Combined use of androgen synthesis inhibitor and PARP inhibitor for treating prostate cancer

Abstract

The combined use of an androgen synthesis inhibitor and a PARP inhibitor for treating prostate cancer. Specifically provided is the use of a compound as represented by formula 1 or a pharmaceutically acceptable salt thereof and an androgen synthesis inhibitor in the preparation of a drug for treating prostate cancer.

Description

The combination of androgen synthesis inhibitors and PARP inhibitors is used to treat prostate cancer. Technical Field

[0001] This disclosure relates to the biopharmaceutical field, specifically to PARP inhibitors and androgen synthesis inhibitors used in the preparation of drugs for the treatment of prostate cancer, and pharmaceutical compositions thereof. Background Technology

[0002] Poly(ADP-ribose) polymerases (PARPs) are a class of multifunctional protein post-translational modification enzymes widely found in eukaryotic cells, playing important roles in maintaining gene stability and telomere length. The PARP superfamily currently has 17 known members, with only PARP1, PARP2, and PARP3 involved in DNA repair. PARP1 accounts for 80-90% of the PARP family enzyme activity and is a key factor in DNA damage repair.

[0003] Recent studies have shown that PARP2 inhibition is closely related to hematological toxicity, and the synthetic lethal effects of BRCA mutations are mainly driven by PARP1. Therefore, it can be inferred that developing highly selective PARP1 inhibitors will be beneficial in reducing hematological toxicity and improving the therapeutic index, thus meeting higher clinical treatment needs. Summary of the Invention

[0004] This disclosure provides the use of PARP inhibitors and androgen synthesis inhibitors in the preparation of medicaments for the treatment of prostate cancer.

[0005] In some embodiments, the PARP inhibitor is selected from the compounds shown in Formula 1 or their pharmaceutically acceptable salts.

[0006] In some embodiments, the pharmaceutically acceptable salt of the compound represented by Formula 1 is selected from hydrochloride, sulfate, phosphate, methanesulfonate, succinate, fumarate, maleate, p-toluenesulfonate, L-tartrate, D-malate, L-malate, and citrate. In some specific embodiments, the pharmaceutically acceptable salt of the compound represented by Formula 1 is succinate. In some specific embodiments, the pharmaceutically acceptable salt of the compound represented by Formula 1 is fumarate.

[0007] In some embodiments, the dosage of the compound of Formula 1 or its pharmaceutically acceptable salt is 10-300 mg. For example, the dosage of the compound of Formula 1 or its pharmaceutically acceptable salt is 10-250 mg, 10-200 mg, 10-150 mg, or 10-100 mg.

[0008] In some embodiments, the dosage of the compound of Formula 1 or its pharmaceutically acceptable salt is selected from: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 75 mg, and 100 mg.

[0009] In some embodiments, the frequency of administration of the compound of Formula 1 or its pharmaceutically acceptable salt is selected from once daily, twice daily, or three times daily.

[0010] In some embodiments, the frequency of administration of the compound of Formula 1 or its pharmaceutically acceptable salt is selected from once daily.

[0011] This disclosure also provides a pharmaceutical composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof, and further comprising one or more pharmaceutically acceptable excipients.

[0012] In some embodiments, the androgen synthesis inhibitor is selected from abiraterone or its pharmaceutically acceptable salts; in some specific embodiments, the androgen synthesis inhibitor is abiraterone acetate.

[0013] In some embodiments, the dosage of the androgen synthesis inhibitor is selected from 100-2000 mg.

[0014] In some embodiments, the dosage of the androgen synthesis inhibitor is selected from 100-1500 mg.

[0015] In some embodiments, the dosage of the androgen synthesis inhibitor is selected from 100-1000 mg.

[0016] In some embodiments, the dosage of the androgen synthesis inhibitor is selected from 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, and 1000 mg.

[0017] In a specific implementation plan, the dosage of the androgen synthesis inhibitor is 300 mg.

[0018] In some embodiments, the frequency of administration of the androgen synthesis inhibitor is selected from once daily, twice daily, or three times daily. In a specific embodiment, the frequency of administration of the androgen synthesis inhibitor is selected from once daily. In a specific embodiment, the frequency of administration of the androgen synthesis inhibitor is selected from twice daily.

[0019] This disclosure also provides the use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof in combination with an androgen synthesis inhibitor in the preparation of a medicament for treating prostate cancer.

[0020] This disclosure also provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof used in combination with an androgen synthesis inhibitor for the treatment of prostate cancer.

[0021] This disclosure also provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof in combination with an inhibitor of androgen synthesis for the treatment of prostate cancer.

[0022] This disclosure also provides the use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer, wherein the compound of Formula 1 or a pharmaceutically acceptable salt thereof is used in combination with an androgen synthesis inhibitor.

[0023] This disclosure also provides the use of an androgen synthesis inhibitor for the treatment of prostate cancer, wherein the androgen synthesis inhibitor is used in combination with a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0024] This disclosure also provides an androgen synthesis inhibitor for the treatment of prostate cancer, wherein the androgen synthesis inhibitor is used in combination with a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0025] This disclosure also provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof for treating prostate cancer, wherein the compound of Formula 1 or a pharmaceutically acceptable salt thereof is used in combination with an androgen synthesis inhibitor.

[0026] This disclosure also provides a method for treating prostate cancer, comprising administering a subject a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof and an inhibitor of androgen synthesis.

[0027] This disclosure also provides the use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of prostate cancer in combination with an androgen synthesis inhibitor.

[0028] In some implementations, the uses or methods described in this disclosure further include use in combination with prednisone or prednisolone.

[0029] In some embodiments, the dosage of prednisone or prednisolone is selected from 1-20 mg, such as 1-15 mg or 1-10 mg.

[0030] In some embodiments, the dosage of prednisone or prednisolone is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, and 10 mg.

[0031] In some embodiments, the dosage of prednisone or prednisolone is selected from 5 mg.

[0032] In some implementations, the frequency of administration of the prednisone or prednisolone is selected from once daily, twice daily, or three times daily.

[0033] In some implementations, the prednisone or prednisolone is administered twice daily.

[0034] In some implementations, the prostate cancer is selected from metastatic prostate cancer.

[0035] In some implementations, the prostate cancer is selected from metastatic castration-resistant prostate cancer.

[0036] In some implementations, the prostate cancer is selected from metastatic hormone-sensitive prostate cancer.

[0037] In some embodiments, the prostate cancer is selected from metastatic castration-resistant prostate cancer that has previously undergone at least one novel endocrine therapy.

[0038] In some implementations, the prostate cancer is selected from prostate cancer that has failed previous treatment with at least one novel endocrine drug.

[0039] In some embodiments, the novel endocrine drug described in this disclosure is selected from abiraterone, enzalutamide, revelutamide, dalotamide, apatamide, etc.

[0040] In some embodiments, the prostate cancer described in this disclosure is selected from prostate cancer with mutations in the HRR-related gene.

[0041] In some embodiments, the prostate cancer described in this disclosure is selected from prostate cancer with at least one mutation in ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C.

[0042] In some embodiments, the prostate cancer described in this disclosure is selected from BRCA1-mutated prostate cancer.

[0043] In some embodiments, the prostate cancer described in this disclosure is selected from BRCA2-mutated prostate cancer.

[0044] In some embodiments, the prostate cancer described in this disclosure is selected from PALB2-mutated prostate cancer.

[0045] In some implementations, treatment failure as described in this disclosure refers to disease progression during treatment, including PSA progression or radiographic progression. In cases of PSA progression only, the PSA level during the screening period should be >1 ng / mL.

[0046] In some embodiments, the disease progression described in this disclosure refers to the occurrence of at least one of the following three: ① PSA progression, defined as a PSA level ≥1 ng / mL with at least two consecutive previous elevations, measured at least one week apart; ② progression of lymph node or visceral disease as defined in RECIST 1.1; ③ progression of skeletal disease as defined in PCWG3 criteria, i.e., the discovery of ≥2 new lesions on a bone scan.

[0047] Subjects are required to receive or maintain androgen deprivation therapy (ADT) during the study period, i.e., continuous luteinizing hormone-releasing hormone analog (LHRHa) therapy (medical castration) or have previously undergone bilateral orchiectomy (surgical castration); subjects who have not undergone bilateral orchiectomy must maintain effective LHRHa therapy for 4 weeks prior to enrollment and throughout the planned study period; and testosterone levels at screening must be at castration levels (≤50 ng / dL or 1.73 nmol / L).

[0048] This disclosure also provides a pharmaceutical composition comprising an inhibitor of androgen synthesis, and further comprising one or more pharmaceutically acceptable excipients.

[0049] In some embodiments, the pharmaceutical composition comprising an inhibitor of androgen synthesis is selected from pharmaceutical compositions comprising abiraterone or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the pharmaceutical composition comprising an inhibitor of androgen synthesis is selected from pharmaceutical compositions comprising abiraterone acetate.

[0051] In some embodiments, the aforementioned uses or methods of this disclosure may be used to apply the aforementioned pharmaceutical composition.

[0052] This disclosure also provides a pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof and an inhibitor of androgen synthesis.

[0053] This disclosure also provides a pharmaceutical kit comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof and an inhibitor of androgen synthesis.

[0054] In some embodiments, the compound of Formula 1 or its pharmaceutically acceptable salt in the pharmaceutical kit described herein is packaged separately from the androgen synthesis inhibitor.

[0055] This disclosure also provides a pharmaceutical kit comprising the aforementioned pharmaceutical combination, wherein the compound of preferred formula 1 or its pharmaceutically acceptable salt and the androgen synthesis inhibitor are packaged separately.

[0056] In some implementations, the drug kit is used to treat prostate cancer.

[0057] This disclosure describes the combination administration of the compound shown in Formula 1 or a pharmaceutically acceptable salt thereof with an androgen synthesis inhibitor, which improves the treatment efficacy for prostate cancer. Detailed Implementation

[0058] definition

[0059] To facilitate understanding of this disclosure, certain techniques and scientific methods are specifically defined below. Unless otherwise expressly defined in this disclosure, all other techniques and scientific methods used in this disclosure have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0060] Unless the context clearly requires otherwise, throughout the specification and claims, the words “comprising,” “having,” “including,” etc., should be understood as having an inclusive meaning, rather than an exclusive or exhaustive meaning; that is, the meaning of “including but not limited to.”

[0061] The values ​​in this disclosure are instrument measurements or calculated values ​​after instrument measurement, and are subject to a certain degree of error. Generally speaking, ±10% is within the reasonable error range. Of course, the context in which the value is used needs to be considered. For example, for the content of total impurities, the value is defined as having an error variation of no more than ±10% after measurement, and can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0062] "Effective amount" includes an amount sufficient to improve or prevent the symptoms or condition of a medical condition. Effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount used on a subject may vary depending on factors such as the condition to be treated, the subject's overall health, the route and dosage of administration, and the severity of side effects. Effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity. Subjects in this disclosure may be animal or human subjects.

[0063] The term "pharmaceutical composition" refers to a mixture containing one or more of the active ingredients described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0064] The term "pharmaceutically acceptable excipient" includes any material that, when combined with an active ingredient, allows that ingredient to retain its biological activity and does not react with the subject's immune system. Examples include, but are not limited to, any standard pharmaceutical carrier, such as phosphate-buffered saline solution, water, emulsions such as oil / water emulsions, and various types of wetting agents. In some embodiments, the diluent for aerosol or parenteral administration is phosphate-buffered saline (PBS) or physiological (0.9%) saline. Compositions containing such carriers are formulated using well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, editor, Mack Publishing Co., Easton, PA, 1990; and R. Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing, 2000).

[0065] The terms “cancer,” “cancerous,” “proliferative disease,” and “tumor” are not mutually exclusive when used in this disclosure.

[0066] The terms “give,” “apply,” and “treat,” when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid, such as in therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Cellular treatment includes contact between a reagent and a cell, as well as contact between a reagent and a fluid, wherein the fluid is in contact with the cell. “Give,” “apply,” and “treat” also mean treatment, such as of cells, by means of a reagent, diagnostic agent, conjugate composition, or by means of another cell in vitro and ex vivo. When applied to humans, veterinary, or research subjects, it refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic applications.

[0067] The term "treatment" means administering a therapeutic agent, such as a fusion protein or insulin analog comprising any of the present disclosure, to a subject who has, is suspected of having, or is predisposed to having one or more diabetes or hyperglycemia-related diseases or their symptoms, and the therapeutic agent is known to have a therapeutic effect on these symptoms. Typically, a therapeutic agent is administered in a treated subject or population in an amount that effectively relieves symptoms of one or more diseases by preventing or delaying the onset of symptoms or complications, reducing symptoms or complications, or eliminating the disease, condition, or symptom to any clinically measurable degree. The amount of a therapeutic agent that effectively relieves symptoms of any specific disease (also referred to as a "therapeuticly effective amount") can vary depending on a variety of factors, such as the subject's disease state, age, and weight, and the drug's ability to produce the desired therapeutic effect in the subject. Whether the disease symptoms have been relieved can be evaluated using any clinical test that a physician or other healthcare professional typically uses to assess the severity or progression of the symptoms. Although the embodiments of this disclosure (e.g., treatment methods or products) may be ineffective in alleviating the symptoms of the target disease in a particular subject, they should alleviate the symptoms of the target disease in a statistically significant number of subjects, as determined by any statistical test known in the art, such as the Student t-test, chi-square test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test. The patients to be treated are mammals, and preferably humans.

[0068] The term “prevention” refers to reducing the risk or incidence of one or more conditions, symptoms, complications or ailments, or eliminating or slowing the progression of one or more conditions, symptoms, complications or ailments.

[0069] The terms “subject” and “patient” refer to mammals, especially primates, and particularly humans.

[0070] The term "combination" as used in this disclosure refers to a route of administration in which at least one dose of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, and at least one dose of an androgen synthesis inhibitor, are administered within a specified time period, wherein both drugs exhibit pharmacological effects. The time period can be within a dosing cycle, preferably within 4 weeks, 3 weeks, 2 weeks, 1 week, or within 24 hours, more preferably within 12 hours. The compound of Formula 1 or a pharmaceutically acceptable salt thereof and the androgen synthesis inhibitor may be administered simultaneously or sequentially. This period includes treatment in which the compound of Formula 1 or a pharmaceutically acceptable salt thereof and the androgen synthesis inhibitor are administered via the same or different routes of administration. The route of administration for the combination described in this disclosure is selected from simultaneous administration, independently formulated and co-administered, or independently formulated and sequentially administered.

[0071] Overall survival (OS) refers to the period from randomization to death from any cause. For subjects still alive at the last follow-up, the OS is defined as the time to the last follow-up, indicating data loss. For subjects lost to follow-up, the OS is defined as the time to the last confirmed survival prior to loss to follow-up, indicating data loss. OS with data censoring is defined as the time from randomization to censoring.

[0072] The objective response rate (ORR) refers to the proportion of patients whose tumors shrink to a certain extent and remain so for a certain period of time, including cases of complete response (CR) and partial response (PR). The RECIST 1.1 criteria are used to assess objective response. Subjects must have measurable tumor lesions at baseline. The efficacy assessment criteria, according to RECIST 1.1, are divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).

[0073] The Disease Control Rate (DCR) is the percentage of patients with confirmed complete remission, partial remission, and stable disease (≥8 weeks) among those with evaluable efficacy.

[0074] Complete remission (CR): All target lesions disappear and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10 mm.

[0075] Partial remission (PR): The sum of the diameters of the target lesions is reduced by at least 30% compared to the baseline level.

[0076] Disease progression (PD): The minimum sum of the diameters of all target lesions measured throughout the entire experimental study is used as a reference, with a relative increase of at least 20% in the sum of diameters (or the baseline value if the baseline measurement is the minimum); in addition, the absolute value of the sum of diameters must increase by at least 5 mm (the appearance of one or more new lesions is also considered disease progression).

[0077] Disease stability (SD): The degree of reduction in target lesions does not reach the PR level, nor does the degree of increase reach the PD level; it falls between the two. The minimum value of the sum of diameters can be used as a reference in studies.

[0078] Example

[0079] The following examples are used to further describe this disclosure, but these examples are not intended to limit the scope of this disclosure. Example 1. Treatment of prostate cancer with the compound of Formula 1 in combination with an androgen synthesis inhibitor.

[0080] 1. Test drug

[0081] (1) The fumarate of the compound shown in Formula 1 can be prepared by referring to WO2022247816A, which was provided by Jiangsu Hengrui Medicine Co., Ltd. in this experiment.

[0082] (2) Abiraterone, which was provided by Jiangsu Hengrui Medicine Co., Ltd. in this study.

[0083] (3) Prednisone, produced by Zhejiang Xianju Pharmaceutical Co., Ltd.

[0084] 2. Enrolled subjects

[0085] (1) Prostate adenocarcinoma diagnosed by cytology or histology, excluding subjects with small cell, neuroendocrine, sarcomatoid, or signet ring cell histological pathological features.

[0086] (2) Metastatic lesions were confirmed by CT / MRI or radiographic bone scan (99mTc).

[0087] (3) Failure of at least one novel endocrine therapy (such as abiraterone, enzalutamide, revelutamide, darotamide, apatamide, etc.) as recorded in the medical record (meaning disease progression during treatment, including PSA progression or radiographic progression. In the case of PSA progression only, the PSA level during the screening period should be >1 ng / mL);

[0088] (4) Previous systemic chemotherapy treatment ≤ 1 line;

[0089] (5) Received or maintained androgen deprivation therapy (ADT) during the planned study period, i.e., continuous luteinizing hormone-releasing hormone analog (LHRHa) therapy (medical castration) or had previously undergone bilateral orchiectomy (surgical castration).

[0090] (6) Testosterone levels were at castration levels (≤50 ng / dL or 1.73 nmol / L) during screening;

[0091] 3. Administration method

[0092] Abiraterone acetate 300 mg once daily (QD), prednisone (or prednisolone) 5 mg twice daily (BID). Or abiraterone acetate 1000 mg once daily (QD), prednisone (or prednisolone) 5 mg twice daily (BID).

[0093] The compound shown in Formula 1 is administered orally once daily (QD) with a starting dose of 50 mg. Tolerance is observed in combination with abiraterone acetate and prednisone. If this dose level is not tolerated, the dose of the compound shown in Formula 1 is increased to 30 mg, and the tolerability of the combination therapy is observed.

[0094] 4. Results Evaluation

[0095] Efficacy measures include investigator-assessed ORR, DCR, DoR, PFS, and OS.

[0096] Safety evaluation: The safety of the study drug was evaluated through adverse event records (including serious adverse events), laboratory tests, vital signs and physical examinations, electrocardiograms, and echocardiograms.

[0097] Preliminary efficacy results showed that the compound represented by Formula 1, in combination with AA-P (abiraterone acetate and prednisone), significantly reduced PSA in patients with mCRPC. The PSA50 was 94.1% in patients with BRCAM (N=17) and 48.8% in patients with HRR gene mutations (N=41). For patients with baseline target lesions, the ORR was 80% and DCR was 100% in patients with BRCAM (N=5), and 45.5% and DCR was 90.9% in patients with HRR gene mutations (N=11). Predictable rPFS and OS data are expected.

[0098] While specific embodiments of this disclosure have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of this disclosure. Therefore, the scope of protection of this disclosure is defined by the appended claims.

Claims

1. Use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, along with an inhibitor of androgen synthesis, in the preparation of a medicament for treating prostate cancer, preferably wherein the prostate cancer is selected from metastatic prostate cancer.

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

3. The use according to claim 1 or 2, wherein the prostate cancer is selected from prostate cancer that has failed prior treatment with at least one novel endocrine drug, preferably the novel endocrine drug is selected from abiraterone, enzalutamide, revelutamide, darotamide, apatamide.

4. The use according to any one of claims 1-3, wherein the prostate is selected from prostate cancer with mutations in the HRR-related gene; preferably, the prostate cancer is selected from prostate cancer with mutations in at least one of ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2 and RAD51C.

5. The use according to any one of claims 1-4, wherein, The androgen synthesis inhibitor is selected from abiraterone or its pharmaceutically acceptable salts, preferably abiraterone acetate.

6. The use according to any one of claims 1-5, wherein, The pharmaceutically acceptable salt of the compound shown in Formula 1 is selected from hydrochloride, sulfate, phosphate, methanesulfonate, succinate, fumarate, maleate, p-toluenesulfonate, L-tartrate, D-malate, L-malate and citrate, preferably, the pharmaceutically acceptable salt of the compound shown in Formula 1 is fumarate.

7. The use according to any one of claims 1-6, wherein, The dosage of the compound of Formula 1 or its pharmaceutically acceptable salt is selected from 10-300 mg, preferably 10-250 mg, more preferably 10-150 mg, and most preferably 25 mg, 30 mg, 50 mg, 75 mg, or 100 mg.

8. The use according to any one of claims 1-7, wherein, The frequency of administration of the compound of Formula 1 or its pharmaceutically acceptable salt is selected from once daily, twice daily, or three times daily.

9. The use according to any one of claims 1-8, wherein, The dosage of the androgen synthesis inhibitor is selected from 100-2000 mg, preferably 100-1500 mg, more preferably 100-1000 mg, and most preferably 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, and 1000 mg.

10. The use according to any one of claims 1-9, wherein, The dosing frequency of the androgen synthesis inhibitor is selected from once daily, twice daily, or three times daily.

11. The use according to any one of claims 1-10, wherein, It also includes use in combination with prednisone or prednisolone.

12. The use according to claim 11, wherein, The dosage of prednisone or prednisolone is selected from 1-20 mg, preferably 1-15 mg, more preferably 1-10 mg, and most preferably 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.

13. The use according to claim 12, wherein, The frequency of administration of the prednisone or prednisolone is selected from once daily, twice daily, or three times daily.

14. A pharmaceutical kit comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof and an androgen synthesis inhibitor, preferably the compound of Formula 1 or a pharmaceutically acceptable salt thereof and the androgen synthesis inhibitor are packaged separately.

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