Patent Publication Number: US-11389432-B2

Title: Methods of treating cancer comprising administration of a glucocorticoid receptor modulator and a cancer chemotherapy agent

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of, and priority to, U.S. Provisional Patent Application 62/782,120, filed Dec. 19, 2018; U.S. Provisional Patent Application 62/847,772, filed May 14, 2019; and U.S. Provisional Patent Application 62/854,768, filed May 30, 2019, the entire contents of all of which applications is hereby incorporated by reference in their entireties. 
    
    
     BACKGROUND 
     The glucocorticoid receptor (GR) is a is a nuclear hormone receptor that controls the transcription of multiple genes. The GR is found in most bodily tissues, and plays important roles in the body&#39;s response to stress, metabolism, glucose regulation, blood pressure, immune response, muscle and bone health, memory, mood, and other systems and responses. GR action is triggered by binding of glucocorticoids (GC) to GR, forming complex comprising the GR and the GC, leading to activation of the GR, its translocation to the cell nucleus, and interaction of the complex with nuclear genetic material. A GC is a GR agonist, and the binding of a GC to GR activates the GR. In humans and many other mammals, the primary GC is cortisol; however, in rodents, for example, corticosterone plays that role. Other GCs include, for example, dexamethasone, prednisone, hydrocortisone, beclamethasone, and other natural and synthetic compounds. Some transcriptional effects of GCs have been described in healthy patients (Olnes et al., 2016). Some transcriptional effects of mifepristone, a steroidal glucocorticoid and progesterone receptor antagonist, have also been described in breast cancer patients (Maranville et al., 2014). However, the transcriptional effects of a selective nonsteroidal glucocorticoid receptor modulator in patients with other cancers, such as, e.g., pancreatic, ovarian, cervical, vulvar, or other solid tumor types have not been described. Further, a relationship between GR-mediated transcriptional response and tumor progression has not been described. 
     Cancer patients may be treated surgically to remove, as much as possible, cancerous tissue. Cancer patients may receive medical treatment, such as chemotherapy or radiation treatment. Cancer patients may receive both surgical and medical treatment for cancer. 
     As noted above, the GR is found in most tissues of the body in normal subjects, and also in solid tumor malignancies (Block et al. Cancer Management Res. 9:65-72 (2017)). It has been proposed that activation of GR in cancer cells may have anti-cancer effect. However, the relationship, if any, to GR expression in cancer, in the response to cancer, and in response to cancer chemotherapy, remains uncertain: see, e.g.: Maranville et al. Gene expression of peripheral blood cells reveals pathways downstream of glucocorticoid receptor antagonism and nab-paclitaxel treatment.  Pharmacogenet Genomics . September; 24(9):451-8, 2014. Olnes et al. Effects of Systemically Administered Hydrocortisone on the Human Immunome.  Scientific Reports.  14; 6:23002, 2016. Thus, the role of GR in cancer and in its treatment is unclear. 
     Accordingly, methods for identifying patients most likely to benefit from treatment, and methods for treating cancer patients so identified, are lacking in the art and are required. 
     SUMMARY 
     Novel methods for treating cancer are disclosed. In embodiments, the cancer may comprise a solid tumor. In embodiments, the novel methods for treating cancer include methods of administering a glucocorticoid receptor (GR) modulator (GRM) along with a cancer chemotherapeutic agent, effective to treat cancer. In embodiments, the GRM is a GR antagonist (GRA). In embodiments, the GRM may be a heteroaryl ketone fused azadecalin GRM or an octahydro fused azadecalin GRM. In preferred embodiments, the GRM is relacorilant. 
     Applicant describes herein the effects of administration of a GRM such as relacorilant on the expression of multiple genes in human subjects, and describes differences in that gene expression between normal subjects and cancer patients. The transcriptional effects of a selective nonsteroidal glucocorticoid receptor modulator in patients with pancreatic, ovarian, cervical, vulvar, or other solid tumor types have not previously been described. It is notable that systemic transcriptional effects on gene expression have not been described for other steroid hormone systems (e.g., androgen receptor (AR) antagonists or estrogen receptor (ER) antagonists). As described below, administration of the AR antagonist enzalutamide does not cause significant effects on gene expression such as those reported here following administration of the GRM relacorilant. Thus, the whole-blood transcriptional effects of GR antagonism disclosed herein were surprising and unexpected. Further, a relationship between GR-mediated transcriptional response and tumor progression previously has not been described. The novel treatment methods disclosed herein utilize these differences in gene expression, and these relationships between GR-mediated transcriptional response and tumor progression, providing improved cancer treatments. 
     Applicant discloses herein methods for identifying cancer patients likely to benefit from treatments that include GRM administration, and in particular that include relacorilant administration, by measuring transcription of specific genes isolated from blood. Applicant discloses herein that relacorilant administration led to decreases in the expression levels of several genes in cancer patients who derived benefit from combined treatment with a GRM and a cancer chemotherapeutic agent. Similar cancer patients, who received the same combined treatment with a GRM and a cancer chemotherapeutic agent, did not show relacorilant-related decreased gene expression levels, and did not experience benefit from the combined therapy. 
     Applicant discloses herein that a decrease in gene expression levels, following treatment with a GRM, such as relacorilant, of the following genes are indicative of patients who are likely to benefit from combined treatment with a GRM and a cancer chemotherapeutic agent: APC, CLEC4E, ENTPD1, ICAM3, RELN, BID, CLEC7A, ESYT1, IL10RA, RICTOR, CCL5, COL6A3, F2RL1, IL32, RPL7A, CCR5, COX2, FBP1, IL7R, SELP, CD27, CXCL1, FCGR3A/B, ITGA6, THBD, CD300A, CXCL2, FCGRT, KLRB1, TMEM173, CD3E, CXCR3, GIMAP6, LCK, TNFRSF9, CD3G, CXCR6, GOT2, LDHB, TNKS, CD40LG, EDN1, GZMK, MRE11, TP53, CEACAM3, EIF2B4, ICAM2, MYC, and TREM1. In embodiments, the at least one gene is selected from the group of genes consisting of ICAM3, TREM1, FCGRT, GIMAP6, IL10RA, IL7R, CEACAM3, and COL6A3. In embodiments, the at least one gene is selected from the group of genes consisting of IL32, EDN1, CD3G, CCL5, RICTOR, and BID. In embodiments, the at least one gene is selected from the group of genes consisting of CXCL2, FBP1, CD27, TNKS, CD40LG, CXCR3, LDHB, THBD, TNFRSF9, and RPL7A. In embodiments, the at least one gene is selected from the group of genes consisting of EIF2B4, MRE11, CD3E, GOT2, ICAM2, TP53, CLEC7A, and COX2. In embodiments, the at least one gene is selected from the group of genes consisting of GZMK, CD300A, TMEM173, MYC, ENTPD1, CXCR6, RELN, CXCL1, CLEC4E, CCR5, ITGA6, APC, and F2RL1. In embodiments, the expression levels of at least two of said genes are measured, and wherein said GRM (e.g., relacorilant) and said cancer chemotherapy agent are administered to the patient if the first expression levels of the two genes are greater than the second expression levels of the two genes. In embodiments, the expression levels of at least three genes are measured, and wherein said GRM (e.g., relacorilant) and said cancer chemotherapy agent are administered to the patient if the first expression level of said at least three genes is greater than the first expression level of said at least three genes. In embodiments, the expression levels of at least four, or five, or more genes are measured, and wherein said GRM (e.g., relacorilant) and said cancer chemotherapy agent are administered to the patient if the first expression level of said at least four, or five, or more genes is greater than the first expression level of said at least four, or five, or more genes. 
     In embodiments, the same GRM is used to identify a patient likely to benefit from combined treatment with a GRM and a cancer chemotherapeutic agent, and is used in the combined GRM and cancer chemotherapeutic agent of that patient. In embodiments, relacorilant is used for identifying a patient for such treatment, and is used in the combined GRM and cancer chemotherapeutic agent of that patient. In embodiments, the cancer chemotherapy agent comprises a taxane, which may be selected from, e.g., paclitaxel, nab-paclitaxel, docetaxel, larotaxel, tesetaxel, cabazitaxel, and ortataxel. In embodiments, the gene expression levels are measured in a blood sample obtained from the patient. In embodiments, the gene expression levels mRNA levels. 
     Applicant discloses herein that a decrease in gene expression levels, following treatment with a GRM, such as relacorilant, of the following genes are indicative of patients who are likely to benefit from combined treatment with a GRM and a cancer chemotherapeutic agent: COX2; DUSP1; GSK3b; MCL-1; PIK3CG; RGS-2; SGK1; and STAT3. Applicant further discloses herein that a decrease in gene expression levels of GSK3b or MCL-1, or both; or in COX2 and DUSP1, or both; or in any two, or three, or all four of GSK3b, MCL-1, COX2, and DUSP1, in a patient following treatment with a GRM such as relacorilant is indicative that the patient is likely to benefit from combined treatment with a GRM (e.g., relacorilant) and a cancer chemotherapeutic agent. Applicant further discloses herein that patients in whom gene expression levels of these genes does not decrease, following treatment with a GRM (e.g., relacorilant), are likely not to benefit from such combined treatment with a GRM and a cancer chemotherapeutic agent. In embodiments, the gene expression levels are mRNA expression levels. 
     The methods disclosed herein are useful to treat cancer patients likely to benefit from cancer chemotherapy combined with administration of a GRM (e.g., relacorilant) to the cancer patient. In preferred embodiments, the GRM of the present methods is relacorilant. The methods are useful to identify cancer patients likely to benefit from cancer chemotherapy combined with administration of a GRM. The methods include: administering a GRM (e.g., relacorilant) to a patient, and determining whether or not the expression level of a gene is decreased in comparison with baseline expression levels of the gene measured in the patient prior to the GRM administration. The treatment methods include: administering a GRM (e.g., relacorilant) to a patient, determining whether or not the expression level of a gene is decreased in comparison with baseline expression levels of the gene measured in the patient prior to the GRM administration, and treating the patient with a combination of a GRM and a cancer chemotherapy agent. In embodiments of the treatment methods, the GRM of the combination of a GRM and a cancer chemotherapy agent is relacorilant. The methods further include identifying a patient in whom the expression level of a gene is decreased in comparison with corresponding gene baseline levels as a patient likely to benefit from chemotherapy combined with administration of a GRM. The methods further include administering cancer chemotherapy and a GRM to a patient identified by such methods as a patient likely to benefit from cancer chemotherapy combined with administration of a GRM, whereby the cancer is treated in the patient. In embodiments, the cancer chemotherapy comprises administration of a taxane, and the methods further include administering taxane cancer chemotherapy in conjunction with GRM administration to a patient identified by such methods as a patient likely to benefit from cancer chemotherapy combined with administration of a GRM. In embodiments, the taxane is selected paclitaxel, nab-paclitaxel, docetaxel, larotaxel, tesetaxel, cabazitaxel, and ortataxel. 
     In embodiments, the gene expression level is a mRNA level measured from a blood sample taken from the patient. In embodiments, the gene for which the expression level is measured is a gene selected from COX2, DUSP1, GSK3b, MCL-1, PIK3CG, RGS-2, SGK1, and STAT3. In some preferred embodiments, the gene for which the expression level is measured is GSK3b, or MCL-1, or both GSK3b and MCL-1. In some preferred embodiments, the gene for which the expression level is measured is COX2, or DUSP1, or both COX2 and DUSP1. In embodiments, the level of expression of the gene prior to administration of a GRM is compared to the level of expression of the gene following administration of the GRM, and, a patient whose gene expression level decreases following administration of the GRM is identified as a patient likely to benefit from administration of a GRM and a cancer therapeutic agent. In embodiments where the level of expression of the gene is not decreased after GRM administration as compared to the level of expression of the gene prior to administration of the GRM, the patient is identified as a patient not likely to benefit from administration of a GRM and a cancer therapeutic agent. 
     In embodiments, the expression levels of two, or three, or four, or five, or more genes are measured from a blood sample taken from the patient. In embodiments, the mRNA levels of two, three, four, five, or more genes are measured from a blood sample taken from the patient. In embodiments, the genes for which the expression levels of two, or three, or four, or five, or more genes are measured are genes selected from COX2, DUSP1, GSK3b, MCL-1, PIK3CG, RGS-2, SGK1, and STAT3. In preferred embodiments, the genes for which the expression levels of two genes are measured are GSK3b and MCL-1. In preferred embodiments, the genes for which the expression levels of three genes are measured include GSK3b and MCL-1. In preferred embodiments, the genes for which the expression levels of four, five, or more genes are measured include GSK3b and MCL-1. In preferred embodiments, the genes for which the expression levels of two genes are measured are COX2 and DUSP1. In preferred embodiments, the genes for which the expression levels of three genes are measured include COX2 and DUSP1. In preferred embodiments, the genes for which the expression levels of four, five, or more genes are measured include COX2 and DUSP1. 
     In embodiments, the levels of expression of each of the two, or three, or four, or five, or more genes prior to administration of a GRM is compared to the levels of expression of these genes following administration of the GRM, and, a patient whose gene expression levels decrease following administration of the GRM is identified as a patient likely to benefit from administration of a GRM and a cancer therapeutic agent. In embodiments where the level of expression of any one of the two, or three, or four, or five, or more genes is decreased after GRM administration as compared to the level of expression of that gene prior to administration of the GRM, the patient is identified as a patient likely to benefit from administration of a GRM and a cancer therapeutic agent. In embodiments where the levels of expression of some of the two, or three, or four, or five, or more genes is decreased after GRM administration as compared to the levels of expression of these genes prior to administration of the GRM, the patient is identified as a patient likely to benefit from administration of a GRM and a cancer therapeutic agent. In embodiments where the levels of expression of each of the two, or three, or four, or five, or more genes is decreased after GRM administration as compared to the levels of expression of these genes prior to administration of the GRM, the patient is identified as a patient likely to benefit from administration of a GRM and a cancer therapeutic agent. The methods further include administering cancer chemotherapy and a GRM to a patient identified by such methods, e.g., identifying a patient as likely to benefit from such treatments where the levels of expression of each of the two, or three, or four, or five, or more genes is decreased after GRM administration as compared to the levels of expression of these genes prior to administration of the GRM, whereby the cancer is treated in the patient. In embodiments where the levels of expression of none of these genes is decreased after GRM administration as compared to the levels of expression of these genes prior to administration of the GRM, the patient is identified as a patient not likely to benefit from administration of a GRM and a cancer therapeutic agent. 
     In embodiments, the GRM is a glucocorticoid receptor antagonist (GRA). In embodiments of the methods disclosed herein, the GRM is a non-steroidal GRM, and may be a heteroaryl ketone fused azadecalin GRM, and may be an octahydro fused azadecalin GRM. In embodiments of the methods disclosed herein, the GRM is relacorilant. 
     By identifying patients likely to benefit from cancer chemotherapy combined with GRM administration, administration of cancer treatment is improved and treatment outcomes are improved, by a) providing appropriate chemotherapy, including cancer chemotherapy combined with GRM administration, to patients likely to derive benefit from that therapy, and b) avoiding administering unnecessary or inappropriate therapy to patients unlikely to derive benefit therefrom, thus allowing or directing those patients to receive alternative therapy better adapted to their clinical situation. The present methods provide methods for treating cancer patients with cancer chemotherapy combined with GRM administration, determined to be a therapy from which the patient is likely to derive benefit, thereby improving cancer treatment improving cancer treatment outcomes. 
     The methods disclosed herein provide improved treatment regimens for cancer patients, the regimens comprising administration of a cancer chemotherapy agent and GRM. The methods disclosed herein also provide improved methods for identifying cancer patients likely to benefit from treatments comprising a cancer chemotherapy agent and GRM. Identifying patients likely to respond to a specific therapy improves treatment, improves the efficiency of clinical trials, and avoids unnecessary exposure of patients to non-beneficial therapies. 
     Other objects, features, and advantages of the methods disclosed herein will be apparent to one of skill in the art from the following detailed description and figures. 
    
    
     
       DESCRIPTION OF THE FIGURES 
         FIG. 1 : Segment I Continuous-Dosing Regimen 
         FIG. 2 : Segment II Intermittent-Dosing Regimen 
         FIG. 3 : Pairwise correlations in raw counts between candidate housekeeping genes 
         FIG. 4 : Normalized DUSP1 mRNA counts at baseline and C1D15 in all patients and patient sub-sets. 
         FIG. 5 : Genes with a significant change from baseline in patients who benefited from relacorilant+nab-paclitaxel. 
         FIG. 6A . Pharmacokinetic:Pharmacodynamic (PK:PD) relationships. The average change from baseline to C1D15 for 10 GR-induced RNAs is plotted as a function of relacorilant C max  for continuous relacorilant dosing. Segment I (6A, 6B) is continuous relacorilant dosing while Segment II (6C, 6D) is intermittent. 
         FIG. 6B . Pharmacokinetic:Pharmacodynamic (PK:PD) relationships. The average change from baseline to C1D15 for 10 GR-induced RNAs is plotted as a function of relacorilant AUC 0-24  for continuous relacorilant dosing. 
         FIG. 6C . Pharmacokinetic:Pharmacodynamic (PK:PD) relationships. The average change from baseline to C1D15 for 10 GR-induced RNAs is plotted as a function of relacorilant C max  for intermittent relacorilant dosing. 
         FIG. 6D . Pharmacokinetic:Pharmacodynamic (PK:PD) relationships. The average change from baseline to C1D15 for 10 GR-induced RNAs is plotted as a function of relacorilant AUC 0-24  for intermittent relacorilant dosing. 
         FIG. 7A . Overview of whole blood gene expression fold change.  FIG. 7A  shows that transcriptional effects of relacorilant+nab-paclitaxel (Abx) are pronounced in patients with SD, PR, or CR vs PD. Genes expression in patients with progressive disease (PD) are indicated by squares. Genes expression in patients with stable disease (SD), partial response (PR), or complete response (CR) are indicated by circles. The transcriptional changes (mRNA measurements) in whole blood from baseline to C1D15 were compared between patients and separated by best overall response. Inset details genes downregulated in SD/PR/CR (92 genes) vs PD (30 genes) patients. Dotted line represents an adjusted p-value of 0.05 (markers above that line have adjusted p&lt;0.05). 
         FIG. 7B . Overview of whole blood gene expression fold change due to enzalutamide (an androgen receptor antagonist).  FIG. 7B  shows that no significant transcriptional effects of enzalutamide were observed after 28 days of enzalutamide administration. The small circular markers indicate the change in gene expression for individual genes. None of the gene expression levels changes following enzalutamide (as compared to baseline levels) reach significance (all adjusted p-values are greater than 0.5). 
         FIG. 8 . Comparison of genes induced by prednisone (dark grey, left) to genes suppressed by relacorilant+nab-paclitaxel (right) in patients who benefited (light grey, top) or had progressive disease (white, bottom). 
         FIG. 9A . Identification of a superior set of genes capable of identifying patients who benefit from relacorilant. The 10 genes identified from the 33 gene panel (left) are compared to the 50 genes identified from the 800 gene panel (right). 
         FIG. 9B . A receiver operator curve shows the superior true positive rate and false positive rate of the 8-gene panel derived from the 800 gene set. Squares represent the 50 genes panel derived from the 800 gene set, circles represent the 10 gene panel derived from the earlier 33 gene set, and triangle represent unity. The HUGO gene names for the 50 genes identified from the 800 gene panel are listed in Table 2. 
         FIG. 10A . Relacorilant sensitizes the MIA PaCa-2 xenograft to paclitaxel. 7.5 mg/kg paclitaxel dosed three times (dashed lines) was ineffective alone. Addition of Relacorilant delayed tumor growth (left, p&lt;0.0001) compared to paclitaxel alone. 
         FIG. 10B . Relacorilant with Paclitaxel Reduces MIA PaCa-2 xenograft Tumor Volume.  FIG. 10B  shows the fraction of xenograft tumors (as %) whose volume remained below 400 mm 3  on the days indicated along the horizontal axis. Tumor-bearing mice were treated with vehicle, relacorilant (30 mg/kg every day), paclitaxel (three doses of 7.5 mg/kg paclitaxel, one dose administered on each of the days indicated in  FIG. 10A ), and the combination relacorilant (30 mg/kg every day) with paclitaxel (7.5 mg/kg doses of paclitaxel each administered on days 8, 12, and 16 post implantation). The tumor sizes in mice administered vehicle (DMSO) are indicated by the darkest line (extreme left); in mice daily administered 300 nM relacorilant by the lighter gray line, nearly superimposed on the vehicle line at left; in mice administered paclitaxel (7.5 mg/kg paclitaxel dosed on days 8, 12, and 16 after tumor implantation) are indicated by the dark gray line between the other lines; and in mice administered daily 300 nM relacorilant and the same three doses of paclitaxel (right-most light gray line). Addition of 300 nM relacorilant to the paclitaxel doses delayed the time to progression (p&lt;0.0001) compared to paclitaxel alone (right-most light gray line). 
         FIG. 11A . Relacorilant restores chemotherapy sensitivity in vitro. Glucocorticoid reduced the maximum effect of paclitaxel in the ovarian OVCAR-5 cell line. Relacorilant restored sensitivity to this agent in the presence of glucocorticoid. 
         FIG. 11B . Relacorilant restores chemotherapy sensitivity in vitro. Glucocorticoid (100 nM dexamethasone) reduced the half-maximal potency of oxaliplatin in the ovarian OVCAR-5 cell line. Relacorilant restored sensitivity to this agent in the presence of glucocorticoid. 
         FIG. 11C . Relacorilant restores chemotherapy sensitivity in vitro. Glucocorticoid reduced the maximum effect of gemcitabine in the ovarian OVCAR-5 cell line. Relacorilant restored sensitivity to this agent in the presence of glucocorticoid. 
         FIG. 12 . Potency of carboplatin is dose-dependently increased by Relacorilant in vitro. OVCAR-5 ovarian cells were grown in the presence of glucocorticoid. Carboplatin was titrated against increasing amounts of Relacorilant. 
         FIG. 13 . Relacorilant overcomes the effect of dexamethasone on OVCAR-5 cell survival in the presence of pemetrexed in vitro. Vertical axis shows cell survival as percent of original cell numbers; horizontal axis shows the several concentrations of pemextred to which the OVCAR-5 cells were exposed. Dexamethasone (100 nM) increased cell proliferation (squares) as compared to dimethyl sulfoxide (DMSO) vehicle alone (filled circles). Relacorilant (300 nM) overcame the effect of dexamethasone; OVCAR-5 cell proliferation in the presence of 300 nM relacorilant was similar to that of vehicle (downwardly pointing triangles). 
         FIG. 14 . Relacorilant effects on dexamethasone effects on OVCAR-5 cell growth. This figure shows the effects of relacorilant on OVCAR-5 cell growth in vitro. The vertical scale shows luminosity, which serves as a measure of cell number. The cell numbers in the presence of the indicated concentrations of cancer chemotherapy agents and in vehicle (DMSO), 100 nM dexamethasone (Dex), the combination of 100 nM dexamethasone and 300 nM relacorilant (Dex+CORT125134), and 300 nM relacorilant (CORT125134) are shown. Dexamethasone increased cell numbers in the presence of bortezumib and palbociclib (as compared to vehicle); this increase was opposed by relacorilant. 
     
    
    
     DETAILED DESCRIPTION 
     I. Introduction 
     Provided herein are methods for treating a cancer patient by methods comprising combined administration of a glucocorticoid receptor (GR) modulator (GRM) and a cancer chemotherapeutic agent. In embodiments, the GRM is a GR antagonist (GRA). In embodiments, the methods include identifying cancer patients likely to benefit from combined administration of a GRM and a cancer chemotherapeutic agent, and administering a GRM and a cancer chemotherapeutic agent to the patient. Identification of cancer patients likely to benefit from such combined administration of a GRM and a cancer chemotherapeutic agent includes determining gene expression levels in the cancer patient following administration of a GRM to the cancer patient. In embodiments, the GRM administered to the patient in combination with a cancer chemotherapeutic agent is the same GRM as was used to determine gene expression levels in the cancer patient. 
     Accordingly, Applicant discloses herein methods of treating cancer in a patient suffering from cancer, the methods comprising: Measuring a first expression level of a gene in a sample obtained from said patient; Administering an effective amount of a glucocorticoid receptor modulator (GRM) to said patient; then Measuring a second expression level of a gene in a sample obtained from said patient; and Administering a GRM and a cancer chemotherapy agent to the patient if the second expression level is less than said first expression level, Whereby said cancer is treated. In embodiments, the measured gene expression levels are mRNA levels. In embodiments, the measured genes include genes selected from COX2, DUSP1, GSK3b, MCL-1, PIK3CG, RGS-2, SGK1, and STAT3. In some preferred embodiments, the genes for which the gene expression levels are measured include GSK3b and MCL-1. In some preferred embodiments, the genes for which the gene expression levels are measured include COX2 and DUSP. In preferred embodiments, the GRM is relacorilant. 
     Applicant further discloses herein methods of identifying a cancer patient likely to benefit from combined administration of a glucocorticoid receptor modulator (GRM) and a cancer chemotherapy agent, the method comprising: Measuring a first expression level of a gene in a sample obtained from said patient; Administering an effective amount of a glucocorticoid receptor modulator (GRM) to said patient; then Measuring a second expression level of a gene in a sample obtained from said patient; and Identifying the patient as likely to benefit from combined administration of a GRM and a cancer chemotherapy agent if the second expression level is less than said first expression level, Whereby said patient likely to benefit from combined administration of a GRM and a cancer chemotherapy agent is identified. In embodiments, the measured gene expression levels are mRNA levels. In embodiments, the measured genes include genes selected from COX2, DUSP1, GSK3b, MCL-1, PIK3CG, RGS-2, SGK1, and STAT3. In some preferred embodiments, the genes for which the gene expression levels are measured include GSK3b and MCL-1. In some preferred embodiments, the genes for which the gene expression levels are measured include COX2 and DUSP-1. In preferred embodiments, the GRM is relacorilant. 
     In embodiments of the methods disclosed herein, said expression levels of said gene are measured in a blood sample obtained from the patient. In embodiments of the methods disclosed herein, the gene expression levels of are mRNA levels. In embodiments of the methods disclosed herein, the gene expression levels are mRNA levels measured in a blood sample obtained from the patient. In embodiments of the methods disclosed herein, the gene is selected from the group of genes consisting of COX2, DUSP1, GSK3b, MCL-1, PIK3CG, RGS-2, SGK1, and STAT3. In embodiments of the methods disclosed herein, the gene may be selected from the group of genes consisting of COX2, DUSP1, GSK3b, and MCL-1. In preferred embodiments, the genes for which the gene expression levels are measured include GSK3b and MCL-1. 
     In embodiments of the methods disclosed herein, at least two gene expression levels are measured in a sample obtained from a patient; the sample may be a blood sample, and the gene expression levels may be mRNA levels. In preferred embodiments of the methods in which expression of at least two genes is measured, the genes include GSK3b and MCL-1. In embodiments of the methods disclosed herein, at least three, or at least four, or at least five, or at least six, or at least seven, or at least eight gene expression levels are measured in a sample obtained from a patient; the sample may be a blood sample, and the gene expression levels may be mRNA levels. 
     Accordingly, Applicant discloses herein methods of treating cancer in a patient suffering from cancer, the methods comprising: Measuring a first expression level of each of two or more genes in a sample obtained from said patient; Administering an effective amount of a glucocorticoid receptor modulator (GRM) to said patient; then Measuring a second expression level of each of said two or more genes in a sample obtained from said patient; and Administering a GRM and a cancer chemotherapy agent to the patient if, for at least one of said two or more genes, the second expression level is less than said first expression level, Whereby said cancer is treated. In embodiments, a GRM and a cancer chemotherapy agent is administered to the patient if, for each of said two or more genes, the second expression level is less than said first expression level, Whereby said cancer is treated. In embodiments, a GRM and a cancer chemotherapy agent is administered to the patient if, where three or more gene expression levels are measured, for the majority of the three or more genes, the second expression level is less than said first expression level, Whereby said cancer is treated. In embodiments, the genes may be selected from the group of genes consisting of COX2, DUSP1, GSK3b, and MCL-1. In preferred embodiments, the genes for which the gene expression levels are measured include GSK3b and MCL-1. In preferred embodiments, the GRM is relacorilant. 
     Accordingly, Applicant discloses herein methods of identifying a cancer patient likely to benefit from combined administration of a glucocorticoid receptor modulator (GRM) and a cancer chemotherapy agent, the methods comprising: Measuring a first expression level of each of two or more genes in a sample obtained from said patient; Administering an effective amount of a glucocorticoid receptor modulator (GRM) to said patient; then Measuring a second expression level of each of said two or more genes in a sample obtained from said patient; and Identifying the patient as likely to benefit from combined administration of a GRM and a cancer chemotherapy agent if, for at least one of said two or more genes, the second expression level is less than said first expression level, Whereby said patient likely to benefit from combined administration of a GRM and a cancer chemotherapy agent is identified. In embodiments, a patient likely to benefit from combined administration of a GRM and a cancer chemotherapy agent is identified if, for each of said two or more genes, the second expression level is less than said first expression level. In embodiments, a patient likely to benefit from combined administration of a GRM and a cancer chemotherapy agent is identified if, where three or more gene expression levels are measured, for the majority of the three or more genes, the second expression level is less than said first expression level. 
     In embodiments of the methods disclosed herein, where more than one gene expression level is measured, the genes are selected from the group of genes consisting of COX2, DUSP1, GSK3b, MCL-1, PIK3CG, RGS-2, SGK1, and STAT3. In embodiments of the methods disclosed herein, where more than one gene expression level is measured, the genes may be selected from the group of genes consisting of COX2, DUSP1, GSK3b, MCL-1, PIK3CG, RGS-2, SGK1, and STAT3. In embodiments of the methods disclosed herein, at least two genes are selected from the group of genes consisting of COX2, DUSP1, MCL-1, and GSK3b. In preferred embodiments, the genes for which the gene expression levels are measured include GSK3b and MCL-1. In preferred embodiments, the GRM is relacorilant. 
     In embodiments, gene expression levels are quantified by polymerase chain reaction. In embodiments, gene expression levels are quantified by sequencing techniques, by use of microarrays, by NanoString technology, or by a comparable technology known in the art. In embodiments, gene expression levels are determined by identifying and measuring the amounts of the protein or amino acid sequences encoded by mRNA in the blood sample. 
     In embodiments, an average or weighted average of gene levels is calculated based on the levels of multiple genes. For example, in embodiments, an average or weighted average of gene levels is calculated based on the levels of multiple genes selected from COX2, DUSP1, GSK3b, MCL-1, PIK3CG, RGS-2, SGK1, and STAT3. In other embodiments, an average or weighted average of gene levels is calculated based on the levels of multiple genes selected from COX2, DUSP1, MCL-1, and GSK3b. In preferred embodiments, the genes for which the gene expression levels are measured include GSK3b and MCL-1. 
     In embodiments of the methods disclosed herein, the cancer comprises a solid tumor. In embodiments, the cancer comprises a metastatic tumor. In embodiments, the cancer comprises a cancer selected from the group of cancers consisting of cancer of the bone, breast, prostate, ovary, skin, brain, bladder, cervix, liver, pancreas, lung, colon, stomach, intestine, adrenal gland, kidney, blood, or other organ or tissue. 
     In embodiments of the methods disclosed herein, the cancer chemotherapy agent comprises a taxane. In embodiments, the cancer chemotherapy agent comprises a taxane selected from paclitaxel, nab-paclitaxel, docetaxel, larotaxel, tesetaxel, cabazitaxel, and ortataxel. In embodiments, the cancer chemotherapy agent comprises paclitaxel. In embodiments, the cancer chemotherapy agent comprises nab-paclitaxel. 
     In embodiments of the methods disclosed herein, the cancer chemotherapy agent is administered to the patient at least once per month. In embodiments, administration of said cancer chemotherapy agent comprises administration of said cancer chemotherapy agent according to a 28-day cycle of administration. In embodiments, administration of said cancer chemotherapy agent comprises administration of said cancer chemotherapy agent at least twice per month. In embodiments, administration of said cancer chemotherapy agent at least three times per month. 
     In embodiments, the GRM is a non-steroidal compound, and may be administered orally to the patient. In embodiments, the GRM administration comprises administration of said GRM at least once per week. In embodiments, the GRM administration comprises administration of said GRM at least twice per week. In embodiments, the GRM administration comprises administration of said GRM at least three times per week. In embodiments, the GRM doses are selected from 10 milligrams (mg) to about 1000 mg. In embodiments, the GRM is administered once every other day, or once every third day. In embodiments, the GRM dose is a daily dose. In embodiments, the GRM is administered twice per day, or is administered three times per day. In embodiments, the GRM dose is administered once per day (i.e., is a once-daily dose). In embodiments, the GRM is administered once per day at about the same time of day each day. In embodiments, the GRM is administered with food. In embodiments, the GRM is administered to a patient without food. In embodiments, the GRM is administered without food in the morning to a patient prior to the patient&#39;s morning meal. 
     In embodiments of the methods disclosed herein, the glucocorticoid receptor modulator (GRM) is a glucocorticoid receptor antagonist (GRA); and may be a non-steroidal GRM. In embodiments, the GRM is a non-steroidal GRM having a backbone structure selected from a cyclohexyl-pyrimidine backbone, a fused azadecalin backbone, a heteroaryl ketone fused azadecalin backbone, and an octahydro fused azadecalin backbone. In embodiments, the GRM is a heteroaryl ketone fused azadecalin GRM. 
     In preferred embodiments, the GRM is relacorilant: 
     (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a, 5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (also termed “CORT125134”), which has the following structure: 
     
       
         
         
             
             
         
       
     
     II. Definitions 
     The terms “a,” “an,” or “the” as used herein not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and reference to “the agent” includes reference to one or more agents known to those skilled in the art, and so forth. 
     The terms “tumor” and “cancerous tumor” as used herein refer to, masses of abnormal tissue; such abnormal tissue comprises neoplasmic tissue (i.e., tumor, as used herein, refers to a neoplasm). Unless explicitly termed “non-cancerous”, the term “tumor” as used herein refers to a cancerous tumor. Tumors include, but are not limited to, carcinoma, adenocarcinoma, adenoma, neuroendocrine, neuroepithelial, neuroblastoma, glioblastoma, and other cancerous masses of any form or origin. A tumor may be of any size, including, e.g., measuring less than about 5 millimeters (mm) in diameter, or measuring less than about 10 millimeters (mm) in diameter, or measuring greater than about 10 mm in diameter but less than about 1 centimeter (cm) in diameter, or measuring greater than about 10 mm in diameter but less than about 2 centimeters (cm) in diameter, or measuring greater than about 2 cm in diameter. A tumor may be a primary tumor (e.g., a tumor which remains in the general location in which it originated in the body), and may be a metastatic tumor (e.g., a tumor which grew from cancerous cells or tissues that have migrated from a different location in the body). A tumor may be, for example, a tumor of the bone, breast, prostate, ovary, skin, brain, bladder, cervix, liver, pancreas, lung, colon, stomach, intestine, adrenal gland, kidney, blood, or other organ or tissue. A tumor, such as a metastatic tumor, or cells that lead to a metastatic tumor, may be a blood-borne. 
     The term “solid tumor” as used herein refers to a cancerous tumor in which cancerous cells adhere to each other, to form a continuous, or at least partially continuous, tissue comprising cancerous cells. A solid tumor may also include pre-cancerous cells and tissue, and may also include non-cancerous cells and tissue. A solid tumor may include fluid, including fluid-filled spaces or cavities. 
     “Patient,” “individual” or “subject” is used interchangeably to refer to a human subject. In some cases, the individual is suspected of having adrenal insufficiency. 
     As used herein, the terms “did not experience benefit”, “patients experiencing no benefit”, and “patients not experiencing benefit” refer to cancer patients suffering from progressive disease, i.e., whose tumors progress in size, or metastasize, or otherwise progress during the study period. 
     The term “administering” includes oral administration, topical contact, administration as a suppository, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, epicutaneous, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. 
     The term “sample” refers to a biological sample obtained from a human subject. Such samples are typically removed from the subject, and, when obtained, become entirely separate from the subject (i.e., are in vitro samples). The sample can be any cell, tissue or fluid sample obtained from a human subject. The sample may be, e.g., a blood sample, a saliva sample, a urine sample, or other sample obtained from the patient. Samples can be subject to various treatment, storage or processing procedures before being analyzed according to the methods described herein. Generally, the terms “sample” or “samples” are not intended to be limited by their source, origin, manner of procurement, treatment, processing, storage or analysis, or any modification. Thus, in embodiments, samples are in vitro samples and may be analyzed using in vitro methods. The methods disclosed herein are in vitro methods when used with samples obtained from, and removed from, the human subject. 
     The term “glucocorticoid” (“GC”) includes any compound known in the art that is referred to as a glucocorticoid receptor agonist, glucocorticoid, glucocorticosteroid, corticoid, corticosteroid, or steroid that binds to and activates a glucocorticoid receptor. “Glucocorticosteroid” refers to a steroid hormone or steroidal molecule that binds to the glucocorticoid receptor. Glucocorticosteroids are GCs. Glucocorticosteroids are typically characterized by having 21 carbon atoms, an α,β-unsaturated ketone in ring A, and an α-ketol group attached to ring D. They differ in the extent of oxygenation or hydroxylation at C-11, C-17 and C-19 (Rawn, “Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives,” in Biochemistry, Daisy et al. (eds.), 1989, pg. 567). GCs include, for example, dexamethasone, prednisone, prednisolone, triamcinolone, and hydroxycortisone. 
     “Glucocorticoid receptor” (“GR”) refers to the type II GR which specifically binds to cortisol and/or cortisol analogs such as dexamethasone (See, e.g., Turner &amp; Muller,  J Mol Endocrinol,  2005 35 283-292). The GR is also referred to as the cortisol receptor. The term includes isoforms of GR, recombinant GR and mutated GR. Inhibition constants (K i ) against the human GR receptor type II (Genbank: P04150) are between 0.0001 nM to 1,000 nM; preferably between 0.0005 nM to 10 nM, and most preferably between 0.001 nM to 1 nM. 
     The term “glucocorticoid receptor modulator” or “GRM” refers to a composition or compound which binds to GR and changes (“modulates”) the binding of a GC to GR, or modulates the effects of such GR binding. GCs (GR agonists) include cortisol and cortisol analogs, synthetic or natural, as discussed above. Thus, a GRM alters the effect of GR agonist binding that would occur in the absence of the GRM. 
     The term “glucocorticoid receptor antagonist” or “GRA” refers to any composition or compound which partially or completely inhibits (antagonizes) the binding of a glucocorticoid receptor (GR) agonist, such as cortisol, or cortisol analogs, synthetic or natural, to a GR. A GRA is a GRM which provides antagonistic modulation of the effect of GR agonist binding that would occur in the absence of the GRA. A “specific glucocorticoid receptor antagonist” refers to any composition or compound which inhibits any biological response associated with the binding of a GR to an agonist. By “specific,” the drug preferentially binds to the GR rather than other nuclear receptors, such as mineralocorticoid receptor (MR), androgen receptor (AR), or progesterone receptor (PR). It is preferred that the specific glucocorticoid receptor antagonist bind GR with an affinity that is 10× greater ( 1/10 th  the K d  value) than its affinity to the MR, AR, or PR, both the MR and PR, both the MR and AR, both the AR and PR, or to the MR, AR, and PR. In a more preferred embodiment, the specific glucocorticoid receptor antagonist binds GR with an affinity that is 100× greater ( 1/100 th  the K d  value) than its affinity to the MR, AR, or PR, both the MR and PR, both the MR and AR, both the AR and PR, or to the MR, AR, and PR. 
     Non-steroidal GRM compounds include glucocorticoid receptor antagonists having a heteroaryl ketone fused azadecalin backbone, or an octahydro fused azadecalin backbone. Exemplary GRMs having a heteroaryl ketone fused azadecalin backbone include those described in U.S. Pat. Nos. 8,859,774; 9,273,047; 9,707,223; and 9,956,216. Exemplary GRMs having an octohydro fused azadecalin backbone include those described in U.S. Pat. No. 10,047,082. 
     All patents, patent applications, patent publications, and published articles cited herein, both supra and infra, are hereby incorporated by reference in their entireties, including all compounds and compositions disclosed in the patents, patent applications, patent publications, and published articles cited herein. 
     As used herein, the term “relacorilant” (also known as CORT125134) refers to the heteroaryl ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (Example 18 of U.S. Pat. No. 8,859,774), which has the following structure: 
     
       
         
         
             
             
         
       
     
     As used herein, the term “CORT122928” refers to the heteroaryl ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,-7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone (Example 1C of U.S. Pat. No. 8,859,774), which has the following structure: 
     
       
         
         
             
             
         
       
     
     As used herein, the term “CORT113176” refers to the heteroaryl ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl) sulfonyl)-4,4a, 5,6,7,8-hexahydro-1-H-pyrazolo P,4-g]isoquinolin-4a-yl) (pyridin-2-yl)methanone (Example 1 of U.S. Pat. No. 8,859,774) which has the following structure: 
     
       
         
         
             
             
         
       
     
     As used herein, the term “CORT125281” refers to the octahydro fused azadecalin 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 (Example 2C of U.S. Pat. No. 10,047,082), which has the structure: 
     
       
         
         
             
             
         
       
     
     “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer&#39;s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors, and the like. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention. 
     In addition to, or along with, the methods disclosed herein, cancers may be treated with cancer chemotherapeutic agents. As used herein, the terms “cancer chemotherapeutic”, “cancer chemotherapeutic agent”, “cancer therapeutic”, and “cancer chemotherapy agent” refer to compounds and compositions used to treat cancer. Cancer chemotherapeutic agents and treatments by such agents include hormones and hormone modifiers used in “anti-hormonal” cancer treatments, antibody treatments, chemotoxic compounds and formulations that are typically toxic to cancer cells (and often non-cancerous cells as well), antiproliferative agents (reducing cancer cell growth or replication), agents that are anti-metastatic (reducing metastases), and other agents and treatments that inhibit, stop, or reverse the growth or spread of cancer in a cancer patient. 
     Cancer chemotherapeutic agents include, but are not limited to, doxorubicin, vincristine, cyclophosphamide, fluorouracil (e.g., 5-fluorouracil (5-FU)), topotecan, interferons, platinum derivatives, taxanes (e.g., paclitaxel, nab-paclitaxel, docetaxel, larotaxel, tesetaxel, cabazitaxel, and ortataxel), vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g., etoposide), cisplatin, an mTOR inhibitor (e.g., a rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, camptothecin, cisplatin, metronidazole, and imatinib mesylate, among others. 
     As used herein, an “antiproliferative agent” is a compound or composition used to reduce the growth or spread of cancer in a patient. As used herein, antiproliferative agents are cancer chemotherapeutic agents. Antiproliferative agents typically slow or arrest the growth or replication of cancer cells. Chemotherapeutic or antiproliferative agents may also include biologic agents such as, e.g., bevacizumab, panitumumab, pertuzumab, lapatinib. 
     Chemotherapeutic agents as defined herein include “anti-hormonal agents” which act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer. They may be hormones themselves, including, but not limited to: anti-estrogens with mixed agonist/antagonist profile, including, tamoxifen (NOLVADEX®), 4-hydroxytamoxifen, toremifene (FARESTON®), idoxifene, droloxifene, raloxifene (EVISTA®), trioxifene, keoxifene, and selective estrogen receptor modulators (SERMs) such as SERM3; pure anti-estrogens without agonist properties, such as fulvestrant (FASLODEX®), and EM800 (such agents may block estrogen receptor (ER) dimerization, inhibit DNA binding, increase ER turnover, and/or suppress ER levels); aromatase inhibitors, including steroidal aromatase inhibitors such as formestane and exemestane (AROMASIN®), and nonsteroidal aromatase inhibitors such as anastrazole (ARIMIDEX®), letrozole (FEMARA®) and aminoglutethimide, and other aromatase inhibitors include vorozole (RIVISOR®), megestrol acetate (MEGASE®), fadrozole, and 4(5)-imidazoles; luteinizing hormone-releasing hormone agonists, including leuprolide (LUPRON® and ELIGARD®), goserelin, buserelin, and triptorelin; sex steroids, including progestins such as megestrol acetate and medroxyprogesterone acetate, estrogens such as diethylstilbestrol and premarin, and androgens/retinoids such as fluoxymesterone, all transretionic acid and fenretinide; onapristone; anti-progesterones; estrogen receptor down-regulators (ERDs); anti-androgens such as flutamide, nilutamide and bicalutamide; anti-androgens such as, e.g., enzalutamide, darolutamide, and apalutamide; and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above. 
     Cancer chemotherapeutic agents, such as antiproliferative agents and chemotoxic compounds and formulations include, e.g., abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, BCG live, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, camptothecin, carboplatin, carmustine, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin hydrochloride, dromostanolone propionate, epirubicin, epoetin alfa, erlotinib, enzalutamide, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate, and zoledronic acid. 
     The terms “cancer chemotherapeutic” and “cancer chemotherapeutic agent”, “cancer therapeutic”, and “cancer chemotherapy agent” thus include chemical compounds useful in the treatment of cancer. Examples of cancer chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethyl enethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ1I and calicheamicin Ω1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), “Abx”, albumin-engineered nanoparticle formulations of paclitaxel also known as nab-paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above. 
     As used herein, the terms “cancer chemotherapeutic” and “cancer chemotherapy agent” also include (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifene citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN®, rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above. 
     As used herein, the terms “cancer chemotherapeutic” and “cancer chemotherapy agent” also include antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®), Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti-interleukin-12 (ABT-874/1695, Wyeth Research and Abbott Laboratories) which is a recombinant exclusively human-sequence, full-length IgG 1  λ antibody genetically modified to recognize interleukin-12 p40 protein. 
     As used herein, the terms “cancer chemotherapeutic” and “cancer chemotherapy agent” also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.” Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No. 4,943,533, Mendelsohn et al.) and variants thereof, such as chimerized 225 (C225 or Cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see, WO 96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in U.S. Pat. No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen); EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6. 3 and E7.6. 3 and described in U.S. Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)). The anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules such as compounds described in U.S. Pat. Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: WO98/14451, WO98/50038, WO99/09016, and WO99/24037. Particular small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quin-azolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3′-Chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoli-ne, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol)-; (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimi-dine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(-dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3 fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine). 
     As used herein, the terms “cancer chemotherapeutic” and “cancer chemotherapy agent” also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules (e.g. those that bind to HER-encoding nucleic acid); quinoxalines (U.S. Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinib mesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®); or as described in any of the following patent publications: U.S. Pat. No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca). 
     The terms “cancer chemotherapeutic” and “cancer chemotherapy agent” also include interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof. 
     The terms “cancer chemotherapeutic” and “cancer chemotherapy agent” also include immune selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); Interleukin 13 (IL-13) blockers such as lebrikizumab; Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-M1 prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTa1/β2 blockers such as Anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g.,  211 At,  131 I,  125 I,  90 Y,  186 Re,  188 Re,  153 Sm,  212 Bi,  32 P,  212 Pb and radioactive isotopes of Lu); miscellaneous investigational agents such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH 3 , or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone; farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN™) combined with 5-FU and leucovorin. 
     Methods of measuring gene expression levels are known in the art. For example, gene expression levels may be measured using polymerase chain reaction methods (PCR), including real-time PCR, quantitative PCR (qPCR), reverse-transcription PCR (RT-PCR), and other PCR methods; by sequencing techniques, by use of microarrays, by NanoString technology (e.g., NanoString XT expression assay (Nanostring Technologies, Seattle Wash., USA), or by a comparable technology known in the art; see, e.g.,  Molecular Cloning: A Laboratory Manual  (written by Green and Sambrook, published by Cold Spring Harbor Laboratory, 2012);  DNA MicroArrays: A Molecular Cloning Manual , by Bowtell and Sambrook, published by Cold Spring Harbor Laboratory, 2003); Shalon, et al., “A DNA microarray system for analyzing complex DNA samples using two-color fluorescent probe hybridization”. Genome Res. 6 (7): 639-645 (1996); Pollack et al., “Genome-wide analysis of DNA copy-number changes using cDNA microarrays”. Nat Genet. 23 (1): 41-46 (1999). In addition, gene expression levels may be determined by identifying and measuring the amounts of the protein or amino acid sequences encoded by mRNA in the blood sample. See, e.g.,  Proteins and Proteomics , by Simpson, Cold Spring Harbor Laboratories, 2003 ; Proteomics in Practice , by Westheimer, Naven, and Hopker, Wiley-Blackwell, 2008. 
     As used herein, the terms “experienced benefit” and “patients experiencing benefit” refer to cancer patients who exhibit stable disease (SD), or exhibit a partial response (PR), or exhibit a complete response (CR), during or pursuant to the treatment. Stable disease refers to those patients whose tumors do not grow, and do not exhibit metastases, during the study period, although the tumor does not shrink in size. A patient in remission has stable disease. A partial response is seen in those patients whose tumors shrink, during the study period, although the tumor does not disappear. A complete response refers to those patients whose tumors shrink to such a size as to become negligible, or no longer palpable or visible under standard examination. 
     Methods of Treatment and Differential Diagnosis 
     Glucocorticoid Receptor Antagonists 
     The methods of the present invention generally provide administering a glucocorticoid receptor modulator (GRM), which may be a glucocorticoid receptor antagonist (GRA). In embodiments, the GRM has a heteroaryl ketone fused azadecalin backbone or has an octohydro fused azadecalin backbone. Exemplary GRMs having a heteroaryl ketone fused azadecalin backbone include those described in U.S. Pat. No. 8,859,774. Exemplary GRMs having an octohydro fused azadecalin backbone include those described in U.S. Pat. No. 10,047,082, entitled Octahydro Fused Azadecalin Glucocorticoid Receptor Modulators. In embodiments, the GRM is selected from relacorilant (also known as CORT125134), CORT122928, CORT113176, and CORT125281. In preferred embodiments, the GRM is relacorilant. 
     Pharmaceutical Compositions of Glucocorticoid Receptor Modulators 
     The GRM administered in the practice of the methods disclosed herein can be prepared in any suitable form, including in a wide variety of oral, parenteral and topical dosage forms. Oral preparations of either include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. The GRM compositions of the present invention can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the GRM compositions described herein can be administered by inhalation, for example, intranasally. Additionally, the GRM compositions of the present invention can be administered transdermally. The GRM compositions of this invention can also be administered by intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Accordingly, the present invention provides pharmaceutical compositions of a GRM including a pharmaceutically acceptable carrier or excipient and a GRM compound as disclosed herein. 
     For preparing pharmaceutical compositions from the GRM compound as disclosed herein, pharmaceutically acceptable carriers can be either 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 an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington&#39;s Pharmaceutical Sciences, Maack Publishing Co, Easton Pa. (“Remington&#39;s”). 
     In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5% or 10% to 70% of the compounds of the present invention. 
     Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins including, but not limited to, gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate. 
     Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage). Pharmaceutical preparations of the invention can also be used orally using, for example, 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 can contain the compounds of the present invention mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the compounds of the present invention may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers. 
     For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the compounds of the present invention are dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify. 
     Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. 
     Aqueous solutions suitable for oral use can be prepared by dissolving one or more compounds of the present invention in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring 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 mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can 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. Formulations can be adjusted for osmolarity. 
     Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. 
     Oil suspensions can be formulated by suspending the compounds of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent. 
     Glucocorticoid Receptor Modulator and Cancer Chemotherapeutic Agent Administration 
     The GRM or the cancer chemotherapeutic agent may be administered once, or twice, or more times during a day. The GRM may be administered at a different time than the cancer chemotherapeutic agent is administered; or, in embodiments, and on one or more days, the GRM may be administered on the same day that the cancer chemotherapeutic agent is administered. The GRM may be administered for one day; for two days; for three days; or for more days. The GRM may be administered on a day, or on days, in which a cancer chemotherapeutic agent is also administered to the patient. In embodiments, the GRM is administered on a day, or on days, other than a day in which a cancer chemotherapeutic agent is also administered to the patient. In embodiments, a GRM is administered on a daily basis to a patient, while a cancer chemotherapeutic agent is administered on an intermittent basis, such as, e.g., administration of a cancer chemotherapeutic agent once every week, or administration of a cancer chemotherapeutic agent once every other week, or administration of a cancer chemotherapeutic agent once every three weeks, or administration of a cancer chemotherapeutic agent once every month, for a period of time selected from: one, two, or three weeks, or one, two, three, four, five, or six months. 
     The GRM compounds, or the cancer chemotherapeutic agents, or both, can be delivered by any suitable means, including oral, parenteral (e.g., intravenous injection or intramuscular injection) and topical methods. The GRM, or the cancer chemotherapeutic agent, or both, can be administered orally. For example, the GRM can be administered as a pill, a capsule, or liquid formulation as described herein. Alternatively, GRMs can be provided via parenteral administration. For example, the GRM, or the cancer chemotherapeutic agent, or both, can be administered intravenously (e.g., by injection or infusion into a vein). the GRM, or the cancer chemotherapeutic agent, or both, can be administered intra-arteriorly (e.g., by injection or infusion into an artery or arteriole). In embodiments, the GRM, or the cancer chemotherapeutic agent, or both, can be administered by injection or infusion into a lymphatic vessel, lymph node, a body cavity, or into the peritoneum, or elsewhere. Transdermal administration methods, by a topical route, can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Additional methods of administration of the compounds described herein, and pharmaceutical compositions or formulations thereof, are described herein. 
     The GRM, or the cancer chemotherapeutic agent, or both, may be administered at any time during the day or night. In embodiments of the methods provided herein, a GRM, or cancer chemotherapeutic agent, or both, may be administered in the morning; and may be administered in the morning prior to the morning meal (“fasted” administration) or may be administered in the morning within about 30 minutes or within about one hour after the patient begins eating the morning meal (“fed” administration). 
     The GRM and the cancer chemotherapeutic agent may be provided in a pharmaceutical preparation, and may be provided in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the compounds and compositions of the present invention. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. 
     In some embodiments, the GRM, or the cancer chemotherapeutic agent, or both, is administered in one dose. In other embodiments, the GRM, or the cancer chemotherapeutic agent, or both, is administered in more than one dose, e.g., 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, or more. In some cases, the doses are of an equivalent amount. In other cases, the doses are of different amounts. The doses can increase or taper over the duration of administration. The amount will vary according to, for example, the GRM properties and patient characteristics. 
     Any suitable GRM dose, or cancer chemotherapeutic agent dose, may be used in the methods disclosed herein. The administered dose can be at least about 300 milligrams (mg) per day, or about 600 mg/day, e.g., 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, where the GRA is relacorilant, the GRM dose may be, e.g., 10 mg/day, or 25 mg/day, or 50 mg/day, or 75 mg/day, or 100 mg/day, or 150 mg/day, or 200 mg/day, or 250 mg/day, or 300 mg/day, or 400 mg/day, or 500 mg/day, of relacorilant. For example, where the GRA is mifepristone, the GRM dose may be, e.g., 300 mg/day, or 600 mg/day, or 900 mg/day, or 1200 mg/day of mifepristone. In embodiments, the GRM, or the cancer chemotherapeutic agent, or both, is administered orally. In some embodiments, the GRM, or the cancer chemotherapeutic agent, or both, is administered in at least one dose. In other words, the GRM or the cancer chemotherapeutic agent, or both, can be administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses. In embodiments, the GRM, or the cancer chemotherapeutic agent, or both, is administered orally in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses. 
     The subject may be administered at least one dose of GRM, or cancer chemotherapeutic agent, or both, in one or more doses over, for example, a 2-48 hour period. In some embodiments, the GRM, or the cancer chemotherapeutic agent, or both, is administered as a single dose. In other embodiments, the GRM, or the cancer chemotherapeutic agent, or both, is administered in more than one dose, e.g. 2 doses, 3 doses, 4 doses, 5 doses, or more doses over a 2-48 hour period, e.g., 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, or the cancer chemotherapeutic agent, or both, is administered over 2-48 hours, 2-36 hours, 2-24 hours, 2-12 hours, 2-8 hours, 8-12 hours, 8-24 hours, 8-36 hours, 8-48 hours, 9-36 hours, 9-24 hours, 9-20 hours, 9-12 hours, 12-48 hours, 12-36 hours, 12-24 hours, 18-48 hours, 18-36 hours, 18-24 hours, 24-36 hours, 24-48 hours, 36-48 hours, or 42-48 hours. 
     III. Examples 
     The following examples are offered to illustrate, but not to limit, the claimed invention. 
     Example 1 
     In the following, reference is made to RECIST and RECIST 1.1, which refer to the Response Evaluation Criteria for Solid Tumors. These criteria, first promulgated in 2000, and updated in 2009 (as RECIST 1.1), are generally accepted, and nearly universally used criteria for clinical trials of therapies for solid tumors. See, e.g., Schwartz et al., Eur J Cancer. July; 62: 132-137 (2016). The study described in this Example was performed and evaluated according to these criteria. Detection of the ovarian cancer marker CA-125 was also used, per Gynecologic Cancer Intergroup (GCIG) criteria, in evaluating the patient samples. 
     Patients 
     Patients with solid tumors were enrolled in study NCT02762981, a phase 1/2 study of CORT125134 (aka relacorilant) in combination with nab-paclitaxel. The patients were all 18 years of age or older, with advanced or metastatic solid tumors who have disease progression; all patients gave informed consent to participate in this study. 
     Key inclusion criteria included that the patients be 18 years of age or older, with advanced or metastatic solid tumors who have disease progression; the patients must have been treated with up to three prior lines of therapy in the advanced setting (previous treatment with nab-paclitaxel was allowed); the patients must have an ECOG-PS (Eastern Cooperative Oncology Group Performance Status) of 0-1; must have adequate renal, hepatic, and bone marrow function; and must have measurable or evaluable disease. 
     For patients enrolled in a specific dose-finding pancreatic cohort, the key inclusion criteria also included: histologically confirmed diagnosis of pancreatic adenocarcinoma; CA19-9 (or CEA, CA-125 in non-CA 19-9 elevated tumors) measured within 14 days prior to first dose of study drug; and Metastatic (non-irradiated) lesion that is measurable by RECIST 1.1. (Patients with pancreatic neuroendocrine tumors, lymphoma of the pancreas, or ampullary cancer were not eligible for this specific cohort.) 
     Key exclusion criteria further included: Requirement for treatment with chronic or frequently used oral corticosteroids for medical conditions or illnesses (eg, rheumatoid arthritis, immunosuppression after organ transplantation). 
     Patients received one or more cycles of treatments as describe schematically in  FIGS. 1 and 2 . The treatment schedules of each 28-day cycle are shown in those figures. Patients in Segment I of the study received continuous dosing of relacorilant (“CORT125134”); that is, relacorilant was administered to the patients on a daily basis. Patients in Segment II of the study received intermittent dosing of relacorilant (“CORT125134”); that is, relacorilant was administered to the patients on those days indicated by the diamond symbols, but not on other days. The first cycle of treatment is termed “cycle 1” (abbreviated as “C1”), the second cycle as “cycle 2” (“C2”), and so forth. The days of each cycle are numbered; thus, day 1 of cycle one is “C1D1” and day 15 of cycle 1 is “C1D15”. Thus, the days of relacorilant administration to patients in cycle 1 of Segment II of the study are C1D-1, C1D1, C1D2, C1D7, C1D8, C1D9, C1D14, C1D15, C1D16, and C1D28 (as shown in  FIG. 2 , where day-1 is the baseline day, during which the patients received the “lead-in” dose of relacorilant). Relacorilant dosing followed the same schedule during subsequent cycles of treatment. 
     Tumor Assessments 
     Tumor assessments were performed at screening, end of cycle 2, and every 6-8 weeks thereafter with confirmation of tumor response performed as needed per RECIST (version 1.1). Ovarian, fallopian tube, or primary peritoneal cancer tumors also included CA-125 assessment and response per GCIG criteria. Patients were dosed with relacorilant daily (see  FIG. 1 ) or intermittently (see  FIG. 2 ), and nab-paclitaxel was administered on a 28-day cycle. 
       FIG. 1  illustrates the dosing schedule for cancer patients receiving both nab-paclitaxel (“Nab-Pac”) and relacorilant (“CORT125134”), showing Segment I of the clinical experimentation, in which cancer patients received nab-paclitaxel (“Nab-Pac”) and relacorilant pursuant to a Continuous-Dosing Regimen, consisting of two phases, a Dose-Finding phase and Dose-Extension phase. The schematic diagram illustrates the initial phase (“Part 1: Dose Finding”) and the subsequent phase (“Part 2: Dose-Extension”). In this study, cancer patients received nab-paclitaxel intermittently, and, once relacorilant was administered following the nab-paclitaxel lead-in period, the cancer patients also received daily relacorilant. The Dose Finding phase began with “Nab-Pac Lead-In”, in which patients received nab-paclitaxel on Day 1 (indicated by the square symbol), and had eight blood draws on Day 1, and a single blood draw on Day 2 (indicated by the open circle symbols). Blood obtained from these blood draws was analyzed and stored as detailed in the text below. The “Nab-Pac Lead-In” portion of the regimen was followed by the “CORT125134 Lead-In” phase, which began daily administration of relacorilant (also known as CORT125134). The daily relacorilant administration began on Day 1 of the CORT125134 Lead-In phase (a further blood draw was obtained on that day as well), and continued daily through day 7 of that “lead-in” phase (and further on a daily basis for 28 days after day 7 of the “lead-in”). Relacorilant administration is indicated by the solid diamond symbols. Further blood draws were obtained on Day 7 of the “lead-in” phase as well (indicated by the open circles). Following the 7 days of nab-paclitaxel Lead-In, and following the 7 days of CORT125134 Lead-In that followed that nab-paclitaxel Lead-In, a “28-Day Cycle” of administration of both nab-paclitaxel (on days 1, 8, and 15 of the 28-day cycle, indicated by the square symbols) and relacorilant (daily administration on days 1 through 28, as indicated by the diamond symbols) was performed. The open circles indicate blood draws. 
     In the second phase shown in  FIG. 1  (“Part 2: Dose Extension”), patients received relacorilant on days 1 through 7 of the “CORT125134 Lead-In” of the Dose Extension study. Following this 7 days of daily relacorilant, a further “28-Day Cycle” began, in which the patients received nab-paclitaxel on Day 1, Day 8, and Day 15 of the 28-Day cycle, while continuing to receive daily relacorilant on days 1 through 28 of this 28-Day cycle. Blood was drawn on Day 1, Day 8, and Day 15 as indicated by the open circles. 
       FIG. 2  illustrates the dosing schedule for cancer patients receiving both nab-paclitaxel (“Nab-Pac”) and relacorilant (“CORT125134”) according to an Intermittent Dosing Regime, showing Segment II of the clinical study. In this study, cancer patients received relacorilant on Day-1 (which served as the Baseline Day and the relacorilant lead-in day). Following Day-1, a 28-Day cycle began, in which cancer patients received nab-paclitaxel intermittently, and received relacorilant intermittently. The cancer patients received relacorilant on Days 1 and 2, on Days 7-9, on Days 14-16, and on Day 28 (as indicated by the filled diamond symbols). The cancer patients received nab-paclitaxel on Day 1, on Day 8, and on Day 15 (as indicated by the square symbols). Blood was drawn on Day 1, Day 8, and Day 15 as indicated by the open circles. 
     Specimen Collection 
     Blood was collected at baseline, prior to administration of relacorilant or nab-paclitaxel. Blood was also drawn in the morning, pre-dose, on cycle 1, day 15. Blood (in the amount of 2.5 milliLiters (mL)) was drawn into a PAXGene blood RNA tube (Qiagen) using a butterfly needle. The tube was sealed and gently inverted 10 times. The tube was frozen in dry ice and stored at −80° C. until RNA extraction. 
     RNA Isolation and Quantification 
     Paired baseline and cycle 1, day 15 (C1D15) specimens were thawed and processed in the same batch. RNA was isolated using the PAXgene Blood RNA kit (Qiagen) using the protocol recommended by the manufacturer. RNA yield was quantified using a NanoDrop ND-2000 spectrophotometer (ThermoFisher Scientific). RNA was assessed using a custom 33-gene panel after mRNA sample preparation and hybridization using NanoString nCounter XT Assay, following the operation and maintenance instructions for the NanoString prep station and digital analyzer. Specific RNA transcripts were quantified using a Nanostring nCounter FLEX instrument (NanoString Technologies) and analyzed using nSolver 3.0. (Nanostring Technologies, Seattle Wash., USA). 
     Data Normalization and Analysis 
     Housekeeping gene pairwise correlations were determined using nSolver 3.0 (NanoString Technologies). Test genes were normalized to the housekeeping genes HPRT1, PPIB, TRAP1, EEF1A1, and TBP. Change from baseline was calculated using the RNA counts at baseline and cycle 1, day 15 as follows:
         Change from Baseline=(C1D15−baseline)/(baseline)
 
Results
 
Housekeeping Genes Selection
       

     The glucocorticoid receptor controls the expression of many genes, so it is critical that GR-independent housekeeping genes are selected. Pairwise correlation coefficients were determined using the raw counts of the 9 candidate housekeeping genes ACTA, GAPDH, FPGS, HPRT1, PPIB, TRAP1, RPLPO, EEF1A1, and TBP. The subset including HPRT1, PPIB, TRAP1, EEF1A1, and TBP were selected as true housekeeping genes due to consistent pairwise correlation coefficients greater than 0.87. 
     Normalized Counts of GR-Responsive Genes 
     Pairwise correlations between candidate housekeeping genes is shown in  FIG. 3 . The darkness of the hue of each cell in the figure gives an indication of the positive magnitude of the correlation (thus, the darkest hues are found on the diagonal, as each gene expression level shows maximal correlation (1.0) with itself). These correlations were based on raw counts (mRNA expression levels). After normalization to GR-independent housekeeping genes, the remaining 24 genes in the Nanostring panel were analyzed. These genes were pre-selected based on literature and Corcept studies (NCT03335956, data on file at Corcept) suggesting they are induced by synthetic or endogenous corticosteroids. These genes are not expected to be affected by nab-paclitaxel (Maranville et al., 2014). A full list of assessed genes is provided in Table 1. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Genes Analyzed in This Study 
               
            
           
           
               
               
               
               
            
               
                 Common 
                   
                 HUGO 
                   
               
               
                 name 
                 Accession 
                 name 
                 NSID 
               
               
                   
               
               
                 ACTB 
                 NM_001101.2 
                 ACTB 
                 NM_001101.2:1010 
               
               
                 B2M 
                 NM_004048.2 
                 B2M 
                 NM_004048.2:25 
               
               
                 cIAP2 
                 NM_182962.2 
                 BIRC3 
                 NM_182962.2:275 
               
               
                 DUSP1 
                 NM_004417.2 
                 DUSP1 
                 NM_004417.2:987 
               
               
                 EEF1A1 
                 NM_001402.5 
                 EEF1A1 
                 NM_001402.5:790 
               
               
                 FKBP4 
                 NM_002014.3 
                 FKBP4 
                 NM_002014.3:310 
               
               
                 FKBP5 
                 NM_001145775.1 
                 FKBP5 
                 NM_001145775.1:540 
               
               
                 FPGS 
                 NM_001018078.1 
                 FPGS 
                 NM_001018078.1:633 
               
               
                 GAPDH 
                 NM_002046.5 
                 GAPDH 
                 NM_002046.5:350 
               
               
                 GATA-3 
                 NM_001002295.1 
                 GATA3 
                 NM_001002295.1:1691 
               
               
                 GSK3b 
                 NM_002093.2 
                 GSK3B 
                 NM_002093.2:925 
               
               
                 HPRT1 
                 NM_000194.1 
                 HPRT1 
                 NM_000194.1:240 
               
               
                 HSP-90 
                 NM_001017963.2 
                 HSP90AA1 
                 NM_001017963.2:1655 
               
               
                 IL10 
                 NM_000572.2 
                 IL10 
                 NM_000572.2:230 
               
               
                 IL6 
                 NM_000600.3 
                 IL6 
                 NM_000600.3:364 
               
               
                 MCL-1 
                 NM_021960.3 
                 MCL1 
                 NM_021960.3:1260 
               
               
                 NF- 
                 NM_003998.2 
                 NFKB1 
                 NM_003998.2:1675 
               
               
                 kappaB 
               
               
                 PEPCK 
                 NM_002591.2 
                 PCK1 
                 NM_002591.2:1870 
               
               
                 Per1 
                 NM_002616.2 
                 PER1 
                 NM_002616.2:4365 
               
               
                 PIK3CG 
                 NM_002649.2 
                 PIK3CG 
                 NM_002649.2:2125 
               
               
                 POMC 
                 NM_000939.2 
                 POMC 
                 NM_000939.2:1092 
               
               
                 PPIB 
                 NM_000942.4 
                 PPIB 
                 NM_000942.4:272 
               
               
                 COX2 
                 NM_000963.3 
                 PTGS2 
                 NM_000963.3:450 
               
               
                 PTX-3 
                 NM_002852.3 
                 PTX3 
                 NM_002852.3:1152 
               
               
                 RGS-2 
                 NM_002923.1 
                 RGS2 
                 NM_002923.1:855 
               
               
                 RPLPO 
                 NM_001002.3 
                 RPLP0 
                 NM_001002.3:250 
               
               
                 SGK1 
                 NM_005627.2 
                 SGK1 
                 NM_005627.2:1790 
               
               
                 SOCS-1 
                 NM_003745.1 
                 SOCS1 
                 NM_003745.1:1025 
               
               
                 STAT1 
                 NM_139266.1 
                 STAT1 
                 NM_139266.1:455 
               
               
                 STAT3 
                 NM_003150.3 
                 STAT3 
                 NM_003150.3:2060 
               
               
                 TBP 
                 NM_001172085.1 
                 TBP 
                 NM_001172085.1:587 
               
               
                 TGFB1 
                 NM_000660.3 
                 TGFB1 
                 NM_000660.3:1260 
               
               
                 TRAP1 
                 NM_016292.2 
                 TRAP1 
                 NM_016292.2:1293 
               
               
                   
               
            
           
         
       
     
     To determine the effect of relacorilant on the expression levels of these genes, the counts at cycle 1, day 15 were compared to the counts as baseline. As shown in  FIG. 4  for DUSP1 mRNA expression levels, some (nine) patients suffered progressive disease (shown in the graph at upper right of the figure) but several (seven) patients received benefit, experiencing stable, partial, or complete response to the combined nab-paclitaxel and relacorilant treatment. 
     When all patients were analyzed, the normalized mRNA counts for the gene DUSP1 ( FIG. 4 ) were not significantly different between baseline and cycle 1, day 15 (paired t-test p=0.065). However, within patients experiencing benefit, as defined by stable disease (SD), partial response (PR), or complete response (CR), there was a significant decrease in DUSP1 counts from baseline to cycle 1, day 15 (paired t-test p=0.015). This decrease was not observed in the patients who did not experience a benefit, as defined by progressive disease. Baseline DUSP1 levels, independent of levels at cycle 1, day 15, were not different between patients with progressive disease and patients who benefited from therapy (data not shown). Thus, it appears that decreasing DUSP1 mRNA expression levels after combined nab-paclitaxel and relacorilant treatment are indicative of patient benefit. 
     Given the observation that DUSP1 levels decrease in the patients who benefited from therapy, change from baseline was calculated for all measured genes and in all matched samples in this study. A subset of genes was identified in which mRNA expression was found to be significantly suppressed in the patients who benefit from therapy as compared to the patients with progressive disease ( FIG. 5 ). No change from baseline (where 1.0 is no change from baseline) in the expression levels of these genes was observed in patients experiencing progressive disease. The p-values shown for each gene are Mann-Whitney p-values that represent the difference in change from baseline between the patients with progressive disease compared to the patients who benefited from therapy. 
     Relacorilant is known to reduce or block cortisol activation of glucocorticoid receptors (GR); the expression levels of many genes is affected by GR activation; levels of the genes COX2, DUSP1, GSK3b, MCL-1, PIK3CG, RGS-2, SGK1, and STAT3 are affected by GR activation, and were measured in patients receiving relacorilant. Many patients receiving relacorilant had better-than-expected outcomes (stable disease (SD), complete response CR), or partial response (PR)) and so appeared to derive benefit from relacorilant treatment.  FIG. 5  compares the expression of several genes in patients who derived benefit from relacorilant treatment, to those patients who did not derive benefit from relacorilant treatment. As shown in  FIG. 5 , the expression levels of levels COX2, DUSP1, GSK3b, MCL-1, PIK3CG, RGS-2, SGK1, and STAT3 (as measured by mRNA levels) decreased as compared to baseline in those patients who derived benefit from relacorilant+nab-paclitaxel treatment. In contrast, patients whose cancer progressed did not exhibit decreased levels of the genes COX2, DUSP1, GSK3b, MCL-1, PIK3CG, RGS-2, SGK1. 
     Thus, a decrease in mRNA expression level of other genes, in addition to DUSP1, is indicative of patient benefit, as shown in  FIG. 5 . Thus, decreases in mRNA expression levels of the following genes are indicative of patients who are likely to benefit from combined treatment with nab-paclitaxel and relacorilant: COX2; DUSP1; GSK3b; MCL-1; PIK3CG; RGS-2; SGK1; and STAT3. Similarly, these results also indicate that patients in whom mRNA expression levels of these genes does not decrease are likely not to benefit from combined treatment with nab-paclitaxel and relacorilant. 
     Conclusions 
     Identifying patients likely to respond to a specific therapy improves the efficiency of clinical trials and avoids unnecessary exposure of patients to non-beneficial therapies. This study assessed the effect of relacorilant, a selective glucocorticoid receptor modulator, on the transcription of genes known to be induced by synthetic or endogenous glucorcorticoid receptor agonists. Relacorilant suppressed a subset of genes in the patients who benefited from therapy. These same genes were not altered in patients who experience progressive disease. This observation suggests a possible difference in endogenous cortisol activity (sometimes called “cortisol tone” or “functional hypercortisolism”) that is enriched in the patients likely to benefit from combined therapy comprising administration of relacorilant and nab-Paclitaxel. Baseline levels of these transcripts did not identify patients likely to benefit. Instead, the change from baseline after relacorilant dosing can be used to identify patients likely to benefit from therapy with relacorilant and nab-Paclitaxel. 
     Example 2 
     The previous Example, Example 1, describes a method for identifying cancer patients likely to benefit from therapy including relacorilant, a nonsteroidal selective glucocorticoid receptor (GR) modulator, by measuring gene expression in whole blood of 33 genes. The gene expression pharmacodynamic (PD) data were analyzed against the pharmacokinetic (PK) parameters to establish a PK:PD relationship. A correlation of gene suppression by relacorilant with exposure (C max  or AUC) to relacorilant was also observed. Terms and methods used in this Example 2, and not otherwise defined, are the same as those terms and methods used as described in Example 1. 
     The present example, Example 2, examines a larger set containing 800 genes. Analysis of this larger gene set identified additional genes that may be useful in identifying cancer patients likely to benefit from therapy including relacorilant. Additionally, the genes suppressed by relacorilant were compared to the genes induced by a single dose of 25 mg prednisone. The overlap between the genes induced by prednisone and suppressed in patients who benefited from relacorilant+nab-paclitaxel was significant (p&lt;1×10 −30 ). Such overlap suggests that relacorilant antagonizes the transcription of genes are agonized by prednisone. 
     These observations strengthen the evidence that the genes identified are indeed affected by relacorilant, are glucocorticoid-receptor controlled genes, and could be useful in identifying patients likely to respond to therapies containing relacorilant. These findings also suggest that the benefit observed in patients treated with relacorilant plus chemotherapy are due to relacorilant and not, solely, chemotherapy. 
     Calculations 
     For  FIG. 6 , the normalized counts of 10 GR-controlled genes were averaged. Change from baseline of these averaged values was calculated per patient using the formula:
 
Percent change from baseline=((average value at C1D15)−(average value at baseline))/(average value at baseline)*100
 
Gene set enrichment statistics were calculated using the program available at the URL:
 
     Nemates.org/MA/progs/overlap_stats_prog.html 
     RNA Isolation and Quantification 
     RNA was assessed using a custom 800-gene panel after mRNA sample preparation and hybridization using NanoString nCounter Assay, following the operation and maintenance instructions for the NanoString prep station and digital analyzer. The 800 gene panel was comprised of the Nanostring IO360™ panel plus the following 10 custom probes: 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Further Genes Analyzed in This Study 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 HUGO 
                   
               
               
                 Common 
                   
                 Gene 
               
               
                 Name 
                 Accession 
                 Name 
                 Accession 
               
               
                   
               
               
                 ESYT1 
                 NM_015292.2 
                 ESYT1 
                 NM_015292.2:1385 
               
               
                 FKBP5 
                 NM_001145775.1 
                 FKBP5 
                 NM_001145775.1:540 
               
               
                 GSK3B 
                 NM_002093.2 
                 GSK3B 
                 NM_002093.2:925 
               
               
                 IL12A 
                 NM_000882.2 
                 IL12A 
                 NM_000882.2:775 
               
               
                 IPO7 
                 NM_006391.1 
                 IPO7 
                 NM_006391.1:2325 
               
               
                 (IMPORTIN 
               
               
                 7) 
               
               
                 MCL1 
                 NM_021960.3 
                 MCL1 
                 NM_021960.3:1260 
               
               
                 NR3C1 
                 NM_001018077.1 
                 NR3C1 
                 NM_001018077.1:2822 
               
               
                 PER1 
                 NM_002616.2 
                 PER1 
                 NM_002616.2:4365 
               
               
                 RGS2 
                 NM_002923.1 
                 RGS2 
                 NM_002923.1:855 
               
               
                 GILZ 
                 NM_198057.2 
                 TSC22D3 
                 NM_198057.2:1400 
               
               
                   
               
            
           
         
       
     
     Data Normalization and Analysis 
     Housekeeping gene pairwise correlations were determined using advanced analysis in nSolver 3.0 (NanoString Technologies). Test genes were normalized to the housekeeping genes selected by geNORM. 
     Pharmacokinetic Assessments and Calculations 
     Relacorilant and nab-paclitaxel levels (concentrations) in plasma were measured using standard methods (e.g., Liquid Chromatography mass spectroscopy/mass spectroscopy (LC-MS/MS)). 
     Results 
     Correlation of gene suppression with relacorilant exposure or C max    
     To determine if transcriptional changes observed in whole blood were a function of circulating relacorilant levels, the pharmacodynamic (PD) effects were compared the exposure or C max  pharmacokinetic (PK) parameters. The values for 10 related glucocorticoid-controlled genes were averaged for each specimen, and then the change from baseline to cycle 1 day 15 for each average was calculated. For NCT02762981 segment 1 (continuous relacorilant), the PK parameters at cycle 1 day 8 were determined. For NCT02762981 segment 2 (intermittent relacorilant), the PK parameters for cycle 1 day 15 were determined.  FIG. 1  shows that the exposure (AUC) and C max  for relacorilant are correlated with the average suppression of these 10 genes. A similar analysis conducted with the AUC and Cmax for paclitaxel showed no correlation (data not shown). For this analysis, PK outliers with out-of-range AUC and C max  values are not shown. 
     In  FIG. 6 , Pharmacokinetic-Pharmacodynamic relationships in NCT02762981 are shown.  FIGS. 6A and 6B  show the PK:PD relationship in Segment I and  FIGS. 6C and 6D  show the PK:PD relationship in Segment 2. In  FIG. 6A , the average change from baseline to C1D15 for 10 GR-induced RNAs is plotted as a function of relacorilant C max  for continuous relacorilant dosing. Segment I (6A, 6B) is continuous relacorilant dosing while Segment II (6C, 6D) is intermittent. (GR-induced means that the expression of the subject RNA is increased in the presence of glucocorticoid, such as the prednisone used in these experiments.)  FIG. 6B  shows the average change from baseline to C1D15 for 10 GR-induced RNAs is plotted as a function of relacorilant AUC 0-24  for continuous relacorilant dosing.  FIG. 6C  shows the average change from baseline to C1D15 for 10 GR-induced RNAs is plotted as a function of relacorilant C max  for intermittent relacorilant dosing.  FIG. 6D  shows the average change from baseline to C1D15 for 10 GR-induced RNAs is plotted as a function of relacorilant AUC 0-24  for intermittent relacorilant dosing. 
     Identification of Genes Upregulated by Prednisone and Suppressed in Patients Who Benefited from Relacorilant Therapy 
     Previous findings suggested that GR controlled genes are modulated by relacorilant plus nab-paclitaxel in patients who benefited (stable disease (SD), partial response (PR), or complete response (CR)). Thus, the patients with progressive disease (PD) were analyzed separately from the patients who benefited from therapy. The study included 21 paired samples from NCT02762981 analyzed at baseline and Cycle 1 Day 15. Of those 21 patients, 10 experienced progressive disease and 11 experienced benefit from therapy. As a comparator, 3 healthy subjects were assessed pre- or 4-hr-post-prednisone alone. A summary of the fold changes and respective p-value is shown in  FIG. 7A . Gene expression was measured using mRNA levels. 
       FIG. 7A  provides an overview of whole blood gene expression fold change; the figure shows that transcriptional effects of relacorilant+nab-paclitaxel (Abx) are pronounced in patients with SD, PR, or CR but not PD. (Where SD indicates stable disease, PR indicates partial response, CR indicates complete response, and PD indicates progressive disease.) The transcriptional changes in whole blood from baseline to C1D15 were compared between patients and separated by best overall response. Inset details genes downregulated in SD/PR/CR (92 genes) versus PD (30 genes) patients. The dotted line represents and adjusted p-value of 0.05. These measurements allow for differentiation between patients in whom relacorilant has a beneficial effect (i.e., SD, PR, or CR, shown with circles) and those whose disease progressed (PD, shown with squares) despite the treatment. Determining whether or not some or all of these genes are downregulated by relacorilant treatment provides a basis for identifying patients likely to benefit from treatments with relacorilant combined with cancer chemotherapy. 
     Enzalutamide is an androgen receptor antagonist used in the treatment of hormone-sensitive cancers such as prostate cancer. In contrast to the significant changes in gene expression shown in  FIG. 7A , 28 days of enzalutamide treatment administered to human cancer patients did not result in any significant changes (as compared to baseline levels) in gene expression levels in these patients (see  FIG. 7B ). The small circular markers indicate the change in gene expression for individual genes. None of the gene expression levels changes following enzalutamide (as compared to baseline levels) reach significance (all p-values are greater than 0.5). 
     Comparison of Genes Upregulated by Prednisone and Suppressed after Treatment with Relacorilant 
     To determine if the suppressed genes observed in  FIG. 7A  were controlled by the glucocorticoid receptor (GR), relacorilant+nab-paclitaxel suppressed genes were compared to genes induced by prednisone. The 200 genes with the largest induction post prednisone were compared to the 200 genes with the largest suppression following relacorilant+nab-paclitaxel. Gene enrichment analysis was conducted by determining the number of overlapping genes within each 200 gene set ( FIG. 8 ). There was a significant enrichment of genes shared in the sets induced by prednisone and suppressed by relacorilant in patients who benefited (116 genes, 2.2-fold enrichment, p=3×10 −30 ). The overlap between genes induced by prednisone and suppressed by relacorilant in patients with progressive disease was less than expected if the genes were identified at random (38 genes, 0.7-fold enrichment). 
       FIG. 8 . Comparison of genes induced by prednisone (dark grey, left) to genes suppressed by relacorilant+nab-paclitaxel (right) in patients who benefited (light grey, top) or had progressive disease (white, bottom). Glucocorticoid-induced genes are suppressed by relacorilant+nab-paclitaxel. Transcriptional changes were measured 4 hours post dose with 25 mg prednisone alone in a separate study. Top 200 genes with the largest change from baseline were compared. A significant overlap in genes induced by prednisone and suppressed in relacorilant+nab-paclitaxel was observed only in the patients with a best overall response of SD, PR, or CR. 
     Identification of Gene Signature to Identify Patients Who Benefit from Relacorilant+Nab-Paclitaxel 
     In Example, 1, a set of genes that was suppressed only in the patients who benefited from relacorilant+nab-paclitaxel was reported. A similar analysis was conducted from the 800-gene panel reported in  FIG. 7 . The fold change from baseline to cycle 1 day 15 for 50 genes was calculated. Because the 800 gene panel included both glucocorticoid receptor antagonist induced and suppressed genes, a correction was applied to the induced genes. The predictive value was compared between the top 50 genes from the 800 gene panel and the top 10 genes from the 33 gene panel ( FIG. 9A ). For this analysis, the change from baseline for each gene was calculated and the geometric mean across the 10-50 genes was determined per patient. 
       FIGS. 9A and 9B . Identification of a superior set of genes capable of identifying patients who benefit from relacorilant.  FIG. 9A  shows the 10 genes identified from the 33 gene panel (left) are compared to the 50 genes identified from the 800 gene panel (right).  FIG. 9B  shows a receiver operator curve demonstrating the superior true positive rate and false positive rate of the 8-gene panel derived from the 800 gene set. Squares represent the 50 genes panel derived from the 800 gene set, circles represent the 10 gene panel derived from the earlier 33 gene set, and triangle represent unity. The HUGO gene names for the 50 genes identified from the 800 gene panel are listed in Table 3. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 50 Genes for which whole blood RNA change post-therapy differed 
               
               
                 in patients with progressive disease versus patients with benefit 
               
            
           
           
               
               
               
               
            
               
                 Common 
                   
                 HUGO 
                   
               
               
                 name 
                 Accession 
                 name 
                 NSID 
               
               
                   
               
               
                 APC 
                 NM_001127510.2 
                 APC 
                 NM_001127510.2:462 
               
               
                 BID 
                 NM_001196.3 
                 BID 
                 NM_001196.3:1604 
               
               
                 CCL5 
                 NM_002985.2 
                 CCL5 
                 NM_002985.2:277 
               
               
                 CCR5 
                 NM_000579.3 
                 CCR5 
                 NM_000579.3:366 
               
               
                 CD27 
                 NM_001242.4 
                 CD27 
                 NM_001242.4:326 
               
               
                 CD300A 
                 NM_001256841.1 
                 CD300A 
                 NM_001256841.1:371 
               
               
                 CD3E 
                 NM_000733.3 
                 CD3E 
                 NM_000733.3:233 
               
               
                 CD3G 
                 NM_000073.2 
                 CD3G 
                 NM_000073.2:404 
               
               
                 CD40LG 
                 NM_000074.2 
                 CD40LG 
                 NM_000074.2:1225 
               
               
                 CEACAM3 
                 NM_001277163.2 
                 CEACAM3 
                 NM_001277163.2:807 
               
               
                 CLEC4E 
                 NM_014358.3 
                 CLEC4E 
                 NM_014358.3:1392 
               
               
                 CLEC7A 
                 NM_197954.2 
                 CLEC7A 
                 NM_197954.2:55 
               
               
                 COL6A3 
                 NM_004369.3 
                 COL6A3 
                 NM_004369.3:3293 
               
               
                 COX2 
                 NM_000963.3 
                 PTGS2 
                 NM_000963.3:450 
               
               
                 CXCL1 
                 NM_001511.3 
                 CXCL1 
                 NM_001511.3:743 
               
               
                 CXCL2 
                 NM_002089.1 
                 CXCL2 
                 NM_002089.1:435 
               
               
                 CXCR3 
                 NM_001142797.1 
                 CXCR3 
                 NM_001142797.1:654 
               
               
                 CXCR6 
                 NM_006564.1 
                 CXCR6 
                 NM_006564.1:97 
               
               
                 EDN1 
                 NM_001955.2 
                 EDN1 
                 NM_001955.2:770 
               
               
                 EIF2B4 
                 NM_001034116.1 
                 EIF2B4 
                 NM_001034116.1:1258 
               
               
                 ENTPD1 
                 NM_001098175.1 
                 ENTPD1 
                 NM_001098175.1:1418 
               
               
                 ESYT1 
                 NM_015292.2 
                 ESYT1 
                 NM_015292.2:1385 
               
               
                 F2RL1 
                 NM_005242.4 
                 F2RL1 
                 NM_005242.4:1388 
               
               
                 FBP1 
                 NM_001127628.1 
                 FBP1 
                 NM_001127628.1:488 
               
               
                 FCGR3A/B 
                 NM_000570.4 
                 FCGR3B 
                 NM_000570.4:255 
               
               
                 FCGRT 
                 NM_004107.4 
                 FCGRT 
                 NM_004107.4:1260 
               
               
                 GIMAP6 
                 NR_024115.1 
                 GIMAP6 
                 NR_024115.1:2175 
               
               
                 GOT2 
                 NM_002080.3 
                 GOT2 
                 NM_002080.3:674 
               
               
                 GZMK 
                 NM_002104.2 
                 GZMK 
                 NM_002104.2:634 
               
               
                 ICAM2 
                 NM_000873.3 
                 ICAM2 
                 NM_000873.3:415 
               
               
                 ICAM3 
                 NM_002162.3 
                 ICAM3 
                 NM_002162.3:1225 
               
               
                 IL10RA 
                 NM_001558.2 
                 IL10RA 
                 NM_001558.2:150 
               
               
                 IL32 
                 NM_004221.4 
                 IL32 
                 NM_004221.4:358 
               
               
                 IL7R 
                 NM_002185.3 
                 IL7R 
                 NM_002185.3:1355 
               
               
                 ITGA6 
                 NM_001316306.1 
                 ITGA6 
                 NM_001316306.1:1982 
               
               
                 KLRB1 
                 NM_002258.2 
                 KLRB1 
                 NM_002258.2:85 
               
               
                 LCK 
                 NM_005356.4 
                 LCK 
                 NM_005356.4:1723 
               
               
                 LDHB 
                 NM_001174097.2 
                 LDHB 
                 NM_001174097.2:1200 
               
               
                 MRE11 
                 NM_001330347.1 
                 MRE11 
                 NM_001330347.1:2169 
               
               
                 MYC 
                 NM_002467.3 
                 MYC 
                 NM_002467.3:1615 
               
               
                 RELN 
                 NM_005045.3 
                 RELN 
                 NM_005045.3:988 
               
               
                 RICTOR 
                 NM_001285439.1 
                 RICTOR 
                 NM_001285439.1:117 
               
               
                 RPL7A 
                 NM_000972.2 
                 RPL7A 
                 NM_000972.2:657 
               
               
                 SELP 
                 NM_003005.3 
                 SELP 
                 NM_003005.3:120 
               
               
                 THBD 
                 NM_000361.2 
                 THBD 
                 NM_000361.2:1674 
               
               
                 TMEM173 
                 NM_198282.1 
                 TMEM173 
                 NM_198282.1:725 
               
               
                 TNFRSF9 
                 NM_001561.5 
                 TNFRSF9 
                 NM_001561.5:567 
               
               
                 TNKS 
                 NM_003747.2 
                 TNKS 
                 NM_003747.2:1948 
               
               
                 TP53 
                 NM_000546.2 
                 TP53 
                 NM_000546.2:1330 
               
               
                 TREM1 
                 NM_001242589.2 
                 TREM1 
                 NM_001242589.2:101 
               
               
                   
               
            
           
         
       
     
     Table 3 above lists the top 50 genes from the 800 gene panel. These 50 genes show a superior ability to distinguish patients who benefit from those with progressive disease as compared to the 10 gene set derived from the original 33 gene panel. The PK:PD relationships described here provide further evidence that the observed gene changes are due to relacorilant and not nab-paclitaxel. The observation that GR-controlled genes are suppressed in patients who benefit provides further evidences that the benefits are due, at least in part, to relacorilant. The superior ability of the top 50 genes from the 800 gene panel to distinguish patients who benefit from those with progressive disease as compared to the 10 gene set derived from the original 33 gene panel confirm and extend the findings of Example 1. Together, these new findings support our previous hypothesis and claims. 
     Subsets of the 50 genes listed in Table 3 may prove useful in identifying patients likely to respond to treatment. Examples of such subsets include the subsets listed in columns A through E of Table 4. It will be understood that other subsets of the 50 genes listed in Table 3 may be used to identify patients likely to respond to treatment, and may be useful for identifying patients likely to respond to treatment. 
                     TABLE 4                  Five Exemplary Subsets of the 50 Genes of Table 3                                 Column A   Column B   Column C   Column D   Column E               ICAM3   IL32   CXCL2   EIF2B4   GZMK       TREM1   EDN1   FBP1   MRE11   CD300A       FCGRT   CD3G   CD27   CD3E   TMEM173       GIMAP6   CCL5   TNKS   GOT2   MYC       IL10RA   RICTOR   CD40LG   ICAM2   ENTPD1       IL7R   BID   CXCR3   TP53   CXCR6       CEACAM3       LDHB   CLEC7A   RELN       COL6A3       THBD   COX2   CXCL1       SELP       TNFRSF9       CLEC4E       KLRB1       RPL7A       CCR5       FCGR3A/B               ITGA6       LCK               APC       ESYT1               F2RL1                    
Conclusions
 
     Identifying patients likely to respond to a specific therapy improves the efficiency of clinical trials and avoids unnecessary exposure of patients to non-beneficial therapies. This study assessed the effect of relacorilant, a selective glucocorticoid receptor modulator, on the transcription of genes known to be induced by synthetic or endogenous glucocorticoid receptor agonists. 
     Example 3 Relacorilant Combined with Chemotherapy Agents Reduces Tumor Volume 
     The present example, Example 3, provides results of administration of the glucocorticoid receptor modulator relacorilant to cancerous cells. These results demonstrate that relacorilant increases tumor cell sensitivity to chemotherapeutic agents both in vitro and in vivo (xenograft studies). As noted above, relacorilant is a glucocorticoid receptor modulator that potently binds the glucocorticoid receptor and does not bind to the androgen receptor or the progesterone receptor (K i &gt;10 μM; see, e.g., Hunt et al., J Med Chem. 60(8):3405-3421 (2017)). The MIA PaCa-2 xenograft model uses MIA PaCa-2 cell-line cells (pancreatic tumor cells derived from a pancreatic adenocarcinoma from a 65-year-old Caucasian male patient) engrafted into immunodeficient mice. The ovarian OVCAR-5 cell line is derived from a human epithelial carcinoma of the ovary, and was established from ascitic fluid obtained (prior to cytotoxic treatment) from a female patient with progressive ovarian adenocarcinoma. 
       FIG. 10A . Relacorilant sensitizes the MIA PaCa-2 xenograft to paclitaxel. Tumor volume of PaCa-2 xenograft tumors implanted in immunodeficient mice is shown as a function of time (days) after implantation in the presence of vehicle (filled circles), paclitaxel (7.5 mg/kg; filled squares), relacorilant alone (upwardly pointing triangles), and relacorilant+7.5 mg/kg paclitaxel (downwardly pointing triangles). 7.5 mg/kg paclitaxel was administered three times (at the days indicated by the dashed vertical lines, indicating days 8, 12, and 16 following tumor implantation into the mice). These doses of paclitaxel were ineffective in delaying tumor growth of the pancreatic tumor cells engrafted in the immunodeficient mice. Addition of relacorilant delayed tumor growth (p&lt;0.0001) compared to paclitaxel alone. Thus, relacorilant restored sensitivity to paclitaxel in the pancreatic MIA PaCa-2 xenograft model. 
       FIG. 10B . Relacorilant with Paclitaxel Reduces MIA PaCa-2 xenograft Tumor Volume. Initial tumor volume of PaCa-2 xenograft tumors implanted in immunodeficient mice was less than 400 cubic millimeters (mm 3 ).  FIG. 10B  shows the fraction of xenograft tumors (as %) whose volume remained below 400 mm 3  on the days indicated along the horizontal axis. Tumor size progression is thus indicated by lines descending from the top (100%) value. The tumor-bearing mice were treated with vehicle, relacorilant (30 mg/kg every day), paclitaxel (three doses of 7.5 mg/kg paclitaxel, one dose administered on each of the days indicated in  FIG. 10A ), and the combination relacorilant (30 mg/kg every day) with paclitaxel (7.5 mg/kg doses of paclitaxel each administered on days 8, 12, and 16 post implantation). The two left-most lines indicate tumor sizes over time in mice administered vehicle (DMSO, the darkest line) and in mice administered 300 nM relacorilant alone (lighter gray line, nearly superimposed on the vehicle line). Administration of 7.5 mg/kg paclitaxel dosed three times (on days 8, 12, and 16 after tumor implantation) was ineffective alone in delaying tumor growth of the pancreatic tumor cells engrafted in the immunodeficient mice (dark gray line between the other lines). Addition of 300 nM relacorilant to the paclitaxel doses delayed the time to progression (p&lt;0.0001) compared to paclitaxel alone (right-most light gray line). Xenograft tumor growth was slowed by combined relacorilant+paclitaxel as compared to either paclitaxel alone or relacorilant alone. Relacorilant thus enhanced sensitivity to paclitaxel in the pancreatic MIA PaCa-2 xenograft model. 
       FIG. 11A . Relacorilant restores chemotherapy sensitivity in vitro. Glucocorticoid (100 nM dexamethasone) reduced the maximum effect of paclitaxel in the ovarian OVCAR-5 cell line. Relacorilant restored sensitivity to paclitaxel in the presence of the glucocorticoid. 
       FIG. 11B . Relacorilant restores chemotherapy sensitivity in vitro. Glucocorticoid (100 nM dexamethasone) reduced the half-maximal potency of oxaliplatin in the ovarian OVCAR-5 cell line. Relacorilant restored sensitivity to oxaliplatin in the presence of the glucocorticoid. 
       FIG. 11C . Relacorilant restores chemotherapy sensitivity in vitro. Glucocorticoid (100 nM dexamethasone) reduced the maximum effect of gemcitabine in the ovarian OVCAR-5 cell line. Relacorilant restored sensitivity to gemcitabine in the presence of the glucocorticoid. 
       FIG. 12 . Potency of carboplatin is dose-dependently increased by relacorilant in vitro. OVCAR-5 ovarian cells were grown in the presence of glucocorticoid (100 nM dexamethasone). Carboplatin was titrated against increasing amounts of relacorilant. The carboplatin effect was dose dependent, with cell viability decreasing as the concentration of carboplatin increased from 1 nM carboplatin to 2187 nM carboplatin. 
     Example 4 Relacorilant Combined with Chemotherapy Agents Reduces Tumor Volume 
     The effects of several cancer chemotherapy agents, with and without relacorilant and/or dexamethasone, on cell proliferation in vitro were studied. In the present example, human-derived cancer cell line OVCAR-5 were subjected to treatment with several cancer chemotherapy agents and also relacorilant alone, dexamethasone alone, and the combination of relacorilant and dexamethasone. Dexamethasone increased OVCAR-5 proliferation in the presence of many of the cancer chemotherapy agents; relacorilant was able to inhibit such increased cell proliferation for several cancer chemotherapy agents. 
     The effects of various chemotherapeutic agents on cell growth of OVCAR-5 human ovarian cancer cells in vitro were studied in the presence and absence of dexamethasone and relacorilant. The amounts of the various chemotherapeutic agents required to inhibit growth of the OVCAR5 human ovarian cancer cell line by fifty percent (IC50) was determined in the presence of dexamethasone, relacorilant, and the combination of dexamethasone and relacorilant. In these experiments, the concentrations of dexamethasone and relacorilant were as follows: 100 nanomolar (nM) dexamethasone; 300 nM relacorilant. 
     The tumor cells were seeded (4,000 cells plated/well) in a volume of 200 μL/well of FBS-medium (2.5% fetal bovine serum diluted in cell culture medium) in a white polystyrene 96-well microculture plate with or without a fixed dose of dexamethasone or relacorilant. The initial cell density was chosen to be low enough to allow for several population doublings (typically 3 to 5) during the indicated incubation period. The cells were incubated in a humidified incubator at 37° C. with 5% CO2 and 95% air. After 48 hours of incubation, serially diluted test agents in growth medium were added to each well. After 72 hours of culture, the plated cells and Cell Titer-Glo® (Promega G7571) reagents were brought to room temperature to equilibrate for 30 minutes. 200 μL of Cell Titer-Glo® reagent was then added to each well, the plate was shaken for two minutes, and then left to equilibrate for ten minutes. The Cell Titer-Glo® cell viability assay uses ATP levels to determine cell numbers. After this equilibration, luminescence was read on the Biotech Synergy II microplate reader. The percent control (% C) of cell growth for each test concentration was calculated relative to untreated wells. All tests were performed in quadruplicate. Individual assay plates were evaluated for appropriate signal and well-to-well variance in the control wells for quality control. 
     The results of such tests are reported in  FIGS. 13 and 14  and in Table 4. 
       FIG. 13 . Relacorilant overcomes the effect of dexamethasone on OVCAR-5 cell survival in the presence of pemetrexed in vitro. Cell proliferation in the presence of the various concentrations of pemetrexed was increased by 100 nM dexamethasone (squares) as compared to dimethyl sulfoxide (DMSO) vehicle alone (filled circles). OVCAR-5 cell proliferation in the presence of 300 nM relacorilant was similar to that of vehicle (downwardly pointing triangles). Relacorilant antagonized the effect of dexamethasone: cell numbers were similar to those of vehicle for relacorilant administered together with dexamethasone alone (upwardly pointing triangles). The vertical axis shows cell numbers as percent of control (zero or lowest concentration of pemetrexed). The horizontal axis shows pemetrexed concentration. 
       FIG. 14 . Relacorilant effects on dexamethasone effects on OVCAR-5 cell growth. The effects of relacorilant on OVCAR-5 cell growth in vitro are shown in  FIG. 14 . The vertical scale shows luminosity, which serves as a measure of cell number. The cell numbers in the presence of the indicated concentrations of cancer chemotherapy agents and in vehicle (DMSO), 100 nM dexamethasone (Dex), the combination of 100 nM dexamethasone and 300 nM relacorilant (Dex+CORT125134), and 300 nM relacorilant (CORT125134) are shown for the chemotherapy agents bortezumib (500 μM); palbociclib (100 μM); AMG-232 (50 μM); AT506 (500 μM); letrozole (200 μM); and vehicle (DMSO). In the presence of bortezumib and palbociclib, dexamethasone increased cell numbers as compared to those in vehicle; this increase was opposed by relacorilant. 
     Several chemotherapeutic agents were tested on OVCAR-5 cells in vitro, providing an indication of these cells&#39; differing responses to dexamethasone and to relacorilant in the presence of different chemotherapeutic agents. Relacorilant reversed the effects of dexamethasone in all cases. The effects of relacorilant on the half-maximal inhibition concentration (IC 50 ) of several cancer chemotherapy agents, and the effects of relacorilant on the maximal amount of cell growth inhibition by these agents are provided in Table 5. A rightward shift on graphs such as in  FIG. 13  indicates an increase in IC 50 . A leftward shift on the graphs such as in  FIG. 13  indicates a decrease in IC 50 . These results are summarized in Table 5 in the column labeled “IC50”. In the column labeled “IC50” the symbol “++” indicates that there was a greater than 60% decrease in IC 50  from the dexamethasone-alone to the relacorilant+dexamethasone treatments; the symbol “+” indicates that there was an about 10% to about 59% decrease in IC 50  from the dexamethasone-alone to the relacorilant+dexamethasone treatments; and the symbol “−” indicates that there was no decrease, or only an equivocal increase, in IC 50  from the dexamethasone-alone to the relacorilant+dexamethasone treatments. 
     In the presence of high chemotherapy concentrations, dexamethasone decreased the maximal toxicity (thus increasing cell viability in the presence of high chemotherapeutic concentrations) and relacorilant reversed this ( FIG. 13 ). The “effect” that is the subject of the column “Max effect” in Table 5 is the increase in maximal cell toxicity caused by addition of relacorilant to the cancer chemotherapeutic agent in the presence of dexamethasone (relacorilant+dexamethasone), as compared to the cancer chemotherapeutic agent plus dexamethasone in the absence of relacorilant (“dexamethasone-alone”). In the column labeled “Max effect” the symbol “++” indicates that there was a consistent increase of 40% or greater in toxicity at high doses of chemotherapeutic from the dexamethasone-alone to the relacorilant+dexamethasone treatments; the symbol “+” indicates that there was a consistent increase in toxicity of about 0% to about 40% at high doses of chemotherapeutic from the dexamethasone-alone to the relacorilant+dexamethasone treatments; and the symbol “−” indicates that there was no increase, or only an inconsistent increase, in toxicity at high doses of chemotherapeutic from the dexamethasone-alone to the relacorilant+dexamethasone treatments. 
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE 5 
               
               
                   
                   
               
               
                   
                 Agent 
                 IC50 
                 Max effect 
               
               
                   
                   
               
             
            
               
                   
                 Eribulin 
                 ++ 
                 ++ 
               
               
                   
                 Vinorelbine 
                 + 
                 ++ 
               
               
                   
                 Plinabulin 
                 − 
                 ++ 
               
               
                   
                 Venetoclax 
                 + 
                 − 
               
               
                   
                 Lapatinib 
                 + 
                 − 
               
               
                   
                 Doxorubicin 
                 + 
                 + 
               
               
                   
                 Etoposide 
                 + 
                 − 
               
               
                   
                 Pemetrexed 
                 ++ 
                 + 
               
               
                   
                 cisplatin 
                 + 
                 + 
               
               
                   
                 Erlotinib 
                 − 
                 + 
               
               
                   
                 Pazopanib 
                 NA 
                 + 
               
               
                   
                 Tamoxifen 
                 − 
                 − 
               
               
                   
                 5-FU 
                 + 
                 − 
               
               
                   
                 Irinotecan 
                 + 
                 − 
               
               
                   
                 CHIR-99021 (GSK3) 
                 − 
                 − 
               
               
                   
                 GSK650394 (SGK) 
                 − 
                 − 
               
               
                   
                 Olaparib 
                 − 
                 − 
               
               
                   
                 Chloroquine 
                 − 
                 + 
               
               
                   
                 Trametinib 
                 − 
                 − 
               
               
                   
                   
               
               
                   
                 IC50: 
               
               
                   
                 ++ &gt;60% decrease in IC 50  from the dexamethasone-alone to the relacorilant + dexamethasone treatments; 
               
               
                   
                 + ~10-59% decrease in IC 50  from the dexamethasone-alone to the relacorilant + dexamethasone treatments; 
               
               
                   
                 − no decrease or equivocal decrease in IC50 from the dexamethasone-alone to the relacorilant + dexamethasone treatments. 
               
               
                   
                 Max effect: 
               
               
                   
                 ++ consistent &gt;40% increase in toxicity at high doses of chemotherapeutic from the dexamethasone-alone to the relacorilant + dexamethasone treatments; 
               
               
                   
                 + consistent ~0-40% increase in toxicity at high doses of chemotherapeutic from the dexamethasone-alone to the relacorilant + dexamethasone treatments; 
               
               
                   
                 − no increase or inconsistent increase in toxicity high doses of chemotherapeutic from the dexamethasone-alone to the relacorilant + dexamethasone treatments. 
               
            
           
         
       
     
     Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.