Method for treating prostate cancer

Abstract

The present invention relates to a method for treating prostate cancer. Specifically, the present invention relates to use of an EZH2 inhibitor in combination with an AR degrader in the preparation of a drug for treating prostate cancer, wherein the AR degrader is selected from a compound structure represented by formula (I) or a pharmaceutically acceptable salt thereof.

Description

Methods of treating prostate cancer TECHNICAL FIELD

[0001] The present application relates to the field of medicine, and specifically to the use of an EZH2 inhibitor in combination with an AR degrader in the preparation of a medicament for treating prostate cancer. BACKGROUND

[0002] Prostate cancer is the second most common cancer and the fifth leading cause of death in men worldwide. According to the GLOBOCAN 2022 report, there were approximately 1.47 million new cases of prostate cancer and approximately 397,000 deaths worldwide in 2022. Prostate acinar cells undergo apoptosis in the absence of androgen stimulation, indicating their dependence on the androgen receptor (AR) signaling pathway. In 1941, Huggins and Hodges discovered that surgical castration therapy (ADT) and estrogen can delay the progression of metastatic prostate cancer, providing the first evidence of the responsiveness of prostate cancer to androgen removal. Currently, anti-androgen endocrine therapy has become the basis of treatment for prostate cancer. In addition to surgical / drug ADT and inhibitors of the key enzyme CYP17A1 for testosterone synthesis (such as abiraterone acetate) to inhibit testosterone synthesis, AR antagonists (such as the first-generation AR inhibitor bicalutamide, the second-generation AR inhibitor enzalutamide, and the like) are also used to block the binding of androgens to intracellular AR and inhibit the activation of the AR signaling pathway, thereby exerting an anti-prostate cancer effect.

[0003] Currently, new AR-targeted drugs (including CYP-17 inhibitors such as abiraterone and new AR inhibitors such as enzalutamide, apalutamide, and darolutamide) in combination with ADT therapy have shown superior therapeutic effects compared to simple ADT therapy or ADT combined with first-generation AR inhibitors. They have been recommended by guidelines as the preferred treatment for advanced prostate cancer such as metastatic hormone-sensitive prostate cancer (mHSPC) and hormone-resistant prostate cancer (CRPC).

[0004] Although the development and application of new AR-targeted drugs have significantly improved the prognosis of prostate cancer patients, especially providing additional treatment options for mCRPC patients in addition to chemotherapy, patients still develop resistance to new AR-targeted drugs. AR degraders are a new type of anti-androgen endocrine therapy drug that can specifically degrade intracellular AR proteins, especially mutant AR proteins, thereby more comprehensively inhibiting the activation of the AR signaling pathway, and have shown anti-prostate cancer activity in preclinical and early clinical studies, and may become a new treatment for advanced prostate cancer. SUMMARY

[0005] The present disclosure provides the use of an EZH2 inhibitor in combination with an AR degrader in the preparation of a medicament for treating prostate cancer.

[0006] In certain embodiments, the present disclosure provides a method of treating prostate cancer, comprising administering to a patient a therapeutically effective amount of an EZH2 inhibitor and an AR degrader.

[0007] In certain embodiments, the present disclosure provides use of an EZH2 inhibitor for treating prostate cancer, wherein the EZH2 inhibitor is used in combination with an AR degrader.

[0008] In certain embodiments, the present disclosure provides use of an AR degrader for treating prostate cancer, wherein the AR degrader is used in combination with an EZH2 inhibitor.

[0009] In some embodiments, the AR degrader is selected from a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof,

[0010] In some embodiments, the EZH2 inhibitor is selected from a compound represented by Formula (II) or a pharmaceutically acceptable salt thereof,

[0011] In some embodiments, the prostate cancer described in the present disclosure is selected from histologically or cytologically confirmed adenocarcinoma of the prostate and is not diagnosed as neuroendocrine carcinoma or small cell carcinoma.

[0012] In some embodiments, the prostate cancer described in the present disclosure is selected from metastatic castration-resistant prostate cancer or metastatic hormone-sensitive prostate cancer.

[0013] In some embodiments, the prostate cancer described in the present disclosure is selected from metastatic castration-resistant prostate cancer.

[0014] In certain embodiments, the metastatic castration-resistant prostate cancer described in the present disclosure is metastatic castration-resistant prostate cancer that is drug-castrated or surgically castrated.

[0015] In certain embodiments, the metastatic castration-resistant prostate cancer described in the present disclosure is selected from metastatic castration-resistant prostate cancer that is continuously treated with luteinizing hormone-releasing hormone analog (LHRHA) (drug-castrated), or previously received bilateral orchiectomy (surgically castrated), or did not receive bilateral orchiectomy but is treated with LHRHA post-maintenance effective.

[0016] In certain embodiments, the patient with metastatic castration-resistant prostate cancer described in the present disclosure has testosterone at castration level (≦50 ng / dL or 1.73 nmol / L).

[0017] In certain embodiments, the metastatic castration-resistant prostate cancer described in the present disclosure is metastatic castration-resistant prostate cancer that has failed at least one novel endocrine drug treatment.

[0018] In certain embodiments, the metastatic castration-resistant prostate cancer described in the present disclosure is metastatic castration-resistant prostate cancer that has failed at least one prior endocrine therapy.

[0019] In certain embodiments, the novel endocrine therapy described in the present disclosure is selected from the group consisting of abiraterone, enzalutamide, apalutamide, seviteronel, darolutamide.

[0020] In certain embodiments, the endocrine therapy described in the present disclosure is selected from the group consisting of abiraterone, enzalutamide, apalutamide, seviteronel, darolutamide.

[0021] In certain embodiments, the treatment failure described in the present disclosure refers to disease progression during treatment, including PSA progression or imaging progression. In case of PSA progression only, the screening PSA level should be > 1 ng / mL.

[0022] In some embodiments, the prostate cancer described in the present disclosure is selected from metastatic hormone-sensitive prostate cancer.

[0023] In some embodiments, the metastatic hormone-sensitive prostate cancer described in the present disclosure is selected from metastatic hormone-sensitive prostate cancer that is receiving or maintaining androgen deprivation therapy (ADT) at the time of study entry.

[0024] In some embodiments, the metastatic hormone-sensitive prostate cancer described in the present disclosure is selected from metastatic hormone-sensitive prostate cancer that is receiving luteinizing hormone-releasing hormone analog (LHRHa) treatment (medical castration) or has undergone bilateral orchiectomy (surgical castration) in the past.

[0025] In some embodiments, the metastatic hormone-sensitive prostate cancer described in the present disclosure has imaging findings that meet at least one of the following conditions:

[0026] 1) Technetium-99m bone scan finds bone metastases > 4 (at least 1 is not in the pelvis or spine);

[0027] 2) CT / MRI suggests visceral metastasis (excluding lymph nodes).

[0028] In some embodiments, the metastatic hormone-sensitive prostate cancer described in the present disclosure is selected from metastatic hormone-sensitive prostate cancer that has not had imaging or PSA progression within 3 months prior to the first dose of the drug (with or without anti-androgen therapy, including NHA class drugs) and is receiving androgen deprivation therapy (ADT).

[0029] In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1000 mg, preferably at a dose of 20 mg to 500 mg, more preferably at a dose of 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg.

[0030] In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 30 mg or 90 mg or 180 mg or 240 mg or 360 mg or 540 mg or 720 mg.

[0031] In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 30 mg or 90 mg or 180 mg or 240 mg or 360 mg or 540 mg or 720 mg.

[0032] In certain embodiments, the dose or unit dose of the present disclosure is based on the weight of the compound of Formula (I).

[0033] In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a frequency selected from the group consisting of three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once a week.

[0034] In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a human subject.

[0035] In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0036] In certain embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof described in the present disclosure is administered at a dose of 10-800 mg, which can be 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, or any value in between, preferably 200-500 mg.

[0037] The compound of Formula (II) or a pharmaceutically acceptable salt thereof described in the present disclosure is administered at a frequency of twice a day, once a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in two weeks, once in three weeks, once in four weeks, or once in a month, preferably twice a day or once a day.

[0038] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered at a dose selected from 1-800 mg, at a frequency of twice a day or once a day.

[0039] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered at a dose selected from 50 mg, 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, at a frequency of twice a day or once a day.

[0040] In some embodiments, the dosage of the compound of Formula (II) or a pharmaceutically acceptable salt thereof for administration in a human subject is selected from 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, with a frequency of twice a day.

[0041] The present disclosure also provides a pharmaceutical composition comprising an AR degrader as described above and an EZH2 inhibitor.

[0042] The present disclosure also provides a pharmaceutical kit comprising an AR degrader as described above and an EZH2 inhibitor, preferably an AR degrader as described above and an EZH2 inhibitor are packaged separately.

[0043] In certain embodiments, the dosage or unit dose described in the present disclosure is in terms of the weight of the compound of Formula (II).

[0044] In certain embodiments, the subject of administration of the compound of Formula (II) or a pharmaceutically acceptable salt thereof described in the present disclosure is a human.

[0045] In certain embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof described in the present disclosure is administered in the form of a pharmaceutical composition comprising the compound of Formula (II) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0046] For the purposes of the present disclosure, certain technical and scientific terms are specifically defined below. Unless specifically defined herein, all other technical and scientific terms used in the present disclosure have the meanings that are commonly understood by one of ordinary skill in the art in the field of the present disclosure.

[0047] Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

[0048] In the present disclosure, numerical values are instrumentally measured values or calculated values after instrumentally measured values, and there is a certain degree of error. Generally speaking, plus or minus 10% is within a reasonable error range. Of course, the context in which the numerical value is used needs to be considered, for example, the content of total impurities, the error variation after measurement of the numerical value is not more than plus or minus 10%, which can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.

[0049] An "effective amount" includes an amount sufficient to effect an improvement in the condition or to prevent the condition or symptoms of the medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. An effective amount for a subject can vary according to factors such as the condition to be treated, the overall health status of the subject, the method route and dose of administration, and the severity of side effects. An effective amount can be the maximum dose or administration regimen that avoids significant side effects or toxic effects. A subject of the present disclosure can be an animal or a human subject.

[0050] The term "pharmaceutical composition" means a mixture of one or more of the active ingredients described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject and to facilitate absorption of the active ingredient.

[0051] The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable excipient" includes any material that, when combined with an active ingredient, allows the ingredient to retain biological activity and does not cause an immune response in a subject. Examples include, but are not limited to, any standard pharmaceutical carrier, such as a 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 normal (0.9%) saline. Compositions containing such carriers are formulated by well-known conventional methodology (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed., A. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990; and R Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000).

[0052] The terms "administering," "administered," and "treatment" when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, mean the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid, such as therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Treatment of a cell includes contact of the agent with the cell, as well as contact of the agent with a fluid that is in contact with the cell. "Administering," "administered," and "treatment" also mean treatment by an agent, diagnostic, binding composition, or by another cell in vitro and ex vivo, such as a cell. When applied to a human, veterinary, or research subject, it means therapeutic treatment, prophylaxis or preventative measures, research, and diagnostic applications.

[0053] The term "treatment" means the administration of a therapeutic agent, such as a therapeutic agent comprising any one of the EZH2 inhibitors or AR degraders of the present disclosure, to a subject who already has, is suspected of having, is predisposed to having, or is susceptible to, a related disease or a symptom thereof, and the therapeutic agent is known to have a therapeutic effect on these symptoms. Generally, a therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the treated subject or population to any clinically measurable extent by preventing or delaying the onset of symptoms or complications, lessening the symptoms or complications, or eliminating the disease, condition, or disorder. The amount of a therapeutic agent effective to alleviate any particular symptom of the disease (also referred to as a "therapeutically effective amount") can vary according to factors such as the disease state, age, and weight of the subject, and the ability of the drug to elicit a desired effect in the subject. Whether a disease symptom has been alleviated can be assessed by any clinical detection method conventionally used by a physician or other health care professional to assess the severity or progression of the symptom. While an embodiment of the present disclosure (e.g., a method of treatment or article of manufacture) can not be effective in alleviating a target disease symptom in a certain subject, it should be determined that the target disease symptom should be alleviated in a statistically significant number of subjects according to any statistical test known in the art, such as Student's t-test, chi-square test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test. The patient to be treated is a mammal, and preferably a human.

[0054] The term "prevention" means reducing the risk or incidence of, or eliminating or slowing the progression of, one or more conditions, symptoms, complications, or disorders.

[0055] The term "subject," "patient" means a mammal, especially a primate, and especially a human.

[0056] The "combination" of the present disclosure is a mode of administration, meaning that at least one dose of an AR degrader and at least one dose of an EZH2 inhibitor are administered within a time period, wherein both administered drugs show a pharmacological effect. The time period can be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. The AR degrader and the EZH2 inhibitor can be administered simultaneously or sequentially. This time period includes treatments wherein the AR degrader and the EZH2 inhibitor are administered by the same administration route or by different administration routes. The mode of administration of the combination of the present disclosure is selected from the group consisting of simultaneous administration, separate formulation and co-administration, or separate formulation and sequential administration.

[0057] Overall survival (OS) refers to the time from randomization to death from any cause. Subjects who are alive at the time of the last follow-up have OS censored at the time of the last follow-up. Subjects who are lost to follow-up have OS censored at the time of the last confirmed survival before loss. OS censored is defined as the time from randomization to censoring.

[0058] Objective response rate (ORR) refers to the proportion of patients whose tumors shrink to a certain extent and remain that way for a certain period of time, including CR and PR cases. The tumor response evaluation criteria (RECIST 1.1 criteria) are used to assess tumor objective response. Subjects must have measurable tumor lesions at baseline, and the efficacy evaluation criteria are divided into complete remission (CR), partial remission (PR), stable disease (SD), and progression (PD) according to the RECIST 1.1 criteria.

[0059] Disease control rate (DCR) refers to the percentage of confirmed complete remission, partial remission, and stable disease (≥8 weeks) cases among patients who can be evaluated for efficacy.

[0060] Complete remission (CR): all target lesions disappear, and the short diameter of all pathological lymph nodes (including target nodes and non-target nodes) must be reduced to <10 mm.

[0061] Partial remission (PR): the sum of the diameters of the target lesions is reduced by at least 30% compared to the baseline level.

[0062] Disease progression (PD): the minimum value of the sum of the diameters of all measured target lesions throughout the experimental study is taken as the reference, and the diameter and relative increase is at least 20% (if the baseline measurement is the minimum, the baseline value is taken as the reference); in addition, the absolute value of the diameter and must increase by at least 5 mm (the appearance of one or more new lesions is also considered as disease progression).

[0063] Stable disease (SD): the degree of target lesion reduction does not reach PR, and the degree of increase also does not reach PD level, which is between the two, and the minimum value of the sum of the diameters can be used as a reference during the study.

[0064] ADT: androgen deprivation therapy or castration therapy, which removes or inhibits androgen activity to inhibit or control prostate cancer cell growth. The main ways of ADT treatment are:

[0065] 1) simple castration therapy: mainly including surgical castration and drug castration, surgical castration mainly achieves the purpose of castration by removing both testes; drug castration mainly includes but is not limited to luteinizing hormone-releasing hormone agonists (such as leuprolide, goserelin, triptorelin, etc.), luteinizing hormone-releasing hormone antagonists (such as degarelix).

[0066] 2) Simple anti-androgen drug therapy (blockade of androgen receptors). 3) Combination therapy based on drug or surgical castration. DETAILED DESCRIPTION

[0067] Example 1 Clinical study of the combination of the compound of formula (I) and the compound of formula (II) in the treatment of prostate cancer in subjects

[0068] 1. Study drug

[0069] Test drug 1: pharmaceutical composition containing the compound of formula I, specifications: 15 mg / tablet, 60 mg / tablet, prepared according to WO2023093845A, produced and provided by Jiangsu Hengrui Medicine Co., Ltd.

[0070] Test drug 2: pharmaceutical composition containing the compound of formula II, specifications: 50 mg / tablet, 200 mg / tablet; prepared according to WO2017084494A, produced and provided by Jiangsu Hengrui Medicine Co., Ltd.

[0071] 2. Inclusion criteria

[0072] 1. Prostate adenocarcinoma confirmed by histological or cytological examination, and not diagnosed as neuroendocrine carcinoma or small cell carcinoma.

[0073] - metastatic castration-resistant prostate cancer, which must meet the following criteria:

[0074] a) Continuous luteinizing hormone-releasing hormone analogue (LHRHa) therapy (drug castration) or previous bilateral orchiectomy (surgical castration); subjects who have not undergone bilateral orchiectomy must maintain effective LHRHa therapy throughout the study period;

[0075] b) Testosterone at castration level (<50 ng / dl or 1.7 nmol / L) at the time of screening;

[0076] c) At least one previous treatment failure (disease progression during treatment, including PSA progression or imaging progression) of a new endocrine drug (such as abiraterone, enzalutamide, seviteronel, darolutamide, apalutamide, etc.) recorded in the medical record;

[0077] d) Metastatic lesions confirmed by CT / MRI or radiological bone scan (99mTc) imaging; - metastatic hormone-sensitive prostate cancer, which must meet the following criteria

[0078] a) planned study period received or maintained ADT, i.e. continuously received luteinizing hormone-releasing hormone analogues (LHRH a) treatment (medical castration) or had undergone bilateral orchiectomy (surgical castration);

[0079] b) high tumor burden, i.e. imaging results met at least one of the following conditions: 1) technetium-99m bone scan found bone metastases ≥ 4 (at least 1 was not in the pelvis or spine); 2) CT / MRI suggested visceral metastases (excluding lymph nodes);

[0080] c) ADT (with or without anti-androgen drug treatment, including NHA drugs) within 3 months before the first administration and no imaging or PSA progression;

[0081] 3. Administration mode

[0082] Test drug 1: tablet, orally administered 180 mg or 360 mg QD, or orally administered 240 mg BID, once a day, orally taken within 30 min after breakfast in the morning, continuously taken, twice a day, taken within 30 min after meals, with an interval of 12 ± 2 hours between the two times, continuously taken.

[0083] Test drug 2: tablet, orally administered 350 mg BID, taken before or after meals, with an interval of 12 ± 2 hours between the two times.

[0084] 4. Therapeutic effect

[0085] A total of 10 patients received treatment, and the treatment data are shown in Table 1. Compound I and compound II were administered in combination, and the tolerability was good, the toxicity was controllable, and it was tolerable. Compared with single drug, it showed certain efficacy enhancement.

[0086] *AR-LBD WT: including AR-amplification or AR-V7 positive.

Claims

1. Use of an EZH2 inhibitor in combination with an AR degrader in the manufacture of a medicament for treating prostate cancer, wherein the AR degrader is selected from the group consisting of a compound structure represented by Formula (I) or a pharmaceutically acceptable salt thereof, 2. Use according to claim 1, wherein the prostate cancer is selected from metastatic castration-resistant prostate cancer or metastatic hormone-sensitive prostate cancer.

3. Use according to claim 2, wherein the metastatic castration-resistant prostate cancer is selected from metastatic castration-resistant prostate cancer after drug castration, or surgical castration.

4. Use according to claim 2, wherein the metastatic castration-resistant prostate cancer is metastatic castration-resistant prostate cancer after failure of at least one endocrine drug therapy; preferably the endocrine drug is selected from apalutide, enzalutamide, abiraterone, darolutamide, or dutasteride.

5. Use according to claim 2, wherein the metastatic hormone-sensitive prostate cancer is metastatic hormone-sensitive prostate cancer after the patient receives or maintains androgen deprivation therapy (ADT).

6. The use according to any one of claims 1-5, wherein the EZH2 inhibitor is selected from a compound represented by Formula (II) or a pharmaceutically acceptable salt thereof, 7. Use according to any one of claims 1-6, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1000 mg, preferably at a dose of 20 mg to 500 mg, preferably at a dose of 90 mg or 180 mg or 240 mg or 360 mg or 540 mg or 720 mg.

8. Use according to any one of claims 1-7, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a frequency selected from three times a day, twice a day, once a day, every two days, every three days, every four days, every five days, once a week.

9. Use according to any one of claims 1-8, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered at a dose of 10-800 mg, preferably at a dose selected from 200-500 mg; more preferably at a dose selected from 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg.

10. Use according to any one of claims 1-9, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered at a frequency of twice a day, once a day, two days once, three days once, four days once, five days once, six days once, one week once, two weeks once, three weeks once, four weeks once, or one month once, preferably twice a day, once a day.

11. A pharmaceutical kit comprising an AR degrader and an EZH2 inhibitor as described in any one of claims 1-10, preferably the AR degrader and the EZH2 inhibitor are packaged separately.

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