Prostate cancer treatment methods

Abstract

To provide methods of treating prostate cancer.SOLUTION: Disclosed are methods of treating prostate cancer by administering niraparib to a subject in need thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) Not applicable.

[0002] FIELD OF THE INVENTION The present invention provides a method for the treatment of rheumatoid arthritis in humans by administering a safe and / or effective amount of niraparib to humans. The present invention relates to the treatment of metastatic hormone-naive prostate cancer. [Background technology]

[0003] Prostate cancer is the most common non-cutaneous malignancy in men and affects 100,000 men in Western countries. Prostate cancer is caused by the uncontrolled growth of abnormal cells in the prostate gland. When prostate cancer tumors develop, androgens such as testosterone are released into the prostate. In its early stages, localized prostate cancer, e.g., It is often treated with localized treatments, including surgical removal and radiation therapy. However, if local treatments are not curative, as is the case in one-third of men, The disease is incurable metastatic disease (i.e., the cancer spreads from one part of the body to another). It progresses to a disease.

[0004] Androgen deprivation therapy ("ADT") or androgen therapy for metastatic prostate cancer Suppression therapy is used to reduce testosterone production in the testicles. Surgical castration (removal of the testicles) or luteinizing hormone-releasing hormone ("LHRH") An example of an LHRH antagonist is Examples of LHRH agonists include goserelin acetate, histone Examples include leuprolide acetate, leuprolide acetate, and triptorelin palmate.

[0005] Abiraterone acetate is a prodrug of abiraterone and is a potent inhibitor of androgen biosynthesis. The main enzyme involved in the production of 17α-hydroxylase / C17,20-lyase (cytochrome P450 Abiraterone acetate inhibits CYP17 (CYP17). Metastatic castration-resistant prostate cancer (mCRPC) who has received prior docetaxel-containing chemotherapy Avila is approved for the treatment of men with mCRPC. Telon acetate (tablet dose of 1,000 mg / day) and prednisone (5 mg twice daily) The efficacy and safety of the treatment were both evaluated in a phase 3, multinational, randomized, double-blind, placebo-controlled study. This is established by the results of studies COU-AA-301 and COU-AA-302. Study COU-AA-301 utilizes CYP17 inhibition with abiraterone acetate to further testing to concentrations lower than those achieved by antidepressant therapy ("ADT"). Lowering steroid levels has been shown to improve survival in patients with mCRPC. COU-AA-302 was the first phase 3 trial to evaluate placebo plus prednisone. Patients with mCRPC treated with abiraterone acetate plus prednisone compared with those without abiraterone acetate Overall survival ("OS") and radiographic survival ("OS") in chemotherapy-naive patients with It showed a significant improvement in progression-free survival ("rPFS").

[0006] Improved rPFS and OS in subjects with mHNPC with high-risk prognostic factors in patients with abiraterone acetate plus low-dose prednisone and ADT compared with ADT alone. Data are needed to determine whether combination therapy with Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, niraparib may be beneficial in patients with mCRPC, including those with DNA repair defects. PARP inhibition by α-glucanase improves the prostate gland, including castration-resistant prostate cancer and metastatic castration-resistant prostate cancer Treatment of cancer. This treatment may be given following chemotherapy or in chemotherapy-naive patients. This treatment may be administered to patients with rheumatoid arthritis, for example, enzalutamide, apalutamide, and bicalcotaxel. Niraparib may be used as an alternative treatment following AR-targeting agents such as ibuprofen. You can give options. [Means for solving the problem]

[0008] The present invention provides a method for treating prostate cancer in a human in need thereof, comprising administering to the human a therapeutic agent. a therapeutically effective amount of niraparib About how to become.

[0009] In one embodiment, the present invention provides a method for treating prostate cancer in a human in need thereof. 1. A method comprising administering to a human a therapeutically effective amount of niraparib; and and / or a method consisting essentially of the above, wherein the prostate cancer is castration-resistant prostate cancer ("CRP"). C"), metastatic castration-resistant prostate cancer, and / or antiandrogen-resistant prostate cancer; Regarding the method.

[0010] In another embodiment, the present invention provides a method for treating prostate cancer in a human in need thereof. comprising, consisting of, and / or consisting of administering niraparib to a human being. The method essentially comprises: B2, CHEK2, BRIP1, HDAC2, and / or ATM. The present invention relates to a method for treating a subject having at least one DNA repair defect.

[0011] In another embodiment, the present invention provides a method for treating prostate cancer in a human in need thereof. comprising, consisting of, and / or consisting of administering niraparib to a human being. The method consists essentially of: a human having a BRCA-1 or BRCA-2 attenuated gene; The present invention relates to a method for treating a subject having at least one DNA repair defect.

[0012] In another embodiment, the present invention provides a method for treating prostate cancer in a human in need thereof. and administering niraparib to a human, preferably at a dose of about 30 mg / day to about 400 mg / day, more preferably Preferably in an amount of 300 mg / day, most preferably in three 100 mg oral dosage forms once daily. Methods comprising, consisting of, and / or consisting essentially of oral administration .

[0013] In another embodiment, the present invention relates to a method for treating prostate cancer, antiandrogen-resistant prostate cancer, castration-resistant prostate cancer, or Prostate cancer and compositions comprising niraparib for treating metastatic castration-resistant prostate cancer do. [Brief explanation of the drawings]

[0014] [Figure 1] 1 shows that niraparib inhibits the growth of human prostate tumor cell lines in vitro. [Figure 2]We show that niraparib inhibits PAR production in two human prostate tumor cell lines in vitro. [Figure 3] 1 shows that niraparib treatment induces a dose-dependent increase in γ-H2AX in 22RV1 cells as measured by flow cytometry. [Figure 4] 1 shows that niraparib induces γ-H2AX in 22RV1, LNCaP AR-TB, and C4-2B cells in vitro. [Figure 5] 1 shows that niraparib treatment inhibits the growth of C4-2B-luc prostate tumors in NSG male mice. DETAILED DESCRIPTION OF THE INVENTION

[0015] The term "subject" refers to a person who has been or is the object of treatment, observation, or testing. The term "human" refers to a mammal, most preferably a human.

[0016] The term "treatment" refers to the treatment of a subject affected by a pathological condition, including killing cancer cells. It not only has the effect of alleviating the condition by using the drug, but also has the effect of inhibiting the progression of the condition. and includes slowing the rate of progression, stopping the rate of progression, ameliorating the condition, and curing the condition. This also includes treatment as a treatment (i.e., prophylaxis).

[0017] The term "therapeutically effective amount" refers to the amount of a substance that a researcher, veterinarian, physician, or other clinical professional would use in a tissue system. The alleviation or partial relief of the symptoms of the disease, syndrome, condition, or disorder being treated that is sought to be obtained through The dose of niraparib that produces a biological or pharmaceutical response, including partial relief of symptoms.

[0018] "Safe and effective amount" means an amount sufficient to prevent disease progression and unacceptable toxicity in humans or This refers to the amount of niraparib that produces relief.

[0019] The term "composition" is sometimes used to refer to a pharmaceutical product containing a therapeutically effective amount of a specified ingredient, as well as a pharmaceutical product containing a specified "Chemicals" refers to any product obtained directly or indirectly from a combination of specified ingredients in selected amounts.

[0020] As used herein, the term "pharmaceutically acceptable" means any substance that is acceptable within the scope of sound medical judgment. within the limits of the limits, with excessive toxicity, irritation, allergic reactions, or other problems or complications. compounds suitable for use in contact with human tissue, without the risk of harm and with a reasonable benefit / risk ratio; Each carrier, excipient, etc., is intended to be used in combination with other ingredients of the formulation. All must be "acceptable" in the sense of being compatible.

[0021] As used herein, the term "androgen receptor" refers to a receptor that binds to a wild-type androgen androgen-resistant AR and / or AR receptors associated with castration-resistant prostate cancer This includes natural variants.

[0022] As used herein, the term "antiandrogen" refers to an androgen that is normally reactive in the body. androgen-dependent biological effects on tissues that have In some embodiments, the anti-inflammatory compounds Antiandrogens are small molecules. Antiandrogens include enzalutamide and apalutamide. and abiraterone acetate.

[0023] As used herein, the term "first generation antiandrogen" refers to an antiandrogen that inhibits the wild-type AR receptor. However, first-generation anti- Androgens may potentially act as agonists in CRPC. It differs from second-generation antiandrogens in that

[0024] Exemplary first generation antiandrogens include, but are not limited to, Examples include lutamide, nilutamide, and bicalutamide.

[0025] As used herein, the term "second-generation antiandrogen" refers to an antiandrogen that inhibits the activity of a wild-type AR receptor. This refers to drugs that exhibit complete antagonist activity against the polypeptide. The agent is a complete antagonist in cells with increased AR expression levels, such as in CRPC. They differ from first-generation antiandrogens in that they act as inhibitors. Alternative antiandrogens include 4-[7-(6-cyano-5-trifluoromethylpyridinyl]- (3-phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octo- 5-yl]-2-fluoro-N-methylbenzamide (also known as ARN-509; CAS No. 956104-40-8; 4-(3-(4-cyano-3-(trifluoromethyl) (ethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine-l- (yl)-2-fluoro-N-methylbenzamide (MDV3100 or enzalutamide) Also known as RD162 (CAS No. 915087-33-1) and RD162 (CAS No. 9 In some embodiments, second-generation AR anti- The androgenic agent binds to the AR polypeptide at or near the ligand binding site of the AR polypeptide. It connects to the

[0026] As used herein, the term "third generation antiandrogen" refers to a compound that is a compound of formula (I) or (II), as described below. , wild-type AR polypeptide, and within the ligand binding domain (LBD) of the AR polypeptide. It exhibits full antagonist activity against mutant AR polypeptides in which mutations occur. Third-generation antiandrogens are drugs that inhibit the expression level of AR in patients with CRPC, for example. It is a first-generation anti-inflammatory drug in that it acts as a complete antagonist in cells in which the It is different from androgens.

[0027] As used herein, the term "mutant" refers to a nucleic acid that has been altered (compared to a reference) or or a polypeptide, or a modified nucleic acid or polypeptide containing or refers to the cell or organism in which it is expressed.

[0028] As used herein, unless otherwise specified, the term "anticoagulant" refers to a substance that is affected by antagonism of the AR. "affect" or "affected" (when referring to an affected disease, syndrome, condition, or disorder) The term refers to the frequency and / or severity of one or more symptoms or manifestations of a disease, syndrome, condition, or disorder. and / or one or more symptoms or a decrease in the severity of a disease, syndrome, condition or disorder includes preventing the occurrence of a condition, or preventing the occurrence of a disease, condition, syndrome or disorder.

[0029] Embodiments of the present invention include prodrugs of niraparib. A suitable prodrug is a functional derivative of a compound that is readily convertible in vivo into the required compound. Therefore, in the embodiment of the treatment or prevention method of the present invention, "administering" The term "compound" includes compounds that are specifically disclosed or that are not specifically disclosed. In some cases, the compounds described are converted to specific compounds in vivo after administration to a patient. The present invention encompasses the treatment or prevention of various diseases, conditions, syndromes and disorders. Conventional procedures for the selection and preparation of protease derivatives are described, for example, in "Design of Protease Derivatives" "Medicine Drugs," edited by H. Bundgaard, Elsevier, 1985. do.

[0030] Androgen receptor (AR) Androgens bind to specific receptors called androgen receptors (AR) in the cells of target tissues. AR is expressed in many tissues of the body and binds to testosterone (T) and dihydrotestosterone (DHT). Physiology and pathophysiology of endogenous androgen ligands such as dihydrotestosterone (DHT) Structurally, the AR consists of a ligand-binding domain (LBD), It consists of three main functional domains: a DNA-binding domain, and an amino-terminal domain. Compounds that bind to AR and mimic the action of endogenous AR ligands are called AR agonists. Compounds that inhibit the action of endogenous AR ligands are called AR antagonists. The binding of androgens to the receptor activates the receptor and causes it to activate target genes. From there, the receptor binds to a DNA-binding site adjacent to the coactivator protein and They interact with the ubiquitous transcription factors and basal transcription factors to regulate gene expression. Androgens induce changes in gene expression within cells. These changes are then transmitted to the cells. Ultimately, the target tissue will have visible results in the catalysis, differentiation, or proliferation of the target tissue in a physiological state. In the prostate, androgens are present in the cytoplasm of androgen-sensitive tissues. By binding to the AR, it stimulates the growth of prostate tissue and prostate cancer cells.

[0031] Compounds that selectively modulate AR include, but are not limited to, compounds for treating prostate cancer, good oral steroids, and steroid hormone receptor agonists. Prostatic hyperplasia, female hirsutism, alopecia, anorexia, breast cancer, acne, musculoskeletal conditions such as bone disease conditions related to hematopoiesis, neuromuscular diseases, rheumatic diseases, cancer, AIDS, cachexia hormones used in male contraception for the treatment or prevention of various diseases, conditions, and cancers, including For hormone replacement therapy (HRT), male enhancement, male reproductive conditions, and primary or secondary It is clinically important in male hypogonadism.

[0032] Castration-resistant prostate cancer Drugs that block the action of endogenous hormones (e.g., testosterone) (antiandrogens) is highly effective and is routinely used to treat prostate cancer (androgen deprivation therapy). These androgen deprivation therapies are effective in suppressing tumor growth in the early stages, but In almost all cases, it eventually becomes ineffective and leads to CRPC. Some prostate cancer cells initially respond to androgen deprivation therapy. Adenocarcinoma cells have responded to the selective pressure created by androgen deprivation therapy, At this point, the tumor is no longer responding to treatment, so over time, a surviving population of prostate cancer cells emerges. Not only does the primary cancer no longer respond to the therapy being used, but cancer cells also grow out of the primary tumor. They can break off from the tumor, travel through the bloodstream, and spread the disease to distant sites, especially bone. Among other effects, this can lead to a condition known as mCRPC. This can cause significant pain and even bone fragility in some patients.

[0033] In some embodiments, the patient's prostate cancer is a cancer of the prostate gland, including, but not limited to, enzalutamide. androgen-resistant or -resistant to antiandrogen therapy such as abiraterone acetate, apalutamide, and abiraterone acetate. are non-responsive ("antiandrogen resistant").

[0034] Niraparib (2-[4-[(3S)-piperidin-3-yl]phenyl]indazole The preparation of benzophenone-7-carboxamides is described in U.S. Provisional Patent Application No. 2010 / 02 / 16 filed on February 16, 2010. 60 / 921,310, issued December 6, 2011, claiming the benefit of “Amide Substituted Indazoles as Poly(ADP) PARP Inhibitors No. 8,071,623, and U.S. Provisional Patent Application No. 61 / 624, filed January 8, 2008. 010,333, issued May 7, 2013, entitled "Pharm No. 010,333." aceutically Acceptable Salts of 2-[4-[(3 S)-piperidin-3-yl]phenyl]-2H-indazole-7- This can be seen in U.S. Patent No. 8,436,185, which is a patent for "carboxamide." All of these documents are incorporated herein by reference.

[0035] The present invention also provides a pharmaceutical composition comprising niraparib and a pharmaceutically acceptable carrier. Pharmaceutical compositions containing the ingredients can be prepared in the form of, for example, tablets, troches, lozenges, aqueous or oily suspensions, or the like. Suspension, dispersible powder or granules, emulsion, hard or soft capsule, or syrup It can be in a form suitable for oral use such as a drop or elixir.

[0036] Compositions intended for oral use may be prepared by any method known in the art for the manufacture of pharmaceutical compositions. The compositions can be prepared according to the method and are pharmaceutically elegant and palatable. one selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives to provide a The tablets may contain the active ingredient in a non-toxic pharmaceutical preparation suitable for the manufacture of tablets. These excipients may be, for example, calcium carbonate. calcium, sodium carbonate, lactose, calcium phosphate, or sodium phosphate, etc. inert diluents; e.g., microcrystalline cellulose, croscarmellose sodium, corn starch Granulating and disintegrating agents such as starch, gelatin, polyvinyl alcohol, or alginic acid; binders, such as methylpyrrolidone or acacia; and binders, such as magnesium stearate, sucrose, The tablets may be coated with lubricants such as stearic acid or talc. or to mask the unpleasant taste of the drug or to delay disintegration and absorption in the gastrointestinal tract. This allows the coating to be applied by known techniques to provide long-lasting action. For example, hydroxypropyl methylcellulose or hydroxypropyl methylcellulose may be used. Water-soluble masking materials such as propyl cellulose, or ethyl cellulose, acetate butyrate A time delay material such as cellulose can be used.

[0037] Formulations for oral use may contain the active ingredient in, for example, calcium carbonate, calcium phosphate, or is available as a hard gelatin capsule mixed with an inert solid diluent such as kaolin. Alternatively, the active ingredient may be mixed with a water-soluble carrier such as polyethylene glycol, or Soft gelatin mixed with an oily medium such as nut oil, liquid paraffin, or olive oil It can also be given as a chin capsule.

[0038] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include, for example, sodium carboxymethylcellulose, methylcellulose, Hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone suspending agents such as gum tragacanth and gum acacia; dispersing or wetting agents include Naturally occurring phosphatides, such as lecithin, or alkylene oxides and fatty acids Condensation products of ethylene oxide and long chain ethylene oxide (e.g., polyoxyethylene stearate) condensation products with aliphatic alcohols (e.g., heptadecaethyleneoxycetanal), or Condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or ethylene oxide and fat Condensation products of fatty acids and partial esters derived from hexitol anhydrides (e.g., polyesters) The aqueous suspension may be, for example, p-hydroxybenzoate (sorbitan monooleate). One or more preservatives such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate an agent, one or more coloring agents, one or more flavoring agents, and sucrose, saccharin, or asparagus. One or more sweetening agents such as luteam may also be included.

[0039] Oily suspensions may contain the active ingredient in, for example, arachis oil, olive oil, sesame oil or coconut oil. The compound is formulated by suspending it in a vegetable oil such as corn oil or a mineral oil such as liquid paraffin. The oily suspensions can be prepared in a range of solutions, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavoring agents such as those described above may be added. These compositions contain butylated hydroxyanisole. The extract may be preserved by the addition of an antioxidant such as ethanol or alpha-tocopherol.

[0040] Dispersible powders and granules suitable for preparation of an aqueous suspension by adding water The active ingredient is then mixed with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as taste, flavor and coloring agents may also be present. It can be preserved by the addition of an antioxidant such as glutaric acid.

[0041] The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. vegetable oils, such as olive oil or arachis oil, or mineral oils, such as liquid paraffin; or mixtures thereof. Suitable emulsifiers include naturally occurring phosphatides, (e.g., soybean lecithin), and esters derived from fatty acids and hexitol anhydrides or is a partial ester (e.g., sorbitan monooleate), and the partial ester and ethylene and condensation products with hydroxybenzoates (e.g., polyoxyethylene sorbitan monooleate). The emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants. do.

[0042] Syrups and elixirs can be formulated with, for example, glycerol, propylene glycol, sol. It may be formulated with sweeteners such as sorbitol or sucrose. The pharmaceutical composition may further comprise an antiseptic, a flavoring and coloring agent, and an antioxidant. The compound may be in the form of a sterile injectable aqueous solution. Solvents and solvents include water, Ringer's solution, and isotonic sodium chloride solution.

[0043] The sterile injectable formulation is a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. This oily solution can then be introduced into a mixture of water and glycerol and treated. The mixture is then reacted to form a microemulsion.

[0044] The injectable solutions or microemulsions are introduced into a patient's bloodstream by local bolus injection. Alternatively, the solution or microemulsion can be placed in a constant circulating concentration of the compound. In some cases, it may be advantageous to administer the drug in a manner that maintains a constant concentration. To maintain the blood flow, a continuous intravenous delivery device can be utilized. and the Deltec CADD-PLUS™ Model 5400 intravenous pump.

[0045] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension can be prepared using suitable dispersing or wetting agents and suspending agents such as those mentioned above. The sterile injectable formulation can be formulated according to known techniques using non-toxic parenteral Sterile injectable solutions or suspensions in a physiologically acceptable diluent or solvent, for example 1,3-butanediol In addition, sterile, fixed oils are conveniently used as solvents or suspending media. For this purpose, any sterile glycerol containing synthetic mono- or diglycerides is suitable. In addition, fatty acids such as oleic acid can be used in the preparation of injectable formulations. It can be used.

[0046] Niraparib may also be administered in the form of suppositories for rectal administration of the drug. The substance is a drug that is solid at normal temperatures but liquid at rectal temperatures, and therefore It can be prepared by mixing it with a suitable non-irritating excipient that dissolves in the Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, and molecular weight Mixtures of polyethylene glycols with different molecular weights and fatty acid esters of polyethylene glycol Examples include:

[0047] For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds may be used. (For purposes of this application, topical application includes mouthwashes and gargles. )

[0048] Niraparib can be administered in intranasal form by topical use of a suitable intranasal vehicle and delivery device. Alternatively, it can be administered transdermally using transdermal patch formulations well known to those skilled in the art. For administration in the form of a transdermal delivery system, the dosage administration will, of course, be carried out over the entire dosage regimen. Niraparib is administered continuously, rather than intermittently, throughout the day. Polyethylene glycol and polyethylene glycol fats of different molecular weights. It can also be delivered as a suppository using a base such as a mixture with fatty acid esters.

[0049] When niraparib is administered to a subject, the dose level selected may include, but is not limited to: However, the activity of the particular compound, the severity of the individual's symptoms, the route of administration, the duration of administration, and the compound The rate of excretion of the drug, the duration of treatment, other drugs, compounds, and / or materials used concomitantly, and the patient's The dosage will depend on a variety of factors, including the patient's age, sex, weight, condition, general health, and medical history. The amount and route of administration of niraparib are ultimately at the discretion of the physician, but the dose Generally, the desired effect at the site of action is achieved without producing significant harmful or toxic side effects. This is to achieve a local concentration that satisfies the above equation.

[0050] In vivo administration can be in one dose, continuous or intermittent (e.g., as appropriate) throughout the course of treatment. The most effective means and dosage can be determined. The methods for administering the therapeutic agent are well known to those skilled in the art, and include the formulation used for the treatment, the purpose of the treatment, and the target cells to be treated. Depending on the cell and / or subject being treated, single or multiple administrations may be administered. Dosage levels and pattern can be selected by a physician.

[0051] In general, a suitable dose of niraparib is approximately 100 mg / kg of subject body weight per day. The range is from 100 μg to about 250 mg. When the active compound is a salt, ester, prodrug, etc. In this case, the amount administered is calculated based on the parent compound, so the actual weight used will depend on that. becomes proportionally larger.

[0052] A therapeutically effective amount of niraparib or a pharmaceutical composition thereof for treating prostate cancer is about 30 a dose range of niraparib from about 400 mg / day to about 400 mg / day, or any specific amount within that range or range, specifically about 300 mg / day, and three 100 mg oral dosage forms daily. One oral dose is given.

[0053] The optimal dose of niraparib to be administered can be readily determined and will depend on the particular compound used. The dosage varies depending on the product, dosage form, strength of the formulation, and the progression of the disease, syndrome, condition, or disorder. In addition, the specific subject being treated, such as the subject's sex, age, weight, diet, and time of administration, may be considered. Dosage should be adjusted to achieve appropriate therapeutic levels and the desired therapeutic effect, depending on subject-related factors. Therefore, the above dosages are examples of average cases. There may be individual instances where higher or lower dosage ranges are effective; these are within the scope of the present invention. It is included in the range of light.

[0054] Niraparib should be administered as directed above if its use is required for subjects who require it. by any of the compositions and administration regimens described above or established in the art. The compositions and administration regimens described herein can be used to administer the compounds of the present invention. [Example]

[0055] The following examples are included to aid in the understanding of the present invention and are incorporated by reference in their entirety. It is not intended to limit in any way the invention described in the claims. is not, and should not be construed as,

[0056] Example 1 In vitro cytotoxicity of niraparib in human prostate tumor lines The cytotoxicity of niraparib was tested in vitro in multiple human prostate tumor lines. None of the tumor lines are known to be BRCA-1 or BRCA-2 deficient.

[0057] method: The in vitro cytotoxicity of niraparib was evaluated in five prostate cancer cell lines: C4-2B, LNCaP, and L Evaluated in NCaP AR.TB, VCaP, and 22Rv1. C4-2B, LNCaP , LNCaP AR.TB, and 22Rv1 cell lines were supplemented with 10% heat-inactivated fetal bovine serum (F BS) (Life Technologies #16140-071) and non-essential amines Neo-acetyl-2-amino-2-hydroxybenzoic acid (NEAA) (Life Technologies #11140-050) was added. RPMI1640 + GlutaMAX™-I medium (Life Technology VCaP cells were grown in 10% FBS (Division #61870-036). and DMEM + GlutaMAX™-I medium (Life Technologies) supplemented with NEAA. VCaP cells were grown in a medium containing 100% ethanol (Technologies ##10569-010). The other strains were subcultured every 3 to 4 days.

[0058] The cell growth kinetics of each cell line was evaluated by seeding cells at multiple densities and monitoring growth at intervals of up to 7 days. The titer was measured by Promega Cell TiterGlo Reagent (#G7 571) to measure proliferation, and cells were analyzed by the chemiluminescence luciferin-luciferase reaction. Cellular ATP was measured using Perkin-Elmer Envision plates. The luminescence values ​​were read using a reader and plotted to determine the seeding density and desired time point at which logarithmic growth occurred. The cell density within the linear range of the Cell TiterGlo assay was determined.

[0059] For niraparib cytotoxicity experiments, cells were harvested by brief trypsinization and 100% of each strain was cultured. The cells were seeded at an appropriate density into the inner 60 wells of a 96-well plate in 10 μL of medium and incubated for 7 days. The outer wells of each plate were covered with a protective layer to reduce evaporation from the test wells. Dulbecco's phosphate-buffered saline (DPBS; Life Technologies The cells were incubated in a humidified 5% CO2 incubator at 37°C. The plates were incubated overnight in a refrigerator. 50 μL of 3X niraparib in the appropriate medium was added. (Final concentration 500, 125, 31.3, 7.8, 1.95, 0.49, 0.12, 0.0 Treatment was initiated by adding 0.3 μM of vehicle (3 μM) to triplicate wells. The final vehicle concentration was The concentration was 0.5% DMSO.

[0060] The cells were cultured for 7 days. Relative cell viability after treatment was determined using the Cell Tit assay, as described above. All luminescence output values ​​were measured using erGlo reagent. Normalized to % inhibition based on mean luminescence and the mean of vehicle control wells The average percent inhibition was subtracted from each treatment value. The percent inhibition was calculated using GraphPad Prism. The values ​​were plotted against the logarithm of the μM concentration at 7.00. Nonlinear regression and EC 50 Calculate the value , log(agonist) / response--performed using a variable slope (four parameter) fit.

[0061] result: The results of the cytotoxicity assay are shown in Figure 1 and Table 1. The proliferation of each cell line increased with increasing concentration of niraparib. The effect of EC4-2B cells was reduced in a dose-dependent manner by increasing the EC4-2B concentration. 50 The value is about 1.2 VCaP cells were most sensitive to EC 50 The value is 4.1 μM and appeared to be the least sensitive.

[0062] [Table 1]

[0063] Example 2 Inhibition of PAR formation by niraparib The ability of niraparib to inhibit the formation of poly(ADP)-ribose (PAR) was evaluated in two human preclinical studies. The test was carried out in vitro on prostate tumor lines. All tumor lines expressed either BRCA-1 or BRCA-2. It is not known as a defect.

[0064] method: PAR inhibition with niraparib was performed on two human prostate cancer cells, C4-2B and VCaP. The C4-2B cell line was cultured in RPMI16 supplemented with 10% FBS and NEAA. Grown in 40+GlutaMAX™-I medium and split every 3-4 days. CaP cells were cultured in DMEM + GlutaMAX™-I supplemented with FBS and NEAA. They were grown in culture medium and subcultured every 7 days.

[0065] Cells were harvested by brief trypsinization and each strain was plated in 1 mL of medium in a 6-well plate. An additional 500 μL of complete medium was added to each well for a total volume of 1.5 mL. The cells were incubated overnight in a humidified 5% CO2 incubator at 37°C. The next day, the medium was removed from the plates, and the cells were replated with 1 mL of serum-free medium (RPM The cells were washed with 1 mL of niraparib (0.1 mL) dissolved in the appropriate medium. % DMSO, final concentrations of 100, 10, 1, 0.1, 0.01, and 0 μM) were added. Treatment was initiated by dividing the wells into triplicates. The plate was then placed in an incubator for 2 hours. I put it back.

[0066] After treatment, HT-PARP in vivo Pharmacodynamic Assay The reagents and procedures given in the Ay II (Trevigen #4520-096-K) were used. The medium was removed from each well and the extracts were placed in separate labeled microcentrifuge tubes. The tubes were then placed on ice and the plate was spun at high speed at 1500 rpm for 4 minutes. Spin the plates to pellet any cells that detached from the plate during incubation with the drug. 250 μL of 100 mM PMSF (ethanol solution, Sigma #93 482) and 250 μL of 100X Protease Inhibitor Cocktail 24.5 mL with tail (Thermo Scientific #78429) The lysis buffer was prepared using the cell lysis reagent. The lysis buffer (300 μL) was placed on ice. The adherent cells were scraped into the lysis buffer and placed on ice for a short time. The supernatant was removed from the microtube and the 6-well plate was 100 ml of cell lysate was added to each tube. SDS (20 w / v%) was added to each tube. The final SDS concentration was adjusted to 1%. The cell extract was heated to 95-100°C for 5 minutes. After cooling to room temperature, add 0.01 volume of 100X magnesium cation and 3 μL of DNase. The tubes were vortexed briefly and placed in a 37°C incubator for 9 After incubation, the tubes were centrifuged at 10,000x G for 10 minutes at room temperature. If a pellet was present, it was removed using a pipette tip and the extraction The cells were then transferred to a 96-well dilution plate. The cell extracts were then analyzed for protein quantification and PAR. The samples were frozen at -80°C until use in the ELISA assay. ELISA Assay Protocol was performed according to the manufacturer's instructions.

[0067] Protein quantification was performed using Biorad Quick Start Bovine Serum Albumin. Detergent-compatible Biorad D with standard set (#5000207) C Protein Assay Kit II (#500-0002) was prepared using the manufacturer's 96-well plate. The ELISA was performed according to the protocol. Add the same volume of PBS to all sample wells to determine the solubilities for protein measurements. The effect of the solution buffer was corrected. Samples were assayed in duplicate. Buffer A' (25 1 μL) to all wells of the plate, and immediately add 200 μL of Buffer B to each well. The plate was incubated on a shaker at room temperature for 15 minutes. The absorbance was measured as follows: DC Protein Assay Protocol in SoftMax Pro Version 6.3 Software 750 s in a Molecular Devices M5 plate reader using a col The readings were taken at 100 nm. Linear regression of the standard curve, interpolation of the sample protein values, and averaging of the replicates were performed. Equalization was performed by the software. Data was exported to Excel and the sample dilution was recorded. Correction was made.

[0068] PAR ELISA standards and sample luminescence values ​​were analyzed using GraphPad Prism. Analysis was performed using Section 7, and linear regression of the standard curve and interpolation of the sample values ​​were calculated. Correct the R value (PAR (pg) / mL) for the dilution of the sample and the corresponding protein concentration The PAR (pg) per mg of protein was calculated by dividing the values ​​by 1. Graphed using ad Prism v7.

[0069] result: The results of the PAR assay are shown in Figure 2. PAR increased the concentration of niraparib in each cell line. The effect was reduced in a dose-dependent manner by increasing the dose.

[0070] Example 3 Niraparib induces γ-H2AX in human prostate tumor lines in vitro The ability of niraparib to induce double-strand breaks in DNA was examined in 22RV1, LNCaP AR. The activity of the TB and C4-2B human prostate cancer cells was measured following DNA double-strand breaks. The phosphorylation of the adjacent histone γ-H2AX occurs, and this phosphorylation is confirmed by antibody staining and fluorescence. It can be measured by flow cytometry.

[0071] method: The 22RV1, LNCaP AR.TB, and C4-2B cell lines were used as outlined above. The cell lines were propagated as follows: The cells were passaged every 3 to 4 days.

[0072] For each cell line, 2 x 10 5 Plate 100 cells in 1 mL of medium in a 12-well plate ( The cells were seeded into each well of a humidified 5% CO2-freeze buffer (Falcon #353043) at 37°C. After overnight incubation in a CO2 incubator, the plates were filled with 2x concentrated serially diluted niraparib. Add 1 mL of medium and measure the following: 200, 100, 50, 25, 12.5, 6.25, 3.13 , 1.57, 0.78, 0.39, 0.2, and 0.1 μM final concentrations in triplicate wells The final concentration was 0.2% DMSO, and the vehicle and medium were used for each cell line. Triplicate control wells were also obtained. Plates were incubated for an additional 18 hours.

[0073] After 18 hours of incubation with the drug, each well of cells was filled with 2 mL of medium for 15 min. The cells were harvested by first transferring them into a 1 L conical tube (Corning #430798). Next, add 500 μL of cell dissociation buffer (Gibco #13151-014) to the well. Using a 1 mL pipette, add 1 mL of medium to the wells. The cells were detached by pipetting and the cell-containing medium was transferred to the corresponding 15 mL conical tube. The tube was centrifuged at 1200 rpm for 5 minutes, the supernatant was discarded, and the pellet was The cells were resuspended and transferred to a 96-well V-bottom plate (Costar #3896). Centrifuge at 1800 rpm for 3 minutes, discard the supernatant, and then fill the wells with 200 μL of DP The cells were then washed with PBS. This process was repeated for a total of three washes. The cells were then washed with PBS at a dilution factor of 1. 1:800 Invitrogen Live / Dead fixable aqua ( Invitrogen #L34957) in 100 μL of DPBS for 20 min at 4°C. The cells were then stained with 150 μL of BD Pharmingen Stain Bulb. Wash with Buffer (Staining Buffer; BD #554657) at 1800 rpm for 3 min. The cells were washed again twice with 200 μL of staining buffer, then diluted with DPBS. Washed twice.

[0074] Fix the cells with 100 μL of -20°C 70% ethanol / HO and place the plate in a -20 The cells were washed with staining buffer by centrifugation at 2200 rpm for 3 minutes between each wash. The cells were then washed three times with 100 μL of a 1:1 dilution of staining buffer and AX ELL Biotin-Free Fc Receptor Blocker (Accurate Chemical & Scientific Corp #NB309) for 20 minutes at 4°C. The cells were washed with 150 μL of staining buffer and then centrifuged at 2200 rpm for 3 minutes. The supernatant was discarded, and the cells were then resuspended in 50 μL of 0.2 v / v% Triton X-100. staining buffer (Acros Organics #21568-2500) for 2 hours , γ-H2AX antibody (Biolegend #6134) at a dilution of 1:100 in the dark at room temperature. 08).

[0075] The cells were then soaked in 200 μL of staining buffer containing 0.2% v / v Triton X-100. The cells were washed once with 200 μL of staining buffer alone. Resuspend in 10 μL of staining buffer and transfer 50 μL to a BD Fortessa flow cytometer. Data were analyzed using TreeStar FlowJo v9.8.5. After gating the data on live cells and distinguishing doublets, the entire population was analyzed using γ- H2AX antibody signal was assessed. Results were analyzed using GraphPad Prism v7. I graphed it.

[0076] result: Representative histograms of the 22RV1 cell line showing the effect of different concentrations of niraparib are shown. Drug-treated samples were compared with vehicle and medium controls and the graphs are shown in Figure 4. The lowest concentrations at which the γ-H2AX signal was significantly higher than the vehicle control are shown in Table 2. These results show that niraparib induces γ-H2AX in a dose-dependent manner in each prostate tumor line. This indicates that it will lead to

[0077] [Table 2]

[0078] Example 4 Niraparib inhibits the growth of C4-2B human prostate tumors in mice.

[0079] The activity of niraparib was assessed in patients with non-obese diabetes (NOD), severe combined immunodeficiency (scid), and gamma (NO D. Pre-established human phenotype in Cg-Prkdc (Il2rg / SzJ) (NSG) mice The tumor model was tested in a human prostate subcutaneous C4-2B model. This tumor model was characterized by the expression of BRCA-1 or BRCA-2. It is not considered to be an A-2 deficiency.

[0080] method: The vehicle was 0.5% methylcellulose (Methocete) prepared and kept in the dark at 4°C. All formulations were administered at a volume of 10 mL per kg of body weight. NSG male mice (Jackson Laboratories) were used. The animals were acclimated for one week prior to the experimental procedures. Mice were then placed in a 12-hour The mice were housed in disposable IVC cages (In) at a temperature of 19-22°C and humidity of 35-40% under a 24-hour light-dark cycle. The animals were housed in groups in a 2-bedroom kennel (Central Park, San Diego, CA, USA). Mice were fed autoclaved high-fat (6%) laboratory chow and Water was available ad libitum.

[0081] Mice were inoculated with LNCaP C4-2B-luc-tagged cells (volume 200 μl) into the right flank. Cultrex®: 1 x 10 in RPMI 1640 medium 6 tumor cells (1: 1 ratio). Tumor volume was 241 ± 14 in 10 mice per treatment group. mm 3Mice were randomized to receive either vehicle or the chive treatments listed below. Either parib or vehicle was administered orally at a dose volume of 10 mL / kg. Treatment was started on day 1. Mice were treated until day 24 of the experiment.

[0082] Group 1: 0 mg / kg vehicle (0.5% Methocel F4M) administered orally once daily . Group 2: 25 mg / kg niraparib in 0.5% Methocel F4M once daily Administered orally. Group 3: niraparib 50 mg / kg once daily in 0.5% Methocel F4M Administered orally.

[0083] For each individual animal, the body weight and tumor volume [a is the length of the tumor measured with a vernier caliper] were measured. where b represents the width, and the formula: tumor volume (mm 3 )=(a×b 2 / 2) was used] The time course of tumor growth was measured twice weekly throughout the experiment. The results are expressed as the mean ± standard error of the mean (SEM).

[0084] result: Vehicle-treated mice reached the ethical limit of tumor volume from approximately day 22 of the study. (See Figure 5 for individual tumor volumes.) Tumor volume data were collected up to day 24 of the experiment. (9 of 10 vehicle-treated mice remained in the experiment). After 24 days, Group 3, who received 50 mg / kg of niraparib orally daily, showed no significant tumor growth. showed significant inhibition / delay of tumor growth, with tumor growth inhibition (TGI) values ​​of approximately 40% during these periods. Significant differences in tumor growth were observed on days 18, 22, and 24 ( * p<0.05, * * p<0.01, *** p<0.001). Mice administered 25 mg / kg niraparib Although the drug did not show significant tumor growth inhibition, it did show some TGI of about 12% in the 22 and 2 It was recognized on the fourth day.

[0085] Example 5 A multicenter open-label study was conducted to evaluate patients who received at least one line of taxane chemotherapy and and at least one line of antiandrogen therapy (e.g., abiraterone acetate, Enzalutamide, 18-year-olds with mCRPC and DNA repair defects who have previously received rituximab (prescription or nonprescription rituximab, apalutamide) Efficacy and safety of 300 mg of niraparib administered once daily in these male subjects The study will be conducted on approximately 100 subjects. The subjects will be Safety monitoring will continue until 30 days after the last dose of drug. Treatment will continue until disease progression, tolerated, or The study will continue until there is unacceptable toxicity, death, or the sponsor discontinues the study.

[0086] The study will consist of a pre-screening phase in which only biomarker evaluation is performed, a screening phase It consists of four phases: the clinical phase, the treatment phase, and the follow-up phase. The evaluation included the following: tumor measurements; CT or MRI of the chest, abdomen, and pelvis. scan, as well as a whole-body bone scan ( 99mTc ), serum PSA, viability status, CTC, and symptomatic skeletal-related events (SSEs).

[0087] Niraparib (300 mg) is administered orally once daily as capsules (3 × 100 mg). The capsules must be swallowed whole. Subjects were given the The dose must be taken daily (with or without food). Non-castrated subjects must continue to take their regularly prescribed GnRHa. All GnRHa therapy must be recorded in the concomitant medications section of the eCRF. It must be.

[0088] A treatment cycle is defined as 28 days. Subjects will receive niraparib on Day 1 of Cycle 1. A sufficient amount of niraparib will be distributed on the first day of each treatment cycle. If a subject misses a dose, the subject will regain consciousness within approximately 12 hours. If the dose was missed, the subject must refill the dose. The next dose should be taken the next day without making up the missed dose. Doses must be recorded on the eCRF.

[0089] Pre-screening phase for biomarker evaluation In the pre-screening phase, potential subjects are screened for DNA repair defects. All subjects will be assessed for marker positivity in the pre-screening phase. Sign a specific ICF for the patient and obtain baseline demographic and disease-specific information. The pre-screening phase is This can be done at any time before the deadline.

[0090] The process for determining biomarker positivity is available with blood-based assays Blood-based assays are available for subjects entering a pre-screening phase before becoming a These are different from subjects who enter the pre-screening phase after the study is available. The two processes are described below.

[0091] A process to determine biomarker positivity before blood-based assays are available Process Subjects will sign a pre-screening ICF. If subjects have previously completed the Foundation If tumor tissue is being analyzed using the nOne® gene panel, the subject's consent is required. After consent, FoundationOne® data was reviewed and the results were as defined in Table 1. Eligibility can be determined based on criteria. If a subject is biomarker positive, Subjects must be eligible to enter the screening phase. If tumor tissue has not been analyzed with the ionOne® gene panel, Patients were analyzed for biomarker positivity by sponsor-approved studies have either archived or recently obtained (preferred) tumor tissue. If a subject is biomarker positive, they must be admitted to the screening phase. Those who are eligible to enter the program must be qualified.

[0092] Blood samples were also collected from all subjects during the pre-screening phase, and blood-based blood-based assays will be kept in reserve for when they become available. When available, stored blood samples were analyzed for concordance with tumor tissue sample results. This analysis can be performed at any time after blood-based assays become available. It is possible.

[0093] To determine biomarker positivity once blood-based assays become available process Subjects sign a pre-screening ICF. Subjects' blood is drawn and biomarkers are If the subject has previously used FoundationOne (registered), the data will be sent for analysis to determine whether the subject is carcinogenic. If tumor tissue is analyzed using a gene panel (registered trademark), after subject consent, The data from the DataOne® database was reviewed and based on the criteria defined in Table 1, If the subject is biomarker positive, the subject is screened. The patient must be eligible to enter the lean phase and await the results of the blood-based analysis. If the FoundationOne® gene panel is negative, the patient A person who tests positive for a biomarker by a blood-based assay can still receive If the subject has previously completed FoundationOn e(R) gene panel analysis of tumor tissue has not been performed and archived tissue is not available. If available, a request will be initiated to obtain and analyze the archived tumor tissue. If the results of the biomarker-based assay are positive, the subject will be admitted to the screening phase. The patient must be eligible for inclusion in the study and must not have to wait for the results of analyses based on archived tumor tissue. If results from analyses based on archived tumor tissue are available, they should be compared with blood-based analyses. It can be used for concordance and bridging studies in conjunction with the results of the study.

[0094] At the discretion of the study sponsor, if the blood-based assay results are negative: Results based on archived tumor tissue may be used to determine suitability.

[0095] If no archived tumor tissue is available, the subject must consent to tumor tissue collection.

[0096] If the blood-based assay results are positive for the biomarker, concordance and bridging Recent tumor tissue must be collected prior to Day 1 of Cycle 1 for later use in the sequencing study. Analysis of recently obtained tumor tissue may be performed at any time during the study. and results may not be required before the subject enters the screening phase.

[0097] At the discretion of the study sponsor, if the blood-based assay results are negative: Suitability may be determined using recently harvested tumor tissue.

[0098] Subjects were biomarker positive during the pre-screening phase The screening phase must begin within 30 days of the date of the application.

[0099] Screening Phase All biomarker-positive subjects were included in all study participants during the screening phase. The ICF for the main study must be signed prior to the implementation of any related procedures. The eligibility criteria have been reviewed and are fully implemented as outlined in the "Schedule of Times and Events." Unless otherwise specified, screening procedures will begin on Day 1 of Cycle 1. Imaging is permitted up to 8 weeks prior to Day 1 of Cycle 1. Screening clinical safety laboratory assessments will be performed within Day 14 of Cycle 1. If performed, it can be used at the Cycle 1 Day 1 evaluation.

[0100] Subjects who did not meet all inclusion criteria or who met the exclusion criteria were rescreened again. Rescreening is at the discretion of the investigator and is subject to the sponsor's discretion. Approval and consent are required. Subjects undergoing rescreening must be A new ICF must be signed by the applicant. Subjects undergoing screening will be screened based on initial screening clinical test results, computed tomography scans, and Computed tomography (CT) / magnetic resonance imaging (MRI), and bone scan (8 days after day 1 of cycle 1) (if within weeks) to determine eligibility, even if it is not a reason for rescreening. It is possible.

[0101] Treatment Phase The treatment phase begins on Day 1 of Cycle 1 and continues until study drug is discontinued. Last measurement taken before administration of study drug or on Day 1 of Cycle 1 at screening The value (whichever value is the last) is defined as the baseline value. Unless otherwise specified, the study visit begins on Day 1 of Cycle 1. Subjects are required to undergo imaging within ±7 days of the visit requiring imaging. Treatment visits and evaluations during the treatment phase can be scheduled in the "Time and Event Schedule" Please refer to the "Rules".

[0102] On PK and pharmacology sample collection days, subjects were to take the study medication at home on the morning of their study visit. The study drug must be taken on-site. PK and pharmacological Details of sample collection dates and times are provided in the "Schedule of Times and Events." Further details regarding sample collection are provided in Section 9.3. PK and Pharmacokinetics Detailed procedures for handling and storing blood samples are provided in the laboratory manual.

[0103] Clinical evaluation and laboratory tests may be repeated more frequently if clinically indicated. Treatment with the study drug may be discontinued unless the patient is diagnosed with disease progression, unacceptable toxicity, death, or other adverse events as determined by the sponsor. Continue until study discontinuation. If a subject discontinues study medication, the subject will continue to receive study medication. Complete an End-of-Treatment (EoT) visit within 30 days of the last dose of , a follow-up phase must be entered.

[0104] Visit at the end of treatment End-of-treatment visit must be within 30 days of the last dose of study drug or new anti-prostate cancer drug The EoT visit must be scheduled before the administration of the If unable to attend the testing site, subjects must be admitted within 30 days of their last dose of study medication. Contact should be made to collect any AEs that occur.

[0105] Follow-up Phase Once subjects completed the treatment phase, survival follow-up and SSE were performed via clinic visits, telephone Conducted every 3 months by oral interview, chart review, or other convenient method. Fatalities and SAEs considered to be related to the study drug, regardless of causality, were reported at the time of event discovery. or collected and reported within 24 hours of notification. Follow-up information will be obtained by telephone contact. If so, there must be a transcript of the call for review in the source documents. It must be.

[0106] Biomarker-positive samples for DNA repair defects It is more convenient for subjects to assess whether they are biomarker positive. However, it offers a more rapid method than tissue-based analysis for determining biomarker positive status. Blood-based assays may become available during the study period. Before assays based on this method were available, tumor tissue (archived or recently obtained) Analysis of all participants, regardless of when they entered the study, is required. The same biomarkers are available for analysis (i.e., matching and bridging studies). Both tumor tissue and blood samples were used for pre-screening to obtain the target data. Obtained from all subjects who signed an Informed Consent Form (ICF). The process for determining marker positivity was developed before blood-based assays were available. A blood-based assay will be available for subjects entering the pre-screening phase. However, this differs from subjects who enter the pre-screening phase after Biomarker positivity status in both tumor tissue and blood was assessed for all subjects. Do the following.

[0107] To be considered eligible for the study, subjects must have tumor tissue (archived or otherwise) recently drawn) or blood tests, if available, to confirm positive biomarkers. The biomarkers and biomarkers targeted in this study must be confirmed. The criteria for marker positivity are shown in Table 3. Surrogates for biallelic loss (e.g., copy number) Analysis was performed to define the co-occurrence frequency of mutations with loss of function, and these The theory can be used to determine biomarker positivity when such information becomes available. do.

[0108] [Table 3] Monoallelic loss in all genes is consistent with existing algorithms for biallelic loss. Entry into the study will be permitted until the rhythm is validated.

[0109] Circulating tumor cells Blood samples were taken into the Cellsave tube at the times indicated in the "Schedule of Times and Events." CTC counts will be assessed in a central clinical laboratory to assess response to study medication. .

[0110] Whole blood for RNA Whole blood samples are collected in Paxgene tubes. Multiple ribonucleic acids found in prostate tumors. (RNA) transcripts are detectable in RNA, and analysis of these samples has shown that niraparib This allows for evaluation of potential mechanisms of resistance that may arise.

[0111] Circulating tumor DNA Circulating tumor DNA (ctDNA) was analyzed over time using plasma samples collected during treatment. Screening for changes in the level or type of DNA repair abnormalities observed Monitor for potential markers of resistance to rabies.

[0112] While the foregoing specification, together with examples given for purposes of illustration, teaches the principles of the present invention, it will be understood that the practice of the invention encompasses all ordinary variations, adaptations and / or modifications that come within the scope of the following claims and equivalents thereof. The following aspects may be included. [1] A method of treating prostate cancer in a human in need thereof, comprising administering to said human a safe and effective amount of niraparib. [2] The method according to [1] above, wherein the prostate cancer is castration-resistant prostate cancer or metastatic castration-resistant prostate cancer. [3] The method according to [2] above, wherein the prostate cancer is antiandrogen-resistant. [4] The method described in [3] above, wherein the human has at least one DNA repair defect selected from the group consisting of BRCA-1, BRCA-2, FANCA, PALB2, CHEK2, BRIP1, HDAC2, and ATM. [5] The method according to [4] above, wherein the DNA repair abnormality is BRCA-1 or BRCA-2. [6] The method according to [5] above, wherein the prostate cancer is castration-resistant prostate cancer. [7] The method according to [5] above, wherein the prostate cancer is metastatic castration-resistant prostate cancer. [8] The method according to [6] above, wherein niraparib is administered in an amount of about 30 mg / day to about 400 mg / day. [9] The method according to [8] above, wherein the amount of niraparib administered is about 300 mg / day.

[10] The method of [9] above, wherein niraparib is administered orally once daily in three 100 mg oral dosage forms.

[11] A method of treating castration-resistant prostate cancer and antiandrogen-resistant prostate cancer in a human, comprising administering to the human three 100 mg oral dosage forms of niraparib once daily.

Claims

1. A pharmaceutical composition for use in a method for treating metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer in a human, comprising niraparib or a salt thereof, said method comprising administering to said human an amount of niraparib or a salt thereof of about 30 mg / day to about 400 mg / day, wherein said human has at least one DNA repair abnormality in a gene selected from the group consisting of BRCA-1 and BRCA-2.

2. A pharmaceutical composition for use as described in claim 1, wherein the metastatic prostate cancer is metastatic castration-resistant prostate cancer.

3. A pharmaceutical composition for use as described in claim 2, wherein the metastatic prostate cancer is antiandrogen resistant.

4. A pharmaceutical composition for use as described in claim 1, wherein the metastatic prostate cancer is metastatic castration-sensitive prostate cancer.

5. The pharmaceutical composition for use according to claim 1, wherein the amount of niraparib or its salt administered is about 50 mg / day.

6. The pharmaceutical composition for use according to claim 1, wherein the amount of niraparib or its salt administered is about 100 mg / day.

7. The pharmaceutical composition for use according to claim 1, wherein the amount of niraparib or its salt administered is about 200 mg / day.

8. The pharmaceutical composition for use according to claim 1, wherein the amount of niraparib or its salt administered is about 300 mg / day.

9. The pharmaceutical composition for use according to claim 6, wherein niraparib or a salt thereof is administered as a once-daily oral dose in a 100 mg oral dosage form.

10. The pharmaceutical composition for use according to claim 7, wherein niraparib or a salt thereof is administered as a once-daily oral dose in a 100 mg oral dosage form.

11. The pharmaceutical composition for use according to claim 8, wherein niraparib or a salt thereof is administered as a once-daily oral dose in a 100 mg oral dosage form.

12. The pharmaceutical composition for use according to claim 1, wherein the human has undergone at least one line of taxane chemotherapy.

13. A pharmaceutical composition for use as described in claim 1, wherein the metastatic prostate cancer has been exposed to at least one line of antiandrogen therapy with enzalutamide, apalutamide, or abiraterone acetate.

14. A pharmaceutical composition for use as described in claim 1, wherein the DNA repair abnormality is genomic damage.

15. A pharmaceutical composition for use as described in claim 14, wherein the genomic damage is a homozygous deletion, a heterozygous deletion plus a deleterious mutation, or a heterozygous copy-neutral loss plus a deleterious mutation.

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