WO2021247869A2

WO2021247869A2 - Glucocorticoid receptor gene signature

Info

Publication number: WO2021247869A2
Application number: PCT/US2021/035708
Authority: WO
Inventors: Aleksandr PANKOV; Haiying Zhou; Anneleen Daemen
Original assignee: Oric Pharmaceuticals, Inc.
Priority date: 2020-06-04
Filing date: 2021-06-03
Publication date: 2021-12-09
Also published as: WO2021247869A3

Abstract

The present invention relates generally to the use of a predictive response signature to select a treatment for treating cancer, specifically solid tumors.

Description

GLUCOCORTICOID RECEPTOR GENE SIGNATURE

CROSS REFERENCE

[0001] This application claims the benefit of U.S. Application Ser. No. 63/034,848 filed June 4, 2020 and U.S. Application Ser. No. 63/193,709 filed May 27, 2021, which are hereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

[0002] A need exists in the art for an effective treatment of cancer and neoplastic disease.

SUMMARY OF THE INVENTION

[0003] In certain aspects, disclosed herein, is a method comprising selecting a subject with cancer for treatment with a therapy comprising a glucocorticoid receptor (GR) antagonist based on a predictive response signature (PRS) detected in a sample obtained from the subject by an assay, the PRS comprising an expression level of one or more gene products. In certain aspects, disclosed herein, is a method of selecting a subject with cancer for treatment with a therapy comprising a glucocorticoid receptor (GR) antagonist based on a predictive response signature (PRS), the method comprising: a) receiving a sample from a subject with cancer; and b) measuring, by an assay, an expression level of one or more gene products in the sample, wherein the one or more gene products make up a predictive response signature (PRS) to the therapy comprising the glucocorticoid receptor (GR) antagonist. In certain aspects, disclosed herein, is a method comprising: a) performing an assay to detect a predictive response signature (PRS) comprising an expression level of one or more gene products in a sample obtained from a subject with cancer; and b) in a programmed computer, comparing the expression level of the one or more gene products with reference expression levels of the one or more gene products to: i) classify the sample as a non-responder to a therapy comprising a glucocorticoid receptor (GR) antagonist, if there is an absence of the PRS detected in the sample; or ii)classify the sample as a responder to the therapy, if there is a presence of the PRS detected in the sample. In certain aspects, disclosed herein, is a method of predicting a therapeutic response to a therapy comprising a glucocorticoid receptor (GR) antagonist in a subject for the treatment of cancer, the method comprising: a) detecting with an assay a presence of a predictive response signature (PRS) comprising one or more gene products in a sample obtained from a subject with cancer; and b) determining whether the subject is likely to respond to a treatment comprising administering to the subject the therapy comprising the glucocorticoid receptor (GR) antagonist. In certain aspects, disclosed herein, is a method comprising administering to a subject with cancer a second dosage of a therapy comprising a glucocorticoid receptor (GR) antagonist, wherein a first dosage of the therapy previously administered to the subject was determined to lack therapeutic efficacy to treat the cancer based on detecting an absence of a predictive response signature (PRS) in a sample obtained from the subject, wherein the second dosage is different than the first dosage. In certain aspects, disclosed herein, is a method of treating cancer in a subject with a therapy comprising a glucocorticoid receptor (GR) antagonist, the method comprising: a) administering to the subject with cancer a first dosage of the therapy comprising the glucocorticoid receptor (GR) antagonist; b) determining whether the first dosage of the therapy is therapeutically effective to treat the cancer in the subject by: i) obtaining a sample from the subject; ii) performing an assay on the sample to detect a presence or an absence of a predictive response signature (PRS) comprising one or more gene products; and iii) detecting the absence of the PRS in the sample; and c) administering to the subject a second dosage that is different than the first dosage. In certain aspects, disclosed herein, is a method of monitoring a treatment with a therapy comprising a glucocorticoid receptor (GR) antagonist to treat cancer in a subject, the method comprising determining that a dosage of the therapy administered to a subject with cancer is therapeutically effective to treat the cancer in the subject by detecting by an assay, in a sample obtained from the subject, a presence or an absence of a predictive response signature (PRS). In certain aspects, disclosed herein, is a method of treating cancer in a subject comprising administering to the subject a therapeutically effective dosage of a therapy comprising a glucocorticoid receptor (GR) antagonist, wherein the subject is selected for treatment based on a presence of a predictive response signature (PRS) comprising one or more gene products detected in a sample obtained from the subject using an assay. In certain aspects, disclosed herein, is a method comprising administering a therapeutically effective dosage of a therapy comprising a glucocorticoid receptor (GR) antagonist to a subject with cancer to treat the cancer, wherein the subject is known to express a predictive response signature (PRS) comprising one or more gene products as determined by detecting the PRS in a sample obtained from the subject with an assay. In certain aspects, disclosed herein, is a method of treating cancer in a subject with cancer, the method comprising: a) determining whether a subject with cancer will likely therapeutically respond to a therapy comprising a glucocorticoid receptor (GR) antagonist by: i) obtaining or having obtained a sample from the subject; ii) performing or having performed an assay on the sample to detect a presence or an absence of a predictive response signature (PRS) comprising one or more gene products in the sample; and iii) detecting the presence of the PRS in the sample; and b) administering to the subject the therapy comprising the glucocorticoid receptor (GR) antagonist, thereby treating the cancer in the subject. In certain aspects, disclosed herein, is a composition comprising a therapy comprising a glucocorticoid receptor (GR) antagonist for use in treating cancer in a subject, wherein the subject expresses a predictive response signature (PRS) comprising a gene products comprising FKBP5, ER1, KL9, TSC22D3, ALPP, BIRC3, KRT6A, NEBL, SAA1, SAA2, and SCN 1A.

[0004] In some embodiments, the PRS comprises an expression level of the one or more gene products, the expression level deviating from a reference expression level. In some embodiments, the expression level is high, relative to the reference expression level. In some embodiments, the expression level is low, relative to the reference expression level. In some embodiments, the reference expression level is derived from an individual, or a group of individuals, that do not have cancer. In some embodiments, the reference expression level is derived from an individual, or a group of individuals, that have cancer that does not therapeutically respond to the glucocorticoid receptor (GR) antagonist. In some embodiments, the expression level deviates from the reference expression level by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%. In some embodiments, the assay is selected from quantitative polymerase chain reaction (qPCR), microarray, and RNA sequencing. In some embodiments, the assay is RNA sequencing and the one or more gene products comprises a nucleic acid sequence that is at least or about 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more of SEQ ID NOs: 1-11. In some embodiments, the assay comprises the steps of: a) reverse -transcribing the messenger ribonucleic acid (mRNA) molecule comprising a mRNA sequence that is at least or about 75% identical to one of SEQ ID NOs: 1-11 to produce a corresponding complementary DNA (cDNA) molecule; b) contacting the cDNA molecule with a nucleic acid probe comprising a nucleic acid sequence that is complementary to a nucleic acid sequence of the cDNA molecule; and c)detecting a double -stranded hybridization product between the nucleic acid probe and the cDNA molecule. In some embodiments, the method, composition, or therapy further comprises amplifying the hybridization product using a pair of primers. In some embodiments, the pair of primers comprises: d) a first primer with a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within a nucleic acid sequence provided any one of SEQ ID NOs: 1-11 that binds to a top strand of the double-stranded hybridization product; and e) a second primer with a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within a nucleic acid sequence that is reverse complement to the nucleic acid sequence provided in any one of SEQ ID NOs: 1- 11 that binds to a bottom strand of the double -stranded hybridization product. In some embodiments, the mRNA sequence is at least or about 80% identical to one or more of SEQ ID NOs: 1-11. In some embodiments, the mRNA sequence is at least or about 85% identical to one or more of SEQ ID NOs: 1- 11. In some embodiments, the mRNA sequence is at least or about 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more of SEQ ID NOs: 1-11.

[0005] In some embodiments, the sample comprises peripheral blood mononuclear cells. In some embodiments, the sample comprises ctRNA. In some embodiments, the sample comprises a tumor biopsy, liquid biopsy, PBMC, or ctRNA. In some embodiments, the therapy further comprises one or more additional anti-cancer therapy. In some embodiments, the additional anti-cancer therapy is surgery, radiation, or chemotherapy. In some embodiments, the additional anti -cancer therapy is chemotherapy. In some embodiments, the chemotherapy is an androgen receptor antagonist, a mitotic inhibitor, an antimetabolite, a platinum-based agent. In some embodiments, the androgen receptor antagonist is apalutamide, flutamide, nilutamide, bicalutamide, or enzalutamide. In some embodiments, the androgen receptor antagonist is enzalutamide. In some embodiments, the mitotic inhibitor is a taxane or a vinca alkaloid. In some embodiments, the taxane is paclitaxel, docetaxel, cabazitaxel, tesetaxel, or nab- paclitaxel. In some embodiments, the taxane is nab-paclitaxel. In some embodiments, the vinca alkaloid is vinblastine, vincristine, vindesine, or vinorelbine. In some embodiments, the antimetabolite is 5- Fluorouracil, 6-mercaptopurine, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxycarbamide, methotrexate, pemetrexed, or phototrexate. In some embodiments, the platinum- based agent is cisplatin, carboplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, or triplatin tetranitrate. In some embodiments, the glucocorticoid receptor (GR) antagonist is a selective GR antagonist. In some embodiments, the glucocorticoid receptor

(GR) antagonist is Compound

pharmaceutically acceptable salt or solvate thereof. In some embodiments, Compound 1 is administered in a form selected from the group consisting of a softgel, a tablet, and a capsule. In some embodiments, the cancer comprises a cancer selected from the group consisting of uterine corpus endometrioid carcinoma, colon adenocarcinoma, rectum adenocarcinoma, uveal melanoma, testicular germ cell tumor, bladder urothelial carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, kidney chromophobe, prostate adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, cervical cancer, endocervical cancer, breast invasive carcinoma, pancreatic adenocarcinoma, kidney papillary cell carcinoma, lung squamous cell carcinoma, liver hepatocellular carcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, pheochromocytoma, paraganglioma, glioblastoma multiforme, lung adenocarcinoma, brain lower grade glioma, and kidney clear cell carcinoma. In some embodiments, the cancer is testicular cancer.

[0006] In certain aspects, disclosed herein is a kit useful for the treatment of cancer with a therapy comprising a glucocorticoid receptor (GR) antagonist, the kit comprising a nucleic acid molecule comprising: a) at least about 10 but not more than 100 contiguous nucleic acids within a nucleic acid sequence provided in any one of SEQ ID NOs: 1-11; and b) a detectable moiety. In some embodiments, the kit further comprises a pair of primers comprising: c) a first primer comprising at least 10 but not more than 50 contiguous nucleic acids within a nucleic acid sequence provided any one of SEQ ID NOs: 1-11; and d) a second primer comprising at least 10 but not more than 50 contiguous nucleic acids within a nucleic acid sequence that is reverse complement to the nucleic acid sequence provided in any one of SEQ ID NOs: 1-11.

[0007] In certain aspects, disclosed herein is a method of treating cancer in a subject comprising administering to the subject a therapeutically effective dosage of a therapy comprising a glucocorticoid receptor (GR) antagonist, wherein the subject is selected for treatment based on a presence of a predictive response signature (PRS) comprising one or more gene products detected in a sample obtained from the subject using an assay, wherein the one or more gene products is selected from a group consisting of

FKBP5, PERI, KLF9, TSC22D3, ALPP, BIRC3, KRT6A, NEBL, SAA1, SAA2, and SCNN1A. In some embodiments, the predictive response signature (PRS) comprises two or more of the gene products, three or more of the gene products, four or more of the gene products, five or more of the gene products, six or more of the gene products, seven or more of the gene products, eight or more of the gene products, nine or more of the gene products, ten or more of the gene products, or the eleven gene products. In some embodiments, the predictive response signature (PRS) comprises the gene products FKBP5, PERI, KLF9, and TSC22D3. In other embodiments, the predictive response signature (PRS) further comprises one or more gene products selected from the group consisting of ALPP, NEBL, SAA2, and SCN 1A. In certain embodiments, the predictive response signature (PRS) further comprises one or more gene products selected from the group consisting of BIRC3, KRT6A, and SAA1. In other embodiments, the predictive response signature (PRS) further comprises two or more gene products selected from the group consisting of ALPP, NEBL, SAA2, and SCNN1A. In some embodiments, the predictive response signature (PRS) comprises three or more gene products selected from the group consisting of ALPP, NEBL, SAA2, and SCNN1A. In certain embodiments, the predictive response signature (PRS) comprises the gene products ALPP, NEBL, SAA2, and SCNN1A. In other embodiments, the predictive response signature (PRS) further comprises one or more gene products selected from the group consisting of FKBP5, PERI, KLF9, and TSC22D3. In some embodiments, the predictive response signature (PRS) further comprises one or more gene products selected from the group consisting of BIRC3, KRT6A, and SAA1. In some embodiments, the predictive response signature (PRS) comprises the gene products

FKBP5, PERI, KLF9, TSC22D3, ALPP, BIRC3, KRT6A, NEBL, SAA1, SAA2, and SCNN1A. In some embodiments, the sample obtained from the subject comprises a tumor biopsy, liquid biopsy, PBMC, or ctRNA. In some embodiments, the therapy further comprises one or more additional anti -cancer therapy selected from surgery, radiation, and chemotherapy. In certain embodiments, the chemotherapy is an androgen receptor antagonist, a mitotic inhibitor, an antimetabolite, or a platinum-based agent. In some embodiments, the androgen receptor antagonist is apalutamide, flutamide, nilutamide, bicalutamide, or enzalutamide. In some embodiments, the mitotic inhibitor is paclitaxel, docetaxel, cabazitaxel, tesetaxel, or nab-paclitaxel. In some embodiments, the glucocorticoid receptor (GR) antagonist is Compound 1:

pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is uterine corpus endometrioid carcinoma, colon adenocarcinoma, rectum adenocarcinoma, uveal melanoma, testicular germ cell tumor, bladder urothelial carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, kidney chromophobe, prostate adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, cervical cancer, endocervical cancer, breast invasive carcinoma, pancreatic adenocarcinoma, kidney papillary cell carcinoma, lung squamous cell carcinoma, liver hepatocellular carcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, pheochromocytoma, paraganglioma, glioblastoma multiforme, lung adenocarcinoma, brain lower grade glioma, or kidney clear cell carcinoma.

INCORPORATION BY REFERENCE

[0008] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE FIGURES

[0009] FIG. 1A depicts a heatmap showing the log2 fold change (Dex vs. Vehicle (Veh)) for the TNBC- specific GR-associated genes (as rows), defined as significantly altered with Dex treatment relative to Veh (adjusted p-value < 0.05, absolute fold change > 2) in at least 50% of the 9 TNBC cell lines. Cell lines (as columns) are shown in order of their GR expression, from low (left) to high (right).

[0010] FIG. IB depicts a heatmap showing the log2 fold change (Dex vs. Veh) for the NSCLC-specific GR-associated genes (as rows), defined as significantly altered with Dex treatment relative to Veh (adjusted p-value < 0.05, absolute fold change > 2) in at least 50% of the 12 NSCLC cell lines. Cell lines (as columns) are shown in order of their GR expression, from low (left) to high (right).

[0011] FIG. 1C depicts a heatmap showing the log2 fold change (Dex vs. Veh) for the PDAC-specific GR-associated genes (as rows), defined as significantly altered with Dex treatment relative to Veh (adjusted p-value < 0.05, absolute fold change > 2) in at least 50% of the 12 PDAC cell lines. Cell lines (as columns) are shown in order of their GR expression, from low (left) to high (right).

[0012] FIG. 2A depicts a volcano plot showing the average log2 fold change across all indications on the x-axis and the average -loglO adjusted p-value on the y-axis. The genes represented as triangles are common to 2 out of 3 indications; the genes represented as squares are common to all 3 indications (TNBC, NSCLC, PDAC).

[0013] FIG. 2B depicts a Venn diagram showing the overlap of the significant genes across TNBC, NSCLC, and PDAC cell lines. The upregulated genes are in black and the downregulated genes are in gray. The overlap of all 3 indications is the common GR activation signature.

[0014] FIG. 3 depicts a bar graph showing the proportion of 32 TNBC, NSCLC and PDAC cell lines in which Dex-induced expression levels are reverted back with Compound 1 treatment to expression levels that are indistinguishable from Vehicle levels.

[0015] FIG. 4A shows the fold change in expression observed in the DU145 prostate cell line for the 11 GR activation signature genes. The circles show the fold change from vehicle after Dex treatment (Dex vs. Veh); the squares show the fold change from vehicle after Compound 1 treatment (Dex + Compound 1 vs. Veh). The grayscale of circles represents whether a gene is significantly altered with Dex treatment relative to vehicle expression levels. The grayscale of squares represents whether a gene is significantly reverted back to vehicle expression levels after Compound 1 treatment. The line type between the square and the circle represents the inhibition from the Dex condition after Compound 1 treatment (Dex + Compound 1 vs. Dex).

[0016] FIG. 4B shows the fold change in expression observed in the PC3 prostate cell line for the 11 GR activation signature genes. The circles show the fold change from vehicle after Dex treatment (Dex vs. Veh); the squares show the fold change from vehicle after Compound 1 treatment (Dex + Compound 1 vs. Veh). The grayscale of circles represents whether a gene is significantly altered with Dex treatment relative to vehicle expression levels. The grayscale of squares represents whether a gene is significantly reverted back to vehicle expression levels after Compound 1 treatment. The line type between the square and the circle represents the inhibition from the Dex condition after Compound 1 treatment (Dex +

Compound 1 vs. Dex).

[0017] FIG. 5 shows the enrichment of key pathways for selected TNBC, NSCLC, PDAC, and prostate cancer cell lines under both the Dex and Compound 1 (Dex + Compound 1) conditions. The grayscale represents the degree of significance as measured by -log 10 of the fisher’s exact test p-value.

[0018] FIG. 6 shows permutation p-values for the significance of the correlation between the GR activation signature and each of the pathways from FIG. 5 in primary TCGA tumors for TNBC (depicted in circles), NSCLC (triangles) and PDAC (squares). The size of the points represents the magnitude of difference of the observed correlation against an average background correlation across permutations. [0019] FIG. 7A depicts a heatmap showing the median expression of each GR activation signature gene in log2 transcripts per million (TPM, rows) across the tumor samples for 25 oncology indications (columns) from The Cancer Genome Atlas cohort.

[0020] FIG. 7B depicts boxplots showing the average gene-gene correlation across the tumor samples for 25 oncology indications from The Cancer Genome Atlas cohort. Each dot represents the average Pearson correlation of the expression of one signature gene with the expression of other signature genes within the same class of genes across all tumors per indication. The genes in the GR activation signature are separated into a core signature class, consisting of TSC22D3, PERI, KLF9, and FKB5 and a secondary signature class with the remaining seven genes. The separation of genes into 2 classes is determined by observing robust median expression in the core signature genes and more variable expression across indications in the secondary signature genes, as shown in FIG. 7A.

[0021] FIG. 8 shows the dose-dependent inhibition of signature genes FKBP5 and GILZ (TSC22D3) by GR antagonist Compound 1 in HCC1806 (top panels) and MDA-MB-231 (MDA231, bottom panels) TNBC cell lines using a GR target gene assay.

[0022] FIG. 9 shows the dose-dependent inhibition of signature genes FKBP5 and GILZ (TSC22D3) by GR antagonist Compound 1 in OVCAR5 (top panels) and COV362 (bottom panels) ovarian cancer cell lines using a GR target gene assay.

[0023] FIG. 10 shows that GR antagonist Compound 1 fully inhibits Dex-induced FKBP5 and GILZ (TSC22D3) expression in three PDAC (top panels) and three NSCLC (bottom panels) cell lines using RT-qPCR assay. Transcript levels in the Veh group were set as 1, those of all the other treatment groups were relative to the respective Veh groups. Data are presented as mean ± SEM. Veh: DMSO; Dex: 30 nM dexamethasone; 1: 0.5 mM Compound 1.

[0024] FIG. 11 shows the dose-dependent inhibition of signature genes FKBP5 and GILZ (TSC22D3) by GR antagonist Compound 1 in PBMCs using RT-qPCR analysis. One representative image is shown from three independent repeats.

[0025] FIG. 12A shows the normalized expression of signature genes, as the average expression across triplicates, in isolated human PMBCs in vivo treated with or without Compound 1 with cortisol in drinking water. Expression is shown for six signature genes that are expressed in both conditions (i.e. at least one replicate with 20 or more read counts per condition). [0026] FIG. 12B shows the normalized expression of signature genes, as the average expression across triplicates, in isolated human PMBCs ex vivo treated with DMSO, dex or dex + Compound 1. Expression is shown for seven signature genes that are expressed in all conditions (i.e. at least one replicate with 20 or more read counts per condition).

[0027] FIG. 13A depicts a boxplot showing expression of signature gene FKBP5 (qRT-PCR) for six subjects treated with 200 mg/day Compound 1 and six subjects treated with 350 mg/day Compound 1 for ten consecutive days as part of a phase la healthy volunteer trial. PBMCs were collected at 4 timepoints on day 1 for each subject. The timepoints are indicated relative to the time of Compound 1 administration (Ohr, representing 9am). Compound 1 administration was associated with downregulation of GR activation signature gene FKBP5.

[0028] FIG. 13B depicts a boxplot showing expression of signature gene GILZ (TSC22D3) (qRT-PCR) for six subjects treated with 200 mg/day Compound 1 and six subjects treated with 350 mg/day Compound 1 for ten consecutive days as part of a phase la healthy volunteer trial. PBMCs were collected at 4 timepoints on day 1 for each subject. The timepoints are indicated relative to the time of Compound 1 administration (Ohr, representing 9am). Compound 1 administration was associated with downregulation of GR activation signature gene GILZ.

[0029] FIG. 13C depicts a boxplot showing expression of signature gene PERI (qRT-PCR) for six subjects treated with 200 mg/day Compound 1 and six subjects treated with 350 mg/day Compound 1 for ten consecutive days as part of a phase la healthy volunteer trial. PBMCs were collected at 4 timepoints on day 1 for each subject. The timepoints are indicated relative to the time of Compound 1 administration (Ohr, representing 9am). Compound 1 administration was associated with downregulation of GR activation signature gene PERI.

[0030] FIG. 13D depicts a boxplot showing expression of signature gene KLF9 (qRT-PCR) for six subjects treated with 200 mg/day Compound 1 and six subjects treated with 350 mg/day Compound 1 for ten consecutive days as part of a phase la healthy volunteer trial. PBMCs were collected at 4 timepoints on day 1 for each subject. The timepoints are indicated relative to the time of Compound 1 administration (Ohr, representing 9am). Compound 1 administration was associated with downregulation of GR activation signature gene KLF9.

[0031] FIG. 14 depicts a density plot showing a simulated distribution of the GR activation score from a reference cohort of 862 tumor samples. The horizontal lines show hypothetical pre-treatment GR activation scores and treatment-induced changes in the score for individual patients. The dotted line shows the reference distribution of GR activation scores. The circles represent hypothetical pre-treatment GR activation score expression levels projected within the reference distribution. Similarly, the squares represent the respective end of treatment expression levels.

[0032] FIG. 15A shows the normalized expression of signature genes in tumor biopsies collected at time of screening and at the end of treatment with Compound 1 and nab-paclitaxel, for patient A. Expression is shown for all 11 signature genes across the two time points. A solid line represents a significant change in expression, with fold change >2 and adjusted p-value <0.01. A dashed line represents non-significant changes in expression. Expression levels are shown as counts per million (CPM) on a log2 scale.

[0033] FIG. 15B shows the normalized expression of signature genes in tumor biopsies collected at time of screening and after two 28-day cycles of treatment with Compound 1 and nab-paclitaxel, for patient B. Expression is shown for all 11 signature genes across the two time points. A solid line represents a significant change in expression, with fold change >2 and adjusted p-value <0.01. A dashed line represents non-significant changes in expression. Expression levels are shown as counts per million (CPM) on a log2 scale.

[0034] FIG. 16 depicts change in the average expression of 11 GR activation signature genes in MDA- MB-231 xenografts treated with either (a) PTX, (b) PTX + cortisol, or (c) PTX + cortisol + Compound 1, shown as log2 reads per million (RPM). Significant changes between PTX vs. PTX + cortisol are indicated as solid line, with gene symbols correspondingly shown in black. Non-significant changes are shown as dashed lines and gray text. For PTX + cortisol + Compound 1 vs. PTX + cortisol, the change in expression is considered significant (solid line) if either the fold change in gene reduction for this comparison exceeds 2 or the expression difference between PTX + cortisol + Compound 1 vs. PTX did not reach significance.

[0035] FIG. 17A shows the normalized expression of signature genes in tumor biopsies collected at time of screening and after two 28-day cycles of treatment with Compound 1 and nab-paclitaxel, for Patient C who participated in clinical trial NCT03928314. Expression is shown for all 11 signature genes across the two time points. A solid line represents a significant change in expression, with fold change >2 and adjusted p-value <0.01. A dashed line represents non-significant changes in expression. Expression levels are shown as counts per million (CPM) on a log2 scale.

[0036] FIG. 17B shows the normalized expression of signature genes in tumor biopsies collected at time of screening and after two 28-day cycles of treatment with Compound 1 and nab-paclitaxel, for Patient D who participated in clinical trial NCT03928314. Expression is shown for all 11 signature genes across the two time points. A solid line represents a significant change in expression, with fold change >2 and adjusted p-value <0.01. A dashed line represents non-significant changes in expression. Expression levels are shown as counts per million (CPM) on a log2 scale.

[0037] FIG. 18A depicts a density plot showing the distribution of the GR activation score based on all 11 signature genes from a cohort of 10 tumor samples from human subjects who participated in clinical trial NCT03928314. The horizontal lines show observed changes of pre-treatment GR activation scores and treatment-induced changes in the score for each human subject with paired tumor biopsies occurring pre-treatment and either after two 28-day cycles of treatment or at the end of treatment with Compound 1 and nab-paclitaxel. The dotted line shows the reference distribution of GR activation scores using all 11 signature genes. The circles represent observed pre-treatment GR activation score expression levels projected within the reference distribution. Similarly, the squares represent the respective end of treatment or on-treatment expression levels for human subjects with paired samples. [0038] FIG. 18B depicts a density plot showing the distribution of the GR activation score based on the 4 core signature genes (TSC22D3, PERI, KLF9, and FKB5) from a cohort of 10 tumor samples from human subjects who participated in clinical trial NCT03928314. The horizontal lines show observed changes of pre-treatment GR activation scores and treatment-induced changes in the score for each human subject with paired tumor biopsies occurring pre-treatment and either after two 28-day cycles of treatment or at the end of treatment with Compound 1 and nab-paclitaxel. The dotted line shows the reference distribution of GR activation scores using 4 core signature genes. The circles represent observed pre-treatment GR activation score expression levels projected within the reference distribution. Similarly, the squares represent the respective end of treatment or on-treatment expression levels for human subjects with paired samples.

DETAILED DESCRIPTION OF THE INVENTION [0039] The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily of ligand- activated transcription factors. GR is activated by endogenous glucocorticoid ligands, the steroid hormones cortisol and corticosterone, and by synthetic glucocorticoid drugs such as dexamethasone. Upon ligand binding, GR translocates to the nucleus where it transcriptionally activates a spectrum of genes that mediate multiple biological effects. GR is involved in mediating resistance to both targeted therapies and conventional chemotherapies in epithelial cancers. Glucocorticoids have been reported to confer resistance to antimetabolites, taxanes and platinum compounds in lung, prostate, bladder, renal, ovarian and triple negative breast cancers. GR has also been reported to confer resistance to antiandrogen therapy in prostate cancer. As such, GR antagonists are useful in the treatment of cancer. Described herein are GR antagonists useful in the treatment of cancer.

[0040] Disclosed herein is a predictive response signal (PRS) that was discovered by a molecular analysis of multiple tumor subtypes treated with a GR receptor agonist. The PRS may comprise one of more gene products selected from a group consisting of FKBP Prolyl Isomerase 5 (FKBP5), Period Circadian Regulator 1 (PERI), Kruppel Like Factor 9 (KLF9), TSC22 Domain Family Member 3(TSC22D3), Alkaline Phosphatase, Placental (ALPP), Baculoviral IAP Repeat Containing 3(BIRC3), Keratin 6A (KRT6A), Nebulette (NEBL), Serum Amyloid A1 (SAA1), Serum Amyloid A2 (SAA2), and Sodium Channel Epithelial 1 Subunit Alpha (SCN 1A). The PRS may be useful in the diagnosis and treatment of subjects with cancer. For example, the PRS may be used to identify subjects that are likely to respond to treatment with a GR receptor antagonist or to predict the therapeutic response to a therapy with a GR antagonist.

[0041] Described herein in certain aspects are methods of identifying a predictive response signature and uses thereof in the treatment of cancer. In certain aspects, the predictive response signature may be used in a method of selecting a subject with cancer for treatment with a therapy comprising a GR antagonist. In certain aspects the predictive response signature may be used in a method of determining the response of a patient with cancer to a therapy comprising a GR antagonist. In certain aspects, the predictive response signature may be used in a method of treating a subject with cancer to determine if a dose of a GR antagonist is therapeutically effective.

Methods

[0042] Described herein are method of predicting whether a subject with cancer is likely to therapeutically respond to a GR antagonist described herein to treat a proliferative disease (e.g. cancer), based on a presence of a predictive response signature (PRS). In some aspects described herein, the method comprises selecting a subject with cancer for treatment with a therapy comprising a GR antagonist based on a PRS. In some aspects described herein, the method comprises determining if a dosage of a therapy is therapeutically effective based on the absences or presence of a PRS in a sample obtained from the patient.

Methods of Predicting Response to a Therapy Using PRS

[0043] Disclosed herein are methods of predicting whether a subject in need thereof will therapeutically respond to an induction or maintenance of a therapy described herein (e.g., GR antagonist ). In some embodiments, the GR antagonist is Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the GR antagonist is a compound of Formula (I) or Formula (I)a. In some embodiments, the GR antagonist comprises mifepristone, Relacorilant (CORT125134), Exicorilant (CORT125281), Miricorilant (CORT118335), CORT113176, CORT108297, PT150 (formerly Org34517), PT157, and PT162.

[0044] Methods of the present disclosure comprise selecting a subject with a proliferative disease or condition (e.g., cancer) for treatment with a therapy comprising an GR antagonist based on a predictive response signature (PRS) detected in a sample obtained from the subject by an assay, the PRS comprising an expression level of one or more gene products.

[0045] Some aspects disclosed herein, are methods of selecting a subject with cancer for treatment with a therapy comprising an GR antagonist based on a predictive response signature (PRS), the method comprising: (a) receiving a sample from a subject with cancer; and (b) measuring, by an assay, an expression level of one or more gene products in the sample, wherein the one or more gene products make up a predictive response signature (PRS) to a therapy comprising an GR antagonist.

[0046] Aspects disclosed herein provide methods comprising: (a) performing an assay to detect a predictive response signature (PRS) comprising an expression level of one or more gene products in a sample obtained from a subject with cancer; and (b) in a programmed computer, comparing the expression level of the one or more gene products with reference expression levels of the one or more gene products to: (i) classify the sample as a non-responder to a therapy comprising an GR antagonist, if there is an absence of the PRS detected in the sample; or (ii) classify the sample as a responder to the therapy, if there is a presence of the PRS detected in the sample.

[0047] Aspects disclosed herein provide methods of predicting a therapeutic response to a therapy comprising an GR antagonist in a subject for the treatment of cancer, the method comprising: (a) detecting with an assay a presence of a predictive response signature (PRS) comprising one or more gene products in a sample obtained from a subject with cancer; and (b) determining whether the subject is likely to respond to a treatment comprising administering to the subject a therapy comprising an GR antagonist.

Methods of Monitoring Treatment of Cancer with a Therapy Based On PRS [0048] Disclosed herein are methods of monitoring or optimizing a treatment of a subject in need thereof with a therapy described herein (e.g., a GR antagonist), based on a presence of the PRS detected in a sample obtained from the subject. Samples may be obtained from the subject periodically, throughout a treatment course, with the therapies described herein for the purpose of assaying the sample to detect a presence or an absence of the PRS.

[0049] Aspects disclosed herein provide methods comprising (a) administering to the subject with cancer a first dosage of the therapy comprising the glucocorticoid receptor (GR) antagonist; (b) determining whether the first dosage of the therapy is therapeutically effective to treat the cancer in the subject by: (i) obtaining a sample from the subject; (ii) performing an assay on the sample to detect a presence or an absence of a predictive response signature (PRS) comprising one or more gene products; and (iii) detecting the absence of the PRS in the sample; and (c)administering to the subject a second dosage that is different than the first dosage. In some cases, the therapy comprises an GR antagonist that is Compound 1, or a pharmaceutically acceptable salt thereof.

[0050] Aspects disclosed herein provide methods of monitoring a treatment with a therapy comprising an GR antagonist to treat cancer in a subject, the method comprising determining that a dosage of the therapy administered to a subject with cancer is therapeutically effective to treat the cancer in the subject by detecting by an assay, in a sample obtained from the subject, a presence or an absence of a predictive response signature (PRS). Some aspects disclosed herein provide methods of treating cancer in a subject comprising administering to the subject a therapeutically effective dosage of a therapy comprising an GR antagonist, wherein the subject is selected for treatment based on a presence of a predictive response signature (PRS) comprising one or more gene products detected in a sample obtained from the subject using an assay. In further aspects disclosed herein methods are provided comprising administering a therapeutically effective dosage of a therapy comprising an GR antagonist to a subject with cancer to treat the cancer, wherein the subject is known to express a predictive response signature (PRS) comprising one or more gene products as determined by detecting the PRS in a sample obtained from the subject with an assay.

Methods of Treating Cancer in a Subject Expressing a PRS with a Therapy

[0051] Disclosed herein are methods of treating a proliferative disease or condition in a subject in need thereof using a predictive response signature.

[0052] Aspects disclosed herein provide methods of treating cancer in a subject with cancer, the method comprising: (a) determining whether a subject with cancer will likely therapeutically respond to a therapy comprising a therapy comprising an GR antagonist by: (i) obtaining or having obtained a sample obtained from the subject; (ii) performing or having performed an assay on the sample to detect a presence or an absence of a predictive response signature (PRS) comprising one or more gene products in the sample; and (iii) detecting the presence of the PRS in the sample; and (b) administering to the subject a therapy comprising an GR antagonist, thereby treating the cancer in the subject.

[0053] Aspects disclosed herein provide compositions comprising a therapy comprising an GR antagonist for use in treating cancer in a subject, wherein the subject expresses a predictive response signature (PRS) comprising one or more gene products as measured in a sample obtained from the subject by an assay. Some aspects disclosed herein provide therapies comprising an GR antagonist for use in treating cancer in a subject identified as having a predictive response signature (PRS) comprising one or more gene products as measured in a sample obtained from the subject by an assay.

Predictive Response Signature

[0054] Disclosed herein, in some embodiments, a presence or an absence, and/or or a level of expression of the one or more gene products is detected in the sample obtained from a subject by analyzing the genetic material in the sample. In some instances, the subject may be human. In some embodiments, the genetic material is obtained from a subject having a proliferative disease or condition disclosed herein. In some cases, the genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine, and other techniques known by one of skill in the art. In some embodiments the sample comprises circulating tumor RNA (ctRNA). In some embodiments the sample comprises peripheral blood mononuclear cells (PBMCs). In some cases, the genetic material is obtained from a tumor biopsy or liquid biopsy. In some embodiments, a tumor biopsy comprises a formalin-fixed paraffin embedded biopsy, a fresh frozen biopsy, a fresh biopsy, or a frozen biopsy. In some embodiments, a liquid biopsy comprises PBMCs, circulating tumor RNA, plasma cell-free RNA, or circulating tumor cells (CTCs). Tumor biopsies can undergo additional analytic processing for sample dissociation, cell sorting, and enrichment of cell populations of interest.

[0055] The PRS may comprise one of more gene products selected from a group consisting of FKBP5, PERI, KLF9, TSC22D3, ALPP, BIRC3, KRT6A, NEBL, SAA1, SAA2, and SCNN1A. In some embodiments, the one or more gene products comprises FKBP Prolyl Isomerase 5 (FKBP5). In some embodiments, the one or more gene products comprises Period Circadian Regulator 1 (PERI). In some embodiments, the one or more gene products comprises Kruppel Like Factor 9 (KLF9). In some embodiments, the one or more gene products comprises TSC22 Domain Family Member 3(TSC22D3), also referred to as GILZ. In some embodiments, the one or more gene products comprises Alkaline Phosphatase, Placental (ALPP). In some embodiments, the one or more gene products comprises Baculoviral IAP Repeat Containing 3(BIRC3). In some embodiments, the one or more gene products comprises Keratin 6A (KRT6A). In some embodiments, the one or more gene products comprises Nebulette (NEBL). In some embodiments, the one or more gene products comprises Serum Amyloid A1 (SAA1). In some embodiments, the one or more gene products comprises Serum Amyloid A2 (SAA2). In some embodiments, the one or more gene products comprises Sodium Channel Epithelial 1 Subunit Alpha (SCNN1A). In some embodiments, the PRS comprises the gene products comprising FKBP5,

ER1, KL9, TSC22D3, ALPP, BIRC3, KRT6A, NEBL, SAA1, SAA2, and SCNN1A. [0056] In some embodiments, the PRS comprises two or more gene products, three or more gene products, four or more gene products, five or more gene products, six or more gene products, seven or more gene products, eight or more gene products, nine or more gene products, ten or more gene products, or eleven gene products.

[0057] In some embodiments, the PRS comprises the gene products FKBP5, PERI, KLF9, and TSC22D3. In some embodiments, the PRS further comprises one or more gene products selected from the group consisting of ALPP, NEBL, SAA2, and SCNN1A. In some embodiments, the PRS further comprises two or more gene products selected from the group consisting of ALPP, NEBL, SAA2, and SCN 1A. In some embodiments, the PRS further comprises three or more gene products selected from the group consisting of ALPP, NEBL, SAA2, and SCNN1A. In some embodiments, the PRS further comprises four gene products comprising ALPP, NEBL, SAA2, and SCNN1A. In some embodiments, the PRS further comprises one or more gene products selected from the group consisting of BIRC3, KRT6A, and SAA1. In some embodiments, the PRS further comprises two or more gene products selected from the group consisting of BIRC3, KRT6A, and SAA1. In some embodiments, the PRS further comprises three gene products comprising of BIRC3, KRT6A, and SAA1.

[0058] In some embodiments, the PRS comprises one or more gene products selected from the group consisting of ALPP, NEBL, SAA2, and SCNN1A. In some embodiments, the PRS comprises two or more gene products selected from the group consisting of ALPP, NEBL, SAA2, and SCNN1A. In some embodiments, the PRS comprises three or more gene products selected from the group consisting of ALPP, NEBL, SAA2, and SCNN1A. In some embodiments, the PRS comprises the gene products comprising ALPP, NEBL, SAA2, and SCNN1A. In some embodiments, the PRS further comprises one or more gene products selected from the group consisting of FKBP5, PERI, KLF9, and TSC22D3. In some embodiments, the PRS further comprises two or more gene products selected from the group consisting of FKBP5, PERI, KLF9, and TSC22D3. In some embodiments, the PRS further comprises three or more gene products selected from the group consisting of FKBP5, PERI, KLF9, and TSC22D3. In some embodiments, the PRS further comprises four gene products comprising FKBP5, PERI, KLF9, and TSC22D3. In some embodiments, the PRS further comprises one or more gene products selected from the group consisting of BIRC3, KRT6A, and SAA1. In some embodiments, the PRS further comprises two or more gene products selected from the group consisting of BIRC3, KRT6A, and SAA1. In some embodiments, the PRS further comprises three gene products comprising of BIRC3, KRT6A, and SAA1

[0059] In some embodiments, PRS comprises one or more gene products comprising FKBP5. In some embodiments, the PRS comprises two or more gene products, three or more gene products, four or more gene products, five or more gene products, six or more gene products, seven or more gene products, eight or more gene products, nine or more gene products, ten or more gene products, or eleven gene products. In some embodiments, the PRS further comprises PERI . In some embodiments, the PRS further comprises KLF9. In some embodiments, the PRS further comprises TSC22D3. In some embodiments, the PRS further comprises ALPP. In some embodiments, the PRS further comprises BIRC3. In some embodiments, the PRS further comprises KRT6A. In some embodiments, the PRS further comprises

NEBL. In some embodiments, the PRS further comprises SAA1. In some embodiments, the PRS further comprises SAA2. In some embodiments, the PRS further comprises SCNN1A.

[0060] In some embodiments, PRS comprises one or more gene products comprising PERI . In some embodiments, the PRS comprises two or more gene products, three or more gene products, four or more gene products, five or more gene products, six or more gene products, seven or more gene products, eight or more gene products, nine or more gene products, ten or more gene products, or eleven gene products. In some embodiments, the PRS further comprises FKBP5. In some embodiments, the PRS further comprises KLF9. In some embodiments, the PRS further comprises TSC22D3. In some embodiments, the PRS further comprises ALPP. In some embodiments, the PRS further comprises BIRC3. In some embodiments, the PRS further comprises KRT6A. In some embodiments, the PRS further comprises NEBL. In some embodiments, the PRS further comprises SAA1. In some embodiments, the PRS further comprises SAA2. In some embodiments, the PRS further comprises SCN 1A.

[0061] In some embodiments, PRS comprises one or more gene products comprising KLF9. In some embodiments, the PRS comprises two or more gene products, three or more gene products, four or more gene products, five or more gene products, six or more gene products, seven or more gene products, eight or more gene products, nine or more gene products, ten or more gene products, or eleven gene products. In some embodiments, the PRS further comprises FKBP5. In some embodiments, the PRS further comprises PERI. In some embodiments, the PRS further comprises TSC22D3. In some embodiments, the PRS further comprises ALPP. In some embodiments, the PRS further comprises BIRC3. In some embodiments, the PRS further comprises KRT6A. In some embodiments, the PRS further comprises NEBL. In some embodiments, the PRS further comprises SAA1. In some embodiments, the PRS further comprises SAA2. In some embodiments, the PRS further comprises SCNN1A.

[0062] In some embodiments, PRS comprises one or more gene products comprising TSC22D3. In some embodiments, the PRS comprises two or more gene products, three or more gene products, four or more gene products, five or more gene products, six or more gene products, seven or more gene products, eight or more gene products, nine or more gene products, ten or more gene products, or eleven gene products. In some embodiments, the PRS further comprises FKBP5. In some embodiments, the PRS further comprises PERI. In some embodiments, the PRS further comprises KLF9. In some embodiments, the PRS further comprises ALPP. In some embodiments, the PRS further comprises BIRC3. In some embodiments, the PRS further comprises KRT6A. In some embodiments, the PRS further comprises NEBL. In some embodiments, the PRS further comprises SAA1. In some embodiments, the PRS further comprises SAA2. In some embodiments, the PRS further comprises SCNN1A.

[0063] In some embodiments, PRS comprises one or more gene products comprising ALPP. In some embodiments, the PRS comprises two or more gene products, three or more gene products, four or more gene products, five or more gene products, six or more gene products, seven or more gene products, eight or more gene products, nine or more gene products, ten or more gene products, or eleven gene products. In some embodiments, the PRS further comprises FKBP5. In some embodiments, the PRS further comprises PERI. In some embodiments, the PRS further comprises KLF9. In some embodiments, the PRS further comprises TSC22D3. In some embodiments, the PRS further comprises BIRC3. In some embodiments, the PRS further comprises KRT6A. In some embodiments, the PRS further comprises NEBL. In some embodiments, the PRS further comprises SAA1. In some embodiments, the PRS further comprises SAA2. In some embodiments, the PRS further comprises SCNN1A.

[0064] In some embodiments, PRS comprises one or more gene products comprising BIRC3. In some embodiments, the PRS comprises two or more gene products, three or more gene products, four or more gene products, five or more gene products, six or more gene products, seven or more gene products, eight or more gene products, nine or more gene products, ten or more gene products, or eleven gene products. In some embodiments, the PRS further comprises FKBP5. In some embodiments, the PRS further comprises PERI. In some embodiments, the PRS further comprises KLF9. In some embodiments, the PRS further comprises TSC22D3. In some embodiments, the PRS further comprises ALPP. In some embodiments, the PRS further comprises KRT6A. In some embodiments, the PRS further comprises NEBL. In some embodiments, the PRS further comprises SAA1. In some embodiments, the PRS further comprises SAA2. In some embodiments, the PRS further comprises SCN 1A.

[0065] In some embodiments, PRS comprises one or more gene products comprising KRT6A. In some embodiments, the PRS comprises two or more gene products, three or more gene products, four or more gene products, five or more gene products, six or more gene products, seven or more gene products, eight or more gene products, nine or more gene products, ten or more gene products, or eleven gene products. In some embodiments, the PRS further comprises FKBP5. In some embodiments, the PRS further comprises PERI. In some embodiments, the PRS further comprises KLF9. In some embodiments, the PRS further comprises TSC22D3. In some embodiments, the PRS further comprises ALPP. In some embodiments, the PRS further comprises BIRC3. In some embodiments, the PRS further comprises NEBL. In some embodiments, the PRS further comprises SAA1. In some embodiments, the PRS further comprises SAA2. In some embodiments, the PRS further comprises SCNN1A.

[0066] In some embodiments, PRS comprises one or more gene products comprising NEBL. In some embodiments, the PRS comprises two or more gene products, three or more gene products, four or more gene products, five or more gene products, six or more gene products, seven or more gene products, eight or more gene products, nine or more gene products, ten or more gene products, or eleven gene products. In some embodiments, the PRS further comprises FKBP5. In some embodiments, the PRS further comprises PERI. In some embodiments, the PRS further comprises KLF9. In some embodiments, the PRS further comprises TSC22D3. In some embodiments, the PRS further comprises ALPP. In some embodiments, the PRS further comprises BIRC3. In some embodiments, the PRS further comprises KRT6A. In some embodiments, the PRS further comprises SAA1. In some embodiments, the PRS further comprises SAA2. In some embodiments, the PRS further comprises SCNN1A.

[0067] In some embodiments, PRS comprises one or more gene products comprising SAA1. In some embodiments, the PRS comprises two or more gene products, three or more gene products, four or more gene products, five or more gene products, six or more gene products, seven or more gene products, eight or more gene products, nine or more gene products, ten or more gene products, or eleven gene products. In some embodiments, the PRS further comprises FKBP5. In some embodiments, the PRS further comprises PERI. In some embodiments, the PRS further comprises KLF9. In some embodiments, the PRS further comprises TSC22D3. In some embodiments, the PRS further comprises ALPP. In some embodiments, the PRS further comprises BIRC3. In some embodiments, the PRS further comprises KRT6A. In some embodiments, the PRS further comprises NEBL. In some embodiments, the PRS further comprises SAA2. In some embodiments, the PRS further comprises SCNN1A.

[0068] In some embodiments, PRS comprises one or more gene products comprising SCNN1A. In some embodiments, the PRS comprises two or more gene products, three or more gene products, four or more gene products, five or more gene products, six or more gene products, seven or more gene products, eight or more gene products, nine or more gene products, ten or more gene products, or eleven gene products. In some embodiments, the PRS further comprises FKBP5. In some embodiments, the PRS further comprises PERI. In some embodiments, the PRS further comprises KLF9. In some embodiments, the PRS further comprises TSC22D3. In some embodiments, the PRS further comprises ALPP. In some embodiments, the PRS further comprises BIRC3. In some embodiments, the PRS further comprises KRT6A. In some embodiments, the PRS further comprises NEBL. In some embodiments, the PRS further comprises SAAl. In some embodiments, the PRS further comprises SCN 1A.

[0069] In some embodiments, PRS comprises one or more gene products comprising SAA2. In some embodiments, the PRS comprises two or more gene products, three or more gene products, four or more gene products, five or more gene products, six or more gene products, seven or more gene products, eight or more gene products, nine or more gene products, ten or more gene products, or eleven gene products. In some embodiments, the PRS further comprises FKBP5. In some embodiments, the PRS further comprises PERI. In some embodiments, the PRS further comprises KLF9. In some embodiments, the PRS further comprises TSC22D3. In some embodiments, the PRS further comprises ALPP. In some embodiments, the PRS further comprises BIRC3. In some embodiments, the PRS further comprises KRT6A. In some embodiments, the PRS further comprises NEBL. In some embodiments, the PRS further comprises SAAl. In some embodiments, the PRS further comprises SAA2.

[0070] In some embodiments, the PRS comprises an expression level of the one or more gene products, the expression level deviating from a reference expression level. In some embodiments, the expression levels of the one or more gene products are standardized, such as through a z-score. In some embodiments, the expression levels of the two or more gene products is calculated by averaging the standardized values of the two or more gene products. In some embodiments, the expression level is high, relative to the reference expression level. In some embodiments, the expression level is low, relative to the reference expression level. In some embodiments, the reference expression level is derived from an individual, or a group of individuals, that do not have cancer. In some embodiments, the reference expression level is derived from an individual, or a group of individuals, that have cancer that does not therapeutically respond to the glucocorticoid receptor (GR) antagonist. In some embodiments, the expression level deviates from the reference expression level by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0071] In some embodiments, the reference expression level is a distribution based on a reference population. In some embodiments, the expression levels of the one or more gene products are standardized, such as through a z-score. In some embodiments, the expression levels of the two or more gene products is calculated by averaging the standardized values of the two or more gene products.

Methods of detecting the PRS

[0072] Disclosed herein, in some embodiments, are methods of detecting a presence, absence, or level, of a gene product (e.g., biomarker) in a sample obtained from a subject. In some instances, the methods of detection disclosed herein are useful for predicting a therapeutic response to a therapy described herein (e.g., GR antagonist) in, monitor the treatment using the therapy of, and treating with the therapy, a proliferative disease or condition described herein in a subject.

[0073] In some embodiments, methods of detecting a presence, absence, or level of a biomarker in the sample obtained from the subject involve detecting a nucleic acid sequence. In some cases, the nucleic acid sequence comprises deoxyribonucleic acid (DNA), such as in the case of detecting complementary DNA (cDNA) of an mRNA transcript. In some instances, the nucleic acid sequence comprises a denatured DNA molecule or fragment thereof. In some instances, the nucleic acid sequence comprises DNA selected from: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA. In some instances, the DNA is single-stranded DNA (ssDNA), double -stranded DNA, denaturing double -stranded DNA, synthetic DNA, and combinations thereof. The circular DNA may be cleaved or fragmented. In some instances, the nucleic acid sequence comprises ribonucleic acid (RNA). In some instances, the nucleic acid sequence comprises fragmented RNA. In some instances, the nucleic acid sequence comprises partially degraded RNA. In some instances, the nucleic acid sequence comprises a microRNA or portion thereof. In some instances, the nucleic acid sequence comprises an RNA molecule or a fragmented RNA molecule (RNA fragments) selected from: a microRNA (miRNA), a pre-miRNA, a pri-miRNA, a mRNA, a pre-mRNA, a viral RNA, a viroid RNA, a virusoid RNA, circular RNA (circRNA), a ribosomal RNA (rRNA), a transfer RNA (tRNA), a pre-tRNA, a long non-coding RNA (IncRNA), a small nuclear RNA (snRNA), a circulating RNA, a cell-free RNA, an exosomal RNA, a vector-expressed RNA, an RNA transcript, a synthetic RNA, and combinations thereof.

[0074] Disclosed herein, in some embodiments, the biomarker is detected by subjecting a sample obtained from the subject to a nucleic acid-based detection assay. In some instances, the nucleic acid- based detection assay comprises quantitative polymerase chain reaction (qPCR), gel electrophoresis

(including for e.g., Northern or Southern blot), immunochemistry, in situ hybridization such as fluorescent in situ hybridization (FISH), cytochemistry, microarray, or sequencing. In some embodiments, the sequencing technique comprises next generation sequencing. In some embodiments, the methods involve a hybridization assay such as fluorogenic qPCR (e.g., TaqMan™, SYBR green,

SYBR green I, SYBR green II, SYBR gold, ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, Blue View or phycoerythrin), which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acid probes comprising a detectable moiety or molecule that is specific to a target nucleic acid sequence. In some instances, a number of amplification cycles for detecting a target nucleic acid in a qPCR assay is about 5 to about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles. For TaqMan™ methods, the probe may be a hydrolysable probe comprising a fluorophore and quencher that is hydrolyzed by DNA polymerase when hybridized to a target nucleic acid. In some cases, the presence of a target nucleic acid is determined when the number of amplification cycles to reach a threshold value is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles. In some instances, hybridization may occur at standard hybridization temperatures, e.g., between about 35 °C and about 65 °C in a standard PCR buffer.

[0075] An additional exemplary nucleic acid-based detection assay comprises the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi-well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence. In some instances, the nucleic acid probe is specific to one or more gene products described herein (of the PRS). In some instances, the nucleic acid probe specific to a biomarker comprises a nucleic acid probe sequence sufficiently complementary to the polynucleotide sequence of the biomarker. In some instances, the biomarker comprises a transcribed polynucleotide sequence (e.g., RNA, cDNA). In some embodiments, the nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length and sufficient to specifically hybridize under standard hybridization conditions to the target nucleic acid sequence. In some embodiments, the target nucleic acid sequence is immobilized on a solid surface and contacted with a probe, for example by running the isolated target nucleic acid sequence on an agarose gel and transferring the target nucleic acid sequence from the gel to a membrane, such as nitrocellulose. In some embodiments, the probe(s) are immobilized on a solid surface, for example, in an Affymetrix gene chip array, and the probe(s) are contacted with the target nucleic acid sequence.

[0076] In some embodiments, the term “probe” with regards to nucleic acids, refers to any nucleic acid molecule that is capable of selectively binding to a specifically intended target nucleic acid sequence. In some instances, probes are specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags that are known in the art. In some instances, the fluorescent label comprises a fluorophore. In some instances, the fluorophore is an aromatic or heteroaromatic compound. In some instances, the fluorophore is a pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzindole, oxazole, thiazole, benzothiazole, canine, carbocyanine, salicylate, anthranilate, xanthenes dye, coumarin. Exemplary xanthene dyes include, e.g., fluorescein and rhodamine dyes. Fluorescein and rhodamine dyes include, but are not limited to 6-carboxyfluorescein (FAM), 2'7'-dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N; N'-tetramethyl-6- carboxyrhodamine (TAMRA), 6-carboxy-X-rhodamine (ROX). Suitable fluorescent probes also include the naphthylamine dyes that have an amino group in the alpha or beta position. For example, naphthylamino compounds include l-dimethylaminonaphthyl-5-sulfonate, l-anilino-8-naphthalene sulfonate and 2-p-toluidinyl-6-naphthalene sulfonate, 5-(2'-aminoethyl)aminonaphthalene-l -sulfonic acid (EDANS). Exemplary coumarins include, e.g., 3-phenyl-7-isocyanatocoumarin; acridines, such as 9- isothiocyanatoacridine and acridine orange; N-(p-(2-benzoxazolyl)phenyl) maleimide; cyanines, such as, e.g., indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3-(- carboxy-pentyl)-3'-ethyl-5,5'-dimethyloxacarbocyanine (CyA); 1H, 5H, 11H, 15H-Xantheno[2,3, 4-ij:

5,6, 7-i'j']diquinolizin-18-ium, 9-[2 (or 4)-[[[6-[2,5-dioxo-l-pyrrolidinyl)oxy]-6- oxohexyl]amino]sulfonyl]-4 (or 2)-sulfophenyl]-2,3, 6,7, 12,13, 16, 17-octahydro-inner salt (TR or Texas Red); or BODIPYTM dyes. In some cases, the probe comprises FAM as the dye label.

[0077] In some embodiments, detecting the one or more gene products in the PRS comprises sequencing genetic material obtained from a sample from the subject. Sequencing can be performed with any appropriate sequencing technology, including but not limited to single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis. Sequencing methods also include next-generation sequencing, e.g., modem sequencing technologies such as Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed.

[0078] In some instances, a number of nucleotides that are sequenced are at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 300, 400, 500, 2000, 4000, 6000, 8000, 10000, 20000, 50000, 100000, or more than 100000 nucleotides. In some instances, the number of nucleotides sequenced is in a range of about 1 to about 100000 nucleotides, about 1 to about 10000 nucleotides, about 1 to about 1000 nucleotides, about 1 to about 500 nucleotides, about 1 to about 300 nucleotides, about 1 to about 200 nucleotides, about 1 to about 100 nucleotides, about 5 to about 100000 nucleotides, about 5 to about 10000 nucleotides, about 5 to about 1000 nucleotides, about 5 to about 500 nucleotides, about 5 to about 300 nucleotides, about 5 to about 200 nucleotides, about 5 to about 100 nucleotides, about 10 to about 100000 nucleotides, about 10 to about 10000 nucleotides, about 10 to about 1000 nucleotides, about 10 to about 500 nucleotides, about 10 to about 300 nucleotides, about 10 to about 200 nucleotides, about 10 to about 100 nucleotides, about 20 to about 100000 nucleotides, about 20 to about 10000 nucleotides, about 20 to about 1000 nucleotides, about 20 to about 500 nucleotides, about 20 to about 300 nucleotides, about 20 to about 200 nucleotides, about 20 to about 100 nucleotides, about 30 to about 100000 nucleotides, about 30 to about 10000 nucleotides, about 30 to about 1000 nucleotides, about 30 to about 500 nucleotides, about 30 to about 300 nucleotides, about 30 to about 200 nucleotides, about 30 to about 100 nucleotides, about 50 to about 100000 nucleotides, about 50 to about 10000 nucleotides, about 50 to about 1000 nucleotides, about 50 to about 500 nucleotides, about 50 to about 300 nucleotides, about 50 to about 200 nucleotides, or about 50 to about 100 nucleotides.

[0079] Disclosed herein are methods comprising: (a) providing a sample obtained from a subject with a proliferative disease or condition (e.g., cancer); (b) assaying to detect in the sample obtained from the subject a presence of the PRS; and (c) detecting the presence of the PRS in the sample using the methods described herein. In some cases, a hybridization assay, such as those described herein, is used to detect the PRS in the sample. Exemplary probe sequences that are hybridizable to a target nucleic acid sequence (e.g., one or more genes in the PRS) comprise at least 10, but no more than 100 contiguous nucleotides provided in any one of SEQ ID NOS: 1-11. In some cases, RNA sequencing (RNAseq) is used to detect the one or more genes in the PRS.

[0080] Detection of the one or more gene products in the PRS, in some cases, amplification of the subject’s nucleic acid by the polymerase chain reaction (PCR). In some embodiments, the PCR assay involves use of a pair of primers capable of amplifying at least about 10 contiguous nucleobases within a nucleic acid sequence provided in SEQ ID NOS: 1-11, thereby amplifying the one or more gene products in the PRS. In some embodiments, at least one primer comprises a sequence selected from SEQ ID NO: 12-33. In fluorogenic quantitative PCR, quantitation is based on amount of fluorescence signals (TaqMan and SYBR green). In some embodiments, the nucleic acid probe is conjugated to a detectable molecule. The detectable molecule may be a fluorophore. The nucleic acid probe may also be conjugated to a quencher.

[0081] The one or more gene products from the PRS, in some cases, is detected by detecting at least or about 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of any one of SEQ ID NOS: 1-11. In some instances, at least one (1), 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 gene products comprising a nucleic acid sequence that is at least or about 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of any one of SEQ ID NOS: 1-11, is detected.

[0082] In some embodiments, the assay comprises reverse-transcribing the mRNA molecule comprising a mRNA sequence that is at least 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of any one of SEQ ID NOS: 1-11 to produce a corresponding complementary DNA (cDNA) molecule). In some embodiments, the assay further comprises contacting the cDNA molecule with a nucleic acid probe comprising a nucleic acid sequence that is complementary to a nucleic acid sequence of the cDNA molecule. In some embodiments, the assay comprises detecting a double-stranded hybridization product between the nucleic acid probe and the cDNA molecule. In some embodiments, the hybridization product is further amplified using a pair of primers. In some embodiments, the primers comprises a first primer with a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within a nucleic acid sequence provided any one of SEQ ID NOs: 1-11 that binds to a top strand of the double-stranded hybridization product; and a second primer with a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within a nucleic acid sequence that is reverse complement to the nucleic acid sequence provided in any one of SEQ ID NOs: 1-11 that binds to a bottom strand of the double -stranded hybridization product

[0083] Disclosed herein, in some embodiments, are methods comprising preparing a complementary DNA (cDNA) library. In some embodiments, the cDNA library is sequenced using suitable sequence methodologies disclosed herein. In some embodiments, the cDNA library is labeled, a plurality of nucleic acid probes is generated, and fixed to an immobile surface (such as a microarray). In some embodiments, the plurality of nucleic acid probes is capable of hybridizing to at least about 10 contiguous nucleotides of the two or more genes in a sample obtained from the subject. In some embodiments, detecting the presence of the predictive response signature includes detecting a high or a low level of expression of the two or more genes from the PRS, as compared to a reference level.

[0084] Disclosed herein, in some embodiments, genetic material is extracted from a sample obtained from a subject, e.g., a sample of blood or serum. In certain embodiments where nucleic acids are extracted, the nucleic acids are extracted using any technique that does not interfere with subsequent analysis. In certain embodiments, this technique uses alcohol precipitation using ethanol, methanol or isopropyl alcohol. In certain embodiments, this technique uses phenol, chloroform, or any combination thereof. In certain embodiments, this technique uses cesium chloride. In certain embodiments, this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA. In certain embodiments, this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In certain embodiments, after extraction the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis. In an exemplary embodiment, the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification. In certain embodiments, RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol/guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasy RNA preparation kits (Qiagen) or PAXgene (PreAnalytix,

Switzerland).

Circulating Tumor RNA (ctRNA)

[0085] In some aspects, circulating tumor RNA (ctRNA) is used to assess the expression levels of RNA molecules shed by the tumor into the blood stream.

[0086] In some embodiments, detection of ctRNA is useful, for example, for detecting and diagnosing a tumor. Diagnosing the type of tumor using ctRNA can reduce the need for getting a sample of the tumor tissue (tumor biopsy), which can be challenging when a tumor is difficult to access, such as a tumor in the brain or lung. [0087] In some embodiments, a decrease in the quantity of ctRNA suggests the solid tumor is shrinking and treatment with a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof is effective. In some embodiments, a lack of ctRNA in the bloodstream indicates that the cancer has not returned after treatment with a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof.

[0088] Described herein are methods of assessing gene expression by ctRNA genomic profiling. In some embodiments, the genomic profiling is performed after each treatment cycle with a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof. In some embodiments, the gene expression indicates that the cancer is becoming resistant to the treatment with a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof. In some embodiments, the gene expression indicates that the cancer is not becoming resistant to the treatment with a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof.

Cancers and additional anti-cancer therapies

[0089] Disclosed herein is a method of treating cancer in a subject in need thereof; the method comprising administering a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof (e.g., Compound 1, or a pharmaceutically acceptable salt thereof), and chemotherapy.

[0090] In some embodiments, the cancer is a GR positive cancer. In some embodiments, the cancer expresses GR. In some embodiments, the cancer is selected from the group consisting of uterine corpus endometrioid carcinoma, colon adenocarcinoma, rectum adenocarcinoma, uveal melanoma, testicular germ cell tumor, bladder urothelial carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, kidney chromophobe, prostate adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, cervical cancer, endocervical cancer, breast invasive carcinoma, pancreatic adenocarcinoma, kidney papillary cell carcinoma, lung squamous cell carcinoma, liver hepatocellular carcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, pheochromocytoma, paraganglioma, glioblastoma multiforme, lung adenocarcinoma, brain lower grade glioma, and kidney clear cell carcinoma. In some embodiments, the solid tumor is prostate cancer. In some embodiments, the prostate cancer is metastatic prostate cancer. In some embodiments, the solid tumor is breast cancer. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the breast cancer is ER negative breast cancer. In some embodiments, the solid tumor is testicular cancer.

[0091] In some embodiments, the method comprises administering one or more additional anti-cancer therapy. The additional anti -cancer therapy may include, without limitations, surgery, radiation, or chemotherapy. The chemotherapy may be an androgen receptor antagonist, a mitotic inhibitor, an antimetabolite, a platinum-based agent. Examples of androgen receptor antagonist include, without limitations, apalutamide, flutamide, nilutamide, bicalutamide, or enzalutamide. Examples of mitotic inhibitors include, without limitations, ataxane (e.g. paclitaxel, docetaxel, paclitaxel, docetaxel, cabazitaxel, tesetaxel, or nab-paclitaxel) or a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, or vinorelbine). Examples of antimetabolites include, without limitations, 5-Fluorouracil, 6-mercaptopurine, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxycarbamide, methotrexate, pemetrexed, or phototrexate. Examples of platinum-based agents include, without limitations, cisplatin, carboplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, or triplatin tetranitrate. The additional anti -cancer therapy may comprise an anti-PDLl agent, an anti -PD 1 agent or an anti CTLA-4 agent. The anti-PD-Ll agent may comprise atezolizumab, avelumab, durvalumab, MPDL3280A (RG7446), MDX-1105 (BMS-936559) or BMS-935559, MSB0010718C, and MEDI4736. The anti-PDl agent may comprise pembrolizumab, nivolumab, cemiplimab, partalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, or AMP-514 (MEDI0680). The anti-CTLA agent may comprise ipilimumab, or tremelimumab.

Prostate Cancer

[0092] Prostate cancer is the second most common cause of cancer death in men in the United States, and approximately one in every six American men will be diagnosed with the disease during his lifetime. Treatment aimed at eradicating the tumor is unsuccessful in 30% of men.

[0093] One embodiment provides a method of treating prostate cancer in a subject in need thereof, comprising administering to the subject a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof (e.g., Compound 1, or a pharmaceutically acceptable salt thereof).

[0094] In some embodiments, the prostate cancer is chemoresistant cancer, radio resistant cancer, antiandrogen resistant, or refractory cancer. In some embodiments, the prostate cancer is relapsed cancer, persistent cancer, or recurrent cancer.

[0095] In some embodiments, the prostate cancer is acinar adenocarcinoma, atrophic carcinoma, foamy carcinoma, colloid carcinoma, or signet ring carcinoma. In some embodiments, the prostate cancer is ductal adenocarcinoma, transitional cell cancer, urothelial cancer, squamous cell cancer, carcinoid cancer, small cell cancer, sarcoma cancer, or sarcomatoid cancer. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer, doubly-resistant prostate cancer, castration- resistant prostate cancer, hormone-resistant prostate cancer, androgen-independent, or androgen- refractory cancer.

[0096] In some embodiments, the prostate cancer is castration-resistant prostate cancer (CRPC). In some embodiments, the prostate cancer is castration-sensitive prostate cancer.

[0097] In some instances, antiandrogens are useful for the treatment of prostate cancer during its early stages. In some instances, prostate cancer cells depend on androgen receptor (AR) for their proliferation and survival. Some prostate cancer patients are physically castrated or chemically castrated by treatment with agents that block production of testosterone (e.g. GnRH agonists), alone or in combination with antiandrogens, which antagonize effects of any residual testosterone. [0098] In some instances, prostate cancer advances to a hormone-refractory state in which the disease progresses despite continued androgen ablation or antiandrogen therapy. The hormone -refractory state to which most patients eventually progresses in the presence of continued androgen ablation or anti androgen therapy is known as “castration resistant” prostate cancer (CRPC). CRPC is associated with an overexpression of AR. AR is expressed in most prostate cancer cells and overexpression of AR is necessary and sufficient for androgen-independent growth of prostate cancer cells. Failure in hormonal therapy, resulting from development of androgen-independent growth, is an obstacle for successful management of advanced prostate cancer.

[0099] While a small minority of CRPC does bypass the requirement for AR signaling, the vast majority of CRPC, though frequently termed “androgen independent prostate cancer” or “hormone refractory prostate cancer,” retains its lineage dependence on AR signaling.

[00100] Recently approved therapies that target androgen receptor (AR) signaling such as abiraterone and enzalutamide have been utilized for treating CRPC. Despite these successes, sustained response with these agents is limited by acquired resistance which typically develops within 6-12 months. Doubly resistant prostate cancer is characterized in that tumor cells have become castration resistant and overexpress AR, a hallmark of CRPC. However, cells remain resistant when treated with second generation antiandrogens. Doubly resistant prostate cancer cells are characterized by a lack of effectiveness of second generation antiandrogens in inhibiting tumor growth.

[00101] Resistant prostate cancer (e.g., doubly resistant and castration resistant prostate cancers) occurs when cancer cells overexpress androgen receptors (AR). AR target gene expression is inhibited when the cells are treated with a second generation antiandrogen. In some instances, increased signaling through the glucocorticoid receptor (GR) compensates for inhibition of androgen receptor signaling in resistant prostate cancer. Double resistant prostate cancer develops when expression of a subset of those AR target genes is restored. In some instances, GR activation is responsible for this target gene activation. In some embodiments, GR transcription is activated in patients susceptible to or suffering from resistant prostate cancer (e.g., doubly resistant and castration resistant prostate cancers). In some instances, GR upregulation in cancer cells confers resistance to antiandrogens.

[00102] Some embodiments provided herein describe the use of the GR inhibitors for treating prostate cancer in a subject in need thereof, including doubly resistant prostate cancer and castration resistant prostate cancer. In some embodiments, the subject in need has elevated tumor GR expression. In some embodiments, the GR inhibitor is also an AR signaling inhibitor or antiandrogen.

[00103] In some embodiments, the compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is used in combination with an anti -cancer agent or an AR signaling inhibitor or antiandrogen. [00104] In some embodiments, the second or additional agent is an AR signaling inhibitor or antiandrogen. In certain embodiments, the AR signaling inhibitor is an AR antagonist. In some embodiments, the second or additional therapeutic agent is selected from finasteride, dutasteride, alfatradiol, cyproterone acetate, spironolactone, danazol, gestrinone, ketoconazole, abiraterone acetate, enzalutamide, apalutamide, darolutamide, danazol, gestrinone, danazol, simvastatin, aminoglutethimide, atorvastatin, simvastatin, progesterone, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, spironolactone, drospirenone, estradiol, ethinyl estradiol, diethylstilbestrol, conjugated equine estrogens, buserelin, deslorebn, gonadorebn, goserebn, histrebn, leuprorelin, nafarelin, triptorelin, abarebx, cetrorelix, degarebx, ganirebx, or any combinations or any salts thereof. In some embodiments, the second or additional therapeutic agent is selected from flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, darolutamide, cyproterone acetate, megestrol acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, cimetidine, or any combinations or any salts thereof. In some embodiments, the AR signaling inhibitor is 3,3 ’-diindolylm ethane (DIM), abiraterone acetate, apalutamide, darolutamide, bexlosteride, bicalutamide, dutasteride, epristeride, enzalutamide, finasteride, flutamide, izonsteride, ketoconazole, N-butylbenzene- sulfonamide, nilutamide, megestrol, steroidal antiandrogens, turosteride, or any combinations thereof. In some embodiments, the AR signaling inhibitor is flutamide, nilutamide, bicalutamide, or megestrol. In some embodiments, the AR signaling inhibitor is apalutamide. In other embodiments, the AR signaling inhibitor is enzalutamide.

[00105] In some embodiments, the anti-cancer agent is mitoxantrone, estramustine, etoposide, vinblastine, carboplatin, vinorelbine, paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin. In some embodiments, the anti-cancer agent is paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin. In certain embodiments, the anti-cancer agent is docetaxel.

Breast Cancer

[00106] Breast cancer is the second leading cause of cancer among women in the United States. Triple negative breast cancers are among the most aggressive and difficult to treat of all the breast cancer types. Triple-negative breast cancer is a form of the disease in which the three receptors that fuel most breast cancer growth - estrogen, progesterone and the HER-2 - are not present. Because the tumor cells lack these receptors, treatments that target estrogen, progesterone and HER-2 are ineffective. Approximately 40,000 women are diagnosed with triple-negative breast cancer each year. It is estimated that more than half of these women’s tumor cells express significant amounts of GR.

[00107] In some instances, GR expression is associated with a poor prognosis in estrogen receptor (ER)- negative early stage breast cancer. In some instances, GR activation in triple-negative breast cancer cells initiates an anti-apoptotic gene expression profile that is associated with inhibiting chemotherapy- induced tumor cell death. GR activity in these cancer cells correlate with chemotherapy resistance and increased recurrence of cancer.

[00108] Provided herein in some embodiments are methods of treating breast cancer, the method comprising administering to a subject in need thereof a formulation comprising a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof (e.g., Compound 1, or a pharmaceutically acceptable salt thereof). In some embodiments, a GR inhibitor described herein is used in combination with a second therapeutic agent (e.g., a chemotherapeutic agent) for treating breast cancer. In some embodiments, the combination of the GR inhibitor with the second therapeutic agent

(e.g., a chemotherapeutic agent) provides a more effective initial therapy for treating breast cancer compared to the second therapeutic agent (e.g., a chemotherapeutic agent) administered alone.

[00109] In some embodiments, the breast cancer is chemoresistant cancer, radio resistant cancer, or refractory cancer. In some embodiments, the breast cancer is relapsed cancer, persistent cancer, or recurrent cancer. Breast cancers may include, but are not limited to, ductal carcinoma, invasive ductal carcinoma, tubular carcinoma of the breast, medullary carcinoma of the breast, mecinous carcinoma of the breast, papillary carcinoma of the breast, cribriform carcinoma of the breast, invasive lobular carcinoma, inflammatory breast cancer, lobular carcinoma in situ, male breast cancer, Paget disease of the nipple, phyllodes tumor of the breast, recurrent and metastatic breast cancer, triple -negative breast cancer, or combinations thereof.

[00110] In some embodiments, the breast cancer is recurrent and metastatic breast cancer, triple-negative breast cancer, or combinations thereof. In some embodiments, the breast cancer is chemoresistant triple negative breast cancer or estrogen receptor (ER) negative breast cancer. In some embodiments, the breast cancer is chemoresistant triple-negative breast cancer. In some embodiments, the breast cancer is estrogen receptor (ER) negative breast cancer. In some embodiments, the breast cancer is GR+ triple negative breast cancer. In some embodiments, the breast cancer is GR+ estrogen receptor (ER) negative breast cancer.

[00111] Some embodiments provided herein describe the use of a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) for treating breast cancer in a patient, including triple negative breast cancer or ER negative breast cancer. In some embodiments, GR inhibitors inhibit the anti-apoptotic signaling pathways of GR and increase the cytotoxic efficiency of secondary chemotherapeutic agents or androgen receptor antagonists. In some embodiments, the GR inhibitors described herein enhance the efficacy of chemotherapy in breast cancer patients, such as triple negative breast cancer patients. In some embodiments, the breast cancer patient has elevated tumor GR expression.

[00112] In some embodiments, the formulation comprising a GR inhibitor described herein is used in combination with a second therapeutic agent, such as chemotherapy or immunotherapy. In some embodiments, a GR inhibitor described herein is used in combination with one or more additional therapeutic agents. In some embodiments, the second or additional chemotherapeutic agent is cisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine, paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin, melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide, irinotecan, eribulin, etoposide, doxorubicin, liposomal doxorubicin, camptothecin, pemetrexed, topotecan, vinorelbine, vinblastine, daunorubicin, 5-fluorouracil, mitomycin, thiotepa, vincristine, everolimus, veliparib, glembatumumab vedotin, pertuzumab, trastuzumab, or any combinations or any salts thereof.

In some embodiments, the second or additional therapeutic agent is an anti-PD-L 1 agent. In certain embodiments, the anti-PD-Ll agent is MPDL3280A or avelumab. In certain embodiments, the anti-PD- L1 agent comprises atezolizumab, avelumab, durvalumab, MPDL3280A (RG7446), MDX-1105 (BMS- 936559) or BMS-935559, MSB0010718C, and MEDI4736. In some embodiments, the second or additional therapeutic agent is an anti -PD 1 agent. In certain embodiments, the anti -PD 1 agent is nivolumab or permbrolizumab. In certain embodiments, the anti -PD 1 agent comprises pembrolizumab, nivolumab, cemiplimab, partalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP -224, or AMP -514 (MEDI0680). In some embodiments, the second or additional therapeutic agent is an anti-CTLA-4 agent. In certain embodiments, the anti-CTLA agent comprises ipilimumab, or tremelimumab.In some embodiments, the second or additional therapeutic agent is a CAR-T cell therapy. In some embodiments, the second or additional therapeutic agent is an IDO-1 inhibitor. In some embodiments, the second or additional therapeutic agent is a cancer vaccine.

[00113] Some embodiments provided herein describe methods of treating estrogen positive breast cancer. In some instances, estrogen positive breast cancer patients become resistant to estrogen receptor modulators. In some embodiments, the GR inhibitors described herein enhance the efficacy of estrogen receptor modulators in estrogen positive breast cancer patients. In some embodiments, the breast cancer patient has elevated tumor GR expression. In some embodiments, a GR inhibitor described herein is used in combination with an estrogen receptor modulator. In some embodiments, the estrogen receptor modulator is tamoxifen, raloxifene, toremifene, tibolone, fulvestrant, lasofoxifene, clomifene, ormeloxifene, or ospemifene. In some embodiments, the estrogen receptor modulator is tamoxifen, raloxifene, toremifene, tibolone, or fulvestrant. In some embodiments, the estrogen receptor modulator is tamoxifen, raloxifene, or toremifene. In certain embodiments, the estrogen receptor modulator is tamoxifen. In certain embodiments, the second therapeutic agent is an AR antagonist. In some embodiments, the AR signaling inhibitor is flutamide, nilutamide, bicalutamide, or megestrol. In some embodiments, the AR signaling inhibitor is apalutamide. In other embodiments, the AR signaling inhibitor is enzalutamide.

Ovarian Cancer

[00114] Ovarian cancer is the leading cause of death from gynecologic malignancies. Some ovarian cancers (e.g., high grade serous ovarian cancer) are initially sensitive to platinum -based therapy, but relapse rates remain high.

[00115] One embodiment provides a method of treating ovarian cancer in a patient in need thereof, comprising administering to the patient a formulation comprising a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof (e.g., Compound 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the patient has elevated tumor GR expression. In some embodiments, a formulation comprising a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is used in combination with a second therapeutic agent (e.g., a chemotherapeutic agent) for treating ovarian cancer. In some embodiments, the combination of the GR inhibitor with the second therapeutic agent (e.g., a chemotherapeutic agent) provides a more effective initial therapy for treating ovarian cancer compared to the second therapeutic agent (e.g., a chemotherapeutic agent) administered alone.

[00116] In some instances, GR activation increases resistance to chemotherapy in ovarian cancer (e.g., high-grade serous ovarian cancer). In some instances, GR activation significantly inhibits chemotherapy induced apoptosis in ovarian cancer cells. Provided herein in some embodiments are methods of treating ovarian cancer in a subject, the method comprising treating the subject with a GR inhibitor (e.g., GR antagonist) to improve sensitivity to chemotherapy. In some embodiments, the ovarian cancer has become resistant to chemotherapy. In some embodiments, the ovarian cancer cells are resistant to cisplatin, paclitaxel, carboplatin, gemcitabine, alone or in combination. In some embodiments, the GR inhibitor or antagonist reverses the cell survival effect.

[00117] Ovarian cancers may include, but are not limited to, epithelial ovarian cancers, such as serous epithelial ovarian cancer, endometrioid epithelial ovarian cancer, clear cell epithelial ovarian cancer, mucinous epithelial ovarian cancer, undifferentiated or unclassifiable epithelial ovarian cancer, refractory ovarian cancer, sex cord-stromal tumors, Sertoli and Sertoli-Leydig cell tumors, germ cell tumors, such as dysgerminoma and nondysgerminomatous tumors, Brenner tumors, primary peritoneal carcinoma, fallopian tube cancer, or combinations thereof.

[00118] In some embodiments, the formulation comprising a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is used in combination with at least a second therapeutic agent, such as chemotherapy or immunotherapy. In some embodiments, the second or additional chemotherapeutic agent is cisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine, paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin, melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide, irinotecan, eribulin, etoposide, doxorubicin, liposomal doxorubicin, camptothecin, pemetrexed, topotecan, vinorelbine, vinblastine, daunorubicin, 5-fluorouracil, mitomycin, thiotepa, vincristine, everolimus, veliparib, glembatumumab vedotin, pertuzumab, trastuzumab, or any combinations or any salts thereof. In some embodiments, the second or additional chemotherapeutic agent is gemcitabine. In some embodiments, the second or additional chemotherapeutic agent is carboplatin. In some embodiments, the second or additional chemotherapeutic agent is cisplatin. In some embodiments, the second or additional agent is paclitaxel. In some embodiments, the GR inhibitor is used in combination with gemcitabine and carboplatin. In some embodiments, the GR inhibitor is used in combination with carboplatin and cisplatin. In some embodiments, the second or additional therapeutic agent is an anti-PD- L1 agent. In certain embodiments, the anti-PD-Ll agent is MPDL3280A or avelumab. In certain embodiments, the anti-PD-Ll agent comprises atezolizumab, avelumab, durvalumab, MPDL3280A (RG7446), MDX-1105 (BMS-936559) or BMS-935559, MSB0010718C, and MEDI4736. In some embodiments, the second or additional therapeutic agent is an anti -PD 1 agent. In certain embodiments, the anti -PD 1 agent is nivolumab or pembrolizumab. . In certain embodiments, the anti -PD 1 agent comprises pembrolizumab, nivolumab, cemiplimab, partalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, or AMP-514 (MEDI0680). In some embodiments, the second or additional therapeutic agent is an anti-CTLA-4 agent. In certain embodiments, the anti-CTLA agent comprises ipilimumab, or tremelimumab. In some embodiments, the second or additional therapeutic agent is a CAR-T cell therapy. In some embodiments, the second or additional therapeutic agent is an IDO-1 inhibitor. In some embodiments, the second or additional therapeutic agent is a cancer vaccine. Non-Small Cell Lung Cancer

[00119] One embodiment provides a method of treating non-small cell lung cancer (NSCLC) in a patient in need thereof, comprising administering to the patient a formulation provided herein. In some embodiments, the patient has elevated tumor GR expression. In some embodiments, a GR inhibitor described herein is used in combination with a second therapeutic agent (e.g., a chemotherapeutic agent) for treating NSCLC. In some embodiments, the combination of the GR inhibitor with the second therapeutic agent (e.g., a chemotherapeutic agent) provides a more effective initial therapy for treating NSCLC compared to the second therapeutic agent (e.g., a chemotherapeutic agent) administered alone. [00120] In some embodiments, the formulation comprising a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is used in combination with at least a second therapeutic agent, such as a chemotherapeutic agent or immunotherapy. In some embodiments, the second or additional chemotherapeutic agent is cisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine, paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin, melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide, irinotecan, eribulin, etoposide, doxorubicin, liposomal doxorubicin, camptothecin, pemetrexed, topotecan, vinorelbine, vinblastine, daunorubicin, 5-fluorouracil, mitomycin, thiotepa, vincristine, everolimus, veliparib, glembatumumab vedotin, pertuzumab, trastuzumab, or any combinations or any salts thereof. In some embodiments, the second or additional chemotherapeutic agent is gemcitabine. In some embodiments, the second or additional chemotherapeutic agent is carboplatin. In some embodiments, the second or additional chemotherapeutic agent is cisplatin. In some embodiments, the second or additional agent is paclitaxel. In some embodiments, the GR inhibitor is used in combination with gemcitabine and carboplatin. In some embodiments, the GR inhibitor is used in combination with carboplatin and cisplatin. . In some embodiments, the second or additional therapeutic agent is an anti-PD-Ll agent. In certain embodiments, the anti-PD-Ll agent is MPDL3280A or avelumab. In certain embodiments, the anti-PD-Ll agent comprises atezolizumab, avelumab, durvalumab, MPDL3280A (RG7446), MDX-1105 (BMS-936559) or BMS-935559, MSB0010718C, and MEDI4736. In some embodiments, the second or additional therapeutic agent is an anti-PDl agent. In certain embodiments, the anti-PDl agent is nivolumab or pembrolizumab. . In certain embodiments, the anti-PDl agent comprises pembrolizumab, nivolumab, cemiplimab, partalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, or AMP-514 (MEDI0680).

In some embodiments, the second or additional therapeutic agent is an anti-CTLA-4 agent. In certain embodiments, the anti-CTLA agent comprises ipilimumab, or tremelimumab. In some embodiments, the second or additional therapeutic agent is a CAR-T cell therapy. In some embodiments, the second or additional therapeutic agent is an IDO-1 inhibitor. In some embodiments, the second or additional therapeutic agent is a cancer vaccine.

GR Antagonists

[00121] Disclosed herein are method, composition, or therapy disclosed herein, wherein the glucocorticoid receptor (GR) antagonist is a selective GR antagonist. Disclosed herein are method, composition, or therapy disclosed herein, wherein the glucocorticoid receptor (GR) antagonist is an unselective GR antagonist. In some embodiments, the GR antagonist comprises mifepristone, cyproterone acetate, Relacorilant (CORT125134), Exicorilant (CORT125281), Miricorilant (CORT118335), CORT113176, CORT108297, PT150 (formerly Org34517), PT157, or PT162. [00122] In some embodiments, the GR antagonist comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof:

Formula (I) wherein ring A is a heteroaryl or aryl;

R¹ is -NR^4aR^5a; each R² is independently -NR⁴R⁵, halo, -OR⁶, -OH, optionally substituted alkyl, or haloalkyl;

R³ is optionally substituted C2-8 alkyl, halo, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, -Si(R⁶)₃, -OR⁶, or -S(0)₂R⁷;

R^4a is C2-8 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;

R^5ais -H, optionally substituted alkyl, or haloalkyl; or R^4a and R^5a are taken together with the N atom to which they are attached to form an optionally substituted heterocycloalkyl;

R⁴ and R⁵ are each independently -H, optionally substituted alkyl, or haloalkyl; or R⁴ and R⁵ are taken together with the N atom to which they are attached to form an optionally substituted heterocycloalkyl; each R⁶ is independently optionally substituted alkyl or haloalkyl;

R⁷ is optionally substituted alkyl or haloalkyl; R⁸ and R⁹ are each independently -H, optionally substituted alkyl, haloalkyl, or halo;

R¹⁰ and R¹¹ are each independently -H, optionally substituted alkyl, halo, or haloalkyl;

R¹² is hydrogen, optionally substituted alkyl, haloalkyl, hydroxy, or halo; n is 0, 1, or 2.

[00123] In some embodiments of compounds of Formula (I), R¹² is Ci-₆ alkyl or hydrogen. In some embodiments of compounds of Formula (I), R¹² is methyl. In some embodiments of compounds of Formula (I), R¹² is H. In some embodiments of compounds of Formula (I), ring A is phenyl. In some embodiments of compounds of Formula (I), R^4a is C2-8 alkyl. In some embodiments of compounds of Formula (I), R^4a is C3-6 alkyl. In some embodiments of compounds of Formula (I), R^4a is C2-4 alkyl. In some embodiments of compounds of Formula (I), R^4a is ethyl, i-propyl, or t-butyl. In some embodiments of compounds of Formula (I), R^5a is -H, optionally substituted alkyl, or haloalkyl. In some embodiments of compounds of Formula (I), R^5a is -H or alkyl. In some embodiments of compounds of Formula (I), R^5a is Ci-₆ alkyl. In some embodiments of compounds of Formula (I), n is 0 or 1. In some embodiments of compounds of Formula (I), each R² is independently halo. In some embodiments of compounds of Formula (I), R³is optionally substituted C2-8 alkyl, haloalkyl, or optionally substituted cycloalkyl. In some embodiments of compounds of Formula (I), R³is C4-8 alkyl. In some embodiments of compounds of Formula (I), R⁸ and R⁹ are -H. In some embodiments of compounds of Formula (I), R¹⁰ and R¹¹ are each -H.

[00124] In some embodiments of compounds of Formula (I), the compound has the structure of Formula (la):

Rio R¹¹

Formula (la).

[00125] In some embodiments of compounds of Formula (I), the compound is compound 1:

pharmaceutically acceptable salt thereof.

[00126] In some embodiments, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Dosing

[00127] In one aspect, the compositions described herein are used for the treatment of diseases and conditions described herein. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of compositions in therapeutically effective amounts to said subject.

[00128] Dosages of compositions described herein can be determined by any suitable method. Maximum tolerated doses (MTD) and maximum response doses (MRD) for a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) can be determined via established animal and human experimental protocols as well as in the examples described herein. For example, toxicity and therapeutic efficacy of a compound of a glucocorticoid receptor antagonist, or a pharmaceutically acceptable salt thereof (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Additional relative dosages, represented as a percent of maximal response or of maximum tolerated dose, are readily obtained via the protocols.

[00129] In some embodiments, the GR antagonist, or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount between about 10 mg to 500 mg. In some embodiments, the GR antagonist, or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount that is between about 50 mg and about 400 mg. In some embodiments, the GR antagonist, or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount that is between about 100 mg and about 400 mg. In some embodiments, the GR antagonist, or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount that is between about 100 mg and about 300 mg. In some embodiments, the GR antagonist, or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount that is between about 200 mg and about 400 mg. In some embodiments, the GR antagonist, or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount that is between about 200 mg and about 300 mg. In some embodiments, the GR antagonist, or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount that is between about 40 mg and about 480 mg. In some embodiments, the GR antagonist, or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount that is between about 100 mg and about 480 mg. In some embodiments, the GR antagonist, or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount that is between about 200 mg and about 480 mg. In some embodiments, the GR antagonist, or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount that is between about 80 mg and about 250 mg. In some embodiments, the GR antagonist, or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered in an amount that is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about

200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about

270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about

340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about

410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about

480 mg, about 490 mg, or about 500 mg.

[00130] In some embodiments, the amount of a given GR antagonist, or a pharmaceutically acceptable salt thereof (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) formulation that corresponds to such an amount varies depending upon factors such as the particular salt or form, disease condition and its severity, the identity (e.g., age, weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid formulation type, the condition being treated, and the subject or host being treated.

Administration

[00131] Administration of the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof described is at a dosage described herein or at other dose levels and compositions determined and contemplated by a medical practitioner. In certain embodiments, the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof is administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof is administered to a patient already suffering from a disease in an amount sufficient to cure the disease or at least partially arrest or ameliorate the symptoms. Amounts effective for this use depend on the age of the patient, severity of the disease, previous therapy, the patient's health status, weight, and response to the compositions, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial.

[00132] In prophylactic applications, the compositions described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, e.g., cancer. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's age, state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the risk or susceptibility of developing the particular disease, previous therapy, the patient's health status and response to the compositions, and the judgment of the treating physician.

[00133] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of a composition described herein are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease. In other embodiments, administration of a composition continues until complete or partial response of a disease.

[00134] In some embodiments, the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments, the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof is administered three times a day.

[00135] In some embodiments, the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof is administered to a subject who is in a fasted state. A fasted state refers to a subject who has gone without food or fasted for a certain period of time. General fasting periods include at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours and at least 16 hours without food. In some embodiments, the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof is administered to a subject who is in a fasted state for at least 8 hours. In other embodiments, the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof is administered to a subject who is in a fasted state for at least 10 hours. In yet other embodiments, the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof is administered to a subject who is in a fasted state for at least 12 hours. In other embodiments, the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof is administered to a subject who has fasted overnight.

[00136] In other embodiments, the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof is administered to a subject who is in a fed state. A fed state refers to a subject who has taken food or has had a meal. In certain embodiments, a composition is administered to a subject in a fed state 5 minutes post-meal, 10 minutes post-meal, 15 minutes post-meal, 20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50 minutes post-meal, 1 hour post-meal, or 2 hours post-meal. In certain instances, the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof is administered to a subject in a fed state 30 minutes post-meal. In other instances, the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof is administered to a subject in a fed state 1 hour post-meal. In yet further embodiments, the compound of a glucocorticoid receptor agonist, or a pharmaceutically acceptable salt thereof is administered to a subject with food.

[00137] In some instances, the methods described herein further comprise administering the compositions and formulations comprising a compound of a glucocorticoid receptor antagonist, or pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent to the subject or patient in need thereof in multiple cycles repeated on a regular schedule with periods of rest in between each cycle. For example, in some instances, treatment is given for one week followed by three weeks of rest is one treatment cycle.

[00138] The length of a treatment cycle depends on the treatment being given. In some embodiments, the length of a treatment cycle ranges from two to six weeks. In some embodiments, the length of a treatment cycle ranges from three to six weeks. In some embodiments, the length of a treatment cycle ranges from three to four weeks. In some embodiments, the length of a treatment cycle is three weeks (or 21 days). In some embodiments, the length of a treatment cycle is four weeks (28 days). In some embodiments, the length of a treatment cycle is 56 days. In some embodiments, a treatment cycle lasts one, two, three, or four weeks. In some embodiments, a treatment cycle lasts three weeks. In some embodiments, a treatment cycle lasts four weeks. The number of treatment doses scheduled within each cycle also varies depending on the drugs being given.

Combination with chemotherapy

[00139] In some embodiments of the methods for use of the predictive response signature (PRS) disclosed herein, the method comprises administering to the subject in need thereof: (a) Formula (I) (e.g., compound

pharmaceutically acceptable salt thereof; and (b) a chemotherapy.

[00140] In some embodiments, the solid tumor is prostate cancer, breast cancer, endometrial cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, non-small cell lung cancer, squamous head & neck cancer, hepatocellular cancer, esophageal cancer, ovarian cancer, or gastric cancer. In some embodiments, the solid tumor is prostate cancer.

[00141] In some embodiments, the solid tumor is breast cancer. In some embodiments, the solid tumor is endometrial cancer. In some embodiments, the solid tumor is pancreatic cancer. In some embodiments, the solid tumor is pancreatic ductal adenocarcinoma. In some embodiments, the solid tumor is non-small cell lung cancer. In some embodiments, the solid tumor is squamous head & neck cancer. In some embodiments, the solid tumor is hepatocellular cancer. In some embodiments, the solid tumor is esophageal cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is gastric cancer. In some embodiments, the solid tumor is prostate cancer.

[00142] In some embodiments, the solid tumor is prostate cancer. In some embodiments, the prostate cancer is metastatic prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer (CRPC). In some embodiments, the prostate cancer is castration-sensitive prostate cancer. [00143] In some embodiments, the solid tumor is breast cancer. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the breast cancer is ER negative breast cancer.

[00144] In some embodiments, the chemotherapy is nab-paclitaxel, paclitaxel, docetaxel, cabazitaxel, tesetaxel, cisplatin, carboplatin, gemcitabine, capecitabine, or pemetrexed. In some embodiments, the chemotherapy is nab-paclitaxel. In some embodiments, the chemotherapy is administered in an amount that is between about 10 mg/m² and about 200 mg/m². In some embodiments, the chemotherapy is administered in an amount that is about 75 mg/m². In some embodiments, the chemotherapy is administered in an amount that is about 125 mg/m².

[00145] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, and the chemotherapy are both administered in 28-day cycles.

[00146] In some embodiments, the chemotherapy is administered for multiple 28-day cycles.

[00147] In some embodiments, the chemotherapy is administered for at least one 28-day cycle.

[00148] In some embodiments, the chemotherapy is administered for at least two 28-day cycles.

[00149] In some embodiments, the chemotherapy is administered for at least three 28-day cycles.

[00150] In some embodiments, the chemotherapy is administered on days 1, 8, and 15 of each 28-day cycle. [00151] In some embodiments, the chemotherapy is administered on days 1 and 8 of each 28-day cycle. [00152] In some embodiments, the chemotherapy is administered on days 8 and 15 of each 28-day cycle. [00153] In some embodiments, the chemotherapy is administered on days 1-7 of each 28-day cycle. [00154] In some embodiments, the chemotherapy is administered on day 1 of each 28-day cycle.

[00155] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for multiple 28-day cycles.

[00156] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

[00157] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least two 28-day cycles.

[00158] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least three 28-day cycles.

[00159] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 28-day cycle.

[00160] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 28-day cycle.

[00161] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 28-day cycle.

[00162] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-28 of each 28-day cycle.

[00163] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1, 8, and 15 of each 28-day cycle.

[00164] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1 and 15 of each 28-day cycle.

[00165] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 8 and 15 of each 28-day cycle.

[00166] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1 and 8 of each 28-day cycle.

[00167] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 7, and 14 of each 28-day cycle.

[00168] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1 and 7 of each 28-day cycle.

[00169] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1 and 14 of each 28-day cycle.

[00170] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 7 and 14 of each 28-day cycle.

[00171] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 2, 9, and 16 of each 28-day cycle. [00172] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 2 and 16 of each 28-day cycle.

[00173] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 9 and 16 of each 28-day cycle.

[00174] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 2 and 9 of each 28-day cycle.

[00175] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-3, 8-10, and 15-17 of each 28-day cycle.

[00176] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1, 2, 7-9, and 14-16 of each 28-day cycle.

[00177] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-4, 8-11, and 15-18 of each 28-day cycle.

[00178] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-3, 7-10, and 14-17 of each 28-day cycle.

[00179] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-5, 8-12, and 15-19 of each 28-day cycle.

[00180] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-4, 7-11, and 14-18 of each 28-day cycle.

[00181] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-6, 8-13, and 15-20 of each 28-day cycle.

[00182] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1-5, 7-12, and 14-19 of each 28-day cycle.

[00183] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof and the chemotherapy are both administered in 21 -day cycles.

[00184] In some embodiments, the chemotherapy is administered for multiple 21-day cycles.

[00185] In some embodiments, the chemotherapy is administered for at least one 21 -day cycle.

[00186] In some embodiments, the chemotherapy is administered for at least two 21-day cycles.

[00187] In some embodiments, the chemotherapy is administered for at least three 21-day cycles.

[00188] In some embodiments, the chemotherapy is administered on days 1, 8, and 15 of each 21 -day cycle.

[00189] In some embodiments, the chemotherapy is administered on days 1 and 8 of each 21 -day cycle. [00190] In some embodiments, the chemotherapy is administered on days 8 and 15 of each 21-day cycle. [00191] In some embodiments, the chemotherapy is administered on days 1-7 of each 21-day cycle. [00192] In some embodiments, the chemotherapy is administered on day 1 of each 21-day cycle.

[00193] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for multiple 21-day cycles.

[00194] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least one 21 -day cycle. [00195] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least two 21 -day cycles.

[00196] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least three 21 -day cycles.

[00197] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 21 -day cycle.

[00198] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 21 -day cycle.

[00199] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 21 -day cycle.

[00200] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1, 8, and 15 of each 21-day cycle.

[00201] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1 and 15 of each 21 -day cycle.

[00202] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on day 1 and 8 of each 21 -day cycle.

[00203] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 8 and 15 of each 21 -day cycle.

[00204] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 2, 9, and 16 of each 21 -day cycle.

[00205] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 2 and 9 of each 21 -day cycle.

[00206] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 2 and 16 of each 21 -day cycle.

[00207] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 9 and 16 of each 21 -day cycle.

[00208] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-3, 8-10, and 15-17 of each 21-day cycle.

[00209] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-3 and 8-10 of each 21-day cycle.

[00210] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1, 2, 7-9, and 14-16 of each 21 -day cycle.

[00211] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1, 2, and 7-9 of each 21 -day cycle.

[00212] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1, 2 and 7-9 of each 21 -day cycle.

[00213] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-4, 8-11, and 15-18 of each 21-day cycle. [00214] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-4 and 8-11 of each 21-day cycle.

[00215] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-3, 7-10, and 14-17 of each 21 -day cycle.

[00216] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-3, and 7-10 of each 21 -day cycle.

[00217] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-5, 8-12, and 15-19 of each 21-day cycle.

[00218] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-5 and 8-12 of each 21-day cycle.

[00219] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-4, 7-11, and 14-18 of each 21 -day cycle.

[00220] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-4, and 7-11 of each 21 -day cycle.

[00221] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-6, 8-13, and 15-20 of each 21-day cycle.

[00222] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-6 and 8-13 of each 21-day cycle.

[00223] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-5, 7-12, and 15-19 of each 21 -day cycle.

[00224] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-5 and 7-12 of each 21 -day cycle.

[00225] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered between about 2 hours before and about 2 hours after administration of the chemotherapy.

[00226] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered about 2 hours before administration of the chemotherapy.

[00227] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered about 30 mins after administration of the chemotherapy.

[00228] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered at the same time as the chemotherapy.

[00229] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered first thing in the morning. In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered just before sleep.

[00230] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating pancreatic ductal adenocarcinoma (PDAC) in a subject in need thereof; the method comprising administering to the subject in need thereof:

and

(b) nab-paclitaxel.

[00231] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject in 28-day cycles.

[00232] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least one 28 -day cycle.

[00233] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least two 28-day cycles.

[00234] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least three 28-day cycles.

[00235] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least four 28-day cycles.

[00236] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least five 28-day cycles.

[00237] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least six 28-day cycles.

[00238] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least seven 28 -day cycles.

[00239] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least eight 28-day cycles.

[00240] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least nine 28-day cycles. [00241] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 1028 -day cycles.

[00242] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 15 28 -day cycles.

[00243] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 2028-day cycles.

[00244] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 25 28-day cycles.

[00245] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.

[00246] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00247] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00248] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00249] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.

[00250] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00251] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00252] In some embodiments of a method of treating pancreatic ductal adenocarcinoma (PDAC), compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00253] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating ovarian cancer in a subject in need thereof; the method comprising administering to the subject in need thereof:

(Compound 1) or a pharmaceutically acceptable salt thereof; and

(b) nab-paclitaxel.

[00254] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject in 28-day cycles.

[00255] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least one 28-day cycle.

[00256] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least two 28-day cycles.

[00257] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least three 28-day cycles.

[00258] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least four 28-day cycles.

[00259] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least five 28-day cycles.

[00260] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least six 28-day cycles. [00261] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least seven 28-day cycles.

[00262] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least eight 28-day cycles.

[00263] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least nine 28-day cycles.

[00264] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 1028-day cycles.

[00265] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 15 28-day cycles.

[00266] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 2028-day cycles.

[00267] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 25 28-day cycles.

[00268] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle and nab- paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.

[00269] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00270] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00271] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day. [00272] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.

[00273] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m² per day.

[00274] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m² per day.

[00275] In some embodiments of a method of treating ovarian cancer, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m² per day.

[00276] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating triple negative breast cancer (TNBC); the method comprising administering to the subject in need thereof:

(Compound 1) or a pharmaceutically acceptable salt thereof; and

(b) nab-paclitaxel.

[00277] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject in 28- day cycles.

[00278] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least one 28 -day cycle.

[00279] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least two 28-day cycles.

[00280] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least three 28-day cycles. [00281] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least four 28-day cycles.

[00282] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least five 28 -day cycles.

[00283] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least six 28-day cycles.

[00284] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least seven 28-day cycles.

[00285] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least eight 28 -day cycles.

[00286] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least nine 28-day cycles.

[00287] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 1028-day cycles.

[00288] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 15 28-day cycles.

[00289] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 2028-day cycles.

[00290] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 25 28-day cycles.

[00291] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.

[00292] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day. [00293] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00294] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00295] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.

[00296] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00297] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00298] In some embodiments of a method of treating triple negative breast cancer (TNBC), compound 1 , or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00299] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating metastatic solid tumors in a subject in need thereof; the method comprising administering to the subject in need thereof:

and

(b) nab-paclitaxel.

[00300] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered in 28-day cycles. [00301] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least one 28-day cycle.

[00302] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least two 28-day cycles.

[00303] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least three 28- day cycles.

[00304] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least four 28-day cycles.

[00305] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least five 28-day cycles.

[00306] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least six 28-day cycles.

[00307] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least seven 28- day cycles.

[00308] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least eight 28- day cycles.

[00309] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least nine 28-day cycles.

[00310] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least 1028-day cycles.

[00311] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least 15 28-day cycles.

[00312] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered for at least 2028-day cycles. [00313] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and the chemotherapy are both administered for at least 25 28- day cycles.

[00314] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.

[00315] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m² per day.

[00316] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m² per day.

[00317] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m² per day.

[00318] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.

[00319] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00320] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00321] In some embodiments of a method of treating metastatic solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00322] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating solid tumors in a subject in need thereof; the method comprising administering to the subject in need thereof:

and

(b) nab-paclitaxel.

[00323] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject in 28-day cycles.

[00324] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least one 28-day cycle.

[00325] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least two 28-day cycles.

[00326] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least three 28-day cycles.

[00327] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least four 28-day cycles.

[00328] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least five 28-day cycles.

[00329] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least six 28-day cycles.

[00330] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least seven 28-day cycles.

[00331] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least eight 28-day cycles.

[00332] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least nine 28-day cycles. [00333] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 1028-day cycles.

[00334] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 15 28-day cycles.

[00335] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 2028-day cycles.

[00336] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, and nab-paclitaxel are both administered to the subject for at least 25 28-day cycles.

[00337] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle and nab- paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.

[00338] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00339] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00340] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-21 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle at a dose of 75 mg/m² per day.

[00341] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day cycle.

[00342] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 80 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m² per day.

[00343] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 160 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m² per day. [00344] In some embodiments of a method of treating solid tumors, compound 1, or pharmaceutically acceptable salt thereof, is administered to the subject on days 1-5, 8-12, and 15-19 of each 28-day cycle at a dose of 240 mg per day and nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28 -day cycle at a dose of 75 mg/m² per day.

Combination with Androgen Receptor Modulator

[00345] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating a prostate cancer in a subject in need thereof; the method comprising administering to the subject in need thereof:

(a) Formula (I) (e.g., compound

pharmaceutically acceptable salt thereof; and

(b) an androgen receptor modulator.

[00346] In some embodiments, the androgen receptor modulator is enzalutamide, apalutamide, darolutamide, abiraterone, or bicalutamide. In some embodiments, the androgen receptor modulator is enzalutamide. In some embodiments, the androgen receptor modulator is apalutamide. In some embodiments, the androgen receptor modulator is administered in an amount that is between about 60 mg and about 400 mg. In some embodiments, the androgen receptor modulator is administered in an amount that is between about 160 mg and about 240 mg. In some embodiments, the androgen receptor modulator is administered in an amount that is about 80 mg. In some embodiments, the androgen receptor modulator is administered in an amount that is about 120 mg. In some embodiments, the androgen receptor modulator is administered in an amount that is about 160 mg. In some embodiments, the androgen receptor modulator is administered in an amount that is about 180 mg. In some embodiments, the androgen receptor modulator is administered in an amount that is about 240 mg. In some embodiments, the androgen receptor modulator is enzalutamide and is administered to the subject once per day at a dose of 160 mg.

[00347] In some embodiments, the prostate cancer is metastatic prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer (CRPC). In some embodiments, the prostate cancer is castration-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic prostate cancer progressing on AR-inhibitors, including, but not limited to, enzalutamide. In some embodiments, the prostate cancer is metastatic prostate cancer progressing on enzalutamide [00348] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, and the androgen receptor modulator are administered daily. In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, and the androgen receptor modulator are administered in 28-day cycles. [00349] In some embodiments, the androgen receptor modulator is administered for multiple 28-day cycles.

[00350] In some embodiments, the androgen receptor modulator is administered for at least one 28-day cycle.

[00351] In some embodiments, the androgen receptor modulator is administered for at least two 28-day cycles.

[00352] In some embodiments, the androgen receptor modulator is administered for at least three 28-day cycles.

[00353] In some embodiments, the androgen receptor modulator is administered on days 1-7 of each 28- day cycle.

[00354] In some embodiments, the androgen receptor modulator is administered on days 1-14 of each 28- day cycle.

[00355] In some embodiments, the androgen receptor modulator is administered on days 1-21 of each 28- day cycle.

[00356] In some embodiments, the androgen receptor modulator is administered on days 1-28 of each 28- day cycle.

[00357] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered in 28-day cycles.

[00358] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for multiple 28-day cycles.

[00359] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

[00360] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least two 28-day cycles.

[00361] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered for at least three 28-day cycles.

[00362] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 28-day cycle.

[00363] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-6 of each 28-day cycle.

[00364] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 28-day cycle.

[00365] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-13 of each 28-day cycle.

[00366] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 28-day cycle.

[00367] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-20 of each 28-day cycle. [00368] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days 1-28 of each 28-day cycle.

[00369] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered on days -1, 1-27 of each 28-day cycle.

[00370] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered between about 2 hours before and about 2 hours after administration of the androgen receptor modulator.

[00371] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered about 2 hours before administration of the androgen receptor modulator.

[00372] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered about 30 mins after administration of the androgen receptor modulator.

[00373] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered at the same time as the androgen receptor modulator.

[00374] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered first thing in the morning.

[00375] In some embodiments, the compound of Formula (I) (e.g., compound 1), or pharmaceutically acceptable salt thereof, is administered just before sleep.

[00376] In some embodiments, the androgen receptor modulator is administered first thing in the morning.

[00377] In some embodiments, the androgen receptor modulator is administered just before sleep.

[00378] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof:

(compound 1), or a pharmaceutically acceptable salt thereof; and

(b) enzalutamide.

[00379] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one week.

[00380] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two weeks. [00381] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three weeks.

[00382] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one month.

[00383] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two months.

[00384] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three months.

[00385] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least four months.

[00386] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least five months.

[00387] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least six months.

[00388] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one year.

[00389] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two years.

[00390] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject until disease progression.

[00391] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 120 mg per day.

[00392] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day. [00393] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 160 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00394] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 240 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00395] In some embodiments of a method of treating prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 320 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00396] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating metastatic prostate cancer in a subject in need thereof; the method comprising administering to the subject in need thereof:

(compound 1) or a pharmaceutically acceptable salt thereof; and

(b) enzalutamide.

[00397] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one week.

[00398] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two weeks.

[00399] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three weeks.

[00400] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one month.

[00401] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two months.

[00402] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three months. [00403] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least four months.

[00404] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least five months.

[00405] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least six months.

[00406] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one year.

[00407] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two years.

[00408] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject until disease progression.

[00409] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 120 mg per day.

[00410] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00411] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 160 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00412] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 240 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00413] In some embodiments of a method of treating metastatic prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 320 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00414] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating metastatic prostate cancer in a subject in need thereof, wherein the prostate cancer has progressed after treatment with an androgen receptor modulator, the method comprising administering to the subject in need thereof:

(compound 1) or a pharmaceutically acceptable salt thereof; and

(b) enzalutamide.

[00415] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, the androgen receptor modulator is enzalutamide, apalutamide, darolutamide, abiraterone, or bicalutamide. In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, the androgen receptor modulator is enzalutamide. In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, the androgen receptor modulator is apalutamide.

[00416] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one week.

[00417] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two weeks.

[00418] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three weeks.

[00419] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one month.

[00420] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two months.

[00421] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three months.

[00422] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least four months.

[00423] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least five months. [00424] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least six months.

[00425] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one year.

[00426] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two years.

[00427] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject until disease progression.

[00428] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 120 mg per day.

[00429] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00430] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 160 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00431] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 240 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00432] In some embodiments of a method of treating metastatic prostate cancer that has progressed after treatment with an androgen receptor modulator, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 320 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00433] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating castrate resistant prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof:

(compound 1) or a pharmaceutically acceptable salt thereof; and

(b) enzalutamide.

[00434] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one week.

[00435] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two weeks.

[00436] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three weeks.

[00437] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one month.

[00438] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two months.

[00439] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least three months.

[00440] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least four months.

[00441] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least five months.

[00442] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least six months.

[00443] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least one year. [00444] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject for at least two years.

[00445] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, and enzalutamide are both administered to the subject until disease progression.

[00446] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 120 mg per day.

[00447] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 80 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00448] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 160 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00449] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 240 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00450] In some embodiments of a method of treating castrate resistant prostate cancer, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of 320 mg per day and enzalutamide is administered to the subject at a dose of 160 mg per day.

[00451] In any of the embodiments disclosed herein, the dose of compound 1, or a pharmaceutically acceptable salt thereof, administered to the subject in need thereof may be administered to the subject as a single dose, or two doses, or three doses, or four doses, or five doses, or 6 doses. In one embodiment, the dose of compound 1, or a pharmaceutically acceptable salt thereof, administered to the subject in need thereof is administered to the subject as a single dose. For example, a dose of 80 mg, or 160 mg, or 240 mg, or 320 mg of compound 1, or a pharmaceutically acceptable salt thereof, to be administered to the subject may be administered in the form of one or more dosage units, such as one or more capsules or tablets. When the total dose compound 1, or a pharmaceutically acceptable salt thereof, is contained in two or more dosage units, such as two capsules or two tablets, each dosage unit may contain the same amount or different amounts of compound 1, or a pharmaceutically acceptable salt thereof. When the total dose of compound 1, or a pharmaceutically acceptable salt thereof, is contained in two or more dosage units, and the total dose is administered to the subject once per day, each dosage unit may be administered to the subject at the same time or as close in time as is convenient for the subject. For example, a dose of 160 mg of compound 1, or a pharmaceutically acceptable salt thereof, to be administered to the subject once per day may be administered to the subject as two dosage units, each containing 80 mg of compound 1, or a pharmaceutically acceptable salt thereof, each of which is administered to the subject at the same time or as close in time as is convenient for the subject. In another example, a dose of 160 mg of compound 1, or a pharmaceutically acceptable salt thereof, to be administered to the subject once per day may be administered to the subject as two dosage units, each containing 80 mg of compound 1, or a pharmaceutically acceptable salt thereof, and each of which is administered to the subject during the same 24-hour period but with some period of time in between the administration of each, such as 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 11 hours, or 12 hours. In some embodiments disclosed herein, the dose of compound 1, or a pharmaceutically acceptable salt thereof, to be administered to the subject daily is administered as a single dose (e.g., two capsules, each containing 80 mg of compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject at the same time or as close in time as is convenient for the subject).

[00452] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of (i) a glucocorticoid receptor (GR) antagonist (e.g., compound 1, or a pharmaceutically acceptable salt thereof) and (ii) an androgen receptor (AR) degrader. In some embodiments, the AR degrader is ARV-110, ARV-330, SARD279, SARD033, ARCC-4, UT-34, ARD-111, ARD-86, ARD-77, ARD-69, ARD-61, LX-1, or LX-2. In some embodiments, the AR degrader is ARV-110.

[00453] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of (i) a glucocorticoid receptor (GR) antagonist (e.g., compound 1, or a pharmaceutically acceptable salt thereof), (ii) an antiandrogen, and (iii) a third agent, wherein the third agent is selected from one or more of an AKT inhibitor, a PI3K inhibitor, and an mTOR inhibitor. In some embodiments, the AKT inhibitor is ipatasertib (GDC-0068), capivasertib (AZD5363), MK2206, afuresertib (GSK2110183), uprosertib (GSK2141795), perifosine (KRX- 0401), PHT-427 (CS-0223), or Akti-1/2. In some embodiments, the AKT inhibitor is ipatasertib (GDC-0068). In some embodiments, the PI3K inhibitor is taselisib (GDC-0032), GDC-0077, perifosine, idelalisib, buparlisib (B KM 120), duvelisib, (IPI-145), copanlisib (BAY 80-6946), PX-866, dactolisib, CUDC-907, voxtalisib (SAR245409, XL765), ME-401, IPI-549, SF1126, RP6530, INK1117, pictilisib (GDC-0941), XL 147 (SAR245408), palomid 529, GSK1059615, ZSTK474, or PWT33597. In some embodiments, the mTOR inhibitor is sirolimus, everolimus, temsirolimus, umirolimus, ridaforolimus, zotarolimus, dactolisib, voxtalisib, omipalisib (GSK2126458), torkinib, gedatolisib (PF-05212384, PKI- 587), BGT226, SF1126, PKI-587, sapanisertib (MLN0128, INK128), AZD8055, AZD2014, PI-103, or AZD 8055. In some embodiments, the antiandrogen is enzalutamide, apalutamide, darolutamide, abiraterone, 3,3'-diindolylmethane (DIM), abiraterone acetate, bexlosteride, bicalutamide, dutasteride, epristeride, finasteride, flutamide, izonsteride, ketoconazole, N-butylbenzene -sulfonamide, nilutamide, megestrol, steroidal antiandrogens, EPI-7386, or turosteride. In some embodiments, the antiandrogen is enzalutamide. In some embodiments, the antiandrogen is apalutamide. In some embodiments, the antiandrogen is darolutamide. [00454] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a glucocorticoid receptor (GR) antagonist (e.g., compound 1, or a pharmaceutically acceptable salt thereof), wherein the prostate cancer in the subject has been determined not to express an L702H mutation in the androgen receptor (AR).

[00455] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of (a) a glucocorticoid receptor (GR) antagonist (e.g., compound 1, or a pharmaceutically acceptable salt thereof), and (b) enzalutamide, wherein the prostate cancer in the subject has been determined not to express an F877L mutation in the androgen receptor (AR).

[00456] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating prostate cancer in a subject, wherein the prostate cancer in the subject has been determined to express an F877L mutation in the androgen receptor (AR), comprising administering to the subject a therapeutically effective amount of (a) a glucocorticoid receptor (GR) antagonist (e.g., compound 1, or a pharmaceutically acceptable salt thereof), and (b) an antiandrogen, wherein the antiandrogen is not enzalutamide.

[00457] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of (a) a glucocorticoid receptor (GR) antagonist (e.g., compound 1, or a pharmaceutically acceptable salt thereof), and (b) enzalutamide, wherein the prostate cancer in the subject has been determined not to exhibit amplification of DNA encoding for the androgen receptor

(AR).

[00458] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of (a) a glucocorticoid receptor (GR) antagonist (e.g., compound 1, or a pharmaceutically acceptable salt thereof) and (b) an antiandrogen selected from enzalutamide or apalutamide, wherein the prostate cancer in the subject has been determined not to express one or more combinations of mutations in the androgen receptor (AR) selected from H875Y/T878A, F877L/T878A, and M896V/S889G.

[00459] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating prostate cancer in a subject, wherein the prostate cancer in the subject has been determined to express one or more combinations of mutations in the androgen receptor (AR) selected from H875Y/T878A, F877L/T878A, and M896V/S889G, comprising administering to the subject a therapeutically effective amount of (a) a glucocorticoid receptor (GR) antagonist (e.g., compound 1, or a pharmaceutically acceptable salt thereof), and (b) an antiandrogen, wherein the antiandrogen is not enzalutamide or apalutamide.

[00460] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of (a) a glucocorticoid receptor (GR) antagonist (e.g., compound 1, or a pharmaceutically acceptable salt thereof) and (b) enzalutamide, wherein the prostate cancer in the subject has been determined not to express an androgen receptor (AR) splice variant lacking the ligand-binding domain in the androgen receptor (AR).

[00461] In some embodiments for use of the predictive response signature (PRS), the methods disclosed herein are methods of treating prostate cancer in a subject, wherein the prostate cancer in the subject has been determined to express an androgen receptor (AR) splice variant lacking the ligand-binding domain in the androgen receptor (AR), comprising administering to the subject a therapeutically effective amount of (a) a glucocorticoid receptor (GR) antagonist (e.g., compound 1, or a pharmaceutically acceptable salt thereof) and (b) an antiandrogen, wherein the antiandrogen is not enzalutamide or abiraterone.

Softgel Formulations

[00462] Provided herein is a softgel formulation comprising:

(a) a GR antagonist or a pharmaceutically acceptable salt thereof; and (a) a pharmaceutically acceptable excipient.

[00463] In some embodiments, the GR antagonist comprises a compound of Formula (I) or Formula (la). In some embodiments, the compound comprises compound 1. In some embodiments, the compound comprises a compound selected from:

Pharmaceutically acceptable excipient [00464] In some embodiments of a softgel formulation, the pharmaceutically acceptable excipient is propylene glycol monocaprylate, Capryol®, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, ethyl oleate, soybean oil, glyceryl caprylate/caprate, Campul®, glyceryl behenate, Compritol® 888 ATO, glyceryl palmitostearate, Precirol® ATO 5, glyceryl monostearate, Geleol™, glyceryl monolinoleate, Maisine™ 35-1, glyceryl monooleate, Peceol™, medium -chain triglycerides, Labrafac™ Lipophile WL1349, propylene glycol monolaurate, Lauroglycol™ 90, oleoyl macrogol-6 glycerides, Labrafd® M1944CS, polyglyceryl-3 dioleate, Plurol Oleique® CC 497, diethylene glycol monoethyl ether, Transcutol® HP, caprylic/capric triglyceride, Crodamol™, macroglycerol ricinoleate, Kolliphor EL®, Cremophor EL®, caprylocaproyl polyoxyl-8 glyceride, Labrasol®, lauroyl polyoxyl-6 glycerides, Labrafd® M 2130 CS, lauroyl polyoxyl-32 glyceride, Gelucire® 44/14, polyethylene glycol monostearate, Gelucire® 48/16, polyoxyethylene hydrogenated castor oil 60, HCO-60, polysorbate 80, Tween®-80, polyethylene glycol sorbitan monolaurate, Tween®- 20, polyoxyethylene sorbitan trioleate, Tween®-85, polyoxyethyelene glyceryl trioleate, Tagot-TO, sorbitan monooleate, Span®-80, sorbitan monolaurate, Span®-20, or any combinations thereof.

[00465] In some embodiments of a softgel formulation, the pharmaceutically acceptable excipient is caprylic acid, Maisine™ 35-1, Lauroglycol™ 90, Transcutol® HP, Crodamol™, Labrasol®, or any combinations thereof.

[00466] In some embodiments of a softgel formulation, the pharmaceutically acceptable excipient is caprylic acid.

[00467] In some embodiments of a softgel formulation, the pharmaceutically acceptable excipient is a combination of caprylic acid and Lauroglycol™ 90.

[00468] In some embodiments of a softgel formulation, the pharmaceutically acceptable excipient is a combination of caprylic acid, Transcutol® HP, and Labrasol®.

[00469] In some embodiments of a softgel formulation, the pharmaceutically acceptable excipient is a combination of caprylic acid and Crodamol™.

[00470] In some embodiments of a softgel formulation, the pharmaceutically acceptable excipient is a combination of caprylic acid, Transcutol® HP, Lauroglycol™ 90, and Crodamol™.

[00471] In some embodiments of a softgel formulation, the pharmaceutically acceptable excipient is a combination of caprylic acid, Lauroglycol™ 90, and Crodamol™.

[00472] In some embodiments of a softgel formulation, the pharmaceutically acceptable excipient is a combination of caprylic acid, Transcutol® HP, Maisine™ 35-1, and Crodamol™.

[00473] In some embodiments of a softgel formulation, the pharmaceutically acceptable excipient is a combination of caprylic acid, Transcutol® HP, glyceryl monolinoleate, and Labrasol®.

[00474] In some embodiments of a softgel formulation, the pharmaceutically acceptable excipient is a combination of Transcutol® HP, Lauroglycol™ 90, and Labrasol®.

[00475] In some embodiments of a softgel formulation, the pharmaceutically acceptable excipient is a combination of Transcutol® HP, Crodamol™, and Labrasol®. [00476] In some embodiments of a softgel formulation, the pharmaceutically acceptable excipient is a combination of Crodamol™ and Labrasol®.

[00477] In some embodiments of a softgel formulation, the pharmaceutically acceptable excipient forms a self-emulsifying drug delivery system (SEDDS) in an aqueous solution.

[00478] Some embodiments provided herein describe a self-dispersing pharmaceutical compositions, wherein the composition is self-dispersing when added to water and forms an emulsion, microemulsion, or nanoemulsion. In some embodiments, the pharmaceutically acceptable excipient inside the softgel formulation is in the form of a self-nanoemulsifying drug delivery system (SNEDDS), a self- microemulsifying drug delivery system (SMEDDS), or a self-emulsifying drug delivery system (SEDDS), wherein the excipient forms an emulsion in an aqueous solution. In some instances, the excipient is “self-emulsifying” and is classified based on the particle sizes that will form upon entry into an aqueous environment, as self-emulsifying drug delivery systems (“SEDDs”) producing particle sizes substantially less than 1 pm, self-microemulsifying drug delivery systems (“SMEDDS”) with smaller particles, and self-nanoemulsifying drug delivery systems (“SNEDDS”) with the smallest particles. In some embodiments, the self-dispersing excipient provided herein form SEDDS upon contact with gastric and/or intestinal media in the body, wherein the excipient forms an emulsion comprising micelle particles. In some embodiments, the emulsion provides for increased or improved stability of the active agent (e.g., The GR antagonist) for uptake in the body and/or provide increased or improved surface area for absorption. In some instances, SEDDS provide for enhanced or improved hydrolysis, solubility, bioavailability, absorption, or any combinations thereof of the active agent in vivo. In some embodiments, the SEDDS facilitates the dispersion, dissolution, stability and absorption of the drug, thus improving the bioavailability of said drug. In some embodiments, the self-dispersing excipient provided herein improve the solubility of The GR antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the self-dispersing excipient provided herein improve the bioavailability of The GR antagonist or a pharmaceutically acceptable salt thereof.

Antioxidant

[00479] In some embodiments of a softgel formulation, the softgel further comprises an antioxidant. In some embodiments of a softgel formulation, the antioxidant is a-tocopherol, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, potassium metabisulfite, propyl gallate, ascorbic acid, monothioglycerol, propionic acid, sodium ascorbate, sodium bisulfite, sodium sulfite, and cysteine (CYS), or any combinations thereof. In some embodiments of a softgel formulation, the antioxidant is a-tocopherol, ascorbyl palmitate, or any combinations thereof. In some embodiments of a softgel, the antioxidant is a-tocopherol. In some embodiments of a softgel formulation, the antioxidant is ascorbyl palmitate.

Softgel

[00480] A softgel is an oral dosage form consisting of a gelatin-based shell surrounding a liquid fill. In some embodiments, the softgel shell is a combination of gelatin, water, opacifier, and a plasticiser such as glycerin or sorbitol. In some embodiments, starch or carrageenan is used in place of gelatin. In some embodiments, the softgels are produced in a process known as encapsulation using the Rotary Die Encapsulation process. The encapsulation process has been described as a form/fill/seal process. Two flat ribbons of shell material are manufactured on the machine and brought together on a twin set of rotating dies. The dies contain recesses in the desired size and shape, which cut out the ribbons into a two- dimensional shape, and form a seal around the outside. At the same time a pump delivers a precise dose of fill material through a nozzle incorporated into a filling wedge whose tip sits between the two ribbons in between two die pockets at the point of cut out. The wedge is heated to facilitate the sealing process. The wedge injection causes the two flat ribbons to expand into the die pockets, giving rise to the three- dimensional finished product. After encapsulation, the softgels are dried for two days to two weeks depending on the product.

[00481] In some embodiments of a softgel formulation, the headspace volume inside the softgel is reduced as compared to a capsule formulation. In some embodiments of a softgel formulation, the headspace volume inside the softgel is 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% smaller than the headspace volume in a capsule formulation.

In some embodiments, the reduction in the headspace volume results in increased stability of The GR antagonist or its pharmaceutically acceptable salt and the pharmaceutically acceptable excipient. In some embodiments, the stability is increased by 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%,

10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% as compared to a capsule formulation.

[00482] In some embodiments of a softgel formulation, the risk of leakage from the softgel is reduced as compared to a capsule formulation.

Dosage in Softgel

[00483] In some embodiments of a softgel formulation, the amount of compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is between about 10 mg and about 1000 mg. In some embodiments of a softgel formulation, the amount of compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is between about 10 mg and about 300 mg. In some embodiments of a softgel formulation, the amount of compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is between about 10 mg and about 100 mg. In some embodiments of a softgel formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is between about 20 mg and about 80 mg. In some embodiments of a softgel formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is between about 30 mg and about 50 mg. In some embodiments of a softgel formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is between about 40 mg and about 60 mg. In some embodiments of a softgel formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is between about 60 mg and about 100 mg. In some embodiments of a softgel formulation, the amount of compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In some embodiments of a softgel formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is about 40 mg. In some embodiments of a softgel formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is about 50 mg. In some embodiments of a softgel formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is about 60 mg. In some embodiments of a softgel formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is about 70 mg. In some embodiments of a softgel formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is about 80 mg. In some embodiments of a softgel formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is about 90 mg. In some embodiments of a softgel formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the softgel is about 100 mg.

Impurity Profile

[00484] In some embodiments, the softgel formulation comprises less than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% impurities. In some embodiments, the impurities comprise one or more related substances shown in tables la and lb.

Table la

Table lb

Suspension

[00485] Provided herein is a suspension comprising The GR antagonist, or a pharmaceutically acceptable salt thereof.

[00486] In some embodiment of a suspension, the concentration of The GR antagonist, or its pharmaceutically acceptable salt in the suspension is between about 1 mg/mL and about 20 mg/mL. In some embodiment of a suspension, the concentration of The GR antagonist, or its pharmaceutically acceptable salt in the suspension is between about 5 mg/mL and about 20 mg/mL. In some embodiment of a suspension, the concentration of The GR antagonist, or its pharmaceutically acceptable salt in the suspension is between about 10 mg/mL and about 20 mg/mL.

[00487] In some embodiment of a suspension, the concentration of The GR antagonist, or its pharmaceutically acceptable salt in the suspension is about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, or about 20 mg/mL. In some embodiment of a suspension, the concentration of The GR antagonist, or its pharmaceutically acceptable salt in the suspension is about 16 mg/mL.

[00488] In some embodiment of a suspension, the suspension further comprises a liquid carrier.

[00489] In some embodiment of a suspension, the liquid carrier is an aqueous carrier. In some embodiment of a suspension, the liquid carrier comprises sweetening agents, flavoring agents, buffering agents, preservatives, gelling agents, thickening agents, stabilizing agents, or any combinations thereof. [00490] In some embodiments, the liquid carrier is a syrup. In some embodiments, the liquid carrier is Ora-Sweet® flavored syrup. In some embodiments, the liquid carrier is Ora-Blend® syrup. pH of the Suspension

[00491] In some embodiments of a suspension, the suspension has a pH between about 3 and about 9. In some embodiments of a suspension, the suspension has a pH between about 3 and about 8. In some embodiments of a suspension, the suspension has a pH between about 3 and about 7. In some embodiments of a suspension, the suspension has a pH between about 5 and about 8. In some embodiments of a suspension, the suspension has a pH between about 5 and about 7. In some embodiments of a suspension, the suspension has a pH between about 3 and about 6. In some embodiments of a suspension, the suspension has a pH between about 3 and about 5. In some embodiments of a suspension, the suspension has a pH between about 3 and about 4.

Tablet [00492] Provided herein is a tablet comprising a GR antagonist, or a pharmaceutically acceptable salt thereof.

[00493] In some embodiments of a tablet, the tablet comprises:

(a) a plurality of granules comprising a GR antagonist a pharmaceutically acceptable salt thereof; and

(b) extra-granular excipients.

[00494] In some embodiments, the GR antagonist comprises a compound of Formula (I) or Formula (la). In some embodiments, the GR antagonist comprises Compound l.In some embodiments, the GR antagonist comprises a compound selected from:

Granules

[00495] In some embodiments of a tablet, the plurality of granules comprises The GR antagonist or its pharmaceutically acceptable salt thereof in the form of a spray dried dispersion (SDD).

Spray Dried Dispersion (SDD)

[00496] In some embodiments of a tablet, the spray dried dispersion further comprises a dispersion polymer. Dispersion polymers are selected from hydroxypropyl methylcellulose (HPMC), hypromellose acetate succinate (hydroxypropyl methyl cellulose acetate succinate; HPMCAS, such as HPMCAS-H, HPMCAS-L, or HPMCAS-M), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylene - polyoxypropylene block copolymers, and combinations thereof.

[00497] In some embodiments of a tablet, the dispersion polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS). In some embodiments of a tablet, the dispersion polymer is hydroxypropylmethylcellulose acetate succinate (HPMC).

[00498] In some embodiments of a tablet, the ratio of The GR antagonist or its pharmaceutically acceptable salt thereof to the dispersion polymer is between about 1:5 and about 2: 1 wt/wt. In some embodiments of a tablet, the ratio of The GR antagonist or its pharmaceutically acceptable salt thereof to the dispersion polymer is between about 1 : 3 and about 1 : 1 wt/wt. In some embodiments of a tablet, the ratio of The GR antagonist or its pharmaceutically acceptable salt thereof to the dispersion polymer is about 1 : 3 wt/wt. In some embodiments of a tablet, the ratio of The GR antagonist or its pharmaceutically acceptable salt thereof to the dispersion polymer is about 1:2.2 wt/wt. In some embodiments of a tablet, the ratio of The GR antagonist or its pharmaceutically acceptable salt thereof to the dispersion polymer is about 1:1.7 wt/wt. In some embodiments of a tablet, the ratio of The GR antagonist or its pharmaceutically acceptable salt thereof to the dispersion polymer is about 1 : 1 wt/wt.

[00499] In some embodiments of a tablet, the spray dried dispersion (SDD) comprising The GR antagonist or its pharmaceutically acceptable salt thereof represents between about 30% and about 70% by weight of the total tablet. In some embodiments of a tablet, the spray dried dispersion (SDD) comprising The GR antagonist or its pharmaceutically acceptable salt thereof represents between about 40% and about 60% by weight of the total tablet. In some embodiments of a tablet, the spray dried dispersion (SDD) comprising The GR antagonist or its pharmaceutically acceptable salt thereof represents between about 45% and about 55% by weight of the total tablet. In some embodiments of a tablet, the spray dried dispersion (SDD) comprising The GR antagonist or its pharmaceutically acceptable salt thereof represents about 30% by weight of the total tablet. In some embodiments of a tablet, the spray dried dispersion (SDD) comprising The GR antagonist or its pharmaceutically acceptable salt thereof represents about 40% by weight of the total tablet. In some embodiments of a tablet, the spray dried dispersion (SDD) comprising The GR antagonist or its pharmaceutically acceptable salt thereof represents about 50% by weight of the total tablet. In some embodiments of a tablet, the spray dried dispersion (SDD) comprising The GR antagonist or its pharmaceutically acceptable salt thereof represents about 60% by weight of the total tablet.

[00500] In some embodiments of a tablet, the spray dried dispersion (SDD) comprising The GR antagonist or its pharmaceutically acceptable salt thereof represents between about 40% and about 80% by weight of the plurality of granules. In some embodiments of a tablet, the spray dried dispersion (SDD) comprising The GR antagonist or its pharmaceutically acceptable salt thereof represents between about 50% and about 70% by weight of the plurality of granules. In some embodiments of a tablet, the spray dried dispersion (SDD) comprising The GR antagonist or its pharmaceutically acceptable salt thereof represents about 50% by weight of the plurality of granules. In some embodiments of a tablet, the spray dried dispersion (SDD) comprising The GR antagonist or its pharmaceutically acceptable salt thereof represents about 60% by weight of the plurality of granules. In some embodiments of a tablet, the spray dried dispersion (SDD) comprising The GR antagonist or its pharmaceutically acceptable salt thereof represents about 70% by weight of the plurality of granules. In some embodiments of a tablet, the spray dried dispersion (SDD) comprising The GR antagonist or its pharmaceutically acceptable salt thereof represents about 80% by weight of the plurality of granules.

[00501] In some embodiments is provided a pharmaceutical tablet as set forth in Table 2.

Table 2

[00502] In some embodiments is provided a pharmaceutical tablet as set forth in Table 3.

Table 3

[00503] In some embodiments of a tablet, the plurality of granules further comprises excipients. In some embodiments of a tablet, the excipients comprise a filler/binder, a disintegrant, a lubricant, or any combination thereof.

[00504] In some embodiments of a tablet, the plurality of granules further comprises a filler/binder. [00505] Fillers/binders are selected from celluloses (such as microcrystalline cellulose, carboxymethylcellulose, ethyl cellulose and methyl cellulose), starch, gelatin, sugars (such as sucrose, glucose, dextrose, and lactose), natural and synthetic gums (such as acacia, sodium alginate, panwar gum, and ghatti gum), polyvinylpyrrolidinone, polyethylene glycol, waxes, and any combinations thereof. In some embodiments of a tablet, the filler/binder in the plurality of granules comprises microcrystalline cellulose.

[00506] In some embodiments of a tablet, the filler/binder in the plurality of granules represents between about 20% and about 40% by weight of the total tablet. In some embodiments of a tablet, the filler/binder in the plurality of granules represents between about 25% and about 35% by weight of the total tablet. In some embodiments of a tablet, the filler/binder in the plurality of granules represents about 20% by weight of the total tablet. In some embodiments of a tablet, the filler/binder in the plurality of granules represents between about 30% by weight of the total tablet. In some embodiments of a tablet, the filler/binder in the plurality of granules represents between about 40% by weight of the total tablet. [00507] In some embodiments of a tablet, the filler/binder in the plurality of granules represents between about 20% and about 50% by weight of the plurality of granules. In some embodiments of a tablet, the filler/binder in the plurality of granules represents between about 30% and about 40% by weight of the plurality of granules. In some embodiments of a tablet, the filler/binder in the plurality of granules represents about 35% by weight of the plurality of granules. In some embodiments of a tablet, the filler/binder in the plurality of granules represents about 30% by weight of the plurality of granules. In some embodiments of a tablet, the filler/binder in the plurality of granules represents between about 40% by weight of the plurality of granules.

[00508] In some embodiments of a tablet, the plurality of granules further comprises a disintegrant. [00509] Disintegrants are selected from croscarmellose sodium, crospovidone, sodium starch glycolate, veegum HV, methylcellulose, agar, bentonite, cellulose, carboxymethyl cellulose, and any combination thereof. In some embodiments of a tablet, the disintegrant in the plurality of granules comprises croscarmellose sodium.

[00510] In some embodiments of a tablet, the disintegrant in the plurality of granules represents between about 1% and about 10% by weight of the total tablet. In some embodiments of a tablet, the disintegrant in the plurality of granules represents between about 3% and about 6% by weight of the total tablet. In some embodiments of a tablet, the disintegrant in the plurality of granules represents about 4% by weight of the total tablet.

[00511] In some embodiments of a tablet, the disintegrant in the plurality of granules represents between about 1% and about 10% by weight of the plurality of granules. In some embodiments of a tablet, the disintegrant in the plurality of granules represents between about 3% and about 6% by weight of the plurality of granules. In some embodiments of a tablet, the disintegrant in the plurality of granules represents about 5% by weight of the plurality of granules.

[00512] In some embodiments of a tablet, the plurality of granules further comprises a lubricant.

[00513] Lubricants are selected from talc, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, and any combinations thereof. In some embodiments of a tablet, the lubricant comprises sodium stearyl fumarate, magnesium stearate, or any combination thereof. In some embodiments of a tablet, the lubricant in the plurality of granules comprises sodium stearyl fumarate. In some embodiments of a tablet, the lubricant comprises magnesium stearate.

[00514] In some embodiments of a tablet, the lubricant in the plurality of granules represents between about 0.1% and about 2% by weight of the total tablet. In some embodiments of a tablet, the lubricant in the plurality of granules represents between about 0.2% and about 0.8% by weight of the total tablet. In some embodiments of a tablet, the lubricant in the plurality of granules represents about 0.5% by weight of the total tablet.

[00515] In some embodiments of a tablet, the lubricant in the plurality of granules represents between about 0.1% and about 2% by weight of the plurality of granules. In some embodiments of a tablet, the lubricant in the plurality of granules represents between about 0.2% and about 0.8% by weight of the plurality of granules. In some embodiments of a tablet, the lubricant in the plurality of granules represents about 0.5% by weight of the plurality of granules.

Extra-granular excipients

[00516] In some embodiments of a tablet, the extra-granular excipients comprise a filler/binder, a disintegrant, a lubricant, or any combination thereof.

[00517] In some embodiments of a tablet, the extra-granular excipients comprise a filler/binder.

[00518] Fillers/binders are selected from celluloses (such as microcrystalline cellulose, carboxymethylcellulose, ethyl cellulose and methyl cellulose), starch, gelatin, sugars (such as sucrose, glucose, dextrose, and lactose), natural and synthetic gums (such as acacia, sodium alginate, panwar gum, and ghatti gum), polyvinylpyrrolidinone, polyethylene glycol, waxes, and any combinations thereof. In some embodiments of a tablet, the filler/binder comprises microcrystalline cellulose. In some embodiments of a tablet, the filler/binder in the extra-granular excipients comprises microcrystalline cellulose.

[00519] In some embodiments of a tablet, the filler/binder in the extra-granular excipients represents between about 5% and about 20% by weight of the total tablet. In some embodiments of a tablet, the filler/binder in the extra-granular excipients represents between about 8% and about 15% by weight of the total tablet. In some embodiments of a tablet, the filler/binder in the extra-granular excipients represents about 11% by weight of the total tablet.

[00520] In some embodiments of a tablet, the extra-granular excipients comprise a disintegrant.

[00521] Disintegrants are selected from croscarmellose sodium, crospovidone, sodium starch glycolate, veegum HV, methylcellulose, agar, bentonite, cellulose, carboxymethyl cellulose, and any combination thereof. In some embodiments of a tablet, the disintegrant in the extra-granular excipients comprises croscarmellose sodium.

[00522] In some embodiments of a tablet, the disintegrant in the extra-granular excipients represents between about 1% and about 10% by weight of the total tablet. In some embodiments of a tablet, the disintegrant in the extra-granular excipients represents between about 3% and about 6% by weight of the total tablet. In some embodiments of a tablet, the disintegrant in the extra-granular excipients represents about 3.5% by weight of the total tablet.

[00523] In some embodiments of a tablet, the extra-granular excipients comprise a lubricant.

[00524] Lubricants are selected from talc, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, and any combinations thereof. In some embodiments of a tablet, the lubricant in the extra-granular excipients comprises sodium stearyl fumarate, magnesium stearate, or any combination thereof. In some embodiments of a tablet, the lubricant in the extra-granular excipients comprises sodium stearyl fumarate. In some embodiments of a tablet, the lubricant in the extra-granular excipients comprises magnesium stearate.

[00525] In some embodiments of a tablet, the lubricant in the extra-granular excipients represents between about 0.1% and about 2% by weight of the total tablet. In some embodiments of a tablet, the lubricant in the extra-granular excipients represents between about 0.2% and about 0.8% by weight of the total tablet. In some embodiments of a tablet, the lubricant in the extra-granular excipients represents about 0.25% by weight of the total tablet. In some embodiments of a tablet, the lubricant in the extra- granular excipients represents about 0.25% by weight of the total tablet.

Additional Excipients

[00526] In some embodiments, the tablet described herein comprises additional excipients including, but not limited, to buffering agents, glidants, preservatives, and coloring agents. Additional excipients such as bulking agents, tonicity agents, and chelating agents are within the scope of the embodiments. [00527] Non-limiting examples of buffering agents include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonate co precipitate, a mixture of an amino acid and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include sodium citrate, sodium tartarate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts.

[00528] In some embodiments, the tablet described herein comprises a glidant. Suitable glidants include, but are not limited to, calcium phosphate tribasic, calcium silicate, cellulose (powdered), colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc and the like.

[00529] In some embodiments, the tablet described herein comprises a preservative. Preservatives include anti-microbials, anti-oxidants, and agents that enhance sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (methyl-, ethyl-, butyl-), benzoic acid, potassium sorbate, vanillin, and the like.

[00530] In some embodiments, the tablet described herein comprises a coloring agent for identity and/or aesthetic purposes of the resultant liquid form. Suitable coloring agents illustratively include FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide and mixtures thereof.

[00531] Additional excipients are contemplated in the tablet embodiments. These additional excipients are selected based on function and compatibility with the tablet compositions described herein and may be found, for example in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, PA: Mack Publishing Company, 1995); Hoover, John E., Remington ’s Pharmaceutical Sciences, (Easton, PA: Mack Publishing Co 1975); Fiberman, H.A. and Fachman, F., Eds., Pharmaceutical Dosage Forms (New York, NY : Marcel Decker 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Fippincott Williams & Wilkins 1999), herein incorporated by reference in their entirety. Dosage in the Tablet

[00532] In some embodiments of a tablet, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt is between about 10 mg and about 1000 mg.

[00533] In some embodiments of a tablet, the amount of The GR antagonist or its pharmaceutically acceptable salt in the tablet is between about 10 mg and about 300 mg. In some embodiments of a tablet, the amount of The GR antagonist or its pharmaceutically acceptable salt in the tablet is between about 10 mg and about 100 mg. In some embodiments of a tablet, the amount of The GR antagonist or its pharmaceutically acceptable salt in the tablet is between about 20 mg and about 80 mg. In some embodiments of a tablet, the amount of The GR antagonist or its pharmaceutically acceptable salt in the tablet is between about 30 mg and about 50 mg. In some embodiments of a tablet, the amount of The GR antagonist or its pharmaceutically acceptable salt in the tablet is between about 40 mg and about 60 mg. In some embodiments of a tablet, the amount of The GR antagonist or its pharmaceutically acceptable salt in the tablet is between about 60 mg and about 100 mg.

[00534] In some embodiments of a tablet, the amount of The GR antagonist or its pharmaceutically acceptable salt in the tablet is about 30 mg. In some embodiments of a tablet, the amount of The GR antagonist or its pharmaceutically acceptable salt in the tablet is about 40 mg. In some embodiments of a tablet, the amount of The GR antagonist or its pharmaceutically acceptable salt in the tablet is about 50 mg. In some embodiments of a tablet, the amount of The GR antagonist or its pharmaceutically acceptable salt in the tablet is about 60 mg. In some embodiments of a tablet, the amount of The GR antagonist or its pharmaceutically acceptable salt in the tablet is about 70 mg. In some embodiments of a tablet, the amount of The GR antagonist or its pharmaceutically acceptable salt in the tablet is about 80 mg. In some embodiments of a tablet, the amount of The GR antagonist or its pharmaceutically acceptable salt in the tablet is about 90 mg. In some embodiments of a tablet, the amount of The GR antagonist or its pharmaceutically acceptable salt in the tablet is about 100 mg.

Impurity Profile

[00535] In some embodiments, the tablet comprises less than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% impurities. In some embodiments, the impurities comprise one or more related substances shown in tables la and lb.

Lipid-Based Formulations

[00536] Provided herein is a lipid-based formulation comprising:

(a) a lipid; and

(b) a GR antagonist, or a pharmaceutically acceptable salt thereof.

[00537] In some embodiments, the GR antagonist comprises a compound of Formula (I) or Formula (la). In some embodiments, the GR antagonist comprises Compound 1. In some embodiments, the GR antagonist comprises a compound selected from

[00538] In some embodiments, the lipid-based formulations provided herein improve the solubility of The GR antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the lipid-based formulations provided herein improve the bioavailability of The GR antagonist or a pharmaceutically acceptable salt thereof.

[00539] Some embodiments provided herein describe a self-dispersing pharmaceutical compositions, wherein the composition is self-dispersing when added to water and forms an emulsion, microemulsion, or nanoemulsion. In some embodiments, the lipid-based formulations described herein further comprise a surfactant and are in a form of a self-nanoemulsifying drug delivery system (SNEDDS), a self- microemulsifying drug delivery system (SMEDDS), or a self-emulsifying drug delivery system (SEDDS), wherein the lipid-based formulation forms an emulsion in an aqueous solution. In some instances, the lipid-based formulation is “self-emulsifying” and is classified based on the particle sizes that will form upon entry into an aqueous environment, as self-emulsifying drug delivery systems (“SEDDs”) producing particle sizes substantially less than 1 pm, self-microemulsifying drug delivery systems (“SMEDDS”) with smaller particles, and self-nanoemulsifying drug delivery systems (“SNEDDS”) with the smallest particles. In some embodiments, the self-dispersing lipid-based formulations provided herein form SEDDS upon contact with gastric and/or intestinal media in the body, wherein the lipid-based formulation forms an emulsion comprising micelle particles. In some embodiments, the emulsion provides for increased or improved stability of the active agent (e.g., The GR antagonist) for uptake in the body and/or provide increased or improved surface area for absorption. In some instances, SEDDS provide for enhanced or improved hydrolysis, solubility, bioavailability, absorption, or any combinations thereof of the active agent in vivo. In some embodiments, the SEDDS facilitates the dispersion, dissolution, stability and absorption of the drug, thus improving the bioavailability of said drug. In some embodiments, the self-dispersing lipid-based formulations provided herein improve the solubility of The GR antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, the self-dispersing lipid-based formulations provided herein improve the bioavailability of The GR antagonist or a pharmaceutically acceptable salt thereof.

Lipid

[00540] In some embodiments of a lipid-based formulation, the lipid is a long- or medium-chain triglyceride oils with different degrees of saturation. [00541] In some embodiments of a lipid-based formulation, the lipid is propylene glycol monocaprylate (Capryol®), caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, ethyl oleate, soybean oil, glyceryl caprylate/caprate (Campul®) glyceryl behenate (Compritol® 888 ATO), glyceryl palmitostearate (Precirol® ATO 5), glyceryl monostearate (Geleol™), glyceryl monolinoleate (Maisine™ 35-1), glyceryl monooleate, (Peceol™), medium-chain triglycerides (Labrafac™ Lipophile WL1349), propylene glycol monolaurate (Lauroglycol™ 90), oleoyl macrogol-6 glycerides (Labrafd® M1944CS), polyglyceryl-3 dioleate (Plurol Oleique® CC 497), diethylene glycol monoethyl ether (Transcutol® HP), or any combinations thereof. In some embodiments of a lipid-based formulation, the lipid is propylene glycol monocaprylate (Capryol®) or caprylic acid. In some embodiments of a lipid-based formulation, the lipid is propylene glycol monocaprylate (Capryol®). In some embodiments of a lipid-based formulation, the lipid is caprylic acid.

Surfactant

[00542] In some embodiments of a lipid-based formulation, the lipid-based formulation further comprises a surfactant.

[00543] In some embodiments of a lipid-based formulation, the surfactant is macroglycerol ricinoleate (Kolliphor EL® or Cremophor EL®), caprylocaproyl polyoxyl-8 glyceride (Labrasol®), lauroyl polyoxyl-6 glycerides (Labrafd® M 2130 CS), lauroyl polyoxyl-32 glyceride (Gelucire® 44/14), polyethylene glycol monostearate (Gelucire® 48/16), polyoxyethylene hydrogenated castor oil 60 (HCO- 60), polysorbate 80 (Tween®-80), polyethylene glycol sorbitan monolaurate (Tween®-20), polyoxyethylene sorbitan trioleate (Tween®-85), polyoxyethyelene glyceryl trioleate (tagot-TO), sorbitan monooleate (Span®-80), sorbitan monolaurate (Span®-20), or any combinations thereof.

[00544] In some embodiments of a lipid-based formulation, the surfactant is macroglycerol ricinoleate (Kolliphor EL® or Cremophor EL®), caprylocaproyl polyoxyl-8 glyceride (Labrasol®), Lauroyl polyoxyl-32 glyceride (Gelucire ®44/ 14), polyoxyethylene hydrogenated castor oil 60 (HCO-60), polysorbate 80 (Tween®-80), polyoxyethylene sorbitan trioleate (Tween®-85), polyoxyethyelene glyceryl trioleate (tagot-TO), or any combinations thereof. In some embodiments of a lipid-based formulation, the surfactant is macroglycerol ricinoleate (Kolliphor EL® or Cremophor EL®).

[00545] In some embodiments of a lipid-based formulation, the formulation comprises propylene glycol monocaprylate (Capryol®) and macroglycerol ricinoleate (Kolliphor EL® or Cremophor EL®). In some embodiments of a lipid-based formulation, the lipid-based formulation forms a self-emulsifying drug delivery system (SEDDS) in an aqueous solution.

Antioxidant

[00546] In some embodiments of a lipid-based formulation, the lipid-based formulation further comprises an antioxidant. In some embodiments of a lipid-based formulation, the antioxidant is a-tocopherol, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, potassium metabisulfite, propyl gallate, ascorbic acid, monothioglycerol, propionic acid, sodium ascorbate, sodium bisulfite, sodium sulfite, and cysteine (CYS), or any combinations thereof. In some embodiments of a lipid-based formulation, the antioxidant is a-tocopherol, ascorbyl palmitate, or any combinations thereof. In some embodiments of a lipid-based formulation, the antioxidant is a- tocopherol. In some embodiments of a lipid-based formulation, the antioxidant is ascorbyl palmitate.

Solvent

[00547] In some embodiments of a lipid-based formulation, the lipid-based formulation further comprises a solvent. In some embodiments of a lipid-based formulation, the solvent is polyethylene glycol, propylene glycol, glycerin, diethylene glycol monoethyl ether (Transcutol®), triacetin (Kollisolv®

GTA), medium chain triglycerides (Miglyol® 812N), or any combinations thereof.

Capsule

[00548] In some embodiments of a lipid-based formulation, the formulation is encapsulated.

[00549] In some embodiments, the lipid-based formulation is encapsulated into discrete units. In some embodiments, the lipid-based formulation described herein is enclosed in a capsule.

[00550] In some embodiments, the capsule is formed using materials which include, but are not limited to, natural or synthetic gelatin, pectin, casein, collagen, protein, modified starch, polyvinylpyrrolidone, acrylic polymers, cellulose derivatives, or combinations thereof. In some embodiments, the capsule is coated. In some embodiments, the coating covering the capsule includes, but is not limited to, immediate release coatings, protective coatings, enteric or delayed release coatings, sustained release coatings, barrier coatings, seal coatings, or combinations thereof. In some embodiments, a capsule herein is hard or soft. In some embodiments, the capsule is seamless. In some embodiments, the shape and size of the capsule also vary. Examples of capsule shapes include, but are not limited to, round, oval, tubular, oblong, twist off, or a non-standard shape. The size of the capsule may vary according to the volume of the lipid-based formulation. In some embodiments, the size of the capsule is adjusted based on the volume of the lipid-based formulation. Hard or soft gelatin capsules may be manufactured in accordance with conventional methods as a single body unit comprising the standard capsule shape. A single-body soft gelatin capsule typically may be provided, for example, in sizes from 3 to 22 minims (1 minims being equal to 0.0616 ml) and in shapes of oval, oblong or others. The gelatin capsule may also be manufactured in accordance with conventional methods, for example, as a two-piece hard gelatin capsule, sealed or unsealed, typically in standard shape and various standard sizes, conventionally designated as (000), (00), (0), (1), (2), (3), (4), and (5). The largest number corresponds to the smallest size.

Dosage in Capsule

[00551] In some embodiments of a lipid-based formulation, the amount of compound of The GR antagonist or its pharmaceutically acceptable salt in the capsule is between about 10 mg and about 100 mg.

[00552] In some embodiments of a lipid-based formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the capsule is between about 20 mg and about 80 mg. [00553] In some embodiments of a lipid-based formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the capsule is between about 40 mg and about 60 mg. [00554] In some embodiments of a lipid-based formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the capsule is between about 60 mg and about 100 mg.

[00555] In some embodiments of a lipid-based formulation, the amount of compound of The GR antagonist or its pharmaceutically acceptable salt in the capsule is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.

[00556] In some embodiments of a lipid-based formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the capsule is about 50 mg.

[00557] In some embodiments of a lipid-based formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the capsule is about 60 mg.

[00558] In some embodiments of a lipid-based formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the capsule is about 70 mg.

[00559] In some embodiments of a lipid-based formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the capsule is about 80 mg.

[00560] In some embodiments of a lipid-based formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the capsule is about 90 mg.

[00561] In some embodiments of a lipid-based formulation, the amount of the compound of The GR antagonist or its pharmaceutically acceptable salt in the capsule is about 100 mg.

[00562] In some embodiments of a lipid-based formulation, the amount of lipid in the capsule is between about 100 mg and about 1000 mg. In some embodiments of a lipid-based formulation, the amount of lipid in the capsule is about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg. In some embodiments of a lipid-based formulation, the amount of lipid in the capsule is between about 500 mg and about 900 mg. In some embodiments of a lipid-based formulation, the amount of lipid in the capsule is between about 700 mg and about 800 mg. In some embodiments of a lipid-based formulation, the amount of lipid in the capsule is between about 600 mg and about 700 mg. In some embodiments of a lipid-based formulation, the amount of lipid in the capsule is about 676 mg. In some embodiments of a lipid-based formulation, the amount of lipid in the capsule is about 750 mg. In some embodiments of a lipid-based formulation, the amount of lipid in the capsule is about 735 mg.

[00563] In some embodiments of a lipid-based formulation, the amount of surfactant in the capsule is between about 100 mg and about 500 mg. In some embodiments of a lipid-based formulation, the amount of surfactant in the capsule is about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In some embodiments of a lipid-based formulation, the amount of surfactant in the capsule is between about 100 mg and about 200 mg. In some embodiments of a lipid-based formulation, the amount of surfactant in the capsule is about 174 mg.

[00564] In some embodiments of a lipid-based formulation, the amount of antioxidant in the capsule is between about 0.1 mg and about 10 mg. In some embodiments of a lipid-based formulation, the amount of antioxidant in the capsule is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg. In some embodiments of a lipid-based formulation, the amount of antioxidant in the capsule is between about 0.1 mg and about 5 mg. In some embodiments of a lipid-based formulation, the amount of antioxidant in the capsule is between about 0.1 mg and about 1 mg. In some embodiments of a lipid- based formulation, the amount of antioxidant in the capsule is between about 0.1 mg and about 0.5 mg. In some embodiments of a lipid-based formulation, the amount of antioxidant in the capsule is between about 1 mg and about 5 mg. In some embodiments of a lipid-based formulation, the amount of antioxidant in the capsule is between about 3 mg and about 5 mg. In some embodiments of a lipid-based formulation, the amount of antioxidant in the capsule is about 0.25 mg. In some embodiments of a lipid- based formulation, the amount of antioxidant in the capsule is about 4.1 mg.

Kits and articles of manufacture

[00565] Disclosed herein, in certain embodiments, are kits and articles of manufacture for use with one or more methods and compositions described herein. Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.

[00566] A kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

[00567] In one embodiment, a label is on or associated with the container. In one embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In one embodiment, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.

[00568] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for drugs, or the approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[00569] In some embodiments, the kit comprises the nucleic acid probes and/or primers described herein, that are useful for detecting the one or more gene products in the predictive response signature (PRS). Disclosed herein are methods of treating a subject with a proliferative disease described herein, by assay a sample obtained from the subject using a kit described herein, to first determine whether they are likely to therapeutically response to an induction or maintenance of the GR antagonist therapies, alone, or in combination with an additional anti-cancer therapy. In certain embodiments, the kit comprises a nucleic acid molecule comprising at least about 10 but not more than 100 contiguous nucleic acids within a nucleic acid sequence provided in any one of SEQ ID NOs: 1-11; and a detectable moiety. In certain embodiments, the kit comprises a first primer comprising at least 10 but not more than 50 contiguous nucleic acids within a nucleic acid sequence provided any one of SEQ ID NOs: 1-11; and a second primer comprising at least 10 but not more than 50 contiguous nucleic acids within a nucleic acid sequence that is reverse complement to the nucleic acid sequence provided in any one of SEQ ID NOs: 1- 11

Definitions

[00570] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features. [00571] As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient. In some embodiments, a therapeutic agent such as a Compound 1 is directed to the treatment and/or the amelioration of cancers.

[00572] “Administering” when used in conjunction with a therapeutic means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering”, when used in conjunction with a composition described herein, can include, but is not limited to, providing a composition into or onto the target tissue; providing a composition systemically to a patient by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells. “Administering” a composition may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques.

[00573] The term “animal” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals. As used herein, the terms “patient,” “subject” and “individual” are intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the patient is a primate. In certain embodiments, the primate or subject is a human. In certain instances, the human is an adult. In certain instances, the human is child. In further instances, the human is under the age of 12 years. In certain instances, the human is elderly. In other instances, the human is 60 years of age or older. Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with hypertensive pathology.

[00574] By “pharmaceutically acceptable”, it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[00575] The term “pharmaceutical composition” shall mean a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

[00576] A “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).

[00577] The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. A prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, stabilization of a condition, or decreasing the likelihood of occurrence of a condition. As used herein, “treat,” “treated,” “treatment,” or “treating” includes prophylaxis in some embodiments.

[00578] The term “substantially the same as” as used herein, refers to a powder x-ray diffraction pattern or differential scanning calorimetry pattern that is non-identical to those depicted herein, but that falls within the limits of experimental error, when considered by one of ordinary skill in the art.

[00579] “Alkyl” refers to a straight or branched chain hydrocarbon monoradical, which may be fully saturated or unsaturated, having from one to about ten carbon atoms, or from one to six carbon atoms. Examples of saturated hydrocarbon monoradical include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl- 1 -propyl, 2-methyl-2-propyl, 2-methyl- 1 -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl- 1 -propyl, 2-methyl- 1 -pentyl, 3-methyl- 1 -pentyl, 4-methyl- 1 -pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl- 1 -butyl, 3,3-dimethyl-l-butyl, 2-ethyl- 1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as CrG, alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-Cio alkyl, a Ci- C₉ alkyl, a Ci-C₈ alkyl, a C₁-C₇ alkyl, a Ci-C₆ alkyl, a C₁-C₅ alkyl, a Ci-C₄ alkyl, a C₁-C₃ alkyl, a Ci-C₂ alkyl, or a Ci alkyl. When the alkyl refers to an unsaturated straight or branched chain hydrocarbon monoradical it is known as an “alkenyl” or an “alkynyl”. The alkenyl may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples of alkenyls include, but are not limited to ethenyl (-CEGCEfi), 1-propenyl (-CH₂CEGCH₂), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C₂-C₁₀ alkenyl, a C₂-C₉ alkenyl, a C₂-C₈ alkenyl, a C₂-C₇ alkenyl, a C₂-C₆ alkenyl, a C₂-C₅ alkenyl, a C₂-C₄ alkenyl, a C₂-C₃ alkenyl, or a C₂ alkenyl. Examples of alkynyl include, but are not limited to ethynyl, 2- propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C₂-C₁₀ alkynyl, a C₂-C₉ alkynyl, a C₂-C₈ alkynyl, a C₂-C₇ alkynyl, a C₂-C₆ alkynyl, a C₂-C₅ alkynyl, a C₂-C₄ alkynyl, a C₂-C₃ alkynyl, or a C₂ alkynyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF₃, -OH, -OMe, -NH₂, or - NO₂. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF₃, -OH, or - OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[00580] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, - CF₃, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF₃, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[00581] “Alkoxy” refers to a radical of the formula -OR_a where R_a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF₃, -OH, -OMe, -NH2, or -NO₂. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF₃, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[00582] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as- indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[00583] “Cycloalkyl” refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, decalinyl, bicyclo [3.3.0] octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and

7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[00584] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[00585] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[00586] “Heterocycloalkyl” refers to a 3 - to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrof iryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1 ,3 -dihydroisobenzofiiran- 1 -yl, 3 -oxo- 1 ,3 -dihydroisobenzofiiran- 1 -yl, methyl -2 -oxo- 1 ,3 -dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen. [00587] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)- ), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[00588] “Heteroaryl” refers to a 5 - to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthof iranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzof iranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzof iranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or - OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

EXAMPLES

EXAMPLE 1. Identification of a GR activation signature in a pan-cancer panel of 32 patient- derived cell lines.

[00589] Gene expression levels in patient-derived cell lines were evaluated for their association with GR pathway activity, to identify potential biomarkers for predictive purposes and/or pharmacodynamic (PD) target engagement. These cell lines span four exemplary oncology indications for which preclinical evidence exists in support of a role for GR in mediating resistance to anti-hormonal therapies and conventional chemotherapies. These indications were triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), pancreatic adenocarcinoma (PDAC), and prostate cancer, specifically in 9 TNBC, 12 NSCLC, 12 PDAC and 2 prostate cancer cell lines. Cell lines were selected to capture the transcriptional variability across the tumor subtypes in each oncology indication. For TNBC, NSCLC and PDAC cancers, subtype information from the literature was used to assign the cell lines to their most similar subtype with a classifier approach. Furthermore, GR expression levels in these cell lines spanned a broad spectrum, including cell lines with relatively low GR expression that may not show large GR- activated changes. Two prostate cancer cell lines that are negative for Androgen Receptor (AR) expression but GR positive were also selected. The TNBC cell lines are HCC1143, HCC70, HCC2218, HCC1806, Hs578T, HCC1187, BT549, MDA-MD-468 (MDA468) and MDA231 (MDA-MB-231). The PDAC cell lines are SU8686, CAPAN1, BxPC3, Panc0404, HPAFII, HPAC, SW1990, AsPCl, PSN1, Capan-2, Hs766T, and PANC1. The NSCLC cell lines are H522, H520, H838, H661, H2030, HOP62, HCC95, H1975, H441, H1563, H1568, and H1573. The prostate cancer cell lines are PC3 and DU145. [00590] To derive a transcriptional signature of GR activity, RNA sequencing was performed on cell lines treated for 36 hours with either DMSO (Veh), 30 nM of GR agonist dexamethasone (Dex), or 30 nM dexamethasone plus 0.5 mM of GR antagonist Compound 1 (Dex + 1). Extracted RNA were processed into libraries for RNA-sequencing at Q2 Solutions | EA Genomics (North Carolina, USA). RNA-sequencing data were aligned using Kallisto 0.45.0 (Bray et al, Nature Biotechnology 2016) against the human Gencode 29 reference of the protein coding transcripts (Frankish et al, Nucleic Acids Research 2019). Transcript-level counts were summarized at the gene level using tximport 1.10.1 (Soneson et al, FlOOORes 2015) in Bioconductor 3.8 (Huber et al, Nat Methods 2015). Differential expression analysis was performed with edgeR 3.24.3 using built-in normalization per the default settings, and with additional utilization of the estimateGLMCommonDisp function from edgeR with method-' deviance", robust=TRUE and subset=NULL (Robinson et al, Bioinformatics 2010; McCarthy et al, Nucleic Acids Research 2012).

[00591] For each cell line separately, the Dex vs Veh groups and the Dex + 1 vs Veh groups were contrasted. Genes per contrast were considered significantly differentially expressed if the adjusted p- value was less than 0.05 and the absolute fold change was greater than 2. Treatment with Dex induced transcriptional changes in 147-1407 genes per cell line. Based on the list of significant Dex-suppressed and Dex-induced genes for each individual cell line, indication-specific GR-associated genes were selected as the genes that were significantly altered by Dex relative to Veh in at least 50% of the cell lines for that indication, and this process was repeated for TNBC (FIG. 1A), NSCFC (FIG. IB) and PDAC (FIG. 1C). Despite the variation in the specific genes regulated by GR across the TNBC, NSCFC, and PDAC cancer models (FIG. 1 A-C), a set of 11 genes, denoted as the GR activation signature, emerged as consistently modulated by Dex treatment in all three indications (FIG. 2A-B). Each signature gene was fully reversed back to its vehicle expression level by GR antagonist Compound 1 in at least 85% of the cell lines, making the signature genes suitable as pharmacodynamics (PD) biomarkers of GR inhibition (FIG. 3), in addition to the signature’s potential use as a predictive biomarker. Use of 2 prostate cancer cell lines, DU 145 and PC3, that are negative for AR and positive for GR confirmed that the same genes capture GR activation in prostate cancer. The eleven signature genes were significantly modulated with Dex treatment and reverted back with Compound 1 in one or both prostate lines, DU145 and PC3 (FIG. 4A-B).

EXAMPLE 2. The GR activation signature captures biology that translates from cell lines to human tumors.

[00592] The gene set enrichment analysis for each cell line was applied to genes that were significantly differentially expressed with Dex vs. Veh with adjusted p-value less than 0.05 and the absolute fold change greater than 1.5. Gene set enrichment testing was performed using an over-representation analysis, with the degree of overlap between the significant genes and gene sets of interest captured by the Fisher’s exact test. Gene sets of interest were selected from MSigDB (Subramanian et al, Proc Natl A cad Sci USA 2005; Liberzon et al, Cell Syst 2015; Liberzon et al, Bioinformatics 2011) and corresponding literature (Aran et al, Genome Biology 2017) to represent a broad spectrum of biological functions and include gene sets more specific to GR biology and cancer treatment resistance.

[00593] Pathway enrichment analysis revealed biological convergence towards a common set of GR regulated pathways including epithelial-to-mesenchymal transition (EMT), apoptosis, sternness, hypoxia, inflammation/immune regulation, and extracellular matrix (ECM) (FIG. 5). Gene sets identified in chemotherapy resistance studies were also significantly over-enriched for genes activated by GR (FIG.

5). On the other hand, cancer pathways known to be key drivers of disease formation, including angiogenesis, TGF Beta, MAPK, PI3K, and NFkB were not significantly enriched for GR-associated targets (FIG. 5). Hence, these data indicate that GR-mediated chemotherapy resistance has a specific effect that is independent of the canonical cancer driver pathways, and that GR activation generally leads to increased therapy evasion of tumor cells by modifying the EMT, apoptosis, sternness, ECM, and related properties of the cells across oncology indications. After repeating this gene set enrichment methodology for the significantly differentially expressed genes in the Dex + Compound 1 vs Veh conditions, it was observed that Dex-induced pathway changes were completely reversed by GR antagonist Compound 1 (FIG. 5), demonstrating the ability of GR inhibitor treatment to revert all transcriptional changes caused by GR activation.

[00594] These GR-associated pathways translated from cell lines to human primary tumors from The Cancer Genome Atlas (TCGA). RNA-sequencing data collected by TCGA for TNBC, NSCLC and PDAC tumors were obtained from the UCSC Xena database (Vivan et al, Nat Biotechnol 2017). Using these data, the same pathways were determined to be associated with the GR activation signature in human samples, as observed in the cell lines (FIG. 5). A signature score was calculated as the average z- scored expression of the GR activation signature genes in tumors from the TCGA cohort and correlated with principal component 1 calculated from z-scored expression of the genes per pathway for all pathways displayed in FIG. 5, using the methodology described in (Tomfohr et al, BMC Bioinformatics 2005). The significance of each correlation was assessed by performing a permutation test on the 11 PRS genes and establishing a null distribution of correlations based on sets of 11 randomly selected genes. Many of the same pathways that were significantly activated by Dex in the cell lines (FIG. 5) were also significantly correlated with the GR activation signature in human primary TNBC, NSCFC and/or PDAC tumors (FIG. 6). This finding shows that the GR activation signature translates from cell lines to human tumors.

EXAMPLE 3. The GR activation signature broadly applies across oncology indications.

[00595] The GR activation signature was derived from and confirmed in cell lines spanning four oncology indications (TNBC, NSCFC, PDAC and prostate cancer). For TNBC, NSCFC and PDAC, the signature captured the same biologies in human tumors from the TCGA cohort. For prostate cancer, GR has been correlated with poor outcome in castration-resistant prostate cancer patients treated with enzalutamide (Arora et al, Cell 2013) and is considered an AR-independent resistance mechanism to current anti-AR therapies. The prostate tumors in the TCGA cohort are primary prostate tumors that are still driven by AR. Beyond these four indications, four out of 11 signature genes were consistently and robustly high expressed in primary tumors across a total of 25 oncology indications (FIG. 7A). These genes are FKBP5, GILZ (TSC22D3), PERI and KLF9. Furthermore, these genes are strongly correlated in expression for all these indications (FIG. 7B, referred to as core genes). The other seven signature genes are expressed across most indications, apply more variably to indications, and are positively correlated in expression (FIG. 7A-B, referred to as secondary genes).

[00596] EXAMPLE 4. The GR activation signature and individual signature genes validate as PD biomarkers in vitro and in surrogate tissues

[00597] Two of the 11 signature genes were selected for validation as PD biomarkers in cell lines and peripheral blood mononuclear cells (PBMCs): FKBP5 and GILZ (TSC22D3). The expression of these genes was examined in response to 0.5 uM of GR antagonist Compound 1 upon GR activation with 30 nM dexamethasone as GR ligand in various cell lines and across several indications, including TNBC, Ovarian, PDAC, and NSCLC. Treatment with a GR antagonist Compound 1 inhibited Dex-driven FKBP5 and GILZ mRNA levels in a dose -dependent manner 24 hours after Compound 1 addition, as showcased for two representative TNBC cell lines (FIG. 8) and two ovarian cancer cell lines (FIG. 9). Also in a panel of PDAC (n=10) and NSCLC (n=10) cell lines, 30 nM dexamethasone consistently stimulated FKBP5 and GILZ mRNA levels, and the expression levels of these genes were fully reversed by 0.5 mM of Compound 1 in a pan-cancer fashion measured 24 hours after Compound 1 addition, as shown in FIG. 10 for three representative lines from either PDAC or NSCLC. Furthermore, FKBP5 and GILZ can be used as PD biomarkers in PBMCs to monitor GR target engagement after administration of GR inhibitor treatment, such as Compound 1. An ex vivo study was performed using isolated human PBMCs and examined the FKBP5 and GILZ mRNA levels in response to Compound 1 upon GR activation by 30 nM dexamethasone. The results showed that Compound 1 inhibits Dex-driven FKBP5 and GILZ expression in a dose-dependent manner (FIG. 11). Hence, FKBP5 and GILZ, two representative genes from the GR activation signature, have the potential to be used as PD biomarker in PBMC surrogate tissue and in tumor biopsies, across multiple oncology indications. They also have the potential to be used in PBMC surrogate tissue to monitor GR engagement after administration of a GR antagonist.

[00598] Beyond the validation of individual signature genes as PD biomarkers, the signature was evaluated as a PD biomarker, utilizing RNA-sequencing data generated from human PBMCs treated with Compound 1 in an in vivo and ex vivo experiment. For the in vivo study, isolated human PBMCs were implanted in 8 NSG mice. After 4 weeks, cortisol was added to the animals’ drinking water for 48 hours, followed by treatment with either vehicle or 75mg/kg Compound 1, PO. After 6 hours, PBMCs were collected from all mice, followed by RNA extraction. RNA-sequencing data for PBMCs from vehicle- treated mice with cortisol in drinking water (cortisol) and PBMCs from Compound 1 -treated mice with cortisol in drinking water (cortisol + Compound 1) in triplicates were generated, processed and analyzed at MedGenome (Foster City, USA). Differentially expressed genes were evaluated using DESeq2 for the comparison of cortisol vs. cortisol + Compound 1. Six out of 11 signature genes were expressed in PBMCs in both conditions. Expression of these six genes decreased with Compound 1 treatment (FIG. 12A), with an average 2.87-fold decrease in expression for the signature genes upon Compound 1 treatment.

[00599] For the ex vivo study, isolated human PBMCs were treated with DMSO or 30nM dexamethasone (dex) for 36 hours, with the addition of Compound 1 (dex + Compound 1) for an additional 6 hours, followed by RNA extraction. RNA-sequencing data for PBMCs treated with DMSO, dex or dex + Compound 1 in triplicate were generated, processed and analyzed at MedGenome (Foster City, USA). Differentially expressed genes were evaluated using DESeq2 for the comparison of dex vs. DMSO and dex + Compound 1 vs. DMSO. For each comparison, seven out of 11 signature genes were expressed in PBMCs in both conditions. Expression of these seven genes increased with dex and reverted back to DMSO levels upon Compound 1 addition (FIG. 12B), with an average 3.74-fold increase in expression of the signature genes upon GR activation with dex, and no difference in average expression of the signature genes between DMSO and dex + Compound 1. Both the in vivo and ex vivo PBMC studies provide support for the use of the GR activation signature as PD biomarker.

EXAMPLE 5. Genes from the GR activation signature capture suppression of GR pathway activity in response to Compound 1 in healthy volunteers

[00600] A multi -ascending dose trial with Compound 1 was conducted in healthy volunteers. Compound 1 was administered once daily for ten consecutive days at a dose of 200 mg/day or 350 mg/day. Six subjects were treated at each dose level. Peripheral blood mononuclear cells (PBMCs) were collected and analyzed for expression of genes from the GR activation signature, including FKBP5, GIFZ (TSC22D3), PERI and KFF9. In this analysis, Compound 1 was associated with decreased expression of these key PD biomarkers of GR activity, with the decrease occurring within the first day of Compound 1 exposure (FIG. 13A-D) and persisting for the entire duration of ten days of dosing.

EXAMPLE 6. Use of the GR activation signature as predictive biomarker of response to GR antagonist Compound 1 treatment in patients

[00601] Evaluating the likelihood of response to Compound 1 for an individual cancer patient requires the quantitative assessment of the patient’s expression level of the GR activation signature relative to expected levels in an all-comers population. A distribution of expected expressed levels of the GR activation signature in a broad, relevant patient population covering the full spectrum of GR activity was constructed. Such a reference patient population ought to match the general characteristics of the patients that would be treated with the drug at hand, in terms of cancer type. Gene expression data should be generated, processed and analyzed similarly in the reference population as for the patients considered for treatment. Furthermore, the reference cohort contains data for a sufficient number of tumor samples to guarantee coverage of the full spectrum of GR signaling, from inactive to fully active GR signaling. [00602] As part of a phase 1 trial on the combination of Compound 1 and nab-paclitaxel treatment in patients with advanced or metastatic solid tumors, tumor tissue samples are collected at time of screening, during treatment at the end of two 28-day treatment cycles, and/or at the end of treatment. The FFPE tumor blocks are first sectioned with one slide H&E stained. Using the H&E slide as guiding slide, the tumor area on additional slides is then macrodissected, followed by RNA extraction and RNA- sequencing. The same RNA-sequencing data processing pipeline is used for the clinical trial samples as for the reference cohort. This enables direct comparison of the gene expression between the cohorts. [00603] For the construction of a GR activity reference distribution based on a reference population, first the expression levels of the GR activation signature genes within the reference population is z-score standardized by subtracting the mean and dividing the standard deviation of each gene across all tumor samples in the reference population. Next, the reference of the GR activation score is created by averaging the z-scored gene values of our signature genes for each sample within the reference population and creating a single GR activation score value per patient tumor sample within the reference population (FIG. 14).

[00604] The reference distribution of GR activation scores enables observation of whether GR signaling is active within an individual to identify patients most likely to benefit from Compound 1 treatment. Specifically, the GR activation score for a tumor sample of a patient is calculated, after recentering and rescaling the expression of each signature gene using the mean and standard deviation from the reference population. This places the patient’s GR activity score onto the reference distribution (FIG. 14). This allows predicting that the patient may benefit from Compound 1 if their pre-treatment biopsy GR activation score is above a threshold within the reference distribution. This strategy could further be used to determine the course of treatment for a patient by only selecting patients with a GR activation score above a reference threshold to be treated with Compound 1.

EXAMPLE 7. The GR activation signature captures suppression of GR pathway activity in response to GR antagonist Compound 1 treatment in patients

[00605] A change in expression of the GR activation signature genes during or after Compound 1 treatment relative to a pre-treatment biopsy sample informs about the suppression of GR signaling. FIG. 15 shows results from two patients with advanced or metastatic solid tumors treated with Compound 1 and nab-paclitaxel. The majority of signature genes showed a significant or trending decrease in expression levels in the tumor biopsy samples from patient A, from time of screening to the end of treatment, suggestive of suppressed GR signaling (FIG. 15A). In patient B on the other hand, signature genes did not change consistently in expression from time of screening to the end of the second 28-day treatment cycle (FIG. 15B).

[00606] The strategy described in Example 6 can also be used to monitor whether a patient shows any benefit from Compound 1 treatment by evaluating the change in GR activation score relative to the reference distribution during treatment (FIG. 14). In other words, a decrease in a patient’s overall GR activation score upon Compound 1 treatment informs the inhibition of GR signaling by Compound 1 and the eradication of tumor cells with active GR signaling. To measure the overall change in the signature, the strategy consists of computing the GR activation score in a patient’s tumor samples, collected before and during or before and after Compound 1 treatment, relative to the reference distribution. The initial magnitude of the score before treatment and change upon Compound 1 treatment is then calculated. For example, if a patient has a high score pre-treatment and the score is sufficiently lower after a certain duration of Compound 1 treatment, Compound 1 has an anti-tumor effect. In another example where a patient has a low pretreatment score, there may not be a decline in GR activity since there was weak GR signaling from the onset. Thus, the GR activation score would be used to capture suppression of the GR pathway in response to Compound 1 treatment in cancer patients.

EXAMPLE 8. The GR activation signature validates as PD biomarker in vivo [00607] The GR activation signature was evaluated as a PD biomarker in an in vivo xenograft phenotype study, where mice were treated with paclitaxel (PTX) alone, PTX in the presence of cortisol to activate GR, or PTX in the presence of cortisol plus Compound 1 to repress GR. The study utilized MDA-MB- 231 cells, which are epithelial cells derived from a human breast adenocarcinoma (acquired from ATCC), implanted into mice as described in more detail below.

[00608] Specific pathogen-free homozygous female nude mice (Hsd: Athymic Nude-Foxnlnu, Envigo) at the age of 8-10 weeks old were used in the in vivo studies. Mice were given food and acidified drinking water (Innovive) ad libitum in disposable ventilated cages (Innovive). These animal studies were approved by the Institutional Animal Care and Use Committee of ORIC Pharmaceuticals, Inc. Animals fed with acidified drinking water received MDA-MB-231 cell implantation in the left inguinal 4th and 5th mammary fat pad with 10 million cells in 75 pi volume. When the tumor size reached 270-290 mm³, mice were randomized into 3 groups (n=5 per group) for the following treatment: (1) PTX: 15 mg/kg, Q3Dx2, ip, from Day 1; (2) PTX + cortisol: in addition to PTX, 100 mg/L cortisol-supplemented water replaced acidified water from Day 0; and (3) PTX + cortisol + Compound 1: in addition to PTX and cortisol as in Group 2, Compound 1 was given at 75 mg/kg BID, PO from Day 1. All tumor samples from each group were collected at Day 6, 48 hours after the 2^nd dose of PTX, and snap frozen for RNA processing. It was established in a separate in vivo efficacy study for this xenograft model that tumors undergo regression in the course of treatment at this timepoint.

[00609] RNA was extracted from 2 tumor samples in the PTX group, from 3 tumor samples in the PTX + cortisol group, and from 3 tumor samples in the PTX + cortisol + Compound 1 group. Extracted RNA were processed into libraries for RNA-sequencing at Q2 Solutions | EA Genomics (North Carolina,

USA). The mouse xenograft RNA-sequencing data were aligned using Kallisto 0.45.0 (Bray et al, Nature Biotechnology 2016) against a combined human and mouse reference of Gencode 29 and Gencode M20 of the protein coding transcripts (Frankish et al, Nucleic Acids Research 2019). Transcript-level counts were summarized at the gene level using tximport 1.10.1 (Soneson et al, FlOOORes 2015) in Bioconductor 3.8 (Huber et al, Nat Methods 2015). Gene counts for the human genes were then extracted and subsequent differential expression analysis was done only on those human reads, thereby effectively removing any contamination and bias coming from the mouse system. Differential expression was performed using DESeq2 1.22.2 (Love et al, Genome Biology 2014) for the comparisons of (a) PTX + cortisol vs. PTX, (b) PTX + cortisol + Compound 1 vs. PTX + cortisol, and (c) PTX + cortisol + Compound 1 vs. PTX. Genes were defined as significantly differentially expressed if the p-value was less than 0.001 and the fold change was greater than 2. [00610] A change in expression of the GR activation signature genes after Compound 1 treatment relative to a treatment group without Compound 1 informs about the suppression of GR signaling. FIG. 16 shows expression levels of the 11 signature genes in the MDA-MB-231 xenograft model treated with (1) PTX, (2) PTX + cortisol, or (3) PTX + cortisol + Compound 1. Eight out of 11 signature genes showed a significant, and the remaining three genes a trending, increase in expression levels in MDA-MB-231 tumors engrafted in animals treated with PTX, upon supplementing drinking water with cortisol, as a result of enhanced GR signaling (FIG. 16, PTX + cortisol vs. PTX). Upon the addition of Compound 1, 6 of the 8 genes with a cortisol-induced upregulation showed significantly decreased expression compared to PTX + cortisol, or the expression levels were not significantly different from the PTX group (FIG. 16). These in vivo data support the use of the GR activation signature as PD biomarker in the treatment of subjects having cancer by administration to the subjects of a glucocorticoid receptor (GR) antagonist, including, but not limited to, Compound 1 and other glucocorticoid receptor (GR) antagonists known to those having ordinary skill in the art.

EXAMPLE 9. The GR activation signature captures the change of GR pathway activity in human subjects treated with glucocorticoid receptor (GR) antagonist Compound 1

[00611] A change in expression of the GR activation signature genes during or after the administration to human subjects having cancer the glucocorticoid receptor (GR) antagonist Compound 1 relative to a pre treatment biopsy sample informs about the modulation of GR signaling. The change in signature gene expression was previously disclosed for two human subjects for which paired pre-treatment and on- treatment or end of treatment biopsies were available for transcriptional profiling (FIG. 15). FIG. 17 shows results from two additional human subjects with advanced or metastatic solid tumors treated with Compound 1 and nab-paclitaxel as part of the phase 1 trial, NCT03928314, for which both a pre treatment and on-treatment biopsy was collected that contained sufficient tumor content for transcriptional profiling. Specifically, the FFPE tumor blocks were first sectioned with one slide H&E stained. Using the H&E slide as guiding slide, the tumor area on additional slides was then macrodissected, followed by RNA extraction and RNA-sequencing.

[00612] In Patient C, an increase in the expression of five signature genes was observed in the on- treatment compared to pre-treatment tumor biopsy samples, suggesting the potential presence of additional tumorigenic processes in the cancer in the subject (FIG. 17A). In Patient D, the signature genes did not consistently change in expression from time of screening to the end of the second 28-day treatment cycle (FIG. 17B). The lack of change in expression observed in Patient D could be associated with the regimen of Compound 1 that was administered to the subject being suboptimal.

EXAMPLE 10. The GR activation signature score as a predictive and pharmacodynamic biomarker of GR pathway activity in response to glucocorticoid receptor (GR) antagonist Compound 1 treatment in human subjects

[00613] As a further example to create a reference distribution of GR activity, all available RNA- sequencing data from human subjects with advanced or metastatic solid tumors treated with Compound 1 and nab-paclitaxel during the dose escalation part of the phase 1 trial, NCT03928314 were considered. The reference population consists of ten samples from human subjects for whom only one biopsy was collected, either as archival sample or at the time of screening or during treatment. For the construction of a GR activity reference distribution based on this reference population, first either all 11 GR activation signature genes or the 4 core GR activation signature genes (TSC22D3, PERI, KLF9, and FKB5) within the reference population is z-score standardized by subtracting the mean and dividing the standard deviation of each gene across all tumor samples in the reference population. Next, the reference of the GR activation score is created by averaging the z-scored gene values of our signature genes for each sample within the reference population and creating a single GR activation score value per human subject tumor sample within the reference population (FIG. 18).

[00614] FIG. 18A displays the reference distribution of GR activation scores based on the full set of signature genes, FIG. 18B displays the reference distribution of GR activation scores based on a subset of signature genes. These reference distributions are proposed to be used to assess whether GR signaling is active within an individual and identify human subjects having cancer that would benefit from the administration of a glucocorticoid receptor (GR) antagonist, such as Compound 1. To achieve this, the GR activation score for a tumor sample of a human subject is calculated, after recentering and rescaling the expression of each signature gene used to establish the reference distribution using the mean and standard deviation from the reference population. This places the human subject’s GR activity score onto the reference distribution, as shown in FIG. 18A and 18B for Patients A (FIG. 15 A), B (FIG. 15B), C (FIG. 17A) and D (FIG. 17D). This allows predicting that the human subject will benefit from the administration of a glucocorticoid receptor (GR) antagonist, such as Compound 1, if their pre-treatment biopsy GR activation score is above a threshold within the reference distribution of either all 11 genes or the 4 core genes (TSC22D3, PERI, KLF9, and FKB5). This strategy could further be used to determine the course of treatment for a human subject by only selecting human subjects with a GR activation score above a reference threshold to be treated by the administration of a glucocorticoid receptor (GR) antagonist, such as Compound 1. Furthermore, the reference distribution can be used to monitor whether a human subject shows any benefit from the administration of a glucocorticoid receptor (GR) antagonist, such as Compound 1, by evaluating the change in GR activation score relative to the reference distribution during treatment (FIG. 18). In other words, a decrease in a human subject’s overall GR activation score upon Compound 1 treatment informs the inhibition of GR signaling by the administration of a glucocorticoid receptor (GR) antagonist, such as Compound 1, and the eradication of tumor cells with active GR signaling. Such reduction in GR activation score was observed for Patients A and D, both for the full signature (FIG. 18A) as well as the 4-gene core signature (FIG. 18B), while the GR activation score increased for Patients B and C.

Example 11. Open-Label Phase lb Study of Compound 1 in Combination with Nab-Paclitaxel in Patients with Advance or Metastatic Solid Tumors

[00615] Compound 1 in the form of a pharmaceutical composition was administered to subjects having solid tumors in an open-label, uncontrolled, multi-center, dose-finding study. After the screening period, eligible subjects were enrolled and treated with the pharmaceutical composition comprising compound 1 in combination with nab-paclitaxel until disease progression, unacceptable toxicity, or meeting another criterion for stopping treatment.

Drug Product

[00616] Compound 1 was supplied as a pharmaceutical composition in the form of an 80 mg capsule for oral administration. The capsule contained 80 mg of compound 1 with the inactive excipients caprylic acid, ascorbyl palmitate and alpha tocopherol, which was fdled into a hard gelatin capsule.

Packaging and Labeling

[00617] Compound 1, 80 mg capsules were packaged in an induction-sealed HDPE bottle with a child resistant cap. All study medications were stored at 2°C to 8°C and protected from heat, light, and humidity in a secure, environmentally controlled, and monitored (manual or automated) area in accordance with the labelled storage conditions with access limited to the investigator and authorized site staff.

Nab-Paclitaxel

[00618] Nab-paclitaxel (Abraxane®) was supplied as lyophilized powder in single-use vials for reconstitution.

Treatment Assignment

[00619] The study evaluated an intermittent dosing schedule and a continuous dosing schedule for the oral administration of compound 1 in the form of 80 mg capsules to subjects in an overall 28-day dosing cycle. In the intermittent administration schedule, compound 1 was administered orally to subjects as the 80 mg capsules described above once per day at Dose Level 1A (80 mg once per day), Dose Level 2A (160 mg once per day), or Dose Level 3A (240 mg once per day) on days 1 to 5, 8 to 12, and 15 to 19 of the 28-day cycle, in combination with the administration to the subjects of nab-paclitaxel at a dose of 75 mg/m² on days 1, 8, and 15 of each 28-day cycle. In the continuous administration dosing schedule, compound 1 was administered orally to subjects as the 80 mg capsules described above once per day at Dose Level 2B (160 mg once per day) on days 1 to 21 of the 28-day dosing cycle, in combination with the administration to the subjects of nab-paclitaxel at a dose of 75 mg/m² on days 1, 8, and 15 of each 28- day cycle. The dose levels of compound 1 that were evaluated are described in the table below.

Example 12. Open-Label Phase lb Study of Compound 1 in Combination with Enzalutamide in Patients with Metastatic Prostate Cancer Progressing on Enzalutamide [00620] The study evaluated the administration of compound 1 in the form of 80 mg capsules in an overall 28-day dosing cycle to subjects having metastatic prostate cancer progressing on enzalutamide. [00621] Compound 1 in the form of 80 mg capsules was administered orally to the subjects once per day in combination with the administration of enzalutamide once per day at a dose of 160 mg.

Drug Product

[00622] Compound 1 was supplied as a pharmaceutical composition in the form of an 80 mg capsule for oral administration. The capsule contained 80 mg of compound 1 with the inactive excipients caprylic acid, ascorbyl palmitate and alpha tocopherol, which was filled into a hard gelatin capsule.

Packaging and Labeling

[00623] Compound 1, 80 mg capsules were packaged in an induction-sealed HDPE bottle with a child resistant cap. All study medications were stored at 2°C to 8°C and protected from heat, light, and humidity in a secure, environmentally controlled, and monitored (manual or automated) area in accordance with the labelled storage conditions with access limited to the investigator and authorized site staff.

Enzalutamide

[00624] Enzalutamide (Xtandi®) was supplied as 40 mg capsules.

Treatment Assignment

[00625] Compound 1 in the form of the 80 mg capsules described above was administered orally to the subjects once per day at Dose Level 1 (80 mg once per day), Dose Level 2 (160 mg once per day), or Dose Level 3 (240 mg once per day), in combination with the administration to the subjects once per day of enzalutamide at a dose of 160 mg in 28-day cycles. The three dose levels of compound 1 that were evaluated are described in the table below:

[00626] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

SEQUENCES

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Claims

1. A method of treating cancer in a subject comprising administering to the subject a therapeutically effective dosage of a therapy comprising a glucocorticoid receptor (GR) antagonist, wherein the subject is selected for treatment based on a presence of a predictive response signature (PRS) comprising one or more gene products detected in a sample obtained from the subject using an assay, wherein the one or more gene products is selected from a group consisting of FKBP5, PERI, KLF9, TSC22D3, ALPP, BIRC3, KRT6A, NEBL, SAA1, SAA2, and SCNN1A.

2. The method of claim 1, wherein the predictive response signature (PRS) comprises two or more of the gene products, three or more of the gene products, four or more of the gene products, five or more of the gene products, six or more of the gene products, seven or more of the gene products, eight or more of the gene products, nine or more of the gene products, ten or more of the gene products, or the eleven gene products.

3. The method of claim 1, wherein the predictive response signature (PRS) comprises the gene products FKBP5, PERI, KLF9, and TSC22D3.

4. The method of claim 3, wherein the predictive response signature (PRS) further comprises one or more gene products selected from the group consisting of ALPP, NEBL, SAA2, and SCN 1A.

5. The method of claim 3, wherein the predictive response signature (PRS) further comprises one or more gene products selected from the group consisting of BIRC3, KRT6A, and SAA1.

6. The method of claim 3, wherein the predictive response signature (PRS) further comprises two or more gene products selected from the group consisting of ALPP, NEBL, SAA2, and SCNN1A.

7. The method of claim 3, wherein the predictive response signature (PRS) comprises three or more gene products selected from the group consisting of ALPP, NEBL, SAA2, and SCNN1A.

8. The method of claim 1, wherein the predictive response signature (PRS) comprises the gene products ALPP, NEBL, SAA2, and SCNN1A.

9. The method of claim 8, wherein the predictive response signature (PRS) further comprises one or more gene products selected from the group consisting of FKBP5, PERI, KLF9, and TSC22D3.

10. The method of claim 8, wherein the predictive response signature (PRS) further comprises one or more gene products selected from the group consisting of BIRC3, KRT6A, and SAA1.

11. The method of claim 1, wherein the predictive response signature (PRS) comprises the gene products FKBP5, PERI, KLF9, TSC22D3, ALPP, BIRC3, KRT6A, NEBL, SAA1, SAA2, and SCNN1A.

12. The method of claim 1, wherein the sample obtained from the subject comprises a tumor biopsy, liquid biopsy, PBMC, or ctRNA.

13. The method of claim 1, wherein the therapy further comprises one or more additional anti -cancer therapy selected from surgery, radiation, and chemotherapy.

14. The method of claim 13, wherein the chemotherapy is an androgen receptor antagonist, a mitotic inhibitor, an antimetabolite, or a platinum-based agent.

15. The method of claim 14, wherein the androgen receptor antagonist is apalutamide, flutamide, nilutamide, bicalutamide, or enzalutamide.

16. The method of claim 14, wherein the mitotic inhibitor is paclitaxel, docetaxel, cabazitaxel, tesetaxel, or nab-paclitaxel.

17. The method of claim 1, wherein the glucocorticoid receptor (GR) antagonist is

Compound

pharmaceutically acceptable salt or solvate thereof.

18. The method of claim 1, wherein the cancer is uterine corpus endometrioid carcinoma, colon adenocarcinoma, rectum adenocarcinoma, uveal melanoma, testicular germ cell tumor, bladder urothelial carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, kidney chromophobe, prostate adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, cervical cancer, endocervical cancer, breast invasive carcinoma, pancreatic adenocarcinoma, kidney papillary cell carcinoma, lung squamous cell carcinoma, liver hepatocellular carcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, pheochromocytoma, paraganglioma, glioblastoma multiforme, lung adenocarcinoma, brain lower grade glioma, or kidney clear cell carcinoma.