Methods of treating prostate cancer

Abstract

The present invention relates to methods of treating prostate cancer. Disclosed are methods of treating prostate cancer by administering niraparib to a subject in need thereof.

Description

[0001] This application is a divisional application. The application date of the original application is July 28, 2017, the application number is 201780046876.1 (PCT / US2017 / 044413), and the name of the invention is “Method for treating prostate cancer”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] not applicable. Technical Field

[0004] The present invention relates to methods of treating metastatic, endocrine-naive prostate cancer in humans by administering a safe and / or effective amount of niraparib to such humans. Background Art

[0005] Prostate cancer is the most common non-epithelial malignancy in men, and is the second cause of death of male cancer in Western countries. Prostate cancer is caused by the uncontrolled growth of abnormal cells in the prostate. Once prostate cancer tumor develops, androgen such as testosterone promotes prostate cancer tumor growth. In its early stage, localized prostate cancer usually adopts local therapy, including for example, treatment with surgical removal of the prostate and radiotherapy. However, when local therapy cannot cure prostate cancer as in up to one-third of men, the disease develops into incurable metastatic disease (i.e., cancer has spread to the disease of other positions from one position of the body).

[0006] Treatment of metastatic prostate cancer with androgen deprivation therapy ("ADT") or androgen suppression therapy is performed to reduce testosterone production by the testicles. ADT includes surgical castration (orchiectomy) or the use of luteinizing hormone-releasing hormone ("LHRH") antagonists or agonists. Examples of LHRH antagonists include degarelix. Examples of LHRH agonists include goserelin acetate, histrelin acetate, leuprolide acetate, and triptorelin palmitate.

[0007] Abiraterone acetate is a prodrug of abiraterone that inhibits 17α-hydroxylase / C17,20-lyase (cytochrome P450c17 [CYP17]), a key enzyme in androgen biosynthesis. Abiraterone acetate in combination with prednisone has been approved for the treatment of men with metastatic castration-resistant prostate cancer (“mCRPC”) who have previously received chemotherapy containing docetaxel. The efficacy and safety of abiraterone acetate (1,000 mg tablet daily dose) and prednisone (5 mg twice daily) therapy in patients with mCRPC was established by results from COU-AA-301 and COU-AA-302, both Phase 3, multinational, randomized, double-blind, placebo-controlled studies. Study COU-AA-301 is the first Phase 3 study to demonstrate that further reductions in testosterone concentrations below those achieved with androgen deprivation therapy (“ADT”) with CYP17 inhibition by abiraterone acetate improve survival in patients with mCRPC. COU-AA-302 demonstrated significant improvement in overall survival ("OS") and radiographic progression-free survival ("rPFS") in chemotherapy-naive patients with mCRPC treated with abiraterone acetate + prednisone compared to placebo + prednisone.

[0008] What is needed are data to determine whether abiraterone acetate in combination with low-dose prednisone and ADT is superior to ADT alone in improving rPFS and OS in mHNPC subjects with high-risk prognostic factors.

[0009] Therefore, by inhibiting PARP with niraparib in mCRPC patients (including those with DNA repair abnormalities), prostate cancer including castration-resistant prostate and metastatic castration-resistant prostate is treated. The treatment can be followed by chemotherapy or can be used for chemotherapy-naive subjects. The treatment can be performed after AR targeting agents such as enzalutamide, apalutamide, and bicalutamide. Therefore, niraparib can provide another treatment option. Summary of the invention

[0010] The present invention relates to a method for treating prostate cancer in a human in need of such treatment, the method comprising, consisting of and / or consisting essentially of administering to the human a therapeutically effective amount of niraparib.

[0011] In one embodiment, the invention relates to a method of treating prostate cancer in a human in need of such treatment, the method comprising, consisting of and / or consisting essentially of administering to the human a therapeutically effective amount of niraparib, wherein the prostate cancer is castration-resistant prostate cancer ("CRPC"), metastatic castration-resistant prostate cancer and / or anti-androgen-resistant prostate cancer.

[0012] In another embodiment, the invention relates to a method for treating prostate cancer in a human in need of such treatment, the method comprising, consisting of and / or consisting essentially of administering niraparib to a human, wherein the human carries at least one DNA repair abnormality selected from the group consisting of BRCA-1, BRCA-2, FANCA, PALB2, CHEK2, BRIP1, HDAC2 and ATM.

[0013] In another embodiment, the invention relates to a method for treating prostate cancer in a human in need of such treatment, the method comprising, consisting of and / or consisting essentially of administering niraparib to a human, wherein the human carries at least one DNA repair abnormality, i.e., BRCA-1 or BRCA-2.

[0014] In another embodiment, the invention is directed to a method of treating prostate cancer in a human in need of such treatment, the method comprising, consisting of and / or consisting essentially of administering to the human an amount of niraparib, preferably from about 30 mg / day to about 400 mg / day, more preferably 300 mg / day, and most preferably taken orally once daily as three 100 mg oral dosage forms.

[0015] In another embodiment, the present invention is directed to a composition comprising niraparib for use in the treatment of prostate cancer, anti-androgen resistant prostate cancer, castration resistant prostate cancer, and metastatic castration resistant prostate cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 : Niraparib was shown to inhibit the growth of human prostate tumor cell lines in vitro.

[0017] Figure 2 : Shown that niraparib inhibits PAR formation in two human prostate tumor cell lines in vitro.

[0018] Figure 3 : shows that niraparib treatment induces an increase in γ-H2AX in 22RV1 cells in a dose-dependent manner, as measured by flow cytometry.

[0019] Figure 4 : Shows that niraparib induces γ-H2AX in 22RV1, LNCaP AR-TB and C4-2B cells in vitro.

[0020] Figure 5 : Shown that niraparib treatment inhibits the growth of C4-2B-luc prostate tumors in NSG male mice. DETAILED DESCRIPTION

[0021] The term "subject" refers to a mammal, most preferably a human, who has been or is the object of treatment, observation or experiment.

[0022] The term "treatment" refers to the treatment of a subject with a pathological condition, and refers to the effect of alleviating the condition by killing cancer cells, and also refers to the effect of causing the progression of the condition to be inhibited, and includes the slowing down of the progression rate, the termination of the progression rate, the improvement of the condition, and the cure of the condition. Treatment as a preventive measure (i.e., prevention) is also included.

[0023] The term "therapeutically effective amount" refers to the amount of niraparib that elicits a biological or medical response in a tissue system that is being sought by a researcher, veterinarian, physician or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition or disorder being treated.

[0024] The term "safe and effective amount" refers to an amount of niraparib that causes prevention or amelioration of disease progression and unacceptable toxicity in humans.

[0025] The term "composition" refers to a pharmaceutical product, sometimes comprising specified ingredients in therapeutically effective amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0026] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for contact with human tissues, without excessive toxicity, irritation, allergic reaction, or other problems or complications, and commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Each carrier, excipient, etc. must be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0027] As used herein, the term "androgen receptor" is intended to include wild-type androgen receptor as well as androgen-resistant AR and / or AR mutants associated with castration-resistant prostate cancer.

[0028] As used herein, the term "antiandrogen" refers to a class of hormone receptor antagonist compounds that can prevent or inhibit the biological effects of androgens on normal responsive tissues in the body. In some embodiments, the antiandrogen is a small molecule. Antiandrogens include enzalutamide, apalutamide, and abiraterone acetate.

[0029] As used herein, the term "first generation antiandrogen" refers to an agent that exhibits antagonist activity of a wild-type AR polypeptide. However, first generation antiandrogens differ from second generation antiandrogens in that first generation antiandrogens may act as agonists in CRPC.

[0030] Exemplary first generation antiandrogens include, but are not limited to, flutamide, nilutamide, and bicalutamide.

[0031] As used herein, the term "second generation antiandrogen" refers to an agent that exhibits full antagonist activity of wild-type AR polypeptides. The second generation antiandrogens differ from the first generation antiandrogens in that the second generation antiandrogens act as full antagonists in cells expressing elevated levels of AR, such as, for example, in CRPC. Exemplary second-generation antiandrogens include 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide (also known as ARN-509; CAS No. 956104-40-8); 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (also known as MDV3100 or enzalutamide; CAS No.: 915087-33-1) and RD162 (CAS No. 915087-27-3). In some embodiments, the second-generation antiandrogen binds to the AR polypeptide at or near the ligand binding site of the AR polypeptide.

[0032] As used herein, the term "third generation anti-androgen" refers to an agent that exhibits full antagonist activity against wild-type AR polypeptides and mutant forms of AR polypeptides having mutations produced in the ligand binding domain (LBD) of the AR polypeptide as shown below. The third generation of anti-androgens differs from the first generation of anti-androgens in that the third generation of anti-androgens act as full antagonists in cells expressing elevated levels of AR, such as, for example, in CRPC.

[0033] As used herein, the term "mutant" refers to an altered (compared to a reference) nucleic acid or polypeptide, or to a cell or organism comprising or expressing such an altered nucleic acid or polypeptide.

[0034] Unless otherwise indicated, as used herein, the terms "affect" or "affected" (when referring to a disease, syndrome, condition, or disorder affected by AR antagonism) include a reduction in the frequency and / or severity of one or more symptoms or clinical manifestations of the disease, syndrome, condition, or disorder; and / or include preventing the development of one or more symptoms or clinical manifestations of the disease, syndrome, condition, or disorder or the development of the disease, syndrome, condition, or disorder.

[0035] Embodiments of the present invention include prodrugs of niraparib. Generally speaking, such prodrugs will be functional derivatives of compounds that can be easily converted into the desired compound in vivo. Therefore, in the methods of treatment or prevention of the present invention, the term "administering" covers the use of specifically disclosed compounds or unspecified compounds to treat or prevent the various diseases, conditions, syndromes and disorders described, but the unspecified compounds will be converted into the specified compounds in vivo after administration to the patient. For example, in "Design of Prodrugs", edited by H. Bundgaard, Elsevier, 1985, conventional procedures for selecting and preparing suitable prodrug derivatives are described.

[0036] Androgen receptor (AR)

[0037] Androgen binds to specific receptors in the cells of target tissues, namely androgen receptors (AR). AR is expressed in a variety of body tissues, and the physiological and pathophysiological effects of endogenous androgen ligands such as testosterone (T) and dihydrotestosterone (DHT) are expressed by the receptor. Structurally, AR consists of three main functional domains: ligand binding domain (LBD), DNA binding domain, and amino terminal domain. Compounds that bind AR and simulate the effects of endogenous AR ligands are called AR agonists, while compounds that inhibit the effects of endogenous AR ligands are called AR antagonists. The binding of androgen to receptors activates it and binds it to the DNA binding site adjacent to the target gene. Thus, it interacts with coactivator proteins and basal transcription factors to regulate the expression of the gene. Therefore, via its receptor, androgen causes changes in gene expression in cells. These changes ultimately affect cell metabolism, differentiation or proliferation, which are visible in the physiology of target tissues. In the prostate, androgen stimulates prostate tissue and prostate cancer cell growth by binding to AR present in the cytoplasm of androgen-sensitive tissues.

[0038] With respect to hormone replacement therapy (HRT) for male contraception, male sexual enhancement, male reproductive diseases, and primary or secondary androgenic hypogonadism, compounds that selectively modulate the AR are of clinical importance in the treatment or prevention of a variety of diseases, disorders, and cancers including, but not limited to, prostate cancer, benign prostatic hypertrophy, female hirsutism, alopecia, anorexia nervosa, breast cancer, acne, musculoskeletal diseases such as bone diseases, hematopoietic disorders, neuromuscular diseases, rheumatic diseases, cancer, AIDS, cachexia.

[0039] Castration-resistant prostate cancer

[0040] The reagent (antiandrogen) that blocks the action of endogenous hormones (such as testosterone) is highly effective and is commonly used to treat prostate cancer (androgen withdrawal therapy). Although it is effective to suppress tumor growth initially, these androgen withdrawal therapies eventually fail in almost all cases, resulting in CRPC. Most, but not all, prostate cancer cells initially respond to androgen withdrawal therapy. However, the survival population of prostate cancer cells appears over time because they have responded to the selection pressure produced by androgen withdrawal therapy and are currently difficult to cure with androgen withdrawal therapy. Not only is it difficult to cure primary cancer with available therapy, but cancer cells may also detach from the primary tumor and travel in the bloodstream, thereby spreading the disease to distant sites (especially bones). This is called metastatic castration-resistant prostate cancer ("mCRPC"). Among other effects, this causes severe pain and further bone fragility in subjects.

[0041] In some embodiments, the subject's prostate cancer is resistant or unresponsive to anti-androgen therapy including, but not limited to, enzalutamide, apalutamide, and abiraterone acetate ("anti-androgen resistance").

[0042] The preparation of niraparib, i.e., 2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide, can be found in U.S. Patent No. 8,071,623, filed on December 6, 2011, entitled “Amide Substituted Indazoles as Poly(ADP-Ribose)Polymerase(PARP)Inhibitors,” which claims the benefit of U.S. Provisional Patent Application No. 60 / 921,310, filed on February 16, 2010, and U.S. Patent No. 8,436,185, filed on May 7, 2013, entitled “Pharmaceutically Acceptable Salts of 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide,” which claims the benefit of U.S. Provisional Patent Application No. 61 / 010,333, filed on January 8, 2008, each of which is incorporated herein by reference.

[0043] The present invention also provides a pharmaceutical composition comprising niraparib and a pharmaceutically acceptable carrier. The pharmaceutical composition comprising the active ingredient can be in a form suitable for oral administration, for example, as a tablet, lozenge, lozenge, aqueous or oily suspension, dispersible powder or granules, emulsion, hard or soft capsule, or syrup or elixir.

[0044] Compositions intended for oral administration may be prepared according to any method known in the art for preparing pharmaceutical compositions, and in order to provide pharmaceutically high-quality and palatable preparations, such compositions may contain one or more agents selected from the following: sweeteners, flavoring agents, coloring agents and preservatives. Tablets contain active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, corn starch, or alginic acid; binders such as starch, gelatin, polyvinyl-pyrrolidone or gum arabic, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract, and thereby provide sustained action over a longer period of time. For example, a water soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropyl cellulose, or a time delay material such as ethylcellulose, cellulose acetate butyrate may be employed.

[0045] Formulations for oral administration may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin; or as soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil medium such as peanut oil, liquid paraffin or olive oil.

[0046] Aqueous suspensions contain active substances mixed with excipients suitable for preparing aqueous suspensions. Such excipients are suspending agents, such as sodium hydroxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersants or wetting agents may be naturally occurring phospholipids such as lecithin, or condensation products of oxyalkylene with fatty acids such as polyoxyethylene stearate, or condensation products of oxyalkylene with long-chain aliphatic alcohols such as heptadecaethyleneoxycetanol, or condensation products of oxyalkylene with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of oxyalkylene with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose, saccharin or aspartame.

[0047] Oily suspensions can be prepared by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin. Oily suspensions can include thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweeteners (such as those listed above) and flavoring agents can be added to provide a palatable oral formulation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0048] Dispersible powders and granules suitable for preparing aqueous suspensions by the addition of water provide the active ingredient mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those mentioned above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents may also be present. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0049] Pharmaceutical compositions of the present invention can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture of these. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweeteners, flavoring agents, preservatives and antioxidants.

[0050] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain demulcents, preservatives, flavorings, and coloring agents and antioxidants. Pharmaceutical compositions may also be in the form of sterile injectable aqueous solutions. Among acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution may be used.

[0051] The sterile injectable preparation can also be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient can be first dissolved in a mixture of soybean oil and lecithin. The oil solution is then introduced into a mixture of water and glycerol and processed to form a microemulsion.

[0052] The injectable solution or microemulsion can be introduced into the patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in a manner that maintains a constant circulating concentration of the compound of the invention. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS TM Model 5400 Intravenous Pump.

[0053] The pharmaceutical composition can be in the form of a sterile injectable aqueous suspension or oily suspension for intramuscular and subcutaneous administration. The suspension can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned above. Sterile injection preparations can also be sterile injection solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, such as solutions of 1,3-butanediol. In addition, sterile fixed oils are generally used as solvents or suspension media. For this reason, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can be used in injection preparations.

[0054] Niraparib can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at the rectal temperature and will therefore dissolve in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

[0055] For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds of the invention are employed (for the purposes of this application, topical application shall include mouthwashes and gargles).

[0056] Niraparib can be administered in intranasal form via topical use of a suitable intranasal vehicle and delivery device, or via a transdermal route using those transdermal patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will of course be continuous rather than intermittent throughout the dosage regimen. Niraparib can be delivered as a suppository using a matrix such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

[0057] When niraparib is administered to a subject, the selected dosage level depends on a variety of factors, including but not limited to the activity of the particular compound, the severity of the individual's symptoms, the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds and / or materials used in combination, and the patient's age, sex, weight, condition, general health and past medical history. The amount and route of administration of niraparib will ultimately be determined by the physician, but generally the dosage will be such that the local concentration at the site of action will achieve the desired effect without causing substantial harm or adverse side effects.

[0058] In vivo administration can be carried out continuously or intermittently (e.g., in divided doses at appropriate intervals) in a single dose throughout the course of treatment. Methods for determining the most effective mode of administration and dosage are well known to those skilled in the art and vary with the preparation used for treatment, the purpose of treatment, the target cell to be treated, and the subject to be treated. The treating physician can select the dosage level and pattern for single or multiple administrations.

[0059] Generally, suitable doses of niraparib range from about 100 μg / kg to about 250 mg / kg of subject body weight per day. When the active compound is a salt, ester, prodrug, etc., the amount administered is calculated based on the parent compound so that the actual weight used is increased proportionally.

[0060] The therapeutically effective amount of niraparib or a pharmaceutical composition thereof for treating prostate cancer includes a dosage range of niraparib from about 30 mg / day to about 400 mg / day, or any specific amount or range therein, particularly about 300 mg / day, and three 100 mg oral dosage forms taken orally once a day. The optimal dose of niraparib to be administered can be easily determined and will vary with the specific compound used, the mode of administration, the strength of the formulation, and the course of the disease, syndrome, condition or disorder. In addition, factors related to the specific subject to be treated (including the subject's sex, age, weight, diet, and time of administration) will result in the need to adjust the dose to achieve the appropriate therapeutic level and desired therapeutic effect. Therefore, the above doses are examples of general situations. Of course, there may be individual cases where higher or lower dosage ranges are beneficial, and such cases are also within the scope of the present invention.

[0061] Niraparib may be administered in any of the above compositions and dosing regimens, or by those compositions and dosing regimens established in the art, so long as the use of niraparib is desired by a subject in need thereof.

[0062] Example

[0063] The following examples are presented to aid in understanding the present invention and are not intended to, and should not be construed to, limit in any way the present invention set forth in the claims that follow the examples.

[0064] Example 1

[0065] In vitro cytotoxicity of niraparib in human prostate tumor lines

[0066] In vitro, the cytotoxicity of niraparib was tested in several human prostate tumor lines, none of which were known to be deficient in BRCA-1 or BRCA-2.

[0067] method :

[0068] The in vitro cytotoxicity of niraparib was evaluated in five human prostate cancer cell lines: C4-2B, LNCaP, LNCaPAR.TB, VCaP and 22Rv1. C4-2B, LNCaP, LNCaPAR.TB and 22Rv1 cell lines were grown in RPMI1640+GlutaMAX supplemented with 10% heat-inactivated fetal bovine serum (FBS) (Life Technologies #16140-071) and non-essential amino acids (NEAA) (Life Technologies #11140-050). TM -I medium (Life Technologies #61870-036); and VCaP cells were grown in DMEM + GlutaMAX containing 10% FBS and NEAA TM -I medium (Life Technologies ## 10569-010). VCaP cells were subcultured every 7 days; other lines were split every 3-4 days.

[0069] Cell growth kinetics of each cell line were determined by inoculating cells at several densities and monitoring growth at intervals up to 7 days. Growth was determined using Promega Cell TiterGlo reagent (#G7571) to measure cellular ATP by means of a chemiluminescent luciferin-luciferase reaction. Plates were read on a Perkin-Elmer Envision plate reader, and luminescence values ​​were plotted to determine the inoculation density that resulted in the logarithmic growth phase and the cell density within the linear range of the desired time point Cell TiterGlo assay.

[0070] For niraparib cytotoxicity experiments, cells were harvested by brief trypsinization and each cell line was seeded at an appropriate density into the inner 60 wells of a 96-well plate in 100 μL of culture medium for 7 days of treatment. The outer wells of each plate were filled with Dulbecco's phosphate buffered saline (DPBS; Life Technologies #14190-144) to reduce evaporation from the test wells. The cells were incubated at 37°C in a humidified 5% CO 2 The plates were left to stand overnight in an incubator. Treatments were initiated by adding 50 μL of the appropriate medium containing 3× niraparib (final concentrations of 500 μM, 125 μM, 31.3 μM, 7.8 μM, 1.95 μM, 0.49 μM, 0.12 μM, 0.03 μM) to triplicate wells. The final vehicle concentration was 0.5% DMSO.

[0071] Cells were cultured for 7 days. Relative cell viability after treatment was determined using Cell TiterGlo reagent as above. All luminescence output values ​​were normalized to percent inhibition based on the mean luminescence of the untreated control wells, and the mean percent inhibition of the vehicle control wells was subtracted from each treatment value. Percent inhibition was plotted in GraphPad Prism 7.00 versus log μM concentration. EC was calculated using log(agonist) versus response—variable slope (four-parameter) fitting. 50 Nonlinear regression and calculation of values.

[0072] result :

[0073] The results of the cytotoxicity assay are shown in Figure 1 and Table 1. The growth of each cell line was decreased in a dose-dependent manner by increasing the concentration of niraparib. C4-2B cells appeared to be the most sensitive, and EC 50 The value is about 1.2 μM. VCaP cells appear to be the least sensitive, and EC 50 The value is 4.1 μM.

[0074] Cell lines <![CDATA[EC 50 ,μM <!-- 7 -->]]> C4-2B 1.222 LqCy 3.502 LNCaPAR.TB 2.140 VCaP 4.099 22Rv1 3.517

[0075] Table 1: EC of human prostate tumor cell lines treated with 7-day niraparib 50 value .

[0076] Example 2

[0077] Inhibition of PAR formation by niraparib

[0078] The ability of niraparib to inhibit poly(ADP)ribose (PAR) formation was tested in vitro in two human prostate tumor lines, none of which were known to be deficient in BRCA-1 or BRCA-2.

[0079] method :

[0080] Inhibition of PAR by niraparib was evaluated in two human prostate cancer cell lines, C4-2B and VCaP. C4-2B cell line was grown in RPMI1640+GlutaMAX supplemented with 10% FBS and NEAA. TM -I medium and split every 3-4 days. VCaP cells were grown in DMEM + GlutaMAX containing FBS and NEAA. TM -I medium and subcultured every 7 days.

[0081] Harvest cells by brief trypsinization and seed each cell line at the appropriate density in 1 mL of culture medium in a 6-well plate. Add an additional 500 μL of complete culture medium to a total volume of 1.5 mL per well. Incubate cells at 37°C in a humidified atmosphere of 5% CO. 2 The cells were placed in a plate in an incubator overnight. The next day, the medium was removed from the plate and the cells were washed with 1 mL of serum-free medium (RPMI or DMEM, respectively). The treatment began with the addition of appropriate medium containing 1 mL of niraparib (final concentrations of 100 μM, 10 μM, 1 μM, 0.1 μM, 0.01 μM, and 0 μM in 0.1% DMSO) to triplicate wells. The plate was returned to the incubator for two hours.

[0082] After treatment, extracts were prepared using the reagents and methods provided in the HT PARP In Vivo Pharmacodynamics Assay II (Trevigen #4520-096-K). Media was removed from each well and placed into individually labeled microcentrifuge tubes, and the plates were placed on ice. The tubes were spun at 1500 rpm for 4 minutes to allow any cell pellets that had detached from the plates during drug incubation to settle. Lysis buffer was prepared using 24.5 mL of cell lysis reagent and 250 μL of 100 mM PMSF (dissolved in ethanol; Sigma #93482) and 250 μL of 100× protease inhibitor cocktail (Thermo Scientific #78429). Lysis buffer (300 μL) was added to each well of the plate on ice. Adherent cells were scraped into lysis buffer and kept on ice for at least 15 minutes. Supernatant was removed from the microcentrifuge tubes and cell lysate from the 6-well plate was added to each tube of the corresponding tube. SDS (20% w / v) was added to bring the final SDS concentration to 1%. The cell extracts were heated to 95-100°C for 5 minutes. After cooling to room temperature, 0.01 volume of 100X magnesium cations and 3 μL DNase were added to each tube. The tubes were briefly vortexed and returned to the 37°C incubator for 90 minutes. After incubation, the tubes were centrifuged at 10,000×g for 10 minutes at room temperature. If a precipitate was present, it was removed using a pipette and the extract was transferred to a 96-well dilution plate. The cell extracts were frozen at -80°C until used for protein quantification and PAR ELISA assays. The ELISA assay protocol was performed according to the manufacturer's instructions.

[0083] Protein quantification was performed using a detergent-compatible Biorad DC protein assay kit II (#500-0002) using the Biorad Quick Start bovine serum albumin standard set (#5000207) according to the manufacturer's 96-well plate protocol. ELISA lysis buffer was added to the standards, and an equal volume of PBS was added to all sample wells to correct for any effect of the lysis buffer on the protein readings. The samples were assayed in duplicate. Buffer A' (25 μL) was added to all wells of the plate, and 200 μL of buffer B was immediately added to each well. The plate was incubated on a shaker at room temperature for 15 minutes. In SoftMax Pro version 6.3 software, the DC protein assay protocol was used to read the absorbance at 750 nm on a Molecular Devices M5 plate reader. Linear regression of the standard curve, interpolation of sample protein values, and averaging of replicates were performed in the software. Data were exported to Excel, where any corrections for sample dilutions were performed.

[0084] Luminescence values ​​of PAR ELISA standards and samples were analyzed in GraphPad Prism version 7, where linear regression of the standard curve and sample interpolation were calculated. Interpolated PAR values ​​(pg PAR / mL) were corrected for sample dilution and divided by the corresponding protein concentration to obtain pg PAR / mg of protein. These values ​​were plotted in GraphPad Prism v7.

[0085] result :

[0086] The results of the PAR assay are shown in Figure 2 PAR decreased in a dose-dependent manner with increasing concentrations of niraparib in each cell line.

[0087] Example 3

[0088] Niraparib induces γ-H2AX in human prostate tumor lines in vitro

[0089] The ability of niraparib to induce DNA double-strand breaks was measured in three human prostate cancer cell lines: 22RV1, LNCaP AR.TB, and C4-2B. DNA double-strand breaks are followed by phosphorylation of the adjacent histone γ-H2AX, and this phosphorylation can be measured by antibody staining and flow cytometry.

[0090] method :

[0091] 22RV1, LNCaP AR.TB and C4-2B cell lines were grown as outlined above. Cell lines were passaged every 3-4 days.

[0092] For each cell line, 2 × 10 5 Each well of a 12-well plate (Falcon #353043) was inoculated with 1 mL of culture medium. The cells were incubated at 37°C in a humidified atmosphere of 5% CO. 2 Incubator overnight, then add 1mL medium containing 2× concentrated serial dilutions of niraparib to achieve final concentrations of 200μM, 100μM, 50μM, 25μM, 12.5μM, 6.25μM, 3.13μM, 1.57μM, 0.78μM, 0.39μM, 0.2μM and 0.1μM in triplicate wells. The final vehicle concentration was 0.2% DMSO, and vehicle and medium controls for triplicate wells of each cell line were obtained. The plate was incubated for another 18 hours.

[0093] After 18 hours with drug incubation, by first 2mL culture medium is transferred to 15mL conical tube (Corning#430798) in harvest and obtain the cell of each hole.Then the cell dissociation buffer (Gibco#13151-014) of 500 μ L is added in hole and allowed to stand for 5 minutes.Use 1mL transfer pipette, 1mL culture medium is added in hole, remove cell by suction, and the culture medium comprising cell is transferred in corresponding 15mL conical tube.Pipe is centrifuged at 1200rpm for 5 minutes, discards supernatant, and makes the cell of precipitation resuspend and transfer in 96 hole v bottom flat plate (Costar#3896).Flat plate is centrifuged at 1800rpm for 3 minutes, discards supernatant, and hole is washed with 200 μ L of DPBS subsequently.This process repeats 3 times washing altogether. The cells were then stained with 100 μL of DPBS containing a 1:800 dilution of Invitrogen Live / Dead Fixable Solution (Invitrogen #L34957) at 4°C for 20 minutes. The cells were then washed with 150 μL of BD Pharmingen staining buffer (staining buffer; BD #554657) and centrifuged at 1800 rpm for 3 minutes. The cells were washed twice more with 200 μL of staining buffer and then once with DPBS.

[0094] The cells were washed with 100 μL -20°C 70% ethanol / H 2O fixation and the plate was stored at -20°C for 2 hours. The cells were washed 3 times with staining buffer, centrifuged at 2200 rpm for 3 minutes between each wash. The cells were then incubated at 4°C for 20 minutes with 100 μL of 1:1 diluted staining buffer and AXELL free biotin Fc receptor blocker (Accurate Chemical & Scientific Corp #NB309). The cells were washed with 150 μL of staining buffer, then centrifuged at 2200 rpm for 3 minutes, the supernatant was discarded, and the cells were then incubated with 50 μL of staining buffer containing 0.2% v / v Triton X-100 (Acros Organics #21568-2500) together with a 1:100 diluted γ-H2AX antibody (Biolegend #613408) at room temperature in the dark for 2 hours.

[0095] The cells were washed once with 200 μL of staining buffer containing 0.2% v / v Triton X-100 and then washed once with 200 μL of staining buffer only. The cells were resuspended in 80 μL of staining buffer and 50 μL were analyzed on a BD Fortessa flow cytometer. Data were analyzed using TreeStar FlowJo v9.8.5. Data were gated for live cells and then the γ-H2AX antibody signal was evaluated for the entire population after doublet discrimination. The results are plotted in GraphPadPrismv7.

[0096] result :

[0097] Representative bar graphs of the 22RV1 cell line are shown in Figure 3 In Figure 4, the effects of different concentrations of niraparib are shown. Drug-treated samples were compared with vehicle and medium controls and plotted in Figure 4. The lowest concentration at which the γ-H2AX signal increased significantly above the vehicle control is shown in Table 2. The results show that niraparib induced γ-H2AX in a dose-dependent manner in each prostate tumor line.

[0098]

[0099] Table 2: Minimum concentration of niraparib that induces significant changes in γ-H2AX

[0100] Example 4

[0101] Niraparib inhibits the growth of C4-2B human prostate tumors in mice.

[0102] The activity of niraparib was tested in a pre-established subcutaneous C4-2B model of human prostate in non-obese diabetic (NOD) severe combined immunodeficient (scid) gamma (NOD.Cg-Prkdc Il2rg / SzJ) (NSG) mice. This tumor model is not considered to be BRCA-1 or BRCA-2 deficient.

[0103] method :

[0104] The solvent was 0.5% methylcellulose (Methocel TM F4M) and stored in the dark at 4 ° C. All preparations were prepared to be administered in a volume of 10 mL / kg body weight. NSG male mice (Jackson Laboratories) were used. Animals were adapted for one week before any experimental procedures were performed. Mice were group-housed (5 per cage) in disposable IVC-cages (Innovive, San Diego, CA, USA) at 19 ° C to 22 ° C temperatures and 35% to 40% humidity with a 12-h light: dark cycle. Mice were fed high-fat (6%) laboratory solid feeds sterilized by autoclave and free access to water.

[0105] Mice were injected with LNCaP C4-2B-luc labeled cells (1×10 6 tumor cells) in a volume of 200 μl :RPMI 1640 medium (1:1 ratio). Mice were divided into groups according to tumor volume (tumor volume = 241 ± 14 mm 3 ) were randomized into groups with 10 mice per treatment group. Mice were dosed daily by gavage (po) at a dose volume of 10 mL / kg with vehicle or vehicle containing niraparib as indicated below. Treatment start = Day 1. Mice were treated through study day 24.

[0106] Group 1 0 mg / kg vehicle (0.5% Methocel F4M) was administered QD po

[0107] Group 2: 25 mg / kg niraparib in 0.5% Methocel F4M administered QD po

[0108] Group 3: 50 mg / kg niraparib in 0.5% Methocel F4M administered QD po

[0109] For each individual animal, [using the formula: tumor volume (mm3) = (a × b 2 / 2); where "a" represents length and "b" is tumor width determined by caliper measurement] Body weight and tumor volume were monitored twice a week throughout the study. For pre-existing tumors, the time course of tumor growth was expressed as mean ± standard error of the mean (SEM).

[0110] result :

[0111] Starting around study day 22, tumor volumes in vehicle-treated mice began to reach the ethical limit of tumors (for individual tumor volumes see Figure 5 ). Tumor volume data are presented up to study day 24 (when 9 of 10 vehicle-treated mice remained in the study). Group 3, which was given 50 mg / kg niraparib po daily, showed significant inhibition / delay of tumor growth after 18, 22, and 24 days of treatment, and the tumor growth inhibition (TGI) values ​​for these days were about 40%. Significant differences in tumor growth were observed on days 18, 22, and 24 (*p<0.05; **p<0.01; ***p<0.001). Mice given 25 mg / kg niraparib did not show significant tumor growth inhibition, but there was a modest TGI of about 12% on days 22 and 24.

[0112] Example 5

[0113] A multicenter, open-label study was conducted to evaluate the efficacy and safety of 300 mg of niraparib administered once daily in male subjects aged 18 years and older with mCRPC and DNA-repair abnormalities who had undergone at least one line of taxane-based chemotherapy and at least one line of anti-androgen therapy (e.g., abiraterone acetate, enzalutamide, apalutamide). The study will recruit approximately 100 subjects. The safety of the subjects will be monitored for up to 30 days during the study and after the last dose of the study drug. Treatment will continue until disease progression, unacceptable toxicity, death, or the sponsor terminates the study.

[0114] The study will consist of 4 phases; a prescreening phase for biomarker evaluation only, a screening phase, a treatment phase, and a follow-up phase. Efficacy evaluations will include the following: Tumor measurements: CT or MRI scans of the chest, abdomen, and pelvis and whole-body bone scans ( 99mTc ), serum PSA, survival status, CTC, and symptomatic skeletal events (SSE).

[0115] 300 mg of niraparib will be provided as capsules (3×100 mg) for oral administration once daily. The capsules must be swallowed whole. Subjects should take their dose in the morning (with or without food). Although not taking study medication, subjects who have not undergone surgical castration must continue to receive their regularly prescribed GnRHa. All GnRHa therapy should be recorded in the concomitant medication section of the eCRF.

[0116] The treatment cycle is defined as 28 days. Subjects will start taking niraparib on Day 1 of Cycle 1. An amount of niraparib sufficient for each treatment cycle will be distributed on the first day of each cycle. If a subject misses a dose, the dose should be supplemented if the subject remembers within a window of approximately 12 hours. Otherwise, the subject should take the next dose the next day without compensating for the missed dose. The missed dose should be recorded in the eCRF.

[0117] Pre-screening phase for biomarker evaluation

[0118] If the subject is biomarker positive for a DNA repair abnormality, the prescreening phase will be evaluated. All subjects will be required to sign a specific ICF for the prescreening phase and provide baseline demographic characteristics and medical history of specific diseases. The prescreening phase can occur at any time before the screening phase.

[0119] The process for determining biomarker positivity will be different for subjects who enter the prescreening phase before blood-based assays are available compared to subjects who enter after blood-based assays are available. These two processes are described below.

[0120] The process of determining biomarker positivity before blood-based assays were available

[0121] Subjects sign the pre-screening ICF. Tumor tissue for genomic analysis can be reviewed after the subject gives permission for release. Data were used to determine eligibility based on the criteria defined in Table 1. If a subject was biomarker positive, they were eligible to enter the screening phase. If a subject is biomarker positive, they are eligible to enter the Screening Phase.

[0122] Blood samples will also be collected from all subjects during the prescreening phase and stored until a blood-based assay becomes available. At the point in time when a blood-based assay becomes available, the stored blood samples will be analyzed for consistency with the tumor tissue sample results. This analysis can occur at any time after the blood-based assay becomes available.

[0123] Process for determining biomarker positivity after blood-based assays become available

[0124] Subject signs pre-screening ICF. Blood sample is collected and sent for biomarker positive analysis. Tumor tissue for genomic analysis can be reviewed after the subject gives permission for release. Data were used to determine eligibility based on the criteria defined in Table 1. If subjects were biomarker positive, they were eligible to proceed to the screening phase and did not need to wait for blood-based assay results. If a subject is genomic negative, they may still be considered eligible if they are determined to be biomarker positive by a blood-based assay. If the subject has a tumor tissue that has been genomic analyzed and the archived tissue is available, a request is initiated for the retrieval and analysis of the archived tumor tissue. If the blood-based assay result is positive for the biomarker, the subject is eligible to enter the screening phase and does not need to wait for the results of the archived tumor tissue-based analysis. The results of the archived tumor tissue-based analysis can be used together with the blood-based results when available for consistency and bridging studies.

[0125] At the discretion of the study sponsor, if the blood-based assay result is negative, results based on archived tumor tissue may be used to determine eligibility.

[0126] If no archived tumor tissue was available, the subject had to consent for tumor tissue collection.

[0127] If the blood-based assay is biomarker positive, the most recent tumor tissue must be collected by Cycle 1, Day 1 for subsequent consistency and bridging studies. Analysis of the most recently collected tumor tissue may occur at any time during the study, and results may not be required until the subject enters the Screening Phase.

[0128] At the discretion of the study sponsor, recently collected tumor tissue may be used to determine eligibility if the blood-based assay result is negative.

[0129] Once a subject is identified as biomarker positive during the prescreening phase, the screening phase should begin within 30 days.

[0130] Screening stage

[0131] All biomarker-positive subjects must sign the main study ICF before any study-related procedures are performed during the screening phase. During this phase, the eligibility criteria will be reviewed and a complete clinical evaluation will be performed as specified in the time and event schedule. Unless otherwise specified, the screening process will be performed up to 35 days before Day 1 of Cycle 1. Imaging will be received up to 8 weeks before Day 1 of Cycle 1. If performed within 14 days of Cycle 1, the screening clinical safety laboratory evaluation can be used for Cycle 1 Day 1 evaluation.

[0132] Subjects who do not meet all inclusion criteria or meet exclusion criteria may be rescreened once. Rescreening is at the discretion of the Investigator and requires Sponsor approval and consent. Subjects to be rescreened must sign a new ICF prior to prescreening. Subjects rescreened within 35 days of planned enrollment may have initial screening laboratory results, computed tomography (CT) / magnetic resonance imaging (MRI), and bone scan (if still within 8 weeks of Cycle 1 Day 1) used to determine eligibility if these are not the reason for rescreening.

[0133] Treatment phase

[0134] The treatment phase will begin on Cycle 1 Day 1 and will continue until study drug is discontinued. The last measurement taken on Cycle 1 Day 1 or screening before administration of study drug (whichever value is last) will be defined as the baseline value. Unless otherwise specified, visits to each cycle will have a ±3-day window. Study visits will be calculated from the date of Cycle 1 Day 1. Subjects may be imaged within ±7 days of the visit where images are required. Refer to the time and event schedule for treatment visits and assessments during the treatment phase.

[0135] For PK and pharmacodynamic sampling days, subjects must not take study medication at home on the morning of the study visit. Study medication should be taken on site. Details of PK and pharmacodynamic sampling days and times are provided in the Time and Event Schedule. Additional details on PK sampling are provided in Section 9.3. Details of blood sample handling and storage procedures for PK and pharmacodynamics are provided in the Laboratory Operations Manual.

[0136] Clinical evaluations and laboratory studies may be repeated more frequently if clinically appropriate. Study drug treatment will continue until disease progression, unacceptable toxicity, death, or termination of the study by the sponsor. Once a subject discontinues study drug, the subject must complete an End of Treatment (EoT) visit within 30 days after the last dose of study drug and enter the Follow-up Phase.

[0137] End of treatment visit

[0138] The End of Treatment Visit must be planned within 30 days after the last dose of study drug or before the administration of new anti-prostate cancer therapy (whichever occurs first). If the subject is unable to return to the EoT visit site, the subject should be contacted to collect AEs occurring within 30 days after the last dose of study drug.

[0139] Follow-up phase

[0140] Once the subject completes the treatment phase, survival follow-up and SSE will be conducted every 3 months via clinic visits, telephone interviews, medical record review, or other convenient methods. Deaths regardless of causality and SAEs considered related to study drug will be collected and reported within 24 hours of event discovery or notification. If follow-up information is obtained via telephone contact, written documentation of the communication must be obtained to review the source document.

[0141] Biomarker-positive samples for DNA repair abnormalities

[0142] To evaluate whether a subject is biomarker positive, blood-based assays may become available during the study, which will provide a more rapid method to determine biomarker positive status than tissue-based analysis, while being more convenient for the subject. Tumor tissue (archived or recently collected) will need to be analyzed before blood-based assays become available. In order to ensure that all subjects (regardless of when they enter the study) have the same biomarker data available for analysis (i.e., for consistency and bridging studies), tumor tissue and blood samples will be collected from all subjects who sign the pre-screening informed consent form (ICF). The process for determining biomarker positivity for subjects who enter the pre-screening phase before the blood-based assays are available will be different than for subjects who enter after the blood-based assays are available. However, all subjects will be assessed for biomarker positive status for both tumor tissue and blood.

[0143] To be eligible for the study, subjects must have confirmed biomarker positivity by tumor tissue (archive or recently collected) or blood testing (when available). The biomarkers of interest for this study and the criteria for biomarker positivity are listed in Table 3. Analyses will be performed to define biallelic loss (e.g., mutation co-expression frequency, with copy number loss) surrogate indicators, and these surrogate indicators can be used to determine biomarker positivity when this information becomes available.

[0144] Table 3: Biomarker Panels and Positive Criteria

[0145]

[0146] Monoallelic losses in all genes will be acceptable for entry into the study until existing algorithms for biallelic losses are validated.

[0147] Circulating tumor cells

[0148] At the time points specified in the time and event schedule, blood samples were collected into cell storage tubes. CTC counts were evaluated in a central laboratory to assess response to study drug.

[0149] Whole Blood for RNA

[0150] Whole blood samples will be collected in Paxgene tubes.Multiple ribonucleic acid (RNA) transcripts present in prostate tumors are detectable in RNA, and analysis of these samples will allow evaluation of potential resistance mechanisms that may arise from niraparib.

[0151] Circulating tumor DNA

[0152] Plasma samples collected during the course of treatment were screened for changes over time in the levels or types of DNA repair abnormalities observed via circulating tumor DNA (ctDNA) and to monitor potential markers of niraparib resistance.

[0153] While the above description illustrates the principles of the invention by providing embodiments thereof, it should be understood that the practice of the invention encompasses all general variations, changes and / or modifications within the scope of the following claims and their equivalents.

[0154] This application relates to the following implementation schemes:

[0155] 1. A method of treating prostate cancer in a human in need of such treatment, the method comprising administering to the human a safe and effective amount of niraparib.

[0156] 2. The method according to embodiment 1, wherein the prostate cancer is castration-resistant prostate cancer or metastatic castration-resistant prostate cancer.

[0157] 3. A method according to embodiment 2, wherein the prostate cancer is anti-androgen resistant.

[0158] 4. The method according to embodiment 3, wherein the human carries at least one DNA repair abnormality selected from the group consisting of BRCA-1, BRCA-2, FANCA, PALB2, CHEK2, BRIP1, HDAC2 and ATM.

[0159] 5. The method according to embodiment 4, wherein the DNA repair abnormality is BRCA-1 or BRCA-2.

[0160] 6. A method according to embodiment 5, wherein the prostate cancer is castration-resistant prostate cancer.

[0161] 7. A method according to embodiment 5, wherein the prostate cancer is metastatic castration-resistant prostate cancer.

[0162] 8. The method of embodiment 6, wherein niraparib is administered in an amount of about 30 mg / day to about 400 mg / day.

[0163] 9. The method of embodiment 8, wherein the amount of niraparib administered is about 300 mg / day.

[0164] 10. The method according to embodiment 9, wherein niraparib is orally administered as three 100 mg oral dosage forms once daily.

[0165] 11. A method of treating castration-resistant prostate cancer and anti-androgen-resistant prostate cancer in a human, the method comprising administering three 100 mg oral dosage forms of niraparib once daily to the human.

Claims

1. Use of a therapeutically effective amount of niraparib or a salt thereof in the preparation of a medicament for use in a method for treating metastatic prostate cancer in a human in need of such treatment, wherein the human carries at least one DNA repair abnormality in a gene selected from the group consisting of BRCA-1, BRCA-2, FANCA, PALB2, CHEK2, BRIP1, HDAC2 and ATM.

2. The use according to claim 1, wherein the metastatic prostate cancer is metastatic castration-sensitive prostate cancer or metastatic castration-resistant prostate cancer.

3. The use according to claim 1, wherein the metastatic prostate cancer is anti-androgen resistant.

4. The use according to claim 1, wherein niraparib or a salt thereof is administered in an amount of about 30 mg / day to about 400 mg / day.

5. The use according to claim 4, wherein the amount of niraparib or a salt thereof administered is about 50 mg / day.

6. The use according to claim 4, wherein the amount of niraparib or a salt thereof administered is about 100 mg / day.

7. The use according to claim 4, wherein the amount of niraparib or a salt thereof administered is about 200 mg / day.

8. The use according to claim 4, wherein the amount of niraparib or a salt thereof administered is about 300 mg / day.

9. The use according to claim 6, wherein niraparib or a salt thereof is orally administered in a 100 mg oral dosage form once a day.

10. The use according to claim 7, wherein niraparib or a salt thereof is orally administered in a 100 mg oral dosage form once a day.

11. The use according to claim 8, wherein niraparib or a salt thereof is orally administered once a day in three 100 mg oral dosage forms.

12. Use of niraparib or a salt thereof in the preparation of a medicament for a method for treating metastatic castration-sensitive prostate cancer in a human, the method comprising administering three 100 mg oral dosage forms of niraparib or a salt thereof once daily to the human, wherein the human carries at least one DNA repair abnormality in a gene selected from the group consisting of BRCA-1, BRCA-2, FANCA, PALB2, CHEK2, BRIP1, HDAC2 and ATM.

13. The use according to claim 1, wherein the metastatic castration-sensitive prostate cancer has been treated with at least one line of taxane-based chemotherapy.

14. The use according to claim 1, wherein the metastatic castration-sensitive prostate cancer has been treated with at least one line of chemotherapy based on enzalutamide, apalutamide or abiraterone acetate.

15. The use according to claim 1, wherein the DNA repair abnormality is a genomic lesion.

16. The use according to claim 15, wherein the genomic lesion is a homozygous deletion, a heterozygous deletion + a deletion mutation, or a copy-neutral loss of a heterozygous deletion + a deletion mutation.

17. The use according to claim 12, wherein the DNA repair abnormality is a genomic lesion.

18. The use according to claim 17, wherein the genomic lesion is a homozygous deletion, a heterozygous deletion + a deletion mutation, or a copy-neutral loss of a heterozygous deletion + a deletion mutation.

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