Methods of treating prostate cancer with exicholant and enzalutamide

Abstract

A method for treating prostate cancer, including castration-resistant prostate cancer and metastatic castration-resistant prostate cancer, is disclosed, comprising administering an effective amount of an androgen receptor (AR) antagonist and an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM). The AR antagonist may be enzalutamide. The SGRM may be an octahydro-fused azadecalin compound, such as an exicholant having the structure ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone. The AR antagonist and the SGRM may be administered once a day or with food. The dose of enzalutamide may be 150 to 200 mg / day, for example, 160 mg / day, and the dose of exicholant may be 100 to 350 mg / day, for example, 240 mg / day, 280 mg / day, or 320 mg / day.

Description

[Technical Field]

[0001] The present disclosure relates to new methods of treating prostate cancer. [Background technology]

[0002] Prostate cancer is the most common solid tumor cancer and the second leading cause of cancer-related deaths in men in the United States. Because the growth and proliferation of prostate cancer is typically driven by androgens, treatment can involve androgen deprivation, which can include chemical means to reduce androgen levels, chemical means to reduce androgen activity (e.g., by inhibiting androgen binding to androgen receptors), and chemical means to reduce androgen production in patients. Such androgen deprivation therapy is referred to as "castration" (whether chemical castration or, if indicated, surgical castration). However, such treatments are not always successful, or initial success may not remain successful over time. Castration-resistant prostate cancer (CRPC) is a serious disease with a significant mortality rate, and in men whose tumors have spread (metastatic castration-resistant prostate cancer (mCRPC)), the disease remains incurable and fatal, although multiple classes of treatments are available that slow disease progression and extend lifespan. Prostate-specific antigen (PSA) is often used as an evaluation criterion for the activity of prostate tissue; high PSA level or rapidly increasing PSA level in patients can be a symptom of prostate cancer.If PSA level increases over time, the time it takes for PSA level to double (called "PSA doubling time") can be used as an indicator of the growth rate of prostate tumor, and can also be an indicator of prostate cancer metastasis.Therefore, a shorter PSA doubling time represents faster tumor growth than a longer PSA doubling time.An increase in PSA doubling time after treatment indicates that the treatment has a beneficial effect (for example, slowing down tumor growth or reducing the rate of metastasis).

[0003] Conventional treatment options for CRPC and mCRPC include androgen deprivation ("castration"), surgery (at least for primary tumors in the prostate), radiation therapy (also called "radiotherapy"), and chemotherapy. However, these treatments may not successfully treat the disease. Thus, there is a need for new and improved treatments for mCRPC. Summary of the Invention

[0004] The present disclosure provides a novel method for treating prostate cancer, including castration-resistant prostate cancer (CRPC), comprising administering a selective glucocorticoid receptor modulator (SGRM) to a patient receiving androgen receptor (AR) antagonist therapy. In one embodiment, the AR antagonist is enzalutamide. In one embodiment, the SGRM is exicholant. The present disclosure provides data from a Phase 1 study of 39 men with castration-resistant prostate cancer (CRPC) who were treated with a combination of enzalutamide and exicholant. Fourteen patients were enrolled in segment 1 of the study; 25 patients were enrolled in segment 2 of the study.

[0005] The SGRMs used in the clinical trials disclosed in this disclosure are non-steroidal compounds containing an octahydro-fused azadecalin structure called "exicholant" (also known as "CORT125281"). Exicholant has the structure [ka] The compound having the formula ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone is ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone. Numerous examples of octahydro-fused azadecalin structures and additional compounds having an octahydro-fused azadecalin structure (which may also be referred to as an "octahydro-fused azadecalin backbone") are described and disclosed in U.S. Patent 10,047,082, the contents of which are incorporated by reference in their entirety into this disclosure.

[0006] Without being bound by theory, it is hypothesized that blocking an important tumor escape pathway by treating with an SGRM in combination with the androgen receptor (AR) antagonist enzalutamide may benefit patients with mCRPC through dual antagonism of GR and AR receptors. This was the first study to evaluate the safety, PK, PD, and preliminary efficacy of exicholant in combination with enzalutamide in patients with CRPC.

[0007] Increases in PSA doubling time were seen in more than 50% of patients receiving daily dosing under fed conditions, indicating that treatment had a beneficial effect in more than 50% of treated patients. Although baseline 24-hour urinary free cortisol (UFC) values ​​for most patients were within the normal range, improvements in PSA trajectory after treatment with exicholant in combination with enzalutamide were predominantly seen in patients with baseline UFC levels greater than 17.5 μg / 24 hours (P<0.05).

[0008] The most frequently reported treatment-emergent adverse event (TEAE) assessed as being related to exicholant was fatigue. No grade 4 or grade 5 exicholant-related TEAEs were reported in this study. No clinically significant changes in exposure to enzalutamide or its active metabolite, N-desmethylenzalutamide, were observed when given in combination with exicholant compared with when enzalutamide was administered alone. Modulation of GR target genes was observed in patients receiving exicholant. These modulated GR target genes were the same genes that were suppressed in ovarian cancer patients treated with relaxant, another SGRM. [Brief explanation of the drawings]

[0009] [Figure 1] Figure 1 shows the results of administration of exicholant (left) and exicholant plus enzalutamide (right) on prostate cancer growth in a mouse xenograft model (murine 22Rv1 prostate cancer xenograft). Left: N = 10 mice / group. Castration was performed 5 days after 22Rv1 tumor cell inoculation; exicholant treatment began on day 6 and continued for 21 days. Right: N = 10 mice / group. Castration was performed 3 days before 22Rv1 tumor cell implantation; exicholant treatment began on day 7 and continued for 21 days.

[0010] [Figure 2A] Figure 2A shows a schematic illustration of the clinical trial design. In the figure, "BID" stands for two doses per day; "QD" stands for one dose per day; "DRC" stands for Data Review Committee; and "CORT125281" is another name for exicholant. (Study CORT125281-601 is titled "A Study Evaluating CORT125281 in Combination with Enzalutamide in Patients with mCRPC" and has ClinicalTrials.gov identification number NCT03437941.)

[0011] [Figure 2B] Figure 2B shows a schematic illustration of the Segment 2 clinical trial design. Segment 2 of the study was a double-blind, placebo-controlled phase in patients with rising PSA, in which 25 patients were enrolled and randomized 3:1 to Arm A and Arm B.

[0012] [Figure 3] Figure 3 provides a table listing demographic information about patients enrolled in the study.

[0013] [Figure 4A] FIG. 4A shows the pharmacokinetic results of exicholant in prostate cancer patients receiving enzalutamide and exicholant.

[0014] [Figure 4B] FIG. 4B shows that neither ACTH nor cortisol levels are significantly elevated in prostate cancer patients receiving exicholant and enzalutamide.

[0015] [Figure 5] FIG. 5 shows CDKN1C expression levels in prostate cancer patients receiving enzalutamide and exicholant at baseline and after 2 weeks of 249 milligrams (mg) of exicholant.

[0016] [Figure 6] Figure 6 shows the expression levels of selected genes in fasting patients receiving exicholant and enzalutamide BID without food (Segment 1, shown in the leftmost graph), and in patients receiving exicholant and enzalutamide twice daily (BID) with food (Segment 2, the subsequent three graphs in the figure).

[0017] [Figure 7A]Figure 7A shows baseline urinary free cortisol (UFC) and prostate-specific antigen (PSA) levels in patients receiving exicholant (EXI) and enzalutamide (ENZA). The leftmost column in the figure answers the yes or no question, "Did your PSA doubling time increase on or after day 1 of cycle 1 (C1D1)?"; the center column answers the yes or no question, "Did your PSA doubling time increase on or after day 1 of cycle 2 (C2D1)?"; and the rightmost column answers the yes or no question, "Did your PSA doubling time increase on or after day 1 of cycle 3 (C3D1)?". Compared with patients with lower baseline UFC levels, patients with higher baseline UFC levels (greater than 17.5 μg / 24 h) were more likely to experience an increase in PSA doubling time.

[0018] [Figure 7B] Figure 7B shows 24-hour urinary free cortisol (UFC) levels measured in patients after receiving the indicated daily doses of exicholilant. Exicholilant administration did not increase UFC levels. Data were obtained from Segment 2 subjects who received titrated exicholilant doses to the doses indicated on the horizontal axis. The 24-hour UFC reference range was 10 to 200 μg / day. The 24-hour UFC values ​​for C1D1 (Cycle 1, Day 1) represent initial 24-hour UFC levels.

[0019] [Figure 8A] Figure 8A depicts best overall response and progression-free survival for patients receiving exicolant and enzalutamide.

[0020] [Figure 8B] FIG. 8B shows the decrease in prostate-specific antigen (PSA) compared to baseline PSA measurements.

[0021] [Figure 8C]Figure 8C shows the decrease in prostate-specific antigen (PSA) at various time points during treatment. The lines labeled "purple" are the darker lines in the figure. DETAILED DESCRIPTION OF THE INVENTION

[0022] ●A.Introduction The methods disclosed herein can be used to treat patients suffering from prostate cancer by administering an effective amount of a glucocorticoid receptor modulator (GRM), preferably a selective glucocorticoid receptor modulator (SGRM), in combination with an androgen receptor antagonist effective in treating the cancer. In one embodiment, the prostate cancer is castration-resistant prostate cancer. In one embodiment, the prostate cancer is metastatic prostate cancer, and may be metastatic castration-resistant prostate cancer (mCRPC). In a preferred embodiment, the SGRM is a non-steroidal SGRM, for example, a non-steroidal SGRM having an octahydro-fused azadecalin structure. In one embodiment, the non-steroidal SGRM having an octahydro-fused azadecalin structure is an exicholant, which has the structure [ka] The compound having the formula ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone is a competitive, reversible, full GR antagonist (Ki<1 nM in human GR binding and K<15 nM in human GR functional assays) that is selective for the GR over the ER and AR. A suitable dose of exicholant in combination with an AR antagonist such as enzalutamide may be from about 40 milligrams (mg) per day (mg / day) to about 720 mg / day, e.g., from about 200 mg / day (mg / day) to about 350 mg / day; for example, a suitable dose of exicholant for administration in combination with enzalutamide is 240 mg / day.

[0023] In one embodiment, the androgen receptor (AR) antagonist is enzalutamide (also known as Xtandi®). A suitable dose of enzalutamide in combination with an exicholant can be about 150 mg / day to about 200 mg / day; for example, a suitable dose of enzalutamide for administration in combination with an exicholant is 160 mg / day.

[0024] In a mouse xenograft model, exicholant in combination with castration significantly reduced tumor growth compared to castration alone.In a mouse xenograft model, exicholant in combination with enzalutamide significantly reduced tumor growth compared to enzalutamide alone.

[0025] Androgen receptor (AR) signaling is a key driver of tumor growth in mCRPC, and AR-targeted therapy is administered to many patients with locally advanced or metastatic disease. The androgen receptor (AR) antagonist enzalutamide is commonly used for such treatment, but resistance to enzalutamide typically develops within 6 to 12 months. The glucocorticoid receptor (GR) can provide a tumor escape pathway following antiandrogen therapy. Therefore, GR expression in prostate cancer is associated with poor clinical outcomes. In this disclosure, Applicant presents the results of a clinical trial designed to test the hypothesis that combined administration of an SGRM and an AR antagonist may block this escape pathway through dual antagonism of GR and AR, thereby benefiting patients. In this study, patients with mCRPC were treated with an SGRM exicholant in combination with the AR antagonist enzalutamide.

[0026] ●B definition As used in this disclosure, the terms "tumor" and "cancer" are used interchangeably and both refer to an abnormal growth of tissue resulting from excessive cell division. Tumors that are capable of invading surrounding tissue and / or metastasizing are called "malignant."

[0027] As used in this disclosure, the term "patient" refers to a human who is receiving, will be receiving, or has received medical care for a disease or condition.

[0028] As used in this disclosure, the terms "administer," "administering," "administered," or "administration" refer to giving a compound or composition (e.g., those described in this disclosure) to a subject or patient. For example, the compound or composition may be administered to the patient orally.

[0029] As used in this disclosure, the term "effective amount" or "therapeutic amount" refers to an amount of a pharmacological agent effective to treat, eliminate, or mitigate at least one symptom of the disease being treated. In some cases, a "therapeutically effective amount" or "effective amount" can refer to an amount of a functional agent or an amount of a pharmaceutical composition useful for exhibiting a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The effective amount can be an amount effective to elicit an anti-tumor response. For purposes of this disclosure, an effective amount of an SGRM or an effective amount of an androgen receptor antagonist, respectively, is an amount that, when combined with an androgen receptor antagonist or an SGRM, will result in a reduction in tumor burden or other desired beneficial clinical outcome related to cancer improvement.

[0030] As used in this disclosure, the term "combination therapy" refers to the administration of two or more pharmaceutical agents to a subject to treat a disease. The two agents may be administered simultaneously or sequentially in any order for all or part of the treatment period. The at least two agents may be administered according to the same or different dosing regimens. In some cases, one agent is administered according to a scheduled regimen, and the other agent is administered intermittently. In some cases, both agents are administered intermittently. In some cases, one pharmaceutical agent, e.g., an SGRM, is administered daily, and the other pharmaceutical agent, e.g., an androgen receptor antagonist, is administered every two, three, or four days.

[0031] As used in this disclosure, the term "compound" is used to refer to a molecular moiety of a unique, identifiable chemical structure. A molecular moiety ("compound") may exist in the form of a free species, with no other molecules associated with it. A compound may also exist as part of a larger aggregate, where the compound is associated with other molecules but still maintains its chemical identity. A solute in which a molecular moiety of a defined chemical structure ("compound") has associated molecules of a solvent is an example of such an associated form. A hydrate is a solute in which the associated solvent is water. A reference to a "compound" refers to the molecular moiety itself (of the described structure), regardless of whether it exists in free or associated form.

[0032] As used in this disclosure, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the compositions is contemplated. Supplementary active compounds can also be included in the compositions.

[0033] The term "glucocorticosteroid" ("GC") or "glucocorticoid" refers to a steroid hormone that binds to the glucocorticoid receptor. Glucocorticosteroids typically have 21 carbon atoms and are characterized by an α,β-unsaturated ketone in ring A and an α-ketol group in ring D. They differ from each other in the degree of oxygenation or hydroxylation at C-11, C-17, and C-19; see Rawn, "Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives," in Biochemistry, Daisy et al. (eds.), 1989, pg. 567.

[0034] The mineralocorticoid receptor (MR), also known as the type I glucocorticoid receptor (GRI), is activated by aldosterone in humans.

[0035] As used in this disclosure, the term "glucocorticoid receptor (GR)" refers to type II GR, a family of intracellular receptors that specifically bind cortisol and / or cortisol analogs such as dexamethasone (see, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292). Glucocorticoid receptors are also called cortisol receptors. This term includes GR isoforms, recombinant GRs, and mutated GRs.

[0036] The term "glucocorticoid receptor modulator" (GRM) refers to any compound that modulates the binding of GC to GR or modulates any biological response associated with the binding of GR to an agonist. For example, GRM acting as an agonist, such as dexamethasone, increases the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human liver hepatocellular carcinoma cell line; ECACC, UK). GRM acting as an antagonist reduces the activity of tyrosine aminotransferase (TAT) in HepG2 cells. TAT activity can be measured as outlined in A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452.

[0037] As used in this disclosure, the term "selective glucocorticoid receptor modulator (SGRM)" refers to any composition or compound that modulates the binding of GC to GR or modulates any biological response associated with the binding of GR to an agonist. "Selective" refers to the drug preferentially binding to GR over other nuclear receptors, such as the progesterone receptor (PR), mineralocorticoid receptor (MR), or androgen receptor (AR). Preferably, a selective glucocorticoid receptor modulator binds to GR with an affinity that is 10-fold greater (Kd value 1 / 10) than its affinity to MR, AR, or PR, or to both MR and PR, or to both MR and AR, or to both AR and PR, or to MR, AR, and PR. In a more preferred embodiment, the selective glucocorticoid receptor modulator binds to GR with an affinity that is 100-fold greater (100-fold greater Kd) than its affinity for MR, AR, or PR, than its affinity for both MR and PR, than its affinity for both MR and AR, than its affinity for both AR and PR, or than its affinity for MR, AR, and PR. In other certain embodiments, the selective glucocorticoid receptor modulator binds to GR with an affinity that is 1000-fold greater (1000-fold greater Kd) than its affinity for MR, AR, or PR, than its affinity for both MR and PR, than its affinity for both MR and AR, than its affinity for both AR and PR, or than its affinity for MR, AR, and PR. A relacorilant is an SGRM.

[0038] "Glucocorticoid receptor antagonist (GRA)" refers to any compound that inhibits the binding of GC to GR or inhibits any biological response associated with the binding of GR to an agonist. Thus, GR antagonists can be identified by measuring the ability of a compound to inhibit the effect of dexamethasone. TAT activity can be measured as outlined in A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. GRA is a ... 50(half maximal inhibition concentration) of less than 10 micromolar. See Example 1 of U.S. Pat. No. 8,859,774, which is incorporated herein by reference in its entirety.

[0039] As used in this disclosure, the term "selective glucocorticoid receptor antagonist (SGRA)" refers to any composition or compound that inhibits the binding of GC to GR or inhibits any biological response associated with the binding of GR to an agonist (wherein inhibition is determined relative to the response in the absence of the compound). "Selective" refers to the drug preferentially binding to GR over other nuclear receptors, such as the progesterone receptor (PR), mineralocorticoid receptor (MR), or androgen receptor (AR). Preferably, a selective glucocorticoid receptor modulator binds to GR with an affinity that is 10-fold greater (Kd value 1 / 10) than its affinity to MR, AR, or PR, or to both MR and PR, or to both MR and AR, or to both AR and PR, or to MR, AR, and PR. In a more preferred embodiment, the selective glucocorticoid receptor modulator binds to GR with an affinity that is 100-fold greater (100-fold greater Kd) than its affinity for MR, AR, or PR, than its affinity for both MR and PR, than its affinity for both MR and AR, than its affinity for both AR and PR, or than its affinity for MR, AR, and PR. In other certain embodiments, the selective glucocorticoid receptor modulator binds to GR with an affinity that is 1000-fold greater (1000-fold greater Kd) than its affinity for MR, AR, or PR, than its affinity for both MR and PR, than its affinity for both MR and AR, than its affinity for both AR and PR, or than its affinity for MR, AR, and PR. A relacorilant is an SGRM.

[0040] Non-steroidal GRA, SGRA, GRM, and SGRM compounds include compounds containing a fused azadecalin structure (which can also be referred to as a fused azadecalin backbone), compounds containing a heteroaryl-ketone fused azadecalin structure (which can also be referred to as a heteroaryl-ketone fused azadecalin backbone), compounds containing an octahydro-fused azadecalin structure (which can also be referred to as an octahydro-fused azadecalin backbone), and compounds containing a pyrimidine cyclohexyl backbone.

[0041] Exemplary non-steroidal GRA compounds, SGRA compounds, GRM compounds, and SGRM compounds containing a fused azadecalin structure include those described in U.S. Patent No. 7,928,237 and U.S. Patent No. 8,461,172. Exemplary non-steroidal GRA compounds, SGRA compounds, GRM compounds, and SGRM compounds containing a heteroaryl-ketone fused azadecalin structure include those described in U.S. Patent No. 8,859,774. Exemplary non-steroidal GRA compounds, SGRA compounds, GRM compounds, and SGRM compounds containing an octahydro-fused azadecalin structure include those described in U.S. Patent No. 10,047,082. Exemplary non-steroidal GRA compounds, SGRA compounds, GRM compounds, and SGRM compounds containing a pyrimidine cyclohexyl backbone include those disclosed in U.S. Patent No. 8,685,973. All patents, patent publications, and patent applications disclosed in this disclosure are incorporated herein by reference in their entireties.

[0042] Exemplary glucocorticoid receptor antagonists comprising an octahydrofused azadecalin structure include those described in U.S. Patent No. 10,047,082. In one embodiment, the octahydrofused azadecalin has the formula [ka] or salts and isomers thereof, wherein: R 1 is R 1a is selected from the group consisting of pyridine and thiazole, each optionally substituted with 1 to 4 groups independently selected from Each R 1a are independently hydrogen, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, N-oxide, and C 3~8 cycloalkyl; Ring J is selected from the group consisting of phenyl, pyridine, pyrazole, and triazole; Each R 2 are independently hydrogen, C 1~6 Alkyl, halogen, C 1~6 selected from the group consisting of haloalkyl, and -CN; R 3a is F, The subscript n is an integer from 0 to 3. In certain embodiments, the octahydro-fused azadecalin compound is the compound ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (also known as “exicholant” or “CORT125281”), having the structure [ka] It has.

[0043] In one embodiment, the GRM is a non-steroidal octahydro-fused azadecalin GRM compound having the chemical name ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazolol-2-yl)methanone, designated "CORT125329," and having the formula [ka] It has.

[0044] As used in this disclosure, the term "composition" is intended to encompass products containing specified ingredients in specified amounts, such as the compound, its tautomeric forms, derivatives, analogs, stereoisomers, polymorphs, deuterated species, pharmaceutically acceptable salts, esters, ethers, metabolites, mixtures of isomers, pharmaceutically acceptable solvates, and pharmaceutically acceptable compositions, as well as any product resulting directly or indirectly from the combination of specified ingredients in specified amounts. The term pharmaceutical composition is intended to encompass products containing an active ingredient(s) and an inactive ingredient(s) that constitute the carrier, as well as any product resulting directly or indirectly from the combination, complexation, or aggregation of any two or more of the ingredients, or any product resulting from the dissociation of one or more of the ingredients or any product resulting from any other type of reaction or interaction of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention are intended to encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

[0045] In some embodiments, the term "consisting essentially of" refers to a composition in a formulation in which the only active ingredient is a recited active ingredient, but may include other compounds that stabilize, preserve, etc. the formulation but are not directly involved in the therapeutic effect of the recited active ingredient. In some embodiments, the term "consisting essentially of" can refer to a composition that includes an active ingredient and an ingredient that facilitates release of the active ingredient. For example, a composition may include one or more ingredients that provide extended release of the active ingredient to a subject over time. In some embodiments, the term "consisting essentially of" refers to a composition that includes an active ingredient and a pharmaceutically acceptable carrier or excipient.

[0046] As used in this disclosure, "ECOG" refers to the Eastern Cooperative Oncology Group Performance score, which is an index of a patient's status (e.g., ability to care for themselves, daily activities, physical performance, etc.). A score of 0 indicates perfect health, a score of 5 indicates the patient has died, and intermediate scores indicate levels between these extremes.

[0047] C. Pharmaceutical Compositions and Administration In one embodiment, the present invention provides a pharmaceutical composition for treating prostate cancer, the pharmaceutical composition comprising a pharmaceutically acceptable excipient and an octahydro-fused azadecalin GRM. In one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable excipient and an exicholant. In one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable excipient and CORT125329.

[0048] In some embodiments, the pharmaceutical composition can be administered orally. For example, the GRM or SGRM can be administered as a pill, capsule, or liquid formulation described herein. Alternatively, the GRM can be given parenterally. For example, the GRM can be administered intravenously (by injection or infusion). Additional methods of administering the compounds described herein, as well as pharmaceutical compositions or formulations thereof, are described herein.

[0049] The pharmaceutical compositions can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by a patient. In some embodiments, the pharmaceutical compositions can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. In some embodiments, the pharmaceutical compositions can be administered by inhalation, for example, intranasally. In some embodiments, the pharmaceutical compositions can be administered transdermally.

[0050] For preparing pharmaceutical compositions from GRMs and SGRMs, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating material. Details of techniques for formulation and administration are well described in the scientific and patent literature. See, for example, the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton PA ("Remington's").

[0051] In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient, i.e., GRM or SGRM. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0052] The powders and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "preparation" is intended to include formulations of the active compound with an encapsulating agent as a carrier, which provides a capsule in which the active ingredient is surrounded by the carrier, with or without other carriers, and thus the carrier is in association with the active ingredient. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can also be used as solid dosage forms suitable for oral administration.

[0053] Suitable solid excipients are carbohydrate or protein fillers, including, but not limited to, sugars such as lactose, sucrose, mannitol, or sorbitol; starches derived from corn, wheat, rice, potato, or other plants; celluloses such as methylcellulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose; gums such as gum arabic and gum tragacanth; and proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, examples of which include cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0054] Dragee cores may be provided with a suitable coating, such as a concentrated sugar solution, which may also include gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quality of the active compound (i.e., dosage). The pharmaceutical preparations of the present invention may also be used orally, for example, in push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules may contain the GR modulator mixed with a filler or binder, such as lactose or starch, a lubricant, such as talc or magnesium stearate, and optionally, a stabilizer. In soft capsules, the GR modulator compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.

[0055] Liquid preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be prepared in solution in aqueous polyethylene glycol solution.

[0056] Aqueous solutions suitable for oral use (including GRMS and SGRMS that are water soluble) can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents, as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water containing a viscous material such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, and a dispersing or wetting agent such as a natural phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long-chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol monooleate), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The said aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, aspartame, or saccharin. The preparations may be adjusted for osmolality.

[0057] Also included are solid preparations, which are intended to be converted shortly before use into oral liquid preparations. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0058] Oil suspensions can be made by suspending the SGRM in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin, or a mixture thereof. Oil suspensions can contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners such as glycerol, sorbitol, or sucrose can be added to render the oral preparation palatable. These formulations can be preserved by adding an antioxidant such as ascorbic acid. For examples of injectable oil vehicles, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations of the present invention can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil or a mineral oil, as described above, or a combination thereof. Suitable emulsifiers include natural gums such as gum acacia and gum tragacanth, natural phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitol monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweeteners and flavoring agents, as in the preparation of syrups and elixirs. Such preparations may also contain demulcents, preservatives, or coloring agents.

[0059] GRMs and SGRMs can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols and delivered transdermally and topically.

[0060] GRMs and SGRMs can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres for subcutaneous slow release (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995), as biodegradable injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995), or as oral microspheres (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routes provide consistent delivery over weeks or months.

[0061] Pharmaceutical formulations of the invention for salt-forming GRMSs and SGRMs can be provided as salts and can be formed with a number of acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. In other cases, the preparations may be lyophilized powders in 1 mM to 50 mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol, at a pH range of 4.5 to 5.5, and combined with a buffer prior to use.

[0062] In other embodiments, the formulations of the present invention can be delivered using liposomes that fuse with the cell membrane or are endocytosed, i.e., by using a ligand attached to the liposome or directly attached to the oligonucleotide that binds to a cell surface membrane protein receptor and causes endocytosis. The use of liposomes can concentrate the delivery of GR modulators into target cells in vivo, especially when the liposome surface carries a ligand specific to the target cell or otherwise directed preferentially to a particular organ (see, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

[0063] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient GRM or SGRM. The unit dosage form may be a packaged preparation, the package containing discrete amounts of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0064] The amount of active ingredient in a unit dosage preparation may be varied or adjusted from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 6,000 mg, and most typically from 50 mg to 500 mg. Depending on the particular application and the potency of the active ingredient, suitable dosages include about 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg. If desired, the composition may also contain other compatible therapeutic agents.

[0065] The pharmaceutical preparations are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the compounds and compositions of the present invention. The unit dosage form may be a packaged preparation, the package containing discrete amounts of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0066] In some embodiments, the GRM is administered in one dose. In other embodiments, the GRM is administered in more than one dose, for example, two doses, three doses, four doses, five doses, six doses, seven doses, or more doses. In some embodiments, each dose is an equivalent amount. In other cases, each dose is a different amount. The dose may increase or decrease over the period of administration. The amount will vary depending, for example, on the nature of the GRM and patient characteristics.

[0067] Any suitable GRM dose may be used in the methods disclosed in the present disclosure. The administered dose of GRM may be about 300 milligrams (mg) or more per day, or about 600 mg / day or more, such as about 600 mg / day, about 700 mg / day, about 800 mg / day, about 900 mg / day, about 1000 mg / day, about 1100 mg / day, about 1200 mg / day, or more. For example, if the GRA is mifepristone, the GRM dose may be, for example, 300 mg / day, about 600 mg / day, or 900 mg / day, or 1200 mg / day of mifepristone. In some embodiments, the GRM is administered orally. In some embodiments, the GRM is administered in one or more doses. In other words, the GRM can be administered in one, two, three, four, five, six, seven, eight, nine, ten, or more doses. In one embodiment, the GRM is administered orally in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses.

[0068] A subject may be administered at least one dose of GRM, in one or more doses, for example, over a 2-48 hour period. In some embodiments, the GRM is administered as a single dose. In other embodiments, the GRM is administered more than one dose, for example, two, three, four, five, or more doses, over a 2-48 hour period, for example, a 2 hour period, a 3 hour period, a 4 hour period, a 5 hour period, a 6 hour period, a 7 hour period, a 8 hour period, a 9 hour period, a 10 hour period, a 11 hour period, a 12 hour period, a 14 hour period, a 16 hour period, a 18 hour period, a 20 hour period, a 22 hour period, a 24 hour period, a 26 hour period, a 28 hour period, a 30 hour period, a 32 hour period, a 34 hour period, a 36 hour period, a 38 hour period, a 40 hour period, a 42 hour period, a 44 hour period, a 46 hour period, or a 48 hour period. In some embodiments, the GRM is administered over 2 to 48 hours, 2 to 36 hours, 2 to 24 hours, 2 to 12 hours, 2 to 8 hours, 8 to 12 hours, 8 to 24 hours, 8 to 36 hours, 8 to 48 hours, 9 to 36 hours, 9 to 24 hours, 9 to 20 hours, 9 to 12 hours, 12 to 48 hours, 12 to 36 hours, 12 to 24 hours, 18 to 48 hours, 18 to 36 hours, 18 to 24 hours, 24 to 36 hours, 24 to 48 hours, 36 to 48 hours, or 42 to 48 hours.

[0069] Single or multiple administrations of the formulation can be used, depending on the dosage and frequency required and tolerated by the patient. The formulation should provide a sufficient amount of active agent to effectively treat the condition. Thus, in one embodiment, the pharmaceutical formulation for oral administration of GRM has a daily dose of about 0.01 to about 150 mg per kilogram of body weight per day (mg / kg / day). In some embodiments, the daily dose is about 1.0 to 100 mg / kg / day, 5 to 50 mg / kg / day, 10 to 30 mg / kg / day, and 10 to 20 mg / kg / day. Lower dosages can also be used, particularly when the agent is administered to an anatomically isolated site, such as the cerebrospinal fluid (CSF) space, rather than orally, into a blood vessel, a body cavity, or the lumen of an organ. Substantially higher dosages can be used for local administration. Actual methods for preparing parenterally administrable formulations will be known or apparent to those skilled in the art and are described in more detail in publications such as Remington's, supra. See also Nieman, In "Receptor Mediated Antisteroid Action," Agarwal, et al., eds., De Gruyter, New York (1987).

[0070] The duration of treatment with a GRM or SGRM to treat prostate cancer can vary depending on the severity of the condition in the subject and the subject's response to the GRM or SGRM. In some embodiments, the GRM or SGRM may be administered for a period of about 1 week to 104 weeks (2 years), more typically about 6 weeks to about 80 weeks, and most typically about 9 weeks to 60 weeks. Suitable periods of administration also include 5 to 9 weeks, 5 to 16 weeks, 9 to 16 weeks, 16 to 24 weeks, 16 to 32 weeks, 24 to 32 weeks, 24 to 48 weeks, 32 to 48 weeks, 32 to 52 weeks, 48 ​​to 52 weeks, 48 ​​to 64 weeks, 52 to 64 weeks, 52 to 72 weeks, 64 to 72 weeks, 64 to 80 weeks, 72 to 80 weeks, 72 to 88 weeks, 80 to 88 weeks, 80 to 96 weeks, 88 to 96 weeks, and 96 to 104 weeks. Suitable periods of administration also include 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 24 weeks, 25 weeks, 30 weeks, 32 weeks, 35 weeks, 40 weeks, 45 weeks, 48 ​​weeks, 50 weeks, 52 weeks, 55 weeks, 60 weeks, 64 weeks, 65 weeks, 68 weeks, 70 weeks, 72 weeks, 75 weeks, 80 weeks, 85 weeks, 88 weeks, 90 weeks, 95 weeks, 96 weeks, 100 weeks, and 104 weeks. Generally, administration of a GRM or SGRM should continue until a clinically significant reduction or amelioration is observed. Treatment with a GRM or SGRM according to the present invention may continue for as long as 2 years or even longer.

[0071] In some embodiments, administration of the GRM or SGRM is not continuous, but may be suspended for one or more periods followed by one or more periods when administration is resumed. Suitable periods for suspension of administration include 5 to 9 weeks, 5 to 16 weeks, 9 to 16 weeks, 16 to 24 weeks, 16 to 32 weeks, 24 to 32 weeks, 24 to 48 weeks, 32 to 48 weeks, 32 to 52 weeks, 48 ​​to 52 weeks, 48 ​​to 64 weeks, 52 to 64 weeks, 52 to 72 weeks, 64 to 72 weeks, 64 to 80 weeks, 72 to 80 weeks, 72 to 88 weeks, 80 to 88 weeks, 80 to 96 weeks, 88 to 96 weeks, and 96 to 100 weeks. Suitable periods for which administration is discontinued also include 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 24 weeks, 25 weeks, 30 weeks, 32 weeks, 35 weeks, 40 weeks, 45 weeks, 48 ​​weeks, 50 weeks, 52 weeks, 55 weeks, 60 weeks, 64 weeks, 65 weeks, 68 weeks, 70 weeks, 72 weeks, 75 weeks, 80 weeks, 85 weeks, 88 weeks, 90 weeks, 95 weeks, 96 weeks, and 100 weeks.

[0072] Dosage regimens take into account pharmacokinetic parameters well known in the art, such as absorption rate, bioavailability, metabolism, clearance, etc. (See Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108; latest edition of Remington's, supra). The state of the art allows the clinician to determine the dosage regimen for each individual patient, GR modulator, and disease or condition being treated.

[0073] In some embodiments, co-administration includes administering one active agent, a GRM or SGRM, within 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, or 24 hours of a second active agent, such as an androgen receptor antagonist (e.g., enzalutamide). Co-administration encompasses administering two active agents simultaneously, approximately simultaneously (e.g., within about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents are formulated separately. In other embodiments, the active agents and / or adjunct agents may be linked or conjugated to each other.

[0074] After a pharmaceutical composition containing a GRM or SGRM is formulated in an acceptable carrier, it may be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of a GRM or SGRM, such labeling would include, for example, instructions regarding the amount, frequency, and method of administration.

[0075] D. Combination therapy Various combinations of a GRM or SGRM and an androgen receptor antagonist may be used to reduce tumor burden in prostate cancer patients. The terms "combination therapy" or "in combination with" do not imply that the therapeutic agents must be formulated to be administered simultaneously and / or delivered together, although such delivery methods are within the scope described in this disclosure. The GRM or SGRM and the androgen receptor antagonist can be administered according to the same or different dosing regimens. In some embodiments, the GRM or SGRM and the androgen receptor antagonist are administered sequentially in any order for all or part of the treatment period. In some embodiments, the GRM or SGRM and the anticancer agent are administered simultaneously or approximately simultaneously (e.g., within 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, or 1 hour of each other). Non-limiting examples of combination therapy are as follows, where, for example, for administration of a GRM or SGRM and an androgen receptor antagonist, the GRM or SGRM is "A" and the androgen receptor antagonist is "B."

[0076] A / B / AB / A / BB / B / AA / A / BA / B / BB / A / AA / B / B / BB / A / B / B

[0077] B / B / B / AB / B / A / BA / A / B / B A / B / A / B / A / B / B / A / B / B / A / A

[0078] B / A / B / AB / A / A / BA / A / A / BB / A / A / A A / B / A / AA / A / B / A

[0079] Administration of therapeutic compounds or agents to patients will follow standard protocols for the administration of such compounds, taking into account the toxicity, if any, of the treatment. Surgical intervention may also be applied in combination with the described treatments.

[0080] The method may be combined with other therapeutic modalities such as surgery, radiation, targeted therapy, immunotherapy, the use of growth factor inhibitors, or anti-angiogenic factors.

[0081] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings of this invention that certain changes and modifications can be made thereto without departing from the spirit or scope of the appended claims. [Example]

[0082] The following examples are offered by way of illustration only, and not by way of limitation. Those of skill in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results. <Example>

[0083] This study is investigating the safety and efficacy of exicolilant when administered in combination with enzalutamide in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). The study will help evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of exicolilant and the dose of exicolilant administered in combination with enzalutamide. Patients with histologically confirmed prostate cancer who had received at least two prior cytotoxic chemotherapy regimens were eligible for this study.

[0084] Patients with mCRPC or mCRPC with rising prostate-specific antigen (PSA; 25% increase above nadir, absolute value >1 ng / mL) were treated with both exicholant and enzalutamide (exicholant + enzalutamide) until the patient experienced disease progression, unmanageable toxicity, or other discontinuation criteria.

[0085] Figures 2A and 2B provide a schematic illustration of the test protocol. As shown in Figure 2A: Segment 1 of the study was an open-label design evaluating twice-daily dosing of exicholant. Patients received either exicholant 180 mg twice daily (BID) plus enzalutamide 160 mg once daily (QD), or exicholant 140 mg BID plus enzalutamide 160 mg QD with a 28-day enzalutamide lead-in, or exicholant 140 mg BID plus enzalutamide 160 mg QD without an enzalutamide lead-in. Segment 2 evaluated QD exicholant in a double-blind design, enrolling patients receiving a stable dose of enzalutamide with a rising PSA (25% increase from nadir, absolute value >1 ng / mL). All Segment 2 patients were randomized 3:1 to receive exicholant 240 mg QD plus enzalutamide, titrated to 280 mg or 320 mg exicholant, or placebo.

[0086] As discussed in more detail below, 14 and 25 patients were enrolled in Segments 1 and 2, respectively, and 37 patients received at least one dose of exicholant. The most common exicholant-related adverse events (AEs) included fatigue (57%), back pain (35%), decreased appetite (27%), and pain in extremity (22%). Dose-limiting fatigue, musculoskeletal pain, and pancreatitis were observed in Segment 1. The phase 2 regimen was selected, for which fatigue and / or leg / extremity pain consistent with neuropathy were the most common adverse events. Other adverse events observed in Segment 2 included increased lipase, hypophosphatemia, increased AST / ALT / GGT, back pain, and vomiting. There was a large overlap in exicholant exposure across dose levels in Segment 2. Enzalutamide exposure in combination with exicholant was consistent with historical data for enzalutamide 160 mg alone; no clinically relevant changes in exposure of enzalutamide or its active metabolite were observed. No clinically relevant changes in enzalutamide exposure were observed when given with exicholant.

[0087] Exicholant administration schedule Patients in segment 1 of the study received exicholant twice daily in the fasted state. This segment of the study was conducted in a standard "3 + 3" design, which included one cohort with an enzalutamide-only lead-in. Enzalutamide was administered once daily.

[0088] Patients in segment 2 of the study received exicholant once daily in a fed state. This segment of the study was double-blind and patients were randomized 3:1 to receive exicholant titration (starting at 240 mg, titrated to 280 mg as tolerated starting on day 16 of cycle 1, and then to 320 mg every 2 weeks) or to remain on 240 mg exicholant plus placebo. Enzalutamide was administered once daily.

[0089] Baseline demographics of patients enrolled in the study are shown in Figure 3.

[0090] Overall safety results for this study are shown in Table 1, which shows treatment-emergent adverse events (TEAEs) reported in >10% of patients and Grade 3 TEAEs reported in two or more subjects, regardless of causality. TEAEs seen in patients treated with exicholant plus enzalutamide overlap with the established adverse event profile of enzalutamide alone. There were no Grade 5 adverse events (AEs) and only one Grade 4 AE (sepsis, an unrelated AE). (Exicholant-related TEAEs for Segment 2 only are reported in Table 4 below.) Table 1 [Table 1] Treatment-emergent adverse events (TEAEs) of any grade were reported in more than 15% of patients. There was one grade 4 TEAE (sepsis) unrelated to exicholant and no grade 5 TEAEs.

[0091] No clinically relevant changes were observed in the exposure of enzalutamide or its metabolite, N-desmethylenzalutamide, in patients receiving exicholant (the combination of exicholant and enzalutamide did not alter patients' exposure to enzalutamide). In Segment 1, the exposure of enzalutamide alone (day 1 of the lead-in in cycle 1 (C1D-1)) was compared to the exposure after one cycle of combination treatment (C2D1). A mean ratio of enzalutamide + N-desmethylenzalutamide exposure on C2D1 to C1D-1 of less than 0.75 or greater than 1.4 was considered to represent a notable drug-drug interaction. The observed mean ratios of 1.14 (Cmax) and 1.26 (AUC 0-12 ) indicated no significant drug-drug interactions and indicated that no modification of enzalutamide dose was required for coadministration of enzalutamide with exicholant. Thus, these observed mean ratios indicate that 160 mg enzalutamide once daily represents a safe and effective dose of enzalutamide when combined with exicholant. Enzalutamide pharmacokinetics in the presence and absence of exicholant are provided in Table 2. Table 2 Enzalutamide Pharmacokinetics in the Presence and Absence of Exicholant [Table 2] Table 2 shows the sum of exposures to enzalutamide plus N-desmethylenzalutamide. C max is the maximum observed plasma concentration; AUC 0-12 is the area under the curve from hour 0 to hour 12; C1D-1 is cycle 1 day minus 1 (i.e., the day before cycle 1 day 1); C2D1 is cycle 2 day 1.

[0092] Segment 2 of this study was a double-blind, placebo-controlled study in patients with rising PSA; exicholant was administered once daily with a stepwise dose introduction (in these patients, the dose started at 240 mg / day, titrated to 280 mg / day, and then to 320 mg / day). The study design for Segment 2 is shown in schematic form in Figure 2B. Twenty-five patients were enrolled and randomized 3:1 to either Arm A or Arm B. Exicholant was administered to patients once daily with food; enzalutamide was administered at the currently tolerated, stable dose for each patient. Pharmacokinetic evaluations of both exicholant and enzalutamide were performed on cycle 1 day 15 (C1D15) and 2 weeks after each dose escalation; pharmacokinetic evaluations of exicholant were performed after each dose taper (if any). Pharmacodynamic (PD) assessments were performed on cycle 1 day 1 (C1D1), cycle 1 day 15 (C1D15), and 2 weeks after each dose escalation every 3 cycles from cycle 3 onwards, as well as upon exicholant discontinuation or disease progression.

[0093] The baseline demographics of patients enrolled in Segment 2 of the study, as well as their baseline disease characteristics, are provided in Table 3. Table 3 Baseline demographics and disease characteristics [Table 3]

[0094] Treatment-emergent adverse events (TEAEs) and dose-limiting toxic events (DLTs) were evaluated for patients in segment 2. TEAEs leading to discontinuation of exicholant included fatigue (n=3), back pain (n=2), pain in extremity (n=2), and groin pain (n=1). Serious adverse events (SAEs) included back pain (n=2), sepsis, confusional state, urinary retention, and pelvic pain (n=1 each). Reports of pain in the extremities (legs, feet) and sensory neuropathy (legs, feet, toes) represented neuropathic pain. TEAEs of fatigue and back pain were consistent with enzalutamide treatment and underlying disease but were exacerbated by concomitant treatment with exicholant. No SAEs with fatal outcomes were reported. Only one SAE was assessed as related to exicholant. Three of the 25 Segment 2 patients were still receiving exicholant at the time of tabulation of these results. Most patients had discontinued exicholant due to disease progression or adverse events.

[0095] Dose-limiting toxicities (DLTs) were recorded and defined by the investigator as possibly or probably related to the study drug from the first dose of exicholant through cycle 3. Based on these DLTs, a combination regimen of 240 mg exicholant once daily combined with 160 mg enzalutamide once daily was selected as a tolerable phase 2 regimen.

[0096] TEAEs related to exicholant for patients in segment 2 are given in Table 4. Table 4 Exicholant-related TEAEs in Segment 2 [Table 4] ALT: alanine aminotransferase ALP: alkaline phosphatase Exicholant-related TEAs were reported in more than 15% of patients, and grade 3 exicholant-related TEAs were reported in more than 1 patient. There were no grade 4 or grade 5 exicholant-related AEs.

[0097] A listing of dose-limiting toxicities (DLTs) seen in patients in Segment 2 is provided in Table 5. Table 5 [Table 5] GGT: gamma-glutamyltransferase Exicholant and enzalutamide were administered once daily.

[0098] Pharmacokinetics Enzalutamide exposure was largely overlapping across arms A and B regardless of exicholant dose level and was consistent with historical data for enzalutamide 160 mg alone.

[0099] There was a large overlap in exicolilant exposure across arms and dose levels. A greater increase in exicolilant AUC was seen after dose escalation from 240 mg to 280 mg compared with dose escalation from 280 mg to 320 mg. Mean C of exicolilant max were similar after 280 mg exicholant and after 320 mg exicholant. The pharmacokinetics of exicholant observed in patients in segment 2 are depicted in Figure 4A (data presented as geometric mean + geometric standard deviation) and tabulated in Table 6. Table 6 [Table 6] Geometric mean (geometric coefficient of variation %) "EXI" means exicholant; "ENZA" means enzalutamide. *Each patient in Arm B underwent up to three pharmacokinetic (PK) observations performed after exicholant 240 mg + enzalutamide 160 mg; combined data are presented.

[0100] As shown in Figure 6, the pharmacodynamic effects of exicholant (e.g., effects on gene expression) were greater when exicholant was administered with food compared with when exicholant was administered in the fasted state without food. Exicholant administered once daily (QD) at 240 to 320 milligrams (mg) with food demonstrated similar pharmacodynamic effects, whereas twice-daily (BID) dosing in the fasted state appeared to be significantly less effective. The 240 mg data in Figure 6 include both arms. Placebo titration was excluded from the 280 mg and 320 mg analyses (Arm B only), which were all conducted in the fed state. Segment 1 consisted of 120 to 180 mg BID administered in the fasted state. These results confirm that these genes were not significantly affected by enzalutamide.

[0101] Pharmacodynamics Consistent with previous studies of exicholant and other SGRMs, morning serum cortisol and ACTH levels were not affected in the safety population or in patients titrated to 320 mg exicholant. Thus, exicholant did not affect cortisol or ACTH levels. See Figure 4B for a graphical representation of these results. Figure 4B shows the mean ± standard deviation (SD) of patients' adrenocorticotropic hormone (ACTH) and cortisol levels. Gray bars represent baseline mean ± SD. End of treatment, n = 9; cycle 9 day 1, n = 3; cycle 6 day 1, n = 8; cycle 3 day 1, n = 14; cycle 2 day 1, n = 13; baseline, n = 20.

[0102] Observed regulation of GR target genes The expression levels of several genes in patients receiving exicholant were measured in the blood using NanoString technology (NanoString Technologies, Seattle, WA). For example, CDKN1C is a well-established glucocorticoid-inducible gene that plays an important role in regulating cell growth [Prekovic et al., Nature Communications 4360 (2021)]. Data from the lead-in of segment 1 confirmed that CDKN1C was not affected by enzalutamide alone. CDKN1C expression levels were suppressed after 2 weeks of treatment with exicholant 240 mg plus enzalutamide 160 mg (P<0.0001 by paired t-test). See Figure 5.

[0103] A total of 39 patients were enrolled in both segments (Segment 1, 14 patients with or without prior ENZA exposure; Segment 2, 25 patients with a rising PSA, defined as a 25% increase from nadir and an absolute value of >1 ng / mL, receiving a stable ENZA dose). Of the 25 patients enrolled in Segment 2, there were no radiographic responses, 18 (72%) patients achieved stable best overall response (BOR) per PCWG3 (Prostate Cancer Working Group 3, Scher et al., J Clin Oncol 34:1402-1418 (2016)) criteria, and 1 patient achieved a PSA response (a PSA decrease of ≥50% from baseline). Baseline tumor GR expression was detectable in all evaluated tumors. High levels of nuclear GR immunoreactivity were observed in nearly all evaluable tumor specimens (n ​​= 32), confirming high GR expression in patients with mCRPC refractory to AR antagonists (i.e., patients with rising PSA during enzalutamide treatment). Pharmacodynamic (PD) analysis demonstrated that exicholilant modulated GR target genes, including CDKN1C. Comparable PD effects were observed across exicholilant dose groups (240–320 mg QD). Although baseline 24-hour urinary free cortisol (UFC) levels for most patients were within the normal range (3.5–45 μg / 24 h), improvement in PSA trajectory after exicholilant plus enzalutamide treatment was predominantly observed in patients with baseline UFC levels above 17.5 μg / 24 h (P < 0.05) (see Figure 7A).

[0104] As shown in Figure 7A, although most baseline 24-hour UFC values ​​were within the normal range, higher baseline UFC was associated with improved PSA trajectories after treatment with exicholant plus enzalutamide (P<0.05). Low baseline UFC (not normalized for creatine) is associated with decreased PSA doubling time on study. UFC is not associated with radiographic disease progression. Higher baseline UFC levels (greater than 17.5 μg / 24 hours) are more likely to result in increased PSA doubling time compared with patients with lower baseline UFC levels.

[0105] As shown in Figure 7B, administration of exicholant did not increase UFC levels (in subjects in segment 2 who received titrated exicholant doses during the study). Similarly, exicholant administration did not significantly alter serum cortisol or ACTH levels. This contrasts with the effects of the nonselective GR modulator mifepristone, which typically produces up to a three-fold increase in 24-hour UFC (Gubbi et al., J Clin Endocrinol Metab 106(5):1501 (2021)).

[0106] The time it takes for PSA levels to double in prostate cancer patients provides a measure of tumor progression. A decrease in PSA doubling time (PSADT) indicates more rapid tumor progression; an increase in PSADT indicates a slower rate of tumor progression. Fifty-two percent (12 of 25) of patients in segment 2 experienced an increase in PSADT after treatment with exicholant and enzalutamide. A greater proportion of patients in segment 2 who received more than two cycles of combination therapy, specifically 61.5%, had an increase in PSADT. PSADT was calculated before the first dose of exicholant (patients receiving enzalutamide only), and after C1D1, C2D1, and C3D1 (where "C1D1" represents cycle 1 day 1 of combination therapy, "C2D1" represents cycle 2 day 1 of combination therapy, and "C3D1" represents cycle 3 day 1 of combination therapy). Improvements in PSADT (increased PSADT) were primarily seen in patients with higher baseline UFC. Lower baseline UFC was associated with decreased PSADT while patients were receiving treatment in this study. Table 7 [Table 7]

[0107] Figure 8A shows the best overall response and progression-free survival for patients in Segment 2 who received exicholant and enzalutamide. Because daily (QD) administration of exicholant in a fed state achieved GR modulation and not all patients in Segment 1 were enzalutamide-naive, the efficacy results reported in Figure 8A focus on patients in Segment 2. The median duration of exposure to exicholant was 9.7 weeks (range, 2–61 weeks). For the results shown in Figure 8A, tumor response was assessed by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria incorporating modified Response Evaluation Criteria in Solid Tumors v1.1 (mRECIST v1.1) criteria. Imaging-based PFS was assessed by bone progression per mRECIST v1.1, PCWG3, or death. There were no imaging-based tumor responses per PCWG3 / mRECIST v1.1 criteria. Eighteen patients in segment 2 achieved a best overall response of "stable disease" according to PCWG3 / mRECIST v1.1 criteria.

[0108] Figure 8B shows a decrease in prostate-specific antigen (PSA) compared to baseline PSA measurements. A decrease in PSA compared to baseline PSA levels was observed in 15% of patients (4 of 25). One patient experienced a PSA response (defined as a PSA decrease of more than 50% from baseline) when receiving 320 mg exicholant with 160 mg enzalutamide (PSA decrease in this patient was 71.1%). Another patient experienced a PSA decrease of more than 25% from baseline with 240 mg exicholant plus 160 mg enzalutamide (PSA decrease in this patient was 36.7%).

[0109] Figure 8C shows the PSA decline seen at any time during treatment. PSA declines occurred in 56% (14 of 24 patients) despite PSA elevation at study entry (denoted by the darker line in the figure and called "purple" in the row with the black circle in the title). In 11 of 14 patients, PSA declines occurred by the second on-treatment PSA assessment. However, declines in PSA levels in three patients that occurred after day 84 are not shown in Figure 8C because their data points fall outside the right-most graph boundary.

[0110] PD biomarker analysis confirmed that exicholilant modulated GR target genes, including CDKN1C. Similar PD effects were seen across the 240-320 mg exicholilant dose groups administered once daily (QD) with food. These effects were greater than those seen in fasted patients receiving exicholilant without food (Segment 1 patients).

[0111] The results presented in this example demonstrate that exicholilant in combination with enzalutamide is tolerable and biologically active (e.g., GR-modulating) in patients with prostate cancer. Initial studies identified a combination of 240 mg / day of exicholilant combined with 160 mg / day of enzalutamide as a suitable exicholilant+enzalutamide combination for treating patients with prostate cancer. As noted above, the most common TEAEs were fatigue and back pain; however, it remains unclear whether such TEAEs were due to exicholilant or, instead, to enzalutamide treatment and the underlying disease. Applicant also notes that no clinically significant changes in enzalutamide exposure were observed when given in combination with exicholilant, and no significant changes in cortisol or ACTH levels were observed with exicholilant administration.

[0112] As shown in Table 7 and Figures 8A, 8B, and 8C, combination therapy with exicholant and enzalutamide is effective in slowing prostate cancer progression in some patients. In the segment 2 population of heavily pretreated patients receiving enzalutamide and with rising PSA, the addition of exicholant to enzalutamide treatment resulted in one PSA response (greater than a 50% decrease in PSA) and modest PSA improvement in several other patients. As shown in Figure 7, combination treatment with exicholant and enzalutamide increased PSA doubling time (PSADT) in the majority of patients in segment 2, representing a slowing of disease progression. Two of these patients experienced a greater than 25% increase in PSADT. As shown in Figures 8A, 8B, and 8C, the majority of patients in segment 2 experienced a decrease in PSA at some point during the study. Four of 25 segment 2 patients (16%) had PSA levels that decreased below their baseline PSA levels during the study. Compared with their respective baseline PSA levels, one patient experienced a 71.1% decrease in PSA, and one patient experienced a 36.7% decrease in PSA. These data indicate that combination treatment with exicholant and enzalutamide may be beneficial for patients with histologically confirmed prostate cancer.

[0113] All patents, patent publications, publications, and patent applications cited herein are hereby incorporated by reference in their entirety into this disclosure, to the same extent as if each individual publication / publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. 1. A method of treating a patient suffering from prostate cancer, comprising administering to the patient an effective amount of an androgen receptor antagonist and an effective amount of a non-steroidal selective glucocorticoid receptor modulator (SGRM).

2. 10. The method of claim 1, wherein the patient is suffering from castration-resistant prostate cancer.

3. 10. The method of claim 1, wherein the patient is suffering from metastatic castration-resistant prostate cancer.

4. The method according to any one of claims 1 to 3, wherein the androgen receptor antagonist is enzalutamide.

5. The SGRM has the formula 【Chemical 1】 or salts and isomers thereof, wherein: R １ is R １ａ is selected from the group consisting of pyridine and thiazole, each optionally substituted with 1 to 4 groups independently selected from Each R １ａ are independently hydrogen, C １～６ Alkyl, halogen, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, N-oxide, and C ３～８ cycloalkyl; Ring J is selected from the group consisting of phenyl, pyridine, pyrazole, and triazole; Each R ２ are independently hydrogen, C １～６ Alkyl, halogen, C １～６ selected from the group consisting of haloalkyl, and —CN; R ３ａ is F, The method of any one of claims 1 to 4, wherein the subscript n is an integer from 0 to 3.

6. The octahydro-fused azadecalin compound has the structure 【Chemistry 2】 6. The method of claim 5, wherein the exicholant is ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone having the formula:

7. 7. The method of any one of claims 1 to 6, wherein the androgen receptor antagonist and the SGRM are administered to the patient once per day.

8. The method of any one of claims 1 to 7, wherein the GRM is administered with food.

9. The method of any one of claims 1 to 8, wherein the androgen receptor antagonist is enzalutamide and the dose of enzalutamide is from about 150 milligrams per day (mg / day) to about 200 mg / day.

10. 10. The method of claim 9, wherein the dose of enzalutamide is 160 mg / day.

11. 11. The method of any one of claims 1 to 10, wherein the SGRM is an exicholant and the dose of the exicholant is from about 100 mg / day to about 350 mg / day.

12. 12. The method of claim 11, wherein the dose of exicholant is 140 mg / day.

13. 12. The method of claim 11, wherein the dose of exicholant is 180 mg / day.

14. 12. The method of claim 11, wherein the dose of exicholant is 240 mg / day.

15. 12. The method of claim 11, wherein the dose of exicholant is 280 mg / day.

16. 12. The method of claim 11, wherein the dose of exicholant is 320 mg / day.

17. 12. The method of any one of claims 1 to 11, wherein the SGRM is exicholant and the dose of the exicholant is 140 mg / day, the androgen receptor antagonist is enzalutamide and the dose of enzalutamide is 160 mg / day.

18. 12. The method of any one of claims 1 to 11, wherein the SGRM is exicholant and the dose of the exicholant is 180 mg / day, and the androgen receptor antagonist is enzalutamide and the dose of enzalutamide is 160 mg / day.

19. 12. The method of any one of claims 1 to 11, wherein the SGRM is exicholant and the dose of the exicholant is 240 mg / day, the androgen receptor antagonist is enzalutamide and the dose of enzalutamide is 160 mg / day.

20. 12. The method of any one of claims 1 to 11, wherein the SGRM is exicholant and the dose of the exicholant is 280 mg / day, the androgen receptor antagonist is enzalutamide and the dose of enzalutamide is 160 mg / day.

21. 12. The method of any one of claims 1 to 11, wherein the SGRM is exicholant and the dose of the exicholant is 320 mg / day, the androgen receptor antagonist is enzalutamide and the dose of enzalutamide is 160 mg / day.

22. 22. The method of any one of claims 1 to 21, wherein the patient has a baseline urinary free cortisol (UFC) level greater than 17.5 μg / 24 hours.

23. Use of an effective amount of an androgen receptor antagonist and an effective amount of a non-steroidal selective glucocorticoid receptor modulator (SGRM) for treating prostate cancer.

24. 1. Use of an effective amount of an androgen receptor antagonist and an effective amount of a non-steroidal selective glucocorticoid receptor modulator (SGRM) in the preparation of a medicament for treating prostate cancer.

25. 25. The use of claim 23 or claim 24, wherein the prostate cancer is castration-resistant prostate cancer.

26. 25. The use of claim 23 or claim 24, wherein the prostate cancer is metastatic castration-resistant prostate cancer.

27. The use according to any one of claims 23 to 26, wherein the androgen receptor antagonist is enzalutamide.

28. The SGRM has the formula 【Chemistry 3】 or salts and isomers thereof, wherein: R １ is R １ａ is selected from the group consisting of pyridine and thiazole, each optionally substituted with 1 to 4 groups independently selected from Each R １ａ are independently hydrogen, C １～６ Alkyl, halogen, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, N-oxide, and C ３～８ cycloalkyl; Ring J is selected from the group consisting of phenyl, pyridine, pyrazole, and triazole; Each R ２ are independently hydrogen, C １～６ Alkyl, halogen, C １～６ selected from the group consisting of haloalkyl, and —CN; R ３ａ is F, 28. Use according to any one of claims 23 to 27, wherein the subscript n is an integer from 0 to 3.

29. The octahydro-fused azadecalin compound has the structure 【Chemistry 4】 29. The use according to claim 28, wherein the exicholant is ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone having the formula:

30. The use according to any one of claims 24 to 29, wherein the medicament is for once-per-day use.

31. 30. The use according to any one of claims 24 to 29, wherein the medicament is for use with food.

32. The use of any one of claims 23 to 31, wherein the androgen receptor antagonist is enzalutamide and the amount of enzalutamide in the medicament for each daily use is from about 150 milligrams (mg) to about 200 mg.

33. 33. The use of claim 32, wherein the amount of enzalutamide is 160 mg.

34. 34. The use of any one of claims 23 to 33, wherein the SGRM is an exicholant and the amount of the exicholant is from about 100 mg to about 350 mg.

35. 35. The use of claim 34, wherein the amount of exicholant is 140 mg.

36. 35. The use of claim 34, wherein the amount of exicholant is 180 mg.

37. 35. The use of claim 34, wherein the amount of exicholant is 240 mg.

38. 35. The use of claim 34, wherein the amount of exicholant is 280 mg.

39. 35. The use of claim 34, wherein the amount of exicholant is 320 mg.

40. The use of any one of claims 23 to 34, wherein the SGRM is exicholant and the amount of the exicholant is 140 mg, the androgen receptor antagonist is enzalutamide and the amount of enzalutamide is 160 mg.

41. The use of any one of claims 23 to 34, wherein the SGRM is exicholant and the amount of the exicholant is 180 mg, the androgen receptor antagonist is enzalutamide and the amount of enzalutamide is 160 milligrams mg.

42. The use of any one of claims 23 to 34, wherein the SGRM is exicholant and the amount of the exicholant is 240 mg, the androgen receptor antagonist is enzalutamide and the amount of enzalutamide is 160 mg.

43. The use of any one of claims 23 to 34, wherein the SGRM is exicholant and the amount of the exicholant is 280 mg, the androgen receptor antagonist is enzalutamide and the amount of enzalutamide is 160 mg.

44. The use of any one of claims 23 to 34, wherein the SGRM is exicholant and the amount of the exicholant is 320 mg, the androgen receptor antagonist is enzalutamide and the amount of enzalutamide is 160 mg.

45. 45. The use of any one of claims 23 to 44, wherein the patient has a baseline urinary free cortisol (UFC) level greater than 17.5 μg / 24 hours.

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