 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 defined by two or more of these ranges, or any individual value cited in these ranges.

In some embodiments, the amount of apalutamide and/or relugolix that is given to the patient (for example, the male human) varies depending upon factors such as, but not limited to, condition and severity of the disease or condition, and the identity (e.g., weight) of the human, and the particular additional therapeutic agents that are administered (if applicable). In certain embodiments, the apalutamide and / or the relugolix, are administered to a patient (for example, the male human) as separate units or separate dosage forms, either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides safe and effective levels of the two active ingredients in the body of the human male. In certain embodiments, the relugolix may be administered prior to administration of apalutamide. In certain embodiments, the relugolix may be administered after administration of apalutamide.

Routes of Administration and Pharmaceutical Compositions

Therapeutic agents described herein are administered in any suitable manner or suitable formulation. Suitable routes of administration of the therapeutic agents include, but are not limited to, oral and parenteral (e.g., intravenous, subcutaneous, intramuscular). All formulations are in dosages suitable for administration to a human. A summary 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), herein incorporated by reference for such disclosure.

Studies that look at safety also seek to identify any potential adverse effects that may result from exposure to the drug. Efficacy is often measured by determining whether an active pharmaceutical ingredient demonstrates a health benefit over a placebo or other intervention when tested in an appropriate situation, such as a tightly controlled clinical trial.

Unless otherwise specified, the terms "effective amount" or "therapeutically effective amount," as used herein, refer to an amount of apalutamide or relugolix being administered that treats the underlying disease or condition including, but not limited to, halting or slowing the progression of the disease or condition.

The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means that the beneficial effects of that formulation, composition or ingredient on the general health of the male human being treated substantially outweigh its detrimental effects, to the extent any exist.

In some embodiments, the apalutamide is present in a solid dosage form. In some embodiments, the apalutamide is present in a solid oral dosage form. In some embodiments, the apalutamide is formulated as an oral dose form, a unit oral dose form, or a solid dose form (e.g., a capsule, tablet, or pill). In some embodiments, for example, the apalutamide is formulated as a tablet. Solid oral dosage forms containing the apalutamide may be provided as soft gel capsules as disclosed in WO2014113260 and CN104857157, each of which is incorporated herein by reference, or as tablets as disclosed in WO2016090098, WG20I6090I0I, W02016090105, and W02014043208, each of which is incorporated herein by reference. Techniques suitable for preparing solid oral dosage forms of the present invention are described in Remington's Pharmaceutical Sciences, 18th edition, edited by AR. Gennaro, 1990, Chapter 89, and in Remington - The Science, and Practice of Pharmacy, 21st edition, 2005, Chapter 45.

In some embodiments, the relugolix is present in a solid dosage form. In some embodiments, the relugolix is present in a solid oral dosage form. In some embodiments, the relugolix is formulated as an oral dose form, a unit oral dose form, or a solid dose form (e.g., a capsule, tablet, or pill). In some embodiments, for example, the relugolix is formulated as a tablet.

To prepare the pharmaceutical compositions of this invention, the active pharmaceutical ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g., oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

In solid oral preparations such as, for example, dry powders for reconstitution or inhalation, granules, capsules, caplets, gel caps, pills and tablets (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, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated, gelatin coated, film coated or enteric coated by standard techniques.

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

These formulations are manufactured by conventional formulation techniques. For preparing solid pharmaceutical compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as diluents, binders, adhesives, disintegrants, lubricants, antiadherents, and glidants. Suitable diluents include, but are not limited to, starch (i.e. com, wheat, or potato starch, which may be hydrolized), lactose (granulated, spray dried or anhydrous), sucrose, sucrose-based diluents (confectioner's sugar; sucrose plus about 7 to 10 weight percent invert sugar; sucrose plus about 3 weight percent modified dextrins; sucrose plus invert sugar, about 4 weight percent invert sugar, about 0.1 to 0.2 weight percent cornstarch and magnesium stearate), dextrose, inositol, mannitol, sorbitol, microcrystalline cellulose (i.e. AVICEL microcrystalline cellulose available from FMC Corp.), dicalcium phosphate, calcium sulfate dihydrate, calcium lactate trihydrate and the like. Suitable binders and adhesives include, but are not limited to acacia gum, guar gum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics (i.e. methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like), water soluble or dispersible binders (i.e. alginic acid and salts thereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e. TYLOSE available from Hoechst Celanese], polyethylene glycol, polysaccharide acids, bentonites, polyvinylpyrrolidone, polymethacrylates and pregelatinized starch) and the like. Suitable disintegrants include, but are not limited to, starches (com, potato, etc.), sodium starch glycolates, pregelatinized starches, clays (magnesium aluminum silicate), celluloses (such as crosslinked sodium carboxymethylcellulose and microcrystalline cellulose), alginates, pregelatinized starches (i.e. com starch, etc.), gums (i.e. agar, guar, locust bean, karaya, pectin, and tragacanth gum), cross-linked polyvinylpyrrolidone and the like. Suitable lubricants and antiadherents include, but are not limited to, stearates (magnesium, calcium and sodium), stearic acid, talc waxes, 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 (i.e. CAB-O-SIL silica available from Cabot, SYLOID silica available from W.R. Grace/Davison, and AEROSIL silica available from Degussa) and the like. Sweeteners and flavorants may be added to chewable solid dosage forms to improve the palatability of the oral dosage form. Additionally, colorants and coatings may be added or applied to the solid dosage form for ease of identification of the drug or for aesthetic purposes. These carriers are formulated with the pharmaceutical active to provide an accurate, appropriate dose of the pharmaceutical active with a therapeutic release profile.

An aspect of the invention is a solid dispersion comprising the apalutamide. Various techniques exist for preparing the solid dispersions of the invention including melt-extrusion (e.g. hot melt extrusion), spray-drying and solution-evaporation, in particular hot meltextrusion and spray-drying, spray-drying being preferred. An aspect of the invention is a particle consisting of a solid dispersion as described herein. In an aspect of the invention, the particles as described herein are obtainable, in particular are obtained, by spray drying a mixture comprising apalutamide and HPMCAS in a suitable solvent. In an aspect, the particles are obtainable, in particular are obtained, by melt extrusion.

HPMCAS or hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate (CAS number 71138-97-1) is a mixture of acetic acid and monosuccinic acid esters of hydroxypropylmethyl cellulose (IUPAC name : cellulose, 2-hydroxypropyl methyl ether, acetate, hydrogen butanedioate). Different grades are available differentiated based on degree/ratio of substitution (acetyl content, succinoyl content) and particle size (micronized and granular). In an aspect of the invention, the HPMCAS in the dispersions with ARN-509 is HPMCAS LG (granular grade) or HPMCAS LF (micronized grade) (Shin- Etsu Chemical Co., Ltd), in particular HPMCAS LG.

Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, starches, cellulose, and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose), polyvinyl pyrrolidone, and mixtures thereof.

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

The binder or fdler in pharmaceutical compositions is typically 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 tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise 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, crospovidone, sodium starch glycolate, potato or tapioca starch, pre-gelatinized 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 glycol, other glycols, stearic acid, sodium lauryl sulfate, sodium stearyl fumarate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

Compressed tablet formulations may optionally be film-coated to provide color, light protection, and/or taste-masking. Tablets may also be coated so as to modulate the onset, and/or rate of release in the gastrointestinal tract, so as to optimize or maximize the biological exposure of the patient to the API.

Hard capsule formulations may be produced by filling a blend or granulation of apalutamide, RD 162 or darolutamide into shells consisting of, for example, gelatin, or hypromellose.

Soft gel capsule formulations may be produced.

Pharmaceutical compositions intended for oral use may be prepared from the solid dispersion formulations, and blended materials described above in accordance with the methods described herein, and other methods known to the art for the manufacture of pharmaceutical compositions. Such compositions may further contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, granulating, and disintegrating agents, binding agents, glidants, lubricating agents, and antioxidants, for example, propyl gallate, butylated hydroxyanisole, and butylated hydroxy toluene. The tablets may be uncoated, or they may be film coated to modify their appearance or may be coated with a functional coat to delay disintegration, and absorption in the gastrointestinal tract, and thereby provide a sustained action over a longer period.

Compositions for oral use may also be presented as capsules (e.g., hard gelatin) wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or starch, or as soft gelatin capsules wherein the active ingredient is mixed with liquids or semisolids, for example, peanut oil, liquid paraffin, fractionated glycerides, surfactants or olive oil. Aqueous suspensions contain the active materials in mixture 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 mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. In certain embodiments of the invention, the pharmaceutical compositions of the invention include a diluent system, disintegrant, salt, lubricant, glidant, and filmcoat, at concentrations of 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 respectively, or at from about 18%w/w to about 40%w/w, 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, respectively. In certain embodiments, the solid dispersion formulations are blended with a diluent, one or more disintegrating agents, lubricants, and glidants. An exemplary blended composition or oral dosage form includes mannitol, microcrystalline cellulose, croscarmellose sodium, sodium chloride, colloidal silica, sodium stearyl fumarate, and magnesium stearate.

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

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

In certain embodiments, a single unit dosage (dosage form) of the pharmaceutical composition comprises, consists of, or consists essentially of about 60 mg of apalutamide. In some embodiments, multiple doses of the single unit dosage pharmaceutical composition comprising, consisting of, or consisting essentially of about 60 mg of apalutamide, e.g., 4 multiple or individual unit or divided dosage forms, are administered to the human. The total daily dose of apalutamide may be about 240 mg per day. In certain embodiments, a single unit dosage (dosage form) of the pharmaceutical composition comprises, consists of, or consists essentially of about 120 mg of relugolix.

All formulations for oral administration are in dosage form(s) suitable for such administration.

Kits/Articles of Manufacture

For use in the therapeutic methods of use described herein, kits and articles of manufacture are also described herein. Such kits include a package or container that is compartmentalized to receive one or more dosages of the pharmaceutical compositions disclosed herein. Suitable containers include, for example, bottles. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include, e.g., U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.

A kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

In one embodiment, a label is on or associated with the container. In one embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In one embodiment, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

EXAMPLES

The following example is provided for illustrative purposes only and not to limit the scope of the claims provided herein.

Example 1: Coadministration of apalutamide (APA) and relugolix: substudy results from the Phase 2 Apa-RP study of APA and androgen deprivation therapy (ADT) in patients with localized prostate cancer (LPC) at high risk for metastases post radical prostatectomy (RP)

Background

APA-RP (NCT04523207) is an ongoing single-arm, open-label, multicenter phase 2 study to evaluate the biochemical recurrence-free rate in patients with high-risk localized prostate cancer (LPC) after radical prostatectomy (RP), receiving adjuvant apalutamide and androgen deprivation therapy (ADT). The aim of the APA-RP substudy is to evaluate whether the combination of approved doses of APA and relugolix would maintain castrate testosterone levels in high-risk LPC after RP.

Methods

Patients with LPC who are at high risk of developing metastases post RP and who met all criteria for the main study were enrolled. High risk was defined as prostate-specific antigen >20 ng/mL or Gleason score (GS) > 8 (> 9 in any core, or GS > 8 [4 + 4 or 5 + 3] in >80% in 2 cores, or GS = 8 [4 + 4 or 5 + 3] in 1 core with > 5 other cores of GS > 7.

Patients received relugolix for two weeks (a loading dose of 360 mg at Day -14, followed by 120 mg/d relugolix monotherapy for 2 weeks until Day -1), then daily coadministration of relugolix (120 mg) and apalutamide (240 mg) from Day 1 to Day 28. Serum testosterone (T) was assessed throughout. The end points were rate of maintained castration (testosterone < 50 ng/dL) through Day 28 and safety. Treatment-emergent adverse events (TEAs) were monitored throughout the sub-study.

The study enrolled male patients 18 years of age or older with the following inclusion/exclusion criteria:

Inclusion Criteria:

• A candidate for radical prostatectomy (RP) or status post RP. Eligible to receive study intervention between Day 29 and Day 90 post-RP. Post RP prostate-specific antigen (PSA) of <= 0.2 nanograms per milliliter (ng/mL). Has not received other treatment for prostate cancer

• Have recovered from RP procedure and have had no worsening in cardiac risk in the peri -operative period per the clinical judgement of the investigator

• Adequate organ function (hepatic, renal, hematologic and cerebral) determined at the discretion of the treating physician

• Eastern Cooperative oncology Group (ECOG) Performance Status Score of 0 or 1

• Histologically confirmed adenocarcinoma of the prostate and categorized as high risk for recurrent prostate cancer. High risk can be defined based on PSA alone or biopsy or RP specimen as follows: PSA greater than or equal to (>=) 20 ng/ml or; Gleason Score >= 9 in any core on biopsy or; Gleason Score >= 8 (4+4 or 5+3) in greater than (>) 80 percentage (%) of 2 cores on biopsy or; Gleason Score = 8 (4+4 or 5+3) in 1 core as long 5 or more other cores with minimum Gleason Score of 4+3 on biopsy. The determination of high risk may be based on pathology report of biopsy or equivalent criteria from radical prostatectomy

Exclusion Criteria:

• History or presence of soft tissue/bone metastasis or metastasis in distant lymph nodes (pelvic lymph nodes below the iliac bifurcation that are less than (<) 2 centimeter (cm) in diameter [short axis] either radiographically or pathologically are allowed.)

• History of bilateral orchiectomy

• Received an investigational intervention <= 4 weeks before the planned first dose of study intervention • History of seizure or any condition that in the opinion of the investigator may predispose to seizure or treatment with drugs known to lower the seizure threshold within 4 weeks prior to starting treatment with apalutamide

• Allergy or hypersensitivity to apalutamide, or excipients, unable or unwilling to take androgen deprivation therapy (ADT)

Results

Interim Results

The substudy enrolled 12 patients; 11 patients with median age of 68 years received at least one APA dose. Demographics for the substudy were as listed in Table 1. Testosterone levels were measured prior to the loading dose (first dose) of relugolix (Day -14), after two weeks of relugolix monotherapy (Day 0) and after 4 weeks of combined relugolix and apalutamide treatment (at Day 28), and are listed in Table 2 (median and range values) and Table 3 (mean (SD), median and range values). Eight out of eight patients had <50 ng/dL testosterone levels after 2 weeks of relugolix monotherapy. Seven patients who had Day 28 testosterone levels available were all able to maintain castrate testosterone levels without the need to dose-adjust relugolix.

Treatment-emergent adverse events (TEAEs) were reported in 8/11 (72.7%) patients during relugolix and in 7/11 (63.6%) patients during APA + relugolix treatment phases. The most common TEAE was hot flash occurring in 45.5% and 36.4% of patients treated with relugolix and APA + relugolix. No patients discontinued due to TEAE. The number of subjects with treatment-emergent adverse Events by system organ class, preferred term, and maximum toxicity grade during apalutamide and relugolix treatment phase are provided in Table 4. APA and relugolix safety profiles were consistent with known side effects of these drugs.

Table 1. Demographics - Safety Population _

Apalutamide + Relugolix

Analysis set: Safety population (received at least 1 APA dose) 11

Age, Years N 11

Mean (SD) 64.2 (8.75)

Median 68.0

Range (50; 74)

<65 5 (45.5%)

65-69 2 (18.2%)

70-74 4 (36.4%)

> 75 0 Table 1. Demographics - Safety Population _

Apalutamide + Relugolix

Race

N 11

Asian 2 (18.2%)

Black or African American 2 (18.2%)

White 7 (63.6%)

Ethnicity

N 11

Not Hispanic or Latino 11 (100.0%)

Safety population consists of subjects who received at least 1 Apalutamide dose.

Table 2. Summary of enrollment and Testosterone (ng/dL)

Table 3. Summary of Testosterone (ng/dL)

Apalutamide + Relugolix

Analysis set: Safety population (received at least 1 APA dose) 11

Sub-study Visit 1 (Day -14) Testosterone (ng/dL) N 11

Mean (SD) 377.42 (148.900)

Median 357.00

Range (182.0; 697.0)

Sub-study Visit 2 (Day 1, Baseline Visit) Testosterone (ng/dL) N 8

Mean (SD) 12.80 (8.574)

Median 11.20

Range (3.0; 26.0)

Sub-study Visit 3 (Day 28) Testosterone (ng/dL)

N 7

Mean (SD) 14.14 (9.822)

Median 12.00

Range (4.0; 35.0)

Safety population consists of subjects who received at least one apalutamide dose Table 4. Number of Subjects with Treatment-emergent Adverse Events by System Organ Class, Preferred Term, and Maximum Toxicity Grade During Apalutamide + Relugolix Treatment Phase - Safety Population _

_ Apalutamide + Relugolix _

Total 1 2 3 4

Analysis set: Safety population (received at least 1 APA dose) 11

Subjects with 1 or more TEAEs 7 (63.6%) 5 (45.5%) 1 (9.1%) 1 (9.1%)

System organ class

Preferred term

Vascular disorders 5 (45.5%) 4 (36.4%) 1 (9.1%) 0 0

Hot flush 4 (36.4%) 4 (36.4%) 0 0 0

Hypertension 1 (9.1%) 0 1 (9.1%) 0 0

Nervous system disorders 2 (18.2%) 1 (9.1%) 1 (9.1%) 0 0

Headache 1 (9.1%) 0 1 (9.1%) 0 0

Hypoaesthesia 1 (9.1%) 1 (9.1%) 0 0 0

Restless legs syndrome 1 (9.1%) 1 (9.1%) 0 0 0

Metabolism and nutrition disorders 1 (9.1%) 1 (9.1%) 0 0 0

Increased appetite 1 (9.1%) 1 (9.1%) 0 0 0

Musculoskeletal and connective tissue disorders 1 (9.1%) 1 (9.1%) 0 0 0

Back pain 1 (9.1%) 1 (9.1%) 0 0 0

Psychiatric disorders 1 (9.1%) 1 (9.1%) 0 0 0

Anxiety 1 (9.1%) 1 (9.1%) 0 0 0

Skin and subcutaneous tissue disorders 1 (9.1%) 0 0 1 (9.1%) 0

Rash 1 (9.1%) 0 0 1 (9.1%) 0

Note: Percentages are based on the Safety population (at least 1 Apalutamide dose recipients).

Note: Table does not include Grade 5 events.

Note: Treatment-emergent adverse events are those that occurred between Day 1 and Day 28.

Note: Subjects are counted only once for any given event, regardless of the number of times they actually experienced the event. The event experienced by the subject with the worst toxicity grade is used. If a subject has all adverse events with missing toxicity grades, the subject is only counted in the total column.

Note: Adverse events are coded using Medical Dictionary for Regulatory Activities Version 24.1.

Note: Toxicity grade is based on NCI common toxicity criteria, version 5.0.

Final Results At the final analysis, 12 patients enrolled in the sub-study (median age 68y) received > 1 apalutamide dose and achieved castrate testosterone levels after 2-week relugolix monotherapy (Table 5). Patients maintained castrate testosterone from Day 1 to the end of apalutamide and relugolix coadministration without dose -adjustment of relugolix. TEAEs were reported in 9 (75%) patients during the relugolix monotherapy phase and in 8 (67%) patients during the apalutamide and relugolix coadministration phase; hot flush occurred in 50% and 33% of patients, in the relugolix monotherapy and the apalutamide and relugolix coadministration phases respectively. No patients discontinued the sub-study due to TEAE. All sub-study patients continued on the main study.

Table 5. Testosterone in the APA-RP substudy.

It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the present description.

Claims

What is claimed:

1. A method for treating prostate cancer in a male human comprising administering apalutamide at a dose of about 30 mg per day to about 480 mg per day in combination with relugolix, to a male human in need of such treatment.

2. The method as in Claim 1, wherein administration of apalutamide in combination with relugolix results in maintenance of castrate levels of testosterone in said male human.

3. The method as in Claim 1 or 2, wherein said prostate cancer is localized prostate cancer at high risk for metastases.

4. The method Claims 1-3, wherein said male human received a radical prostatectomy prior to administration of apalutamide in combination with relugolix.

5. The method as in Claims 1-3, wherein said male human is a candidate for radical prostatectomy.

6. The method as in Claims 1-3, wherein said patient does not have a history of the presence of soft tissue/bone metastasis or metastasis in distant lymph nodes.

7. The method as in Claims 1-3, wherein said patient does not have bilateral orchiectomy.

8. The method as in Claims 1-7, wherein the apalutamide is administered daily to the male human.

9. The method as in Claims 1-8, wherein the apalutamide is administered orally to the male human.

10. The method as in Claims 1-9, wherein the apalutamide is administered orally to the male human on a continuous daily dosing schedule.

11. The method as in Claims 1-10, wherein the apalutamide is administered orally to the male human at a dose of about 60 mg per day to about 240 mg per day.

12. The method as in Claims 1-11, wherein the apalutamide is administered orally to the male human at a dose of about 240 mg per day.

13. The method as in Claims 1-12, wherein the apalutamide is administered orally to the male human at a dose of about 240 mg as a single dosage form or as four 60 mg dosage forms, administered simultaneously.

14. The method as in Claims 1-13, wherein the apalutamide is formulated as a solid dosage form.

15. The method as in Claims 1-14, wherein the apalutamide is formulated as a tablet.

16. The method as in Claims 1-15, wherein the relugolix is administered daily to the male human.

17. The method as in Claims 1-16, wherein the relugolix is administered orally to the male human.

18. The method as in Claim 1-77, wherein relugolix is administered at a loading dose of about 360 mg on Day One of treatment, followed by a dose of about 120 mg/day.

19. The method as in Claims 1-18, wherein relugolix is administered at a loading dose of about 360 mg on Day One of treatment, followed by a dose of about 120 mg/day for two weeks.

20. The method as in Claims 1-19, wherein administration of relugolix is administered at a loading dose of about 360 mg on Day One of treatment, followed by a daily dose of about 120 mg/day for two weeks, followed by co-administration of relugolix at a dose of about 120 mg/day and apalutamide at a dose of about 240 mg/day.

21. The method as in Claims 1-20, wherein the relugolix is formulated as a solid dosage form.

22. The method as in Claims 1-21, wherein the relugolix is formulated as a tablet.

23. The method as in Claims 1-22, wherein administration of relugolix results in castrate levels of testosterone in said male human.

24. The method as in Claims 1-23, wherein administration of apalutamide in combination with relugolix results in maintenance of castrate levels of testosterone in said male human.

25. A method of treating localized prostate cancer at high risk for metastases comprising administering to a male human in need of such treatment, relugolix in combination with apalutamide; wherein the relugolix is administered in an amount of about 120 mg/ day; wherein the apalutamide is administered in an amount in the range of from about 60 mg/day to about 240 mg/day; and wherein said treatment results in maintenance of castrate levels of testosterone in the male human.