Method for treating prostate cancer

Abstract

The present disclosure relates to a method for treating prostate cancer. Specifically, the present disclosure relates to use of a compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating prostate cancer caused by at least one androgen receptor mutation.

Description

Treatment methods for prostate cancer Technical Field

[0001] This application relates to the pharmaceutical field and includes the use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating prostate cancer. Background Technology

[0002] The androgen receptor (AR) is a ligand-dependent trans-transcriptional regulatory protein belonging to the nuclear receptor superfamily and primarily located in the cell nucleus. Unligand-bound ARs bind to heat shock proteins (HSPs); upon ligand binding, ARs undergo a conformational change, dissociating from HSPs and exhibiting increased affinity for DNA (AR activation). Activated ARs, in dimer form, bind to specific DNA sequences in the cell nucleus—androgen response elements (AREs)—and interact with other transcription factors, thereby regulating the expression of related genes and producing biological effects. Studies have shown that abnormalities in the AR signaling pathway are closely related to the occurrence and development of diseases such as prostate cancer, benign prostatic hyperplasia, Kennedy's disease, male infertility, androgen insensitivity, and male breast cancer.

[0003] Prostate cancer is one of the most common malignant tumors. Statistics show that in 2018, there were nearly 1.3 million new cases and 359,000 deaths worldwide, accounting for 13.5% of male malignant tumor incidence, ranking second; and 6.7% of male malignant tumor mortality, ranking fifth. Currently, the incidence of prostate cancer is increasing year by year, and it is one of the major causes of death among male cancer patients. Several AR antagonists have been approved for marketing (such as the first-generation AR inhibitor bicalutamide, and second-generation AR inhibitors enzalutamide and revertulamide), and have been successfully applied to the treatment of hormone-sensitive and castration-resistant prostate cancer, becoming a major treatment method for prostate cancer. Although the development and application of new AR-targeted drugs have significantly improved the prognosis of prostate cancer patients, especially providing mCRPC patients with other treatment options besides chemotherapy, patients still develop resistance to new AR-targeted drugs, with AR mutation being a major resistance mechanism. Summary of the Invention

[0004] This disclosure provides a compound of Formula I or a pharmaceutically acceptable salt thereof for the treatment of at least one androgen receptor-mutated prostate cancer.

[0005] In some embodiments, this disclosure provides a method for treating at least one androgen receptor-mutated prostate cancer, comprising administering a patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the at least one androgen receptor mutation is selected from one or a combination of L702H, H875Y, T878A, W742L, F877L or M896V.

[0007] In some embodiments, the at least one androgen receptor mutation is selected from L702H.

[0008] The phrase “at least one androgen receptor mutation selected from L702H” in this disclosure includes only L702H mutation, or a combination of L702H mutation and wild type, or a combination of L702H mutation and other mutations.

[0009] In some implementations, the androgen receptor mutation status is determined by ctDNA sequencing and CTC-PCR analysis.

[0010] In some implementations, the androgen receptor mutation status is determined in a blood sample derived from the individual.

[0011] In some implementations, the androgen receptor mutation status is determined in a solid biopsy derived from an individual tumor.

[0012] In some embodiments, the prostate cancer described in this disclosure is selected from prostate cancer that has undergone medical castration or surgical castration.

[0013] In some embodiments, the prostate cancer described in this disclosure is selected from prostate cancer that has undergone continuous luteinizing hormone-releasing hormone analog (LHRHA) treatment (medical castration), or has previously undergone bilateral orchiectomy (surgical castration), or has not undergone bilateral orchiectomy and has maintained effective LHRHA treatment.

[0014] In some embodiments, the prostate cancer described in this disclosure is selected from metastatic prostate cancer.

[0015] In some embodiments, the prostate cancer described in this disclosure is selected from hormone-sensitive prostate cancer, castration-sensitive prostate cancer, or castration-resistant prostate cancer.

[0016] In some embodiments, the prostate cancer described in this disclosure is selected from metastatic castration-sensitive prostate cancer or metastatic castration-resistant prostate cancer.

[0017] In some embodiments, the metastatic castration-resistant prostate cancer described in this disclosure is metastatic castration-resistant prostate cancer that has not been previously treated with novel endocrine drugs.

[0018] In some embodiments, the metastatic castration-resistant prostate cancer described in this disclosure is metastatic castration-resistant prostate cancer that has failed prior treatment with at least one novel endocrine therapy.

[0019] In some embodiments, the novel endocrine drug described in this disclosure is selected from, for example, abiraterone, enzalutamide, apatamide, revelutamide, and dalotamide.

[0020] Treatment failure as described in this disclosure refers to disease progression occurring during the treatment process.

[0021] In some embodiments, the metastatic castration-resistant prostate cancer described in this disclosure is metastatic castration-resistant prostate cancer that has progressed during or within 6 months of prior use of at least one chemotherapy drug, or that is unsuitable for or intolerant of chemotherapy drugs.

[0022] In some embodiments, the chemotherapeutic agent described in this disclosure is selected from paclitaxel-based chemotherapeutic agents, preferably from docetaxel.

[0023] Disease progression as described in this disclosure is defined as the occurrence of one or more of the following three conditions while the subject is receiving castration treatment:

[0024] ① PSA progression, including progression from HSPC to CRPC (defined as PSA level >1 ng / mL at castration level, with an interval of at least 1 week, and two consecutive PSA levels >50% higher than baseline), and PSA progression during CRPC treatment (according to PCWG3 criteria); for patients treated with flutamide or bicalutamide, PSA progression must also occur after discontinuation of the drug (≥4 weeks and ≥6 weeks, respectively);

[0025] ② Disease progression as defined in RECIST 1.1;

[0026] ③ Progression of bone disease as defined by the PCWG3 standard, i.e., the discovery of ≥2 new lesions on bone scan.

[0027] In some embodiments, the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof described in this disclosure is 10 mg to 1000 mg, preferably 20 mg to 500 mg, and more preferably 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, 2... 60mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430 mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, 590mg, 600mg.

[0028] In some embodiments, the dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof described in this disclosure is 30 mg, 90 mg, 180 mg, 360 mg, 540 mg, or 720 mg.

[0029] In some embodiments, the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof described in this disclosure is selected from 10 mg to 300 mg; preferably 10 mg to 200 mg; more preferably 10 mg to 100 mg; and even more preferably 10 mg to 50 mg.

[0030] In some embodiments, the unit dose of the compound of Formula I or a pharmaceutically acceptable salt thereof described in this disclosure is 10 mg to 300 mg; preferably 10 mg to 200 mg; more preferably 10 mg to 100 mg; and even more preferably 10 mg to 50 mg.

[0031] In some embodiments, the unit dose of the compound of Formula I or its pharmaceutically acceptable salt thereof is 10 mg to 1000 mg, preferably 20 mg to 500 mg, and more preferably 15 mg, 30 mg, 60 mg, 90 mg, 180 mg, 360 mg, 540 mg, or 720 mg.

[0032] In some embodiments, the dosage or unit dose described in this disclosure is expressed by weight of a compound of formula I.

[0033] In some embodiments, the frequency of administration of the compound of Formula I or a pharmaceutically acceptable salt thereof described in this disclosure is selected from three times daily, twice daily, once daily, once every two days, once every three days, once every four days, once every five days, or once weekly.

[0034] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof described in this disclosure is administered to a human being.

[0035] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof described in this disclosure 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 pharmaceutical carriers, excipients, and diluents. Detailed Implementation

[0036] Example 1: Determination of the degradation activity of compound I against AR mutants

[0037] The in vitro cell experiments described below can determine the degradation activity of the test compound on AR mutants induced to be expressed in 293T cells. This activity can be measured using DC... 50 The values ​​are expressed as follows. The AR mutant genes (L702H, H875Y / T878A, H875Y, T878A, W742L, F877L and M896V) were transformed into 293T cells using the Tet-One induction expression system and stable transgenic cells were obtained by selection with the antibiotic puromycin.

[0038] On the first day of the experiment, the cells were seeded at a density of 10,000 cells / well in PDL-coated 96-well plates using fetal bovine serum (Shanghai Bosheng Biotechnology Co., Ltd., S-FBS-AU-045) containing 5% activated charcoal and DMEM / high glucose medium (HyClone, SH30243.01) with 1 μg / mL puromycin. BioCoat TMIn the cell culture plates (356692), 180 μL of cell suspension was added to each well and incubated at 37°C with 5% CO2 for 24 hours. On the second day, 20 μL of Doxycycline was added to each well to induce AR mutant expression, with a final concentration of 50 ng / mL. On the third day, 22 μL of serially diluted test compounds prepared in culture medium was added to each well. The final concentrations of the compounds were determined by a 6-fold serial dilution starting from 2.5 μM. Only the wells containing Doxycycline served as negative controls, and the concentration of DMSO in each well was 0.5%. The plates were then incubated at 37°C with 5% CO2 for 24 hours. On day four, remove the PDL-coated 96-well cell culture plates, discard the cell supernatant, and wash the cells once with 300 μL of ice-cold PBS in each well. Then, add 100 μL of 1× lysis buffer (Cell Signaling Technology, #9803S) diluted with ddH2O and containing 1 mM PMSF to each well. Vortex for 1 minute using a micro-oscillator, then place the plate on ice for lysis for 15–20 minutes. After mixing by pipetting, centrifuge at 4000 rpm and 4°C for 10 minutes. Detect AR protein levels using an AR ELISA kit (Cell Signaling Technology, #12850). Add 80 μL of sample diluent and 20 μL of the centrifuged cell lysis buffer or blank lysis buffer to each well of the 96-well plate, seal the plate, vortex to mix, and incubate at 37°C for 2 hours. Discard the liquid in each well. Add 300 μL of washing buffer to each well and wash five times. Then add 100 μL of the detection antibody working solution. Seal the plate and incubate at 37°C for 1 hour. Discard the liquid in each well. Add 300 μL of washing buffer to each well and wash five times. Then add 100 μL of enzyme conjugate working solution. Seal the plate and incubate at 37°C for 30 minutes. Discard the liquid in each well. Add 300 μL of washing buffer to each well and wash five times. Then add 100 μL of chromogenic solution. Seal the plate and incubate at room temperature in the dark for 5 minutes. Add 100 μL of stop solution to each well. After mixing, immediately place the plate on a microplate reader (BMG Labtech, PHERAstar FS) to read the OD450 and OD540 values. Subtract the corresponding OD540 absorbance value from the OD450 absorbance values ​​of all wells to obtain the corrected OD450 absorbance value (OD450-correction). The AR protein degradation rate for each compound concentration was calculated using the following formula, where the maximum value represents the maximum degradation rate of the compound. GraphPad Prism was used to perform curve fitting based on the logarithmic concentration and degradation rate of the compounds, and DC was calculated. 50 value.

[0039] Degradation rate % = (OD450 - correction) 阴性对照 -OD450-correction 化合物) / (OD450-correction 阴 性对照 -OD450-correction 裂解液对照 )×100%

[0040] The bioactivity of compound I was obtained from the above analysis, and the calculated DC was... 50 The values ​​are shown in the table below:

[0041] Table 1 shows the degradation activity of compound I on intracellular AR mutants.

[0042] Conclusion: Compound I exhibits significant degradation activity against intracellular AR mutants L702H, H875Y / T878A, H875Y, T878A, W742L, F877L, and M896V.

[0043] Example 2: Clinical study of the compound shown in Formula I in subjects with advanced metastatic castration-resistant prostate cancer.

[0044] Patients enrolled were those with metastatic castration-resistant prostate cancer (mCRPC) who had progressed after receiving ≥1 novel hormonal therapy (such as abiraterone or enzalutamide) and ≥1 taxane chemotherapy (unless they refused or were unsuitable for chemotherapy).

[0045] During the dose expansion and indication expansion phase, patients were given oral compound I (manufactured and supplied by Jiangsu Hengrui Medicine Co., Ltd.) at doses of 180–540 mg QD and 240 mg BID, 300 mg BID.

[0046] As of March 10, 2025, a total of 98 patients were enrolled for at least one cycle (28 days), of which 49 carried AR-LBD mutations, 33 were AR-LBD wild-type (WT; excluding AR amplification or AR-V7 positivity), and 16 were AR-LBD WT but had AR amplification or AR-V7 positivity.

[0047] The data for extended doses, categorized by AR-LBD status, are shown in the table.

[0048] Table 2. Treatment Results

[0049] Data are presented as number of cases (percentage, 95% confidence interval) or median (95% confidence interval). *Note: AR-LBD WT excludes patients with AR amplification or AR-V7 positivity.

[0050] As of May 21, 2025, a total of 132 patients were enrolled for at least one cycle (28 days), of which 59 carried AR-LBD mutations, 58 were AR-LBD wild-type (WT; excluding AR amplification or AR-V7 positivity), and 15 were AR-LBD WT but had AR amplification or AR-V7 positivity.

[0051] The data for extended doses, categorized by AR-LBD status, are shown in the table.

[0052] Table 3. Treatment Results

[0053] Data are presented as number of cases (percentage, 95% confidence interval) or median (95% confidence interval). *Note: AR-LBD WT excludes patients with AR amplification or AR-V7 positivity.

[0054] As of December 12, 2025, a total of 156 patients were enrolled, of whom 77 carried AR-LBD mutations and 79 carried AR-LBD wild-type (WT), including patients with AR amplification or AR-V7 positivity.

[0055] The data for extended doses, categorized by AR-LBD status, are shown in the table.

[0056] Table 4. Treatment Results

[0057] Data are expressed as n (%) or median (95% confidence interval). *The subjects were patients who underwent at least one post-baseline PSA assessment, or patients who discontinued treatment due to death / clinical progression and did not undergo a post-baseline PSA assessment; N were 10, 13, 31, 22, 31, and 25, respectively. The evaluation subjects were the entire analysis set; N was 10, 14, 32, 23, 33, and 25, respectively. # The evaluation subjects were patients with baseline target lesions; N was 3, 4, 10, 5, 7, and 9, respectively.

Claims

1. Use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating at least one androgen receptor-mutated prostate cancer.

2. The use according to claim 1, wherein the at least one androgen receptor mutation is selected from one or a combination of L702H, H875Y, T878A, W742L, F877L or M896V.

3. The use according to any one of claims 1-2, wherein the at least one androgen receptor mutation is selected from L702H.

4. The use according to any one of claims 1-3, wherein the prostate cancer is selected from prostate cancer treated by medical castration or surgical castration.

5. The use according to any one of claims 1-4, wherein the prostate cancer is selected from metastatic prostate cancer.

6. The use according to any one of claims 1-5, wherein the prostate cancer is selected from hormone-sensitive prostate cancer, castration-sensitive prostate cancer, or castration-resistant prostate cancer.

7. The use according to any one of claims 1-6, wherein the metastatic castration-resistant prostate cancer is prostate cancer that has not previously received novel endocrine therapy.

8. The use according to any one of claims 1-6, wherein the metastatic castration-resistant prostate cancer is metastatic castration-resistant prostate cancer that has failed prior treatment with at least one novel endocrine drug.

9. The use according to claim 8, wherein the metastatic castration-resistant prostate cancer is metastatic castration-resistant prostate cancer that has been previously treated with at least one chemotherapy drug and has progressed during or within 6 months after chemotherapy, or is unsuitable for or intolerant of chemotherapy drugs.

10. The use according to any one of claims 1-9, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is applied to a human being.

11. The use according to any one of claims 1-10, wherein the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is 10 mg to 1000 mg.

12. The use according to any one of claims 1-10, wherein the unit dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 10 mg to 500 mg.

Images