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Introduction Prostate cancer is one of the most common male malignancies in the world, with the sixth highest mortality rate.
In Asian countries, the incidence and mortality of prostate cancer are not optimistic
.
In 2020, the new cases and deaths of prostate cancer in Asia accounted for 26.
2% and 32.
1% of the global proportion, and the mortality/incidence ratio (MIR) was three times that of North America
.
In recent years, the incidence of prostate cancer in China has been increasing, and the incidence rate in urban areas has risen most significantly, from 5.
8/100,000 in 2004 to 8/100,000 in 2009 [1]
.
In China, only a small number of prostate cancer patients have localized lesions at the initial diagnosis, and most Chinese patients have advanced disease at the time of diagnosis
.
Therefore, how to choose a treatment plan and prolong the survival time of patients is a clinical challenge
.
The first-line treatment option for advanced prostate cancer—AR pathway-targeted drugs After a median of 12 months of endocrine therapy for advanced prostate cancer patients, almost all patients will progress to castration-resistant prostate cancer (CRPC) [2]
.
The androgen receptor (AR) pathway is one of the most significantly enriched genes in metastatic castration-resistant prostate cancer (mCRPC).
AR gene plays an important role in the occurrence and development of prostate cancer.
Expression of downstream genes that promote prostate cancer progression and metastasis
.
There are three common variants in the AR pathway: point mutations, splice variants, and amplification/overexpression
.
Common AR point mutation types are W742C, H875Y, T878A and L702H
.
Hara et al.
in 2003 cultured a human prostate cancer (LNCaP) cell line in an androgen-deprived environment with 1 μM bicalutamide to mimic a clinical setting, and the cell line restarted growth after nearly 6 weeks of culture [3]
.
In subsequent gene sequencing of AR, mutations in W741C and W741L were found, and in a model with this mutation, bicalutamide acts to increase tumor volume and increase plasma PSA levels
.
Point mutations have different effects on different new endocrine drugs.
Preclinical models show that the affinity of different AR receptor inhibitors when binding to T877A mutant AR is: enzalutamide > apalutamide > dalotamide
.
In the AR amplification/overexpression model, AR is sensitive to low levels of androgens after castration, which in turn contributes to disease progression
.
In AR-overexpressing cell lines, enzalutamide inhibited AR binding to DNA and PSA mRNA production compared to bicalutamide, whereas bicalutamide stimulated AR binding to DNA and PSA mRNA production
.
AR splice variant-7 (AR-V7) is a currently known AR splice variant that encodes a functional protein product detectable in clinical samples
.
In a prospective, open-label, multicenter, phase II study evaluating the efficacy of enzalutamide and the role of AR-V7, enzalutamide was included in 67 patients with mCRPC with visceral metastases.
At 3 months of amine treatment, the overall disease control rate was 67%
.
Domestic and foreign guidelines unanimously recommend the use of new endocrine drugs for the treatment of CRPC in the US National Cancer Network (NCCN) prostate cancer clinical practice guidelines [4], the American Urological Association (AUA) prostate cancer guidelines [5] and the European Association of Urology (EAU) prostate cancer The guideline [6] unanimously recommends new endocrine drugs such as enzalutamide, apalutamide or dalotamide for the treatment of CRPC
.
The "Guidelines for Diagnosis and Treatment of Prostate Cancer in Chinese Urology and Andrology Guidelines" for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) are as follows: for patients with high risk of metastasis (PSA-DT≤10 months) In nmCRPC patients, it is recommended to combine apalutamide, enzalutamide, or dalotamide in addition to androgen deprivation (ADT) therapy
.
The Chinese Society of Clinical Oncology (CSCO) guidelines for the diagnosis and treatment of prostate cancer [7] recommend the treatment of CRPC patients as follows: for nmCRPC patients with PSADT ≤ 10 months, apalutamide, dalotamide or enzalutamide are recommended for grade I Treatment (category 1A evidence), PSADT > 10 months, grade II recommends other second-line endocrine therapy (category 2A evidence); for mCRPC patients, grade I recommends ADT + abiraterone acetate + prednisone, ADT + docetaxel Cyclidine + prednisone, ADT + enzalutamide, or ADT + apalutamide as first-line therapy (category 1A); after failure of first-line chemotherapy, enzalutamide or abiraterone acetate can still be used as second-line therapy (category 1A) evidence)
.
Table 1 Efficacy and safety of enzalutamide and abiraterone in patients with CRPC in the treatment of metastatic castration-resistant prostate cancer In the PREVAIL study [8], the Japanese/Asian subgroup was basically the same as the overall population
.
The Japanese subgroup reduced the relative risk of radiographic progression or death by 70% and the East Asian subgroup by 62% (HR=0.
19, P<0.
001); the overall risk of death was reduced by 41% in both the Japanese and East Asian subgroups (HR=0.
83, P<0.
001).
P=0.
0008)
.
The Asian PREVAIL Phase III study [9] found that enzalutamide significantly reduced PSA progression in Asian patients with mCRPC without chemotherapy and prolonged imaging progression-free survival (rPFS).
Enzalutamide was used to treat Asian patients with mCRPC before chemotherapy for 5 years.
The median overall survival (OS) was 39 months
.
The COU-AA-302 study evaluated the benefit of abiraterone acetate in chemotherapy-naïve mCRPC patients
.
The results of the study showed that compared with placebo, abiraterone acetate significantly prolonged the median OS period of patients (53.
6 months vs 41.
8 months, HR=0.
61, P=0.
006) [10]
.
Thus, abiraterone acetate significantly improved overall survival in chemotherapy-naïve mCRPC patients
.
Enzalutamide Resistance Mechanisms and Countermeasures A study published in January 2021[11] summarizes new information on enzalutamide resistance mechanisms in CRPC patients, including androgen receptor-related signaling pathways, Lineage plasticity, cytokine dysregulation and gene polymorphism,
etc.
The study noted that the androgen receptor is highly expressed and transcriptionally active in castration-resistant prostate cancer despite treatment with enzalutamide in CRPC patients
.
The analysis found that the somatic androgen receptor enhancer located at the 650 kb centromere of the androgen receptor is frequently amplified in castration-resistant prostate cancer
.
Furthermore, under low androgen conditions, the insertion of additional copies into this region was sufficient to increase cell proliferation and reduce cell sensitivity to enzalutamide
.
Another study found that galectin-3, a member of the animal lectin family, works by increasing the expression of several androgen receptor target genes, such as kallikrein-related peptidase 3 (KLK3) and transmembrane protease serine 2 (TMPRSS2).
), will significantly inhibit the therapeutic effect of enzalutamide
.
Enhanced androgen receptor transcriptional activity and expression of androgen receptor-related genes can lead to resistance to enzalutamide
.
Based on the above studies, for patients with CRPC resistant to enzalutamide, new potential treatments can be selected, such as targeting the androgen receptor enhancer, BMI1 as a new therapeutic target,
etc.
Summary In summary, for patients with high-burden metastatic cancer and castration-resistant prostate cancer, new endocrine drugs can delay disease progression.
Among them, the most advantageous new endocrine drug is enzalutamide, which is hormone-free.
Related side effects, no hypokalemia-related risks
.
Enzalutamide is an effective treatment for advanced prostate cancer and CRPC, which is why domestic and international guidelines consistently recommend the use of enzalutamide for the treatment of CRPC
.
Expert Profile Hong Zhengdong Deputy Chief Physician Doctor of Medicine, Associate Professor, Master's Tutor
.
He is a candidate for the 100-person voyage project in Jiangxi Province, a candidate for the 215 Talent Project of Nanchang University, an outstanding Communist Party member of the Second Affiliated Hospital of Nanchang University, and a visiting scholar at the University of Nebraska Medical Center
.
Specializes in the minimally invasive treatment of urinary calculi, tumors and benign prostatic hyperplasia
.
He presided over 1 National Natural Science Foundation of China, 1 Jiangxi Provincial Natural Science Foundation, and 3 Jiangxi Provincial Departments and Projects
.
Published 8 papers in SCI journals as the first author or corresponding author, and 8 papers in domestic core journals
.
References: [1] Zheng Rongshou, Sun Kexin, Zhang Siwei, et al.
Analysis of the prevalence of malignant tumors in China in 2015 [J].
Chinese Journal of Oncology, 2019, 41(1): 19-28.
[2] Gao Xu, Sun Yinghao.
Advances in the treatment of non-metastatic castration-resistant prostate cancer[J].
Chinese Journal of Urology,2019,40(11):868-872.
[3] Hara T, Miyazaki J, Araki H, et al.
Novel mutation of androgen receptor: A possible mechanism of bicalutamide withdrawal syndrome [J].
Cancer Res, 2003,63 : 149-153.
[4] NCCN clinical practice guidelines in oncology: prostate cancer.
Version 1.
2022.
https:// /professionals/physician_gls/pdf/prostate.
pdf.
[5] Lowrance WT, Breau RH, Chou R, et al.
Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.
J Urol.
2021 Jan;205(1): 22-29.
[6] N.
Mottet, P.
Cornford, RCN van den Bergh, et al.
EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer.
LIMITED UPDATE 2021.
presented at the EAU Annual Congress Milan 2021.
[7] Organized by the Guidelines Working Committee of the Chinese Society of Clinical Oncology.
Chinese Society of Clinical Oncology (CSCO) Guidelines for the diagnosis and treatment of prostate cancer.
2021[M].
People's Health Publishing House.
2021.
8.
[8] Beer TM,Armstrong AJ, Rathkopf DE, et al.
N Engl J Med.
2014;371(5):424-433.
[9] https:// Ryan CJ, Smith MR, de Bono JS, et al.
Abiraterone in metastatic prostate cancer without previous chemotherapy.
N Engl J Med 2013;368:138-148.
[11] Wang Y, Chen J, Wu Z, et al.
Mechanisms of enzalutamide resistance in castration-resistant prostate cancer and therapeutic strategies to overcome it.
Br J Pharmacol.
2021 Jan;178(2):239-261.
doi: 10.
1111/bph.
15300.
Epub 2020 Dec 14.
Mechanisms of enzalutamide resistance in castration-resistant prostate cancer and therapeutic strategies to overcome it.
Br J Pharmacol.
2021 Jan;178(2):239-261.
doi: 10.
1111/bph.
15300.
Epub 2020 Dec 14.
Mechanisms of enzalutamide resistance in castration-resistant prostate cancer and therapeutic strategies to overcome it.
Br J Pharmacol.
2021 Jan;178(2):239-261.
doi: 10.
1111/bph.
15300.
Epub 2020 Dec 14.
In Asian countries, the incidence and mortality of prostate cancer are not optimistic
.
In 2020, the new cases and deaths of prostate cancer in Asia accounted for 26.
2% and 32.
1% of the global proportion, and the mortality/incidence ratio (MIR) was three times that of North America
.
In recent years, the incidence of prostate cancer in China has been increasing, and the incidence rate in urban areas has risen most significantly, from 5.
8/100,000 in 2004 to 8/100,000 in 2009 [1]
.
In China, only a small number of prostate cancer patients have localized lesions at the initial diagnosis, and most Chinese patients have advanced disease at the time of diagnosis
.
Therefore, how to choose a treatment plan and prolong the survival time of patients is a clinical challenge
.
The first-line treatment option for advanced prostate cancer—AR pathway-targeted drugs After a median of 12 months of endocrine therapy for advanced prostate cancer patients, almost all patients will progress to castration-resistant prostate cancer (CRPC) [2]
.
The androgen receptor (AR) pathway is one of the most significantly enriched genes in metastatic castration-resistant prostate cancer (mCRPC).
AR gene plays an important role in the occurrence and development of prostate cancer.
Expression of downstream genes that promote prostate cancer progression and metastasis
.
There are three common variants in the AR pathway: point mutations, splice variants, and amplification/overexpression
.
Common AR point mutation types are W742C, H875Y, T878A and L702H
.
Hara et al.
in 2003 cultured a human prostate cancer (LNCaP) cell line in an androgen-deprived environment with 1 μM bicalutamide to mimic a clinical setting, and the cell line restarted growth after nearly 6 weeks of culture [3]
.
In subsequent gene sequencing of AR, mutations in W741C and W741L were found, and in a model with this mutation, bicalutamide acts to increase tumor volume and increase plasma PSA levels
.
Point mutations have different effects on different new endocrine drugs.
Preclinical models show that the affinity of different AR receptor inhibitors when binding to T877A mutant AR is: enzalutamide > apalutamide > dalotamide
.
In the AR amplification/overexpression model, AR is sensitive to low levels of androgens after castration, which in turn contributes to disease progression
.
In AR-overexpressing cell lines, enzalutamide inhibited AR binding to DNA and PSA mRNA production compared to bicalutamide, whereas bicalutamide stimulated AR binding to DNA and PSA mRNA production
.
AR splice variant-7 (AR-V7) is a currently known AR splice variant that encodes a functional protein product detectable in clinical samples
.
In a prospective, open-label, multicenter, phase II study evaluating the efficacy of enzalutamide and the role of AR-V7, enzalutamide was included in 67 patients with mCRPC with visceral metastases.
At 3 months of amine treatment, the overall disease control rate was 67%
.
Domestic and foreign guidelines unanimously recommend the use of new endocrine drugs for the treatment of CRPC in the US National Cancer Network (NCCN) prostate cancer clinical practice guidelines [4], the American Urological Association (AUA) prostate cancer guidelines [5] and the European Association of Urology (EAU) prostate cancer The guideline [6] unanimously recommends new endocrine drugs such as enzalutamide, apalutamide or dalotamide for the treatment of CRPC
.
The "Guidelines for Diagnosis and Treatment of Prostate Cancer in Chinese Urology and Andrology Guidelines" for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) are as follows: for patients with high risk of metastasis (PSA-DT≤10 months) In nmCRPC patients, it is recommended to combine apalutamide, enzalutamide, or dalotamide in addition to androgen deprivation (ADT) therapy
.
The Chinese Society of Clinical Oncology (CSCO) guidelines for the diagnosis and treatment of prostate cancer [7] recommend the treatment of CRPC patients as follows: for nmCRPC patients with PSADT ≤ 10 months, apalutamide, dalotamide or enzalutamide are recommended for grade I Treatment (category 1A evidence), PSADT > 10 months, grade II recommends other second-line endocrine therapy (category 2A evidence); for mCRPC patients, grade I recommends ADT + abiraterone acetate + prednisone, ADT + docetaxel Cyclidine + prednisone, ADT + enzalutamide, or ADT + apalutamide as first-line therapy (category 1A); after failure of first-line chemotherapy, enzalutamide or abiraterone acetate can still be used as second-line therapy (category 1A) evidence)
.
Table 1 Efficacy and safety of enzalutamide and abiraterone in patients with CRPC in the treatment of metastatic castration-resistant prostate cancer In the PREVAIL study [8], the Japanese/Asian subgroup was basically the same as the overall population
.
The Japanese subgroup reduced the relative risk of radiographic progression or death by 70% and the East Asian subgroup by 62% (HR=0.
19, P<0.
001); the overall risk of death was reduced by 41% in both the Japanese and East Asian subgroups (HR=0.
83, P<0.
001).
P=0.
0008)
.
The Asian PREVAIL Phase III study [9] found that enzalutamide significantly reduced PSA progression in Asian patients with mCRPC without chemotherapy and prolonged imaging progression-free survival (rPFS).
Enzalutamide was used to treat Asian patients with mCRPC before chemotherapy for 5 years.
The median overall survival (OS) was 39 months
.
The COU-AA-302 study evaluated the benefit of abiraterone acetate in chemotherapy-naïve mCRPC patients
.
The results of the study showed that compared with placebo, abiraterone acetate significantly prolonged the median OS period of patients (53.
6 months vs 41.
8 months, HR=0.
61, P=0.
006) [10]
.
Thus, abiraterone acetate significantly improved overall survival in chemotherapy-naïve mCRPC patients
.
Enzalutamide Resistance Mechanisms and Countermeasures A study published in January 2021[11] summarizes new information on enzalutamide resistance mechanisms in CRPC patients, including androgen receptor-related signaling pathways, Lineage plasticity, cytokine dysregulation and gene polymorphism,
etc.
The study noted that the androgen receptor is highly expressed and transcriptionally active in castration-resistant prostate cancer despite treatment with enzalutamide in CRPC patients
.
The analysis found that the somatic androgen receptor enhancer located at the 650 kb centromere of the androgen receptor is frequently amplified in castration-resistant prostate cancer
.
Furthermore, under low androgen conditions, the insertion of additional copies into this region was sufficient to increase cell proliferation and reduce cell sensitivity to enzalutamide
.
Another study found that galectin-3, a member of the animal lectin family, works by increasing the expression of several androgen receptor target genes, such as kallikrein-related peptidase 3 (KLK3) and transmembrane protease serine 2 (TMPRSS2).
), will significantly inhibit the therapeutic effect of enzalutamide
.
Enhanced androgen receptor transcriptional activity and expression of androgen receptor-related genes can lead to resistance to enzalutamide
.
Based on the above studies, for patients with CRPC resistant to enzalutamide, new potential treatments can be selected, such as targeting the androgen receptor enhancer, BMI1 as a new therapeutic target,
etc.
Summary In summary, for patients with high-burden metastatic cancer and castration-resistant prostate cancer, new endocrine drugs can delay disease progression.
Among them, the most advantageous new endocrine drug is enzalutamide, which is hormone-free.
Related side effects, no hypokalemia-related risks
.
Enzalutamide is an effective treatment for advanced prostate cancer and CRPC, which is why domestic and international guidelines consistently recommend the use of enzalutamide for the treatment of CRPC
.
Expert Profile Hong Zhengdong Deputy Chief Physician Doctor of Medicine, Associate Professor, Master's Tutor
.
He is a candidate for the 100-person voyage project in Jiangxi Province, a candidate for the 215 Talent Project of Nanchang University, an outstanding Communist Party member of the Second Affiliated Hospital of Nanchang University, and a visiting scholar at the University of Nebraska Medical Center
.
Specializes in the minimally invasive treatment of urinary calculi, tumors and benign prostatic hyperplasia
.
He presided over 1 National Natural Science Foundation of China, 1 Jiangxi Provincial Natural Science Foundation, and 3 Jiangxi Provincial Departments and Projects
.
Published 8 papers in SCI journals as the first author or corresponding author, and 8 papers in domestic core journals
.
References: [1] Zheng Rongshou, Sun Kexin, Zhang Siwei, et al.
Analysis of the prevalence of malignant tumors in China in 2015 [J].
Chinese Journal of Oncology, 2019, 41(1): 19-28.
[2] Gao Xu, Sun Yinghao.
Advances in the treatment of non-metastatic castration-resistant prostate cancer[J].
Chinese Journal of Urology,2019,40(11):868-872.
[3] Hara T, Miyazaki J, Araki H, et al.
Novel mutation of androgen receptor: A possible mechanism of bicalutamide withdrawal syndrome [J].
Cancer Res, 2003,63 : 149-153.
[4] NCCN clinical practice guidelines in oncology: prostate cancer.
Version 1.
2022.
https:// /professionals/physician_gls/pdf/prostate.
pdf.
[5] Lowrance WT, Breau RH, Chou R, et al.
Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.
J Urol.
2021 Jan;205(1): 22-29.
[6] N.
Mottet, P.
Cornford, RCN van den Bergh, et al.
EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer.
LIMITED UPDATE 2021.
presented at the EAU Annual Congress Milan 2021.
[7] Organized by the Guidelines Working Committee of the Chinese Society of Clinical Oncology.
Chinese Society of Clinical Oncology (CSCO) Guidelines for the diagnosis and treatment of prostate cancer.
2021[M].
People's Health Publishing House.
2021.
8.
[8] Beer TM,Armstrong AJ, Rathkopf DE, et al.
N Engl J Med.
2014;371(5):424-433.
[9] https:// Ryan CJ, Smith MR, de Bono JS, et al.
Abiraterone in metastatic prostate cancer without previous chemotherapy.
N Engl J Med 2013;368:138-148.
[11] Wang Y, Chen J, Wu Z, et al.
Mechanisms of enzalutamide resistance in castration-resistant prostate cancer and therapeutic strategies to overcome it.
Br J Pharmacol.
2021 Jan;178(2):239-261.
doi: 10.
1111/bph.
15300.
Epub 2020 Dec 14.
Mechanisms of enzalutamide resistance in castration-resistant prostate cancer and therapeutic strategies to overcome it.
Br J Pharmacol.
2021 Jan;178(2):239-261.
doi: 10.
1111/bph.
15300.
Epub 2020 Dec 14.
Mechanisms of enzalutamide resistance in castration-resistant prostate cancer and therapeutic strategies to overcome it.
Br J Pharmacol.
2021 Jan;178(2):239-261.
doi: 10.
1111/bph.
15300.
Epub 2020 Dec 14.
