Innovative mechanism, excellent curative effect, expect "apatamide" to be included in the national medical insurance, find the fulcrum to improve the survival rate of prostate cancer

*Only for medical professionals to read the reference introduction.
Advanced prostate cancer innovative drug "Apatamide" is China's first and currently the only new androgen approved for "all types" of metastatic endocrine therapy sensitive prostate cancer (mHSPC) indications Receptor (AR) inhibitors are also China’s first new type of AR inhibitors approved for high-risk non-metastatic castration-resistant prostate cancer (NM-CRPC) indications.
Through the treatment concept of early active intervention, it will bring the treatment of prostate cancer.
Here comes the survival benefit of comprehensive innovation
.

Triple potent inhibitory mechanism, structural innovation and upgrade based on enzalutamide molecule, higher affinity, lower blood-brain barrier permeability, and safer central nervous system
.

With the mission of "for people's livelihood and health", let the people use and afford good medicines and new medicines, and benefit more prostate cancer patients
.

It is expected that apatamide will enter the national medical insurance as soon as possible and bring high-quality survival benefits to prostate cancer patients
.

A difficult city, the 5-year survival rate of prostate cancer patients in China.
Prostate cancer is the most common malignant tumor in men
.

According to the latest GLOBOCAN data, there will be more than 1.
4 million new cases of prostate cancer worldwide in 2020, and the incidence is the second highest among men
.

[1-2] According to the data of the global cancer survival monitoring project CONCORD, the five-year survival rate of prostate cancer in Japan and South Korea increased by nearly 12% annually from 1995 to 2014, and the 5-year survival rate has reached nearly 90%; prostate cancer in China The five-year survival rate has increased by 3.
7% annually, which is still about 36% lower than other countries [3].
There is still huge room for improvement in the survival rate of prostate cancer patients in China
.

A series of top-level designs such as the "14th Five-Year Plan" and the "Healthy China 2030 Planning Outline" have clarified the timetable, roadmap and mission statement.
How to achieve the overall 5-year cancer survival rate of Healthy China 2030 is a difficult point that we urgently need to break through
.

Clinically, the disease process of prostate cancer can be roughly divided into: limited/local advanced prostate cancer→biochemical recurrence (BCR)→mHSPC or NM-CRPC→mCRPC→end-stage disease (death)
.

As the disease progresses, the risk of death can increase three-fold [4]
.

The mHSPC stage disease is characterized by metastasis and heterogeneity in biological and clinical manifestations, ranging from indolent to aggressive and rapidly fatal forms.
The median survival time without failure for simple long-term castration therapy is less than 1 year and 5 years survival The rate is only 30%, the clinical outcome is worse, and survival and life treatments have dropped significantly
.

The risk of bone metastasis in the NM-CRPC stage is increased by 12 times, and the risk of death is increased by 4 times.
Once metastasis occurs, bone-related events (SREs) such as pain, fractures, and spinal cord compression may occur, which will further lead to disability and death, and increase the use of medical resources.
And treatment costs
.

If timely and effective treatment can be given in the mHSPC and NM-CRPC stages, patients still hope to maintain better disease control and prolong survival
.

On May 29, 2019, apatamide was included in the second batch of clinically urgently needed overseas new drugs list of the Center for Drug Evaluation (CDE) of the State Drug Administration of China
.

On September 5 of the same year, apatamide was approved by China for accelerated listing, becoming China's first drug for the treatment of NM-CRPC
.

In February 2020, apatamide was once again included in the CDE priority review list
.

On August 12, 2020, the indication for apatamide mHSPC was approved in China at an accelerated pace, becoming China’s first and currently the only new androgen (AR) receptor drug for the treatment of mHSPC
.

Coming from the waves, the innovative structure of apatamide is upgraded, and the mechanism of action is innovative.
The new generation of AR inhibitor apatamide has proven its excellent efficacy and good safety in clinical studies.
The reasons for the improvement of its safety are mainly based on the Structural optimization of enzalutamide
.

Due to the close structure of AR and GABA-A (γ-aminobutyric acid type A receptor), enzalutamide inhibits the function of GABA-A receptors in the brain through an off-target mechanism, and induces seizures, fatigue and other central nervous systems ( CNS) related adverse reactions
.

Based on this, the research team optimized the structure of enzalutamide, replacing the phenyl group with a pyridyl group on the molecular structure of enzalutamide, optimizing the general active group of non-steroidal AR inhibitors, and apatamide came into being
.

Figure 1 Apataamide is the product of enzalutamide molecular structure optimization.
As the product of enzalutamide molecular structure optimization, the molecular polarity of apatamide increases and its ability to penetrate the blood-brain barrier decreases, thus Successfully reduce central toxicity and the risk of epileptic seizures, thereby consuming less medical resources; at the same time, it brings lower plasma accumulation and peripheral toxicity, showing better safety
.

Table 1 The incidence of CNS-related adverse events above grade 3 in the clinical study of apatamide/enzalutamide As a new type of androgen receptor (AR) inhibitor, apatamide has an innovative triple mechanism of action: ①blocking The combination of androgen and AR; ②block the androgen-AR complex from entering the nucleus; ③block the binding of AR complex with DNA to block the expression of related signal pathways
.

By closing the "triple door" required for tumor progression, the goal of inhibiting the activation of the AR signaling pathway is finally achieved, thereby effectively inhibiting the proliferation of prostate cancer cells and controlling the progression of prostate cancer disease
.

Previously, a variety of endocrine therapy drugs may have changed from inhibitors to agonists, and from therapeutic drugs that inhibit the proliferation of tumor cells, they may become the culprit that accelerates the proliferation of tumor cells
.

While inhibiting AR, apatamide is currently the only drug with evidence showing that it has a smaller effect on AR variation, which can overcome this treatment dilemma [5-6]
.

Figure 2 The mechanism of action of apatamide, the affinity of the androgen receptor and the anti-tumor activity are important indicators that determine the efficacy of AR inhibitors
.

The affinity of apatamide for androgen receptors is 7-10 times that of the first-generation AR inhibitor, bicalutamide, and higher than that of enzalutamide
.

At the same time, the anti-tumor activity of apatamide is better than that of the other two drugs.
It has stronger anti-tumor activity at a lower dose, which means that apatamide is a more potent new type of androgen receptor inhibitor [ 7-8]
.

Figure 3 The affinity of androgen receptors of different AR inhibitors (left) and anti-tumor activity (right) are also important factors affecting the absorption and distribution of drugs, and apatamide is absorbed rapidly in the body, and The oral bioavailability is 100%, indicating that the drug is completely absorbed after oral administration
.

Part of the metabolite of apatamide (N-methylapathamide) still has anti-tumor activity
.

Based on evidence-based, innovation is written in the field of mHSPC on the therapeutic benefits of apatamide for patients.
TITAN clinical research shows that the apatamide group significantly reduces the risk of death by 48% compared with the placebo group (HR=0.
52, 95% CI: 0.
42～0.
64, P＜0.
0001)
.

Apataamide reduces the risk of imaging progression or death by 52% (HR=0.
48, 95% CI: 0.
39～0.
60, P<0.
0001) [9]
.

Even for some refractory prostate cancer subtypes such as basal subtype, AR low expression active subtype, etc.
, apatamide has shown significant efficacy
.

Regardless of the subsequent choice of endocrine therapy, chemotherapy and other sequential treatment options, the apatamide group can reduce the risk of secondary disease progression/death by 34%, which may be due to the smaller effect of apatamide on AR variants
.

Apataamide can significantly increase the 4-year OS rate by 27%
.

Lay a solid foundation for the overall realization of the overall 5-year survival rate of cancer in "Healthy China"
.

In the field of NM-CRPC, clinical studies [10] confirmed that apatamide can significantly prolong the patient’s metastasis-free survival (MFS) by 24.
3 months and significantly prolong the overall survival by 21.
1 months.
It is currently the only high-risk NM-CRPC patient whose OS exceeds 6 years of medication
.

Regardless of the subsequent choice of sequential treatment options, the apatamide group can reduce the risk of secondary disease progression/death by 45%
.

The indications for apatamide cover all types of mHSPC and NM-CRPC, bringing comprehensively innovative survival benefits to prostate cancer treatment
.

The current guidelines for diagnosis and treatment of urology and andrology diseases in China, the Chinese Society of Clinical Oncology (CSCO) guidelines, the National Comprehensive Cancer Network (NCCN), the American Academy of Urology (AUA) guidelines, and the European Association of Urology (EAU) guidelines all have the highest evidence The first-line level recommends apatamide regimen for the treatment of mHSPC and NM-CRPC patients
.

With the help of the cloud, we look forward to the early inclusion of apatamide into the national medical insurance under the guidance of the "14th Five-Year Plan".
Healthy China will become a national strategy and outline the development picture for the "healthy dream"
.

For patients with metastatic hormone-sensitive prostate cancer (mHSPC) and high-risk non-metastatic castration-resistant prostate cancer (NM-CRPC) stage, apatamide is undoubtedly the initial preferred treatment option for "early diagnosis and early treatment" of prostate cancer.
It is also a solution to make up for the "shortcoming" of the 5-year survival rate of prostate cancer patients in China
.

Apataamide writes a heart-warming "healthy answer sheet" with "innovative pen"
.

With the mission of "for people's livelihood and health", it will further enhance the availability of innovative medicines, make good medicines and new medicines available to the people, and benefit more prostate cancer patients
.

"We look forward to the early entry of apatamide into the national medical insurance, which will bring high-quality survival benefits to prostate cancer patients
.

In the future, a healthy China can be expected! "References: [1].
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CA Cancer J Clin.
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[2].
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PLoS One.
2015;10(10):e0139440.
[5].
Clegg NJ, et al.
ARN-509: a novel anti-androgen for prostate cancer treatment.
Cancer Res 2012; 72: 1494-1503.
[6].
ERLEADA.
US Prescribing Information.
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[7].
Clegg NJ, et al.
Cancer Res 2012; 72: 1494-1503.
[8].
Guerrero J et al.
The Prostate 2013 ; 73: 1291-1305[9].
Chi KN, Chowdhury S, Bjartell A, et al.
J Clin Oncol.
2021;39(20):2294-2303.
[10].
Small E.
, et al.
ASCO 2020 .
Abstract #161.
.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform