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The pathogenesis of prostate cancer is very complex, and its exact pathogenesis is not clear.
Currently, prostate cancer can be successful at an early stage through surgery, radiotherapy, androgen deprivation** (ADT), etc. However, the clinical symptoms of prostate cancer are not obvious in the early stage, so most patients are already in the middle and advanced stages when they are diagnosed.
In recent years, with a series of breakthroughs, the controversy over prostate cancer drugs has undergone new changes.
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**Options are limited
Common **include chemotherapy and endocrine**
The prostate gland is an androgen-dependent organ, and its growth and development are closely related to the androgen receptor (AR) signaling pathway. AR plays an important role in the occurrence and development of prostate cancer. AR pathway inhibitors reduce AR activity in prostate cancer by decreasing circulating testosterone and androgen-AR receptor complexes.
Currently, prostate cancer can be successful at an early stage through surgery, radiotherapy, androgen deprivation** (ADT), etc. However, the early clinical symptoms of prostate cancer are not obvious, so most patients are already in the middle and advanced stages when they are diagnosed, and the first choice for patients with advanced prostate cancer is androgen deprivation (ADT). ADT is the primary systemic basis for patients with advanced metastatic prostate cancer** and is the basis for a variety of novel combination** regimens. ADT includes a variety of implementations, of which castration alone (surgical or pharmacological) is the most widely accepted core modality.
In recent years, there have been a series of breakthroughs, mainly the combination of ADT with novel endocrine drugs or chemotherapy drugs, which have improved the overall ** outcomes of metastatic prostate cancer. Eventually, however, almost all patients develop drug resistance after 36 months of ADT**18 and eventually progress to castration-resistant prostate cancer (CRPC), with a median survival of only about 12 months.
The following figure shows the best methods and medication regimens for prostate cancer to progress to different stages.
Note: This article is for the purpose of information exchange only, and the views in this article do not represent the position of Yaozhi.com, nor are they recommended solutions. If you need to get ** plan guidance, please go to a regular hospital.
Table 1 Classification and mechanism of action of major drugs for prostate cancer.
Data**: Public data, compiled by Yaozhi Consulting.
The launch of new drugs such as second-generation AR antagonists
To stimulate the growth of the prostate cancer market
In 2021, the size of China's prostate cancer drug market was 774.5 billion yuan, with a compound growth rate of 14 from 2017 to 202179%。At the same time,In recent years, a number of second-generation AR antagonists have been marketed in China, including enzalutamide (2019), apalutamide (2020), revilutamide (June 2022), etcIt is expected that the launch of new drugs such as second-generation AR antagonists will promote the continuous growth of the prostate cancer drug market.
Figure 1 The size of China's prostate cancer drug market.
Data**: Pharmaceutical Intelligence data, Pharmaceutical Intelligence Consulting and collation.
In 2021, leuprolide (27.) had the highest market share among prostate cancer drugs** in China16%), followed by goserelin (23.).61%）。These two drugs are GNRH agonists, which are commonly used in androgen deprivation** (ADT), which is the basis of combination drugs for hormone-sensitive prostate cancer, so they have a high market share.
Abiraterone is an irreversible inhibitor of the CYP17A enzyme developed by Johnson & Johnson, CYP17A enzyme is a rate-limiting enzyme in androgen biosynthesis and is found in **, adrenal glands, and prostate cancer cells. It was approved by the FDA in 2011, recommended by the American Urological Association in 2015 for patients with various types of metastatic castration-resistant prostate cancer (MCRPC), and approved for marketing in China in April 2015. Abiraterone entered the medical insurance in 2017 and increased rapidly after entering the medical insurance, with a compound growth rate of 71 from 2017 to 202134%。In 2021, Abiraterone sales reached 139.2 billion yuan, an increase of 5 compared with 202019%。Abiraterone entered the national centralized procurement in 2020, and the sales of Abiraterone still maintained growth after entering the centralized procurement.
Enzalutamide was developed in collaboration with Medivation and AstellasIn 2012, it was approved by the FDA for **CRPC, and in 2019, it was approved for marketing in China. Enzalutamide is a second-generation non-steroidal anti-androgen drug that has several times stronger anti-AR activity than first-generation AR inhibitors, which only competitively bind to AR. Enzalutamide is one of the few options that does not require a combination of steroids** and has a significant safety advantage over abiraterone (which requires combination with prednisone to control adverse effects). Enzalutamide has the largest market share in the global anti-prostate cancer market so far in 2019The domestic drug was launched in 2019, and its sales have grown rapidly after listing, with a market size of 19.6 billion yuan, an increase of 4170 compared with 202032%, it is expected that the domestic drug structure will be in line with the world in the future, and enzalutamide will maintain rapid growth.
There are a large number of drugs under development
The targets are concentrated in FOLH1, AR, etc
There are about 657 prostate cancer drugs under development in the world, and about 145 prostate cancer drugs under development in ChinaThe global research targets are concentrated in PSMA (folh1), AR, gnR receptor and other targets.
Figure 2 The number and targets of drugs under development for prostate cancer** in the world and in China.
PharmaIntelligence Data - Global Pharmaceutical Analysis System.
Prostate-specific membrane antigen (PSMA, also known as folate hydrolase 1 (FOLH1)) is a transmembrane glycoprotein that has been overexpressed in more than 90% of prostate cancer cells and is more highly expressed in cancer cells from advanced and castration-resistant patients. Compared with traditional scanning, PSMA PET CT has unique advantages in detecting prostate cancer lesions, and can make more effective judgments in the early stage and disease stage of prostate cancer.
At present, most of the PSMA drugs on the market and under development are radiopharmaceuticals, including the marketed drug 177lu-PSMA-617, and the drug investigational drug PNT2002 (177LU-labeled radiopharmaceutical I-MIP-1095 (131I-labeled radiopharmaceutical ac-psma-i&t (225AC-labeled radiopharmaceutical)). Among them, Novartis' radioligand** (177lu-PSMA-617) was approved by the FDA in March 2022 to include patients with prostate cancer who have spread and have undergone other**. 177LU-PSMA-617 includes a targeted compound (PSMA-617) and a **sexual isotope (177LUs) that enable precision cancer**. 177LU-PSMA-617 binds to PSMA-expressing prostate cancer cells, and the radiation generated by the reflective element is more concentrated in the tumor tissue, killing cancer cells while reducing damage to healthy cells.
At present, the first-line of MCRPC** mainly recommends the preferred new endocrine ** (NHT), and the available regimens in China include enzalutamide, abiraterone, etc. However, clinical results have found that the new endocrine ** drugs are not effective for all castration-resistant prostate cancer (CRPC), and some patients have primary resistance to these drugs, and for patients with initially effective MCRPC, secondary resistance eventually occurs. The mechanism of drug resistance is mainly due to the mutation of AR genes, including AR amplification, AR mutations, AR splice variants (ARVS), etc. The strategy of silencing AR gene expression is a potentially effective method for CRPC. Antisense oligonucleotides (ASOs) have emerged as alternatives** for a variety of human diseases because they can essentially block specific gene targets and prevent the synthesis of their associated proteins.
AstraZeneca has developed the antisense nucleotide AZD5321, and preclinical studies have shown that AZD5312 hybridizes to AR mRNA, thereby blocking the translation of AR proteins, and can effectively inhibit the expression of full-length AR (AR-FL) and its splice variants, which can both inhibit AR-induced tumor cell growth and promote AR-overexpressing tumor cell apoptosis, thereby generating anti-tumor activity in enzalutamide-resistant CRPC models. However, the drug began phase I clinical trials in 2014 and has not progressed so far.
Summary
At present, the pathway for advanced prostate cancer is limited, and it is deeply affected by the bottleneck of cross-drug resistance of existing regimensThe median survival time of MCRPC is short, and patients often lose motivation when they progress to the second line, and there is a huge unmet clinical need. There is an urgent need for a new way and concept to lead clinical patients out of the predicament.
Note: This article is for the purpose of information exchange only, and the views in this article do not represent the position of Yaozhi.com, nor are they recommended solutions. If you need to get ** plan guidance, please go to a regular hospital.
References: 1] Min Shuhui, Hu Yi, Guo Ruiqi. Disease burden analysis and trends of prostate cancer in China, 1990-2019**. Chinese Journal of Oncology ISSN 1004-0242, CN 11-2859 R
3]de velasco ma,kura y,sakai k,hatanaka y,d**ies br,campbell h,klein s,kim y,macleod ar,sugimoto k,yoshikawa k,nishio k,uemura h.targeting castration-resistant prostate cancer with androgen receptor antisense oligonucleotide therapy.jci insight.2019 sep 5;4(17):e122688.
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