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Preface Prostate cancer is one of the most common male malignancies in the world, and its mortality rate ranks sixth.
In Asian countries, the incidence and mortality of prostate cancer are not optimistic
.
In 2020, new cases and deaths of prostate cancer in Asia accounted for 26.
2% and 32.
1% of the global total, and the mortality/morbidity ratio (MIR) was three times that of North America
.
In recent years, the incidence of prostate cancer in China has shown an increasing trend, with the most significant increase in the incidence in urban areas, from 5.
8 per 100,000 in 2004 to 8 per 100,000 in 2009 [1]
.
In China, there are only a small number of prostate cancer patients with localized lesions at the first diagnosis, and most Chinese patients have advanced to the middle and advanced stages of the disease at the time of diagnosis
.
Therefore, how to choose a treatment plan and prolong the survival time of patients has always been a difficult problem in clinical practice
.
The first-line treatment option for advanced prostate cancer-AR pathway targeted drugs.
After a median of 12 months of endocrine therapy in patients with advanced prostate cancer, 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).
The AR gene plays an important role in the occurrence and development of prostate cancer.
It can regulate The expression of downstream genes promotes the progression and metastasis of prostate cancer
.
There are three common variants in the AR pathway: point mutations, splice variants, and amplification/overexpression
.
Common types of AR point mutations are W742C, H875Y, T878A and L702H
.
Hara et al.
cultured the human prostate cancer (LNCaP) cell line in an androgen deprivation environment in 2003, and simulated the clinical environment with 1 μM bicalutamide.
The cell line resumed growth after nearly 6 weeks of culture [3]
.
In subsequent gene sequencing of AR, mutations of W741C and W741L were found.
In models with this mutation, bicalutamide acts to increase tumor volume and increase the level of PSA in plasma
.
Point mutations have different effects on different new endocrine drugs.
Preclinical models indicate that the affinity of different AR receptor inhibitors when binding to T877A mutant AR is in the order of enzalutamide> apatamide> dalotamide
.
In the AR amplification/overexpression model, AR is sensitive to low levels of androgens after castration, which can lead to disease progression
.
In cell lines overexpressing AR, in contrast to bicalutamide, enzalutamide inhibits the binding of AR to DNA and the production of PSA mRNA, while bicalutamide stimulates the binding of AR to DNA and the production of PSA mRNA
.
AR splice variant-7 (AR-V7) is a currently known AR splice variant that can encode a functional protein product that can be detected in clinical samples
.
In a prospective, open-label, multi-center, phase II study evaluating the efficacy of enzalutamide and the effects of AR-V7, 67 mCRPC patients with visceral metastases were treated with enzalutamide.
The results showed that enzalut At 3 months of amine treatment, the overall disease control rate was 67%
.
Domestic and international guidelines unanimously recommend the use of new endocrine drugs for the treatment of CRPC.
National Cancer Network (NCCN) prostate cancer clinical practice guidelines [4], American Urological Association (AUA) prostate cancer guidelines [5] and European Association of Urology (EAU) prostate cancer The guidelines [6] unanimously recommend new endocrine drugs such as enzalutamide, apatamide or dalotamide for the treatment of CRPC
.
The "Guidelines for the Diagnosis and Treatment of Chinese Urology and Andrology Diseases of Prostate Cancer" for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) are: For those with a higher risk of metastasis (PSA-DT≤10 months) For patients with nmCRPC, it is recommended to combine apatamide, enzalutamide or dalotamide on the basis of androgen deprivation (ADT) treatment
.
The Chinese Society of Clinical Oncology (CSCO) Guidelines for Diagnosis and Treatment of Prostate Cancer[7] The recommendations for the treatment of CRPC patients are: For nmCRPC patients with PSADT ≤ 10 months, the level I recommends the use of apatamide, dalotamide or enzalutamide Treatment (1A evidence), PSADT> 10 months, level II recommends other second-line endocrine therapy (2A evidence); for mCRPC patients, level I recommends the use of ADT + abiraterone acetate + prednisone, ADT + docetal As a first-line treatment plan, ADT+prednisone, ADT+enzalutamide or ADT+apatamide (class 1A evidence); after the failure of first-line chemotherapy, enzalutamide or abiraterone acetate can still be used for second-line treatment (class 1A) Evidence)
.
Table 1 The efficacy and safety of enzalutamide and abiraterone for CRPC patients in the treatment of metastatic castration-resistant prostate cancer In the PREVALIL study [8], the efficacy of the Japanese/Asian subgroup is basically the same as that of the overall population
.
The Japanese subgroup reduced the relative risk of imaging progression or death by 70%, and the East Asian subgroup reduced 62% (HR=0.
19, P＜0.
001); the overall risk of death in both the Japanese subgroup and the East Asian subgroup was reduced by 41% (HR=0.
83, P=0.
0008)
.
The Asian PREVAIL Phase III study [9] found that enzalutamide significantly reduced the PSA progression of Asian mCRPC patients without chemotherapy and prolonged the imaging progression-free survival (rPFS).
Enzalutamide was used to treat Asian patients with mCRPC before chemotherapy for 5 years.
The median overall survival (OS) can reach 39 months
.
The COU-AA-302 study evaluated the benefit of abiraterone acetate for mCRPC patients who had not received chemotherapy
.
The results of the study showed that compared with placebo, abiraterone acetate significantly prolonged the median OS phase of patients (53.
6 months vs 41.
8 months, HR=0.
61, P=0.
006) [10]
.
Therefore, abiraterone acetate can significantly improve the overall survival of patients with mCRPC without chemotherapy
.
Enzalutamide resistance mechanism and countermeasures A study published in January 2021 [11] summarized new information about the resistance mechanism of enzalutamide in CRPC patients, including androgen receptor-related signaling pathways, lineage plasticity, and disorders of cytokine gene polymorphism
.
Studies have pointed out that although CRPC patients are treated with enzalutamide, androgen receptors are still highly expressed and transcriptionally active in castration-resistant prostate cancer
.
The analysis found that the soma-derived androgen receptor enhancer located at the 650 kb centromere of the androgen receptor is frequently amplified in castration-resistant prostate cancer
.
In addition, under low androgenic conditions, extra copies inserted into this region are sufficient to increase cell proliferation and reduce the sensitivity of cells to enzalutamide
.
Another study found that galectin-3, a member of the animal lectin family, increases 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
.
The enhancement of androgen receptor transcriptional activity and the expression of androgen receptor related genes can lead to resistance to enzalutamide
.
Based on the above research, for patients with enzalutamide-resistant CRPC, new potential treatments can be selected, such as targeting the androgen receptor enhancer and BMI1 as a new therapeutic target
.
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 risk related to low potassium
.
Enzalutamide is an effective treatment for advanced prostate cancer and CRPC, which is why domestic and foreign guidelines unanimously recommend the use of enzalutamide to treat CRPC
.
Expert profile Hong Zhengdong Deputy Chief Physician Doctor of Medicine, associate professor, master tutor
.
Selected from the Jiangxi Province Hundred Talents Voyage Project, selected from the 215 Talent Project of Nanchang University, outstanding Communist Party member of the Second Affiliated Hospital of Nanchang University, and visiting scholar at the University of Nebraska Medical Center in the United States
.
Specializes in minimally invasive treatment of urinary stones, tumors and benign prostatic hyperplasia
.
Presided over 1 National Natural Science Foundation of China, 1 Natural Science Foundation of Jiangxi Province, Jiangxi Provincial Department and 3 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.
Progress 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] Chinese Society of Clinical Oncology Guidelines Working Committee Organization and Compilation.
Chinese Society of Clinical Oncology (CSCO) Guidelines for Diagnosis and Treatment of Prostate Cancer.
2021[M].
People's Medical 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, new cases and deaths of prostate cancer in Asia accounted for 26.
2% and 32.
1% of the global total, and the mortality/morbidity ratio (MIR) was three times that of North America
.
In recent years, the incidence of prostate cancer in China has shown an increasing trend, with the most significant increase in the incidence in urban areas, from 5.
8 per 100,000 in 2004 to 8 per 100,000 in 2009 [1]
.
In China, there are only a small number of prostate cancer patients with localized lesions at the first diagnosis, and most Chinese patients have advanced to the middle and advanced stages of the disease at the time of diagnosis
.
Therefore, how to choose a treatment plan and prolong the survival time of patients has always been a difficult problem in clinical practice
.
The first-line treatment option for advanced prostate cancer-AR pathway targeted drugs.
After a median of 12 months of endocrine therapy in patients with advanced prostate cancer, 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).
The AR gene plays an important role in the occurrence and development of prostate cancer.
It can regulate The expression of downstream genes promotes the progression and metastasis of prostate cancer
.
There are three common variants in the AR pathway: point mutations, splice variants, and amplification/overexpression
.
Common types of AR point mutations are W742C, H875Y, T878A and L702H
.
Hara et al.
cultured the human prostate cancer (LNCaP) cell line in an androgen deprivation environment in 2003, and simulated the clinical environment with 1 μM bicalutamide.
The cell line resumed growth after nearly 6 weeks of culture [3]
.
In subsequent gene sequencing of AR, mutations of W741C and W741L were found.
In models with this mutation, bicalutamide acts to increase tumor volume and increase the level of PSA in plasma
.
Point mutations have different effects on different new endocrine drugs.
Preclinical models indicate that the affinity of different AR receptor inhibitors when binding to T877A mutant AR is in the order of enzalutamide> apatamide> dalotamide
.
In the AR amplification/overexpression model, AR is sensitive to low levels of androgens after castration, which can lead to disease progression
.
In cell lines overexpressing AR, in contrast to bicalutamide, enzalutamide inhibits the binding of AR to DNA and the production of PSA mRNA, while bicalutamide stimulates the binding of AR to DNA and the production of PSA mRNA
.
AR splice variant-7 (AR-V7) is a currently known AR splice variant that can encode a functional protein product that can be detected in clinical samples
.
In a prospective, open-label, multi-center, phase II study evaluating the efficacy of enzalutamide and the effects of AR-V7, 67 mCRPC patients with visceral metastases were treated with enzalutamide.
The results showed that enzalut At 3 months of amine treatment, the overall disease control rate was 67%
.
Domestic and international guidelines unanimously recommend the use of new endocrine drugs for the treatment of CRPC.
National Cancer Network (NCCN) prostate cancer clinical practice guidelines [4], American Urological Association (AUA) prostate cancer guidelines [5] and European Association of Urology (EAU) prostate cancer The guidelines [6] unanimously recommend new endocrine drugs such as enzalutamide, apatamide or dalotamide for the treatment of CRPC
.
The "Guidelines for the Diagnosis and Treatment of Chinese Urology and Andrology Diseases of Prostate Cancer" for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) are: For those with a higher risk of metastasis (PSA-DT≤10 months) For patients with nmCRPC, it is recommended to combine apatamide, enzalutamide or dalotamide on the basis of androgen deprivation (ADT) treatment
.
The Chinese Society of Clinical Oncology (CSCO) Guidelines for Diagnosis and Treatment of Prostate Cancer[7] The recommendations for the treatment of CRPC patients are: For nmCRPC patients with PSADT ≤ 10 months, the level I recommends the use of apatamide, dalotamide or enzalutamide Treatment (1A evidence), PSADT> 10 months, level II recommends other second-line endocrine therapy (2A evidence); for mCRPC patients, level I recommends the use of ADT + abiraterone acetate + prednisone, ADT + docetal As a first-line treatment plan, ADT+prednisone, ADT+enzalutamide or ADT+apatamide (class 1A evidence); after the failure of first-line chemotherapy, enzalutamide or abiraterone acetate can still be used for second-line treatment (class 1A) Evidence)
.
Table 1 The efficacy and safety of enzalutamide and abiraterone for CRPC patients in the treatment of metastatic castration-resistant prostate cancer In the PREVALIL study [8], the efficacy of the Japanese/Asian subgroup is basically the same as that of the overall population
.
The Japanese subgroup reduced the relative risk of imaging progression or death by 70%, and the East Asian subgroup reduced 62% (HR=0.
19, P＜0.
001); the overall risk of death in both the Japanese subgroup and the East Asian subgroup was reduced by 41% (HR=0.
83, P=0.
0008)
.
The Asian PREVAIL Phase III study [9] found that enzalutamide significantly reduced the PSA progression of Asian mCRPC patients without chemotherapy and prolonged the imaging progression-free survival (rPFS).
Enzalutamide was used to treat Asian patients with mCRPC before chemotherapy for 5 years.
The median overall survival (OS) can reach 39 months
.
The COU-AA-302 study evaluated the benefit of abiraterone acetate for mCRPC patients who had not received chemotherapy
.
The results of the study showed that compared with placebo, abiraterone acetate significantly prolonged the median OS phase of patients (53.
6 months vs 41.
8 months, HR=0.
61, P=0.
006) [10]
.
Therefore, abiraterone acetate can significantly improve the overall survival of patients with mCRPC without chemotherapy
.
Enzalutamide resistance mechanism and countermeasures A study published in January 2021 [11] summarized new information about the resistance mechanism of enzalutamide in CRPC patients, including androgen receptor-related signaling pathways, lineage plasticity, and disorders of cytokine gene polymorphism
.
Studies have pointed out that although CRPC patients are treated with enzalutamide, androgen receptors are still highly expressed and transcriptionally active in castration-resistant prostate cancer
.
The analysis found that the soma-derived androgen receptor enhancer located at the 650 kb centromere of the androgen receptor is frequently amplified in castration-resistant prostate cancer
.
In addition, under low androgenic conditions, extra copies inserted into this region are sufficient to increase cell proliferation and reduce the sensitivity of cells to enzalutamide
.
Another study found that galectin-3, a member of the animal lectin family, increases 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
.
The enhancement of androgen receptor transcriptional activity and the expression of androgen receptor related genes can lead to resistance to enzalutamide
.
Based on the above research, for patients with enzalutamide-resistant CRPC, new potential treatments can be selected, such as targeting the androgen receptor enhancer and BMI1 as a new therapeutic target
.
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 risk related to low potassium
.
Enzalutamide is an effective treatment for advanced prostate cancer and CRPC, which is why domestic and foreign guidelines unanimously recommend the use of enzalutamide to treat CRPC
.
Expert profile Hong Zhengdong Deputy Chief Physician Doctor of Medicine, associate professor, master tutor
.
Selected from the Jiangxi Province Hundred Talents Voyage Project, selected from the 215 Talent Project of Nanchang University, outstanding Communist Party member of the Second Affiliated Hospital of Nanchang University, and visiting scholar at the University of Nebraska Medical Center in the United States
.
Specializes in minimally invasive treatment of urinary stones, tumors and benign prostatic hyperplasia
.
Presided over 1 National Natural Science Foundation of China, 1 Natural Science Foundation of Jiangxi Province, Jiangxi Provincial Department and 3 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.
Progress 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] Chinese Society of Clinical Oncology Guidelines Working Committee Organization and Compilation.
Chinese Society of Clinical Oncology (CSCO) Guidelines for Diagnosis and Treatment of Prostate Cancer.
2021[M].
People's Medical 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.
