WO2023147135A1 - Nk receptor antagonists for treatment of prostate cancer - Google Patents

Abstract

The present disclosure relates generally to a method of treating prostate cancer or delaying progression of prostate cancer comprising administration of a neurokinin (NK) receptor antagonist to a patient.

Description

NK RECEPTOR ANTAGONISTS FOR TREATMENT OF PROSTATE CANCER

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of United States Provisional Application Serial Number 63/305,209, filed January 31, 2022, and United States Provisional Application Serial Number 63/306,215, filed February 3, 2022, the contents of which are hereby incorporated by reference in their entirety.

FIELD

[0002] Provided herein are methods for treating prostate cancer or delaying progression of prostate cancer by administering a neurokinin (NK) receptor antagonist.

BACKGROUND

[0003] Prostate cancer is a hormonally responsive tumor. Achieving and maintaining effective suppression of serum testosterone levels in men can assist with the management of prostate cancer. Historically, a serum testosterone below 50 ng/dL was considered to be the castrate level. Current data suggest that the new target for either surgical or chemical castration is a serum testosterone level of lower than 20 ng/dL. Currently used androgen deprivation therapies may cause testosterone levels to periodically rise, sometimes to non-castrate levels.

[0004] There is a need for therapies that can maximize therapeutic outcomes for prostate cancer by consistently achieving and/or maintaining the lowest testosterone levels possible.

SUMMARY

[0005] Provided herein is a method for prostate cancer or delaying progression of prostate cancer in a patient comprising administering a Neurokinin 3 receptor (NK3) antagonist to the patient in need thereof. In some embodiments, the NK3 antagonist is administered in an amount to reversibly lower the patient’s serum testosterone to lower than or equal to 50 ng/dL, 20 ng/dL, or 10 ng/dL, or the testosterone level is undetectable. In some embodiments, the NK3 antagonist is osanetant. In some embodiments, the patient is a low risk patient, an intermediate risk patient, or a high risk patient. In some embodiments, the patient has previously undergone or is currently undergoing androgen deprivation therapy (ADT). In some embodiments, the prostate cancer is hormone responsive. DETAILED DESCRIPTION

[0006] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0007] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. As used herein, the below terms have the following meanings unless specified otherwise. Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of the compositions and methods described herein. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references referred to herein are incorporated by reference in their entirety.

[0008] The term “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, references to “the agent” includes a plurality of such agents.

[0009] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X.”

[0010] Hormone responsive prostate cancer is any prostate cancer that may be treated, or delayed from progression, by a lowering of serum testosterone levels in a prostate cancer patient.

[0011] “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for human or veterinary pharmaceutical use.

[0012] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2- dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0013] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0014] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.

[0015] A “prodrug” is any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g. , N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein and the like. Preparation, selection and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety.

[0016] As used herein, the term “solvate” refers to a complex formed by combining a compound and a solvent.

[0017] As used herein, the term “hydrate” refers to a complex formed by combining a compound and water (i.e., a solvate when the solvent is water).

[0018] As used herein, the term “acid salt hydrate” refers to a complex formed by combining an acid salt compound with water.

[0019] As used herein, the term “N-oxide” refers to an oxidized tertiary or pyridinyl amine moiety.

[0020] As used herein, the term “isomorphic crystalline form” refers to two or more crystalline forms that have the same space group, unit-cell dimensions, and types and positions of atoms, with the exception of a replacement of one or more atoms in one isomorphic crystalline form with a different atom in its counterpart isomorphic crystalline form.

[0021] As used herein, the term “administration” refers to introducing an agent into a patient. For example, a therapeutic amount can be administered to the patient, which can be determined by the treating physician, medical professional, or the like. In some embodiments, a therapeutic amount is administered orally. In some embodiments, a therapeutic amount is administered subcutaneously. In some embodiments, a therapeutic amount is administered transdermally. In some embodiments, a therapeutic amount is administered intravenously. The related terms and phrases “administering” and “administration of,” when used in connection with a compound or tablet (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by self- administration by the patient, and/or to indirect administration, which may be the act of prescribing a drug. Administration entails delivery to the patient of the drug.

[0022] The term “dose” or “dosage” refers to the total amount of an active agent (e.g., osanetant or a pharmaceutically acceptable salt thereof) administered to a patient in a single day (24-hour period). The desired dose can be administered once daily. In some embodiments, the desired dose may be administered in one, two, three, four or more sub-doses at appropriate intervals throughout the day, where the cumulative amount of the sub-doses equals the amount of the desired dose administered in a single day. The terms “dose” and “dosage” are used interchangeably herein.

[0023] As used herein, “effective amount,” “therapeutically effective amount,” or “therapeutic amount” refers to an amount of a drug or an agent (e.g., osanetant or a pharmaceutically acceptable salt thereof) that when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient. The full therapeutic effect does not necessarily occur by administration of one dose, and can occur only after administration of a series of doses and can be administered in one dose form or multiples thereof. For example, 500 mg of the drug can be administered in a single 500 mg strength tablet or two 250 mg strength tablets. Thus, a therapeutically effective amount may be administered in one or more administrations.

[0024] As used herein, the term “patient” or “subject” refers to a mammal, such as a human, bovine, rat, mouse, dog, monkey, ape, goat, sheep, cow, or deer. A patient as described herein can be a human. The patient can be a male or a female.

[0025] As used herein, “treatment,” “treating,” and “treat” are defined as acting upon a disease, disorder, or condition with an agent to reduce or ameliorate the harmful or any other undesired effects of the disease, disorder, or condition and/or its symptoms. Treatment, as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the disease but not yet diagnosed as having the condition, (b) impeding the development of the condition, and/or (c) relieving the condition, i.e., causing regression of the condition and/or relieving one or more symptoms of the condition.

[0026] “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition. Methods

[0027] Provided herein is a method for treating prostate cancer or delaying progression of prostate cancer in a patient comprising administering a Neurokinin 3 receptor (NK3) antagonist to the patient in need thereof. In some embodiments, the prostate cancer is hormone responsive prostate cancer. In some embodiments, the NK3 antagonist is administered in an amount to reversibly lower the patient’s serum testosterone to castration levels. In some embodiments, the patient’s serum testosterone is reversibly reduced to lower than or equal to about 20 ng/dL. In some embodiments, the patient’s serum testosterone is reversibly reduced to lower than or equal to about 15 ng/dL. In some embodiments, the patient’s serum testosterone is reversibly reduced to lower than or equal to about 12 ng/dL. In some embodiments, the patient’s serum testosterone is reversibly reduced to lower than or equal to about 10 ng/dL. In some embodiments, the patient’s serum testosterone is reversibly reduced to lower than or equal to about 8 ng/dL. In some embodiments, the patient’s serum testosterone is reversibly reduced to lower than or equal to about 5 ng/dL.

[0028] In some embodiments, the patient’s serum testosterone is reversibly reduced to lower than or equal to about 50 ng/dL. In some embodiments, the patient’s serum testosterone is reversibly reduced to lower than or equal to 40 ng/dL. In some embodiments, the patient’s serum testosterone is reversibly reduced to lower than or equal to 25 ng/dL.

[0029] In some embodiments, the NK3 antagonist is a dual NK1/NK3 antagonist. In some embodiments, the NK3 antagonist is a selective NK3 antagonist.

[0030] In some embodiments, the NK3 antagonist is selected from osanetant (SR-142,801), elinzanetant (NT-814), fezolinetant (ESN-364), talnetant (SB-223,412), pavinetant (AZD-4901/AZD- 2624), and SJX-653, or a pharmaceutically acceptable salt of each thereof.

[0031] In some embodiments, the NK3 antagonist is selected from osanetant (SR-142,801), elinzanetant (NT-814), fezolinetant (ESN-364), talnetant (SB-223,412), and pavinetant (AZD-4901/AZD- 2624), or a pharmaceutically acceptable salt of each thereof.

[0032] In some embodiments, the NK3 antagonist is administered to the patient once a day. In some embodiments, the NK3 antagonist is administered to the patient twice a day.

[0033] In some embodiments, the NK3 antagonist is osanetant, or a pharmaceutically acceptable salt thereof. In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered to the patient once or twice a day for a total daily dose ranging from about 10 mg to about 800 mg, about 25 to about 750 mg per day, about 50 to about 700 mg per day, about 50 to about 600 mg per day, about 50 to about 500 mg per day, about 50 to about 400 mg per day, about 75 to about 650 mg per day, about 70 to about 500 mg per day, about 75 to about 400 mg per day, about 100 to about 600 mg per day, about 100 to about 500 mg per day, or about 100 to about 400 mg per day.

[0034] In some embodiment the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is less than about 400 mg per day. In some embodiments, the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is from about 10 to about 350 mg per day. In some embodiments, the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is less than about 200 mg per day. In some embodiments, the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is from about 10 to about 150 mg per day. In some embodiments, the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is about 300 mg per day. In some embodiments, the osanetant is administered once a day. In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered twice a day, each dose being about 150 mg.

[0035] In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered to the patient twice a day for a total daily dose ranging from about 10 mg to about 800 mg, about 25 to about 750 mg per day, about 50 to about 700 mg per day, about 50 to about 600 mg per day, about 50 to about 500 mg per day, about 50 to about 400 mg per day, about 75 to about 650 mg per day, about 70 to about 500 mg per day, about 75 to about 400 mg per day, about 100 to about 600 mg per day, about 100 to about 500 mg per day, or about 100 to about 400 mg per day. In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered twice a day, each dose an equal fraction of the total daily dose and comprising from about 5 mg to about 400 mg of osanetant, or a pharmaceutically acceptable salt thereof.

[0036] For men suffering from prostate cancer, surgical resection of the prostate (prostatectomy), seminal vesicles, and neighboring lymph nodes, as well as androgen suppression or deprivation therapy (ADT) are common treatments for the disease. In situations of advanced prostate cancer, removal of the testes (orchiectomy), the primary source of endogenous testosterone in the male body, can be undertaken to further limit the growth and spread of the hormone-dependent prostate cancer.

[0037] For hormone-dependent cancers, such as prostate, and testicular cancers, the proliferation of cells is driven by hormone -receptor interactions on cell surfaces. In the presence of these sex hormones, namely estrogen, progesterone, and testosterone, the hormone-dependent cells replicate more frequently, increasing the opportunity for genetic errors to occur and accumulate, potentially leading to cancer. Pharmaceutical interventions, e.g. hormone deprivation therapy such as androgen deprivation therapy, for the treatment or prevention of hormone-dependent cancers include compounds that inhibit the synthesis of these sex hormones, such as gonadotropin-releasing hormone (GnRH) agonists and antagonists, or nonsteroidal antiandrogens (NS A As). In certain embodiments, the patient will be undergoing hormone deprivation therapy. For instance, in the case of prostate cancer, the patient may be undergoing androgen deprivation therapy (ADT). In some embodiments, the ADT comprises administration of a gonadotropin releasing hormone (GnRH) agonist, a GnRH antagonist, a histamine H2 receptor antagonist, a nonsteroidal antiandrogen (NSAA), or an androgen receptor antagonist. In some embodiments, the androgen deprivation therapy comprises surgical castration, luteinizing hormone -releasing hormone (LHRH) agonists (e.g. leuprolide, goserelin, triptorelin, or leuprolide mesylate), LHRH antagonists (e.g., degarelix, relugolix, elagolix), abiraterone, ketoconzale, etc.

[0038] Many patients opt for medical or surgical interventions to remove the cancer and surrounding tissues. Many patients also elect for the removal of sex hormone producing organs, namely the testes. In certain embodiments, the patient to be treated will be undergoing removal of testes. In certain embodiments, the patient will already be receiving a GnRH agonist e.g., leuprolide (also known as leuprorelin), or a GnRH antagonist, e.g. elagolix, linzagolix, relugolix, goserelin, triptorelin, buserelin, deslorelin, fertirelin, gonadorelin, histrelin, lecirelin, nafarelin, peforelin, triptorelin, abarelix, cetrorelix, degarelix, or ganirelix. In certain embodiments, the patient will already be receiving an androgen receptor antagonist (e.g., darolutamide).

[0039] In some embodiments, the patient is undergoing androgen deprivation therapy and the NK3 antagonist is administered in combination with the androgen deprivation therapy. In some embodiments, the androgen deprivation therapy is leuprolide, darulotamide, elagolix, linzagolix, or relugolix. In some embodiments, the androgen deprivation therapy is leuprolide, elagolix, linzagolix, relugolix, goserelin, triptorelin, buserelin, deslorelin, fertirelin, gonadorelin, histrelin, lecirelin, nafarelin, peforelin, triptorelin, abarelix, cetrorelix, degarelix, or ganirelix. In some embodiments, the hormone deprivation therapy is surgery e.g., orchiectomy.

[0040] In some embodiments, the patient is co-administered estrogen deprivation therapy. In some embodiments, gynemastia and breast pain is reduced. In some embodiments, the estrogen deprivation therapy is selected from a selective estrogen modulator (SERM) or a selective estrogen receptor degrader (SERD). In some embodiments, the estrogen deprivation therapy is tamoxifen. In some embodiments, the SERM is raloxifene, toremifene, arzoxifene, or lasofoxifene, broparestrol, clomifene (E, or Z), cyclofenil, ormeloxifene. ospemifene, acolbifene, afimoxifene (4-hydroxy tamoxifen), elacestrant, endoxifen (4-hydroxy-N-desmethyltamoxifen), clomiphene N-oxide, droloxifene (3-hydroxytamoxifen), etacstil, fispemifene, afimoxiphene, bazedoxifene, hydroxyetacstil, idoxifene (pyrrolidino-4- iodotamoxifen), levormeloxifene ((L)-ormeloxifene), miproxifene, nafoxidine, nitromifene (CI-628), NNC 45-0095, panomifene, pipendoxifene (ERA-923), trioxifene, or zindoxifene (D-16726). In some embodiments, the estrogen deprivation therapy is treatment with a selective estrogen receptor degrader (SERD). Examples of SERDs include and are not limited to

[0041] In some embodiments, the osanetant is administered for a short period prior to onset of the androgen deprivation therapy, e.g., prior to prostatectomy or orchiectomy or prior to start of treatment with ADT (e.g., leuprolide, elagolix, linzagolix, or relugolix). In some embodiments, the osanetant is administered for a period of 1 day to 1 month prior to onset of androgen deprivation therapy. In some embodiments, the osanetant is administered for a period of 1 day to 3 weeks prior to onset of androgen deprivation therapy. In some embodiments, the osanetant is administered for a period of 1 day to 2 weeks prior to onset of androgen deprivation therapy. In some embodiments, the osanetant is administered for a period of 1 day to 1 week prior to onset of androgen deprivation therapy. In some embodiments, the osanetant is administered for a period of 1 day to 5 days prior to onset of androgen deprivation therapy. In some embodiments, the osanetant is administered for a period of 1 day to 3 days prior to onset of androgen deprivation therapy. [0042] In some embodiments, the osanetant is administered prior to onset of androgen deprivation therapy, and during the androgen deprivation therapy. In some embodiments, the osanetant is administered after the androgen deprivation therapy (e.g., as maintenance therapy after cessation of primary tumor treatment (e.g., after prostatectomy or after orchiectomy).

[0043] In some embodiments, the patient is a male patient with high levels of testosterone.

[0044] In some embodiments, the patient is undergoing androgen deprivation therapy (ADT) and the

NK3 antagonist is administered in combination with the ADT. In some embodiments, the ADT is leuprolide, elagolix, linzagolix, relugolix, goserelin, triptorelin, buserelin, deslorelin, fertirelin, gonadorelin, histrelin, lecirelin, nafarelin, peforelin, triptorelin, abarelix, cetrorelix, degarelix, ganirelix, flutamide, nilutamide, bicalutamide, topilutamide, apalutamide, enzalutamide, darolutamide, cimetidine, proxalutamide, seviteronel, cioteronel, inocoterone acetate, RU-58841 (CAS No. 154992-24-2), dimethylcurcumin, AZ3514, arv-110 (CAS No. 2222112-77-6), MTX-23, ARD-61, UT-34 (2168525-92- 4), FL442, MK-4541 (CAS No. 796885-38-6), LY2452473 (Cas No. 1029692-15-6), GTx- 024/Enobosarm (CAS No. 841205-47-8), or GSK2881078 (CAS No. 1539314-06-1). In some embodiments, the ADT is elagolix, linzagolix, or relugolix. In some embodiments, the ADT is leuprolide. In some embodiments, the ADT is darolutamide. In some embodiments of the methods, the patient treated with an NK3 antagonist is not undergoing ADT. In some embodiments of the methods, the NK3 antagonist is administered in combination with radiation. In some embodiments of the methods, the NK3 antagonist is administered in combination with ADT and radiation.

[0045] In some embodiments of the methods, the levels of luteinizing hormone (LH) and/or testosterone (T) in the patient are each reduced by at least 70% compared to baseline levels of LH and T.

[0046] In some embodiments, the patient has undergone prostatectomy. In some embodiments, the patient has undergone prostatectomy and is undergoing ADT and/or radiation therapy.

[0047] In some embodiments, the methods described herein lower LH and/or testosterone levels in the patient and the reduction in levels of LH and/or T is reversible. In some embodiments, the methods described herein may reversibly lower LH, FSH, and estradiol levels.

[0048] In some embodiments, the patient is suffering from non-metastatic prostate cancer. In some of such embodiments, the patient is not undergoing ADT. In some of such embodiments, administration of NK3 antagonists is useful in maintaining low levels of testosterone thereby slowing or delaying progression of prostate cancer. [0049] In some embodiments, the NK3 antagonist is administered for a period of at least 8 days. In some embodiments, the NK3 antagonist is administered for a period of 8 to 28 days. In some embodiments, the NK3 antagonist is administered for a period of at least 28 days. In some embodiments, the NK3 antagonist is administered for a period of at least 8 days at a first dose and thereafter administration is continued for a further period of at least 8 days at a second dose which is the same as, or different from, the first dose.

[0050] In some embodiments, the androgen deprivation therapy is treatment with a gonadotropinreleasing hormone (GnRH) agonist or antagonist. In some of such embodiments, the patient is a male patient. In some embodiments, the GnRH agonist is leuprolide. In some embodiments, the GnRH antagonist is elagolix. In some embodiments, the GnRH antagonist is relugolix. In some embodiments, the GnRH antagonist is linzagolix.

[0051] In some embodiments, the cancer is hormone receptor-positive cancer. In some embodiments, the hormone receptor-positive cancer is prostate cancer.

[0052] In some embodiments, the neurokinin receptor antagonist is administered to a patient for a time period prior to the androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy as described herein. In some embodiments, the NK antagonist is administered concurrently with androgen deprivation therapy, a medical and/or surgical procedure and/or radiation therapy. In some embodiments, the patient continues to receive a NK antagonist after the androgen deprivation therapy, a medical and/or surgical procedure and/or radiation therapy. In some embodiments, the patient receives a NK antagonist after short-term (e.g., 1 to 6 months, 1 to 3 months, 1 month, 1-3 weeks, 1 week) androgen deprivation therapy. Any combination of these therapeutic regimens is contemplated within the scope of embodiments presented herein.

NK Antagonists

[0053] As discussed above, NK antagonists are useful in the methods described herein. As used herein, “NK receptor,” “neurokinin receptor,” or “tachykinin receptor” is a transmembrane G-protein coupled receptor. The three known tachykinin receptors are NK1, NK2, and NK3. These receptors act on a variety of human functions, which regulate numerous biological systems, including the reproductive system.

[0054] As used herein, “NK receptor antagonists,” “neurokinin receptor antagonists,” or “tachykinin receptor antagonists” are a class of drugs which interact with tachykinin receptors NK1, NK2, and NK3, and dampen the normal agonist-mediated biological responses. The tachykinin receptors have been associated with the transmission of stress signals and pain, the contraction of smooth muscles, inflammation, and modulating the hypothalamus-pituitary-gonadal axis. NK receptor antagonists are indicated for the treatment of migraine, emesis, gastrointestinal disorders, disorders of the reproductive system, and psychiatric disorders, including anxiety, addiction, depression, and schizophrenia. In certain embodiments, the NK antagonist is a NK1, NK2, or NK3 antagonist or a combination thereof.

[0055] In certain embodiments, the NK antagonist is a NK1 receptor antagonist selected from aprepitant, casopitant, ezlopitant, fosaprepitant, lanepitant, maropitant, rolapitant, vestipitant, L-733,060, L-741,671, L-742,694, RP-67580, RPR-100,893, CP-96345, CP-99994, GR-205,171, TAK-637, T-2328, and combinations thereof. In certain embodiments, the NK antagonist is a NK2 receptor antagonist selected from ibodutant, saredutant, GR-159,897, MEN-10376, and combinations thereof. In certain embodiments, the NK antagonist is a NK3 receptor antagonist selected from fezolinetant, osanetant, pavinetant, talnetant, SB-222,200 (structure below), SB-218,795 (structure below), NT-814 (structure below), and combinations thereof.

[0056] In certain embodiments, the NK antagonist is a NK3 antagonist. The NK3 receptor, and its associated tachykinin neuropeptide, neurokinin B, act on a variety of human functions, affecting the hypothalamus-pituitary-gonadal axis, which regulates numerous biological systems, including the reproductive system. In certain embodiments, the NK3 antagonist is osanetant. [0057] In certain embodiments, the neurokinin-3 receptor antagonist is selected from osanetant, fezolinetant, pavinetant, talnetant, SB-222,200, SB-218,795, and NT-814. In certain embodiments, the neurokinin-3 receptor antagonist is osanetant. In certain embodiments, the neurokinin-3 receptor antagonist is fezolinetant. In certain embodiments, the neurokinin-3 receptor antagonist is pavinetant. In certain embodiments, the neurokinin-3 receptor antagonist is talnetant. In certain embodiments, the neurokinin-3 receptor antagonist is SB-222,200. In certain embodiments, the neurokinin-3 receptor antagonist is SB-218,795. In certain embodiments, the neurokinin-3 receptor antagonist is NT-814. In certain embodiments, the NK3 antagonist is osanetant.

[0058] Osanetant was originally developed for the treatment of schizophrenia and other central nervous system disorders. In certain embodiments the NK antagonist is osanetant or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof. The chemical name of osanetant is (R)-N-(l-(3-(l-benzoyl-3-(3,4- dichlorophenyl)piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide, and has the following structure:

[0059] Osanetant can also form pharmaceutically acceptable salts, such as osanetant hydrochloride, osanetant hydrobromide, osanetant sulfate, osanetant hydrogen sulfate, osanetant dihydrogen phosphate, osanetant methanesulfonate, osanetant methyl sulfate, osanetant maleate, osanetant fumarate, osanetant 2- naphthalenesulfonate, osanetant benzenesulfonate, osanetant glycolate, osanetant gluconate, and osanetant citrate, osanetant isethionate, osanetant p-toluenesulfonate, and the like. In some embodiments provided herein, osanetant is administered as a hydrochloride salt thereof.

[0060] Osanetant, as well as pharmaceutically acceptable salts thereof, can be purchased from commercial sources or can synthesized using published procedures. Patient Selection

[0061] In some embodiments, a patient selected for treatment using the methods described herein is a low risk patient, an intermediate risk patient, or a high risk patient.

[0062] In some embodiments, a patient selected for treatment using the methods described herein is a low risk patient. A low risk patient may be deemed to have “low risk prostate cancer”. Prostate cancer is described as “low risk” if it is only found in the prostate (localized) and it is highly likely to grow only very slowly, or not at all (low risk of progression). The medical criteria for low risk prostate cancer are: 1) the cancer is found in only one of the two sides (lobes) of the prostate; 2) the cancer takes up less than half of the affected prostate lobe; 3) the cancer cells have not mutated much and are not very aggressive; and/or 4) the cancer has not spread to any lymph nodes or led to the growth of tumors in other parts of the body.

[0063] “Low risk patient” is intended to encompass patients having low risk prostate cancer, e.g., a patient suffering from non-metastatic hormone responsive/sensitive cancer or a slow progression cancer. In some embodiments such a low risk patient does not elect to undergo androgen deprivation therapy. In some embodiments, a patient selected for treatment using the methods described herein is undergoing radiation therapy with or without radiation therapy. In some embodiments, a patient selected for treatment using methods described herein is being treated with lower doses of androgen deprivation therapy compared to the recommended dosing of androgen deprivation treatment. In some embodiments, a patient selected for treatment using the methods described herein is suffering from severe side effects of androgen deprivation therapy and is treated with lower doses of androgen deprivation therapy compared to the recommended dosing along with an NK receptor antagonist. Additionally, a “low risk patient” is also intended to include those patients who elect active surveillance over other therapies; who are older or have serious illnesses, where other therapies can be detrimental to their current conditions. Active surveillance can include regular PSA tests and/or biopsies.

[0064] In some embodiments, in a low risk patient, the tumor is confined to the prostate, and the PSA is <10 ng/mL or grade is group 1 (Gleason score is 6). In some embodiments, a low risk patient suffers from slow-growing tumors and may be a “very low risk” patient in which fewer than 3 biopsy tissue samples contain cancer cells and the cancer is not detectable by a digital rectal exam.

[0065] In some embodiments, a patient selected for treatment using the methods described herein is an intermediate risk patient where the tumor is confined to the prostate, the PSA is between 10 and 20 ng/mL, or the grade is group 2 or 3 (Gleason score of 7). In some of such embodiments, the patient may have a “favorable” or an “unfavorable” intermediate risk.

[0066] In some embodiments, a patient selected for treatment using the methods described herein is a high risk patient in whom the tumor extends outside the prostate, the PSA is >20 ng/mL, or grade group 4 or 5 (Gleason score 8 to 10). In some embodiments, a high risk patient has a subset of aggressive tumors and is a “very high risk” patient in whom the tumor has extended into the seminal vesicles (T3b) or the rectum or bladder (T4), or there are multiple biopsy samples with high grade cancer.

[0067] In some embodiments, a patient selected for treatment using the methods described herein is a patient who will benefit from castration or lowering of testosterone levels to castration levels.

[0068] In some embodiments, a patient selected for treatment using the methods described herein has been treated with higher than recommended doses or recommended doses of androgen deprivation therapy but has not had a lowering of testosterone to castration levels (e.g., lower than 20 ng/dL, or lower than 10 ng/dL). In some of such embodiments, the methods described herein provide for treatment with lower doses of the androgen deprivation therapeutic compared to the recommended dosing, and/or for a longer duration of time compared to the recommended duration, along with administration of an NK receptor antagonist, thereby reversibly lowering testosterone to castration levels in the patient. As used herein “recommended dosing” or “recommended duration” refers to dosing and/or durations approved by health agencies and/or provided on product labels.

[0069] In some embodiments, provided herein is a method to reduce testosterone to non-detectable levels comprising administration of a lower dose of an ADT and driving testosterone to below castrate levels, e.g., less than 20 ng/dL, less than 10 ng/dL. In some of such embodiments, osanetant is administered in combination with the ADT. In some of such embodiments, the reduction in testosterone occurs faster than the reduction if a recommended dose of ADT would have been administered alone. In some of such embodiments, the lowest testosterone level achieved is lower than the level that would be achieved if a recommended dose of ADT would have been administered alone.

[0070] In some embodiments, a patient selected for treatment using the methods described herein is not treated with NK3 antagonist MLE4901 (also known as AZD4901) at a dosage of 40 mg twice daily for 7 days. In some embodiments, a patient selected for treatment using the methods described herein is not treated with NK3 antagonist fezolinetant (ESN-364) at a dose of 3-180 mg as a single dose. In some embodiments, a patient selected for treatment using the methods described herein is not treated with NK3 antagonist fezolinetant (ESN-364) at a dose of 20, 60 or 180 mg once daily for 10 days. In some embodiments, a patient selected for treatment using the methods described herein is not treated with NK3 antagonist SJX-653 at a dose of 0.5 - 90 mg as a single dose.

Administration

[0071] In some embodiments, the time period over which the neurokinin receptor antagonist is administered to a patient prior to the androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy is about 12 weeks or 8 weeks or 4 weeks to the day of the androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy. In some embodiments, the time period over which the neurokinin receptor antagonist is administered to a patient prior to the androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy is about 3 weeks to the day of the androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy. In some embodiments, the time period over which the neurokinin receptor antagonist is administered to a patient prior to the androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy is about 2 weeks to the day of the androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy. In some embodiments, the time period over which the neurokinin receptor antagonist is administered prior to the androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy is about 2 weeks. In some embodiments, the time period over which the neurokinin receptor antagonist is administered prior to the androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy is about 1 week.

[0072] In some embodiments, the neurokinin receptor antagonist is administered to a patient concurrently with the androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy.

[0073] In some embodiments, the time period over which the neurokinin receptor antagonist is administered to a patient after the androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy is about 12 weeks. In some embodiments, the time period over which the neurokinin receptor antagonist is administered to a patient after the androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy is about 8 weeks. In some embodiments, the time period over which the neurokinin receptor antagonist is administered to a patient after the androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy is about 4 weeks.

[0074] In some embodiments, the patient is administered osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, for about 1 week prior to, concurrently with, and for about 12 weeks after, an androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy. In some embodiments, the patient is administered osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, for about 2 weeks prior to, concurrently with, and for about 12 weeks or more after, an androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy.

[0075] In some embodiments, the patient is administered osanetant or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, for about 1 week prior to, concurrently with, and for about 8 weeks after, an androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy. In some embodiments, the patient is administered osanetant for about 2 weeks prior to, concurrently with, and for about 8 weeks after, an androgen deprivation therapy, and/or medical or surgical procedure and/or radiation therapy.

[0076] In some embodiments, the neurokinin receptor antagonist is orally administered.

[0077] In some embodiments, the neurokinin receptor antagonist is subcutaneously administered.

[0078] In some embodiments, the neurokinin receptor antagonist is transdermally administered.

[0079] In some embodiments, the neurokinin receptor antagonist is intravenously administered.

[0080] In some embodiments, the neurokinin receptor antagonist is administered once daily. In some embodiments, the neurokinin receptor antagonist is administered as two, three, four or more sub-doses at appropriate intervals throughout the day, where the cumulative amount of the sub-doses equals the amount of the desired dose administered in a single day.

[0081] In some embodiments, when the NK antagonist is osanetant or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, the therapeutically effective amount of the osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 0.25 mg/day to about 1000 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, osanetant is about 0.5 mg/day to about 500 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 0.75 mg/day to about 450 mg/day, is about 1 mg/day to about 400 mg/day or 10 mg/day to about 350 mg/day. In some embodiments, the osanetant is administered is less than about 400 mg/day. In some embodiments, the osanetant is administered is less than about 200 mg/day or about 10 mg/day to about 150 mg/day.

[0082] In some embodiments, the therapeutically effective amount of the osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N- oxide or isomorphic crystalline form thereof, is about 1 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 50 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 100 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 200 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 300 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 400 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 500 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 600 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 800 mg/day. In some embodiments, the therapeutically effective amount of osanetant is about 1000 mg/day.

[0083] In certain embodiments, osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is dosed at about 0.25 mg/day to about 1 mg/day, in order to treat bone loss while avoiding transient increases in liver transaminase (alanine aminotransferase) concentrations, and maintaining healthy liver function.

[0084] In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of leuprolide, elagolix, relugolix, or linzagolix or any other ADT in a daily dose ranging from about 5 mg per day to about 600 mg per day. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of leuprolide, elagolix, relugolix, or linzagolix or any other ADT in a daily dose ranging from about 25 mg per day to about 500 mg per day. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of leuprolide, elagolix, relugolix, or linzagolix or any other ADT in a daily dose ranging from about 50 mg per day to about 500 mg per day. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of leuprolide, elagolix, relugolix, or linzagolix or any other ADT in a daily dose ranging from about 100 mg per day to about 400 mg per day. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of leuprolide, elagolix, relugolix, or linzagolix or any other ADT in a daily dose ranging from about 150 mg per day to about 300 mg per day. In any of these embodiments, the total daily dose may be administered as a single dose, or split between multiple doses (e.g., daily dose of 300 mg QD or daily dose of 300 mg split into 150 mg BID, or daily dose of 300 mg split into 100 mg TID). In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of leuprolide, elagolix, relugolix, or linzagolix or any other ADT in a daily dose of 300 mg, split into two doses of 150 mg each, i.e., 150 mg BID. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of leuprolide, elagolix, relugolix, or linzagolix or any other ADT in a daily dose of 200 mg, split into two doses of 100 mg each, i.e., 100 mg BID. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of leuprolide, elagolix, relugolix, or linzagolix or any other ADT in a daily dose of 100 mg, split into two doses of 50 mg each, i.e., 50 mg BID. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of leuprolide, elagolix, relugolix, or linzagolix or any other ADT in a daily dose of 50 mg, split into two doses of 25 mg each, i.e., 25 mg BID. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of leuprolide, elagolix, relugolix, or linzagolix or any other ADT in a daily dose of 25 mg, split into two doses of 12.5 mg each, i.e., 12.5 mg BID. In any of such embodiments, the dose of leuprolide, elagolix, relugolix, or linzagolix or any other ADT may be lower than the recommended dosing and may be for a longer duration of time compared to the recommended duration of therapy. Pharmaceutical Compositions

[0085] Also provided herein, in some embodiments, are pharmaceutical compositions that comprise osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, and one or more pharmaceutically acceptable vehicles selected from carrier, adjuvants, and excipients.

[0086] Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0087] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, intravenous, subcutaneous, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0088] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0089] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable vehicle, for example as a solution in 1,3-butanediol. Among the acceptable vehicles that may be employed are water, Ringer's solution, 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 may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be useful in the preparation of injectables. Such solutions may be formulated as 0.01% -10% isotonic solutions, pH 5-7, with appropriate salts. [0090] The compound described herein may be administered parenterally in a sterile medium. Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrathecal injection or infusion techniques. The compound described herein, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. In many pharmaceutical compositions for parenteral administration the carrier comprises at least 90% by weight of the total composition. In some embodiments, the carrier for parenteral administration is chosen from propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.

[0091] A pharmaceutical composition, for example, for injection, may comprise a cyclodextrin. The cyclodextrin may be, for example, a hydroxypropyl cyclodextrin or a sulfobutylether cyclodextrin. The cyclodextrin may be, for example, an a-cyclodextrin, a P-cyclodextrin, or a y-cyclodextrin.

[0092] A compound described herein may also be administered via microspheres, liposomes, other microparticulate delivery systems or sustained release formulations placed in certain tissues including blood. Suitable examples of sustained release carriers include semi-permeable polymer matrices in the form of shared articles, e.g., suppositories or microcapsules. Examples can be found, e.g., in Remington's Pharmaceutical Sciences, 18th edition, Gennaro, A. R., Lippincott Williams & Wilkins; 20th edition (Dec. 15, 2000) ISBN 0-912734-04-3 and Pharmaceutical Dosage Forms and Drug Delivery Systems; Ansel, N. C. et al. 7th Edition ISBN 0-683305-72-7, the entire disclosures of which are herein incorporated by reference.

[0093] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0094] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents.

[0095] The compositions that include at least one compound described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0096] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0097] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0098] The compound described herein can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, for example. Furthermore, pharmaceutical compositions containing the compound described herein can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can contain conventional additives, such as suspending agents (e.g., sorbitol syrup, methyl cellulose, glucose/sugar, syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats), emulsifying agents (e.g., lecithin, sorbitan monooleate, or acacia), non-aqueous vehicles, which can include edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol and ethyl alcohol), and preservatives (e.g., methyl or propyl p-hydroxybenzoate and sorbic acid).

[0099] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, orally from devices that deliver the formulation in an appropriate manner.

[0100] The forms in which the pharmaceutical compositions described herein may be administered, for example, as quick-dissolving tablets, lozenges, powders, sprays, ointments, gels, or liquid suspensions.

[0101] Some examples of suitable mucoadhesive agents include agarose, chitosan, trimethylated chitosan, chitosan-EDTA, gelatin, hyaluronic acid, guar gum, hakea gum, xanthan gum, gellan gum, carrageenan, pectin, sodium alginate, cellulose derivatives, CMC, thiolated CMC, sodium CMC, HEC, HPC, HPMC, MC, poly(acrylic acid)-based polymers, CP, PC, PAA, copolymers of acrylic acid and PEG, PVA, PVP, CP, aminodextran, dimethylaminoethyl-dextran, hydroxyethyl starch, poly(ethylene oxide), scleroglucan, cyanoacrylate, hydroxylated methacrylate, and poly(methacrylic acid). Some examples of suitable penetration enhancers include sodium lauryl sulfate, cetyl pyridinium chloride, Poloxamer, Brij, Span, Myrj, Tween, sodium glycocholate, sodium tauro deoxycholate, sodium tauro cholate, oleic acid, caprylic acid, lauric acid, lyso phosphatidyl choline, phosphatidyl choline, a-, P-, and y-cyclodextrin, methylated P-cyclodextrin, EDTA, citric acid, sodium salicylate, methoxy salicylate, chitosan, trimethyl chitosan, poly-L-arginine, and L-lysine. Some examples of suitable enzyme inhibitors include aprotinin, bestatin, and puromycin. Combination Therapy

[0102] The neurokinin receptor antagonist may be administered in combination with one or more additional active agents. In some embodiments, the neurokinin receptor antagonist may be administered in combination with a second active agent that the patient is being treated with. In some embodiments, the second active agent is an androgen deprivation agent such as a GnRH agonist, e.g. leuprolide. In some embodiments, the second active agent is an androgen deprivation agent such as a GnRH antagonist, e.g. elagolix, linzagolix, relugolix, goserelin, triptorelin, buserelin, deslorelin, fertirelin, gonadorelin, histrelin, lecirelin, nafarelin, peforelin, triptorelin, abarelix, cetrorelix, degarelix, or ganirelix. In some embodiments, the second active agent is an androgen deprivation agent such as a nonsteroidal antiandrogen (NSAA), including, but not limited to, flutamide, nilutamide, bicalutamide, topilutamide, apalutamide, enzalutamide, darolutamide, cimetidine, proxalutamide, seviteronel, cioteronel, inocoterone acetate, and RU-58841. In some embodiments, the second active agent is an androgen deprivation agent is a selective androgen receptor degrader (SARD), including, but not limited to, dimethylcurcumin, AZ3514, arv-110, MTX-23, ARD-61, and UT-34.

[0103] In some embodiments, the second active agent is an androgen deprivation agent is a selective androgen receptor modulator (SARM), including, but not limited to, FL442, MK-4541, LY2452473, GTx-024/Enobosarm, and GSK2881078.

[0104] As used herein, “gonadotropin-releasing hormone agonists and antagonists” or “GnRH agonists and antagonists” are classes of drugs which prevent the GnRH-mediated release of sex hormones. GnRH is a peptide hormone produced by GnRH neurons in the hypothalamus, responsible for the release of follicle-stimulating hormone and luteinizing hormone from the pituitary gland, beginning the hypothalamic -pituitary-gonadal axis synthesis and release of sex hormones.

[0105] Also provided is a pharmaceutical composition comprising osanetant and a second active agent.

EXAMPLES

[0106] It is understood that modifications which do not substantially affect the activity of the various embodiments of this disclosure are also included within the definition of the disclosure provided herein. Accordingly, the following examples are intended to illustrate but not limit the present disclosure.

Example 1

[0107] This study will evaluate the use of osanetant to reduce testosterone in men with adenocarcinoma of the prostate. [0108] The study is a single-arm pilot study. This study involves 10 patients with prostate cancer. All 10 will undergo prostatectomy and measurement of 4 hormones FSH, LH, Estradiol, and Testosterone) at baseline and days 2, 3, 7, 14, and 28.

[0109] Protocol synopsis: Men will undergo baseline screening (serum PSA and testosterone and history and physical examination). Those men who met inclusion criteria and elect to participate will be scheduled for the study protocol, which begins 35 days prior to scheduled surgery. Osanetant will be administered by the investigational pharmacy at a dosing of 200 mg BID. On days 2, 3, 7, and 14, and 28, an AM (0800 +/- 30 min) testosterone, LH, FSH, and Estradiol levels will be obtained. On day 35 (1 week after completing protocol therapy), the patient will undergo standard of care surgery. On day 42 post-operatively (+/- 3 days) serum testosterone, LH, FSH, Estradiol, and PSA will be obtained.

[0110] Patient Sample: Adult men with clinically localized prostate cancer (cTl-3bN0M0) who are scheduled for radical prostatectomy.

[0111] Inclusion criteria: Age >18; Clinically localized disease: cTl-3bN0M0; Testosterone >150 ng/ml

[0112] Exclusion criteria: Current or recent (within 6 months) use of testosterone/estrogen modulating agents (leuprolide, degarelix, bicalutamide, enzalutamide, apalutamide, darolutamide, abiraterone, systemic ketoconazole, tamoxifen, etc); Current use of CYP3A4 inhibitors; Cognitive impairment (defined as the presence of diagnosed dementia); Impaired renal function: Cr >1.8; Medical history of osteoporosis; Current systemic corticosteroid, long-term opioid, spironolactone, or eplerenone use.

[0113] Endpoints: Testosterone levels during treatment; LH, FSH, and Estradiol levels during treatment; PSA response to Osanetant; Rate of development of castrate testosterone levels (defined as testosterone <50 ng/mL); Reversibility of hormonal changes.

[0114] Patients will serve as their own comparator and hormonal labs will be compared at all timepoints, as will the trajectory of hormone levels over the study period. PSA response will be evaluated using percent reduction in PSA compared to baseline will be used to quantify response. The proportion of patients achieving castrate testosterone levels during the study period will be evaluated.

* * * [0115] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

What is claimed is:

1. A method for treating prostate cancer or delaying progression of prostate cancer in a patient comprising administering a Neurokinin 3 receptor (NK3) antagonist to the patient in need thereof.

2. The method of claim 1, wherein the prostate cancer is a hormone responsive prostate cancer.

3. The method of claim 1, wherein the NK3 antagonist is administered in an amount to reversibly lower the patient’s serum testosterone to lower than or equal to about 20 ng/dL.

4. The method of claim 1 , wherein the NK3 antagonist is administered in an amount to reversibly lower the patient’s serum testosterone to lower than or equal to about 10 ng/dL.

5. The method of claim 1, wherein the NK3 antagonist is a dual NK1/NK3 antagonist.

6. The method of claim 1, wherein the NK3 antagonist is a selective NK3 antagonist.

7. The method of any one of claims 1-6, wherein the NK3 antagonist is selected from osanetant

(SR-142,801), elinzanetant (NT-814), fezolinetant (ESN-364), talnetant (SB-223,412), pavinetant (AZD- 4901 / AZD-2624 / MLE4901), and SJX-653, or a pharmaceutically acceptable salt of each thereof.

8. The method of any one of claims 1-7, wherein the NK3 antagonist is selected from osanetant (SR-142,801), elinzanetant (NT-814), fezolinetant (ESN-364), talnetant (SB-223,412), and pavinetant (AZD-4901/AZD-2624), or a pharmaceutically acceptable salt of each thereof.

9. The method of any one of claims 1-8, wherein the NK3 antagonist is administered to the patient once a day.

10. The method of any one of claims 1-8, wherein the NK3 antagonist is administered to the patient twice a day.

11. The method of any preceding claim, wherein the NK3 antagonist is osanetant, or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the osanetant, or a pharmaceutically acceptable salt thereof, is administered to the patient twice a day for a total daily dose ranging from about 50 mg to about 600 mg.

13. The method of claim 11, wherein the osanetant, or a pharmaceutically acceptable salt thereof, is administered to the patient twice a day for a total daily dose ranging from about 100 mg to about 400 mg.

14. The method of claim 11, wherein the osanetant, or a pharmaceutically acceptable salt thereof, is administered twice a day, each dose comprising from about 25 mg to about 300 mg of osanetant, or a pharmaceutically acceptable salt thereof.

15. The method of any preceding claim, wherein the patient is a low risk patient, an intermediate risk patient, or a high risk patient.

16. The method of any preceding claim, wherein the patient is not undergoing ADT.

17. The method of any preceding claim, wherein the patient is undergoing androgen deprivation therapy (ADT) and the NK3 antagonist is administered in combination with the ADT.

18. The method of claim 17 wherein the ADT comprises administration of a gonadotropin releasing hormone (GnRH) agonist, a GnRH antagonist, a histamine H2 receptor antagonist, a non-steroidal antiandrogen (NSAA), or an androgen receptor antagonist.

19. The method of claim 18, wherein the ADT is leuprolide, elagolix, linzagolix, relugolix, goserelin, triptorelin, buserelin, deslorelin, fertirelin, gonadorelin, histrelin, lecirelin, nafarelin, peforelin, triptorelin, abarelix, cetrorelix, degarelix, ganirelix, flutamide, nilutamide, bicalutamide, topilutamide, apalutamide, enzalutamide, darolutamide, cimetidine, proxalutamide, seviteronel, cioteronel, inocoterone acetate, RU-58841, dimethylcurcumin, AZ3514, arv-110, MTX-23, ARD-61, UT-34, FL442, MK-4541, LY2452473, GTx-024/Enobosarm, or GSK2881078.

20. The method of any preceding claim, wherein the NK3 antagonist is administered in combination with radiation treatment.

21. The method of any preceding claim, wherein the levels of lutenizing hormone (LH) and/or testosterone (T) in the patient are each reduced by at least 70% compared to baseline levels of LH and T.

22. The method of any preceding claim, wherein the patient has undergone prostatectomy.

23. The method of any preceding claim, wherein the reduction in levels of LH and/or T is reversible.

24. The method of any preceding claim, wherein the patient is suffering from non-metastatic prostate cancer.

25. The method of any preceding claim, wherein the NK3 antagonist is administered for a period of at least 8 days.

26. The method of any preceding claim, wherein the NK3 antagonist is administered for a period of 8 to 28 days.

27. The method of any preceding claim, wherein the NK3 antagonist is administered for a period of at least 28 days.

28. The method of any preceding claim, wherein the NK3 antagonist is administered for a period of at least 8 days at a first dose and thereafter administration is continued for a further period of at least 8 days at a second dose which is the same as, or different from, the first dose.