WO2012158884A1

WO2012158884A1 - Pharmaceutical compositions and methods for treating cancer

Info

Publication number: WO2012158884A1
Application number: PCT/US2012/038292
Authority: WO
Inventors: Oliver Rosen; Iain James WEBB
Original assignee: Takeda Pharmaceutical Company Limited
Priority date: 2011-05-17
Filing date: 2012-05-17
Publication date: 2012-11-22
Also published as: EP2709614A4; AR086444A1; TW201309291A; JP2014513730A; EP2709614A1; UY34078A; CA2836277A1

Abstract

The present invention provides pharmaceutical compositions and methods for treating cancer comprising administering a therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor.

Description

PHARMACEUTICAL COMPOSITIONS AND METHODS FOR TREATING CANCER

BACKGROUND OF THE INVENTION

[0001] Cancer is a group of diseases characterized by uncontrolled growth of abnormal cells and subsequent invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (i.e., metastasis). Cancer is believed to be caused by both external factors (tobacco, infectious organisms, chemicals, and radiation) and internal factors (inherited mutations, hormones, immune conditions, and mutations that occur from metabolism). These causal factors may act together or in sequence to initiate or promote carcinogensis. Significantly, cancer is currently the second leading cause of death in the United States after heart disease, and the number of people diagnosed with cancer has significantly increased and continues to rise at an alarming rate. Of particular concern are individuals dignosed with hormone-dependent disorders (e.g., androgen- dependent and estrogen-dependent) such as prostate cancer (androgen-dependent) and breast, uterine and ovarian cancer (estrogen-dependent), since such cancers are among the most common and fatal forms of cancer and such diagnoses are rapidly increasing.

[0002] Prostate cancer is currently the most common non-skin cancer and the second leading cause of cancer-related death in men after lung cancer. The primary course of treatment for patients disagnosed with organ-confined prostate cancer is usually prostatectomy or radiotherapy. Not only are these treatments highly invasive and characterized by undesirable and serious side effects, such localized treatments are not effective on prostate cancer after it has metastasized. Moreover, surgery can be contraindicated due to the health of the patient or may be unacceptable to the patient, and a surgical procedure may not completely remove cancerous tissue. Radiation therapy is effective only when the irradiated neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue. Furthermore, a large percent of individuals who receive localized treatments such as surgery or radiotherapy will suffer from recurring cancer and widespread metastases.

[0003] There are many parallels between prostate cancer and breast cancer, both in underlying disease biology and therapeutic approaches. Similar to treatments for prostate cancer as described above, most options for women diagnosed with breast cancer are highly invasive and have significant side- effects. Such treatments include surgery, radiation and chemotherapy. As with surgery and radiation therapies, there are many drawbacks to chemotherapy, including the fact that almost all chemotherapeutic agents are toxic, and chemotherapy causes significant, often dangerous, side effects, including severe nausea, bone marrow depression, and immunosuppression. Additionally, many tumor cells are resistant or become resistant to chemotherapeutic agents through multi-drug resistance. Moreover, some patients for whom chemotherapy initially works may suffer from relapsing or recurring cancer. [0004] Hormone therapy is another treatment option for individuals diagnosed with prostate or breast cancer. Hormone therapy is a form of systemic treatment for prostate or breast cancer, wherein hormone ablation agents are used to suppress the production or block the effects of hormones, such as estrogen and progesterone, which are believed to promote the growth of prostate cancer. This therapy is less invasive than surgery and does not have many of the side effects associated with chemotherapy or radiation. In addition, hormone therapy may be used by itself or in addition to localized therapy.

[0005] While hormone therapy is less invasive and may be used on more advanced stages of cancer, some individuals administered current hormone therapy treatments may not respond completely, or even partially, to such treatments. Current hormone therapy treatments may offer temporal remission of cancer, but these treated cancers can relapse or recur, and upon recurrence, these cancers often have developed a resistance to hormonal therapy. Due to the typically aggressive nature of these recurrent cancers, and their resistance to hormonal therapy, patients with these conditions are often left with few options for treatment.

[0001] Other cancers in which sex hormones may play a role in the progression of the cancer include uterine cancer, endometrial cancer, non-small cell lung cancer and colorectal cancer (Folkerd, E.J. and Dowsett M., J. Clin. Oncol 2010, 28: 4038-4044; Paggi M.G. et al , Cancer Lett. 2010, 298(1): 1-8; Fucic A. et al, Toxicol. Pathol. 2010, 38(6):849-55; Gambacciani M. et al, Best Tract Res Clin Endocrinol Metab. 2003 17(1): 139-47.

[0002] Thus, there remains a need to find new treatments for cancers, particularly hormonally-driven cancers, that would avoid or ameliorate the harsh side effects of some of the currently existing therapies.

DETAILED DESCRIPTION OF THE INVENTION [0003] 1. General Description

[0004] As discussed above, there remains a need to provide alternate therapies for the treatment of cancer, particularly those that avoid or ameliorate the harsh side effects of currently existing therapies. Accordingly, the present invention relates to pharmaceutical compositions and methods for the treatment of certain cancers comprising administering to a patient in need thereof a therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor without the concomitant or sequential administration of a steroid. In certain embodiments, the 17-alpha hydroxylase/C17, 20-lyase inhibitor is selective for CI 7, 20-lyase. In other embodiments, the 17-alpha hydroxylase/C17, 20-lyase inhibitor is a compound that does not have a steroid backbone. In yet other embodiments, the 17-alpha hydroxylase/C17, 20-lyase inhibitor is a compound that is selective for CI 7, 20-lyase and also does not have a steroid backbone. [0005] In another aspect, A method of treating cancer is provided, comprising administering a therapeutically effective amount of a 17-alpha hydroxylase/C17,20-Iyase inhibitor without the concomitant or sequential administration of a steroid, wherein the administering of a therapeutically effective amount of a 17-alpha hydroxylase/C17,20-lyase inhibitor without the concomitant or sequential administration of a steroid results in an improved clinical outcome for the patient as measured by enhanced progression-free survival or time to metastatis as compared to standard therapy.

[0006] In still another aspect, a method of treating cancer is provided, comprising administering a therapeutically effective amount of 6-[(7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-7-yl]-N- methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof without the concomitant or sequential administration of a steroid, wherein the administering of a therapeutically effective amount of a 17-alpha hydroxyIase/C17,20-lyase inhibitor without the concomitant or sequential administration of a steroid results in an improved clinical outcome for the patient as measured by enhanced progression-free survival or time to metastasis as compared to standard therapy.

[0007] Γ^η another aspect, the present invention provides a method for treating cancer wherein the monitoring of a patients blood pressure, and serum levels of one or more of corticosterone, Cortisol or potassium enables selectively adjusting dose levels to achieve safe and efficacious dose levels in a patient, particularly safe and efficacious dose levels of a 17-alpha hydroxylase/C17, 20-lyase inhibitor that can be administered without concomitant or sequential administration of a steroid. Accordingly, a method of treating cancer is provided comprising:

(a) measuring the patient levels of one or more of blood pressure or serum levels of one or more of corticosterone, Cortisol or potassium at a first point in time;

(b) administering to the patient a first dose level of a therapeutically effective amount of a 17- alpha hydroxy lase/C 17, 20-lyase inhibitor;

(c) measuring the patient levels of one or more of blood pressure or serum levels of one or more of corticosterone, Cortisol or potassium after the administration of a first dose level of a therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor; and

(d) administering to a patient a second dose level of a therapeutically effective amount of then- alpha hydroxylase/C17, 20 lyase inhibitor, wherein the second dose level is greater than, equal to, or less than the first dose level.

[0008] 2. Definitions

[0009] As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or disregulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites. The term "cancer" includes, but is not limited to, solid tumors and bloodborne tumors. The term "cancer" encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels. The term "cancer" further encompasses primary and metastatic cancers.

[0010] As used herein, the term "recurring cancer" refers to cancer that has returned after a patient has been earlier diagnosed with cancer, has undergone treatment and/or had been previously diagnosed as cancer-free.

[0011] As used herein the term "relapse cancer" refers to cancer that was at one time responsive to an anti-cancer treatment, but has become no longer responsive to such treatment or is no longer responding sufficiently to such treatment.

[0012] As used herein, the term "refractory cancer" refers to a cancer that is not responding to an anti-cancer treatment or cancer that is not responding sufficiently to an anti-cancer treatment, including recurring or relapsed cancer.

[0013] As used herein, and unless otherwise defined, the phrases "hormone-refractory cancer" or "cancer that is refractory to hormone therapy" mean cancer that is not responding to a hormone therapy, cancer that is no longer responding to or has progressed through a hormone therapy, or cancer that is not responding sufficiently to a hormone therapy.

[0014] As used herein, and unless otherwise defined, the phrase 'hormone-refractory patient" means a patient who has hormone-refractory cancer.

[0015] As used herein, and unless otherwise defined, the phrases "chemo-refractory cancer" or "cancer that is refractory to chemotherapy" mean cancer that is not responding to chemotherapy, cancer that is no longer responding to or has progressed through chemotherapy, or cancer that is not responding sufficiently to chemotherapy.

[0016] As used herein, and unless otherwise defined, the phrase "chemo-refractory patient", means a patient who has chemo-refractory cancer.

[0017] As used herein, and unless otherwise defined, the phrases "castration-refractory cancer" or "cancer that is refractory to castration" mean cancer that is not responding to castration, cancer that is no longer responding to or has progressed through castration, or cancer that is not responding sufficiently to castration.

[0018] As used herein, and unless otherwise defined, the phrases "chemotherapy-naive patient" or "patient who is chemotherapy naive" refer to a patient who has never undergone chemotherapy treatment or who has never undergone chemotherapy treatment for a particular cancer. [0019] As used herein, and unless otherwise defined, the phrases "hormone therapy-naive patient" or "patient who is hormone-therapy naive" refer to a patient who has never undergone hormone therapy treatment or who has never undergone hormone therapy treatment for a particular cancer.

[0020] As used herein, and unless otherwise defined, the term "PSA" refers to prostate-specific antigen, which is a protein produced by the cells of the prostate gland.

[0021] As used herein, and unless otherwise defined, the term "castration levels of PSA" refers to the levels of PSA circulating in the blood of a patient who has had either one or both testicles surgically removed or has been chemically castrated, meaning the patient has been administered certain hormonal drugs to temporarily inhibit hormones that stimulate the testicles to produce testosterone.

[0022] As used herein, and unless otherwise defined, the term "castration levels of testosterone" refers to the levels of testosterone circulating in the blood of a patient who has had either one or both testicles surgically removed or has been chemically castrated, meaning the patient has been administered certain hormonal drugs to temporarily inhibit hormones that stimulate the testicles to produce testosterone.

[0023] As used herein, and unless otherwise defined, the phrase "number of circulating tumor cells" refers to the number of cancer cells that have detached from a primary tumor and are circulating in the bloodstream or bone marrow of a cancer patient.

[0024] As used herein, the term "hormonal agent" includes, but is not limited to, "androgen ablation agents" and "estrogen ablation agents". It will be appreciated that the term "hormonal agent" can comprise more than one hormonal agent.

[0025] As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

[0026] As used herein, the term "therapeutically effective amount" refers to the amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition that is effective for treating or preventing the disease or disorder.

[0027] As used therein, the term "steroid" refers to "corticosteroids" which are group of natural and synthetic analogues of the hormones secreted by the hypothalamic-anterior pituitary-adrenocortical (HPA) axis, more commonly referred to as the pituitary gland. These include glucocorticoids, which are anti-inflammatory agents with a large number of other functions; mineralocorticoids, which control salt and water balance primarily through action on the kidneys; and corticotropins, which control secretion of hormones by the pituitary gland. In certain embodiments, as used herein, the term "steroid" refers to dexamethasone, prednisone, prednisolone, betamethasone, and trimacinolone. In certain other embodiments, the term "steroid" refers to glucocorticoids. [002S] As used herein, the term "without the concomitant or sequential administration of a steroid" refers to a dose cycle wherein the patient is not given a steroid with the 17-alpha hydroxylase/C17, 20- lyase inhibitor either sequentially or concomitantly. In one embodiment, the term is not intended to exclude any previous administration of steroid for any purpose (e.g., steroid administration for asthma), or previous therapies received with steroids. In some embodiments, the administration refers to a dose given on the same day. In other embodiments, the administration refers to a dose cycle with the 17-alpha hydroxylase/C17, 20-lyase inhibitor lasting 1 week, 2 weeks, 3 weeks, 4 weeks, 28 days, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.

[0029] As used herein, the term "steroid backbone" refers to a general class of chemical substances that are structurally related to one another and share the same chemical skeleton (a tetracyclic cyclopenta[a]phenanthrene skeleton).

[0030] 3. Detailed Description

[0031] As detailed above, the present invention relates to pharmaceutical compositions and methods for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor without the concomitant or sequential administration of a steroid. As outlined above, there remains a need to develop treatments for cancer that minimize and/or avoid the prolonged exposure to steroids and their side effects, and the present invention provides such a treatment for cancer without the use of steroids. In certain other embodiments, the present invention provides a method of treating cancer comprising administering a therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor in combination with one or more additional therapeutic agents, wherein the one or more additional therapeutic agents is not a steroid. In certain other embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor and one or more additional therapeutic agents, wherein the one or more additional therapeutic agents is not a steroid.

[0032] 17-alpha hydroxylase/CI 7-20 lyase inhibitors

[0033] Exemplary 17-alpha hydroxyIase/C17, 20-lyase inhibitors and pharmaceutical compositions thereof are described in WO02/40484 and WO09/057795, the entire contents of which are hereby incorporated by reference.

[0034] Without being bound by any particular theory, it is believed that inhibitors that are selective for C17, 20-lyase over 17-alpha hydroxylase will result in fewer side effects since the incomplete inhibition of 17-hydroxylase could maintain Cortisol concentrations and prevent mineralocorticoid excess. In certain embodiments, the 17-alpha hydroxylase/C17, 20-lyase inhibitor is a selective inhibitor of CI 7, 20-lyase over 17-alpha hydroxylase. In yet other embodiments, the 17-alpha hydroxylase/C17, 20-lyase inhibitor is about 3 to about 8 fold selective for CI 7, 20-lyase over 17-alpha hydroxylase. Γη yet other embodiments, the 17-alpha hydroxylase/C17, 20-lyase inhibitor is about 4 to about 7 fold selective for CI 7, 20-lyase over 17-alpha hydroxylase. In still other embodiments, the 17-alpha hydroxylase/C17, 20- lyase inhibitor is about 5 fold selective for CI 7, 20-lyase over 17-alpha hydroxylase.

[0035] In certain other embodiments, the 17-alpha hydroxylase/C17, 20-lyase inhibitor does not have a steroid backbone.

[0036] Without being bound by any particular theory, it is believed that inhibitors that are selective for CI 7-20 over 17-alpha hydroxylase and other human CYP family enzymes also result in fewer side effects since the other CYP drug metabolizing enzymes will be minimally affected. In still other embodiments, the 17-alpha hydroxylase/C17, 20-lyase inhibitor is a selective inhibitor of CI 7, 20 over 17-alpha hydroxylase and other human CYP family enzymes. In some embodiments, the 17-alpha hydroxylase/C17, 20-lyase inhibitor has an IC₅o value for human CYP family enzymes other than CI 7, 20-lyase of greater than 10 μΜ. In other embodiments, the 17-alpha hydroxylase/C17, 20-lyase inhibitor has an IC₅₍₎ value for human CYP family enzymes other than CI 7, 20-lyase of greater than 20 μΜ. In still other embodiments, the 17-alpha hydroxylase/C17, 20-lyase inhibitor has an IC₅₀ value for human CYP family enzymes other than CI 7, 20-lyase of greater than 30 μΜ.

[0037] In certain embodiments, the 17, 20-lyase inhibitor is 6-[(7S)-7-hydroxy-6,7-dihydro-5H- pyrrolo[l,2-c]imidazol-7-yl]-N-methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0038] Dosages of, Combination Therapy, and Administration of 17-alpha hydroxylase/C17-20 lyase inhibitors

[0039] The therapeutically effective amounts or suitable dosages of the 17-alpha hydroxylase/C17, 20-lyase inhibitor depends upon a number of factors, including the nature of the severity of the condition to be treated, the particular inhibitor, the route of administration and the age, weight, and response of the individual patient. In certain embodiments, the suitable dose level is one that achieves a therapeutic response as measured by PSA levels, tumor regression, or other standard measures of disease progression. In other embodiments, the suitable dose level is one that achieves this therapeutic response and also minimizes any side effects associated with the administration of the therapeutic agent.

[0040] In still other embodiments, a suitable dose level is one that achieves an improved clinical outcome for the patient as measured by enhanced progression-free survival or time to metastasis as compared to standard therapy. In certain embodiments, progression-free survivial is enhanced by at least 9 months as compared to standard therapy. Γη other embodiments, progression-free survival is enhanced by at least 12 months as compared to standard therapy. In yet other embodiments, progression-free survival is enhanced by at least 15 months as compared to standard therapy.

[0041] In yet other embodiments, a suitable dose level is one that results in an improved clinical outcome as measured by a favorable safety risk/benefit ratio, whereby the risk associated with the administering of the 17-alpha hydroxylase/C17,20-Iyase inhibitor without the concomitant or sequential administration of a steroid is outweighed by the benefit associated with avoiding prolonged steroid use. In certain embodiments, the risks associated with the administering of a 17-alpha hydroxylase/C17,20-lyase inhibitor without the concomitant or sequential administration of a steroid is measured by monitoring the patient for evidence of mineralocorticoid excess. In some embodiments, the patient is monitored for one of more of ACTH corticosterone profile, hypertension, hypokalemia, edema, or cardiovascular symptoms.

[0042] Suitable daily dosages of 17-alpha hydroxylase/C17, 20-lyase inhibitors can generally range, in single or divided or multiple doses, from about 400 mg to about 1200 mg per day. Other suitable daily dosages of 17-alpha hydroxylase/C17, 20-lyase inhibitors can generally range, in single or divided or multiple doses, from about 600 mg to about 1200 mg per day. In certain embodiments, the suitable dosages are from about 200 mg twice daily to about 600 mg twice daily. In some other embodiments, the suitable dosages are from about 300 mg twice daily to about 600 mg twice daily. In other embodiments, suitable dosages are about 800 mg per day. In certain other embodiments, suitable dosages are about 400 mg twice daily. In still other embodiments, suitable dosages are about 600 mg per day. In other embodiments, suitable dosages are 300 mg twice daily. In still other embodiments, suitable dosages are 200 mg twice daily. In yet other embodiments, suitable dosages are from about 300 mg to about 600 mg once daily. In yet other embodiments, suitable dosages are from about 200 mg to about 600 mg once daily. In still other embodiments, a suitable dosage is about 600 once daily. In yet other embodiments, a suitable dosage is about 600 mg once daily taken in the morning. In still other embodiments, the suitable dosage amount is taken with a meal.

[0043] Additionally, it will be appreciated that the frequency with which any of these inhibitors can be administered can be once or more than once over a period of about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 20 days, about 28 days, about a week, about 2 weeks, about 3 weeks, about 4 weeks, about a month, about every 2 months, about every 3 months, about every 4 months, about every 5 months, about every 6 months, about every 7 months, about every 8 months, about every 9 months, about every 10 months, about every 11 months, about every year, about every 2 years, about every 3 years, about every 4 years, or about every 5 years. [0044] Furthermore, the above frequencies of administration can occur continuously or non- continuously over certain time periods. For example, a certain amount of the 17-alpha hydroxylase/C17, 20-lyase inhibitor can be administered daily continuously over 28 days. Time periods over which the frequencies of administration can occur continuously or non-continuously include without limitation 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, about 20 days, about 28 days, about a week about 2 weeks, about 3 weeks, about 4 weeks, about a month, about every 2 months, about every 3 months, about every 4 months, about evey 5 months, about every 6 months, about every 7 months, about every 8 months, about every 9 months, about every 10 months, about every 11 months, about every year, about every 2 years, about every 3 years, about every 4 years, or about every 5 years.

[0045] In some embodiments, the therapeutically effective amount of the 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered using dose cycling or a dosing regimen in which the 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered at a certain frequency, such as those described above. The treatment period is then followed by a non-treatment period of a particular time duration, such as the time periods described above, in which the 17-alpha hydroxylase/C17, 20-lyase inhibitor is not administered to the patient.

[0046] This non-treatment period can then be followed by a series of subsequent treatment and non- treatment periods of the same or different frequencies or the same or different lengths of time. In some embodiments, the treatment and non-treatment periods are alternated, hi other embodiments, a first treatment period in which a first amount of the 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered can be followed by another treatment period in which a same or different amount of the same or a different 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered. The second treatment period can be followed by other treatment periods. During the treatment and non-treatment periods, one or more additional non-steroidal therapeutic agents can be administered to the patient.

[0047] The 17-alpha hydroxyIase/C17, 20-lyase inhibitor can be administered by any method known to one skilled in the art. The 17-alpha hydroxylase/C17, 20-lyase inhibitor can be administered in the form of a composition, in one embodiment a pharmaceutical composition, such as those described herein. Preferably, the pharmaceutical composition is suitable for oral administration. In other embodiments, the pharmaceutical composition is a tablet for oral administration. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0048] In some embodiments, the method comprises administration of a therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor in combination with an additional therapeutic agent wherein the additional therapeutic agent is not a steroid. In certain embodiments, the therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered without the concomitant or sequential administration dexamethasone, prednisone, prednisolone, betamethasone, or trimacinolone. In still other embodiments, the therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered without the concomitant or sequential administration of prednisone. It will be appreciated that combination therapy includes administration of the therapeutic agents concurrently or sequentially. Alternatively, the therapeutic agents can be combined into one composition which is administered to the patient.

[0049] In certain embodiments, the additional therapeutic agent includes, but is not limited to, hormone ablation agents, anti-androgen agents/anti-androgens, differentiating agents, anti-neoplastic agents, kinase inhibitors, anti-metabolite agents, alkylating agents, antibiotic agents, immunological agents, interferon-type agents, DNA-damaging agents (e.g., intercalating agents), growth factor inhibitors, cell-cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloprotease inhibitoris, anti-resorptives, monoclonal antibodies, adhesion molecules, growth factors, proapoptotic agents, antisense agents, vitamin D analogs, RNAi agents, modified peptides, enzyme inhibitors, agents ameliorating the side effects of therapy, and genetic therapeutics. Examples of some of the above classes of additional therapeutic agents are listed below for purposes of illustration and not for purposes of limitation, as these examples are not all-inclusive. Many of the examples below could be listed in multiple classes of anti-cancer agents and are not restricted in any way to the class in which they are listed.

[0050] Examples of hormonal ablation agents include, but are not limited to, androgen ablation agents and estrogen-ablation agents. In some embodiments, hormonal ablation agents include, but are not limited to, deslorelin, leuprolide, goserelin or triptorelin.

[0051] Examples of anti-androgen agents include, but are not limited to, bicalutamide, flutamide, spironolactone, cyproterone acetate, finasteride, dutasteride, and nilutamide. An example of an antiestrogen agent includes, but is not limited to, tamoxifen.

[0052] Examples of differentiating agents include, but are not limited to polyamine inhibitors, vitamin D and its analogues, such as calcitriol, doxercalciferol, ergocalciferol, 22-oxacalcitriol, dihydrotachysterol, paricalcitol, and seocalcitol; inhibitors of vitamin A metabolism, such as RAMBAS, e.g., liarozole, metabolites of vitamin A, such as ATRA; retinoic acid; retinoids; short chain fatty acids; phenylbutyrate; and nonsteroidal anti-inflammatory agents.

[0053] Examples of anti-neoplastic agents include, but are not limited to tubulin interacting agents, topoisomerase inhibitors and agents, acitretin, alstonine, amonafide, amphethinile, amsacrine, ankinomycin, anti-neoplaston, aphidicolin glycinate, asparaginase, baccharin, batracyclin, benfluron, benzotrips, bromofosamide, caracemide, carmethizole hydrochloride, chlorsulfaquinoxalone, clanfenur, claviridenone, crisnatol, curaderm, cytarabine, cytocytin, dacarbazine, datelliptinium, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, docetaxel, elliprabin, elliptinium acetate, epothilones, ergotamine, etoposide, etretinate, fenretinide, hydroxyurea, ilmofosine, isoglutamine, isotretinoin, leukoregulin, lonidamine, merbarone, merocyanlne derivatives, methylanilinoacridine, minactivin, mitonafide, mitoquidone, mitoxantrone, mopidamol, motretinide, N-(retinoyl)amino acids, N-acylated- dehydroalanines, nafazatrom, nocodazole derivative, octreotide, oquizanocine, paclitaxel, pancratistatin, pazelliptine, piroxantrone, polyhaematoporphyrin, polypreic acid, probimane, procarbazine, progiumide, razoxane, retelliptine, spatol, spirocyclopropane derivatives, spirogermanium, strypoldinone, superoxide dismutase, teniposide, thaliblastine, tocotrienol, topotecan, ukrain, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, and withanolides.

[0054] Examples of kinase inhibitors include, but are not limited to, p38 inhibitors; CDK inhibitors; TNF inhibitors; matrixmetallo proteinase (MMP) inhibitors; COX-2 inhibitors; including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib; and SOD mimics.

[0055] Examples of anti-metabolite agents include 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, doxifluridine, fazarabine, floxuridine, fludarabine phosphate, 5-fIuorouracil, N-(2'-furanidyl)— 5-flurouracil, inhibitors of essential amino acids, isopropyl pyrrolizine, methobenzaprim, methotrexate, norspermidine, ornithine decarboxylantion inhibitors, pentostatin, piritrexim, plicamycin, thioguanine, tiazofurin, trimetrexate, tyrosine kinase inhibitors, and uricytin.

[0056] Non-limiting examples of DNA damaging chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and analogs or metabolites thereof, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators, free radical generators such as bleomycin; and nucleoside mimetics (e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine, cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea), estrogen receptor antagonists (e.g. tamoxifen, fulvestrant), and aromatase inhibitors (e.g. exemestane, anastrozole or letrozole)

[0057] Chemotherapeutic agents that disrupt cell replication include: paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; thalidomide, lenalidomide, and related analogs (e.g., CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylate, gefitinib, lapatinib); proteasome inhibitors (e.g., bortezomib); NF-κΒ inhibitors, including inhibitors of IKB kinase; antibodies which bind to proteins overexpressed in cancers and thereby downregulate cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes known to be upregulated, over-expressed or activated in cancers, the inhibition of which downregulates cell replication.

[0058] Non-limiting examples of antibiotic agents include aclarubicin, actinomycin D, actinoplanone, adriamycin, aeroplysinin derivative, amrubicin, anthracycline, azinomycin-A, bisucaberine, bleomycin sulfate, bryostatin-1, calichemycin, chromoximycin, dactinomycin, daunorubicin, ditrisarubicin B, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb, fostriecin, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, menogaril, mitomycin, neoenactin, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindanycin A, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenimycin, sorangicin-A, sparsomycin, talisomycin, terpentecin, thrazine, tricrozarin A, and zorubicin.

[0059] Non-limiting examples of enzyme inhibitors include a 17-alpha hydroxylase/C17,20-lyase inhibitor, imidazole, azole, or an antifungal agents, for example, ketoconazole.

(0060] Non-limiting examples of monoclonal antibodies include rituximab, trastuzumab, gentuzumab, ozogamicin, alemtuzumab, ibritumomab, tiuxetan, tositumomab, cetuximab, bevacizumab, panitumumab, and ofatumumab.

[0061] Non-limiting examples of antisense agents include Genasense (oblimersen), affmitak (ISIS3521), ISIS 112989 (OGX 011), ISIS 23722, AP 12009, GEM 231, GEM 240, IGF-IR/AS ODN, MG98, LErafAON, Ki-67 antisense oligonuclotide, GTI-2040, ISIS 2503, and API 1014.

[0062] Non-limiting examples of peptides and/or modified peptides include peptides or modified peptides as inhibitors, ligands or vaccines having for example a T-cell response against cancer cells and/or anti-cancer activity.

[0063] Non-limiting examples of agents ameliorating the side effects of therapy include diuretics, pain relievers, analgesics, anti-inflammatory agents, eplerenone, proton pump inhibitors, H2 receptor antagonists, lipid lowering agents, antiresorptive agents, or antipsychotic agents. In certain embodiments, the one or more additional treatments are selected from radiation, chemotherapy, immunotherapy, a nonsteroidal hormone ablation therapy, or a non-steroidal therapy for the management of the side effects of therapy. In certain other embodiments, the one or more additional treaments are selected from sipuleucel- T, paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, 5-fluorouracil, cyclophosphamide, doxorubicin, cytarabine, cabazitaxel, tamoxifen, fulvestrant, cisplatin, exemestane, anastrozole, letrozole, trastuzumab, lapatinib, radioisotopes, hormone ablation agent, hormone deprivation treatment, antiandrogen, ketoconazole, aromatase inhibitor, bicalutamide, eplerenone, spironolactone, or triampterine. In still other embodiments, the one or more additional treatments includes an androgen receptor inhibitor. In certain embodiments, the androgen receptor inhibitor is MDV-3100 (4-(3-(4-cyano- 3-(trifIuoromethyl)phenyl)-5 , 5 -dimemyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzam or ARN-509 (4-(7-(6-cyano-5-(trifluoromemyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5- yl)-2-fluoro-N-methylbenzamide) .

[0064] As described above, the 17-alpha hydroxylase/C17, 20-lyase inhibitor can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[0065] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term "inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of 17-alpha hydroxylase/C17,20-lyase.

[0066] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et at, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N^Cnalk l^ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0067] As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. [0068] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease being treated.

[0069] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0070] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0071] The injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0072] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0073] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0074] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, calcium dihydrogen phosphate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, microcrystalline cellulose and silicic acid, b) binders such as, for example, carboxymethylcellulose, hydroxypropylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium starch glycolateand sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, hi the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0075] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0076] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0077] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0078] Cancers to be Treated with the 17-alpha hydroxylase/C17, 20-lyase inhibitor or Combinations Thereof

[0079] As described above, the 17-alpha hydroxylase/C17, 20-lyase inhibitor is useful for the treatment of cancer. Cancers that can be treated with the methods and compositions described herein include, but are not limited to, those cancers that are hormone-dependent, hormone responsive, or hormone sensitive (collectively "hormone responsive cancers"). In particular, cancers that can be treated include, without limitation, androgen-responsive cancers, such as testosterone-responsive cancers, and estrogen-responsive cancers. Moreover, in some embodiments, the cancer can be a non-hormone responsive cancer of a cancer that was hormone responsive but later becomes non-hormone responsive. Cancers that can be treated include, without limitation, prostate cancer, breast cancer, testicular cancer, penile cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, cancer of the Fallopian tubes or other reproductive organ cancers. In other embodiments, cancers that may be treated include, without limitation, adrenal cancer, cancer of the lymphatic system, such as the lymph nodes, leukemia, lymphoma, myeloma, Waldenstrom's macroglobulinemia, monoclonal gammopathy, benign monoclonal gammopathy, heavy chain disease, bone and connective tissue sarcoma, brain tumors, thyroid cancer, pancreatic cancer, pituitary cancer, eye cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, cholangiocarcinoma, lung cancer, oral cancer, skin cancer, kidney cancers, Wilms' tumor, and bladder cancer.

[0080] In addition, the methods and compositions described herein can be used to treat various stages of a particular cancer or specific forms of a type of cancer, such as breast or prostate cancer. In some embodiments, the methods and compositions can be used to treat a pre-cancerous state, a post- cancerous state, an advanced cancerous state, a pre-metastatic cancer, a cancer that is a metastasis, i.e., that has metastasized from another cancer, a cancer that metastasized to, for example, the bones, lymph nodes, lungs, or a non-metastatic cancer. In one embodiment, the patients treated are newly diagnosed with cancer, such as prostate cancer. In embodiments relating to prostate cancer, the prostate cancer may be non-metastatic; may be pre-metastatic; may have metastasized to the bones, lungs, lymph nodes; or may comprise advanced adenocarcinoma of the prostate. For example, the prostate cancer can be, without limitation, androgen-dependent prostate cancer; androgen-independent prostate cancer (AIPC) such as those that are biochemical-only in nature, asymptomatic with positive scans or symptomatic. The stages of prostate cancer that may be treated by the methods and compositions described herein include, without limitation, stages IA, ΠΒ, II, ΠΙ, IVA, IVB, and JVC; cancers with a Gleason grade of between 1 and 5 or a Gleason sum or score of between 2 and 10; stages A, B, C, or D under the Jewett-Whitmore system; and any combination of TNM scores under the American Joint Committee on Cancer (AJCC) TNM system, including without limitation, TX, TO, Tla, Tib, T2a, T2b, T3a, T3b, T4, NX, NO, Nl, N2, N3, MX, M0, Mia, Mlb, Mlc.

[0081] The methods and compositions described herein can be used for patients who have or had not previously had cancer. For instance, the patient can be a female who currently has ovarian cancer and who has or had breast cancer. Also, the patient can be one who has or has not been previously treated for cancer. Such patients may have had surgery to treat the cancer or another form of cancer, or may not have had surgery to treat the cancer or another form of cancer. For instance, the patient may have had surgery to remove all or a portion of a cancerous or non-cancerous tumor. Also, the patient may have had surgery to remove all or a portion of a body part or an organ with a cancerous growth, such as prostate gland, testicle, breast, ovary, or uterus. Prostate cancer patients treated can also include those who have been castrated prior to administration of a therapeutically effective amount of a 17-alpha hydroxylase/ CI 7, 20-lyase inhibitor, as well as those who have not been castrated. In other embodiments, the patient may be castration-refractory.

[0082] In some embodiments, the patient is chemotherapy-naive or has not been treated with a particular chemotherapy, such as any of the chemotherapies described herein. In other embodiments, the patient has or is currently receiving or will receive chemotherapy. Such chemotherapy includes without limitation the administration of paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, and radioisotopes. In certain embodiments, the patient is chemotherapy refractory to a certain chemotherapy, including any of those mentioned herein.

[0083] Additionally, in some embodiments, the patient is hormone therapy-naive or has not been treated with a particular hormone therapy, such as any of the hormone therapies described herein. In other embodiments, the patient has or is currently receiving or will receive hormone therapy. Such hormone therapy includes without limitation the administration of hormone ablation agents, hormone deprivation treatment, antiandrogens, ketoconazole, aromatast inhibitors such as aminoglutethimide, fiutamide, cyproterone acetate, goserelin, leuprorelin, GnRH agonist, DES, or LHRH analogues. In certain embodiments, the patient is refractory to a certain hormone therapy, including any of those mentioned herein.

[0084] With respect to patients that have been previously treated for prostate cancer, in some embodiments the prostate cancers may include metastatic disease, and in other embodiments, the prostate cancers may include non-metastatic disease.

[0085] In some other embodiments, the patient will have previously received one or more treatments with abiraterone acetate.

{0086] Addititional Methods for Treating Cancer

[0087] In yet another aspect of the present invention, a method for treating cancer is provided wherein the monitoring of a patients blood pressure, and serum levels of one or more of corticosterone, Cortisol or potassium enables selectively adjusting dose levels to achieve safe and efficacious dose levels in a patient. Without being bound by any particular theory, it is believed that ACTH dependent serum corticosterone and Cortisol represent pharmacodynamic markers of lyase inhibition. Accordingly, serum corticosterone and Cortisol guided drug therapy with lyase inhibiting molecules is an approach for individualized dose adjustment. Accordingly, a method of treating cancer is provided comprising:

(b) administering to the patient a first dose level of a therapeutically effective amount of a 17- alpha hydroxylase/C17, 20-lyase inhibitor;

(c) measuring the patient levels of one or moe of blood pressure or serum levels of one or more of corticosterone, Cortisol or potassium after the administration of a first dose level of a therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor; and

(d) administering to a patient a second dose level of a therapeutically effective amount of the 17- alpha hydroxylase/C17, 20-lyase inhibitor, wherein the second dose level is greater than, equal to, or less than the first dose level. [0088] In certain embodiments, the second dose level in step (d) is less than the first dose level. In still other embodiments, the method further comprises repeating steps (a)-(d) until a desired dose level of a therapeutically effective amount of the 17-alpha hydroxylase/C17, 20-lyase inhibitor is achieved.

[0089] In yet other embodiments, the blood pressure measurement after the administration of the first dose level is greater than the blood pressure measurement prior to administration of the first dose level; and

(a) the corticosterone level after the administration of the first dose level is higher than the corticosterone level prior to the administration of the first dose level; or

(b) the Cortisol level after the administration of the first dose level is lower than the Cortisol level prior to the administration of the first dose level; or

(c) the potassium level after the administration of the first dose level is lower than the potassium level prior to the administration of the first dose level.

[0090] In other embodiments, the corticosterone level after administration of the first dose level is higher than the corticosterone level prior to the administration of the first dose level. In still other embodiments, the Cortisol level after the administration of the first dose level is lower than the Cortisol level prior to the administration of the first dose level. In yet other embodiments, the potassium level after the administration of the first dose level is lower than the potassium level prior to the administration of the first dose level.

[0091] In some embodiments, both the first and second dose levels of the 17-alpha hydroxylase/C 17, 20-lyase inhibitor is administered without the concurrent or sequential administration of a steroid.

[0092] In still other embodiments, the cancer to be treated is a hormonally-driven cancer. In some embodiments, the cancer is prostate cancer, breast cancer or ovarian cancer. In othe embodiments, the cancer is prostate cancer. In still other embodiments, the prostate cancer is castration resistant prostate cancer. In yet other embodiments, the prostate cancer is metastatic castration resistant prostate cancer. In still other embodiments, the prostate cancer is non-metastatic castration resistant prostate cancer.

[0093] In some embodiments for the methods described above, the first dose level is from about 200 mg to about 600 mg twice daily. In some other embodiments for the methods described above, the first dose level is from about 300 mg to about 600 mg twice daily. In yet other embodiments, the first dose level is about 400 mg twice daily. In still other embodiments, the first dose level is about 300 mg twice daily. In still other embodiments, the first dose level is about 200 mg twice daily. In further embodiments, the first dose level is from about 200 mg to about 600 mg once daily. In still further embodiments, the first dose level is from about 300 mg to about 600 mg once daily. In yet other embodiments, the first dose level is about 600 once daily. In still other embodiments, the first dose level is about 600 mg once daily taken in the morning. In some other embodiments, the first dose level is taken with a meal. In yet other embodiments, the second dose level is taken with a meal. In still other embodiments, either one of or both of the first or second dose level is taken with a meal. In still other embodiments, the first dose level is about 400 mg twice daily and the second dose level is about 300 mg twice daily. In yet other embodiments, the first dose level is about 300 mg twice daily and the second dose level is about 200 mg twice daily.

[0094] In yet other embodiments, the method further comprises further comprising administering to the patient one or more additional treatments concurrently with or sequentially with either or both of the first or second dose of the 17-alpha hydroxylase/C17, 20-lyase inhibitor, wherein the one or more additional treatments comprises radiation, chemotherapy, immunotherapy, a non-steroidal hormone ablation therapy, or a non-steroidal therapy for the management of side effects of therapy.

[0095] In still other embodiments, the one or more additional treaments are selected from sipuleucel- T, paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, 5-fluorouracil, cyclophosphamide, doxorubicin, cytarabine, cabazitaxel, tamoxifen, fulvestrant, cisplatin, exemestane, anastrozole, letrozole, trastuzumab, lapatinib, radioisotopes, hormone ablation agent, hormone deprivation treatment, antiandrogen, ketoconazole, aromatase inhibitor, bicalutamide, eplerenone, spironolactone, or tri mpterine. In yet other embodiments, the one or more additional treatments is MDV-3100.

[0096] In still other embodiments, the patient will have previously received one or more treatments with abiraterone acetate.

[0097] Determining the Effect of 17-alpha-hydroxylase/Cl 7, 20-fyase Inhibitors in Vivo:

[0098] It will be appreciated that 17-alpha-hydroxylase/C17, 20-inhibitors can be demonstrated to inhibit tumor formation in vivo. A wide variety of animal models of hyperproliferative disorder, including tumorigenesis and metastatic spread, are known in the art. Additionally, a variety of general animal models applicable to many types of cancer have been described.

[0099] For example, a 17-alpha-hydroxylase/C17, 20-lyase inhibitor can be administered to a test animal, preferably a test animal predisposed to develop a tumor, and the test animal subsequently examined for decreased incidence of tumor formation in comparison with controls. Alternative, a 17- alpha-hydroxylase/C17, 20-lyase inhibitor can be administered to test animals having a tumor and subsequently examine the tumor in the test animals for tumor regression in comparison to control animals not administered the 17-alpha-hydroxylase/C17, 20-lyase inhibitor.

[00100] Predictive markers of cancer, such as prostate cancer, can also help measure the effect of the 17-aIpha-hydroxylase/C17, 20-lyase inhibitor. Such predictive markers include, but are not limited to the concentration of prostate-specific antigens (PSAs), plasma concentration of testosterone, circulating tumor cells (CTCs), extent of bone metastasis or lymph node metastasis, tumor size or tumor mass, plasma concentration of alkaline phosphatase (ALP), and extent of pain experienced by patient.

[00101] 4. Experimental Procedures

[00102] Example 1: Study of orteronel in Patients with Metastatic Castration-resistant Prostate Cancer:

[00103] The investigational 17,20-lyase inhibitor orteronel, which is 6-[(7S)-7-hydroxy-6,7-dihydro- 5H-pyrrolo[l,2-c]imidazol-7-yl]-N-methyl-2-naphthalenecarboxamide is a selective 17,20-lyase inhibitor that downregulates androgenic steroid production in vitro and in vivo.

[00104] Methods: Patients received orteronel in a 28-day cycle, in 4 dose cohorts: 300 mg BID, 400 mg BED + prednisone 5 mg BID, 600 mg BID + prednisone, and 600 mg QD. Inclusion criteria are: male patients aged > 18 years, histologically or cytologically confirmed prostate adenocarcinoma with confirmed metastatic (radiograph-documented) progressive disease while on androgen deprivation therapy, ECOG performance status of 0-2, prior orchiectomy or expected to continue receiving luteinizing hormone-releasing hormone (LHRH) therapy, with testosterone <50 ng/dL, and PSA > 5 ngmL.

Exclusion criteria are: prior chemotherapy for prostate cancer, aminoglutethimide, ketoconazole, or radiation therapy within 30 days prior to first dose of study drug; symptoms considered related to prostate cancer, such as bone or pelvic pain, unless the pain is mile, non-opioid-requiring and not indicative of rapidly progressive disease; and uncontrolled hypertension (> 150/90 mmHg).

1. Assessments: AEs were graded using NCI-CTCAE v3.0; serum PSA levels were measured at screening, days 1 and 15 of cycle 1, day 1 of all subsequent cycles, and at the end of the study;

PD analyses were assessed using the following endocrine panel: testosterone,

dehydroepiandrostenedione (DHEA), DHEA-sulfate (DHEA-S), androstenedione, LH, adrenocorticotropic hormone (ACTH), corticosterone, and Cortisol.

[00105] Results: The data shown is for 97 enrolled patients. The baseline patient demographics and disease characteristics are shown in Table 1.

[00106] Table 1: Baseline patient demographics and disease characteristics

[00107] All 97 patients were included in the safety-evaluable population. Patients received a median of 6 (range 0-19) treatment cycles. The safety profile of orteronel is summarized in Table 2. The most common adverse events were fatigue, nausea, constipation, diarrhea, headache, and anorexia (Table 3).

[00108] Table 2: Safety profile of orteronel

SAEs 3 (13) 8 (33) 8 (31) 6 (25)

Drug-related SAEs 1 (4) 1 (4) 4 (15) 1 (4)

[00109] Table 3: Most common AEs (any grade) reported in >20% of patients

[00110] Overall, the most common all-grade AEs in the 300 mg BID and 600 mg QD groups were similar to those in the groups receiving concomitant prednisone. The rates of constipation and anorexia were lower than those in patients receiving prednisone.

[00111] Constipation: 35%/25% with 300 mg BID and 600 mg QD, respectively, compared with 38%/50% for 400 and 600 mg BID plus prednisone, respectively.

[00112] Anorexia: 22%/21% with 300 mg BID and 600 mg QD, respectively, compared with 33%/35% for 400 and 600 mg BID plus prednisone, respectively.

[00113] Grade >3 AEs were also slightly lower in the groups without concomitant prednisone: [00114] 48%/42% with 300 mg BID and 600 mg QD, respectively, versus 54% for both groups receiving concomitant prednisone.

[00115] SAE rates were lower in the cohorts not receiving prednisone, at 13% for the 300 mg BID group and 25% for the 600 mg QD group, compared with 33% and 31% for the 400 and 600 mg BID plus prednisone groups, respectively.

[00116] Efficacy:

[00117] PSA response was evaluable in 83 patients (86%) at 12 weeks. The RECIST-evaluable population included 49 patients (51%). The PSA response at 12 weeks is shown in Figure 1. 44 patients (53%) had PSA decreases > 50%, of whom 21 (25%) had reductions > 90%. Of 56 patients with a 24- week PSA determination, 48 (86%) had PSA decreases, including 36 (64%) who had a PSA decrease of > 50% and 17 (30%) who had reductions > 90%. The majority of patients who did not have a PSA response had received prior adrenal therapy (Figure 1).

[00118] Figure 1: Percent change in PSA at 12 weeks by dose group and prior adrenal therapy

TREATMENT fxV] 300 rag BID (M=23 ) J 400 mg BID + Prednisone (11=24 )

L, SOO mg BID + Prednisone (N=26 ) LVNI 600 mg QDBM (11=24)

X = Prior Adrenal-directed Tneropy

[00119] Testosterone and DUEA-S responses are shown in Table 4. Responses were seen as early as Cycle 1, Day 15.

[00120] Table 4: Effect of orteronel on Testosterone and DHEA-S Levels

[00121] Table 5 depicts that partial responses (PR) were seen in 6 (12%) of the 49 evaluable patients; 25 patients (51%) achieved a best response of stable disease. Mean circulating tumor cell (CTC) numbers decreased in all groups.

[00122] Table 5: Best unconfirmed response by RECIST:

[00123] PSA, hormone and tumor responses were seen in patients not receiving prednisone. In the 300 mg BID group, PSA and hormone responses were seen, and a PR was achieved in 3 patients. In the 600 mg QD group, PSA and hormone responses were seen and a best tumor response was seen in 3 patients.

[00124] It will be appreciated that in patients with androgen-independent metastatic CRPC oral orteronel at doses of orteronel >3 00 mg BID was well tolerated when administered with or without prednisone. Fatigue and nausea were the most common AEs. Orteronel appears active, with similar efficacy when given with or without prednisone. PSA decreases of > 50% were seen in 53% of all patients and 62% of patients who had not received prior adrenal therapy. Objective responses were seen in 12% of patients. Reductions in testosterone and DHEA-S levels suggest selective 17,20-lyase inhibition in patients with metastatic CRPC.

[00125] Evaluation of Circulating Tumor Cells (CTCs) in Chemotherapy-naive Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) receiving orteronel:

[00126] Background: CTC enumeration provides prognostic information in patients with metastatic prostate cancer. In particular, the categorical shift from >5 to <5 cells per 7.5 mL of whole blood may represent a better predictor of overall survival than changes in prostate-specific antigen (PSA) levels. As described above, in a phase 1/2 study in chemotherapy-naive patients with mCRPC (orteronel_201, NCT00569153), the investigational 17,20-lyase inhibitor orteronel, which is 6-[(7S)-7-hydroxy-6,7- dihydro-5H-pyrrolo[l,2-c]imidazol-7-yl]-N-methyl-2-naphthalenecarboxamide, was well tolerated (the most common AE was fatigue) and resulted in profound reductions in circulating concentrations of testosterone and the adrenal androgen DHEA-S. PSA response rate (>50% decrease) at 12 weeks was observed in 52% of patients receiving orteronel at 400 mg BID plus prednisone. Another objective of the trial is the assessment of correlations between CTC levels and response to orteronel (PSA changes and clinical responses) as well as assessment of correlations between the presence or absence of potential candidate biomarkers (TMPRSS2:ERG fusion gene product, androgen receptor (AR) mutations, PTEN deletions) as detected by fluorescence in situ hybridization (FISH) and response to orteronel and CTC levels.

[00127] Blood samples for assessment of CTCs were collected at baseline, on day 1 of cycles 2 and 4, and every three cycles thereafter.

[00128] Samples were collected in a heparinized collection tube and shipped within 8 hours to a central laboratory. CTCs were enumerated using validated Veridex CellSearch^® methodology.⁸

[00129] CTC analyses were performed both in the safety population and in the population without prior adrenal directed therapy (aminoglutethimidine, abiraterone, ketoconazole). CTC levels were assessed as both a dichotomous (<5 versus >5 per 7.5 mL of blood) and a continuous variables. A CTC level of <5 is considered to be a predictor of favorable outcomes, and a level of >5 a predictor of unfavorable outcomes. All nominal associations identified between CTC levels and response were also tested after controlling for age and prior therapy

[00130] At baseline, mean overall CTC count was 16.6 (SD: 33.2; Table 3) among 88 evaluable patients. By 12 weeks, mean overall CTC counts had fallen to 3.9 (SD: 11.2). Overall mean change in CTCs (baseline to week 12) was -8.9.

[00131] Table 6: Summary of CTC values and change from baseline orteronel alone

(steroid-free) Orteronel + prednisone

400 mg 600 mg

300 mg 600 mg BK) + BID +

BID QD prednisone prednisone Overall

CTC/7.5ml blood (n=23) (n=24) (n=24) (n=26) (N=97)

Sample collection 20 22 23 23 88

at baseline,

patients (n)

Mean CTCs at 19.0 23.2 18.6 6.4 (14.5) 16.6

baseline (SD) (43.9) (38.4) (30.2) (33.2)

Mean CTCs at 12- 6.7 3.8 (7.4) 2.5 (7.9) 2.3 (6.3) 3.9

weeks (SD) (18.0) (11.2)

Mean CTCs at 40.1 51.8 63.8 21.8 45.5

end of study visit (86.5) (104.9) (114.3) (41.3) (90.0)

(SD)

Mean change in -13.6 -15.5 -2.5 -2.9 -8.9

CTCs from (32.83) (30.98) (12.20) (7.63) (24.34) baseline at 12

weeks (SD)

Median change in -1.0 (- -1.0 (- -3.0 (-27, 0 (-20, 5) -1.0 (- CTCs from 125, 0) 102, 10) 30) 124, 30) baseline at 12

weeks (range)

[00132] Overall, 48 of 61 patients (79%) with evaluable CTC counts at both baseline and 12 weeks either converted to a favorable CTC count or retained a CTC count of <5 at 12 weeks.

[00133] Overall, 34 of 42 patients (81%) with evaluable CTC counts at both baseline and 24 weeks either converted to a favorable CTC count or retained a CTC count of <5 at 24 weeks.

[00134] In patients with a CTC count of >5 at baseline, 14 (38%) converted to a CTC count of <5 at

12 weeks (Table 7). [00135] In patients with a CTC count of <5 at baseline, 34 (67%) retained a CTC count of <5 at 12 weeks (Table 7).

[00136] Time to disease progression (TTP) for patients with favorable and unfavorable CTCs at baseline is shown in Figure 2.

[00137] Table 7: Shifts in CTC Count from Baseline to 12 and 24 weekd (cells per 7.5 mL of blood)

[00138] Figure 3: TPP in Patients with Favorable and Unfovorable CTCs at Baseline: 100

| Favorable CTC at baseline

EH Unfavorable CTC at baseline

p=0.001

100 200 300 ₄00 500 600 700

Time (days)

[00139] Correlation of baseline CTCs with PSA50 response)

100140] In patients with baseline CTCs <5/7.5 mL, PSA response rate was 62% (24 of 39 patients) versus 52% (12 of 23 patients) in those with baseline CTCs >5/7.5 mL (Table 5).

[00141] There were no significant correlations between CTC count and PSA response in the overall population.

[00142] hi patients with no prior adrenal-directed therapy, among those with baseline CTCs <5/7.5 mL, PSA response rate was 68% (21 of 31 patients) versus 53% ( 10 of 19 patients) in those with baseline CTCs >5/7.5 mL (Table 8); the correlation was not significant.

[00143] Correlation of CTCs with clinical response by RECIST

[00144] In patients with baseline CTCs <5/7.5 mL, clinical response rate by RECIST at week 12 was 25% (6 of 24 RECIST evaluable patients) versus 22% (4 of 18 patients) in those with baseline CTCs >5/7.5 mL (Table 8).

[00145] Table 8: Correlations between baseline CTCs and response at 12 and 24 weeks

iBaseline CTCs! Baseline CTCs P-value

<5/7.5 mL ≥5 7.5 mL (correlation)

PSA50 response at 12 weeks

[00146] Candidate biomarkers by FISH were assessed as follows:

[00147] TMPRSS2:ERG translocations were detected in 13 of 48 patients (27.1%) PTEN deletions were detected in 4 of 50 patients (8.0%). AR amplifications were detected in 8 of 49 patients (16.3%).

[00148] In terms of PSA response:

[00149] PTEN deletion was associated with 12-week PSA50 response (p=0.04, n=31 )

[00150] TMPRSS2 :ERG was not statistically significantly associated with 12-week PSA50 response

(p= .14, n=31) [00151] No correlation with AR amplification (n=32).

[00152] The presence or absence of candidate biomarkers was not significantly correlated with response by RECIST in the overall population:

[00153] TMPRSS2:ERG (n=22): p=0.71

[00154] PTEN (n=23): p=0.42

[00155] AR (n=23): p=0.46

[00156] Similar results were observed when controlled for background covariates and in patients without prior adrenal-directed therapy.

[00157] The results are consistent with recent data by Danila et al. (1. Danila DC, et al, Eur Urol 60 (2011) 897-904) which indicated that TMPRSS2:ERG status was not significantly predictive of PSA decline or of other clinical outcomes.

[00158] The presence of TMPRSS2:ERG was significantly correlated with the absolute change in CTC count from baseline to 24 weeks (n=19, p=0.03, corr=-0.50); however, no other significant correlations were seen between these candidate biomarkers and CTC counts at any timepoint, either dichotomized or as a quantitative variable.

[00159] Conclusions:

[00160] In patients with metastatic CRPC, oral orteronel at doses of >300 mg BID was well tolerated when administered with or without prednisone.

[00161] Orteronel appears active, with similar efficacy when given with or without prednisone.

[00162] PSA50 responses at 12 weeks occurred in 53% of all patients and in 63% of those who had not received prior ketoconazole or adrenal-directed therapy.

[00163] Objective clinical responses by RECIST were observed.

[00164] Reductions in testosterone and DHEA-S levels,9 the PSA50 responses, and the overall safety profile observed when orteronel was dosed at 600 mg BID without prednisone are suggestive of higher selectivity for 17,20-lyase inhibition and the potential for steroid-free dosing in patients with metastatic CRPC.

[00165] At 12 weeks 79% of patients had a favorable CTC count (<5); this included, 38% of patients who had an unfavorable CTC counts (>5) at baseline had converted to a favorable CTC count.

[00166] TTP was significantly longer in patients with a favorable CTC count at baseline compared with patients with an unfavorable CTC count (pO.001).

[00167] Deletion of PTEN was associated with 12-week PSA50 response; however, candidate biomarkers by FISH were not associated with clinical response by RECIST. [00168] Example 2: Phase 2 Study of orteronel in Patients with Nonmetastatic Castration- resistant Prostate Cancer and a Rising Prostate-Specific Antigen

[00169] Androgen signaling continues to be important in CRPC. Orteronel is an investigational, oral, non-steroidal, selective 17,20-lyase inhibitor that suppresses androgen production and is in development for CRPC. Orteronel has limited inhibition of 17a-hydroxylase, and thus, is postulated to have less effect on Cortisol synthesis. Orteronel 300mg BID in men with nonmetastatic CRPC and rising PSA was evaluated (NCT01046916).

[00170] Specifically, an open label phase II study was carried out to evaluate the safety and efficacy of orteronel in patients with castration-resistant prostate cancer (CRPC) without radiographic evidence of metastases who have a rising prostate-specific antigen (PSA).

[00171] [Materials & Methods] Eligible men had baseline PSA >2ng mL + doubling time <8 mo or PSA >8ng/mL + doubling time >8 mo, and surgical or ongoing medical castration, with testosterone <50ng/dL. Prior chemotherapy, aminoglutethimide or ketoconazole, or concomitant corticosteroids were excluded. Starting dose was 300mg BID given continuously in 28-d cycles, increasing to 400mg BID in men not achieving a >50% decrease in PSA (PSA50) at 3 mo, Orteronel was continued until PSA progression or metastases. The primary endpoint is the percentage of men with PSA <0.2ng mL after 3 mo. Secondary endpoints include safety, 3 and 6 mo PSA30, PSA50, PSA90 rates, progression-free survival, time to PSA progression, time to metastases, changes in endocrine markers and circulating tumor cell (CTCs).

[00172] Subjects were orally administered 300 mg of orteronel twice daily on a continuous schedule, without concomitant prednisone. Patients were treated until PSA progression of disease or radiographic progression of disease. After PSA progression, patients were followed every 3 months until (A) development of metastases or (B) the scheduled conclusion of the study.

[00173] Patients not achieiving a 50% PSA response after 3 months may receive 400 mg orteronel BID.

[00174] The following assessments were performed:

1. Effect of orteronel to reduce PSA levels to less than or equal to 0.2 ng/ml following 3 months of treatment in patients. PSA levels were measured for each patient, and the percentage of patients who achieve a PSA less than or equal to to 0.2 ng/ml was determined at 3 months (at "Cycle 4 Day 1") of treatment.

2. PSA response rate (PSA-90, -50, and -30, defined as a PSA decline of at least 90%, 50%, and 30%, respectively, from baseline) at 3 months and 6 months (at "Cycle 7 Day 1") of treatment was determined. 3. Percentage of patients who achieve a PSA of less than or equal to 0.2 ng ml following 6 months of orteronel treatment was determined.

4. Time to PSA progression, time to metastases, and duration of progression-free survival.

5. Monitor levels of endocrine markers (serum testosterone, DHEA-S, LH, ACTH,

corticosterone, and Cortisol concentrations).

[00175] PSA Response Rate was computed as follows:

1. Denominator: PSA-evaluable population. Patients who had 1 baseline and 1 post-baseline PSA measurement.

2. Numerator:

i. 3-month: Patients are responders if patients have a PSA assessment at 3 months (cycle 4 day 1, between day 77- 1) and meet the response criteria. Otherwise patients are considered as non-responders.

ii. 6-month: Patients are responders if patients have a PSA assessment at 6 months (cycle 7 day 1, between day 161-175) and meet the response criteria. Otherwise patients are considered as non-responders.

[00176] Results:

[00177] Interim data from the study shows a PSA decrease and shows good tolerability. No new lesion or no bone lesion was found in all patients. Figure 2 below shows the waterfall plot for PSA percent change from baseline to 3-months from start of trial.

Patients with 3-month (cycle 4 day 1 ) PSA assessments (n=16)

Patient ID [00178] 38 men with a median age 71 y (range 55-81), ECOG PS 0, 1 (84%, 16%), median PSA 12.5ng mL (2.6-67.8), testosterone 0.267nmol/L (0.05-0.60), and ACTH 19.5ng L (n=32; 0-47) were treated. Median number of cycles was 5.5 (1-13); 1 patient had dose reduction due to adverse events (AEs), 1 had dose increase to 400mg BID. 99% of the expected dose was taken. Gr >3 AEs occurred in 16 men (drug-related in 13); most common (>5%) were dyspnea (11%), hypertension (8%), fatigue, hypokalemia, pneumonitis (n=2 ea). 7 men (18%) had serious AEs; most common was pneumonitis (2=Gr3, l=Gr2). 8 men discontinued ortl due to AEs (dyspnea, pneumonitis, adrenal insufficiency, fatigue, hypertension, diarrhea, dysgeusia). 5 men achieved PSA <0.2ng/mL (4 at 3 mo and 1 at 6 mo ). At 3 mo, PSA50 and PSA90 rates were 69% and 34%, respectively. At 3 mo, median PSA decline was 83% to 1.96ng mL (0.12-50.5), and remained at -84% until last assessment; median testosterone declined by 89% to 0.026nmol/L (0.0-0.28), and median ACTH increased by 228% to 55ng L (12-351). Similar results were seen at 6 mo, with changes of -87% to 2,05ng/mL (0.10-12.3), -86% to

0.033nmoI L (0.01-0.41), and +311% to 83.5ng/L (21-173), respectively. 6-mo PSA50 and PSA90 rates were 42% and 17%, respectively. 14 (37%) men were on treatment >6 mo. Of 35 men with baseline CTC/7.5mL values, 7 had CTC >0; 1 had CTC >5. At 3 mo, 1 of 1 patients converted to CTC <5; no patient converted to >5.

[00179] [Conclusion] The current results in these men with nonmetastatic CRPC indicate that orteronel given without steroids has acceptable tolerance and substantial activity as reflected by decreased testosterone and PSA.

Claims

WHAT IS CLAIMED IS:

1. A method of treating cancer comprising administering a therapeutically effective amount of a 17- alpha hydroxylase/C17, 20-lyase inhibitor without the concomitant or sequential administration of a steroid.

2. The method of claim 1, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor is a selective inhibitor of CI 7, 20-lyase over 17-alpha hydroxylase.

3. The method of claim 2, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor is from about 3 to about 8 times as selective for CI 7, 20-lyase over 17-alpha hydroxylase.

4. The method of claim 2, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor is from about 4 to about 7 times as selective for CI 7, 20-lyase over 17-alpha hydroxylase.

5. The method of claim 2, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor is from about 5 times as selective for CI 7, 20-lyase over 17-alpha hydroxylase.

6. The method of claim 1, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor is a selective inhibitor of CI 7, 20-lyase over 17-alpha hydroxylase and other human CYP family enzymes.

7. The method of claim 6, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor has an IC₅₀ value for human CYP family enzymes other than CI 7, 20-lyase of greater than 10 μΜ.

8. The method of claim 6, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor has an IC₅₀ value for human CYP family enzymes other than CI 7, 20-lyase of greater than 20 μΜ.

9. The method of claim 6, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor has an IC₅₀ value for human CYP family enzymes other than CI 7, 20-lyase of greater than 30 μΜ.

10. The method of any one of claims 1-9, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor is 6-[(7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-7-yl]-N-methyl-2- naphthalenecarboxamide, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

11. The method of claim 1 or 10, wherein the therapeutically effective amount is from about 300 to about 600 mg twice daily.

12. The method of claim 1 or 10, wherein the therapeutically effective amount is from about 200 to about 600 mg twice daily.

13. The method of claim 1 or 10, wherein the therapeutically effective amount is about 200 mg twice daily.

14. The method of claim 1 or 10, wherein the therapeutically effective amount is about 400 mg twice daily.

15. The method of claim 1 or 10, wherein the therapeutically effective amount is about 300 mg twice daily.

16. The method of claim 1 or 10, wherein the therapeutically effective amount is from about 300 to about 600 mg once daily.

17. The method of claim 1 or 10, wherein the therapeutically effective amount is about 600 once daily.

18. The method of claim 17, wherein the therapeutically effective amount is about 600 mg once daily taken in the morning.

19. The method of any one of claims 11-18, wherein the therapeutically effective amount is taken with a meal.

20. The method of claim 1 or 10, wherein the therapeutically effective amount of a 17-alpha

hydroxylase/C17, 20-lyase inhibitor is administered without the concomitant or sequential administration dexamethasone, prednisone, prednisolone, betamethasone, or trimacinolone

21. The method of claim 20, wherein the therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered without the concomitant or sequential administration of prednisone.

22. A method of treating cancer comprising administering a therapeutically effective amount of a 17- alpha hydroxylase/C17,20-lyase inhibitor without the concomitant or sequential administration of a steroid, wherein the administering of a therapeutically effective amount of a 17-alpha hydroxylase/C17,20-lyase inhibitor without the concomitant or sequential administration of a steroid results in an improved clinical outcome for the patient as measured by enhanced progression-free survival as compared to standard therapy.

23. The methof of claim 22, wherein the progression-free survival or time to metastasis is enhanced by 9 at least months.

24. The methof of claim 22, wherein the progression-free survival or time to metastasis is enhanced by 12 at least months.

25. The methof of claim 22, wherein the progression-free survival or time to metastasis is enhanced by at least 15months.

26. The method of claim 22, wherein the 17-alpha hydroxylase/C17,20-lyase inhibitor is 6-[(7S)-7- hydroxy-6,7-dihydro-5H-pyrrolo[l,2-c]irnidazol-7-yl]-N-methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

27. The method of claim 22, wherein the cancer is a hormonally-driven cancer.

28. The method of claim 22, wherein the cancer is prostate cancer, breast cancer or ovarian cancer.

29. The method of claim 22, wherein the cancer is prostate cancer.

30. The method of claim 29, wherein the prostate cancer is castration resistant prostate cancer.

31. The method of claim 29, wherein the prostate cancer is metastatic castration resistant prostate cancer.

32. The method of claim 29, wherein the prostate cancer is non-metastatic castration resistant prostate cancer.

33. The method of claim 22, wherein the improved clinical outcome is further measured by a

favorable safety risk/benefit ratio, whereby the risk associated with the administering of a 17- alpha hydroxylase/C17,20-lyase inhibitor without the concomitant or sequential administration of a steroid is outweighed by the benefit associated with avoiding prolonged steroid use.

34. The method of claim 33, wherein the risks associated with the administering of a 17-alpha

hydroxylase/C17,20-lyase inhibitor without the concomitant or sequential administration of a steroid is measured by monitoring the patient for evidence of mineralocorticoid excess.

35. The method of claim 34, wherein the patient is monitored for one or more of

ACTH/corticosterone profile, hypertension, hypokalemia, edema, or cardiovascular symptoms.

36. The method of claim 22, wherein the therapeutically effective amount is from about 300 to about 600 mg twice daily.

37. The method of claim 22, wherein the therapeutically effective amount is from about 200 to about 600 mg twice daily.

38. The method of claim 22, wherein the therapeutically effective amount is about 200 mg twice daily.

39. The method of claim 22, wherein the therapeutically effective amount is about 400 mg twice daily.

40. The method of claim 22, wherein the therapeutically effective amount is about 300 mg twice daily.

41. The method of claim 22, wherein the therapeutically effective amount is from about 300 to about 600 mg once daily.

42. The method of claim 22, wherein the therapeutically effective amount is about 600 once daily.

43. The method of claim 22, wherein the therapeutically effective amount is about 600 mg once daily taken in the morning.

44. The method of any one of claims 36-43, wherein the therapeutically effective amount is taken with a meal.

45. The method of claim 22, wherein the therapeutically effective amount of a 17-alpha

hydroxylase/C17, 20-lyase inhibitor is administered without the concomitant or sequential administration dexamethasone, prednisone, prednisolone, betamethasone, or trimacinolone.

46. The method of claim 45, wherein the therapeutically effective amount of a 17-alpha

hydroxylase/C17, 20-lyase inhibitor is administered without the concomitant or sequential administration of prednisone.

47. A method of treating cancer comprising administering a therapeutically effective amount of a 17- alpha hydroxylase/C17,20~lyase inhibitor which is 6-[(7S)-7-hydroxy-6,7-dihydro-5H- pyrrolo[l,2-c]imidazol-7-yl]-N-methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof without the concomitant or sequential administration of a steroid, wherein the administering of the therapeutically effective amount of the 17-alpha hydroxyIase/C17,20-lyase inhibitor without the concomitant or sequential administration of a steroid results in an improved clinical outcome for the patient as measured by enhanced progression-free survival as compared to standard therapy.

48. The methof of claim 47, wherein the progression-free survival or time to metastasis is enhanced by at least 9 months.

49. The methof of claim 47, wherein the progression-free survival or time to metastasis is enhanced by at least 12 months.

50. The methof of claim 47, wherein the progression-free survival or time to metastasis is enhanced by at least 15 months.

51. The method of claim 47, wherein the cancer is a hormonally-driven cancer.

52. The method of claim 47, wherein the cancer is prostate cancer, breast cancer or ovarian cancer.

53. The method of claim 47, wherein the cancer is prostate cancer.

54. The method of claim 53, wherein the prostate cancer is castration resistant prostate cancer.

55. The method of claim 53, wherein the prostate cancer is metastatic castration resistant prostate cancer.

56. The method of claim 53, wherein the prostate cancer is non-metastatic castration resistant prostate cancer.

57. The method of claim 47, wherein the improved clinical outcome is further measured by a

favorable safety risMtenefit ratio, whereby the risk associated with the administering of a 17- alpha hydroxylase/C17,20-lyase inhibitor without the concomitant or sequential administration of a steroid is outweighed by the benefit associated with avoiding prolonged steroid use.

58. The method of claim 57, wherein the risks associated with the administering of a 17-alpha

59. The method of claim 58, wherein the patient is monitored for one or more of

60. The method of claim 47, wherein the therapeutically effective amount is from about 300 to about 600 mg twice daily.

61. The method of claim 47, wherein the therapeutically effective amount is from about 200 to about 600 mg twice daily.

62. The method of claim 47, wherein the therapeutically effective amount is about 200 mg twice daily.

63. The method of claim 47, wherein the therapeutically effective amount is about 400 mg twice daily.

64. The method of claim 47, wherein the therapeutically effective amount is about 300 mg twice daily.

65. The method of claim 47, wherein the therapeutically effective amount is from about 300 to about 600 mg once daily.

66. The method of claim 47, wherein the therapeutically effective amount is about 600 mg once daily.

67. The method of claim 47, wherein the therapeutically effective amount is about 600 mg once daily taken in the morning.

68. The method of any one of claims 60-67, wherein the therapeutically effective amount is taken with a meal.

The method of claim 47, wherein the therapeutically effective amount of a 17-alpha

The method of claim 69, wherein the therapeutically effective amount of a 17-alpha

71. The method of claim 1, 22, or 47, further comprising:

(a) measuring the patient levels of one or more of blood pressure or serum levels of one or more of corticosterone, Cortisol or potassium prior to the administration of a first dose level of a therapeutically effective amount of a 17-alpha hydroxylase/C 17, 20-lyase inhibitor;

(b) measuring the patient levels of one or more of blood pressure, or serum levels of one or more of corticosterone, Cortisol or potassium after the administration of a first dose level of a therapeutically effective amount of a 17-alpha hydroxylase/C 17, 20-lyase inhibitor; and (c) administering to a patient a second dose level of a therapeutically effective amount of the 17- alpha hydroxylase/C17, 20-lyase inhibitor, wherein the second dose level is greater than, equal to, or less than the first dose level.

72. The method of claim 71, further comprising repeating steps (a)-(c) until a desired dose level of a therapeutically effective amount of the 17-alpha hydroxylase/C17, 20-lyase inhibitor is achieved.

73. The method of claim 71, wherein the blood pressure measurement after the administration of the first dose level is greater than the blood pressure measurement prior to administration of the first dose level; and

74. The method of claim 73, wherein the corticosterone level after administration of the first dose level is higher than the corticosterone level prior to the administration of the first dose level.

75. The method of claim 73, wherein the Cortisol level after the administration of the first dose level is lower than the Cortisol level prior to the administration of the first dose level.

76. The method of claim 73, wherein the potassium level after the administration of the first dose level is lower than the potassium level prior to the administration of the first dose level.

77. The method of claim 1, wherein the cancer is a hormonally-driven cancer.

78. The method of claim 1, wherein the cancer is prostate cancer, breast cancer or ovarian cancer.

79. The method of claim 1, wherein the cancer is prostate cancer.

80. The method of claim 79, wherein the prostate cancer is castration resistant prostate cancer.

81. The method of claim 79, wherein the prostate cancer is metastatic castration resistant prostate cancer.

82. The method of claim 79, wherein the prostate cancer is non-metastatic castration resistant prostate cancer.

83. The method of claim 71, wherein the first dose level is about 400 mg twice daily.

84. The method of claim 71, wherein the second dose level is about 300 mg twice daily.

85. The method of claim 71, wherein the second dose level is about 200 mg twice daily.

86. The method of claim 1, 22, or 47, further comprising administering to the patient one or more additional treatments concurrently with or sequentially with the 17-alpha hydroxylase/C17, 20-lyase inhibitor, wherein the one or more additional treatments comprises:

a. radiation,

b. chemotherapy,

c. immunotherapy,

d. a non-steroidal hormone ablation therapy, or

e. a non-steroidal therapy for the management of side effects of therapy.

87. The method of claim 86, wherein the one or more additional treaments are selected from sipuleucel-T, paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, 5-fluorouracil,

cyclophosphamide, doxorubicin, cytarabine, cabazitaxel, tamoxifen, fulvestrant, cisplatin, exemestane, anastrozole, letrozole, trastuzumab, lapatinib, radioisotopes, hormone ablation agent, hormone deprivation treatment, antiandrogen, ketoconazole, aromatase inhibitor, bicalutamide, eplerenone, spironolactone, or triampterine.

88. The method of claim 86, wherein the one or more additional treatments is an androgen receptor inhibitor.

89. The method of claim 88, wherein the androgen receptor inhibitor is (4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5 , 5 -dimethyl-4-oxo-2-thioxoimidazolidin- 1 -yl)-2-fluoro-N-methylbenzamide) or (4-(7-(6-cyano-5-(trifluoromethyl)^

N-methylbenzamide).

90. A method of treating cancer in a patient comprising:

(d) administering to a patient a second dose level of a therapeutically effective amount of the 17- alpha hydroxylase/C17, 20-lyase inhibitor, wherein the second dose level is greater than, equal to, or less than the first dose level.

91. The method of claim 90, wherein the second dose level in step (d) is less than the first dose level.

92. The method of claim 90, further comprising repeating steps (a)-(d) until a desired dose level of a therapeutically effective amount of the 17-alpha hydroxylase/C17, 20-lyase inhibitor is achieved.

93. The method of claim 90, wherein the blood pressure measurement after the administration of the first dose level is greater than the blood pressure measurement prior to administration of the first dose level; and

94. The method of claim 93, wherein the corticosterone level after administration of the first dose level is higher than the corticosterone level prior to the administration of the first dose level.

95. The method of claim 93, wherein the Cortisol level after the administration of the first dose level is lower than the Cortisol level prior to the administration of the first dose level.

96. The method of claim 93, wherein the potassium level after the administration of the first dose level is lower than the potassium level prior to the administration of the first dose level.

97. The method of claim 90, wherein the cancer is a hormonally-driven cancer.

98. The method of claim 90, wherein the cancer is prostate cancer, breast cancer or ovarian cancer.

99. The method of claim 90, wherein the cancer is prostate cancer.

100. The method of claim 99, wherein the prostate cancer is castration resistant prostate cancer.

101. The method of claim 99, wherein the prostate cancer is metastatic castration resistant prostate cancer.

102. The method of claim 99, wherein the prostate cancer is non-metastatic castration resistant prostate cancer.

103. The method of claim 90, wherein the first dose level is from about 300 to about 600 mg twice daily.

104. The method of claim 90, wherein the first dose level is from about 200 to about 600 mg twice daily.

105. The method of claim 90, wherein the first dose level is about 400 mg twice daily.

106. The method of claim 90, wherein the first dose level is about 300 mg twice daily.

107. The method of claim 90, wherein the first dose level is about 200 mg twice daily.

108. The method of claim 90, wherein the first dose level is from about 300 to about 600 mg once daily.

109, The method of claim 90, wherein the first dose level is from about 200 to about 600 mg once daily.

110. The method of claim 90, wherein the first dose level is about 600 mg once daily.

111. The method of claim 90, wherein the first dose level is about 600 mg once daily taken in the morning.

112. The method of any one of claims 103-111, wherein the first dose level is taken with a meal.

113. The method of claim 90, wherein the first dose level is about 400 mg twice daily.

114. The method of claim 90, wherein the second dose level is about 300 mg twice daily.

115. The method of claim 90, wherein the second dose level is about 200 mg twice daily.

116. The method of claim 90, further comprising administering to the patient one or more additional treatments concurrently with or sequentially with the 17-alpha hydroxylase/C17, 20-lyase inhibitor, wherein the one or more additional treatments comprises:

a. radiation,

b. chemotherapy,

c. immunotherapy,

d. a non-steroidal hormone ablation therapy, or

e. a non-steroidal therapy for the management of side effects of therapy.

117. The method of claim 116, wherein the one or more additional treaments are selected from sipuleucel-T, paclitaxeL docetaxel, mitoxantrone, estramustine, satraplatin, 5-fluorouracil,

118. The method of claim 117, wherein the one or more additional treatments is an androgen receiptor inhibitor.

119. The method of claim 118, wherein the androgen receptor inhibitor is (4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5 , 5-dimethyl-4-oxo-2-thioxoimidazolidin- 1 -yl)-2-fluoro-N-methylbenzamide) or (4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-mioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro- N-methylbenzamide).

120. The method of claim 1, 22 or 47, wherein the patient previously received one or more treatments with abiraterone acetate.

121. A pharmaceutical composition comprising a therapeutically effective amount of a 17-alpha hydroxylase/C17,20-lyase inhibitor as an active ingredient, for the treatment of cancer without the concomitant or sequential administration of a steroid.

122. The pharmaceutical composition of claim 121, wherein the pharmaceutical composition results in an improved clinical outcome for a patient as measured by enhanced progression-free survival as compared to standard therapy.

123. The pharmaceutical composition of claim 121, wherein the progression-free survival or time to metastasis is enhanced by at least 9 months.

124. The pharmaceutical composition of claim 121, wherein the progression-free survival or time to metastasis is enhanced by at least 12 months.

125. The pharmaceutical composition of claim 121, wherein the progression-free survival or time to metastasis is enhanced by at least 15 months.

126. The pharmaceutical composition of claim 121, wherein the 17-alpha hydroxylase/C 17,20-lyase inhibitor is 6-[(7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[ 1 ,2-c]imidazol-7-yI]-N-methyl-2- naphthalenecarboxamide, or a pharmaceutically acceptable salt thereof.

127. The pharmaceutical composition of claim 121, wherein the cancer is a hormonally-driven cancer.

128. The pharmaceutical composition of claim 121, wherein the cancer is prostate cancer, breast cancer or ovarian cancer.

129. The pharmaceutical composition of claim 121 , wherein the cancer is prostate cancer.

130. The pharmaceutical composition of claim 129, wherein the prostate cancer is castration resistant prostate cancer.

131. The pharmaceutical composition of claim 129, wherein the prostate cancer is metastatic castration resistant prostate cancer.

132. The pharmaceutical composition of claim 129, wherein the prostate cancer is non-metastatic castration resistant prostate cancer.

133. The pharmaceutical composition of claim 121, wherein the improved clinical outcome is further measured by a favorable safety risk/benefit ratio, whereby the risk associated with the treating of cancer without the concomitant or sequential administration of a steroid is outweighed by the benefits associated with avoiding prolonged steroid use.

134. The pharmaceutical composition of claim 133, wherein the risks associated with the treating of cancer without the concomitant or sequential administration of a steroid is measured by monitoring a patient for evidence of mineralocorticoid excess.

135. The pharmaceutical composition of claim 134, wherein the patient is monitored for one or more of ACTH/corticosterone profile, hypertension, hypokalemia, edema, or cardiovascular symptoms.

136. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is from about 300 to about 600 mg twice daily.

137. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is from about 200 to about 600 mg twice daily.

138. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is about 200 mg twice daily.

13 . The pharmaceutical composition of claiml21, wherein the therapeutically effective amount is about 400 mg twice daily.

140. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is about 300 mg twice daily.

141. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is from about 300 to about 600 mg once daily.

142. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is about 600 once daily.

143. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is about 600 mg once daily taken in the morning.

144. The pharmaceutical composition of any one of claims 136-143, wherein the therapeutically effective amount is for use with a meal.

145. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor is for the treating of cancer without the concomitant or sequential administration of dexamethasone, prednisone, prednisolone, betamethasone, or trimacinolone.

146. The pharmaceutical composition of claim 145, wherein the therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor is is for the treating of cancer without the concomitant or sequential administration of prednisone.

147. A use of a therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor in the manufacture of a medicament in treatment of cancer without the concomitant or sequential administration of a steroid.

148. The use of claim 147, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor is a selective inhibitor of CI 7, 20-lyase over 17-alpha hydroxylase.

149. The use of claim 148, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor is from about 3 to about 8 times as selective for CI 7, 20-lyase over 17-alpha hydroxylase.

150. The use of claim 148, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor is from about 4 to about 7 times as selective for CI 7, 20-lyase over 1 -alpha hydroxylase.

151. The use of claim 148, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor is from about 5 times as selective for CI 7, 20-lyase over 17-alpha hydroxylase.

152. The use of claim 147, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor is a selective inhibitor of C17, 20-lyase over 17-alpha hydroxylase and other human CYP family enzymes.

1 3. The use of claim 152, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor has an IC₅₀ value for human CYP family enzymes other than CI 7, 20-lyase of greater than 10 μΜ.

154. The use of claim 152, wherein the 17-alpha hydroxylase/C 17, 20-lyase inhibitor has an IC₅₀ value for human CYP family enzymes other than CI 7, 20-lyase of greater than 20 μΜ.

155. The use of claim 152, wherein the 17-alpha hydroxylase/C 17, 20-lyase inhibitor has an IC₅₀ value for human CYP family enzymes other than CI 7, 20-lyase of greater than 30 μΜ.

156. The use of any one of claims 147-155, wherein the 17-alpha hydroxylase/C 17, 20-lyase inhibitor is 6-[(7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[l_^

or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

157. The use of claim 147 or 156, wherein the therapeutically effective amount is from about 300 to about 600 mg twice daily.

158. The use of claim 147 or 156, wherein the therapeutically effective amount is from about 200 to about 600 mg twice daily.

159. The use of claim 147 or 156, wherein the therapeutically effective amount is about 200 mg twice daily.

160. The use of claim 147 or 156, wherein the therapeutically effective amount is about 400 mg twice daily.

161. The use of claim 147 or 156, wherein the therapeutically effective amount is about 300 mg twice daily.

162. The use of claim 147 or 156, wherein the therapeutically effective amount is from about 300 to about 600 mg once daily.

163. The use of claim 147 or 156, wherein the therapeutically effective amount is about 600 once daily.

164. The use of claim 163, wherein the therapeutically effective amount is about 600 mg once daily taken in the morning.

165. The use of any one of claims 157-163, wherein the therapeutically effective amount is taken with a meal.

166. The use of claim 147 or 156, wherein the therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered without the concomitant or sequential administration dexamethasone, prednisone, prednisolone, betamethasone, or trimacinolone

167. The use of claim 166, wherein the therapeutically effective amount of a 17-alpha

168. A use of a therapeutically effective amount of a 17-alpha hydroxylase/C17,20-lyase inhibitor in the manufacture of a medicament in treatment of cancer without the concomitant or sequential administration of a steroid, wherein the administering of a therapeutically effective amount of a 17-alpha hydroxylase/C17,20-lyase inhibitor without the concomitant or sequential administration of a steroid results in an improved clinical outcome for the patient as measured by enhanced progression-free survival as compared to standard therapy.

169. The use of claim 168, wherein the progression-free survival or time to metastasis is enhanced by at least 9 months.

170. The use of claim 168, wherein the progression-free survival or time to metastasis is enhanced by at least 12 months.

171. The use of claim 168, wherein the progression-free survival or time to metastasis is enhanced by at least 15 months.

172. The use of claim 168, wherein the 17-alpha hydroxylase/C17, 20-lyase inhibitor is 6-[(7S)-7- hydroxy-6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-7-yl]-N-methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

173. The use of claim 168, wherein the cancer is a hormonally-driven cancer.

174. The use of claim 168, wherein the cancer is prostate cancer, breast cancer or ovarian cancer.

175. The use of claim 168, wherein the cancer is prostate cancer.

176. The use of claim 175, wherein the prostate cancer is castration resistant prostate cancer.

177. The use of claim 175, wherein the prostate cancer is metastatic castration resistant prostate cancer.

178. The use of claim 175, wherein the prostate cancer is non-metastatic castration resistant prostate cancer.

179. The use of claim 168, wherein the improved clinical outcome is further measured by a favorable safety risk/benefit ratio, whereby the risk associated with the administering of a 17-alpha

hydroxylase/C17, 20-lyase inhibitor without the concomitant or sequential administration of a steroid is outweighed by the benefit associated with avoiding prolonged steroid use.

180. The use of claim 179, wherein the risks associated with the administering of a 17-alpha hydroxylase/C17, 20-lyase inhibitor without the concomitant or sequential administration of a steroid is measured by monitoring the patient for evidence of mineralocorticoid excess.

181. The use of claim 180, wherein the patient is monitored for one or more of ACTH/corticosterone profile, hypertension, hypokalemia, edema, or cardiovascular symptoms.

182. The use of claim 168, wherein the therapeutically effective amount is from about 300 to about 600 mg twice daily.

183. The use of claim 168, wherein the therapeutically effective amount is from about 200 to about 600 mg twice daily.

184. The use of claim 168, wherein the therapeutically effective amount is about 200 mg twice daily.

185. The use of claim 168, wherein the therapeutically effective amount is about 400 mg twice daily.

186. The use of claim 168, wherein the therapeutically effective amount is about 300 mg twice daily.

187. The use of claim 168, wherein the therapeutically effective amount is from about 300 to about 600 mg once daily.

188. The use of claim 168, wherein the therapeutically effective amount is about 600 once daily.

189. The use of claim 168, wherein the therapeutically effective amount is about 600 mg once daily taken in the morning.

190. The use of any one of claims 183-189, wherein the therapeutically effective amount is taken with a meal.

191. The use of claim 168, wherein the therapeutically effective amount of a 17-alpha

192. The use of claim 191, wherein the therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered without the concomitant or sequential administration of prednisone.

193. A use of a therapeutically effective amount of 6-[(7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[l,2- c]imidazol-7-yl]-N-methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt, or a . pharmaceutical composition thereof in the manufacture of a medicament in treatment of cancer without the concomitant or sequential administration of a steroid, wherein the administering of a therapeutically effective amount of a 17-alpha hydroxylase/C17,20-lyase inhibitor without the concomitant or sequential administration of a steroid results in an improved clinical outcome for the patient as measured by enhanced progression-free survival as compared to standard therapy.

194. The use of claim 193, wherein the progression-free survival or time to metastasis is enhanced by at least 9 months.

195. The use of claim 193, wherein the progression-free survival or time to metastasis is enhanced by at least 12 months.

196. The use of claim 193, wherein the progression-free survival or time to metastasis is enhanced by at least 15 months.

1 7. The use of claim 193, wherein the cancer is a hormonally-driven cancer.

198. The use of claim 193, wherein the cancer is prostate cancer, breast cancer or ovarian cancer.

199. The use of claim 193, wherein the cancer is prostate cancer.

200. The use of claim 1 9, wherein the prostate cancer is castration resistant prostate cancer.

201. The use of claim 199, wherein the prostate cancer is metastatic castration resistant prostate cancer.

202. The use of claim 199, wherein the prostate cancer is non-metastatic castration resistant prostate cancer.

203. The use of claim 193, wherein the improved clinical outcome is further measured by a favorable safety risk/benefit ratio, whereby the risk associated with the administering of a 17-alpha

204. The use of claim 203, wherein the risks associated with the administering of a 17-alpha hydroxylase/C17, 20-lyase inhibitor without the concomitant or sequential administration of a steroid is measured by monitoring the patient for evidence of mineralocorticoid excess.

205. The use of claim 205, wherein the patient is monitored for one or more of ACTH/corticosterone profile, hypertension, hypokalemia, edema, or cardiovascular symptoms.

206. The use of claim 1 3, wherein the therapeutically effective amount is from about 300 to about 600 mg twice daily.

207. The use of claim 193, wherein the therapeutically effective amount is from about 200 to about 600 mg twice daily.

208. The use of claim 193, wherein the therapeutically effective amount is about 200 mg twice daily.

209. The use of claim 193, wherein the therapeutically effective amount is about 400 mg twice daily.

210. The use of claim 193, wherein the therapeutically effective amount is about 300 mg twice daily.

211. The use of claim 193, wherein the therapeutically effective amount is from about 300 to about 600 mg once daily.

212. The use of claim 193, wherein the therapeutically effective amount is about 600 once daily.

213. The use of claim 193, wherein the therapeutically effective amount is about 600 mg once daily taken in the morning.

214. The use of any one of claims 206-213, wherein the therapeutically effective amount is taken with a meal.

215. The use of claim 193, wherein the therapeutically effective amount of a 17-alpha

216. The use of claim 215, wherein the therapeutically effective amount of a 17-alpha

hydroxylase/C 17, 20-lyase inhibitor is administered without the concomitant or sequential administration of prednisone.

217. The use of claim 147, 168, or 193, further comprising:

(b) measuring the patient levels of one or more of blood pressure, orserum levels of one or more of corticosterone, Cortisol or potassium after the administration of a first dose level of a therapeutically effective amount of a 17-alpha hydroxylase/C 17, 20-lyase inhibitor; and

(c) administering to a patient a second dose level of a therapeutically effective amount of then- alpha hydroxylase/C 17, 20-lyase inhibitor, wherein the second dose level is greater than, equal to, or less than the first dose level.

218. The use of claim 217, further comprising repeating steps (a)-(c) until a desired dose level of a therapeutically effective amount of the 17-alpha hydroxylase/C 17, 20-lyase inhibitor is achieved.

219. The use of claim 217, wherein the blood pressure measurement after the administration of the first dose level is greater than the blood pressure measurement prior to administration of the first dose level; and

220. The use of claim 219, wherein the corticosterone level after admimstration of the first dose level is higher than the corticosterone level prior to the admimstration of the first dose level.

221. The use of claim 219, wherein the Cortisol level after the admimstration of the first dose level is lower than the Cortisol level prior to the administration of the first dose level.

222. The use of claim 219, wherein the potassium level after the administration of the first dose level is lower than the potassium level prior to the administration of the first dose level.

223. The use of claim 147, wherein the cancer is a hormonally-driven cancer.

224. The use of claim 147, wherein the cancer is prostate cancer, breast cancer or ovarian cancer.

225. The use of claim 147, wherein the cancer is prostate cancer.

226. The use of claim 225, wherein the prostate cancer is castration resistant prostate cancer.

227. The use of claim 225, wherein the prostate cancer is metastatic castration resistant prostate cancer.

228. The use of claim 225, wherein the prostate cancer is non-metastatic castration resistant prostate cancer.

229. The use of claim 168, wherein the first dose level is about 400 mg twice daily.

230. The use of claim 168, wherein the second dose level is about 300 mg twice daily.

231. The use of claim 168, wherein the second dose level is about 200 mg twice daily.

232. The use of claim 147, 168, or 193, further comprising administering to the patient one or more additional treatments concurrently with or sequentially with the 17-alpha hydroxylase/C17, 20-lyase inhibitor, wherein the one or more additional treatments comprises:

a. radiation, b. chemotherapy,

c. immunotherapy,

d. a non-steroidal hormone ablation therapy, or

e. a non-steroidal therapy for the management of side effects of therapy.

233. The use of claim 232, wherein the one or more additional treatments are selected from sipuleucel-T, paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, 5-fluorouracil,

234. The use of claim 232, wherein the one or more additional treatments is an androgen receptor inhibitor.

235. The use of claim 234, wherein the androgen receptor inhibitor is (4-(3-(4-cyano-3-

(tri fluoromethyl)phenyl)-5,5 -dimethyl-4-oxo-2-thioxoirnidazolidin- 1 -yl)-2-fluoro-N-methylbenzamide) or

(4-(7-(6-cyano-5-(trifluoromemyl)pyridin-3-y

N-methylbenzamide).

236. A use of a therapeutically effective amount of a 17-alpha hydroxylase/C 17, 20-lyase inhibitor in the manufacture of a medicament in treatment of cancer in a patient, wherein the use comprising:

(b) administering to the patient a first dose level of a therapeutically effective amount of a 17- alpha hydroxylase/C 17, 20-lyase inhibitor;

(c) measuring the patient levels of one or more of blood pressure or serum levels of one or more of corticosterone, Cortisol or potassium after the administration of a first dose level of a therapeutically effective amount of a 17-alpha hydroxylase/C 17, 20-lyase inhibitor; and

(d) administering to a patient a second dose level of a therapeutically effective amount of the 17- alpha hydroxylase/C 17, 20-lyase inhibitor, wherein the second dose level is greater than, equal to, or less than the first dose level.

237. The use of claim 236, wherein the second dose level in step (d) is less than the first dose level.

238. The use of claim 236, further comprising repeating steps (a)-(d) until a desired dose level of a therapeutically effective amount of the 17-alpha hydroxylase/C17, 20-Iyase inhibitor is achieved.

239. The use of claim 236, wherein the blood pressure measurement after the administration of the first dose level is greater than the blood pressure measurement prior to administration of the first dose level; and

a) the corticosterone level after the administration of the first dose level is higher than the corticosterone level prior to the administration of the first dose level; or

240. The use of claim 239, wherein the corticosterone level after administration of the first dose level is higher than the corticosterone level prior to the adniinistration of the first dose level.

241. The use of claim 239, wherein the Cortisol level after the administration of the first dose level is lower than the Cortisol level prior to the administration of the first dose level.

242. The use of claim 239, wherein the potassium level after the administration of the first dose level is lower than the potassium level prior to the administration of the first dose level.

243. The use of claim 236, wherein the cancer is a hormonally-driven cancer.

244. The use of claim 236, wherein the cancer is prostate cancer, breast cancer or ovarian cancer.

245. The use of claim 236, wherein the cancer is prostate cancer.

246. The use of claim 236, wherein the prostate cancer is castration resistant prostate cancer.

247. The use of claim 236, wherein the prostate cancer is metastatic castration resistant prostate cancer.

248. The use of claim 236, wherein the prostate cancer is non-metastatic castration resistant prostate cancer.

249. The use of claim 236, wherein the first dose level is from about 300 to about 600 mg twice daily.

250. The use of claim 236, wherein the first dose level is from about 200 to about 600 mg twice daily.

251. The use of claim 236, wherein the first dose level is about 400 mg twice daily.

252. The use of claim 236, wherein the first dose level is about 300 mg twice daily.

253. The use of claim 236, wherein the first dose level is about 200 mg twice daily.

254. The use of claim 236, wherein the first dose level is from about 300 to about 600 mg once daily.

255. The use of claim 236, wherein the first dose level is from about 200 to about 600 mg once daily.

256. The use of claim 236, wherein the first dose level is about 600mg once daily.

257. The use of claim 236, wherein the first dose level is about 600 mg once daily taken in the morning.

258. The use of any one of claims 249-257, wherein the first dose level is taken with a meal.

259. The use of claim 236, wherein the first dose level is about 400 mg twice daily.

260. The use of claim 236 wherein the second dose level is about 300 mg twice daily.

261. The use of claim 236, wherein the second dose level is about 200 mg twice daily.

262. The use of claim 236, further comprising administering to the patient one or more additional treatments concurrently with or sequentially with the 17-alpha hydroxylase/C17, 20-lyase inhibitor, wherein the one or more additional treatments comprises:

a. radiation, b. chemotherapy,

c. immunotherapy,

d. a non-steroidal hormone ablation therapy, or

e. a non-steroidal therapy for the management of side effects of therapy.

263. The use of claim 262, wherein the one or more additional treatments are selected from sipuleucel-T, paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, 5-fluorouracil,

cyclophosphamide, doxorubicin, cytarabine, cabazitaxel, tamoxifen, fulvestrant, cisplatin, exemestane, anastrozole, letrozole, trastuzumab, Iapatinib, radioisotopes, hormone ablation agent, hormone deprivation treatment, antiandrogen, ketoconazole, aromatase inhibitor, bicalutamide, eplerenone, spironolactone, or triampterine.

264. The use of claim 263, wherein the one or more additional treatments is an androgen receiptor inhibitor.

265. The use of claim 264, wherein the androgen receptor inhibitor is (4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2^ or (4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fl N-methylbenzamide).

266. The use of claim 147, 168 or 193, wherein the patient previously received one or more treatments with abiraterone acetate.