Treatment of prostate cancer with a combination of abiraterone acetate and niraparib

Abstract

The present invention provides combinations of anticancer drugs and methods for treating prostate cancer using such combinations. [Solution] A pharmaceutical formulation is provided comprising abiraterone acetate and niraparib tosylate monohydrate as a combination preparation for simultaneous, separate, or sequential use with prednisone when treating prostate cancer.

Description

[Technical Field]

[0001] This disclosure relates to a combination of anticancer agents, a method for treating prostate cancer using the said combination, and the said Regarding pharmaceutical formulations, including combinations. [Background technology]

[0002] Prostate cancer is the most common non-cutaneous malignant tumor in men and is the leading cause of cancer in men in Western countries. It is the second leading cause of death.

[0003] Prostate cancer develops when abnormal cells in the prostate gland proliferate uncontrollably. Once a cancerous tumor develops, androgens such as testosterone promote the growth of prostate cancer. In the early stages, localized prostate cancer can be treated with, for example, surgical removal of the prostate and radiation therapy. It is often curable with topical treatments, including [mention specific treatments]. However, this is not the case for up to one-third of men. As such, if prostate cancer is not cured with local therapy, the disease becomes an incurable metastatic disease (that is, (This can progress to a disease where cancer spreads from one part of the body to other parts.)

[0004] To improve survival rates and control progression in men with metastatic castration-resistant prostate cancer (mCRPC) The current treatment options are limited to taxane-based chemotherapy, as well as apalutamide (ER). LEADA (registered trademark) and enzalutamide (XTANDI (registered trademark)), etc. This includes a drug targeting the drag receptor.

[0005] Platinum-based chemotherapy is used in many clinical cases of prostate cancer patients who have not been molecularly selected. Although it has been tested in research, the results are limited, and it has significant toxicity.

[0006] More recently, abiraterone acetate with prednisone added (ZYTIGA (registered The trademark is approved for the treatment of metastatic castration-resistant prostate cancer.

[0007] Niraparib is a PARP-1 and PARP-2 deoxyribonucleic acid (DNA) repair polymer. A highly selective, orally available poly(adenosine diphosphate) with activity against the enzyme. It is an ADP-ribose polymerase (PARP) inhibitor. Jones P, Wi lcoxen K, Rowley M, Toniatti C. Niraparib:A Poly(ADP-ribose) Polymerase(PARP)Inhibit or for the Treatment of Tumors with Defe ctive Homologous Recombination.J Med Che m.2015 Apr 23;58(8):3302-3314.

[0008] PARP repairs DNA single-strand breaks (SSBs) through a process called base excision repair. It is an enzyme responsible for repair. PARP inhibition leads to the accumulation of unrepaired SSBs. This causes the replicated fork to stall and collapse, resulting in a double-strand break (DSB). Normally, DSBs are repaired by homologous recombination (HR). If they are not repaired, DSBs This causes cell death. DNA repair defects involved in the HR pathway (e.g., breast cancer genes [BR When tumor cells containing CA-1 / 2) are treated with a PARP inhibitor, DSBs are efficiently and The body becomes unable to repair itself properly, leading to a synthetic lethal state. Metastatic castration-resistant prostate cancer (mCRP) In men (C), tumors with DNA repair abnormalities account for approximately 20% to 30% of sporadic cancers. ru.

[0009] Treatment options for prostate cancer patients that do not respond initially or have become resistant to existing treatments there exists a need for. Importantly, for treatment options for prostate cancer patients, there is an unmet need. Summary of the Invention

[0010] The present disclosure relates to androgen receptor (AR)-associated diseases or conditions, in particular cancer, more specifically a combination of abiraterone acetate and niraparib that can be administered to mammals, particularly humans, suffering from prostate cancer. .

[0011] These pharmaceutical preparations are fixed-dose combinations of abiraterone acetate and niraparib .

[0012] An object of the present invention is, inter alia, to provide treatment for prostate cancer, including hormone-sensitive prostate cancer, high-risk hormone-naive prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), metastatic castration-sensitive prostate cancer (mCSPC), non-metastatic castration-resistant prostate cancer (nmCRPC), biochemical recur rence (BCR) prostate cancer, and localized prostate cancer (LPC). to provide the above.

[0013] An object of the present invention is to provide a free-dose combination (FrDC) of abiraterone acetate and niraparib tosylate monohydrate; or a fixed-dose combination (FDC) comprising abiraterone acetate and niraparib tosylate monohy drate.

[0014] An object of the present invention is to provide a pharmaceutical preparation that supports patient compliance, treatment adherence, and therapeutic efficacy. to provide the above.

[0015] The objective of this invention is to reduce the burden of tablets on patients, for example, by reducing the number of abiraterone tablets they take per day (6 or 4 tablets). From acetate and niraparib tosylate monohydrate, 3 tablets, or preferably 2 tablets, The objective is to provide a pharmaceutical formulation that reduces the dosage to one tablet.

[0016] The object of the present invention is to provide a drug dosage form that is equivalent to or better than individually formulated drug dosage forms. To provide a fixed-dose combination (FDC) pharmaceutical formulation with improved stability or shelf life. That is the case.

[0017] The objective of the present invention is to provide a fixed drug dosage form that is biologically equivalent to a drug dosage form when administered in different dosage forms. The objective is to provide a combination of dosage-based pharmaceutical formulations.

[0018] The objective of the present invention is to provide immediate-release properties for both abiraterone acetate and niraparib. The objective is to provide a fixed-dose combination pharmaceutical formulation containing rofil.

[0019] The objective of the present invention is to provide good quality abiraterone acetate and niraparib tosylate monohydrate. The aim is to provide a fixed-dose combination pharmaceutical formulation having uniform content or uniform distribution. In some embodiments, abiraterone acetate and niraparib tosylate monohydrate It is uniformly distributed within the granular inner phase. In some embodiments, abiraterone acetate And niraparib tosylate monohydrate is uniformly distributed within the dosage form, for example, a tablet. Biraterone acetate and niraparib tosylate monohydrate are prepared as separate granules. In several embodiments, each granule is uniformly distributed in the granule mixture. In dose combinations, abiraterone acetate and niraparib tosylate monohydrate The active pharmaceutical ingredient has different particle sizes (each 4-5 μm). 50 and d 50 ), different It has a large bulk density and different content (33% and 5-10% (w / w) respectively). If these two active pharmaceutical ingredients are mixed as is, they tend to separate, leading to problems with the uniformity of the mixture. This creates problems with adjusting the dosage of individual tablets. Using the precise and consistent amounts of the two active pharmaceutical ingredients in FDCs is difficult. Administering the drug is important to ensure its safety and effectiveness.

[0020] The uniformity of the content is determined by the inlet air temperature, spray rate, inlet air flow rate during granulation, and dry air during granulation. This can be affected by manufacturing conditions such as drying loss.

[0021] The object of the present invention is to provide abiraterone acetate and ni having good uniformity of layered content. The objective is to provide granules containing raparib tosylate monohydrate.

[0022] The object of the present invention is to provide a desired particle size that can be represented by the values ​​of d10, d50, and / or d90. Contains abiraterone acetate and niraparib tosylate monohydrate, which have an IZ distribution. The objective is to provide granules. If the granules are too small, problems will arise during compression when preparing tablets. This may occur. If the granules are too large, it may result in inconsistent uniformity of content and undesirable separation. Potential issues may arise, including compression problems during tableting, API dissolution, and bioavailability issues. There is.

[0023] The object of the present invention is abiraterone vinegar, whose components are known to be sensitive to oxidative degradation. An immediate-release film coating for oral administration that does not cause such degradation of acid esters. The objective is to provide a combination pharmaceutical formulation with a fixed dose. Organic or inorganic impurities and / or The presence of degradation products and / or metabolites, if deviating from the trend, may affect the patient's safety or treatment. This may affect effectiveness.

[0024] The object of this invention is to provide information on abiraterone acetate and niraparib tosylate monohydrate. The aim is to provide a combination of fixed-dose pharmaceutical formulations having equivalent dissolution profiles. This type of dissolution profile is suitable for both drugs to be administered on the same schedule. Therefore, it is considered that the use of fixed dose combinations can be supported. Another object of the present invention is For example, currently available formulations (abiraterone acetate tablets and niraparib tosylate monohydrate) When compared to one or both of the drugs separately formulated in physical capsules, etc. Furthermore, the solubility profiles of one or both, preferably both, of the active ingredients are equivalent or improved. The objective is to provide a fixed-dose combination formulation. The dissolution profile is determined by the inlet air temperature, Manufacturing conditions such as spraying speed and inlet airflow during granulation, as well as the hardness of the tablets, may affect the result. ru.

[0025] The object of the present invention is to provide a separate formulation (for example, abiraterone acetate tablets and chives) Compared to the drug administered in the currently available formulation (paribtosylate monohydrate capsules), In that case, a fixed-dose set with equivalent or improved bioavailability for each drug. The present invention provides a combination pharmaceutical formulation in which two active ingredients are separate. One or more equivalent pharmacokinetic parameters compared to the formulation (e.g., similar or improved) T max and / or t 1 / 2 , or %C max ) a fixed-dose combination pharmaceutical preparation that shows ) The goal is to provide a solution that reduces the bioavailability of monotherapy, or both drugs. Bioavailability parameters that do not support the same dosing schedule are: This can lead to a decrease in plasma levels, affecting the effectiveness of the treatment, and potentially altering the frequency, number of doses, or other aspects of administration. An increase in both may be necessary.

[0026] The object of the present invention is to provide 500 mg of abiraterone acetate and tosylate monohydrate form. An oral, immediate-administration formulation containing either 50 mg or 100 mg of free base niraparib. The objective is to provide a combination pharmaceutical formulation with a fixed dose and release film coating.

[0027] The object of the present invention is to provide 375 mg of abiraterone acetate and tosylate monohydrate form. An oral, immediate-administration formulation containing either 50 mg or 100 mg of free base niraparib. The objective is to provide a combination pharmaceutical formulation with a fixed dose and release film coating.

[0028] The object of the present invention is to provide 250 mg of abiraterone acetate and tosylate monohydrate form. An oral, immediate-administration formulation containing either 50 mg or 100 mg of free base niraparib. The objective is to provide a combination pharmaceutical formulation with a fixed dose and release film coating.

[0029] The object of the present invention is that, compared to drugs administered separately, (for example, at the same dose) Fixed-dose combinations with equivalent or improved efficacy (due to improved availability) The objective is to provide a pharmaceutical formulation.

[0030] Abiraterone acetate (lipophilic and low bioavailability) and niraparib tosylate Considering the different physicochemical properties of monohydrates (hydrophilic and with moderate to high bioavailability) Furthermore, one of the aims of this invention is to provide a technical solution to compounders when combining two drugs. It is.

[0031] This disclosure relates to glucocorticoids, such as prednisone, hydrocortisone, and dexamethoxazole. Tazone, prednisolone (including methylprednisolone), and the above as described herein. The effective dose of a pharmaceutical preparation containing biraterone acetate and niraparib tosylate monohydrate is administered to the patient. The present invention relates to a method for treating prostate cancer in male human patients, including administration to the subject.

[0032] This disclosure relates to a method for treating mCRPC in male human patients who have mCRPC. The method involves adding prednisone to abiraterone acetate and nirapa as described herein. This includes administering an effective amount of a pharmaceutical preparation containing ribtosylate monohydrate to a patient. mCRPC treatment is the first-line (L1) treatment for mCRPC. In one embodiment, the patient The patient has not been treated with abiraterone acetate with prednisone for more than 5 months. In one embodiment, the patient is positive for homologous recombination deficiency (HRD), or the patient has HRD Not positive for the following. In one aspect, the HRD status is BRCA1 (breast cancer gene 1), BRC A2 (Breast cancer gene 2), ATM (Ataxia vasodilator variant), FANCA (Fanconi - Anemia complementation group A genes), PALB2 (BRCA2 gene partner and local Zar), CHEK2 (checkpoint kinase 2 gene), BRIP1 (BRCA1 phase) Interacting proteins (C-terminal helicase 1 gene), HDAC2 (histone deacetylase) 2) or CDK12 (cyclin-dependent kinase 12), including but not limited to these. Detection is performed by changes in one or both alleles in one or more DNA repair genes. It is administered. In one embodiment, the patient is given gonadal before treatment with a pharmaceutical preparation containing prednisone. Are you receiving dotropin-releasing hormone (GnRHa) therapy, or have you undergone bilateral orchiectomy? They are receiving it. In one aspect, GnRHa therapy is used if the prednisolone is not surgically castrated. Continue this treatment with the medicinal preparation containing zon.

[0033] This disclosure relates to a method for treating mCSPC in male human patients having mCSPC. Such patients have harmful germline or somatic homologous recombination repair (HRR) gene mutations. The method comprises CSPC, and the abiraterone vinegar described herein is further comprising the addition of prednisone. Administer an effective dose of a pharmaceutical preparation containing an acid ester and niraparib tosylate monohydrate to the patient. This includes, in one embodiment, harmful germline or somatic HRR gene mutations are BRCA1 , BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD This includes 51B (RAD51 Paralog B) and RAD54L (RAD54-like), but these It is located in one or more genes, not limited to those mentioned above. In one embodiment, the patient is given prednisone. ADT is received before treatment with a pharmaceutical preparation. In one embodiment, the ADT is internal medicine or Surgical castration. In one embodiment, the ADT is administered by a pharmaceutical preparation containing prednisone. It was initiated within 6 months prior to the procedure, preferably within 14 days. In one embodiment, the patient was The patient receives ADT during treatment with a pharmaceutical preparation containing rednisone. In one embodiment, the patient receives ADT. Androgen signaling inhibitor therapy (e.g., abiraterone acetate, Enzal) (e.g., tamide, apalutamide, darolutamide, nilutamide, flutamide, bicalutamide) The patient has not received any prior treatment. In one embodiment, the patient is given a pharmaceutical preparation containing prednisone. Prior to the procedure, docetaxel or cabazitaxel has been administered. In one embodiment, the patient Prior to treatment with a pharmaceutical preparation containing prednisone, the patient had undergone radiation or surgical intervention. In one embodiment, the patient receives prednisone before treatment with a pharmaceutical preparation containing prednisone. The patient is being administered abiraterone acetate with added prednisolone. In one embodiment, the patient is being given prednisolone. One month prior to treatment with a drug formulation containing zonosone, abiraterone with prednisone added. Acetate esters are being administered. In one embodiment, the patient is given a pharmaceutical preparation containing prednisone. Prior to the procedure, the patient had received treatment for localized prostate cancer. In one instance, the patient had received treatment for localized prostate cancer. The aforementioned treatment must have been completed at least one year prior to treatment with the pharmaceutical preparation containing prednisone. In one embodiment, the treatment for localized prostate cancer includes radiotherapy, prostatectomy, lymph node dissection, Alternatively, it may be an ADT of up to 3 years, including systemic therapy.

[0034] This disclosure applies to individuals with or without DNA repair gene deficiencies (DRDs) or HRDs, at their discretion. Furthermore, mCRPC is present, accompanied by pathogenic changes in cyclin-dependent kinase 12 (CDK12). The present invention relates to a method for treating mCRPC in male human patients, wherein the method involves prednisone In addition, the abiraterone acetate and niraparib tosylate monohydrate described herein This includes administering an effective amount of a pharmaceutical preparation containing to a patient. In one embodiment, the patient is surgically removed If not actively administered, GnRHa therapy should be administered during treatment with a pharmaceutical preparation containing prednisone. Continue. In one embodiment, the patient takes nitric acid before treatment with a pharmaceutical preparation containing prednisone. Tamide, flutamide, bicalutamide, enzalutamide, apalutamide, dalorutamide, and They are exposed to an antiandrogen selected from abiraterone acetate. In one embodiment, The aforementioned antiandrogen is washed before treatment with a pharmaceutical preparation containing prednisone. You'll be out.

[0035] This disclosure relates to the high risk and / or lymph node-positive prostate cancer in male human patients. With respect to a method for treating risk and / or lymph node-positive prostate cancer, the method is radioactive Prednisone and leuprorelin acetate were added before, during, and after the therapy. The medical products comprising abiraterone acetate and niraparib tosylate monohydrate as described herein This includes administering an effective amount of a drug formulation to a patient. In one embodiment, the radiotherapy is stereotactic radiotherapy. This is radiotherapy (SBRT) or ultrafractionated radiotherapy, with a total dose of approximately 37.5 to 40 Gray. (Gy)

[0036] This disclosure relates to the castration of male human patients with castrated or non-metastatic castrated naive prostate cancer. Regarding a method for treating naive prostate cancer, the method is described in which prednisone is added. Pharmaceutical products containing abiraterone acetate and niraparib tosylate monohydrate as described in the details. This includes administering an effective dose of the agent to the patient. In one embodiment, the patient has not been surgically castrated. If not, GnRHa therapy will be continued during treatment with a pharmaceutical preparation containing prednisone.

[0037] This disclosure concerns the treatment of biochemically recurrent prostate cancer in male human patients with biochemically recurrent prostate cancer. Regarding methods for the use of the avilatero described herein, the method is the addition of prednisone. Administer an effective dose of a pharmaceutical preparation containing nitrate acetate and niraparib tosylate monohydrate to the patient. This includes the following: In one embodiment, the biochemically recurrent prostate cancer is i) 2.0n from the lowest point ii) Elevated prostate-specific antigen (PSA) levels of ≥ g / mL; or ii) Positive charge of prostate-specific membrane antigen Next-generation imaging (NGI), including protanotomy with phototransmission tomography (PSMA-PET), can detect In one embodiment, the patient is HRD biomarker positive, high risk, and / or minority. The patient has a metastatic disease. In one embodiment, the positive HRD biomarkers are BRCA1, BRC A2, ATM, BRIP1, CDK12, CDK17, CHEK2, FANCA, HDA One or more of the following: C2, PALB2, PPP2R2A, RAD51B, and RAD54L However, it is not limited to these.

[0038] This disclosure relates to the localized advanced prostate cancer of a male human patient who is a candidate for primary radiotherapy. Regarding a method for treating advanced prostate cancer, the method is described in which prednisone is added. Pharmaceutical products containing abiraterone acetate and niraparib tosylate monohydrate as described in the details. This includes administering an effective dose of the drug to the patient.

[0039] This disclosure concerns patients who have previously received chemotherapy including docetaxel or cabazitaxel at their discretion. The present invention relates to a method for treating mCRPC in male human patients having mCRPC, and the aforementioned method The method involves adding prednisone to abiraterone acetate and nirapari as described herein. This includes administering an effective dose of a pharmaceutical preparation containing butosylate monohydrate to a patient.

[0040] This disclosure relates to a method for treating nmCRPC in male human patients having nmCRPC. The method described herein involves adding prednisone to abiraterone acetate and This includes administering an effective dose of a pharmaceutical preparation containing niraparib tosylate monohydrate to a patient. In one embodiment, the patient has a PSA doubling time of 10 months or less and is HRD positive. In one embodiment, the patient is HRD-positive. In another embodiment, the patient has a high-risk BCR.

[0041] In the treatment method disclosed herein, the pharmaceutical preparation is abiraterone acetate. and a free-dose combination of niraparib tosylate monohydrate (FrDC); or avilatero Fixed-dose combination (FDC) containing nitrate acetate and niraparib tosylate monohydrate This may also be the case. In one embodiment, FrDC or FDC is each independently administered in an amount of approximately 50 mg per A certain amount of niraparib and about 500 mg of abiraterone acetate; about 100 mg equivalent of chives. Parib and approximately 500 mg of abiraterone acetate; approximately 50 mg equivalent of niraparib and Approximately 375 mg of abiraterone acetate; approximately 100 mg equivalent of niraparib and approximately 375 mg of abiraterone acetate; approximately 50 mg equivalent of niraparib and approximately 250 mg of abiraterone acetate Laterone acetate; approximately 100 mg equivalent of niraparib and approximately 250 mg of abiraterone Acetate; approximately 33 mg equivalent of niraparib and approximately 333 mg of abiraterone acetate ; or containing approximately 67 mg equivalents of niraparib and approximately 333 mg of abiraterone acetate In one embodiment, FrDC or FDC is an oral dosage form. In one embodiment, the oral dosage form is a tablet. It comes in the form of a capsule or a small pouch.

[0042] In the treatment methods disclosed herein, abiraterone acetate and niraparib, A fixed-dose combination (FDC), preferably containing niraparib tosylate monohydrate, is used in this As defined through disclosure.

[0043] This disclosure concerns first-line (L1) mCRPC and other mCRPCs for patients with prostate cancer. When administering, combinations of simultaneous, separate, or sequential use with prednisone are available. The blended preparation contains abiraterone acetate and niraparib tosylate monohydrate. Regarding pharmaceutical preparations. In one instance, the patient receives abiraterone acetate and prednisone 5 No treatment has been given for over a month. In one case, the patient has homologous recombination deficiency (HRD). The patient is positive or negative for HRD. In one embodiment, the HRD status is BR CA1 (breast cancer gene 1), BRCA2 (breast cancer gene 2), ATM (vasodilatory ataxia) Atypical), FANCA (Fanconi anemia complementation group A gene), PALB2 (BRCA2 gene) (Genetic partner and localizer), CHEK2 (checkpoint kinase 2 gene) Child), BRIP1 (BRCA1-interacting protein C-terminal helicase 1 gene), HDA C2 (histone deacetylase 2), or CDK12 (cyclin-dependent kinase 12) ) and, but not limited to, a single allele in one or more DNA repair genes It is detected by changes in both alleles. In one embodiment, the patient is given prednisone. Before treatment with pharmaceutical preparations, gonadotropin-releasing hormone agonist (GnRHa) therapy was administered. He has either had a bilateral orchiectomy. In one embodiment, GnRHa therapy is administered surgically. If the animal is not neutered, treatment with a medicated preparation containing prednisone will continue.

[0044] This disclosure concerns harmful germline or somatic homologous recombination repair (HRR) gene mutations in mCSPs. When treating mCSPC in patients with C, with prednisone, simultaneously, separately, or For continuous use, a combination preparation of abiraterone acetate and nirapa is used. This relates to a pharmaceutical preparation containing ribtosylate monohydrate. In one embodiment, harmful germline or body Cellular HRR gene mutations include BRCA1, BRCA2, BRIP1, CDK12, and CHEK 2. Including, but not limited to, FANCA, PALB2, RAD51B, and RAD54L. It is not located in one or more genes. In one embodiment, the patient is given a pharmaceutical product containing prednisone. ADT is received before treatment with the drug. In one embodiment, the ADT is medical or surgical. Castration. In one embodiment, the ADT is performed 6 times before treatment with a pharmaceutical preparation containing prednisone. It was initiated within a month, preferably within at least 14 days. In one embodiment, the patient received prednisolone. ADT is administered during treatment with a pharmaceutical preparation containing zoon. In one embodiment, the patient receives next-generation antimicrobial therapy. Drogen signaling inhibitor therapy (e.g., abiraterone acetate, enzalutamide) (e.g., apalutamide, darolutamide, nilutamide, flutamide, bicalutamide) No prior treatment has been received. In one embodiment, the patient is treated with a pharmaceutical preparation containing prednisone. Prior to the procedure, the patient has been administered docetaxel or cabazitaxel. In one embodiment, the patient is Prior to treatment with a pharmaceutical preparation containing rednisone, the patient has received radiation or surgical intervention. In this configuration, the patient receives prednisone before treatment with a pharmaceutical preparation containing prednisone. The patient is being administered abiraterone acetate. In one embodiment, the patient is given prednisone. In the month prior to treatment with the additional pharmaceutical preparation, abiraterone acetate with prednisone added The patient is being administered sterol. In one embodiment, the patient is treated with a pharmaceutical preparation containing prednisone. Prior to the procedure, the patient has undergone treatment for localized prostate cancer. In one embodiment, the patient has undergone the aforementioned treatment for localized prostate cancer. This was completed at least one year prior to treatment with a pharmaceutical formulation containing prednisone. In this case, the aforementioned treatment for localized prostate cancer is radiotherapy, prostatectomy, lymph node dissection, or total prostatectomy. This is an ADT (Active Therapy) program lasting up to three years, including physical therapy.

[0045] This disclosure applies to individuals with or without DNA repair gene deficiencies (DRDs) or HRDs, at their discretion. Furthermore, it possesses mCRPCs accompanied by pathogenic changes in cyclin-dependent kinase 12 (CDK12). When treating mCRPC in patients, prednisone may be added, simultaneously, separately, or sequentially. As a combination preparation for general use, abiraterone acetate and niraparibut This relates to a pharmaceutical preparation containing a silate monohydrate. In one embodiment, the patient has been surgically castrated. If not available, GnRHa therapy should be continued during treatment with a pharmaceutical formulation containing prednisone. In one embodiment, the patient takes nilutamide and f before treatment with a pharmaceutical preparation containing prednisone. Lutamide, bicalutamide, enzalutamide, apalutamide, darolutamide, and abirate They are exposed to an antiandrogen selected from rhonacetate esters. In one embodiment, the anti Androgens are washed out before treatment with a pharmaceutical formulation containing prednisone. ru.

[0046] This disclosure relates to high-risk and lymph node-positive prostates before, during, and after radiotherapy. When treating high-risk and / or lymph node-positive prostate cancer in patients with cancer, prednisolone For simultaneous, separate, or consecutive use, with zonozolin and leuprorelin acetate added. The combination preparation includes abiraterone acetate and niraparib tosylate monohydrate. This relates to a pharmaceutical formulation including [a specific substance]. In one embodiment, the radiotherapy is stereotactic radiotherapy (SBRT). Alternatively, it may be ultrafractionated radiotherapy, with a total dose of approximately 37.5 to 40 Gy.

[0047] This disclosure relates to castrated naive prostate cancer in patients with metastatic or non-metastatic prostate cancer. When treating prostate cancer, the use of prednisone, either concurrently, separately, or sequentially. As a combination preparation for this purpose, abiraterone acetate and niraparib tosylate - This relates to a pharmaceutical preparation containing a hydrate. In one embodiment, GnRHa therapy is performed on surgically castrated individuals. If not available, continue treatment with a pharmaceutical preparation containing prednisone.

[0048] This disclosure relates to the treatment of biochemically recurrent prostate cancer in patients with biochemically recurrent prostate cancer. , combination preparations for simultaneous, separate, or consecutive use, with prednisone added. For example, a pharmaceutical preparation containing abiraterone acetate and niraparib tosylate monohydrate Regarding this, in one embodiment, the biochemically recurrent prostate cancer is defined as i) 2.0 ng / mL from the lowest point. The above-mentioned elevation of prostate-specific antigen (PSA); or ii) positron emission depletion of prostate-specific membrane antigen Detected by next-generation imaging (NGI), including layered imaging (PSMA-PET). In one embodiment, the patient has HRD biomarker-positive, high-risk, and / or minor metastatic disease. It has. In one embodiment, positive HRD biomarkers are BRCA1, BRCA2, AT M, BRIP1, CDK12, CDK17, CHEK2, FANCA, HDAC2, PA One or more of LB2, PPP2R2A, RAD51B, and RAD54L, This is not limited to these.

[0049] This disclosure relates to locally advanced prostate cancer in patients who are candidates for primary radiotherapy. When treating prostate cancer, the use of prednisone, either concurrently, separately, or sequentially. As a combination preparation for this purpose, abiraterone acetate and niraparib tosylate - Regarding pharmaceutical preparations containing hydrates.

[0050] This disclosure concerns patients who have previously received chemotherapy including docetaxel or cabazitaxel at their discretion. When treating mCRPC in patients with mCRPC, prednisone was added. As combination preparations for use at different times, separately, or consecutively, abiraterone acetate This relates to pharmaceutical preparations containing sterol and niraparib tosylate monohydrate.

[0051] This disclosure describes the use of prednisone when treating nmCRPC in patients with nmCRPC. In addition, as combination preparations for simultaneous, separate, or continuous use, Abirathe This relates to a pharmaceutical preparation containing ronacetate and niraparib tosylate monohydrate. In one embodiment, In one embodiment, the patient has a PSA doubling time of 10 months or less and is HRD positive. The patient is HRD positive. In one embodiment, the patient has a high-risk BCR.

[0052] The pharmaceutical formulations for use disclosed herein are abiraterone acetate and nirapa. Free-dose combination of rib (FrDC); or abiraterone acetate and niraparib It may also be a fixed dose combination (FDC) including the following for the use disclosed herein. The pharmaceutical preparation is FrDC, which is abiraterone acetate and niraparib tosylate monohydrate. ; or FDC containing abiraterone acetate and niraparib tosylate monohydrate In one embodiment, FrDC or FDC may be administered independently in an amount equivalent to about 50 mg of 2. Raparib (niraparib free base equivalent) and approximately 500 mg of abiraterone acetate; approximately 100 mg equivalent of niraparib and approximately 500 mg of abiraterone acetate; approximately 50 mg Equivalent amounts of niraparib and approximately 375 mg of abiraterone acetate; approximately 100 mg equivalent of niraparib Raparib and approximately 375 mg of abiraterone acetate; approximately 50 mg equivalent of niraparib and Approximately 250 mg of abiraterone acetate; approximately 100 mg equivalent of niraparib and approximately 25 0 mg abiraterone acetate; approximately 33 mg equivalent of niraparib and approximately 333 mg of abiraterone acetate; Biraterone acetate; or approximately 67 mg equivalent of niraparib and approximately 333 mg of abiraterone acetate. Contains rhonacetate. In one embodiment, FrDC or FDC is an oral dosage form. The oral dosage form is a tablet, capsule, or pouch.

[0053] Contains abiraterone acetate and niraparib tosylate monohydrate (or niraparib). A fixed dose combination (FDC) is defined as described herein.

[0054] This disclosure includes abiraterone acetate, niraparib, and a pharmaceutically acceptable carrier. This disclosure relates to a granular composition. This disclosure relates to a pharmaceutical formulation, such as an oral dosage form, which includes a granular composition. .

[0055] In one embodiment, the granules contain abiraterone acetate, niraparib, and pharmaceutically acceptable Essentially consists of a carrier. In one embodiment, the granules are d50 The size is approximately 200 to 500 μm. , or approximately 231 to approximately 396 μm; d 10 The thickness is approximately 50 to 250 μm, or approximately 93 It is approximately 192 μm from; and / or d 90 This is approximately 500 to 900 μm, or approximately 616 It has a particle size distribution ranging from approximately 723 μm.

[0056] In one embodiment, the first portion of the granules is abiraterone acetate and pharmaceutically acceptable Essentially consisting of a carrier; the second part of the granules consists of niraparib and a pharmaceutically acceptable carrier. It becomes essential.

[0057] In one embodiment, niraparib is a tosylate monohydrate, sulfate, benzene sulfate, and fumaric acid. Salt, succinate, camphorate, mandelate, cansilate, lauryl sulfate, or tosyl It is a salt form of a mixture of an acid salt monohydrate and a lauryl sulfate. In one embodiment, nirapaributosyl Salt acid monohydrates are in crystalline form. In one embodiment, abiraterone acetate is in crystalline form. In one embodiment, the present disclosure comprises niraparibrauryl sulfate and a pharmaceutically acceptable carrier. This disclosure relates to a pharmaceutical preparation. In one embodiment, this disclosure relates to niraparib tosylate monohydrate and niraparib sulfate monohydrate. This invention relates to a pharmaceutical formulation comprising a mixture of raparibrauril and a pharmaceutically acceptable carrier.

[0058] In one embodiment, the pharmaceutically acceptable carrier of the granular composition is a wetting agent, diluent, disintegrant, or optional. It contains, optionally, a flow promoter, optionally a lubricant, and optionally a binder. In this case, the diluent is lactose, and the lactose is also used as a binder. In this case, the disintegrant is crospovidone.

[0059] This disclosure further relates to pharmaceutical formulations comprising the granular compositions described herein, for example, in oral dosage forms. In one embodiment, the formulation or oral dosage form contains approximately 50 mg equivalent of niraparib and approximately 500 mg of Abiraterone acetate; approximately 100 mg equivalent of niraparib and approximately 500 mg of abiraterone acetate. aviraterone acetate; approximately 50 mg equivalent of niraparib and approximately 375 mg of abiraterone acetate Sterl; approximately 100 mg equivalent of niraparib and approximately 375 mg of abiraterone acetate; Approximately 50 mg equivalent of niraparib and approximately 250 mg of abiraterone acetate; approximately 100 mg g equivalent of niraparib and approximately 250 mg of abiraterone acetate; approximately 33 mg equivalent of niraparib Laparib and approximately 333 mg of abiraterone acetate; or approximately 67 mg equivalent of niraparib. It contains bu and approximately 333 mg of abiraterone acetate.

[0060] In one embodiment, the oral dosage form is a tablet, where the pharmaceutically acceptable carrier is a wetting agent, dilute Disintegrants, disintegrants, flow promoters, lubricants, optionally binders, and optionally coatings Contains a wetting material. In one embodiment, the wetting agent is sodium lauryl sulfate (SLS), and the agent It is present in the form at a ratio of approximately 3 to 6% (w / w). In one embodiment, the wetting agent is SLS. Approximately 0.05:1 to 0.2:1 (SLS: abiraterone acetate), preferably about 0 A ratio of 0.1:1, more preferably about 0.11:1, about 0.12:1, or about 0.123:1 It is present in the final dosage form in a weight ratio relative to biraterone acetate. In one embodiment, SLS is The disintegrant is present in both the inner and outer phases of the tablet granules. In one embodiment, the disintegrant is crospovidone. It is present in both the inner and outer phases of the tablet granules. In one embodiment, it is used as a diluent for the outer phase of the granules. It is silicified microcrystalline cellulose. In one embodiment, the tablet has a hardness of 250 to 350 N. It has. In one embodiment, the tablet contains 75% to 125% or 90% to 110% of the stratified content. It has high uniformity. In one embodiment, the tablets have mixed uniformity with a relative standard deviation of up to 3%. ru.

[0061] In one embodiment, the tablet contains approximately 500 mg of abiraterone acetate and approximately 50 mg equivalent of Contains niraparib, here at pH 4.5, temperature 37.0±0.5℃, 0.25% (w / v) Aqueous solution containing 0.05 mM sodium phosphate buffer containing sodium lauryl sulfate 9 When measured in 00 mL using the USP paddle method at 75 rpm, (i) more than 40% after 5 minutes , or about 50% of abiraterone acetate is dissolved, and (ii) more than 75% after 10 minutes, (iii) After 15 minutes, 8 More than 5%, or about 89% or 90% of abiraterone acetate, is dissolved, (iv)20 After minutes, more than 87% or approximately 92% of abiraterone acetate is dissolved, and (v) after 30 minutes (vi) 91% or more, or about 95%, of abiraterone acetate is dissolved, and after 45 minutes (vii) After 60 minutes, 92% of abiraterone acetate was dissolved, and (vii) 92% (viii) After 90 minutes, 93% of abiraterone acetate is dissolved. (ix) 93% or more of abiraterone acetate is dissolved after 120 minutes. More than % or approximately 98% of abiraterone acetate dissolves.

[0062] In one embodiment, the tablet contains approximately 500 mg of abiraterone acetate and approximately 100 mg equivalent Contains chiraparib, where pH 4.5, temperature 37.0±0.5℃, 0.25% (w / v) Aqueous solution containing 0.05 mM sodium phosphate buffer with sodium lauryl sulfate When measured using the USP paddle method at 75 rpm in a 900 mL volume, (i) 36% after 5 minutes (ii) more than 41% or about 41% of abiraterone acetate is dissolved, and after 10 minutes more than 67%, Alternatively, about 72% of abiraterone acetate dissolves, and (iii) more than 76% after 15 minutes, (iv) After 20 minutes, more than 81% of abiraterone acetate is dissolved, or approximately 86% of abiraterone acetate is dissolved, and (v) after 30 minutes, more than 85% or 86% Alternatively, about 90 or 91% of abiraterone acetate is dissolved, and (vi) after 45 minutes 9 (vii) After 60 minutes, 90% of abiraterone acetate is dissolved. Alternatively, more than 91%, or approximately 95% or 96% of abiraterone acetate is dissolved, ( viii) After 90 minutes, more than 93%, or approximately 98%, of abiraterone acetate is dissolved, and (ix) After 120 minutes, more than 94% or approximately 99% of abiraterone acetate is dissolved. .

[0063] In one embodiment, the tablet contains approximately 500 mg of abiraterone acetate and approximately 50 mg equivalent of Contains niraparib, here at pH 4.5, temperature 37.0±0.5℃, 0.25% (w / v) Aqueous solution containing 0.05 mM sodium phosphate buffer containing sodium lauryl sulfate 9 When measured in 00 mL using the USP paddle method at 75 rpm, (i) after 5 minutes, 30 or (ii) More than 35%, or about 39% or 40% of niraparib, dissolves, and 7 9 or more than 80%, or about 84 or 85%, of niraparib dissolves, (iii) 15 (iv) After 20 minutes, more than 90% or approximately 95% of niraparib was dissolved, and more than 92% was dissolved. Approximately 97% of the niraparib dissolves, and (v) after 30 minutes, more than 93% or approximately 98% of the niraparib dissolves. (vi) After 45 minutes, more than 93% or approximately 98% of the niraparibu has dissolved, (vi i) After 60 minutes, more than 93% or approximately 98% of the niraparib is dissolved, and (viii) after 90 minutes (ix) More than 93% or approximately 98% of niraparib is dissolved, or (ix) more than 93% after 120 minutes, Approximately 98% of the niraparib dissolves.

[0064] In one embodiment, the tablet contains approximately 500 mg of abiraterone acetate and approximately 100 mg equivalent Contains chiraparib, where pH 4.5, temperature 37.0±0.5℃, 0.25% (w / v) Aqueous solution containing 0.05 mM sodium phosphate buffer with sodium lauryl sulfate When measured using the USP paddle method at 75 rpm in a 900 mL volume, (i) 23% after 5 minutes (ii) more than 28% or about 28% of niraparib dissolves, and after 10 minutes more than 64% or about 69% (iii) After 15 minutes, more than 80 or 81%, or about 85% or 86% of niraparib dissolves, and (iv) after 20 minutes, more than 87% or approximately 92% of niraparib dissolves. (v) After 30 minutes, more than 90% or about 95% of the niraparib is dissolved, and (vi) 4 (vii) Over 91% or approximately 96% of niraparib dissolves after 5 minutes, and over 92% dissolves after 60 minutes. (viii) after 90 minutes, more than 92% or about 97% of the niraparib is dissolved, or approximately 97% is dissolved. (ix) After 120 minutes, more than 92% or approximately 97% of the niraparib was dissolved. It dissolves.

[0065] In one embodiment, the tablet dosage form, when administered orally on an equivalent dose basis, contains abiraterone acetate. The free-dose combination of ster and niraparib is bioequivalent (e.g., one or more Pharmacokinetic parameters are measured at 2 times their respective values ​​after administration in a free-dose combination or as a monotherapy. (Within 0%, 10%, or 5%).

[0066] In one embodiment, the oral dosage form is a capsule or pouch, and optionally includes a diluent. .

[0067] In one embodiment, the oral dosage form is a fixed-dose combination (FDC).

[0068] This disclosure relates to the pharmaceutical formulations described herein for use in the treatment of prostate cancer in patients. This also relates to oral dosage forms. Similarly, this disclosure also relates to methods for treating prostate cancer in patients, and the said method The Act includes administering the aforementioned pharmaceutical preparation or oral dosage form to a patient.

[0069] In one embodiment, prostate cancer includes metastatic prostate cancer, advanced prostate cancer, localized prostate cancer, and localized advanced prostate cancer. Localized prostate cancer, localized prostate cancer, non-metastatic prostate cancer, non-metastatic advanced prostate cancer, non-metastatic Localized prostate cancer, non-metastatic locally advanced prostate cancer, non-metastatic localized prostate cancer, hormone-induced necrosis Naive prostate cancer, chemotherapy-naive prostate cancer, castration-naive cancer with or without metastasis, Radiation-naive prostate cancer, castration-resistant prostate cancer (CRPC), non-metastatic CRPC (nmCR). PC), localized CRPC, locally progressive CRPC, local CRPC, progressive CRPC, metastatic CRPC (mCRPC), bi-allele DNA repair gene deficiency (DRD), or HRD mCRPC in patients with single allele DRD or HRD; mCRPC in patients without RD or HRD; in patients with DRD or HRD, taxane and / or mCRPC, docetaxel or cabazita in patients who have received androgen receptor targeted therapy mCRPC in patients who have received a pipe; hormone therapy (e.g., enzalutamide, darolutamide) CRPC in patients who received docetaxel (e.g., apalutamide), taxane therapy (e.g., docetaxel, mi) CRPC in patients who received toxantrone or cabazitaxel; chemotherapy-naive CRPC. , chemotherapy-naive mCRPC, hormone-naive CRPC, hormone-naive mCRP C, CRPC with progression, CRPC with visceral metastasis, hormone therapy (e.g., Enzaluta) CRPC with visceral metastases in patients treated with mid, darolutamide, apalutamide, taxane Internal organs of patients who have received therapy (e.g., docetaxel, mitoxantrone, cabazitaxel) CRPC with metastasis, CRPC with visceral metastasis and progression, castration-sensitive prostate cancer (CSPC) ), non-metastatic CSPC (nmCSPC), localized CSPC, locally progressive CSPC, local CSPC, progressive CSPC, metastatic CSPC (mCSPC), chemotherapy-naive CSPC Chemotherapy-naive mCSPC, hormone-naive CSPC, hormone-naive mCSP C. Hormone-sensitive prostate cancer (HSPC), hormone-dependent prostate cancer, androgen-dependent Sexual prostate cancer, androgen-sensitive prostate cancer, biochemically recurrent HSPC, metastatic HSP C (mHSPC), hormone-resistant prostate cancer (HRPC), non-metastatic HRPC (nmHR PC), localized HRPC, locally progressive HRPC, localized HRPC, progressive HRPC, metastasis Sexual HRPC (mHRPC), recurrent prostate cancer, post-prostatectomy with or without distant metastasis Prostate cancer with persistent or recurrent prostate-specific antigen (PSA), radioactive prostate cancer, and Any combination of these. In one embodiment, the patient has first-line (L1) mCRPC and is positive for DRD or HRD. In one embodiment, the patient has harmful germline or The patient has a somatic homologous recombination repair (HRR) gene mutation (mCSPC). In one embodiment, the patient is The patient has mCRPC or CRPC with visceral metastases and is accompanied by DNA repair gene deficiency (DRD). Or, without accompanying, optional cyclin-dependent kinase 12 (CDK12) pathogenicity changes This is accompanied by... In one embodiment, the patient has high-risk localized prostate cancer.

[0070] In one embodiment, the patient is very low, low, moderately favorable, moderately unfavorable, It belongs to a risk group selected from high, very high, and localized. In one aspect, medical The recommended dosage or method of administration is approximately 666 to 1500 mg / day of abiraterone acetate. Administer; administer approximately 999 to 1500 mg / day of abiraterone acetate. Administer approximately 666 mg / day of abiraterone acetate; or approximately 1000 mg This includes administering abiraterone acetate g / day. In one embodiment, medical use or The treatment method is to administer approximately 33 to 300 mg / day of niraparib equivalent; approximately 100 Administer approximately 200 mg / day of niraparib equivalent; approximately 66 mg / day of niraparib equivalent. Administer approximately 100 mg / day of niraparib equivalent; approximately 134 mg / day Administer the equivalent dose of niraparib; or administer approximately 200 mg / day of niraparib equivalent. This includes, in one embodiment, one, two, or three medical use or treatment methods per day. This includes administering an oral dosage form. In one embodiment, the medical use or treatment method involves administering an oral dosage form. Once a day (qd) or twice a day (bid); preferably once a day, when meals are insufficient. This includes administering the medication at least one hour prior to or at least two hours after a meal. In one embodiment, medical The medicinal use or treatment method comprises separately administering from about 1 to about 60 mg / day of prednisone; about 5 to about 15 mg / day of prednisone; about 9 to about 11 mg / day of prednisone; about 10 mg / day of predni sone; about 5 mg / day of prednisone; or about 5 mg / day of prednisone .

[0071] The present disclosure also (a) preparing a binder solution comprising a wetting agent; (b) mixing the binder solution of step (a) with abiraterone acetate, niraparib, and a diluent, optionally in the presence of a disintegrant; ; (c) wet-granulating the mixture obtained from step (b); (d) drying the product obtained from step (c) , and also relates to a process for preparing the specific granule composition disclosed herein.

[0072] In one aspect, the binder solution comprises a binder, a wetting agent, and a solvent. In one aspect, the step (c) has an inlet air temperature of from 25°C to 65°C during the wet granulation. In one aspect, the step (c) has a spray rate of from 190 to 300 g / min during the wet granulation. In one aspect, the ste p (c) has an inlet air flow rate of from 800 to 1300 m 3 / h during the wet granulation.

[0073] The present disclosure also (a) mixing abiraterone acetate, nirapa rib, a wetting agent, and a diluent, optionally in the presence of a disintegrant and a lubricant; (b) dry-granulating the mixture obtained from step (a); (c) pulverizing the dry-granulated product obtained from step (b); (d) Optionally, the product obtained from step (c) is used as a wetting agent, diluent, or disintegrant. , and the step of mixing with a flow promoter. The invention also relates to a process for preparing certain granular compositions disclosed herein, including the aforementioned.

[0074] This disclosure also states, a) Selectively, niraparib is used as a diluent in the presence of a disintegrant, a flow promoter, and a lubricant. Mixing step; b) A step of dry granulating the mixture obtained from step (a); c) A step of grinding the dry granulated mixture obtained from step (b); d) A step of preparing a binder solution containing a wetting agent; e) Optionally, in the presence of a disintegrant, the binder solution from step (d) is converted to abiraterone acetate. A step of mixing with the ester and diluent; f) A step of wet granulating the mixture obtained from step (e); g) A step of drying the product obtained from step (f). h) In the presence of a wetting agent, diluent, disintegrant, lubricant, and flow promoter, optionally, Step of mixing the granular mixture obtained from steps (c) and (g); The present invention also relates to a process for preparing certain granular compositions disclosed herein, including, Therefore, steps d) to g) may be carried out before or in parallel with steps a) to c).

[0075] In one embodiment, the obtained granular composition is further compressed into tablets using an optional lubricant. It is reduced. In one embodiment, the process involves preparing a coating suspension and the tablets before This further includes coating with the suspension.

[0076] In one embodiment, the obtained granular composition is optionally packaged with a diluent in capsules or pouches. It is then compounded further. [Brief explanation of the drawing]

[0077] [Figure 1] Flowchart of the manufacturing process and in-process control for wet co-granulation of abiraterone acetate and nirapaributosylate monohydrate. [Figure 2] Flowchart of the manufacturing process and in-process control for coated tablets containing abiraterone acetate and nirapaributosylate monohydrate. [Figure 3] Flowchart of the manufacturing process for dry co-granulation and compression into tablets of abiraterone acetate and nirapaributosylate monohydrate. [Figure 4] Flowchart of the manufacturing process and in-process control for the dry granulation of nirapaributosylate monohydrate and the mixing of abiraterone acetate granules prepared by wet granulation. [Figure 5A] Figure 5: Figure 5A shows the in vitro dissolution curves of abiraterone acetate from FDC tablets of the following compositions: i) a single capsule of niraparib (tosylate monohydrate form) 100 mg eq. and two tablets of abiraterone acetate 250 mg; ii) FDC tablets of the compositions shown in Table 2 (niraparib (tosylate monohydrate form) 50 mg eq. and abiraterone acetate 500 mg); and iii) FDC tablets of the compositions shown in Table 4 (niraparib (tosylate monohydrate form) 100 mg eq. and abiraterone acetate 500 mg). Figure 5B shows the in vitro dissolution curves of niraparib from i) a single capsule containing 100 mg eq. of niraparib (tosylate monohydrate) and a combination of two tablets containing 250 mg of abiraterone acetate; ii) FDC tablets of the composition shown in Table 2 (50 mg eq. of niraparib (tosylate monohydrate) and 500 mg of abiraterone acetate); and iii) FDC tablets of the composition shown in Table 4 (100 mg eq. of niraparib (tosylate monohydrate) and 500 mg of abiraterone acetate). [Figure 5B] (As stated above.) [Figure 6]Loss on drying (LOD) profiles for granules with the compositions shown in Tables 1 and 3. [Figure 7] Sieve analysis of the granules in Table 1. [Figure 8] Sieve analysis of the granules in Table 3. [Modes for carrying out the invention]

[0078] The present invention, along with the accompanying embodiments forming part of this disclosure, should be viewed with reference to the detailed description below. This can be more easily understood. This invention is described and / or shown herein. This does not limit the specific products, methods, conditions, or parameters that have been described, and this The terminology used in this specification is intended to illustrate specific embodiments only. We understand that this is not intended to limit the claimed invention. It must.

[0079] Each patent, patent application, and publication disclosure cited or described herein The entire text is incorporated herein by reference.

[0080] definition Where used above and throughout this specification, the following terms and abbreviations are defined as indicated elsewhere. Unless otherwise specified, it shall be understood to have the following meaning.

[0081] In this disclosure, the singular forms "a," "an," and "the" include multiple references and given References to numerical values ​​include at least that value unless otherwise clearly indicated by the context. For example, a reference to "a certain component" means such components and their equivalents known to those skilled in the art, and It is a reference to one or more of the equivalents. Furthermore, a particular element is X, Y, Or, when using Z to indicate "possible," in any case, such usage means It is not intended to exclude other options for that element.

[0082] When a value is expressed as an approximation, the use of the antecedent "approximately" indicates that a particular value is different It will be understood that this forms an embodiment. When used herein, "about X" (this Here, X is a numerical value) preferably ±10% of the listed values ​​(including these as well). It refers to (the range of). For example, the expression "approximately 8" refers to values ​​between 7.2 and 8.8, and these values This also includes; as another example, the expression "about 8%" refers to a value between 7.2% and 8.8%, These values ​​are also included. If they exist, the entire range is included and can be combined. For example, if the range "1 to 5" is listed, this listed range is "1 Ranges of ~4, 1~3, 1~2, 1~2 and 4~5, 1~3 and 5 It should be interpreted that this includes the following. In addition, in situations where a list of options is actively provided In some cases, such lists may also exclude any of these options. This may also include the form of application. For example, if the range "1 to 5" is described, then such a description may be included. Akira may support a situation in which any of 1, 2, 3, 4, or 5 is excluded, and therefore, The enumeration "1-5" means "1 and 3-5 can be supported, but 2 cannot be supported," or simply I support the idea that "2 is not included."

[0083] The term "immediate release" refers to a dosage form (e.g., pharmaceutical formulation, free-dose combination). Fixed-dose combination) When used in the context of (ination), granules, tablets, capsules, etc., the above dosage form This refers to the rapid disintegration and decomposition of the dosage form that releases the active pharmaceutical ingredients it contains. The form is designed to dissolve or disintegrate quickly in the stomach, rapidly dissolving the active pharmaceutical ingredient. It can be absorbed, thereby allowing its effects to manifest rapidly.

[0084] As used herein and unless otherwise defined, "to treat" and "to treat" The terms "and" and "treatment" refer to tumors, or primary, local, or metastatic cancer cells. Eradication, removal, alteration, control, or This includes control and minimizing or delaying the spread of cancer (especially prostate cancer). Minimizing the spread of cancer Or delay includes inhibiting the progression of cancer, reducing the rate of cancer progression, or stopping the rate of cancer progression.

[0085] As used herein and unless otherwise defined, “a therapeutically effective amount” or “a therapeutically effective amount” The phrase "effective amount" refers to the amount of a drug that is effective in treating prostate cancer.

[0086] As used herein and unless otherwise defined, "therapeutically safe" The expression "therapeutic" refers to a safe amount of medication used in the treatment of prostate cancer. do.

[0087] The term "pharmaceutically acceptable" generally means safe, non-toxic, and biologically acceptable. This means that it is not undesirable academically or otherwise, and is not for pharmaceutical use in humans or animals. Includes those permitted for medical use.

[0088] The terms “Preparation” and “Composition” may be used interchangeably in this disclosure. Both "compositions" are combined as either fixed-dose or free-dose formulations. It refers to at least two or more components. Therefore, the term "pharmaceutical preparation" refers to a fixed-dose formulation. This refers to a preparation and a freely-dose combination preparation. In this specification, two or more of these components are referred to as 1) abirate 1) Lonacetate; and 2) Niraparib, and any pharmaceutically acceptable salt forms thereof. , in solvate form and hydrate form (e.g., nirapaributosylate monohydrate) It also includes additional components, which are usually excipients.

[0089] As used herein, a “fixed-dose combination” (FDC) refers to a combination of drugs in a single dosage form. This refers to a preparation or composition containing two or more active ingredients. The minutes include 1) abiraterone acetate; and 2) niraparib, as well as any pharmaceutical ingredients of those. Acceptable salt form, solvate form, and hydrate form (e.g., nirapaributosylate) It is a hydrate.

[0090] In contrast, a "free-dose combination drug" (FrDC) is a combination of two or more drugs in different dosage forms. This refers to a preparation or composition containing the above active ingredients. Here, the two active ingredients are: 1) Abi 1) Laterone acetate; and 2) Niraparib, and any pharmaceutically acceptable salt thereof. These are the form, solvate form, and hydrate form (for example, nirapaributosylate monohydrate). .

[0091] The terms “excipient” and “carrier” are used interchangeably in this disclosure. European Pharmacopoeia ( According to Ph.Eur., excipients are defined as "present in or used in the manufacture of pharmaceuticals." Excipients are all components other than the active ingredient. The intended function of excipients is to serve as carriers for the active ingredient (bihik). It acts as a base or a component of this carrier, and in doing so, stability This contributes to product characteristics such as biopharmaceutical profile, appearance, and patient tolerance, and manufacturing The product can be easily manufactured. Normally, in the formulation of pharmaceuticals, multiple types of excipients are used. The terms "vehicle" and "base" are defined in the same pharmacopoeia as "vehicle is a carrier for the active substance in a liquid formulation (composed of one or more excipients) " and "The base is a carrier (one or more) for the active substance in semi-solid and solid formulations." It is defined as "composed of the following excipients."

[0092] In this specification, "granules," "granulated material," or "granulated particles" are formed by granulation. It contains one or more active pharmaceutical ingredients (APIs) and at least one pharmaceutically acceptable It is defined as particles containing a carrier. The granular composition relating to this disclosure contains two types of APIs and a small amount It comprises at least one pharmaceutically acceptable carrier. A part of the granular composition (i.e., the first part) The granules consist of a certain API and at least one pharmaceutically acceptable carrier. Furthermore, another part of this granular composition (i.e., the second part of the granules) is a different API, and at least It can also essentially consist of one type of pharmaceutically acceptable carrier. In another embodiment, the granular composition Each part (i.e., each granule) contains two types of APIs and at least one type It includes a pharmaceutically acceptable carrier.

[0093] Abiraterone acetate Abiraterone acetate is given by formula: [ka] It is a compound of a steroid 17α-monooxygenase inhibitor or human cytochrome P4 17α-hydro, also known as 5017α, is a major enzyme in testosterone synthesis. Abiraterone is a potent selective oral inhibitor of xylase-C17,20-lyase. It is a prodrug. In patients with prostate cancer, testing with abiraterone acetate It has been proven to inhibit sterone synthesis. This compound is described in International Publication No. 93 / 20097(A 1) Disclosed in Brochure No. 1. In certain aspects of this specification, abiraterone acetate The term "art" is used in crystalline form.

[0094] Abiraterone acetate + prednisone is used for metastatic castration-resistant prostate cancer (mCRPC). It is also approved for use in metastatic hormone-sensitive prostate cancer (mHSPC). Abirathene Lonacetate tablets are currently sold as oral tablets in 250 or 500 mg doses.

[0095] Chive parib Niraparib (i.e., 2-[4-[(3S)-piperidine-3-yl]phenyl]-2H Indazole-7-carboxamide is an orally administered, highly selective poly(adenosine) It is a phosphate [ADP]-ribose) polymerase (PARP) inhibitor, and PARP It has activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA) repair polymerases. The preparation of niraparib is described in U.S. Patent No. 8,071,623 and No. 8,43. These are described in Patent No. 6,185, and both are incorporated herein by reference. Born.

[0096] The currently available capsule formulation (ZEJULA) contains nirapaributoshi as its active ingredient. 159.4 mg of the monohydrate (equivalent (eq.) to 100 mg of niraparib free base) . As an inactive ingredient in the filler of this capsule, magnesium stearate and la ctose monohydrate are included.

Chemical Formula

[0097] As used herein, the term "niraparib" refers to the free base compound 2-[4 -[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxy amide), salt forms of 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazo le-7-carboxamide (e.g., pharmaceutically acceptable salts; for example, 4-methy lbenzenesulfonic acid; 2-[4-[(3S)-piperidin-3-yl]phenyl]-2 H-indazole-7-carboxamide), and / or solvated forms thereof (e.g., hydrated form s; for example, 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-inda zole-7-carboxamide tosylate monohydrate). Such forms may be individually referred to as "niraparib free base", "niraparib tosylate", and "niraparib tosylate monohydrate". Unless otherwise specified, "niraparib " includes all crystalline, polymorphic, pseudopolymorphic, hydrated, monohydrate forms, anhydrous forms, solvates, salt forms, and combinations thereof (where appropriate) of the compound 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide. Examples of salts include, but are not limited to: tosylate or 4-methylbenzene sulfonic acid, without being limited thereto Sulfonate, sulfate, benzene sulfate, fumarate, succinate, can Camphorate, mandelate, cancilate, and laurilsul Phate. In certain aspects, the term "niraparib" refers to niraparib tosylate monohydrate. It refers to an object.

[0098] The term "niraparib" also refers to the amorphous and crystalline polymorphs of this compound, as well as these This includes hydrates, ansolvates, and solvates. Examples of polymorphisms include: This is explained in the publicly released pamphlet No. 2018 / 183354A1, and this pamphlet The following is incorporated herein by reference: 2-[4-[(3S)-piperidine-3-I Crystal form of phenyl-2H-indazole-7-carboxamide tosylate monohydrate I is 9.5±0.2, 12.4±0.2, 13.2±0.2, 17.4±0.2, 18 0.4±0.2, 21.0±0.2, 24.9±0.2, 25.6±0.2, 26.0±0 At least one X-ray diffraction pattern selected from 0.2 and 2θ values ​​of 26.9±0.2 Characterized by reflection. 2-[4-[(3S)-piperidine-3-yl]phenyl]-2H- Crystalline form II of indazole-7-carboxamide tosylate nonstoichiometric hydrate is 9. 7±0.3, 12.8±0.3, 17.9±0.3, 19.7±0.3, and 21.8± It features at least one X-ray diffraction pattern reflection selected from 2θ values ​​of 0.3. -[4-[(3S)-piperidine-3-yl]phenyl]-2H-indazole-7-ka The crystalline form III of luboxamide tosylate in its anhydrous form is 17.8±0.2 and 19.0±0. At least one X-ray diffraction pattern selected from 2θ values ​​of 2, or 22.8±0.2 Characterized by morphism. Crystal form I is preferred. Further examples of polymorphisms are found in International Publication No. 2020 / 07 This is explained in pamphlet No. 2797A1, and this pamphlet is a reference to this specification. It will be incorporated into the book.

[0099] The terms "niraparib eq." or "niraparib equivalent" refer to the free base of niraparib. It refers to quantity.

[0100] Preparation of dosage form The dosage forms of this disclosure can be prepared according to the schemes shown in Figures 1 and 2. Purified water, binder (e.g.) A binder solution containing hypromellose and a wetting agent (e.g., sodium lauryl sulfate) Prepared by mixing in a stirrer / mixer. Abiraterone acetate, niraparibut Silate monohydrate, diluent (e.g., lactose monohydrate), and disintegrant (e.g., cross-po The vidone is sieved and mixed (mixture number 1), and added to this binder solution. Heat, Wet granulation, including spraying and drying, is performed. To ensure compliance with quality requirements, moisture content and particle size are measured. Measure the cloth. Then, add a diluent (e.g., silicified microcrystalline cellulose) and a disintegrant (e.g., chlorocellulose). Spovidone), wetting agent (e.g., sodium lauryl sulfate), and lubricant (e.g., colloidal) The mixture of anhydrous silica is sieved and mixed with the previously obtained granules (mixture number 2). ). The lubricant (e.g., magnesium stearate) is sieved and added to mixture number 2. Finally, the mixture is mixed (mixture number 3), compressed into tablets, and packaged. To ensure compliance with quality requirements... To achieve this, the appearance, weight, hardness, thickness, abrasion, and disintegration of the tablet are measured during compression.

[0101] Then, purified water and coating powder (e.g., Opadry® AMB II) , for example Opadry (registered trademark) AMB II 88A220039 yellow) to prepare a coating suspension. Using this coating suspension, abiraterone acetate and the previously obtained tablet containing niraparib tosylate monohydrate is film-coated . In order to comply with quality requirements, the appearance of the obtained coated tablets is measured. Then, the tab lets are packaged in, for example, blister packs or bottles.

[0102] In another aspect, the dosage form of the present disclosure may be prepared as shown in Figure 3 and Figure 2. Abiraterone acetate and niraparib tosylate monohydrate are subjected to fluidized bed granulation or roller compaction granulation to co-granulate together with suitable excipients. Then, this granulated product is compressed into monolayer tablets.

[0103] Thereafter, purified water and coating powder (e.g., Opadry (registered trademark) AMB II , for example Opadry (registered trademark) AMB II 88A220039 yellow) is used to prepare a coating suspension. Using this coating suspension, abiraterone acetate and the previously obtained tablet containing niraparib tosylate monohydrate is film-coated . In order to comply with quality requirements, the appearance of the obtained coated tablets is measured. Then, the tab lets are packaged in, for example, blister packs or bottles.

[0104] In yet another aspect, the dosage form of the present disclosure may be prepared as shown in Figure 4 and Figure 2. Nirapa rib tosylate monohydrate, diluents (e.g., lactose monohydrate and microcrystalline cellulose), binders (e.g., povidone K30), disintegrants (e.g., crospovidone), lubricants (e.g., colloid idal anhydrous silica), and glidants (e.g., magnesium stearate) are sieved, The mixture was mixed, co-ground, mixed again, and dry-granulated (dry granule composition No. 1). Abiraterone Acetate, diluent (e.g., lactose monohydrate), and disintegrant (e.g., croscarmellol) Mix (sodium) and sift by choice. A binder (e.g., hypromellol) is added. Prepare a binder solution containing (s), a wetting agent (e.g., sodium lauryl sulfate), and purified water. Then, it is added to a mixture of abiraterone acetate, diluent, and disintegrant. Next, a fluidized bed is prepared. Granulation is used to form abiraterone acetate granules, which are then dried (wet granulation composition number (No. 2). This wet granular composition No. 2, diluent (e.g., silicified microcrystalline cellulose), disintegrant. (e.g., crospovidone), wetting agents (e.g., sodium lauryl sulfate), and lubricants (e.g., (Colloidal anhydrous silica) is added to dry granular composition No. 1, and the resulting mixture is sieved. Divide and mix. Add a lubricant (e.g., magnesium stearate) to the mixture. The mixture is then sieved, mixed, compressed into tablets, and packaged. Quality To ensure compliance with requirements, the tablet properties (e.g., appearance, weight, hardness, thickness, abrasion resistance) are measured during compression. , and decay) are measured. Then, purified water and coating powder (e.g., Opadry ( (Registered Trademark) AMB II, for example, Opadory (Registered Trademark) AMB II 88A220 Prepare a coating suspension containing 039 yellow. Therefore, the previously obtained tablets containing abiraterone acetate and nirapaributosylate monohydrate. The resulting coated tablets are film-coated. In order to comply with quality requirements, the appearance of the coated tablets is determined. The measurement is taken. Then, the tablets are packaged, for example, in blister packs or bottles.

[0105] Granulation Granulation is a process that enlarges powdered particles to form particulate aggregates. Granules formed from particles of a drug component (API) and an excipient mixture are transformed into a solid dosage form (e.g., , tablets and capsules), or multiparticulate (for example, Pellets, beads, or spun rayon that are filled into capsules or packaged as a powder. Further processing into an electroloid.

[0106] Abiraterone acetate and niraparib may be co-granulated. Alternatively, 1) Abiraterone The granules of 1) ronacetate and 2) niraparib are prepared separately and then mixed. They may be mixed or further processed.

[0107] Co-formed granules are created by bringing two drugs into contact with each other and adding one or more excipients, such as a binder solution. This is substantially achieved by bringing the mixture into contact with the drug and granulating the entire mixture. Alternatively, it is achieved by granulating the drug. Each is brought into contact with one or more excipients to create separate mixtures, and then these mixtures Gather each of the objects together and bring them into contact with the binder solution.

[0108] Abiraterone acetate and niraparib are further processed, such as by forming them into tablets or capsules. Before processing, dry granulation or wet granulation may be used.

[0109] In one embodiment, abiraterone acetate and niraparib are co-granulated by wet granulation, Further processing is possible. In one embodiment, abiraterone acetate and niraparib are dry granulated. Co-granulation can be performed and further processed. In one embodiment, abiraterone acetate is wet-granulated. Furthermore, niraparib is dry-granulated, the resulting granules are mixed, and then further processed. In one embodiment This involves dry granulation of abiraterone acetate and wet granulation of niraparib, and the resulting granules. The ingredients are mixed together and then further processed.

[0110] wet granulation As used herein, the term “wet granulation” is incorporated herein by reference. Remington: The Science and Practice of In Pharmacy, 20th Edition (2000), Chapter 45... As discussed, the common practice is to use a granulation solution during the granulation process and then form granules. It refers to a process.

[0111] Wet granulation typically involves a mixing process; a wetting and kneading process, i.e., wet granulation. Wet massing process; granulation process; drying process; and sieving process This includes the process. These processes will be discussed in more detail below.

[0112] A wet granulation process involves granulating components in a suitable container for forming a mixture, such as pharmaceuticals. By mixing (i.e., bringing into close contact) the therapeutic compound with at least one other It begins with the formation of a powder mixture with pharmaceutically acceptable excipients. An example of a pharmaceutical granulation apparatus is... The following are examples, but are not limited to: shear granulators combined with vibratory granulators ( For example, Hobart, Collette, Beken; high-speed mixer / granulator (for example) (Diosna, Fielder, Collette-Gral); and subsequent sieving Fluidized bed granulators equipped with the necessary equipment (e.g., Aeromatic, Glatt). Therapeutic compounds. Useful excipients for the initial mixing include, for example, binders, fillers, disintegrants, diluents, and wetting agents. Examples include agents and any combination of the above.

[0113] The next step is to wet the powder mixture with the granulating liquid and form a moist mass. By adding the granulation solution while stirring or kneading, this powder mixture is formed into a wet mass. For example, add 10-30% (w / w) of granulation solution to the powder mixture. Alternatively, Granulation liquid can be added to the mixture at a concentration of 10-25% (w / w) (for example, 20-25%). For example, it is pharmaceutically acceptable and volatile. As an example of a suitable granulation solution, In addition to water, or in combination with organic solvents (e.g., methanol, ethanol, isopropanol), water, or organic solvents (e.g., methanol, ethanol, isopropanol) Examples of combined granulation solutions include water (acetone), but are not limited to these. Examples include ethanol and isopropanol combined.

[0114] Alternatively, the wet granulation process can begin with the therapeutic compound as a powder itself. During the granulation process, the granulating solution introduced into the powder is a solvent containing dissolved excipients (e.g., binders). Regardless of how wet agglomeration is performed, the therapeutic compound and at least one A pharmaceutical composition containing several pharmaceutically acceptable excipients is wetted with a granulating solution. This method uses water as the granulation liquid.

[0115] This moist mass is sieved by arbitrary selection to separate the moist or damp (damp) Forms granules. This moist mass is sieved, for example, by passing it through a mesh. For example, it can be sieved through a screen of 5, 4, 3, 2, or 1 mm, preferably. It can be sieved through a 1-2 mm screen. Those skilled in the art will know the appropriate size screen. By selecting the appropriate option, it is possible to form the optimal granule size.

[0116] Alternatively, instead of this screen or sieve, a commuting mill can be used. l) can be used. Examples of crushers include the Stokes vibrator and the Colton rotary granulator. Examples include the Fitzpatrick shredder and the Stokes Tornado shredder, but this It is not limited to them.

[0117] Alternatively, instead of either a screen or a grinder, for example, a chopper blade could be used. A high-speed mixer equipped with a carbide can be used. This allows for processes such as wet agglomeration, granulation, and powdering. This makes it possible to combine the crushing process into a single step.

[0118] Other wet granulation methods that can be used include high-shear granulation and biaxial granulation. Fractionated granules are often a powder mixture of API and one or more excipients, with a binder added. Adding a solution, and granulating the resulting mixture using a mixing tool and a chopper. This is accompanied by the process. The powder aggregates into large granules, which are held together by a binder. Biaxial granulation is performed. Leistritz Extrusionstechnik GmbH-NANO 16 ,Thermo Fisher Scientific-Pharma 16 TSG This can be achieved using commercially available twin-screw extruders, such as those manufactured by GEA Pha. rma Systems' ConsiGma® system is used for mixing, twin-screw granulation, and drying. This is a complete continuous package, including (semi-continuous), crushed, and partially or fully tableted forms.

[0119] For example, the moist granules are then dried. For example, the moist granules are collected on a tray. The granules can then be transferred to a drying oven. Alternatively, the moist granules can be placed in a circulating airflow and thermostat. It can be placed in a drying cabinet equipped with heating control. Another option is moist granulation. This involves drying a material in a fluidized bed dryer. In this example, the wet granules are suspended, The moist granules are stirred in a warm airflow to maintain a state of movement. For example, The temperature can range from approximately room temperature to approximately 90°C, for example, 70°C. This moist granule is then... Preferably about 3% or 2% or less by weight of the composition, for example, less than 2.6%, less than 2%, e.g. For example, dry to a loss on drying (LOD) of 1-2%. Drying is performed in a pharmaceutical granulation apparatus. It may be said, or it may be done separately from this device.

[0120] Abiraterone acetate and nirapaributyrate prepared by the wet granulation method of the present invention Granules containing tetyl hydrate achieve a 1-2% improvement in LOD. In some cases, granules can cause compression problems during subsequent tableting. In combination, there may be stability issues with the granules.

[0121] After drying, the granules are sieved, either alone or in combination with at least one excipient. This allows for dry sieving, which typically results in more uniform particle size of the granules. Then, preparations are made for further processing of this granule into a solid oral dosage form. Quadro co Using a standard device such as a mil at a constant rotational speed (rpm), the dried granules are sieved. This allows for the production of a substance having the desired particle size and free from aggregates. The engine speed can be 5 to 15 rpm, and preferably 8 to 10 rpm.

[0122] In one preparation method using wet granulation (for example, by fluidized bed granulation), a binder, a wetting agent, and a fine powder are used. The binder solution is prepared by dissolving the purified water until a clear solution is obtained. The compound (mixed with a diluent and a disintegrant as optional) is placed in a suitable wet granulation apparatus. Transfer to a container and heat the resulting mass while fluidizing it. Using wet granulation technology, bind the mass together. The combined solution is sprayed completely. After spraying while fluidizing, the resulting granules are dried. The dried powder is collected and placed in a bag such as an aluminum bag.

[0123] In another preparation method, the therapeutic compound is prepared, for example, with GEA Sirocco 300 or N Drug granules can be wet-granulated using fluidized bed granulators such as the iro Aeromatic D600. The inlet air temperature of the fluidized bed is 25°C to 80°C or 25°C to 70°C, preferably 2°C to 70°C. The temperature can vary between 5°C and 65°C; the outlet air temperature can be 25°C to 50°C, 20°C to 50°C, or 20°C. Temperature can vary between ℃ and 80℃; inlet airflow is 500-2200 m 3 / h, 2000~3000 m 3 / h, 800~1300m 3 / h, or 500-4500m 3 / h may vary; solution The flow rate or spray rate will be 170 to 4200 g / min, depending on the batch size and the capacity of the equipment. Within the range of 190-300g / min, 400-900g / min, or 0.200-2kg / min The spray air pressure can be in the range of 2-6 bar, 3-4 bar, or 1.00-5.00 bar. It may be enclosed. For example, abiraterone acetate and niraparib or niraparib to sile A monohydrate of hypromellose is mixed with a solvent (e.g., water) and a binder (e.g., a polymer, e.g., hypromellose). It can be wet-granulated with a binder solution containing ), and a wetting agent (e.g., sodium lauryl sulfate). In one example, before granulation with a binder solution, abiraterone acetate is used with a suitable diluent (e.g., It can be mixed with lactose monohydrate and a suitable disintegrant (e.g., crospovidone).

[0124] Dry granulation The term "dry granulation" refers to the process of mixing a therapeutic compound with at least one excipient. It means ses. Then, this mixture is compressed or compressed (compact), a compressed substance (i.e., a "compressed material") is formed. Then this material The material is crushed, ground, or cut into dry granules. By selection, these particles can be further processed, such as by further mixing with additional excipients. The crushing, grinding, or cutting process may be, for example, by grinding or by other operations known to those skilled in the art. This involves an operation that reduces the size of a compressed material, which is achieved through this process.

[0125] "Compressed material" refers to a material that has been processed for therapeutic use through slugging or roller compression. A compressed substance formed by processing a compound with optionally selected excipients. That is the case.

[0126] To prepare the mixture, weigh the compressed material and place it in a mixing container. Mix it to a suitable consistency. A mixing device is used to produce a homogeneous mixture over a certain period of time. (Optional) This mixture is then passed through a mesh screen to remove clumps from it. The separated mixture can be returned to the mixing container and mixed for a further period of time. Then, the lubricant The mixture may be added and mixed for a further period of time. Then, the mixture is compressed. To compress or compact to form a compressed object. This mixture can then be subjected to a preliminary compression process such as a rotary tablet press. Compression of Japanese materials can be achieved by techniques known in the relevant field, such as slugging, and this slugging In ging, the mixture includes one or more punch surfaces placed on a press such as a tablet press. It is introduced into a die, and the movement of one or more punch surfaces within this die presses the mixture. A force is applied. Dry granulation can also be carried out by a roller-type compressor. Compressors typically have two or more rollers arranged adjacent to and parallel to each other. The gap between these rollers is fixed or adjustable. Hopper or Due to other feeding devices, the admixture accumulates between the moving rollers, and these rollers Through this action, this mixture is compressed into a compressed substance. A roller-type compressor is a classic example. In terms of type, the compressed material coming out of this roller-type compressor is cut into ribbon-like strips. It is equipped with a device that separates by other means. An example of a roller compressor is the TF-Min i Roller Compactor(Vector Corporation,Ma (rion, IA, Freund)

[0127] Next, the compressed material is typically crushed, pulverized, or cut by suitable mechanical means. Granules are formed in this manner. For example, granules can be formed from compressed material by grinding. Grinding is This process involves applying shear force to the granules to achieve the desired particle size. The process can range from an active process that significantly reduces particle size to one that does not significantly reduce particle size. However, non-aggressive processes are performed only to remove lumps or to break down large clumps of granulation. It could be anything up to Seth.

[0128] In the pharmaceutical industry, grinding is often used to reduce the particle size of solids. Pin mills, hammers Many types of grinders are available, such as mill mills and jet mills. Most commonly One of the types of grinders used is a hammer mill. In a hammer mill, A high-speed rotor to which numerous hammers are attached, either fixed or vibrating. It is used so that either the knife side or the hammer side of the hammer comes into contact with the material. It can be attached to the grinder. When the material is fed into the grinder, it collides with the rotating hammers, It is pulverized into even smaller particles. A screen is installed beneath this hammer, allowing for further processing. Smaller particles pass through the openings of this screen. Larger particles are held in the mill. These particles are then pulverized with a hammer until they are fine enough to pass through the screen. It continues to grow. This substance can be screened out by arbitrary selection. In screening, one substance The desired particle size is obtained by passing through a mesh screen or a series of mesh screens.

[0129] Excipients The formulations of this disclosure (e.g., final dosage forms such as granules and tablets) are one or more conventional It may contain an excipient (a pharmaceutically acceptable carrier), which may be a disintegrant, diluent, or bloc. Examples include mixtures, buffers, lubricants, thickeners, sweeteners, flavorings, and colorants. Excipients can serve multiple purposes. In some embodiments, the formulations of this disclosure may serve as disintegrants, diluents, or This includes fillers, lubricants, and lubricants. In some embodiments, the formulations of the present disclosure include disintegrants, diluents, or This includes fillers, lubricants, lubricants, wetting agents, and binders. In some embodiments, the formulations of the present disclosure are It includes disintegrants, diluents or fillers, lubricants, lubricants, wetting agents, and binders, and wetting agents or the Some of the compounds and binders are present in the granules of abiraterone acetate and niraparib. In some embodiments, the formulations of the present disclosure include disintegrants, diluents or fillers, lubricants, humectants, and The compound contains a binder, and the wetting agent or a part thereof, the binder, and the disintegrant or a part thereof are avilatero It is present in the granules of naacetate and niraparib. In one embodiment, the formulation of the present disclosure is It includes disintegrants, diluents or fillers, lubricants, lubricants, wetting agents, and binders, and wetting agents or the In part, the binder, diluent, and disintegrant, or a portion thereof, are abiraterone acetate and nirapa. It is present in the granules of the rib. In some embodiments, the formulations of the present disclosure are disintegrants, diluents or fillers. It contains agents, lubricants, and wetting agents, and the wetting agent or part thereof is abiraterone acetate. It is also present in the granules of niraparib.

[0130] In some embodiments, the formulations of the present disclosure have an intragranular phase ) and extragranular phase are included.

[0131] In one embodiment, the granular internal phase comprises APIs, diluents or fillers, disintegrants, wetting agents, and binders. Includes. In one embodiment, the granular internal phase is an API, diluent or filler, disintegrant, wetting agent, lubricant , and a lubricant.

[0132] In one embodiment, the granular outer phase contains a diluent or filler, disintegrant, wetting agent, lubricant, and lubricant. include.

[0133] In one embodiment, the inner and outer phases of the granules contain a disintegrant (e.g., crospovidone). The presence of disintegrants in both the inner and outer phases of the particles improves the disintegration properties of tablets and granules. This increases the dissolution of API throughout the body, ultimately reducing the bioavailability of API. Tee increases.

[0134] Suitable wetting agents include anionic, cationic, or nonionic surfactants or surface agents. The agent can be selected from the following. Suitable anionic surfactants include carboxylate ions and sulfones. Examples include those containing acid ions and sulfate ions, such as sodium lauryl sulfate (S LS), sodium laurate, dialkyl sodium sulfosuccinate, especially bis-(2 -Ethylhexyl) sodium sulfosuccinate, sodium stearate, stearyl Examples include potassium iodide and sodium oleate. Suitable cationic surfactants include Examples include those containing long-chain cations, such as benzalkonium chloride and bis-2-hydroxypropyl alcohol. Examples include hydroxyethyl oleylamine. Suitable nonionic surfactants include the following: Examples include: polyoxyethylene sorbitan fatty acid esters, fatty alcohols, for example lauryl alcohol, cetyl alcohol, and stearyl alcohol; glyceryl alcohol Steres, for example, naturally occurring monoglycerides, diglycerides, and triglycerides. Fatty alcohols and fatty acid esters of other alcohols, such as propylene glycol. , polyethylene glycol, sorbitan, sucrose, and cholesterol. In one embodiment The wetting agent is sodium lauryl sulfate.

[0135] The amount of wetting agent in the tablets or pharmaceutical preparations relating to this disclosure is, conveniently, about 0.5 to about 8% (w It can be in the range of / w), preferably about 1-7% (w / w), or about 2-6% (w / w). Alternatively, it may be in the range of approximately 3-6% (w / w). In one embodiment, the wetting agent is sodium lauryl sulfate. It is thorium, and also approximately 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, Approximately 3.7, approximately 3.8, approximately 3.85, approximately 3.9, approximately 4.00, approximately 4.07, approximately 4.1, approximately 4 0.2, approximately 4.3, approximately 4.4, approximately 4.5, approximately 4.6, approximately 4.7, approximately 4.8, approximately 4.9, approximately 5 0.0, approximately 5.1, approximately 5.2, approximately 5.3, approximately 5.4, approximately 5.5, approximately 5.6, approximately 5.7, approximately 5 It is present in the final dosage form at a concentration of 0.8%, or approximately 5.9% by weight.

[0136] In one embodiment, the wetting agent is sodium lauryl sulfate, and in a ratio of about 0.005:1~0 0.02:1 (SLS: abiraterone acetate), preferably about 0.01:1, more preferably Alternatively, in a weight ratio of approximately 0.0112:1 to abiraterone acetate, in the granular composition It exists.

[0137] In one embodiment, the wetting agent is sodium lauryl sulfate, and in a ratio of approximately 0.05:1~0. 2:1 (SLS: abiraterone acetate), preferably about 0.1:1, more preferably For abiraterone acetate in a ratio of approximately 0.11:1, approximately 0.12:1, or approximately 0.123:1 It is present in the final formulation in that weight ratio.

[0138] Suitable disintegrants have a high coefficient of expansion. Examples of pharmaceutically acceptable disintegrants include The following are examples, but are not limited to: starch, clay, cellulose, alginic acid. Salts, gums, hydrophilic, insoluble, or poorly water-soluble crosslinked polymers, such as crospovidone ( Cross-linked polyvinylpyrrolidone, e.g., Kollidon CL-F and Polyplas (commercially available as done XL-10), and croscarmellose sodium ( Cross-linked sodium carboxymethylcellulose). Disintegrant: approximately 1-20% (w / w), Preferably in an amount of about 2 to about 10% (w / w), and especially in an amount of about 3 to 9% or about 5 to 9% (w / w). It may be present in tablets or pharmaceutical preparations.

[0139] In the case of the granular composition of the present invention and an oral dosage form containing this granular composition, the information disclosed herein is provided. In formulations that use excipients that can dissociate into ions, lauryl sulfate is not very desirable. Sodium (wetting agent) and magnesium stearate (lubricant) are exceptions. In terms of application methods, the disintegrant is a non-ionizable disintegrant such as crospovidone.

[0140] Various substances can be used as diluents or fillers. Examples include lactose monohydrate and anhydrous lactose. Lactose, sucrose, dextrose, mannitol, sorbitol, starch, ce Lullose (e.g., microcrystalline cellulose (Avicel®), silicified microcrystalline cellulose) (S) Dihydrated or anhydrous calcium hydrogen phosphate, and those known in the art, and These mixtures (for example, those marketed as MicroceLac®) A spray-dried mixture of cottose monohydrate (75%) and microcrystalline cellulose (25%). The most common materials are microcrystalline cellulose, silicified microcrystalline cellulose, or lactose monohydrate. Lactose monohydrate is usually characterized as a diluent or filler, but within granules It also possesses binding properties particularly useful for granulation of the phase. Diluent in tablets or pharmaceutical preparations according to this disclosure Alternatively, the amount of filler may, for convenience, be in the range of approximately 20% to approximately 70% (w / w). The ratio is approximately 20% to 60% (w / w), or approximately 25% to 35% (w / w), or approximately 25% The concentration may be in the range of ~30% (w / w). Preferably, the diluent is silicified microcrystalline cellulose. The granular outer phase is used. Preferably, the tablet FDC is about 25% to about 30% (w The outer phase contains granular MCC HD90 silicified ( / w). Depending on the content, an optimal compression profile for the tablet is obtained, reducing its abrasion and wear. ru.

[0141] Examples of pharmaceutically acceptable binders include, but are not limited to, the following: Cellulose and its derivatives, e.g., microcrystalline cellulose, e.g., FMC(Ph AVIEL PH, hydroxypropylcellulose, from Iladelphia, PA Hydroxyethylcellulose and hydroxypropylmethylcellulose, for example, D METHOCEL from ow Chemical Corp. (Midland, MI) Cloth; dextrose; corn syrup; polysaccharides; and gelatin. Binding agents include, for example... If present, it may be present in an amount of approximately 0.5% to 5% by weight of the formulation, for example, in an amount of 0.5% to 3%. Preferably, the binder is a low-viscosity grade of hypromellose, for example, HPM The pressure of C 2910 is 15 mPa.s.

[0142] Lubricants and lubricants can be used in the manufacture of certain dosage forms, and are typically used in the manufacture of tablets. Examples of lubricants and lubricants include hydrogenated vegetable oils, such as hydrogenated cottonseed oil and magnesium stearate. M, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal cyanoacrylate Lica, colloidal anhydrous silica talc, mixtures thereof, and other known in the art. The interesting lubricants are magnesium stearate and magnesium stearate. It is a mixture of stearate and colloidal anhydrous silica. A preferred lubricant is magnesium stearate. It is. The preferred lubricant is colloidal anhydrous silica. The lubricant is generally composed It constitutes 0.2-5.0% of the total weight (especially the total weight of the tablets), specifically 0.25 It makes up approximately 1.5%, and more specifically, 0.3-1.0% (w / w). Lubricants such as magnesium stearate are typically added in amounts of 0.2 to 5 parts of the total weight of the tablet. It constitutes 0.0%, specifically 0.5-2.5%, and more specifically 0 It makes up 0.5-2.0%, for example, about 1.0%, about 1.25%, or about 1.5%. It is composed of w / w.

[0143] Final Pharmaceutical Product Granules, together with excipients, are available in oral dosage forms, solid oral dosage forms, tablets, pills, lozenges, and caplets. Lozenges, hard or soft capsules, sachets, lozenges, aqueous or oily suspensions, dispersible powders Alternatively, it can be formulated into granules or other granular products.

[0144] A composition intended for oral use, known in the art with respect to the manufacture of pharmaceutical compositions It can be prepared according to any method, and such a composition is a pharmaceutically refined and palatable preparation. To provide the product, one of the following is selected from the group consisting of sweeteners, flavorings, colorings, and preservatives. Or it may contain multiple types of drugs.

[0145] The tablets are mixed with non-toxic, pharmaceutically acceptable excipients suitable for tablet manufacturing. Contains ingredients. This excipient may be, for example, the following: an inert diluent, such as calcium carbonate. Um, sodium carbonate, lactose monohydrate, silicified microcrystalline cellulose, calcium phosphate M, or sodium phosphate; granulating agents and disintegrants, e.g., crospovidone, microcrystalline cellulose Alginate, croscarmellose sodium, corn starch, or alginic acid; binder, e.g. For example, starch, gelatin, polyvinylpyrrolidone, or acacia; lubricants, e.g., ste Magnesium phosphate, stearic acid, or talc; and colloidal anhydrous silica, etc. Lubricant.

[0146] For example, in order to manufacture tablets, granules are combined with at least one excipient (e.g., a lubricant). Combine or mix to form a mixture. This mixing can be done using any blender such as a V-blender. This can be achieved using conventional pharmaceutical equipment.

[0147] Furthermore, any additional excipients used may be sieved separately from the granules, or as described above. As explained in the drying and sieving process, the granules are sieved and the sieved material is obtained at the same time. Those skilled in the art will understand the required particle size of each component needed for a particular pharmaceutical composition to be formulated. Ro.

[0148] The mixed mixture is then, for example, made into tablets (for example, by using a tablet press). The tablets can be compressed into a formulation or encapsulated. The hardness of the tablets is preferably 250~ The range is 350N. The solid oral dosage form is further processed using conventional methods known to those skilled in the art (e.g., It can be used for imprinting, embossing, or coating.

[0149] The tablets do not need to be coated, or they may be coated using known technologies. It is possible to have the tablets of this disclosure, for example, to improve the taste, to facilitate swallowing and to improve the appearance. To enhance its elegance, it may be further coated with a film. In this technical field, many Suitable polymer film coating materials are known. In one embodiment, this film coating The coating material is Opadry(registered trademark) AMB II 88A170010 beig e, Opadry(R) AMB II 88A210027 green, Opa dry(registered trademark) AMB II 88A620004 yellow, Opadori( (Registered Trademark) AMB II 88A220039 yellow, Opadori (Registered Trademark) ) QX 321A220006 yellow, or Opadry(registered trademark) II 3 This is 2F220009. This film coating material is typically mixed with purified water (Ph.Eur). Mix with to form a coating suspension. A preferred coating suspension is film coating The coating material is Opadry(registered trademark) AMB II 88A170010 bei ge, Opadry® AMB II 88A210027 green, and Opadry(registered trademark) AMB II 88A620004 yellow This is because the resulting coated tablets show no scratches. Suitable film-forming polymers may also be used herein, such as hydroxypropylcellulose. Hydroxypropyl methylcellulose (HPMC), especially HPMC 2910 5m Examples include Pa·s and acrylate-methacrylate copolymers. Preferred fill The coating material is, for example, HPMC coating Opadry II 32F2200. It is a water-permeable film coating material such as 09. In addition to the film-forming polymer, the film The coating consists of a plasticizer (e.g., propylene glycol) and an optional pigment (e.g., dioxide). It may further contain titanium dioxide. The film coating suspension may also contain titanium dioxide as an anti-adhesion agent. It may also include . In the tablets relating to this disclosure, the film coating is preferably, by weight, the tablet It accounts for approximately 5% (w / w) or less of the total weight of the agent.

[0150] To facilitate the swallowing of such formulations by mammals, appropriate formulations (especially tablets) should be made available. Imparting a shape is advantageous. A film coating on the tablet further enhances its ease of swallowing. It may be given. In some aspects of this disclosure, the tablet may be an oval tablet, in particular having a length of 19 m It may be an oval-shaped tablet with a diameter of m or less.

[0151] Other excipients such as colorants and pigments may be added to the formulations of this disclosure. Examples include titanium dioxide and food-grade pigments. The colorants are optional in the formulations of this disclosure. Although it is an optional ingredient, if used, this coloring agent is calculated based on the total weight of the tablets. It can be present in an amount of approximately 1-6% by weight, for example, approximately 2-5% by weight based on the total weight of the tablet. It may be present in amounts of approximately 3-4% by weight, or up to 3.5% by weight.

[0152] The fragrance is optional in this formulation and may consist of synthetic flavor oils and flavor-imparting aromatic oils (fl Avoring aromatics, or natural oils, plant leaves, flowers, fruits, etc. Extracts, as well as combinations thereof, may be selected. These include cinnamon oil, Wintergreen oil, peppermint oil, bay leaf oil, anise oil, yu Potassium or thyme oil may be mentioned. Vanilla and citronella are equally useful as fragrances. Oils, for example, lemon, orange, grape, lime, and grapefruit, In addition to fruit essences, such as apple, banana, pear, peach, strawberry, and raspberry. These include cherries, plums, pineapples, and apricots. The amount of fragrance depends on the desired sensory effect. It can be influenced by many factors, including the above. Generally, fragrances are present in amounts of approximately 0% to 3% (w / w). It will exist.

[0153] Preparations for oral use, as well as solid diluents in which the active ingredient is inactive (e.g., calcium carbonate) Hard gelatin or HPMC mixed with calcium phosphate or kaolin It can also be presented as a capsule, or the active ingredient may be a water-soluble carrier or oil medium (e.g., peanut Soft gelatin capsules mixed with oil, liquid paraffin, or olive oil It can also be presented as a cell.

[0154] Aqueous suspensions are granules in which the therapeutic compound is mixed with excipients suitable for the preparation of aqueous suspensions. Contains granules. Such excipients include suspending agents, for example, carboxymethylcellulose sodium M, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, Polyvinylpyrrolidone, tragacanth gum, and acacia gum, which are dispersants or wetting agents. These include naturally occurring phosphatides, such as lecithin, or alkylene oxides and fatty acids. Condensates with, for example, polyoxyethylene stearate, or ethylene oxide and long-chain lipids. Condensates with fatty alcohols, for example, heptadecaethyleneoxycetanal, or ethyl Condensates of oxides and partial esters derived from fatty acids and hexitol, for example, Polyoxyethylene sorbitol monooleate, or ethylene oxide and fatty acids and Condensates with partial esters derived from xyl anhydride, for example, polyethylene sorbitan It may be a tanmonoleate. The aqueous suspension may also contain one or more preservatives, for example, Ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one type Or multiple flavorings, and one or more sweeteners, for example, sucrose, saccharin, or This may also include aspartame.

[0155] The oily suspension contains granules containing therapeutic compounds in vegetable oil (e.g., peanut oil, olive oil). Suspend in oil, sesame oil, coconut oil, or mineral oil such as liquid paraffin. It can be formulated by the following. This oily suspension can be thickened with a thickener, such as beeswax, solid paraffin, Or it may contain cetyl alcohol. In order to obtain an oral formulation with a pleasant taste, the above-mentioned ingredients etc. Flavorings and fragrances may be added to this composition. It can be preserved by adding antioxidants such as ulfatecopherol.

[0156] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water are dispersants or wetting agents. The present invention provides an active ingredient mixed with a suspension agent and one or more preservatives. Powders or wetting agents and suspensions are exemplified above. Additional excipients, e.g. For example, sweeteners, flavorings, and colorings may also be present. This composition may contain acid-resistant compounds such as ascorbic acid. It can be preserved by adding a preservative.

[0157] In the first case, this disclosure envisions pharmaceutical preparations for oral administration, such as tablets and capsules. However, the pharmaceutical compositions of this disclosure may also be used for rectal administration. Preferred formulations are tablets. It is formed as such and is suitable for oral administration. This is a conventional ingredient or excipient. It can be manufactured using a pharmaceutically acceptable carrier and conventional tableting techniques with a conventional tablet press.

[0158] Treatment methods and medical use The method of treating prostate cancer, or the medical use of this pharmaceutical preparation, is a therapeutically effective amount of PAR. Niraparib, a P inhibitor, and a therapeutically effective dose of abiraterone, a CYP17 inhibitor. Tate, and optionally, a therapeutically effective amount of another drug (e.g., glucocorticoids) For example, prednisone) is administered to patients who require it, and / or comprises and / or from To become essential.

[0159] The method of treating this prostate cancer, or the medical use of this pharmaceutical preparation, is based on niraparib and abirate. A free-dose combination formulation (FrDC) or fixed-dose combination formulation (FDC) of ronacetate is provided as needed. This includes, and / or essentially consists of, administering to a patient, the treatment of prostate cancer. The method, or the medical use of this pharmaceutical preparation, is the same as the free-dose combination preparation or fixed-dose combination preparation described above. This includes administering glucocorticoids (e.g., prednisone) to patients who require them. Consists of and / or essentially consists of

[0160] The treatment methods and medical uses disclosed herein refer to the oral agents as defined herein. The form is to be administered to patients who require it, and the oral dosage form is abiraterone acetate, The administration of a granular composition comprising niraparib and a pharmaceutically acceptable carrier. This oral dosage form and granular composition constitute FDC.

[0161] Similarly disclosed are the oral dosage regimens disclosed herein. Therefore, in a total dose that is therapeutically effective for the treatment of prostate cancer in human patients, niraparib and abiraterone acetaminophen The FDC of Tate, and optional glucocorticoids (e.g., prednisone) are administered. A dosage regimen consisting of, and / or essentially consisting of, including, donating.

[0162] This disclosure also relates to a free-dose combination or fixed-dose formulation containing niraparib and abiraterone acetate. A combination drug and this free-dose or fixed-dose combination drug are administered to human patients with prostate cancer. Kits comprising and / or essentially consisting of, including instructions for administration, are also disclosed. ru.

[0163] This kit contains a free-dose combination or fixed-dose formulation containing niraparib and abiraterone acetate. Dosage combination preparations, separate compositions containing glucocorticoids (e.g., prednisone); and this A free-dose or fixed-dose combination formulation for administering to human patients with prostate cancer. It may include, may consist of, and / or essentially consist of.

[0164] Whereever "prednisone" is specifically referred to in this disclosure, a person skilled in the art can understand that prednisone Donisone is different from other glucocorticoids (e.g., prednisolone, hydrocortisone, You will be aware that it can be replaced with methylprednisolone or dexamethasone. Those skilled in the art can replace prednisone with these other drugs and adjust their dosages as needed. A method for adjusting this is likely already known.

[0165] Specific suitable glucocorticoids include, but are not limited to, the following. (1) Dexamethasone (e.g., Decadron, oral; Decadron-LA) (1) Injection, etc., (2) Prednisolone (e.g., Delta-CORTEF) (Registered trademark), Prednisolone acetate (ECONOPRED®), Prednisolone Sodium phosphate (HYDELTRASOL®), Prednisolone tetraphosphate (3) Prednisone (DELT (ASONE (registered trademark), etc.), or (4) Methylprednisolone (e.g., MEDROL ( Registered trademarks)), and combinations thereof. For example, Goodman & Gilman's s The Pharmacological Basis of Therapeut Please refer to ics, 10th edition 2001.

[0166] The formulations described herein are used to treat prostate cancer patients who are biomarker-negative. It can be used by placing it in a biomarker-positive state. It can be used in methods for treating prostate cancer patients.

[0167] The formulations described herein are positive for homologous recombination deficiency (HRD) biomarkers. It can be used in methods to treat patients with prostate cancer. HRD also involves homologous recombination repair (H Also known as RR deficiency, it can be caused by DNA repair gene deficiency (DRD). D or HRR deficiency-positive status is detected by evaluating changes in somatic or germ cells. It may be possible, or loss of heterozygosity (LOH) throughout the genome or DNA repair genes It can be detected by evaluating the deterioration of homozygosity in the following cases. HRD or HRR deficiency positive. This condition is also synonymous with a positive PARP biomarker status.

[0168] A biomarker-positive state may indicate an HRD-positive state. A biomarker-negative state may indicate an HRD-negative state. The condition may be HRD-negative. The HRD status can be determined by a plasma-based test (Resolu Foundation Me (Bioscience) or tissue-based testing (Foundation Me It can be evaluated by either dicine, specifically, circulating plasma DNA or circulating tumor DNA This can be evaluated by detecting cells. A positive HRD status indicates one or more DNA repair residues. This can be defined as having a single allele or a biallele alteration in the gene, and this DNA The following are examples of repair genes, but are not limited to these: BRCA1 (breast cancer gene) 1) BRCA2 (breast cancer gene 2), ATM (ataxia vasodilator mutation), FANCA (F Fanconi anemia complementation group A gene), PALB2 (BRCA2 gene partner) (and localizer), CHEK2 (checkpoint kinase 2 gene), BRIP1 (BRCA1 interacting protein C-terminal helicase 1 gene), HDAC2 (histone Acetylase 2), CDK12 (cyclin-dependent kinase 12), RAD51B (RA D51 Paralog B), RAD54L (RAD54-like), CDK17 (Cyclone-dependent key Nase 17), or PPP2R2A (protein phosphatase 2 regulatory subunit B Rufa).

[0169] Using gene expression profile analysis and protein biomarkers, prostate cancer is diagnosed. Patients can be risk-stratified to guide treatment decisions. A commercially available test is Prolari. s(Registered Trademark) (Myriad Genetics, Salt Lake City, U T); OncotypeDx (registered trademark) Prostate Cancer Assay (Genomic Health, Redwood City, CA);ProMark (Trademark) Protein Biomarker Test / ProMark (Trademark)Ri sk Score(Metamark Genetics,Cambridge,MA) FoundationOne(registered trademark) CDx(Foundation Medic ine, Cambridge, MA; FoundationOne(registered trademark) Liq uid CDx(Foundation Medicine, Cambridge, MA );Caris Molecular Intelligence(Caris Lif e Sciences,Irving,TX);Guardant360(Guarda nt Health Inc., Redwood City, CA);Prostate Next(registered trademark)(Ambry Genetics,Aliso Viejo,CA );Color Hereditary Cancer Test(Color Gen omics, Burlingame, CA);Invitae Prostate Ca ncer Panel(Invitae Corp., San Francisco,C A);Prostate Gene(GeneHealth,Cambridge,UK );Myriad myRisk(registered trademark) Hereditary Cancer T est(Myriad Genetics Inc.,Salt Lake City, UT) and Decipher® Prostate Cancer Test (GenomeDx Biosciences, San Diego, CA) is one example. The latter refers to the expression levels of 22 RNA markers in biopsy or radical prostatectomy specimens. Based on turns. Prolaris®, OncotypeDx®, Decipher® is a tissue-based gene expression test.

[0170] The formulations described herein are used for biochemical relapse (BCR) or biochemical failure (BF). It can be used in methods for treating prostate cancer patients who have BCR or BF. It can be defined by an elevated prostate-specific antigen (PSA) level without evidence of disease. Primary radiation For patients undergoing radiotherapy, the BCR is currently 2.0 ng / mL above the lowest point. This is defined as an elevated PSA level ("Phoenix criteria"). Patients undergoing primary surgery. In the case of this individual, BCR is currently confirmed to be 2.0 ng / mL or higher than the lowest point of PSA It is defined as an increase.

[0171] Next-generation imaging (NGI), such as prostate-specific membrane antigen positron emission tomography (PS) Using MA-PET, it is possible to detect images that are invisible with conventional imaging diagnostics or that do not meet the Phoenix threshold (immediately). NGI can detect lesions with a PSA level of less than 2.0 ng / mL. Some patients with prostate cancer, BCR, nmCRPC, or nmHRPC are considered pre-metastatic. It can be classified as having prostate carcinoma.

[0172] The formulations described herein have BCR or BF and are HRD biomer It can be used in methods for treating patients with prostate cancer who are KAR-positive and / or high-risk. Iomarker positivity includes BRCA1, BRCA2, ATM, BRIP1, CDK12, and CD K17, CHEK2, FANCA, HDAC2, PALB2, PPP2R2A, RAD5 It may be at least one of 1B and RAD54L.

[0173] The formulations described herein are those that can be detected by conventional imaging diagnostics, such as the patient's BCR or It may be used in methods for treating BF, oligometastatic disease, or localized prostate cancer.

[0174] The formulations described herein may be detected by NGI in patients with BCR or B It can be used in methods for treating oligometastatic disease or localized prostate cancer.

[0175] The formulations described herein are candidates for primary radiotherapy in locally advanced prostate cancer. It can be used in methods for treating patients who have it.

[0176] The formulations described herein are androgen receptor splice variant 7 (AR - Treat cancer patients (especially CRPC patients) who are negative for circulating tumor cell testing in relation to V7). It can be used in the following way. The formulations described herein can be used in androgen receptor splice Cancer patients who test positive for circulating tumor cells (CRPC) in relation to RIANT 7 (AR-V7) (especially CRPC) It can be used in methods of treating patients.

[0177] The formulations described herein are detectable circulating tumor cells (CTCs), circulating DNA, Alternatively, it may be used in a method for treating prostate cancer in patients with reduced plasma DNA. The described formulations are used for detectable CTCs and / or measurable and unmeasurable bone diseases. It can be used in methods for treating metastatic prostate cancer in patients with the disease or lesions. In patients with adenocarcinoma, CTC clearance is 5 or fewer per 7.5 mL of blood at baseline. The method is established when the upper cells are detected and fewer than 5 cells per 7.5 mL of blood are detected at the lowest point. This can be confirmed by a second set of consecutive values ​​obtained more than four weeks later.

[0178] A combination of abiraterone acetate and niraparib in a free-dose or fixed-dose formulation, and A separate composition of any choice containing a cocorticoid (e.g., prednisone) is used with the prostate Subjects, patients, mammals, especially humans, who have cancer, primary peritoneal cancer, breast cancer, or ovarian cancer. It may be administered. In one embodiment, a person suffering from breast cancer or ovarian cancer may be a biomarker-positive patient. He is a person.

[0179] Prostate cancer can be: metastatic prostate cancer, advanced prostate cancer, localized prostate cancer, local Localized advanced prostate cancer, localized prostate cancer, non-metastatic prostate cancer, non-metastatic advanced prostate cancer, non-metastatic Metastatic localized prostate cancer, non-metastatic locally advanced prostate cancer, non-metastatic localized prostate cancer, hormone Prostate cancer that has not undergone treatment, prostate cancer that has not undergone chemotherapy, and prostate cancer that has not undergone castration with or without metastasis. Cancer, prostate cancer that has not undergone radiation therapy, castration-resistant prostate cancer (CRPC), complete remission with DRD PC, non-metastatic CRPC (nmCRPC), PSA doubling time of 10 months or less, and H nmCRPC in patient populations that are RD-positive (or biomarker-enriched) nmCRPC in patients with DRD or HRD, in patients without DRD nmCRPC, nmCRP in patients with high-risk BCR (e.g., DRD+ population) C. nmCRPC in patients monitored with next-generation imaging technology (NGI) Localized CRPC, locally progressive CRPC, localized CRPC, progressive CRPC, metastatic CR In patients with PC (mCRPC) and biallelic DNA repair gene deficiency (DRD) mCRPC, mCRPC in patients with single allele DRD, and DRD Patients without mCRPC, DRD, and taxanes and / or androgens mCRPC in patients receiving receptor-targeted therapy, hormone therapy (e.g., Enzal) CRPC and taxane therapy in patients receiving tamide, darolutamide, and apalutamide. For patients receiving medications (e.g., docetaxel, mitoxantrone, cabazitaxel) CRPC without chemotherapy, CRPC without chemotherapy, mCRPC without hormone therapy CRPC in patients, mCRPC in patients who have not received hormone therapy, CRPC in patients with advanced visceral metastasis CRPC, receiving hormone therapy (e.g., enzalutamide, darolutamide, apalutamide) In patients with visceral metastases in CRPC, taxane therapy (e.g., docetaxel) In patients receiving mitoxantrone or cabazitaxel, visceral metastases CRPC, CRPC with visceral metastasis and progression, castration-sensitive prostate cancer (CSPC) ), non-metastatic CSPC (nmCSPC), localized CSPC, locally progressive CSPC, local CSPC, advanced CSPC, metastatic CSPC (mCSPC), CSPC that has not received chemotherapy mCSPC without chemotherapy, CSPC without hormone therapy, mCSP without hormone therapy C. Hormone-sensitive prostate cancer (HSPC), hormone-dependent prostate cancer, androgen-dependent sexual prostate cancer, androgen-sensitive prostate cancer, biochemically recurrent HSPC, metastatic HSPC ( mHSPC), hormone-resistant prostate cancer (HRPC), non-metastatic HRPC (nmHRPC) ), localized HRPC, locally progressive HRPC, localized HRPC, progressive HRPC, metastatic H RPC (mHRPC), recurrent prostate cancer, with or without distant metastasis, prostatectomy Prostate cancer with persistent or recurrent prostate-specific antigen (PSA) levels, and radiation-resistant prostate cancer. , and any combination thereof.

[0180] The subjects or patients are classified as very low risk, low risk, moderate favorable risk, and moderate risk. Selected from undesirable risk, high risk, very high risk, and localized risk. It may belong to the risk group.

[0181] The subjects may be surgically castrated or chemically castrated.

[0182] Most, though not all, prostate cancers are adenocarcinomas, and patients have a history of adenocarcinoma or sarcoma-based prostate cancer. Prostate cancer may be present. In either of these cases, the prostate cancer may metastasize.

[0183] The patient will receive a combination of niraparib and abiraterone acetate in either a free-dose or fixed-dose formulation. Before the first dose, one or more other types of treatment for prostate cancer may be received. For example The patient will receive a free-dose or fixed-dose combination of niraparib and abiraterone acetate. Prior to administration, taxane-based chemotherapy may be received. In addition, or the patient may receive 2 Before administering a free-dose or fixed-dose combination of raparib and abiraterone acetate , at least one line of androgen receptor targeted therapy (e.g., apalutamide (ER) LEADA (registered trademark) and / or enzalutamide (XTANDI (registered trademark)) It may be received. In one embodiment, the patient may receive niraparib and abiraterone acetate in free doses. Before administering a combination drug or a fixed-dose combination drug, check whether the patient has not initially responded to previous treatments, or Resistance to this treatment has developed. Optionally, niraparib and abiraterone are used. In addition to free-dose or fixed-dose combination formulations of ceteate, glucocorticoids (e.g., pr Rednisone may also be administered.

[0184] Termination of other treatments and free-dose distribution of niraparib and abiraterone acetate in accordance with this disclosure Combination drugs or fixed-dose combination drugs, and optional glucocorticoids (e.g., prednisone) The interval between administration of ) is several years, several months, several weeks, several days, one day, or within 24 hours. obtain.

[0185] A combination of niraparib and abiraterone acetate in a free-dose or fixed-dose configuration, and Optional administration of glucocorticoids (e.g., prednisone) is once or twice daily. , or it could be three times.

[0186] A single fixed-dose combination of niraparib and abiraterone acetate is administered daily. The FDC may be administered to the patient once, twice, or three times per day. All dosage regimens encompassed by the description are intended. In some aspects, nirapa Take one tablet or capsule containing rib and abiraterone acetate FDC once daily. Administer. In one embodiment, two FDCs containing niraparib and abiraterone acetate are administered. The tablets or capsules are administered once daily. In one embodiment, niraparib and abiraterone are used. Administer three tablets or capsules containing acetate FDC once daily. This is a single tablet or capsule containing niraparib and abiraterone acetate FDC. It should be administered once a day, at least one hour before a meal or at least two hours after a meal. In one embodiment, two tablets or capsules containing niraparib and abiraterone acetate FDC Administer the drug once a day, at least one hour before a meal or at least two hours after a meal. In one embodiment, three tablets containing niraparib and abiraterone acetate FDC or Take the capsule once a day, at least one hour before a meal or at least two hours after a meal. In one embodiment, a single tablet containing niraparib and abiraterone acetate FDC. Take the tablet or capsule once a day, at least one hour before a meal or at least two hours after a meal. It is administered with water on an empty stomach. In one embodiment, niraparib and abiraterone acetate are used. Take two tablets or capsules containing FDC once a day, at least one hour before a meal. It is administered with water on an empty stomach at least two hours after a meal. In one embodiment, niraparib And three tablets or capsules containing abiraterone acetate FDC, once daily with food. Administer with water on an empty stomach at least one hour before the event or at least two hours after a meal.

[0187] In one embodiment, glucocorticoids are administered once or twice a day. In another embodiment, Prednisone tablets or capsules are administered once or twice daily.

[0188] In one embodiment, one or two FDCs comprising niraparib and abiraterone acetate Administer tablets or capsules once daily, and use glucocorticoids (e.g., prednisone). Administer one tablet or capsule of ) once or twice daily.

[0189] The niraparib equivalent administered to patients is approximately 30 to 400 mg / day, or approximately 50 to 350 mg / day. g / day, about 66 to about 325 mg / day, about 100 to about 300 mg / day, about 100 to about 275 mg / day, about 125 to about 250 mg / day, about 150 to about 225 mg / day, about 175 to about 2 25 mg / day, or approximately 190-210 mg / day, or approximately 30, 33, 40, or approximately 50, approximately 60, approximately 66, approximately 67, approximately 70, approximately 80, approximately 90, approximately 99, approximately 100, approximately 110 Approximately 120, 130, 132, 134, 140, 150, 160, 170 , approximately 180, approximately 190, approximately 200, approximately 201, approximately 210, approximately 220, approximately 230, approximately 240 , approximately 250, approximately 260, approximately 270, approximately 280, approximately 290, approximately 300, approximately 310, approximately 320 This could be approximately 330, 340, or 350 mg / day.

[0190] The amount of abiraterone acetate administered to patients is approximately 300 to 2000 mg / day. 500~about 1500mg / day, about 700~about 1200mg / day, about 800~about 1200m Is it possible to have g / day, approximately 900-1100 mg / day, or approximately 950-1050 mg / day? Or approximately 300, approximately 333, approximately 500, approximately 600, approximately 666, approximately 700, approximately 750, approximately 80 0, approximately 850, approximately 875, approximately 900, approximately 925, approximately 950, approximately 999, approximately 1000, approximately 1 0.25, approximately 1050, approximately 1075, approximately 1100, approximately 1125, or approximately 1500 mg / It could be a day.

[0191] The amount of prednisone administered to patients is approximately 1 to 25 mg / day, or approximately 2 to 23 mg / day. Approximately 3-20 mg / day, approximately 4-18 mg / day, approximately 5-15 mg / day, approximately 6-12 mg / day The daily doses are approximately mg / day, 7-11 mg / day, 8-11 mg / day, and 9-11 mg / day. You can get, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11 , approximately 12, approximately 13, approximately 14, approximately 15, approximately 16, approximately 17, approximately 18, approximately 19, approximately 20, approximately 21 The dose may be approximately 22, 23, 24, or 25 mg / day. In some embodiments, the patient It has mCSPC, and the amount of prednisone is 5 mg / day. In some embodiments, The patient has mCRPC, and the prednisone dose is 10 mg / day.

[0192] When administering niraparib and abiraterone acetate FDCs to patients, the following conditions apply to each drug. The selected dosage level depends on various factors (e.g., the activity of the specific compound, but not limited to these factors). Sex, severity of symptoms in the individual, route of administration, time of administration, elimination rate of the compound, duration of treatment , other drugs, compounds, and / or substances used in combination, as well as the patient's age and sex The dosage of niraparib will depend on factors such as weight, condition, overall health, and medical history. The amount of abiraterone acetate and the optional amount of prednisone will ultimately be determined by the doctor. While it is at the discretion of the doctor, generally speaking, the dosage is determined based on whether it is substantially harmful or harmful. (deleterious) Site of action that achieves the desired effect without causing side effects This achieves local concentration.

[0193] FDCs include, for example, approximately 33-350 mg of niraparib and approximately 100-1500 mg of... May contain abiraterone acetate.

[0194] For example, this composition may contain, for example, 33 to approximately 350 mg, approximately 33 to approximately 300 mg, approximately 50 mg Approximately 200mg, approximately 50-150mg, approximately 50-100mg, approximately 33-100mg The amount may contain the equivalent of chive parib, or approximately 30, approximately 33, approximately 50, approximately 67, approximately 100, approximately 110, approximately 120, approximately 130, approximately 140, approximately 150, approximately 160, approximately 170, approximately 180, approximately 190, approximately 200, approximately 210, approximately 220, approximately 230, approximately 240, approximately 250, approximately 260, approximately 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, or This may be approximately 350 mg. This composition contains approximately 33, approximately 50, approximately 67, or approximately 100 mg. The quantity may contain the equivalent amount of chive parib.

[0195] This composition also contains, for example, about 100 to about 1500 mg, about 125 to about 1400 mg, about 150~1300mg, 175~1200mg, 200~1175mg, 2 25~1150mg, 250~1100mg, 250~1075mg, 25 0~about 1050mg, about 250~about 1000mg, about 300~about 950mg, about 350~ Approximately 900 mg, approximately 400-850 mg, approximately 450-800 mg, or approximately 500-7 A dose of 00 mg may contain abiraterone acetate, or approximately 100, approximately 150, approximately 175, approximately 200, approximately 225, approximately 250, approximately 275, approximately 300, approximately 325, approximately 350, approximately 375, approximately 400, approximately 450, approximately 500, approximately 550, approximately 600, approximately 650, approximately 700, approximately 750, approximately 800, approximately 850, approximately 900, approximately 950, approximately 1000, approximately 1050, approximately 1100, approximately 11 50, about 1200, about 1250, about 1300, about 1350, about 1400, about 1450, or This may be approximately 1500 mg. This composition is prepared in an amount of approximately 333 or approximately 500 mg of Avilatello. It may contain n.

[0196] This composition contains approximately 33 mg of niraparib equivalent and 333 mg of abiraterone. This composition contains approximately 67 mg of niraparib equivalent and 333 mg of abiratero. This composition may contain approximately 50 mg of niraparib equivalent and 500 mg of avian. May contain laterone. This composition contains approximately 100 mg of niraparib equivalent and 500 mg It may contain a certain amount of abiraterone.

[0197] This treatment regimen also includes, for example, approximately 2 to 15 mg, approximately 2 to 14, approximately 3 to 13, and approximately 4-12, 5-11, 5-10, 6-11, 7-11, 8-11 This includes separate doses of glucocorticoids, such as prednisone, in amounts of approximately 9 to 11 parts. You can get, or about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 1 2. It may be approximately 13, 14, or 15 mg.

[0198] This method involves administering niraparib and avira acetate separately to patients over several days, weeks, months, or years. Theron is administered, and optionally, glucocorticoids or prednisone as FDCs. This may include: Preferably, administration of niraparib and abiraterone acetate FDC is 1 day The treatment is administered once, twice, or three times, and, at the discretion of the patient, separate doses of prednisone are administered on the same day. The procedure is performed once, twice, or three times. Niraparib, abiraterone acetate, and optionally another The amount of prednisone administered can remain constant over time (i.e., day by day). Or, it may increase or decrease over time. For example, administered per day Niraparib, abiraterone acetate, and prednisone, which may be administered separately as an option. Or, any two or all of these amounts, one day after administration, several days after administration, and one week after administration. The dose may be increased or decreased, and the new dose may be adjusted for any desired period, for example. It can be maintained for several days, weeks, or months, or may be increased after the desired period. It may be obtained or reduced. In this form, the method is obtained at least once over time. Administration of niraparib and abiraterone acetate FDC (for example, administered once daily each) This may include increasing or decreasing the amounts of niraparib and abiraterone acetate. Alternatively, this method also involves administering prednisone at least once over time (for example, daily). This may include increasing or decreasing the total amount of prednisone administered. Alternatively, the amount of decrease may be expressed as a percentage, and in such circumstances, the increase Or the amount of a single instance of decrease is approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, and approximately 3%. 0%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 7 0%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, approximately 100%, or more than approximately 100% obtain.

[0199] This specification relates to a method for treating cancer, comprising a therapeutically effective dose of niraparib, avian acetate. Lateron, and optionally, prednisone, prednisolone, and hydramine are administered separately. glucocorticoids such as locortisone, methylprednisolone, and dexamethasone For patients, for example, patients who need it, anticancer drugs (e.g., docetaxel, mitoxantrone, (Cabazitaxel, cisplatin, carboplatin, oxaliplatin, and etoposide) , immunotherapy agents (e.g., pembrolizumab, ciproisel-T), bone targeting therapy (e.g., Denosumab, zoledronic acid, alendronate, radium-223, strontium- 89, Samarium-153), Gonadotropin-releasing hormone agonists (not limited to) Triptorelin, Nafarelin, Goserelin, Leuprorelin or Leuprolide, Histrelin, gonadrelin, and buserelin (GnRHa), and hormone therapy ( For example, nilutamide, flutamide, bicalutamide, goserelin, histrelin, leup Lorid, Triptorelin, Degarelix, Enzalutamide, Apalutamide, Darolutamide This includes, but is not limited to, ketoconazole, diethylstilbestrol, and estrogen. The method of administration is described as being administered in combination with at least one additional therapeutic agent in a therapeutically effective dose. It will be published. Such methods also apply to individuals with refractory cancers, including those currently undergoing cancer treatment. It is possible to provide effective treatment for the individual. Therefore, the method is to provide chemotherapy to the patient. It may also be directed towards treating resistant prostate cancer, in which case a therapeutically effective dose of niraparib is used. In addition, abiraterone acetate is administered to patients currently receiving anticancer drugs.

[0200] Furthermore, the methods for treating cancer described herein include androgen deprivation therapy (A It can be combined with DT. The methods for treating cancer described herein are preferred In some cases, this specification may be used in combination with radiotherapy in the HRD+ population. The methods for treating cancer described in this book are combined with ADT and extracorporeal radiation therapy (EBRT). They can be combined. The methods for treating cancer described herein use intensive focused ultrasound. Combined with alternative energy sources such as HIFU, cryosurgery, and laser therapy. obtain.

[0201] The present invention relates to FDC, and separately administered glucocorticoids (e.g., prednisone, Prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferred (or prednisone or prednisolone) may be administered to patients with metastatic prostate cancer. In particular, the FDC of the present invention and glucocorticoids administered separately (e.g., prednisolone) Nisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone (Preferably prednisone or prednisolone) is the first-line (L1) mCRPC Which patients have mCRPC (e.g., androgen deprivation therapy (ADT) and avira acetate)? In the case of metastatic castration resistance, except for limited exposure to teron + prednisone, It can be administered to patients who are not being treated with other therapies. Patients who are positive for HRD It is also acceptable for the patient to be positive for HRD. Preferably, the patient is positive for HRD. The result is positive. Metastatic prostate cancer is diagnosed by computed tomography (CT) or magnetic resonance imaging. It can be confirmed by a positive bone scan or metastatic lesion on (MRI). The patient has testosterone In cases where the neutering level is ≤50 ng / dL and the patient is under GnRHa therapy... The patient has a history of or has undergone bilateral orchiectomy. Patients may continue GnRHa therapy during treatment. Patients may be part of a group of 0 or 1 US East Coast cancer clinical trials. It may have an ECOG PS (Electric Coherence On-Grade Performance) score.

[0202] ADT reduces the levels of androgens produced in the testes, which then affect the prostate. Surgical intervention or medication is used to stop the deterioration of adenocarcinoma cells. As an ADT, surgery Medical castration or orchiectomy; and medical castration-like luteinizing hormone-releasing hormone (LHRH) Agonists, for example, leuprolide, goserelin, triptorelin, histrelin; L HRH antagonists; abiraterone acetate; ketoconazole; antiandrogen-like flutamide D, bicalutamide, nilutamide, enzalutamide, apalutamide, darlotamide (dar Examples include, but are not limited to, ulotamide or estrogen.

[0203] The present invention relates to FDC, and separately administered glucocorticoids (e.g., prednisone, Prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferred (or prednisone or prednisolone) is mCSPC, for example, harmful germline or It can be administered to patients with somatic homologous recombination repair (HRR) gene mutations (mCSPC). Harmful germline or somatic HRR gene mutations include BRCA1, BRCA2, ATM, and BRI. P1, CDK12, CDK17, CHEK2, FANCA, HDAC2, PALB2, P It could be at least one of PP2R2A, RAD51B, and RAD54L, but these Not limited to, mCSPC is at least one bone lesion on a bone scan; preferably mCSPC can be confirmed by bone metastases further confirmed by CT or MRI. It can be detected by NGI-like PSMA-PET. Patients are in the US East Coast Cancer Clinical Trials (2 or fewer). The patient may have an experimental group performance score (ECOG PS) grade. This may also be under adrogen removal therapy (either medical or surgical castration), and this therapy is It may be started within 6 months prior to FDC + prednisone (or prednisolone) treatment. Preferably, it is a treatment with FDC + prednisone (or prednisolone) It may be started at least 14 days prior. The androgen deprivation therapy is FDC + prednisolone. Treatment may be continued until (or prednisolone) treatment is complete. FDC + prednisone (or prednisolone) Those patients who started GnRHa therapy less than 28 days before Zolone treatment are preferably, First-generation antiandrogens are used, preferably with FDC + prednisone (or prednisolone). It is administered for at least 14 days prior to treatment. The antiandrogen is FDC + prednisone ( The patient must discontinue (or prednisolone) treatment before starting treatment. Patients may be receiving treatment with kiseru or cabazitaxel; preferably, patients may take up to 6 cycles The patient is receiving docetaxel therapy; preferably, the patient receives FDC + prednisone (or (Prednisolone) The last dose of docetaxel or cabazitaxel should be administered within 2 months prior to treatment. He is receiving treatment. Before FDC + prednisone (or prednisolone) therapy, the patient had a prostate infection. You may be receiving radiation therapy or surgical intervention to manage the symptoms of cancer. FDC + Prednisolone Before prednisolone (or d-) therapy, the patient preferably receives FDC + prednisone (or For one month prior to prednisolone therapy, abiraterone acetate + glucocorticoid (for example, Prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexane It is acceptable to be receiving methamphetamine. Before FDC + prednisone (or prednisolone) therapy. Furthermore, the patient may be receiving treatment for localized prostate cancer, preferably these treatments Treatment should be completed at least one year prior to FDC + prednisone (or prednisolone) treatment. It must be; for example, the patient has undergone androgen deprivation therapy for up to 3 years. It is also possible; for example, the patient may undergo radiotherapy, prostatectomy, lymph node dissection, or systemic therapy. It's okay to leave it.

[0204] The present invention relates to FDC, and separately administered glucocorticoids (e.g., prednisone, Prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferred Alternatively, prednisone or prednisolone can treat homologous recombination deficiency (HRD) or DRD. With or without, and by optional choice, cyclin-dependent kinase 12 (CDK12) It may be administered to patients with metastatic castration-resistant prostate cancer (mCRPC) accompanied by pathogenic changes. FDC may be of low intensity: administered orally as a single dose under modified fasting conditions. It is available as 2xFDC tablets (50mg equivalent niraparib / 500mg abiraterone acetate). The given dose is 100 mg equivalent of niraparib / 1000 mg abiraterone acetate. FDC is usually The strength may be: administered orally as one daily dose under modified fasting conditions, 2x It is administered as FDC tablets (100 mg equivalent niraparib / 500 mg abiraterone acetate). 200 mg equivalent of niraparib / 1000 mg abiraterone acetate. The patient was surgically castrated. If not (i.e., not having undergone bilateral orchiectomy), FDC + prednisone ( In some cases, GnRHa therapy can be continued during treatment with (or prednisolone). This refers to a US East Coast cancer clinical trial group performance status (ECOG PS) of 1 or less. ) may have. Before FDC + prednisone (or prednisolone) treatment, the patient may have limited However, nilutamide, flutamide, bicalutamide, enzalutamide, apalutamide, Exposure to antiandrogens including darolutamide or abiraterone acetate is also acceptable; In other words, the previous androgen therapy was FDC + prednisone or prednisolone The drug should be properly discontinued before administering the first dose. Bicalutamide, flutamide, and niltamide In the case of D, the drug-free period is approximately 2 weeks. Regarding enzalutamide, the drug-free period is approximately 8 weeks. Yes, there is. Regarding apalutamide, the drug-free period is approximately 6 weeks.

[0205] The present invention relates to FDC, and separately administered glucocorticoids (e.g., prednisone, Prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferred Alternatively, prednisone or prednisolone is used for high-risk and lymph node-positive prostate cancer. For patients undergoing radiation therapy, leuprorelin acetate (leuprorelin acetate) is administered before, during, and after radiation therapy. It can be administered in combination with (also known as Lorido). Radiation therapy is approximately 37. This may involve stereotactic body radiotherapy (SBRT) or ultrafractionated radiotherapy with a total dose of 5-40 Gy.

[0206] The present invention relates to FDC, and separately administered glucocorticoids (e.g., prednisone, Prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferred (or prednisone or prednisolone) is a castration-sensitive prostate gland with or without metastasis. It may be administered to patients with adenocarcinoma. Patients who are not surgically castrated (i.e., bilateral) (Those who have not undergone orchiectomy), currently receiving FDC + prednisone (or prednisolone) treatment. In some cases, GnRHa therapy can be continued.

[0207] In the disclosed composition, niraparib may be present alone in a therapeutically effective amount. Abiratheron acetate may be present in a therapeutically effective amount alone, and may be optionally added. Prednisone, administered separately, may be present in a therapeutically effective amount on its own, or Two or more of these conditions may apply. In other examples, when considered together, chives The total amount of parib, abiraterone acetate, and prednisone administered separately as an option The amount may be therapeutically effective, meaning that the amount of niraparib alone is not therapeutically effective. Furthermore, the amount of abiraterone acetate is not therapeutically effective on its own, and if present, prednisolone is used. The amount of nizoline alone is unlikely to be therapeutically effective.

[0208] This specification refers to compositions comprising niraparib and abiraterone acetate, and optionally, , compositions containing prednisone, and for administering compositions to human patients with prostate cancer A kit including instructions will also be disclosed. The instructions specify how to administer the medication once, twice, or multiple times a day. Instructions for administering each composition may be provided. For example, the instructions may specify niraparib and A composition containing abiraterone acetate is administered once daily to human patients with prostate cancer. Furthermore, optionally, for administering a composition containing prednisone to a human patient twice daily. I can provide instructions.

[0209] This disclosure further describes the study of niraparib and abiraterone acetate compared to the oral dosage forms of this disclosure. A method for determining the bioequivalence of fixed-dose formulations (FDCs), i) Test Measuring the bioequivalence parameters of FDC formulations and, at the discretion of the present disclosure ii) measuring the bioequivalence parameters of the oral dosage form, and the bioequivalence parameters of the test FDC formulation The physical equivalence parameters are set to the corresponding bioequivalence parameters of the oral dosage forms of this disclosure. Regarding methods that involve comparison.

[0210] In some embodiments, the bioequivalence parameter is AUC (0~t) AUC (0~∞) , residual area, C max and t max AUC (0~72h) , the disappearance rate constant (λ z ), t 1 / 2 AUC (0~τ), C max,ss , t max,ss Ae (0~t) ,and R max Selected from, the bioequivalence parameters are those of bioequivalence and pharmacokinetics. It is well known to those skilled in the art.

[0211] The present invention is further defined in the following embodiments. These embodiments are preferred by the present invention. This illustrates an example of a particular embodiment, but it is provided for illustrative purposes only and is not subject to the attached claims. It should be understood that this should not be interpreted as limiting the scope. From the discussion and these examples, those skilled in the art will be able to grasp the essential features of the present invention. Without departing from its spirit and scope, various modifications and alterations of the present invention may be made in various forms. It can be adapted to the intended use and conditions. [Examples]

[0212] Example 1 - Composition of the formulation

[0213] [Table 1]

[0214] [Table 2]

[0215] [Table 3]

[0216] [Table 4]

[0217] [Table 5]

[0218] [Table 6]

[0219] [Table 7]

[0220] [Table 8]

[0221] [Table 9]

[0222] [Table 10]

[0223] [Table 11]

[0224] [Table 12]

[0225] Example 2 - Abiraterone acetate and niraparib tosylate hydrate prepared by wet granulation Preparation of coated tablets containing cogranules 2.1 Wet granulation of abiraterone acetate and niraparib tosylate hydrate The binder solution was prepared by immersing it in purified water with HPMC 2910 15mP until a clear solution was obtained. It was prepared by dissolving as and sodium lauryl sulfate. The component is avian acetate. Laterone, niraparib tosylate hydrate, lactose monohydrate, and crospovidone are The materials were sorted, pre-mixed, and transferred to a suitable wet granulation machine, the GPCG30 fluidized bed granulator. These components were heated while being fluidized. The complete bound solution was produced using wet granulation technology. The ingredients were sprayed using a solution. The granules were sprayed while becoming fluid, and then dried. Dried powder They were recovered and filled into aluminum bags.

[0226] [Table 13]

[0227] The LOD profiles for the granules of the compositions in Tables 1 and 3 are provided in Figure 6. .

[0228] Sieve analysis is provided in Figure 7 for the granules in Table 1, and in Figure 8 for the granules in Table 3. It will be done.

[0229] 2.2 Granular outer phase and compression Silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and colloid-free Water silica was selected and added to the fluidized bed granules. All materials were selected and mixed in a suitable mixer. It was mixed. Magnesium stearate was selected and added to the container, and all the ingredients were well The mixture was then mixed again in a suitable mixer. Next, the mixture was compressed in tablet module S(KC11). It was compressed into a core tablet using [a specific method / tool].

[0230] The LOD, angle of repose, bulk density, and tap density of the final mixtures of the compositions in Tables 1 and 3 are as follows: This can be found in Table 14.

[0231] [Table 14]

[0232] The results for the mixing uniformity (BU) of the final mixtures of the compositions in Tables 1 and 3 are shown in Tables 15 and 16. The results for stratified content uniformity are given in Tables 17 and 18, respectively. The result is shown in the BU, which indicates that both mixtures are well mixed and both APIs are present in the mixture. This indicates a uniform distribution. The result of stratified content uniformity is a complete manufacturing process. Good and uniform distribution of abiraterone acetate and niraparib tosylate hydrate within the core tablet. The distribution is demonstrated. For the compositions in Table 3, the uniformity of content was also determined and is shown in Table 19. It may be released.

[0233] [Table 15]

[0234] [Table 16]

[0235] [Table 17]

[0236] [Table 18]

[0237] [Table 19]

[0238] The resulting tablets were tested for weight, thickness, hardness, and disintegration time, and the results are shown in Table 20. As shown in [reference], the tablets were collected and packaged in a suitable container.

[0239] [Table 20]

[0240] All these results are for abiraterone acetate / niraparib tosylate, i.e., Table 1 and This demonstrates that we were able to successfully manufacture two clinical batches of composition 3.

[0241] 2.3 Film Coating The coating suspension is prepared by dispersing the coating powder in purified water until a suspension is obtained. It was prepared by the following. The core tablets were transferred to a suitable coating pan. Next, The coating solution was sprayed onto the core tablet using film coating technology. The coated tablets were dried after spraying in the same coating pan. The tablets were collected and packaged in suitable containers.

[0242] The film-coated tablets obtained in Table 2 showed no scuffing, and no other defects were observed. It wasn't done.

[0243] The film-coated tablets obtained in Table 4 showed scuffing defects and surface defects. It did not show white spots.

[0244] In summary, these film-coated tablets in Tables 2 and 4 were found to be free of defects and in good condition. It was manufactured in [year].

[0245] Example 3 - Abiraterone acetate prepared by fluidized bed granulation, and prepared by dry granulation Preparation of coated tablets containing granules of niraparib tosylate hydrate 3.1 Dry granulation of niraparib tosylate hydrate Niraparib tosylate hydrate, lactose monohydrate, microcrystalline cellulose, povidone K3 O, crospovidone, colloidal anhydrous silica, and magnesium stearate were selected. It was mixed in a suitable mixer. The mixture was then ground, and the ground material was further preferred. The mixture was mixed in a mixer. The dried granules were then compressed using a suitable compression technique, such as a roller compressor. The dried granules were prepared and then further ground using a suitable dry grinder.

[0246] 3.2 Wet granulation of abiraterone acetate A mixture of abiraterone acetate, lactose monohydrate, and croscarmellose sodium. The samples were then screened out by arbitrary selection. Hypromellose, sodium lauryl sulfate (SLS) A binder solution containing ) and purified water is prepared, and abiraterone acetate, lactose monohydrate, and The mixture was then added to croscarmellose sodium. Next, the granules were granulated in a fluid bed. It was formed and then dried.

[0247] 3.3 Granular outer phase and compression The obtained abiraterone acetate granules and niraparib tosylate hydrate granules are selected and suitable In a mixer, silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and It was mixed with colloidal anhydrous silica. Magnesium stearate was selected and added to the container. Then, all the materials were mixed again in a suitable mixer.

[0248] Next, the mixture containing niraparib tosylate hydrate granules and abiraterone acetate granules is The tablets were compressed into core tablets using a suitable tablet press. The tablets were recovered and packaged in a suitable container. It was done.

[0249] 3.4 Film Coating The coating suspension is prepared by dispersing the coating powder in purified water until a suspension is obtained. It was prepared by the following. The core tablets were transferred to a suitable coating pan. Next, The coating solution was sprayed onto the core tablet using film coating technology. The coated tablets were dried after spraying in the same coating pan. The tablets were collected and packaged in suitable containers.

[0250] 4.1 Dry granulation of niraparib tosylate hydrate and abiraterone acetate Abiraterone acetate, niraparib tosylate hydrate, lactose monohydrate, crospovid N, sodium lauryl sulfate, colloidal anhydrous silica, microcrystalline cellulose, and stearin Magnesium oxide was selected and mixed in a suitable mixer. The mixture was then pulverized. The crushed material was further mixed in a suitable mixer. The dried granules were compressed using a suitable compression technique, for example. If prepared using a roller compressor, the dried granules are further processed using a suitable dry grinder. It was then pulverized.

[0251] 4.2 Granular outer phase and compression The obtained abiraterone acetate and niraparib tosylate hydrate cogranules were selected, and suitable In the mixer, silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and co It was mixed with Lloyd's anhydrous silica. Magnesium stearate was selected and added to the container. Then, all the materials were mixed again in a suitable mixer.

[0252] Next, the mixture was compressed into core tablets using a suitable tablet press. The tablets were recovered and suitable Packaged in an appropriate container.

[0253] 4.3 Film Coating The coating suspension is prepared by dispersing the coating powder in purified water until a suspension is obtained. It was prepared by the following. The core tablets were transferred to a suitable coating pan. Next, The coating solution was sprayed onto the core tablet using film coating technology. The coated tablets were dried after spraying in the same coating pan. The tablets were collected and packaged in suitable containers.

[0254] Example 5 - Stability data of the prepared dried granules in Tables 1 and 3 After the preparation of the dried granules in Tables 1 and 3, the stability data showed the degradation of abiraterone acetate and chives. Paribtosylate hydrate is not shown. The oxidative decomposition products of abiraterone acetate are shown at 5°C, 2 After 12 months at 5°C / 60%RH and 30°C / 75%RH, and after 6 months at 40°C / 75%RH It remains within specifications after a month.

[0255] Example 6 - Dissolution method for testing the in vitro release of active pharmaceutical ingredients of a prepared composition The parameters for the dissolution method are summarized in Table 21 below.

[0256] [Table 21]

[0257] ● The in vitro solubility curves for abiraterone acetate and niraparib are shown in Figures 5A and 5, respectively. In B, one capsule containing 100 mg equivalent of niraparib in its tosylate hydrate form, and The combination of two 250 mg tablets of abiraterone acetate is provided; ● FDC tablets containing the composition shown in Table 2 (50 mg equivalent of the tosylate hydrate form of nirapa) Rib, and 500 mg of abiraterone acetate; and ● FDC tablets containing the composition shown in Table 4 (100 mg equivalent of the tosylate hydrate form of chives) Parib and 500 mg of abiraterone acetate.

[0258] Example 7 - Abiraterone acetate and prednisolone for the treatment of subjects with metastatic prostate cancer Phase 3 randomized controlled trial of niraparib in combination with abiraterone acetate and prednisone for the treatment of [unclear]. Chemical, placebo-controlled, double-blind trial, MAGNITUDE The primary objective of this trial is to determine progression-free survival (rPFS) based on radiographic findings. Furthermore, niraparib and abiraterone acetate were compared to abiraterone acetate + prednisone and placebo. The objective is to evaluate the effectiveness of laterone plus prednisone (AAP).

[0259] The trial consists of five phases; a pre-screening phase with biomarker evaluation only, and a screening phase with biomarker evaluation only. The initial phase, treatment phase, follow-up phase, and continuation phase (open-label or long-term depending on cohort assignment) (Any of the periods). The treatment cycle is defined as 28 days.

[0260] Cohort 1: Subjects with mCRPC and HRR gene alterations Cohort 1 is L1 mCRPC (i.e., limited exposure to ADT and AAP). (and in a metastatic castration-resistant state, not treated with any therapy) and HRR genetic In subjects with sub-changes, the combination of niraparib and AAP compared to placebo and AAP. We will evaluate the results. This cohort will enroll approximately 400 participants.

[0261] Cohort 2: Subjects with mCRPC and no HRR gene mutations. Cohort 2 is L1 mCRPC (i.e., limited exposure to ADT and AAP). (and has not been treated with any therapy in a metastatic castration-resistant condition), HRR In subjects without genetic mutations, niraparib and AAP compared to placebo and AAP Evaluate the combination. The cohort can enroll approximately 600 participants. The futility analysis involved approximately 200 participants, and in this cohort, approximately 12 It was carried out after five progresses had occurred.

[0262] Cohort 3: Pairs with mCRPCs that accept niraparib and abiraterone acetate FDCs elephant To evaluate the clinical efficacy and safety of FDC tablet formulations of niraparib and abiraterone acetate. To achieve this, a separate open-label cohort was added to the study (Cohort 3). Zero participants were enrolled in Cohort 3 under the same inclusion / exclusion criteria, and in Cohort 3 The patient was able to accept an open-label niraparib + abiraterone acetate tablet formulation instead of a monotherapy. They can be subjected to the same trial procedure as Cohort 1, except for one other step.

[0263] Test group ● Intended Treatment (ITT) population: Randomized subjects from both Cohort 1 and Cohort 2. ● Safety population: Subjects in cohorts 1 and 2 who receive at least one dose of the test drug. . ● FDC population: Subjects in Cohort 3 who receive at least one dose of FDC.

[0264] evaluation ● Effectiveness evaluation includes: ○ Progression-free survival (rPFS; primary endpoint) based on X-ray findings: CT or MRI scan and whole-body bone scan ( 99m It is evaluated by tumor measurement using Tc). The scan is, They are collected and examined by a central vendor. ○ Serum prostate cancer as evaluated by the prostate cancer working group 3 (PCWG3) criteria Glandular specific antigen (measured at a central laboratory). ○ Survival status. ○ Subsequent systemic therapy for prostate cancer. ○ Cancer-related radiotherapy or surgical procedures. ○ Symptomatic progression. ○ Patient-reported outcomes. ● PK evaluation. Blood samples for measuring plasma levels of niraparib and its metabolites are used. (If deemed relevant) Obtained on day 1 of cycles 2-7. Population PK parameters The ter and derived exposure levels are also determined with respect to niraparib. Abiraterone plasma Blood samples for measuring levels are obtained before administration on day 1 of cycles 2 and 3. ● Biomarker evaluation: The state of HRR gene mutations is assessed using blood and tumor tissue (stored data). Evaluation is performed on samples (or recently recovered samples). Other exploratory biomarker analyses are also performed. It will be implemented only if permitted by local regulations. ● Safety evaluation: Safety evaluation includes adverse event reporting, vital sign measurement, physical examination, and clinical safety assessment. Comprehensive clinical tests, US East Coast Cancer Clinical Trials Group Performance Score, ECG, and index Based on a medical review of the results of other safety assessments at a specified point in time.

[0265] Pre-screening eligibility criteria 1. Signed Informed Consent Form (ICF). 2. Age 18 or older (or the legal age of consent in the local area) 3. Histologically confirmed prostate cancer. 4. Blood samples can be provided for determining HRR gene changes. 5.BRCA1, BRCA2, CDK12, FANCA, PALB2, CHEK2, BR Tumor group for determining HRR gene mutations selected from IP1, HDAC2, and ATM We are willing to provide textile samples (either those that have been stored or those that have been recently recovered). 6. Castration-level testosterone (i.e., gonadotropin-releasing hormone analogs [Gn Metastatic prostate in patients with a history of taking RHa or undergoing bilateral orchiectomy at the time of trial participation. cancer.

[0266] Inclusion Criteria 1. The HRR gene mutation status is as follows: a. Cohort 1: Positive for HRR gene mutation b. Cohort 2: Non-positive for HRR gene mutation (i.e., HRR gene mutation is not present) stomach) c. Cohort 3: Those who are positive for HRR gene mutations and have accepted FDC. 2. Positive bone skiving on computed tomography (CT) or magnetic resonance imaging (MRI) Metastatic disease as evidenced by cysts or metastatic lesions. 3. G as evidenced by the progression of prostate-specific antigen (PSA) or radiographic findings. nRHa or castration levels of testosterone ≤50 ng / dL in bilateral orchiectomy Metastatic prostate cancer in this context. 4. If the animal has not been surgically castrated, it must be able to continue GnRHa therapy during the trial. 5.0 or 1 for a US East Coast cancer clinical trial group performance score (ECOG PS) grade 6. Brief Pain Inventory (BPI-SF) Question #3 (Most severe pain in the previous 24 hours) A score of ≤3 for pain. 7. Clinical laboratory values ​​at screening: a. ≥ 1.5 x 10 9 Absolute neutrophil count (ANC) for / L. b. Hemoglobin level ≥ 9.0 g / dL, and transfusion-free for at least 30 days. c. ≥ 100 x 10 9 Platelet count in / L. d. Serum albumin ≥ 3.0 g / dL. e. Calculated or directly measured via 24-hour urine collection, ≥30 mL / min Creatinine clearance. f. Serum potassium ≥ 3.5 mmol / L. g. Serum total bilirubin ≤ 1.5x upper limit of normal range (ULN) or direct bilirubin ≤ 1x ULN Lilirubin (Note: In subjects with Gilbert's syndrome, total bilirubin is >1.5xU) If LN is present, measure direct and indirect bilirubin, and if direct bilirubin is ≤1.5xULN In that case, the subject may be eligible as determined by the medical monitor. h. Aspartate aminotransferase (AST) and alanine with ≤ 3xULN Aminotransferase (ALT). 8. The test drug tablet and capsule must be swallowable in their entirety. 9. During administration of the study drug and for three months after the last dose of the study drug, male subjects will be subject to the principal investigator's supervision. I agree to use sufficient contraception as deemed appropriate by the teacher, and to use sperm You must agree not to provide it. 10. You intend to comply with the prohibitions and restrictions specified in this protocol. To cut.

[0267] Exclusion criteria 1. Previous treatment with PARP inhibitors. 2. Systemic therapy in the context of mCRPC (i.e., enzalutamide, apalutamide, or This includes novel second-generation AR-targeted therapies such as darolutamide; taxane-based chemotherapy; or randomized. AAP for more than 4 months prior to the change; or AAP other than the status of mCRPC. 3. Regarding subjects who received AAP for 2-4 months prior to randomization for the treatment of mCRPC And evidence of progression by PSA during screening (according to PCWG3). These potential The subjects are those who have a PSA level of 2 during the pre-screening and screening period. It is required. The second PSA level should be within two weeks of randomization. If the findings are thought to be due to a flare, the principal investigator should confirm that there is no progression of the X-ray findings. It should be done. 4. Symptomatic brain metastases 5. History or current diagnosis of myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML). 6. Other prior malignancies within ≤2 years prior to randomization (exception: well-treated basal cell or tonsillar tumors) (Squamous cell carcinoma, superficial bladder cancer, or any other cancer currently in situ in vivo that is in complete remission) (or malignant tumors that currently require effective systemic therapy). 7. Severe or unstable angina, requiring coronary artery bypass graft or stent within the previous 6 months. Myocardial infarction or ischemia, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g.) For example, pulmonary embolism, cerebrovascular accidents including transient ischemic attacks, or clinical events within 6 months prior to randomization. Cervical significance of ventricular arrhythmia or New York Heart Association (NYHA) Class II-I V heart disease. 8. Presence of uncontrolled hypertension (sustained systolic blood pressure [BP] ≥ 160 mmHg or diastolic pressure) (BP ≥ 100 mmHg). When BP is controlled within these endpoints by antihypertensive drug treatment. Subjects with a history of hypertension are acceptable. 9. Any of the following current evidence: a. Any medical condition that would make the use of prednisone contraindicated. b. Corticosteroids at a higher dose than 10 mg of prednisone (or equivalent) once daily. Any chronic medical condition requiring an id. 10. Active or symptomatic viral hepatitis or chronic liver disease (ascites resulting secondarily from liver damage) (as evidenced by encephalopathy or hemorrhagic disorder). 11. History of adrenal dysfunction 12. Known allergies, hypersensitivity, or to AA or niraparib or the corresponding excipients. Intolerance. 13. Subjects receiving opioid analogs at the time of screening. 14. Human immunodeficiency virus (HIV) positive individuals who have one or more of the following conditions: a. Not receiving highly active antiretroviral therapy. b. The patient is receiving antiretroviral therapy, which may interfere with the test drug. c. Changes in antiretroviral therapy within 6 months of the start of screening (changes to investigational drugs) (Unless done to avoid potential drug-drug interactions caused by the substance.) d. CD4 count <350 at the time of screening. e. Opportunistic symptoms typical of acquired immunodeficiency syndrome within 6 months of the start of screening infection. 15. Subjects who had the following conditions ≤ 28 days prior to randomization: a. Blood transfusion (platelets or red blood cells). b. Hematopoietic growth factors. c. Investigational drug for prostate cancer. d. Major surgery (for procedures that qualify as major surgery, it is necessary to consult with the sponsor). e. Radiation therapy.

[0268] Example 8 - Harmful germline or somatic homologous recombination repair (HRR) gene mutation-induced castration sensation Abiraterone acetate and prednisolone for the treatment of participants with mCSPC Phase 3 no data on niraparib in combination with abiraterone acetate and prednisone. Manipulation, placebo-controlled, double-blind trial, AMPLITUDE The purpose of this test is, ● Acetate in participants with harmful germline or somatic HRR gene mutations (mCSPC) Compared to abiraterone + prednisone, niraparib and abiraterone acetate + prednisone However, does it offer superior efficacy in improving progression-free survival (rPFS) based on X-ray findings? To decide whether to ask; ● Acetate in participants with harmful germline or somatic HRR gene mutations (mCSPC) Compared to abiraterone + prednisone, niraparib and abiraterone acetate + prednisone To evaluate the clinical usefulness of; In participants with harmful germline or somatic HRR gene mutations (mCSPC), avian acetate was used. Compared to laterone + prednisone, niraparib and abiraterone acetate + prednisone are cheaper. The goal is to characterize the overall sex profile.

[0269] Approximately 788 participants received niraparib 200 mg and abiraterone acetate 10 mg per day. 00mg + prednisone 5mg; or abiraterone acetate 1000mg + prednisone daily. Participants will be randomly assigned in a 1:1 ratio to one of the following 5mg doses. All participants will be... Androgen deprivation therapy (ADT) in the genital area; that is, gonadotropin-releasing hormone therapy. The animal must have undergone a castration or neutering procedure. The examination consists of four stages: Eligible Pre-screening phase for sex-only biomarker evaluation, screening phase, Treatment phase and follow-up phase.

[0270] Inclusion Criteria 1. Each potential participant must meet all of the following criteria to be enrolled in this study. Must be met: 2. Age 18 or older (or the legal age of consent in the local area). 3. Diagnosis of prostate adenocarcinoma. 4. 99m Metastatic disease demonstrated by bone lesions of ≥1 on Tc bone scans. 5. Participants with a single bone lesion must have confirmation of bone metastasis by CT or MRI. No. 6.BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PA Harmful germline or somatic cell HR selected from LB2, RAD51B, and RAD54L It must have at least one R gene mutation. 7. Group Performance Status (ECOG PS) of <2 in US East Coast cancer clinical trials grade. 8. Androgen deprivation therapy (medical or surgical castration) should be initiated >14 days prior to randomization. They must have been treated and have the intention to continue until the treatment period. <28 days prior to randomization Participants starting nRH agonists will have undergone a first-generation anti-androgen treatment for >14 days prior to randomization. It is necessary to take [medication name]. Antiandrogens must be discontinued before randomization. No. 9. Participants who have previously received docetaxel treatment must meet the following criteria: It must be: a. Received up to 6 cycles of docetaxel therapy for mCSPC. b. The last dose of docetaxel was received <2 months prior to randomization. c. Stable disease or worse, as determined by the investigator's assessment of imaging or PSA prior to randomization. The patient maintained a response to docetaxel. 10. Other acceptable prior therapies for mCSPC: a. Up to one course of radiation therapy or surgical intervention to manage the symptoms of prostate cancer. Targeted radiation exposure is not permitted. Radiation exposure must be completed before randomization. I don't know. b. ADT <6 months prior to randomization. c. If necessary, abiraterone acetate + prednisone for 30 days is acceptable. 11. Previous treatment for localized prostate cancer is acceptable (all treatments are ≥1 in randomization). (Must have been completed years ago): a. Total ≤ 3 years of ADT b. All other forms of treatment, including radiotherapy, prostatectomy, lymph node dissection, and systemic therapy. Previous treatment. 12. Clinical laboratory values ​​at screening: a. ≥ 1.5 x 10 9 / L Absolute number of neutrophils b. Hemoglobin ≥ 9.0 g / dL, transfusion-free for at least 28 days. c. ≥ 100 x 10 9 Platelet count / L d. Creatinine < 2x upper limit of normal range (ULN) e. Serum potassium ≥ 3.5 mmol / L f. Serum total bilirubin ≤ 1.5x ULN or direct bilirubin ≤ 1x ULN (Note: Gil In participants with Beer syndrome, if total bilirubin is >1.5xULN, When direct and indirect bilirubin are measured, and direct bilirubin is ≤1.5xULN (Participants may be eligible.) g.AST or ALT ≤ 3 × ULN 13. The test drug tablet must be able to be swallowed whole. 14. Informed consent demonstrating an understanding of the purpose of the examination and the procedures required for the examination. You must sign a consent form (written or remote / virtual) and provide a DNA sample. I am willing to participate in the exam, which includes [specific aspect]. 15. During administration of the study drug and for three months after the last dose of the study drug, male participants were responsible for the clinical trial. Unless you agree to use sufficient contraception as deemed appropriate by your doctor No. 16. Male participants must provide sperm samples during the study treatment and for at least 3 months after the last dose of the study drug. You must agree not to provide it.

[0271] Exclusion criteria Any potential participant who meets any of the following criteria will be excluded from the study. ru: 1. Pathological findings consistent with small cell duct carcinoma or neuroendocrine carcinoma of the prostate. 2. Previous treatment with PARP inhibitors. 3. Except that only abiraterone acetate + prednisone for the 30 days prior to randomization is acceptable. Previous AR-targeted therapies (e.g., ketoconazole, apalutamide, etc. for prostate cancer) (Nzalutamide, darolutamide), immunotherapy, or radiopharmaceuticals. 4. Bisphosphonate or denosumab for the management of bone metastases <28 days prior to randomization The start of treatment. 5. History of adrenal dysfunction 6. Systemic administration of corticosteroids during the study (>5 mg of prednisone or equivalent) Long-term use is not permitted. Short-term use (≤4 weeks, including gradual tapering) is permitted only when clinically necessary. Steroids administered locally (e.g., inhaled, topical, eye drops, and intra-articular) are permissible. It can be done. 7. An ongoing malignant tumor other than the disease in question (i.e., one that has progressed or been cured in the 24 months immediately preceding it) Those requiring a change in treatment will be treated under trial. The following exceptions are permitted: a. Non-muscle invasive bladder cancer; b. Skin cancer (non-melanoma) treated within 24 months immediately prior to being considered completely cured. or melanoma); c. Breast cancer (adequately treated lobular carcinoma or ductal carcinoma in vivo); d. Malignant tumors that have a minimal risk of recurrence and are considered cured. That is all. 8. History or current diagnosis of MDS / AML. 9. Current evidence within 6 months prior to randomization of any of the following: severe / unstable angina, myocardial infarction Infarction, symptomatic congestive heart failure, clinically significant arterial or venous thromboembolic events (e.g.) (e.g., pulmonary embolism), or clinically significant ventricular arrhythmias. 10. Persistent, uncontrolled hypertension (systolic blood pressure > 160 mmHg or diastolic blood pressure > 1 The presence of blood pressure (00 mmHg). Participation is acceptable for individuals with a history of hypertension, but blood pressure is not treated with antihypertensive drugs. This is conditional on being controlled within these endpoints. 11. Excipients of niraparib, abiraterone acetate, or niraparib / abiraterone acetate FDC Known allergies, hypersensitivity, or intolerance to the agent. 12. Current evidence of any medical condition that would contraindicate the use of prednisone. 13. Research intervention within 30 days prior to the scheduled first dose of the investigational drug therapy (research intervention) Have received (including thinning) or used an invasive research medical device. 14. Participants who had the following conditions ≤ 28 days prior to randomization: a. Blood transfusion (platelets or red blood cells); b. Hematopoietic growth factors; c. Major surgery (for procedures that qualify as major surgery, it is necessary to consult with the sponsor). 15. Human immunodeficiency virus-positive participants who have one or more of the following: a. Not having received highly active antiretroviral therapy or having received antiretroviral therapy within the last 4 weeks. Receiving viral therapy. b. Receiving antiretroviral therapy that may interfere with the study drug therapy. (Consult with your sponsor for a review of your drug therapy before registration.) c. Change in antiretroviral therapy within 6 months of the start of screening (exclusion criteria) After consultation with the sponsor, the change was made to address potential drug-drug interactions with the experimental drug therapy. (Unless done to avoid it). d. CD4 count <350 at the time of screening. e. Opportunistic symptoms typical of acquired immunodeficiency syndrome within 6 months of the start of screening infection. f. Human immunodeficiency virus load of >400 copies / mL. 16. Active or symptomatic viral hepatitis or chronic liver disease; encephalopathy resulting secondarily from liver damage Ascites or bleeding disorder. 17. Severe liver injury, class C, according to the Child-Pew classification system.

Claims

1. When treating prostate cancer, the simultaneous, separate, or sequential use of prednisone. As a combination preparation for this purpose, abiraterone acetate and niraparib tosylate - A pharmaceutical preparation containing a hydrate, wherein in male human patients, by optional selection, the prostate cancer This is mCRPC, and by arbitrary selection, the mCRPC is the first-choice (L1) mCRPC. A certain pharmaceutical product.

2. The patient is positive for homologous recombination deficiency (HRD), or the patient has HRD A pharmaceutical preparation for use according to claim 1, which is not positive for [the specified value].

3. The aforementioned HRD status is BRCA1 (breast cancer gene 1), BRCA2 (breast cancer gene 2), AT M (vasodilatory ataxia variant), FANCA (Fanconi anemia complementation group A gene), PALB2 (BRCA2 gene partner and localizer), CHEK2 (checker (C-terminal kinase 2 gene), BRIP1 (BRCA1 interacting protein C-terminal helical Case 1 gene), HDAC2 (histone deacetylase 2), or CDK12 (cyan One or more DNA repair genes, including but not limited to crine-dependent kinases (12) The method described in claim 2, which is detected by changes in a single allele or both alleles in the following: A pharmaceutical preparation for use.

4. The patient, prior to the treatment with the pharmaceutical preparation containing prednisone, experienced gonadotropin If you are receiving steroid-releasing hormone agonist (GnRHa) therapy or have undergone bilateral orchiectomy a pharmaceutical preparation for use according to any one of claims 1 to 3.

5. If the patient has not been surgically castrated, the pharmaceutical preparation containing prednisone may be used. The use according to any one of claims 1 to 4, wherein GnRHa therapy is continued during the aforementioned procedure. A pharmaceutical preparation for that purpose.

6. In male human patients, with or without DNA repair gene deficiency (DRD) or HRD , optionally, mC with cyclin-dependent kinase 12 (CDK12) pathogenicity alteration. When administering RPC, for simultaneous, separate, or sequential use with prednisone. As a combination preparation, abiraterone acetate and niraparib tosylate monohydrate A pharmaceutical preparation containing substances.

7. If the patient has not been surgically castrated, the pharmaceutical preparation containing prednisone may be used. A pharmaceutical formulation for use according to claim 6, wherein GnRHa therapy is continued during the aforementioned treatment.

8. Prior to the treatment with the pharmaceutical preparation containing prednisone, the patient took nilutamide, Flutamide, bicalutamide, enzalutamide, apalutamide, dalorutamide, and avila The person is exposed to an antiandrogen selected from terone acetates, as described in claim 6. A pharmaceutical preparation for use.

9. The anti-androgen was used before the treatment with the pharmaceutical preparation containing prednisone. A pharmaceutical formulation for use according to claim 8, which is swatched out.

10. In male human patients, before, during, and after radiotherapy, high-risk and lymph nodes When treating positive prostate cancer, simultaneous administration of prednisone and leuprorelin acetate is used. As a combination preparation for separate or continuous use, abiraterone acetate ester A pharmaceutical preparation containing tel and niraparib tosylate monohydrate.

11. The radiotherapy is stereotactic radiotherapy (SBRT) or ultrafractionated radiotherapy, and the total radiation A pharmaceutical formulation for use according to claim 10, wherein the amount is approximately 37.5 to 40 Gy.

12. When treating castrated naive prostate cancer with or without metastasis in male human patients , combination preparations for simultaneous, separate, or sequential use with prednisone A pharmaceutical preparation containing abiraterone acetate and niraparib tosylate monohydrate.

13. If the patient has not been surgically castrated, the pharmaceutical preparation containing prednisone may be used. The pharmaceutical formulation for use according to claim 12, wherein GnRHa therapy is continued during the aforementioned treatment. 。

14. In male human patients, when treating biochemically recurrent prostate cancer, prednisone is used in combination with other treatments. As combination preparations for simultaneous, separate, or continuous use, abiraterone acetate A pharmaceutical preparation containing an ester and niraparib tosylate monohydrate.

15. The aforementioned biochemically recurrent prostate cancer is prostate-specific, i) with a concentration of 2.0 ng / mL or higher from the lowest point. Elevated prostate antigen (PSA); or ii) Prostate-specific membrane antigen positron emission tomography (PSMA) The method described in claim 14 involves detection by next-generation imaging (NGI) including PET. A pharmaceutical preparation for use.

16. The aforementioned patient has a disease that is HRD biomarker positive, high risk, and / or has few metastases. , a pharmaceutical formulation for use according to claim 14 or 15.

17. The positive HRD biomarkers are BRCA1, BRCA2, ATM, BRIP1, CDK12, CDK17, CHEK2, FANCA, HDAC2, PALB2, PPP2 One or more of R2A, RAD51B, and RAD54L, but not limited to these. No, a pharmaceutical formulation for use as described in claim 16.

18. When treating locally advanced prostate cancer in male human patients who are candidates for primary radiotherapy Combination preparations for simultaneous, separate, or sequential use with prednisone. A pharmaceutical preparation containing abiraterone acetate and niraparib tosylate monohydrate.

19. Male patients who have previously received chemotherapy including docetaxel or cabazitaxel on an optional basis. In patients with mCRPC, when treating with prednisone, simultaneous, separate, or For continuous use, a combination preparation of abiraterone acetate and nirapa is used. A pharmaceutical preparation containing ribtosylate monohydrate.

20. In male human patients, when treating non-metastatic CRPC (nmCRPC), prednisolone As a combination preparation for simultaneous, separate, or continuous use with a zoon, Abi A pharmaceutical preparation containing laterone acetate and niraparib tosylate monohydrate.

21. The patient described in claim 20 has a PSA doubling time of 10 months or less and is HRD positive. A pharmaceutical preparation for use on a medical device.

22. A pharmaceutical formulation for use according to claim 20, wherein the patient is HRD-positive.

23. The pharmaceutical formulation for use according to claim 20, wherein the patient has a high-risk BCR.

24. The aforementioned pharmaceutical preparation is a free-dose combination of abiraterone acetate and niraparib (F rDC); or FrDC of abiraterone acetate and niraparib tosylate monohydrate. A pharmaceutical formulation for use according to any one of claims 1 to 23, including the above.

25. The aforementioned pharmaceutical formulation is a fixed-dose combination containing abiraterone acetate and niraparib. (FDC); or F containing abiraterone acetate and niraparib tosylate monohydrate A pharmaceutical formulation for use according to any one of claims 1 to 23, including DC.

26. The FrDC or FDC each independently contains approximately 50 mg equivalents of niraparib and approximately 5 00 mg of abiraterone acetate; approximately 100 mg equivalent of niraparib and approximately 500 mg abiraterone acetate; approximately 50 mg equivalent of niraparib and approximately 375 mg of abiraterone acetate. aviraterone acetate; approximately 100 mg equivalent of niraparib and approximately 375 mg of abiraterone acetate. Ester; approximately 50 mg equivalent of niraparib and approximately 250 mg of abiraterone acetate; Approximately 100 mg equivalent of niraparib and approximately 250 mg of abiraterone acetate; approximately 33 mg g equivalent of niraparib and about 333 mg of abiraterone acetate; or about 67 mg equivalent Claim 24 or claim comprising niraparib and approximately 333 mg of abiraterone acetate A pharmaceutical preparation for use as described in item 25.

27. The FrDC or FDC is in oral dosage form, according to any one of claims 24 to 26. A pharmaceutical preparation for use.

28. The oral dosage form is a tablet, capsule, or pouch, for use according to claim 27 Pharmaceutical preparations.

29. The aforementioned pharmaceutical preparation is a fixed dose combination (FDC) defined in any one of Tables 1 to 12. A pharmaceutical formulation for use according to any one of claims 1 to 23, including ).

30. A method for treating prostate cancer, wherein in a male human patient, the following is performed by choice: The prostate cancer is mCRPC, and by arbitrary selection, the mCRPC is the first choice (L1) mC The RPC is an RPC, and the method involves adding prednisone to abiraterone acetate and chives. A method comprising administering an effective amount of a pharmaceutical preparation containing paribtosylate monohydrate to the patient. Law.

31. The patient is positive for homologous recombination deficiency (HRD), or the patient has HRD The method according to claim 30, wherein the result is not positive.

32. The aforementioned HRD status is BRCA1 (breast cancer gene 1), BRCA2 (breast cancer gene 2), AT M (vasodilatory ataxia variant), FANCA (Fanconi anemia complementation group A gene), PALB2 (BRCA2 gene partner and localizer), CHEK2 (checker (C-terminal kinase 2 gene), BRIP1 (BRCA1 interacting protein C-terminal helical Case 1 gene), HDAC2 (histone deacetylase 2), or CDK12 (cyan One or more DNA repair genes, including but not limited to crine-dependent kinases (12) The method described in claim 31 is detected by changes in a single allele or both alleles in the following: The method.

33. The patient, prior to the treatment with the pharmaceutical preparation containing prednisone, experienced gonadotropin If you are receiving steroid-releasing hormone agonist (GnRHa) therapy or have undergone bilateral orchiectomy The method according to any one of claims 30 to 32.

34. If the patient has not been surgically castrated, the pharmaceutical preparation containing prednisone may be used. During the aforementioned procedure, GnRHa therapy is continued, as described in any one of claims 30 to 33. method.

35. In male human patients, with or without DNA repair gene deficiency (DRD) or HRD , optionally, mC with cyclin-dependent kinase 12 (CDK12) pathogenicity alteration. A method for treating RPC, wherein the method is abiraterone with prednisone added. An effective dose of a pharmaceutical preparation containing acetate and niraparib tosylate monohydrate is administered to the patient. A method that includes giving in to something.

36. If the patient has not been surgically castrated, the pharmaceutical preparation containing prednisone may be used. The method according to claim 35, wherein GnRHa therapy is continued during the aforementioned procedure.

37. Prior to the treatment with the pharmaceutical preparation containing prednisone, the patient took nilutamide, Flutamide, bicalutamide, enzalutamide, apalutamide, dalorutamide, and avila The person is exposed to an antiandrogen selected from terone acetates, as described in claim 35. The method.

38. The anti-androgen was used before the treatment with the pharmaceutical preparation containing prednisone. The method according to claim 37, which is swatched.

39. A method for treating high-risk and lymph node-positive prostate cancer in male human patients. The aforementioned method involves prednisone and Lupus before, during, and after radiotherapy. abiraterone acetate and niraparib tosylate monohydrate with added lorelline acetate. A method comprising administering an effective amount of a pharmaceutical preparation containing to the patient.

40. The radiotherapy is stereotactic radiotherapy (SBRT) or ultrafractionated radiotherapy, and the total radiation The method according to claim 39, wherein the amount is approximately 37.5 to 40 Gy.

41. For the treatment of castrated, naive prostate cancer with or without metastasis in male human patients A method wherein the method involves adding prednisone to abiraterone acetate and chives. A method comprising administering an effective amount of a pharmaceutical preparation containing paribtosylate monohydrate to the patient. Law.

42. If the patient has not been surgically castrated, the pharmaceutical preparation containing prednisone may be used. The method according to claim 41, wherein GnRHa therapy is continued during the aforementioned procedure.

43. A method for treating biochemically recurrent prostate cancer in male human patients, the method However, with the addition of prednisone, abiraterone acetate and niraparib tosylate monohydrate were used. A method comprising administering an effective amount of a pharmaceutical preparation containing a substance to the patient.

44. The aforementioned biochemically recurrent prostate cancer is prostate-specific, i) with a concentration of 2.0 ng / mL or higher from the lowest point. Elevated prostate antigen (PSA); or ii) Prostate-specific membrane antigen positron emission tomography (PSMA) Detected by next-generation imaging (NGI) including PET, as described in claim 43. The method.

45. The aforementioned patient has a disease that is HRD biomarker positive, high risk, and / or has few metastases. The method according to claim 43 or 44.

46. The positive HRD biomarkers are BRCA1, BRCA2, ATM, BRIP1, CDK12, CDK17, CHEK2, FANCA, HDAC2, PALB2, PPP2 One or more of R2A, RAD51B, and RAD54L, but not limited to these. No, the method according to claim 45.

47. For the treatment of locally advanced prostate cancer in male human patients who are candidates for primary radiotherapy. A method wherein the method is characterized by adding prednisone to abiraterone acetate and ni This includes administering an effective amount of a pharmaceutical preparation containing raparib tosylate monohydrate to the patient. method.

48. Male patients who have previously received chemotherapy including docetaxel or cabazitaxel on an optional basis. A method for treating mCRPC in a patient, wherein the method involves prednisone In addition, a pharmaceutical preparation containing abiraterone acetate and niraparib tosylate monohydrate A method comprising administering an effective amount to the patient.

49. A method for treating nmCRPC in male human patients, wherein the method is pre Contains abiraterone acetate and niraparib tosylate monohydrate, with the addition of donisone. A method comprising administering an effective amount of a pharmaceutical preparation to the patient.

50. The patient described in claim 49 has a PSA doubling time of 10 months or less and is HRD positive. Method of loading.

51. The method according to claim 49, wherein the patient is HRD positive.

52. The method according to claim 49, wherein the patient has a high-risk BCR.

53. The aforementioned pharmaceutical preparation is a free-dose combination of abiraterone acetate and niraparib (F rDC); or FrDC of abiraterone acetate and niraparib tosylate monohydrate. The method according to any one of claims 1 to 52.

54. The aforementioned pharmaceutical formulation is a fixed-dose combination containing abiraterone acetate and niraparib. (FDC); or F containing abiraterone acetate and niraparib tosylate monohydrate The method according to any one of claims 1 to 52, wherein DC.

55. The FrDC or FDC each independently contains approximately 50 mg equivalents of niraparib and approximately 5 00 mg of abiraterone acetate; approximately 100 mg equivalent of niraparib and approximately 500 mg abiraterone acetate; approximately 50 mg equivalent of niraparib and approximately 375 mg of abiraterone acetate. aviraterone acetate; approximately 100 mg equivalent of niraparib and approximately 375 mg of abiraterone acetate. Ester; approximately 50 mg equivalent of niraparib and approximately 250 mg of abiraterone acetate; Approximately 100 mg equivalent of niraparib and approximately 250 mg of abiraterone acetate; approximately 33 mg g equivalent of niraparib and about 333 mg of abiraterone acetate; or about 67 mg equivalent Claim 53 or 54 comprises niraparib and approximately 333 mg of abiraterone acetate. Methods used.

56. The FrDC or FDC is in oral dosage form, according to any one of claims 53 to 55. method.

57. The method according to claim 56, wherein the oral dosage form is a tablet, a capsule, or a pouch.

58. The aforementioned pharmaceutical preparation is a fixed dose combination (FDC) defined in any one of Tables 1 to 12. The method according to any one of claims 30 to 52.

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