WO2020083187A1 - 一种ar拮抗剂联合parp抑制剂在制备治疗前列腺癌的药物中的用途 - Google Patents

一种ar拮抗剂联合parp抑制剂在制备治疗前列腺癌的药物中的用途 Download PDF

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WO2020083187A1
WO2020083187A1 PCT/CN2019/112214 CN2019112214W WO2020083187A1 WO 2020083187 A1 WO2020083187 A1 WO 2020083187A1 CN 2019112214 W CN2019112214 W CN 2019112214W WO 2020083187 A1 WO2020083187 A1 WO 2020083187A1
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prostate cancer
pharmaceutically acceptable
use according
compound
acceptable salt
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PCT/CN2019/112214
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English (en)
French (fr)
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金春雷
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江苏恒瑞医药股份有限公司
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Priority to CN201980053699.9A priority Critical patent/CN112584836A/zh
Publication of WO2020083187A1 publication Critical patent/WO2020083187A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to the use of an AR antagonist combined with a PARP inhibitor in the preparation of a medicament for treating prostate cancer.
  • Prostate cancer is a malignant tumor with the second highest morbidity rate and the sixth highest mortality rate in the world.
  • the incidence of prostate cancer in China is lower than in Western countries, but in recent years it has shown a rapid upward trend. According to the latest statistics from the National Cancer Center, in 2015, there were about 60,300 new cases of prostate cancer and about 26,600 deaths in China.
  • the morbidity and mortality rates ranked 7th and 10th among male malignancies, respectively.
  • the incidence of prostate cancer is higher in large cities. For example, the incidence of prostate cancer in Beijing, Shanghai and Guangzhou in 2009 has reached 19.30 / 100,000, 32.23 / 100,000 and 17.57 / 100,000, respectively.
  • prostate cancer cells has a characteristic androgen dependence, so endocrine therapy that inhibits androgen action is an important means of prostate cancer treatment, and mainly through the following methods: (1) androgen removal therapy (ADT, including surgical castration Or castration), inhibit testosterone synthesis; (2) block androgen and androgen receptor (AR) binding, that is, use AR antagonists to competitively block androgen and prostate cancer cell cytoplasmic AR binding.
  • ADT androgen removal therapy
  • AR block androgen and androgen receptor
  • Metastatic prostate cancer often undergoes ADT (with or without first-generation AR antagonists, such as bicalutamide) for about 18 to 24 months, and often progresses to metastatic castration-resistant prostate cancer with a higher degree of malignancy (mCRPC).
  • Abiraterone acetate (a new inhibitor of testosterone synthesis key enzyme CYP-17) is the first new AR-targeted drug approved by the FDA to treat mCRPC. It has been widely used in the first-line treatment of mCRPC or after the failure of docetaxel chemotherapy Second-line treatment. However, after 6 to 15 months of treatment with Abiraterone, the patient will develop resistance again, the disease will continue to progress, and the prognosis is poor. Therefore, there is an urgent clinical need for a new treatment for mCRPC that has failed previous abiraterone and docetaxel treatment.
  • imidazole derivatives such as formula I in WO2014036897 have shown significant anti-CRPC effects in animal and phase I / II clinical studies, but previous studies have shown that the same drug enzalutamide is in the past
  • the efficacy of mCRPC in patients with failed Betron therapy is limited, with a PSA response rate of only about 25%. Therefore, the combination of other target drugs may be an important research and development direction for new AR antagonists to treat mCRPC that has failed previous abiraterone and docetaxel treatment.
  • New high-efficiency AR antagonists combined with other target drugs are also likely to obtain better efficacy than AR antagonist single drugs,
  • PARP is a popular therapeutic target in the field of prostate cancer research in recent years. Through a synergistic lethal mechanism, PARP inhibitors have been shown to have a significant antitumor effect on tumors deficient in DNA homologous recombination repair (HRR), and previous studies have found that ⁇ 20% of mCRPC patients have gene mutations that can cause HRR deficiency (such as BRCA1 / 2 and ATM genes).
  • HRR DNA homologous recombination repair
  • the TOPARP phase II study of the PARP inhibitor olaparib was the first to demonstrate the remarkable efficacy of PARP inhibitors on HRR-deficient mCRPC, with a tumor response rate of 88%, and olaparib also received FDA breakthrough therapy. Identify. Therefore, constantly expanding the use of PARP inhibitors and the scope of indications has a good impetus for the development and application of PARP inhibitors.
  • WO2012019427 discloses a PARP inhibitor compound of formula II.
  • the ⁇ 3 grade AEs observed in its phase I study are mainly fatigue, loss of appetite, and hematological toxicity is relatively low.
  • the incidence of hematological toxicity, such as decreased counts and decreased neutrophil counts, was not high in the single-drug Phase I study.
  • the overall safety of single drug oral administration is well tolerated,
  • the present disclosure provides the use of an AR antagonist combined with adenosine polyphosphate ribose polymerase (PARP) inhibitor in the preparation of a medicament for treating prostate cancer, wherein the AR antagonist is a compound of formula I or Its pharmaceutically acceptable salts,
  • PARP adenosine polyphosphate ribose polymerase
  • the PARP inhibitor is selected from olaparib, Talazoparib, Veliparib, Rucaparib, CEP-8983, or BGB-290.
  • the PARP inhibitor is a compound of formula II or a pharmaceutically acceptable salt thereof
  • the compound of formula I or a pharmaceutically acceptable salt thereof in combination with an adenosine polyphosphate ribose polymerase (PARP) inhibitor can reduce adverse drug reactions.
  • the adverse drug reaction is selected from compounds I or a pharmaceutically acceptable salt thereof or caused by an inhibitor of polyadenylate ribose polymerase (PARP).
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 1-1000 mg, which may be 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg,
  • the frequency of administration of the compound of formula I or a pharmaceutically acceptable salt thereof in the present disclosure will vary with the type and severity of the disease, such as once a day, twice a day, three times a day, recommended Once a day.
  • the dosage of the polyadenylate ribose polymerase inhibitor is 1-400 mg, which may be 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg,
  • the frequency of administration varies with the type and severity of the disease, and the frequency of administration of the polyadenylate ribose polymerase inhibitor described in the present disclosure is once a day or twice a day 3. Three times a day, recommended twice a day at 12-hour intervals.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 1-500 mg, and the adenosine polyphosphate ribose polymerase inhibitor is administered at a dose of 1-400 mg.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dosage of 1-500 mg, and the compound of formula II or a pharmaceutically acceptable salt thereof is administered at a dosage of 1-400 mg.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 1 to 500 mg once a day, and the compound of formula II or a pharmaceutically acceptable salt thereof is administered at a dose of 1 to 400 mg twice a day.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 1 to 500 mg once a day, and the adenosine polyphosphate ribose polymerase inhibitor is administered at a dose of 1 to 400 mg twice a day .
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 150 to 300 mg once a day, and the compound of formula II or a pharmaceutically acceptable salt thereof is administered at a dose of 80 to 200 mg twice a day.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 150 to 300 mg once a day, and the polyadenylate ribose polymerase inhibitor is administered at a dose of 80 to 200 mg twice a day .
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 150 to 300 mg once a day, and the polyadenylate ribose polymerase inhibitor is administered at a dose of 80 to 200 mg twice a day , 12 hours apart.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 150 to 300 mg once a day, and the compound of formula II or a pharmaceutically acceptable salt thereof is administered at a dose of 80 to 200 mg twice a day, 12 hours apart,
  • the patients with prostate cancer include those who have not previously received anti-prostate cancer treatment (including only past treatment), or who have received prostate cancer treatment, and the prostate cancer treatment method is selected Since one or more of Docetaxel or Abiraterone treatment.
  • the castration treatment regimen includes surgery or medical castration treatment, with or without first-generation AR antagonists (eg, bicalutamide and flutamide).
  • first-generation AR antagonists eg, bicalutamide and flutamide.
  • the docetaxel treatment regimen includes but is not limited to docetaxel, docetaxel combined with prednisone, and the like.
  • the abiraterone treatment regimen includes but is not limited to abiraterone, the combination of abiraterone and prednisone, and the like.
  • the target lesion diameter of the prostate cancer patient is relatively reduced by at least 30%, and no more than 2 new bone lesions appear.
  • the prostate cancer patient's target lesion has a relatively increased diameter of at least 20% or one or more new lesions (visceral or lymph nodes only), and / or ⁇ 2 new bone lesions.
  • the diameter of the target lesion of the prostate cancer patient is relatively increased by at most 20% or the diameter of the targeted lesion is relatively reduced by at most 30%, and no more than 2 new bone lesions appear.
  • the prostate cancer patient in the present disclosure is a treatment failure.
  • the present disclosure also provides a pharmaceutical composition of an AR inhibitor (such as a compound of formula I or a pharmaceutically acceptable salt thereof) and an adenosine polyphosphate ribose polymerase inhibitor, including optional one or more pharmaceutically acceptable carriers , Excipients and / or diluents.
  • the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form.
  • a pharmaceutical preparation of a polyphosphate adenosine ribose polymerase inhibitor and a compound of formula I or a pharmaceutically acceptable salt thereof can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, Injection (including injection, sterile powder for injection and concentrated solution for injection), suppository, inhalation or spray.
  • the pharmaceutical composition of the present disclosure can also be administered to patients or subjects in need of such treatment in any suitable manner of administration, such as oral, parenteral, rectal, transpulmonary, or topical administration.
  • oral administration the pharmaceutical composition can be made into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, etc .; or, oral liquid preparations, such as oral solutions, oral mixtures Suspension, syrup, etc.
  • the pharmaceutical preparation may further contain suitable fillers, binders, disintegrating agents, lubricants and the like.
  • the present disclosure also provides a method of treating prostate cancer, the method comprising: administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and an adenosine polyphosphate ribose polymerase inhibitor (eg, formula II) to a patient with prostate cancer Shown compounds or pharmaceutically acceptable salts).
  • adenosine polyphosphate ribose polymerase inhibitor eg, formula II
  • the target lesion diameter of the prostate cancer patient is relatively reduced by at least 30%, and no more than 2 new bone lesions appear.
  • the prostate cancer patient's target lesion has a relatively increased diameter of at least 20% or one or more new lesions (visceral or lymph nodes only), and / or ⁇ 2 new bone lesions.
  • the diameter of the target lesion of the prostate cancer patient is relatively increased by at most 20% or the diameter of the targeted lesion is relatively reduced by at most 30%, and no more than 2 new bone lesions appear.
  • the prostate cancer patient in the present disclosure is a treatment failure.
  • the present disclosure also provides a method for reducing adverse reactions caused by an AR inhibitor (such as a compound of formula I or a pharmaceutically acceptable salt thereof) and an adenosine polyphosphate ribose polymerase inhibitor, including administration to patients with prostate cancer A dose of a compound of formula I or a pharmaceutically acceptable salt thereof and an adenosine polyphosphate ribose polymerase inhibitor (eg, a compound of formula II or a pharmaceutically acceptable salt thereof).
  • an AR inhibitor such as a compound of formula I or a pharmaceutically acceptable salt thereof
  • an adenosine polyphosphate ribose polymerase inhibitor eg, a compound of formula II or a pharmaceutically acceptable salt thereof.
  • a method of reducing adverse reactions includes: administering an effective dose of an AR inhibitor (such as a compound of formula I or a pharmaceutically acceptable salt thereof) and a polyphosphate adenosine ribose polymerase inhibitor (such as Compound of formula II or a pharmaceutically acceptable salt thereof).
  • an AR inhibitor such as a compound of formula I or a pharmaceutically acceptable salt thereof
  • a polyphosphate adenosine ribose polymerase inhibitor such as Compound of formula II or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides a method for reducing the dose of an AR inhibitor (such as a compound of formula I or a pharmaceutically acceptable salt thereof) and an adenosine polyphosphate ribose polymerase inhibitor alone, including administering an effective dose to patients with prostate cancer A compound of formula I or a pharmaceutically acceptable salt thereof and an adenosine polyphosphate ribose polymerase inhibitor (eg, a compound of formula II or a pharmaceutically acceptable salt thereof).
  • an AR inhibitor such as a compound of formula I or a pharmaceutically acceptable salt thereof
  • an adenosine polyphosphate ribose polymerase inhibitor alone
  • the method of reducing the dose administered alone includes: simultaneous administration of an effective dose of an AR inhibitor (such as a compound of formula I or a pharmaceutically acceptable salt thereof) and a polyphosphate adenosine ribose polymerase inhibitor to a prostate cancer patient (A compound represented by formula II or a pharmaceutically acceptable salt thereof).
  • an AR inhibitor such as a compound of formula I or a pharmaceutically acceptable salt thereof
  • a polyphosphate adenosine ribose polymerase inhibitor to a prostate cancer patient
  • the prostate cancer refers to prostate adenocarcinoma confirmed by histological or cytological examination, which does not suggest neuroendocrine or small cell characteristics, and the patient has failed previous treatment with abiraterone acetate.
  • the prostate cancer refers to prostate adenocarcinoma confirmed by histological or cytological examination, which does not suggest neuroendocrine or small cell characteristics, and the patient has failed previous docetaxel chemotherapy or has failed docetaxel Chemotherapy intolerance or screening is not suitable for receiving docetaxel treatment.
  • the prostate cancer refers to prostate adenocarcinoma confirmed by histological or cytological examination, which does not suggest neuroendocrine or small cell characteristics, and the patient has failed previous docetaxel chemotherapy or has failed docetaxel Chemotherapy intolerance or screening is not suitable for receiving docetaxel treatment, and previous treatment with abiraterone acetate failed.
  • the present disclosure also provides the use of an AR antagonist combined with a PARP inhibitor in a drug for treating prostate cancer, in which patients with prostate cancer have received treatment with docetaxel and apatinib.
  • the AR antagonist is selected from, but not limited to, Flutamide, Nilutamide, Bicalutamide, Enzalutamide, Apalutamide, Darolutamide, Proxalutamide, TRC-253, ONC1-13B, EPI-001, APC-100, TAS-3681 ( Taiho Company).
  • the AR antagonist is a compound represented by Formula I or a pharmaceutically acceptable salt thereof,
  • the PARP inhibitor is selected from olaparib, Talazoparib, Veliparib, Rucaparib, CEP-8983 or BGB-290.
  • the PARP inhibitor is a compound of formula II or a pharmaceutically acceptable salt thereof
  • the target lesion diameter of the prostate cancer patient is relatively reduced by at least 30%, and no more than 2 new bone lesions appear.
  • the prostate cancer patient's target lesion has a relatively increased diameter of at least 20% or one or more new lesions (visceral or lymph nodes only), and / or ⁇ 2 new bone lesions.
  • the diameter of the target lesion of the prostate cancer patient is relatively increased by at most 20% or the diameter of the targeted lesion is relatively reduced by at most 30%, and no more than 2 new bone lesions appear.
  • the prostate cancer patient in the present disclosure is a treatment failure.
  • the present disclosure also provides a method of treating prostate cancer, the method comprising: administering an effective amount of an AR antagonist and adenosine polyphosphate ribose polymerization to a prostate cancer patient who has received treatment with docetaxel and apatinib Enzyme inhibitor.
  • the target lesion diameter of the prostate cancer patient is relatively reduced by at least 30%, and no more than 2 new bone lesions appear.
  • the prostate cancer patient's target lesion has a relatively increased diameter of at least 20% or one or more new lesions (visceral or lymph nodes only), and / or ⁇ 2 new bone lesions.
  • the diameter of the target lesion of the prostate cancer patient is relatively increased by at most 20% or the diameter of the targeted lesion is relatively reduced by at most 30%, and no more than 2 new bone lesions appear.
  • the prostate cancer patient in the present disclosure is a treatment failure.
  • the AR antagonist is selected from, but not limited to, Flutamide, Nilutamide, Bicalutamide, Enzalutamide, Apalutamide, Darolutamide, Proxalutamide, TRC-253, ONC1-13B, EPI-001, APC-100, TAS-3681 ( Taiho Company).
  • the AR antagonist is a compound represented by Formula I or a pharmaceutically acceptable salt thereof,
  • the PARP inhibitor is selected from olaparib, Talazoparib, Veliparib, Rucaparib, CEP-8983 or BGB-290.
  • the PARP inhibitor is a compound of formula II or a pharmaceutically acceptable salt thereof
  • the so-called “combination” refers to a mode of administration, which refers to the administration of at least one dose of AR antagonist and at least one dose of PARP inhibitor within a certain period of time, wherein both drugs show pharmacological effects Produce pharmacological effects.
  • the time period may 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 two drugs can be administered simultaneously or sequentially.
  • the AR antagonist and PARP inhibitor can be administered simultaneously or sequentially. This period includes treatments in which the AR antagonist and PARP inhibitor are administered by the same route of administration or different routes of administration.
  • the combined administration method of the present disclosure is selected from simultaneous administration, independently formulated and co-administered, or independently formulated and sequentially administered.
  • pharmaceutically acceptable salt refers to a compound such as "a compound of formula I is a pharmaceutically acceptable salt” refers to a substance obtained by forming a salt of a compound of formula I with an acid; "a pharmaceutically acceptable salt of a compound of formula II” refers to a formula II A compound obtained by forming a salt with an acid.
  • the "effective amount" in the present disclosure includes an amount sufficient to improve or prevent the symptoms or conditions of the medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's general health, the route and dosage of the method of administration, and the severity of side effects.
  • the effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • treatment failure refers to a subject with measurable previous adenocarcinoma lesion at baseline, which is disease progression (PD), toxicity intolerance or investigator's judgment according to RECIST 1.1 efficacy evaluation standard Those who could not continue to benefit clinically, or according to the evaluation criteria for prostate cancer PCWG3, 2 or more new bone lesions were considered as disease progression (PD).
  • PD disease progression
  • RECIST 1.1 efficacy evaluation standard Those who could not continue to benefit clinically, or according to the evaluation criteria for prostate cancer PCWG3, 2 or more new bone lesions were considered as disease progression (PD).
  • the "toxic intolerance” mentioned in the present disclosure means that the adverse reaction caused by the drug cannot continue to be treated.
  • PFS Progression-free survival
  • OS Overall survival
  • Objective Remission Rate Defined as the best overall response (BoR), CR and PR subjects accounted for the proportion of the number of subjects who received the drug at least once in each treatment group. BOR is defined as the best response index from the random date to the objectively recorded progression date or the date of subsequent anti-precancerous adenocarcinoma treatment (whichever occurs first). The test taker will determine the BOR based on all remission assessment results.
  • Duration of remission the time from the first PR or CR to the first PD or death.
  • DCR Disease control rate
  • the efficacy evaluation criteria are divided into complete remission (CR), partial remission (PR), stability (SD), and progression (PD).
  • CR Complete remission
  • Partial remission The sum of target lesion diameters is reduced by at least 30% from the baseline level.
  • PD Disease progression: the minimum value of the sum of the diameters of all the measured target lesions in the entire experimental study is taken as the reference, and the diameter and the relative increase are at least 20% (if the baseline measurement is the smallest, the baseline value is used as the reference); otherwise
  • the absolute value of the sum of diameters must be increased by at least 5 mm (the appearance of one or more new lesions is also regarded as disease progression).
  • SD Disease Stability: The target lesions did not decrease in PR to the extent of the increase, nor did they reach the PD level. Between the two, the minimum sum of diameters can be used as a reference during the study.
  • the evaluation standard of efficacy is divided into PD and non-PD according to PCWG3. According to the results of the first bone scan (C4D1), the regulations are as follows:
  • Compound A AR antagonist, compound of formula I (S) -4- (3- (4- (2,3-dihydroxypropoxy) phenyl) -4,4-dimethyl-5-carbonyl-2 -Thioimidazolin-1-yl) -2- (trifluoromethyl) benzonitrile can be prepared according to the method in patent application WO2014036897.
  • the enrolled subjects were prostate adenocarcinomas confirmed by histological or cytological examination, which did not suggest neuroendocrine or small cell characteristics, and the patient had failed previous abiraterone acetate treatment, and the previous docetaxel chemotherapy failed Tasay chemotherapy is not tolerated or is not suitable for receiving docetaxel treatment at the time of screening.
  • Compound A 240 mg, orally, once a day; Compound B: 100 mg or 150 mg, orally, twice a day, co-administered for 28 days as a cycle.
  • the safety assessment of the DLT observation period that is, the first administration of fluzopalizide to the 28th day of the first cycle of the combined administration for a total of 33 days. Can enter the next dose group test in increments. If the fluzoparil 150mg BID dose group also passed the DLT safety assessment, the dose will not be increased.

Abstract

一种式I化合物所示的AR拮抗剂或其可药用盐联合多聚二磷酸腺苷核糖聚合酶抑制剂（PARP抑制剂）在制备治疗前列腺癌的药物中的用途，该联合治疗方案展现较优的疾病控制率和客观响应率。（I）

Description

一种AR拮抗剂联合PARP抑制剂在制备治疗前列腺癌的药物中的用途
本申请要求申请日为2018年10月22日的中国专利申请CN201811227906.1的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开公开中涉及一种AR拮抗剂联合PARP抑制剂在制备治疗前列腺癌的药物中的用途。
背景技术
前列腺癌是全球男性发病率排第2、死亡率排第6的恶性肿瘤。我国的前列腺癌发病率低于西方国家，但近年来呈迅速上升趋势。根据国家癌症中心的最新统计数据，2015年我国新发前列腺癌病例约为6.03万例，死亡病例约2.66万例，发病率和死亡率分别居男性恶性肿瘤的第7和10位。大城市的前列腺癌发病率更高，如2009年北京、上海和广州的前列腺癌发病率已分别达到19.30/10万、32.23/10万和17.57/10万，分别居所在城市男性恶性肿瘤发病率的第5、5和7位。随着人口老龄化和生活方式西方化，可以预见我国前列腺癌发病率在未来还将快速升高。
前列腺癌细胞的生长具有特征性的雄激素依赖性，因此抑制雄激素作用的内分泌治疗是前列腺癌治疗的重要手段，且主要通过以下方式：(1)雄激素去除疗法(ADT，包括手术去势或药物去势)，抑制睾酮合成；(2)阻断雄激素与雄激素受体(AR)结合，即应用AR拮抗剂竞争性阻断雄激素与前列腺癌细胞胞浆内AR的结合。转移性前列腺癌在接受ADT治疗(伴或不伴第一代AR拮抗剂，如比卡鲁胺)约18～24个月后，往往进展成恶性程度更高的转移性去势抵抗性前列腺癌(mCRPC)。醋酸阿比特龙(睾酮合成关键酶CYP-17的新型抑制剂)是FDA批准的第一个治疗mCRPC的新型AR 靶向药物，已广泛用于mCRPC的一线治疗或多西他赛化疗失败后的二线治疗。但是，阿比特龙治疗6～15个月后，患者将再次产生耐药，疾病继续进展，预后差。因此，目前临床上迫切需要一种针对既往阿比特龙和多西他赛治疗失败的mCRPC的新型治疗。
作为一种新型高效AR拮抗剂，WO2014036897中咪唑类衍生物如式I已在动物和I/II期临床研究中显示出显著的抗CRPC作用，但是既往研究显示同类药恩扎鲁胺在既往阿比特龙治疗失败的mCRPC患者中疗效有限，PSA应答率仅约25％。因此，联合其他靶点药物可能是新型AR拮抗剂治疗既往阿比特龙和多西他赛治疗失败的mCRPC的一个重要研发方向，除此外，在包括激素敏感性前列腺癌在内的其他前列腺癌中，新型高效AR拮抗剂联合其他靶点药物也很有可能获得较AR拮抗剂单药更好的疗效，
Figure PCTCN2019112214-appb-000001
PARP是近年来前列腺癌研究领域的热门治疗靶点。通过协同致死机制，PARP抑制剂已被证明对DNA同源重组修复(HRR)缺陷的肿瘤中具有显著抗肿瘤作用，而既往研究发现～20％的mCRPC患者存在可导致HRR缺陷的基因突变(如BRCA1/2和ATM基因)。2015年底，PARP抑制剂奥拉帕尼的TOPARP II期研究率先证明了PARP抑制剂对HRR缺陷mCRPC的显著疗效，肿瘤应答率达到了88％，奥拉帕尼也因此获得的FDA的突破性疗法认定。因此不断拓展PARP抑制剂的使用方式及适应症范围对于PARP抑制剂的研发及应用具有良好的推动作用。
WO2012019427公开了PARP抑制剂式II化合物，在其Ⅰ期研究中观察到的≥3级AE主要为乏力、食欲减退，血液学毒性较轻，同类药如奥拉帕尼常见的重度血红蛋白降低、血小板计数降低、嗜中性粒细胞计数降低等血 液学毒性在单药Ⅰ期研究中发生率并不高。单药口服总体安全耐受性良好，
Figure PCTCN2019112214-appb-000002
联合使用一种以上靶点各异又相互关联的抗肿瘤药物，充分发挥各组分优势，既能提高单药的抗肿瘤活性又可降低药物毒性，是一种被普遍接受的抗肿瘤疗法。
Li L等人(Sci Signal 10,2017)报道了恩扎鲁胺能有效抑制这些基因在AR阳性CRPC细胞中的表达，从而诱导出HRR缺陷表型(BRCAness)，并与奥拉帕尼协同抑制肿瘤细胞的体外增殖和小鼠移植瘤生长；与此一致，Asim M等人报道了比卡鲁胺或恩扎鲁胺联合奥拉帕尼则在体外或体内显示出抗前列腺癌疗效的协同作用(Nat Commun 8:374,2017)；一项在既往多西他赛化疗后mCRPC患者中进行的II期研究(Lancet Oncol,2018)显示，安慰剂联合阿比特龙单药组(N＝71)的中位rPFS为8.2月，而奥拉帕尼联合阿比特龙组(N＝71)的中位rPFS达到13.8月(HR＝0.65，95％CI 0.44-0.97，P＝0.034)。
发明内容
本公开中提供一种AR拮抗剂联合多聚二磷酸腺苷核糖聚合酶(PARP)抑制剂在制备治疗前列腺癌的药物中的用途，其中，AR拮抗剂为结构如式I所示的化合物或其可药用盐，
Figure PCTCN2019112214-appb-000003
在一些实施方案中，所述PARP抑制剂选自奥拉帕尼、Talazoparib、Veliparib、Rucaparib、CEP-8983或BGB-290。
在另一些实施方案中，所述PARP抑制剂为结构如式II所示化合物或其可药用的盐，
Figure PCTCN2019112214-appb-000004
本公开所述联合具有协同药效作用。
在一些实施方案中，所述式I化合物或其可药用盐联合多聚二磷酸腺苷核糖聚合酶(PARP)抑制剂可减少药物不良反应。在一些实施方案中，所述的药物不良反应选自由I化合物或其可药用盐引起或由多聚二磷酸腺苷核糖聚合酶(PARP)抑制剂引起的。
本公开中所述的用途，其中，所述式I所示的化合物或其可药用盐给药剂量为1-1000mg，可以为1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg或 两数值之间任意数值。然而，其它剂量可以是有用的。本公开中疗法的进展易于通过常规的技术和测定法来检测。
在一些实施方案中，本公开中所述式I化合物或其可药用盐的施药的频率会随疾病的类型和严重性而变化，如一日一次、一日两次、一日三次，推荐一日一次。
本公开所述的用途中多聚二磷酸腺苷核糖聚合酶抑制剂给药剂量为1-400mg，可以为1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg或两数值之间任意数值。然而，其它剂量可以是有用的。本公开中疗法的进展易于通过常规的技术和测定法来检测。
在一些实施方案中，施药的频率会随疾病的类型和严重性而变化，本公开中所述多聚二磷酸腺苷核糖聚合酶抑制剂的给药频为一日一次、一日两次、一日三次，推荐一日两次、间隔12小时。
在一些实施方案中，所述式I化合物或其可药用盐给药剂量1～500mg，多聚二磷酸腺苷核糖聚合酶抑制剂给药剂量1～400mg。
在一些实施方案中，所述式I化合物或其可药用盐给药剂量1～500mg，式II化合物或其可药用的盐给药剂量1～400mg。
在一些实施方案中，所述式I化合物或其可药用盐给药剂量1～500mg、 一日一次，式II化合物或其可药用的盐给药剂量1～400mg、一日两次。
在一些实施方案中，所述式I化合物或其可药用盐给药剂量1～500mg、一日一次，多聚二磷酸腺苷核糖聚合酶抑制剂给药剂量1～400mg、一日两次。
在一些实施方案中，所述式I化合物或其可药用盐给药剂量150～300mg、一日一次，式II化合物或其可药用的盐给药剂量80～200mg、一日两次。
在一些实施方案中，所述式I化合物或其可药用盐给药剂量150～300mg、一日一次，多聚二磷酸腺苷核糖聚合酶抑制剂给药剂量80～200mg、一日两次。
在一些实施方案中，所述式I化合物或其可药用盐给药剂量150～300mg、一日一次，多聚二磷酸腺苷核糖聚合酶抑制剂给药剂量80～200mg、一日两次、间隔12小时。
在一些实施方案中，所述式I化合物或其可药用盐给药剂量150～300mg、一日一次，式II化合物或其可药用的盐给药剂量80～200mg、一日两次、间隔12小时，
Figure PCTCN2019112214-appb-000005
进一步地，在可选实施方案中，所述前列腺癌患者包括既往未接受过抗前列腺癌治疗(包括仅接受过去势治疗)的，或曾接受过前列腺癌治疗的，所述前列腺癌治疗方式选自多西他赛或阿比特龙治疗方案中的一种或多种。
在一些实施方案中，所述去势治疗方案包括手术或药物去势治疗，可伴或不伴第一代AR拮抗剂(如比卡鲁胺和氟他胺)。
在一些实施方案中，所述多西他赛治疗方案包括但不限于多西他赛、多西他赛与泼尼松联用等。
在一些实施方案中，所述阿比特龙治疗方案包括但不限于阿比特龙、阿比特龙与泼尼松联用等。
在一些实施方案中，所述前列腺癌患者的靶病灶直径相对减少了至少30％，未出现≥2个新发骨病灶。
在一些实施方案中，所述前列腺癌患者的靶病灶直径相对增加了至少20％或出现一个或多个新病灶(限内脏或淋巴结)，和/或出现≥2个新发骨病灶。
在一些实施方案中，所述前列腺癌患者的靶病灶直径相对增加了至多20％或靶向病灶直径相对减少了至多30％，以及未出现≥2个新发骨病灶。
优选地，本公开中所述前列腺癌患者为治疗失败的。
本公开还提供一种AR抑制剂(如式I化合物或其可药用盐)和多聚二磷酸腺苷核糖聚合酶抑制剂的药物组合物，包含任选的一种或多种药用载体、赋形剂和/或稀释剂。所述药物组合物可以制成药学上可接受的任一剂型。例如，多聚二磷酸腺苷核糖聚合酶抑制剂与式I化合物或其可药用盐的药物制剂可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
此外，本公开的所述药物组合物还可以以任何合适的给药方式，例如口服、肠胃外、直肠、经肺或局部给药等方式施用于需要这种治疗的患者或受试者。当用于口服给药时，所述药物组合物可制成口服制剂，例如口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；或，口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。当制成口服制剂时，所述药物制剂还可包含适宜的填充剂、粘合剂、崩解剂、润滑剂等。
本公开还提供一种治疗前列腺癌的方法，该方法包括：向前列腺癌患者施用有效量的式I化合物或其可药用盐和多聚二磷酸腺苷核糖聚合酶抑制剂(例如式II所示化合物或其可药用的盐)。
在一些实施方案中，所述前列腺癌患者的靶病灶直径相对减少了至少30％，未出现≥2个新发骨病灶。
在一些实施方案中，所述前列腺癌患者的靶病灶直径相对增加了至少20％或出现一个或多个新病灶(限内脏或淋巴结)，和/或出现≥2个新发骨病灶。
在一些实施方案中，所述前列腺癌患者的靶病灶直径相对增加了至多20％或靶向病灶直径相对减少了至多30％，以及未出现≥2个新发骨病灶。
优选地，本公开中所述前列腺癌患者为治疗失败的。
本公开还提供了一种降低AR抑制剂(如式I化合物或其可药用盐)、多聚二磷酸腺苷核糖聚合酶抑制剂所导致的不良反应的方法，包括向前列腺癌患者施用有效剂量的式I化合物或其可药用盐和多聚二磷酸腺苷核糖聚合酶抑制剂(例如式II所示化合物或其可药用的盐)。
在一些实施方案中，降低不良反应的方法包括：向前列腺癌患者施用有效剂量的AR抑制剂(如式I化合物或其可药用盐)和多聚二磷酸腺苷核糖聚合酶抑制剂(如式II所示化合物或其可药用的盐)。
本公开中还提供了一种减少AR抑制剂(如式I化合物或其可药用盐)、多聚二磷酸腺苷核糖聚合酶抑制剂单独施用剂量的方法，包括向前列腺癌患者施用有效剂量的式I化合物或其可药用盐和多聚二磷酸腺苷核糖聚合酶抑制剂(例如式II所示化合物或其可药用的盐)。
在一些实施方案中，减少单独施用剂量的方法包括：同步向前列腺癌患者施用有效剂量的AR抑制剂(如式I化合物或其可药用盐)和多聚二磷酸腺苷核糖聚合酶抑制剂(如式II所示化合物或其可药用的盐)。
在一些实施方案中，所述的前列腺癌是指经组织学或细胞学检查证实的前列腺腺癌，未提示神经内分泌或小细胞特征，且患者既往醋酸阿比特龙治疗失败的。
在一些实施方案中，所述的前列腺癌是指经组织学或细胞学检查证实的 前列腺腺癌，未提示神经内分泌或小细胞特征，且患者既往多西他赛化疗失败或对多西他赛化疗不能耐受或筛选时不适合接受多西他赛治疗的。
在一些实施方案中，所述的前列腺癌是指经组织学或细胞学检查证实的前列腺腺癌，未提示神经内分泌或小细胞特征，且患者既往多西他赛化疗失败或对多西他赛化疗不能耐受或筛选时不适合接受多西他赛治疗，和既往醋酸阿比特龙治疗失败的。
本公开中还提供了一种AR拮抗剂联合PARP抑制剂在治疗前列腺癌的药物中的用途，其中，前列腺癌患者曾接受过多西他赛和阿帕替尼治疗的。
在一些实施方案中，所述AR拮抗剂选自但不限于Flutamide、Nilutamide、Bicalutamide、Enzalutamide、Apalutamide、Darolutamide、Proxalutamide、TRC-253、ONC1-13B、EPI-001、APC-100、TAS-3681(Taiho公司)。
在一些实施方案中，所述AR拮抗剂为如式I所示的化合物或其可药用盐，
Figure PCTCN2019112214-appb-000006
另一方面，所述PARP抑制剂选自奥拉帕尼、Talazoparib、Veliparib、Rucaparib、CEP-8983或BGB-290。
进一步地，所述PARP抑制剂为结构如式II所示化合物或其可药用的盐，
Figure PCTCN2019112214-appb-000007
本公开所述联合具有协同药效作用。
在一些实施方案中，所述前列腺癌患者的靶病灶直径相对减少了至少30％，未出现≥2个新发骨病灶。
在一些实施方案中，所述前列腺癌患者的靶病灶直径相对增加了至少20％或出现一个或多个新病灶(限内脏或淋巴结)，和/或出现≥2个新发骨病灶。
在一些实施方案中，所述前列腺癌患者的靶病灶直径相对增加了至多20％或靶向病灶直径相对减少了至多30％，以及未出现≥2个新发骨病灶。
优选地，本公开中所述前列腺癌患者为治疗失败的。
本公开还提供一种治疗前列腺癌的方法，该方法包括：向曾接受过多西他赛和阿帕替尼治疗的前列腺癌患者施用有效量的AR拮抗剂和多聚二磷酸腺苷核糖聚合酶抑制剂。
在一些实施方案中，所述前列腺癌患者的靶病灶直径相对减少了至少30％，未出现≥2个新发骨病灶。
在一些实施方案中，所述前列腺癌患者的靶病灶直径相对增加了至少20％或出现一个或多个新病灶(限内脏或淋巴结)，和/或出现≥2个新发骨病灶。
在一些实施方案中，所述前列腺癌患者的靶病灶直径相对增加了至多20％或靶向病灶直径相对减少了至多30％，以及未出现≥2个新发骨病灶。
优选地，本公开中所述前列腺癌患者为治疗失败的。
在一些实施方案中，所述AR拮抗剂选自但不限于Flutamide、Nilutamide、Bicalutamide、Enzalutamide、Apalutamide、Darolutamide、Proxalutamide、TRC-253、ONC1-13B、EPI-001、APC-100、TAS-3681(Taiho公司)。
在一些实施方案中，所述AR拮抗剂为如式I所示的化合物或其可药用盐，
Figure PCTCN2019112214-appb-000008
另一方面，所述PARP抑制剂选自奥拉帕尼、Talazoparib、Veliparib、Rucaparib、CEP-8983或BGB-290。
进一步地，所述PARP抑制剂为结构如式II所示化合物或其可药用的盐，
Figure PCTCN2019112214-appb-000009
本公开所述联合具有协同药效作用。
如无相反解释，本公开中术语具有如下含义：
本公开中，所谓“联合”是一种给药方式，是指一定时间期限内给予至少一种剂量的AR拮抗剂和至少一种剂量的PARP抑制剂，其中，两种药物都显示药理学作用产生药理作用。所述的时间期限可以是一个给药周期内，优选4周内，3周内，2周内，1周内，或24小时以内，更优选12小时以内。两种药物可以同时或依次给药。可以同时或依次给予AR拮抗剂和PARP抑制剂。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予AR拮抗剂和PARP抑制剂。本公开所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药。
本公开中所述“可药用盐”是指化合物如“式I化合物可药用盐”是指式I化合物与酸成盐所获得物质；“式II化合物可药用盐”是指式II化合物与酸成盐所获得物质。
本公开中所述“有效量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者 的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
本公开中所述“治疗失败”是指受试者在基线时伴有可测量的前例腺癌病灶，根据RECIST 1.1疗效评定标准为疾病进展(PD)、毒性不可耐受或研究者判断受试者不能继续临床获益，或根据前列腺癌评价标准PCWG3，大于等于2个新发骨病灶被认为疾病进展(PD)。
本公开中所述“毒性不可耐受”是指因药物引起的不良反应不能继续接受治疗。
无进展生存期(PFS)：从随机开始到首次记录前例腺癌客观进展日期或到任何原因导致死亡的时间，以先出现者为准。
总生存期(OS)指从随机日期至任何原因导致死亡的日期。末次随访时仍存活的受试者，其OS以末次随访时间计为数据删失。失访的受试者，其OS以失访前末次证实存活时间计为数据删失。数据删失的OS定义为从随机日期到删失日期。
客观缓解率(ORR)：定义为最佳总体缓解(BoR)，CR和PR的受试者在各治疗组至少用药一次的受试者人数中所占比例。BOR的定义为随机日期开始至客观记录的进展日期或后续抗前例腺癌治疗日期(以先发生者为准)之间的最佳缓解指标，对于没有记录进展或后续抗前例腺癌治疗的受试者，将根据所有的缓解评定结果确定BOR。
缓解持续时间(DoR)：首次PR或者CR至首次PD或者死亡的时间。
疾病控制率(DCR)：CR、PR和SD的受试者在各治疗组至少用药一次的受试者人数中所占比例。DCR从随机日期开始至客观记录的进展日期或后续抗前例腺癌治疗日期(以先发生者为准)之间的最佳缓解指标，对于没有记录进展或后续抗前例腺癌治疗的受试者，将根据所有的缓解评定结果确定DCR。
疗效评定标准根据RECIST 1.1标准分为完全缓解(CR)、部分缓解(PR)、稳定(SD)、进展(PD)。
靶病灶评估：
完全缓解(CR)：所有靶病灶消失，全部病理淋巴结(包括靶结节和非靶结节)短直径必须减少至＜10mm。
部分缓解(PR)：靶病灶直径之和比基线水平减少至少30％。
疾病进展(PD)：以整个实验研究过程中所有测量的靶病灶直径之和的最小值为参照，直径和相对增加至少20％(如果基线测量值最小就以基线值为参照)；除此之外，必须满足直径和的绝对值增加至少5mm(出现一个或多个新病灶也视为疾病进展)。
疾病稳定(SD)：靶病灶减小的程度没达到PR，增加的程度也没达到PD水平，介于两者之间，研究时可以直径之和的最小值作为参考。疗效评价标准根据PCWG3分为PD、非PD，根据首次骨扫描(C4D1)结果的不同，规定分别如下：
1、当C4D1骨扫描较基线发现≧2个新发病灶，判定为PD，继续研究治疗，并在6周后(C5D15)进行复查。若复查较C4D1结果再增加≧2个新病灶(即达到“2+2”标准)，则确认为PD；反之为非PD，且这些受试者之后的骨扫描结果仍需与C4D1结果进行比较，增加≧2个新病灶，方可判定为PD。
2、当C4D1骨扫描较基线发现<2个新发病灶，判定为非PD，无需6周后复查。这些受试者之后的骨扫描结果与C4D1结果比较，增加≧2个新病灶，判定为PD，反之为非PD。
化合物A：AR拮抗剂，式I化合物(S)-4-(3-(4-(2,3-二羟基丙氧基)苯基)-4,4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯基腈，可按照专利申请WO2014036897中方法制备。
化合物B：PARP抑制剂，式II化合物4-[[3-[[2-(三氟甲基)-5,6,7,8-四氢 -[1,2,4]三唑并[1,5-α]吡嗪-7-基]羰基]-4-氟苯基]甲基-1(2H)-酞嗪酮，可按照专利申请WO2012019427A1中的方法制备。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制本公开的范围。
实施例1
入组标准：
入组的受试者为组织学或细胞学检查证实的前列腺腺癌，未提示神经内分泌或小细胞特征，且患者既往醋酸阿比特龙治疗失败，和既往多西他赛化疗失败或对多西他赛化疗不能耐受或筛选时不适合接受多西他赛治疗的。
给药方案：
化合物A：240mg，口服，一日一次；化合物B：100mg或150mg，口服，一日两次，联合给药28天为一周期。受试者完成联合连续给药1周期后，进行DLT观察期(即氟唑帕利单药首次给药至联合给药第1周期第28天，共33天)安全性评估，在确定安全后方可递增进入下一剂量组试验。若氟唑帕利150mg BID剂量组也通过DLT安全性评估，将不再递增剂量。
结论：在9例影像学评价受试者中，6例受试者表现为疾病稳定，3例受试者表现为疾病进展，疾病控制率(Disease Control Rate，DCR)为66.7％。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (19)

  1. 式I化合物或其可药用盐联合多聚二磷酸腺苷核糖聚合酶抑制剂在制备治疗前列腺癌的药物中的用途，
    Figure PCTCN2019112214-appb-100001
  2. 权利要求1所述的用途，其中，所述多聚二磷酸腺苷核糖聚合酶抑制剂选自奥拉帕尼、Talazoparib、Veliparib、Rucaparib、CEP-8983和BGB-290中的一种或多种。
  3. 权利要求1所述的用途，其中，所述多聚二磷酸腺苷核糖聚合酶抑制剂为式II化合物或其可药用盐，
    Figure PCTCN2019112214-appb-100002
  4. 权利要求1-3任一项所述的用途，其中，所述联合具有协同药效作用。
  5. 权利要求1-4任一项所述的用途，其中，所述前列腺癌患者曾接受过前列腺癌治疗，所述前列腺癌治疗方案优选自多西他赛和阿帕替尼治疗方案中的一种或多种。
  6. 权利要求5所述的用途，其中，所述前列腺癌患者为治疗失败的。
  7. 权利要求1-6任一项所述的用途，其中，所述多聚二磷酸腺苷核糖聚合酶抑制剂的给药剂量为1～400mg，优选80mg、100mg、120mg、160mg、200mg或300mg。
  8. 权利要求7所述的用途，其中，所述多聚二磷酸腺苷核糖聚合酶抑制剂的给药频率为一日两次，给药间隔12小时。
  9. 权利要求1-8任一项所述的用途，其中，所述式I化合物或其可药用盐的给药剂量为1～500mg，优选为150～300mg。
  10. 权利要求9所述的用途，其中所述式I化合物或其可药用盐的给药频率为一日一次。
  11. 一种药物组合物，其含有式I化合物或其可药用盐和权利要求1-10任一项所述的多聚二磷酸腺苷核糖聚合酶抑制剂，以及一种或多种可药用的赋形剂、稀释剂或载体，
    Figure PCTCN2019112214-appb-100003
  12. 一种治疗前列腺癌的方法，包括：向癌患者施用有效量的式I化合物或其可药用盐和多聚二磷酸腺苷核糖聚合酶抑制剂，
    Figure PCTCN2019112214-appb-100004
  13. 权利要求12项所述的方法，其中，所述前列腺癌患者曾接受过前列腺癌治疗，所述前列腺癌治疗方案优选自多西他赛和阿帕替尼治疗方案中的一种或多种。
  14. 权利要求12或13所述的方法，其中，所述前列腺癌患者为治疗失败的。
  15. 一种AR拮抗剂联合PARP抑制剂在治疗前列腺癌的药物中的用途，其中，前列腺癌患者曾接受过多西他赛或阿帕替尼治疗。
  16. 权利要求15所述的用途，其中，所述AR拮抗剂选自Flutamide、Nilutamide、Bicalutamide、Enzalutamide、Apalutamide、Darolutamide、 Proxalutamide、TRC-253、ONC1-13B、EPI-001、APC-100和TAS-3681中的一种或多种。
  17. 权利要求15所述的用途，其中所述AR拮抗剂为式I所示的化合物或其可药用盐，
    Figure PCTCN2019112214-appb-100005
  18. 权利要求15-17任一项所述的用途，其中，所述PARP抑制剂选自奥拉帕尼、Talazoparib、Veliparib、Rucaparib、CEP-8983和BGB-290中的一种或多种。
  19. 权利要求15-18任一项所述的用途，其中，所述前列腺癌患者为治疗失败的。
PCT/CN2019/112214 2018-10-22 2019-10-21 一种ar拮抗剂联合parp抑制剂在制备治疗前列腺癌的药物中的用途 WO2020083187A1 (zh)

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