TW202029961A - Use of ar antagonist combined with parp inhibitor in preparation of medicament for treating prostate cancer - Google Patents

Abstract

The invention relates to a use of an AR antagonist combined with a PARP inhibitor in preparation of a medicament for treating prostate cancer. Specifically, a use of a compound of formula I or a pharmaceutically acceptable salt thereof combined with a poly ADP-ribose polymerase inhibitor in preparation of a medicament for treating prostate cancer is provided. This combination therapy shows superior disease control rate and objective response rate, reflects the synergistic effect of the drug combination, and significantly improves the efficacy of immunotherapy.

Description

Application of AR antagonist combined with PARP inhibitor in preparing medicine for treating prostate cancer

The present invention claims the priority of the Chinese patent application CN201811227906.1 whose filing date is October 22, 2018. The present invention quotes the full text of the aforementioned Chinese patent application.

The invention relates to the use of an AR antagonist combined with a PARP inhibitor in the preparation of a medicine for treating prostate cancer.

Prostate cancer is the world's second most common malignant tumor in male incidence and sixth mortality. The incidence of prostate cancer in China is lower than that in Western countries, but it has been rising rapidly in recent years. According to the latest statistics from the National Cancer Center, in 2015, there were approximately 60,300 new cases of prostate cancer in China, and approximately 26,600 deaths. The incidence and mortality ranked 7th and 10th in male malignant tumors respectively. The incidence of prostate cancer in big cities is higher. For example, in 2009, the incidence of prostate cancer in Beijing, Shanghai and Guangzhou reached 19.30/100,000, 32.23/100,000, and 17.57/100,000, respectively. The incidence of malignant tumors in males in the city was respectively The 5th, 5th and 7th positions of With the aging of the population and the westernization of lifestyles, it is foreseeable that the incidence of prostate cancer in China will increase rapidly in the future.

The growth of prostate cancer cells is characterized by androgen dependence. Therefore, endocrine therapy that inhibits androgen action is an important method for the treatment of prostate cancer, and mainly through the following methods: (1) Androgen removal therapy (ADT, including surgical castration or Drug castration), inhibit the synthesis of testosterone; (2) block the binding of androgen and androgen receptor (AR), that is, the application of AR antagonist to competitively block the binding of androgen and AR in the cytoplasm of prostate cancer cells. Metastatic prostate cancer often progresses to more malignant metastatic castration-resistant prostate cancer after receiving ADT treatment (with or without first-generation AR antagonists, such as bicalutamide) for about 18-24 months ( mCRPC). Abiraterone acetate (a new inhibitor of CYP-17, a key enzyme in testosterone synthesis) is the first new AR targeted drug approved by the FDA for the treatment of mCRPC, and has been widely used in the first-line treatment of mCRPC or after the failure of docetaxel chemotherapy Second-line treatment. However, after 6-15 months of abiraterone treatment, the patient will develop resistance again, the disease will continue to progress, and the prognosis will be poor. Therefore, there is an urgent need for a new type of treatment for mCRPC that has failed the previous treatment of abiraterone and docetaxel.

。As a new type of high-efficiency AR antagonist, the 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 has the effect of previous abirate Long therapy failed mCRPC patients with limited efficacy, and the PSA remission rate was 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 the previous treatment of abiraterone and docetaxel. In addition, in other prostate cancers including hormone-sensitive prostate cancer It is also very possible that the new high-efficiency AR antagonist combined with other target drugs will have a better effect than the single AR antagonist.

.

PARP is a popular therapeutic target in the field of prostate cancer research in recent years. Through synthetic lethal mechanisms, PARP inhibitors have been shown to have significant anti-tumor effects in tumors with DNA homologous recombination repair (HRR) defects. Previous studies have found that ~20% of mCRPC patients have gene mutations that can lead to HRR defects (such as BRCA1/2 and ATM genes). At the end of 2015, the TOPARP Phase II study of PARP inhibitor olaparib was the first to prove the significant efficacy of PARP inhibitors on HRR-deficient mCRPC, with a tumor remission rate of 88%, and olaparib also obtained FDA's breakthrough therapy Identified. Therefore, the continuous expansion of the use of PARP inhibitors and the scope of indications has a good role in promoting the development and application of PARP inhibitors.

。WO2012019427 discloses a PARP inhibitor formula II compound. The AEs of grade ≥3 observed in its phase I study are mainly fatigue, loss of appetite, and low hematological toxicity. Similar drugs such as olaparib have common severe hemoglobin reduction and platelet The incidence of hematological toxicity such as decreased count and decreased neutrophil count is not high in the single-drug phase I study. The overall safety of single-drug oral administration is well tolerated,

.

The combined use of more than one anti-tumor drugs with different and interrelated targets can give full play to the advantages of each component, which can not only improve the anti-tumor activity of a single drug but also reduce the toxicity of the drug. It is a generally accepted anti-tumor therapy.

Li L et al. ( Sci Signal 10, 2017) reported that enzalutamide can effectively inhibit the expression of these genes in AR-positive CRPC cells, thereby inducing the HRR-deficient phenotype (BRCAness), and co-inhibiting it with olaparib In vitro proliferation of tumor cells and growth of transplanted tumors in mice; consistent with this, Asim M et al. reported that bicalutamide or enzalutamide combined with olaparib showed a synergistic effect against prostate cancer in vitro or in vivo ( Nat Commun 8:374, 2017); a phase II study in mCRPC patients after docetaxel chemotherapy ( Lancet Oncol , 2018) showed that placebo combined with abiraterone monotherapy group (N=71) The median rPFS was 8.2 months, while the median rPFS in the olaparib combined with abiraterone group (N=71) reached 13.8 months (HR=0.65, 95% CI 0.44-0.97, P=0.034).

。The present invention provides the use of an AR antagonist combined with a polyadenosine diphosphate ribose polymerase (PARP) inhibitor in the preparation of a medicament for the treatment of prostate cancer, wherein the AR antagonist is a compound having the structure shown in formula I or Medicinal salt,

.

In some embodiments, the PARP inhibitor is selected from olaparib, Talazoparib, Veliparib, Rucaparib, CEP-8983, or BGB-290.

。In other embodiments, the PARP inhibitor is a compound represented by formula II or a pharmaceutically acceptable salt thereof,

.

The combination of the present invention has a synergistic effect.

In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof combined with an adenosine polydiphosphate ribose polymerase (PARP) inhibitor can reduce adverse drug reactions. In some embodiments, the adverse drug reaction is selected from the compound of formula I or a pharmaceutically acceptable salt thereof or is caused by an adenosine polydiphosphate ribose polymerase (PARP) inhibitor.

The use according to the present invention, wherein the administration dose of the compound represented by formula I or its pharmaceutically acceptable salt is 1-1000 mg, which can be 1 mg, 5 mg, 10 mg, 15 mg, 20 mg , 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 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, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg , 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg or any value between the two values. However, other dosages may be useful. The progress of the therapy in the present invention can be easily detected by conventional techniques and assays.

In some embodiments, the frequency of administration of the compound of formula I or its pharmaceutically acceptable salt in the present invention 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 polyadenosine diphosphate ribose polymerase inhibitor in the application of the present invention is 1-400 mg, which can be 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 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, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg , 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg or any value between the two values. However, other dosages may be useful. The progress of the therapy in the present invention can be easily detected by conventional techniques and assays.

In some embodiments, the frequency of administration varies with the type and severity of the disease. The frequency of administration of the adenosine polyphosphate ribose polymerase inhibitor in the present invention is once a day and twice a day. , Three times a day, two times a day, 12 hours apart.

In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in a dosage of 1-500 mg, and a polyadenosine diphosphate ribose polymerase inhibitor is administered in a dosage of 1-400 mg.

In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in a dosage of 1-500 mg, and the compound of formula II or a pharmaceutically acceptable salt thereof is administered in a dosage of 1-400 mg.

In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in a dose of 1-500 mg, once a day, and the compound of formula II or a pharmaceutically acceptable salt thereof is administered in a dose of 1-400 mg, once a day. twice.

In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dosage of 1-500 mg, once a day, and a polyadenosine diphosphate ribose polymerase inhibitor is administered at a dosage of 1-400 mg, once a day. Twice a day.

In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 150-300 mg once a day, and the compound of formula II or a pharmaceutically acceptable salt thereof is administered at a dose of 80-200 mg once a day. twice.

In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 150-300 mg, once a day, and a polyadenosine diphosphate ribose polymerase inhibitor is administered at a dose of 80-200 mg, once a day. Twice a day.

In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 150-300 mg, once a day, and a polyadenosine diphosphate ribose polymerase inhibitor is administered at a dose of 80-200 mg, once a day. Twice a day, 12 hours apart.

。In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 150-300 mg once a day, and the compound of formula II or a pharmaceutically acceptable salt thereof is administered at a dose of 80-200 mg once a day. Twice, 12 hours apart,

.

Further, in an optional embodiment, the prostate cancer patients include those who have not previously received anti-prostate cancer treatment (including only past treatment), or those who have received prostate cancer treatment, and the prostate cancer treatment method is selected From one or more of the docetaxel or abiraterone treatment regimens.

In some embodiments, the castration treatment regimen includes surgery or medical castration treatment, with or without first-generation AR antagonists (such as bicalutamide and flutamide).

In some embodiments, the docetaxel treatment regimen includes but is not limited to docetaxel, docetaxel in combination with prednisone, and the like.

In some embodiments, the abiraterone treatment regimen includes but is not limited to abiraterone, abiraterone in combination with prednisone, and the like.

In some embodiments, the target lesion diameter of the prostate cancer patient is relatively reduced by at least 30%, and there are no more than 2 new bone lesions.

In some embodiments, the target lesion diameter of the prostate cancer patient has a relative increase of at least 20% or one or more new lesions (only visceral or lymph nodes) appear, and/or ≥2 new bone lesions appear.

In some embodiments, the target lesion diameter of the prostate cancer patient is relatively increased by at most 20% or the target lesion diameter is relatively reduced by at most 30%, and there are no more than 2 new bone lesions.

Preferably, the prostate cancer patient in the present invention has failed treatment.

The present invention also provides a pharmaceutical composition of an AR inhibitor (such as a compound of formula I or a pharmaceutically acceptable salt thereof) and a polyadenosine ribose polymerase inhibitor, comprising optionally one or more pharmaceutical carriers, excipients Form agent and/or diluent. The pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, a pharmaceutical preparation of a polyadenosine diphosphate ribose polymerase inhibitor and a compound of formula I or a pharmaceutically acceptable salt thereof can be formulated as a tablet, capsule, pill, granule, solution, suspension, syrup , Injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays.

In addition, the pharmaceutical composition of the present invention can also be administered to patients or subjects in need of such treatment in any suitable way of administration, such as oral, parenteral, rectal, pulmonary or topical administration. When used for 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, etc. Suspension, syrup, etc. When made into oral preparations, the pharmaceutical preparations may also contain suitable fillers, binders, disintegrants, lubricants and the like.

The present invention also provides a method for 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 (such as the formula II Show the compound or its pharmaceutically acceptable salt).

In some embodiments, the target lesion diameter of the prostate cancer patient is relatively reduced by at least 30%, and there are no more than 2 new bone lesions.

In some embodiments, the target lesion diameter of the prostate cancer patient has a relative increase of at least 20% or one or more new lesions (only visceral or lymph nodes) appear, and/or ≥2 new bone lesions appear.

In some embodiments, the target lesion diameter of the prostate cancer patient is relatively increased by up to 20% or the reduced size of the target lesion is relatively reduced by at most 30%, and there are no more than 2 new osteophytes.

Preferably, the prostate cancer patient in the present invention has failed treatment.

The present invention also provides a method for reducing the adverse reactions caused by AR inhibitors (such as the compound of formula I instead of pharmaceutically acceptable salts) and polyadenosine ribose polymerase inhibitors, including an effective dose to the plasma of prostate cancer patients A pharmaceutically acceptable salt of the compound of formula I insulin and a polyadenosine ribose polymerase inhibitor (for example, the compound of formula II or a pharmaceutically acceptable salt).

In some embodiments, methods for reducing adverse reactions include: correcting an effective dose of AR inhibitors (such as the pharmaceutically acceptable salt of the compound of formula I) and polyadenosine diphosphate ribose polymerase inhibitors (such as the formula The compound shown in II or a pharmaceutically acceptable salt).

The present invention also provides a method for reducing the single dose of AR inhibitors (such as the compound of formula I instead of pharmaceutically acceptable salts), polyadenosine ribose polymerase inhibitors, including implanting effective The dosage of the compound of formula I insulin pharmaceutically acceptable salt and polyadenosine diphosphate adenosine ribose polymerase inhibitor (for example the compound of formula II or pharmaceutically acceptable salt).

In some embodiments, the method of reducing the dose of a single dose includes: synchronized to a prostate cancer patient's effective dose of AR inhibitor (such as a pharmaceutically acceptable salt of the compound of formula I) and polyadenosine diphosphate ribose polymerase inhibitor (Such as the compound represented by formula II or a pharmaceutically acceptable salt).

In some embodiments, the prostate cancer refers to a prostate adenocarcinoma confirmed by histological or cytological examination, without suggesting neuroendocrine or small cell characteristics, and the patient has failed previous abiraterone acetate treatment.

In some embodiments, the prostate cancer refers to a prostate adenocarcinoma confirmed by histological or cytological examination, which does not suggest neuroendocrine or small cell characteristics, and the patient has failed to docetaxel or is against docetaxel in the past. Those who cannot tolerate chemotherapy or are not suitable for docetaxel treatment at the time of screening.

In some embodiments, the prostate cancer refers to a prostate adenocarcinoma confirmed by histological or cytological examination, without suggesting neuroendocrine or small cell characteristics, and the patient has failed chemotherapy with docetaxel in the past or has been treated with docetaxel. Chemotherapy is intolerable or unsuitable for docetaxel treatment at the time of screening, and previous abiraterone acetate treatment has failed.

The present invention also provides an AR antagonist combined with a PARP inhibitor for the treatment of prostate cancer, wherein the prostate cancer patient has been treated with docetaxel and apatinib.

In some embodiments, 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).

。In some embodiments, the AR antagonist is a compound represented by Formula I or a pharmaceutically acceptable salt thereof,

.

In another aspect, the PARP inhibitor is selected from olaparib, Talazoparib, Veliparib, Rucaparib, CEP-8983 or BGB-290.

。Further, the PARP inhibitor is a compound represented by formula II or a pharmaceutically acceptable salt thereof,

.

The combination of the present invention has a synergistic effect.

In some embodiments, the target lesion diameter of the prostate cancer patient is relatively reduced by at least 30%, and there are no more than 2 new bone lesions.

In some embodiments, the target lesion diameter of the prostate cancer patient has a relative increase of at least 20% or one or more new lesions (only visceral or lymph nodes) appear, and/or ≥2 new bone lesions appear.

In some embodiments, the target lesion diameter of the prostate cancer patient is relatively increased by at most 20% or the target lesion diameter is relatively reduced by at most 30%, and there are no more than 2 new bone lesions.

Preferably, the prostate cancer patient in the present invention has failed treatment.

The present invention also provides a method for treating prostate cancer, the method comprising: administering an effective amount of AR antagonist and polyadenosine ribose polymerase inhibitor to a prostate cancer patient who has been treated with docetaxel and apatinib Agent.

In some embodiments, the target lesion diameter of the prostate cancer patient is relatively reduced by at least 30%, and there are no more than 2 new bone lesions.

In some embodiments, the target lesion diameter of the prostate cancer patient has a relative increase of at least 20% or one or more new lesions (only visceral or lymph nodes) appear, and/or ≥2 new bone lesions appear.

In some embodiments, the target lesion diameter of the prostate cancer patient is relatively increased by at most 20% or the target lesion diameter is relatively reduced by at most 30%, and there are no more than 2 new bone lesions.

Preferably, the prostate cancer patient in the present invention has failed treatment.

In some embodiments, 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).

。In some embodiments, the AR antagonist is a compound represented by Formula I or a pharmaceutically acceptable salt thereof,

.

In another aspect, the PARP inhibitor is selected from olaparib, Talazoparib, Veliparib, Rucaparib, CEP-8983 or BGB-290.

。Further, the PARP inhibitor is a compound represented by formula II or a pharmaceutically acceptable salt thereof,

.

The combination of the present invention has a synergistic effect.

If there is no explanation to the contrary, the terms in the present invention have the following meanings:

In the present invention, the so-called "combination" is a mode of administration, which means that at least one dose of AR antagonist and at least one dose of PARP inhibitor are administered within a certain period of time, wherein both drugs show pharmacological effects and produce pharmacological effects . The time limit 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 the PARP inhibitor are administered by the same route of administration or different routes of administration. The method of administration of the combination of the present invention is selected from simultaneous administration, independent formulation and co-administration, or independent formulation and sequential administration.

In the present invention, "the pharmaceutically acceptable salt of the compound of formula I" refers to the substance obtained by forming a salt of the compound of formula I with an acid; "the pharmaceutically acceptable salt of the compound of formula II" refers to the substance obtained by forming a salt of the compound of formula II with an acid .

The "effective amount" in the present invention includes an amount sufficient to improve or prevent the symptoms or conditions of a 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 method of administration and dosage, and the severity of side effects. The effective amount can be the maximum dose or dosing schedule that avoids significant side effects or toxic effects.

"Treatment failure" in the present invention refers to subjects with measurable prostate cancer lesions at baseline. According to the RECIST 1.1 curative effect evaluation standard, it is disease progression (progressive disease, PD), toxicity intolerance, or researcher's judgment Subjects cannot continue to be clinically benefited, or according to PCWG3, the prostate cancer evaluation standard, 2 or more new bone lesions are considered disease progression (PD).

The "toxicity intolerance" in the present invention refers to the inability to continue receiving treatment due to adverse reactions caused by drugs.

Progression-free survival (PFS): From the beginning of randomization to the date of first recording of the objective progression of prostate cancer or the time to death from any cause, whichever occurs first.

Overall survival (OS) refers to the date from a random date to the date of death from any cause. For subjects who were still alive at the last follow-up, their OS was counted as the limited data based on the last follow-up time. For subjects who are lost to follow-up, their OS is calculated based on the last confirmed survival time before loss to follow-up. The OS of restricted data is defined as from random date to restricted date.

Objective response rate (ORR): Defined as the best overall response (Best overall response, BOR), CR and PR subjects among the number of subjects who took the drug at least once in each treatment group. BOR is defined as the best remission index between the date of randomization and the date of objectively recorded progression or the date of subsequent anti-prostate cancer treatment (whichever occurs first). For subjects who have not recorded progression or follow-up anti-prostate cancer treatment , BOR will be determined based on all mitigation assessment results.

Duration of response (DoR): The time from the first PR or CR to the first PD or death.

Disease control rate (DCR): The proportion of subjects in CR, PR, and SD who took the drug at least once in each treatment group. DCR is the best index of remission from the date of randomization to the date of objectively recorded progression or the date of subsequent anti-prostate cancer treatment (whichever occurs first). For subjects who have not recorded progression or subsequent anti-prostate cancer treatment, the Determine DCR based on the results of all mitigation assessments.

According to the RECIST 1.1 standard, the efficacy evaluation criteria are divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).

Target lesion evaluation:

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

Partial remission (PR): The sum of the target lesion diameter is reduced by at least 30% from the baseline level.

Disease progression (PD): The minimum value of the total diameter of all target lesions measured during the entire experimental study is used as the reference, and the relative increase in diameter sum is at least 20% (if the baseline measurement value is the smallest, the baseline value is used as the reference); In addition, the absolute value of the diameter sum must be increased by at least 5 mm (the appearance of one or more new lesions is also regarded as disease progression).

Stable disease (SD): The degree of reduction of the target lesion does not reach the PR, and the degree of increase does not reach the PD level, which is between the two. The minimum sum of the diameters can be used as a reference during the study. The efficacy evaluation criteria are divided into PD and non-PD according to PCWG3. According to the results of the first bone scan (C4D1), the regulations are as follows:

1. When the C4D1 bone scan finds ≧2 new lesions compared with the baseline, it is judged as PD, and the research and treatment are continued, and the review will be performed 6 weeks later (C5D15). If the re-examination adds ≧2 new lesions compared with the C4D1 result (ie reaching the "2+2" standard), it is confirmed as PD; otherwise it is non-PD, and the subsequent bone scan results of these subjects still need to be compared with the C4D1 results , Add ≧2 new lesions before it can be judged as PD.

2. When the C4D1 bone scan finds more than 2 new lesions compared with the baseline, it is judged as non-PD, and there is no need to review it after 6 weeks. Comparing the bone scan results of these subjects with the C4D1 results, an increase of ≧2 new lesions was judged as PD, and vice versa.

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, which can be prepared according to the method in patent application WO2014036897.

Compound B: PARP inhibitor, compound of formula II 4-[[3-[[2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1 ,5-α]pyrazin-7-yl]carbonyl]-4-fluorophenyl]methyl-1(2H)-phthalazinone can be prepared according to the method in patent application WO2012019427A1.

The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

Example 1

Entry criteria:

The enrolled subjects were prostate adenocarcinoma confirmed by histological or cytological examinations, without suggesting neuroendocrine or small cell characteristics, and the patients had previously failed abiraterone acetate treatment, and had previously failed docetaxel chemotherapy or treated with docetaxel. Those who cannot tolerate chemotherapy or are not suitable for docetaxel treatment at the time of screening.

Dosing regimen:

Compound A: 240 mg orally, once a day; Compound B: 100 mg or 150 mg orally, twice a day, combined administration for 28 days as a cycle. After the subjects complete the combined continuous administration for 1 cycle, the DLT observation period (that is, the first administration of fluzoparib alone to the 28th day of the first cycle of combined administration, 33 days in total) safety assessment, after the safety is determined Can be incremented to enter the next dose group test. If the fluzoparil 150 mg BID dose group also passes the DLT safety assessment, the dose will not be increased.

Conclusion: Among the 9 subjects in imaging evaluation, 6 subjects showed stable disease, 3 subjects showed disease progression, and the disease control rate (DCR) was 66.7%.

Although the specific embodiments of the present invention are described above, those with ordinary knowledge in the technical field should understand that these are only examples, and various changes can be made to these embodiments without departing from the principle and essence of the present invention. Or modify. Therefore, the scope of protection of the present invention is limited by the scope of the attached patent application.

no

no

Claims (19)

Use of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with a polyadenosine diphosphate ribose polymerase inhibitor in the preparation of a medicine for treating prostate cancer,

. The use according to claim 1, wherein the poly-ADP-ribose polymerase inhibitor is selected from one or more of olaparib, Talazoparib, Veliparib, Rucaparib, CEP-8983 and BGB-290. The use according to claim 1, wherein the polyadenosine diphosphate ribose polymerase inhibitor is a compound of formula II or a pharmaceutically acceptable salt thereof,

. The use according to any one of claims 1-3, wherein the combination has a synergistic effect. The use according to any one of claims 1 to 4, wherein the prostate cancer patient has received prostate cancer treatment, and the prostate cancer treatment regimen is preferably one of docetaxel and apatinib treatment regimens Or multiple. The use according to claim 5, wherein the prostate cancer patient has failed treatment. The use according to any one of claims 1-6, wherein the administration dose of the adenosine polyphosphate ribose polymerase inhibitor is 1-400 mg, preferably 80 mg, 100 mg, 120 mg, 160 mg, 200 mg or 300 mg. The use according to claim 7, wherein the frequency of administration of the adenosine polyphosphate ribose polymerase inhibitor is twice a day with an interval of administration of 12 hours. The use according to any one of claims 1-8, wherein the administration dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 1-500 mg, preferably 150-300 mg. The use according to claim 9, wherein the frequency of administration of the compound of formula I or a pharmaceutically acceptable salt thereof is once a day. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, the adenosine polydiphosphate ribose polymerase inhibitor according to any one of claims 1-10, and one or more pharmaceutically acceptable Excipients, diluents or carriers,

. A method for treating prostate cancer, comprising: administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and an adenosine polyphosphate ribose polymerase inhibitor to a cancer patient,

. The method according to claim 12, wherein the prostate cancer patient has received prostate cancer treatment, and the prostate cancer treatment regimen is preferably one or more of docetaxel and apatinib treatment regimens. The method according to claim 12 or 13, wherein the prostate cancer patient has failed treatment. The use of an AR antagonist combined with a PARP inhibitor in a medicine for treating prostate cancer, wherein the prostate cancer patient has been treated with docetaxel or apatinib. The use according to claim 15, wherein the AR antagonist is selected from Flutamide, Nilutamide, Bicalutamide, Enzalutamide, Apalutamide, Darolutamide, Proxalutamide, TRC-253, ONC1-13B, EPI-001, APC-100 and TAS-3681 One or more of. The use according to claim 15, wherein the AR antagonist is a compound represented by formula I or a pharmaceutically acceptable salt thereof,

. The use according to any one of claims 15-17, wherein the PARP inhibitor is selected from one or more of olaparib, Talazoparib, Veliparib, Rucaparib, CEP-8983 and BGB-290. The use according to any one of claims 15-18, wherein the prostate cancer patient has failed treatment.