"Precision Diagnosis and Treatment" helps decision-making in the treatment of prostate cancer, PROfound research opens up the era of targeting——Professor Ye Dingwei talks about guidelines update

*Only for medical professionals to read for reference, Professor Ye Dingwei will show you the update of the CSCO and EAU two major prostate cancer guidelines in 2021! The 2021 Pujiang Prostate Cancer Summit Forum will be held in Shanghai from July 9 to 11, 2021.
Professor Ye Dingwei from the Cancer Hospital of Fudan University participated in the meeting as the chairman of the conference
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In 2021, both the Chinese Society of Clinical Oncology (CSCO) and the European Association of Urology (EAU) have updated the chapters on the diagnosis and treatment of prostate cancer
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At this moment, Olapali's prostate cancer indication was approved in China in June 2021, which has attracted widespread attention in the field of prostate cancer treatment
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Taking this opportunity, the "medical community" specially invited Professor Ye Dingwei from Fudan University Affiliated Cancer Hospital to receive an exclusive interview on the 2021 domestic and foreign guidelines update and polyadenosine diphosphate ribose polymerase (PARP) inhibitor drugs related issues, and organized as follows: The vast number of doctors urged
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Precise diagnosis and treatment guide clinical practice.
The new version of the guidelines is tailored for prostate cancer patients.
The medical community: CSCO prostate cancer diagnosis and treatment guidelines are the first prostate cancer diagnosis and treatment guidelines with both international standards and Chinese characteristics.
Since its release last year, it has been widely trusted and trusted by clinicians.
Application
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This year, CSCO is keeping up with the international academic frontiers and updated its guidelines in chapters including precision diagnosis and treatment of prostate cancer.
Please comment on the update of this guide's precision diagnosis and treatment chapters
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Professor Ye Dingwei: In terms of "precision diagnosis", the new version of the guidelines has updated the types of patients and genes tested, and more importantly, the types of test samples have been added
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First of all, for the types of patients tested, the guidelines recommend early genetic testing to guide clinical practice.
It is recommended that the population move forward from patients with metastatic castration resistant prostate cancer (mCRPC) to patients with metastatic prostate cancer (mPC), in line with current international guidelines.
The recommended timing of genetic testing is basically the same, allowing clinical experts to more clearly determine the timing of testing
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At the same time, it is also possible for patients to perform a precise and personalized molecular typing test at the time of initial diagnosis and transfer, to provide a reference for subsequent treatment decisions
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The second is the update of the types of genes tested
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Due to the poor prognosis of patients with homologous recombination repair mutations (HRRm), chemotherapy and new endocrine treatments are not effective for such patients, this guideline update reorganizes the types of genes recommended for testing
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With reference to the results of the PROfound study of the phase III clinical study of olaparib, for mPC patients, the guideline level I recommends the detection of BRCA1, BRCA2, ATM, CDK12 and other homologous recombination repair related genes
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The frequency of patients carrying the above-mentioned harmful or suspected harmful mutation genes is 27.
9%.
Such patients can benefit from olaparib monotherapy, so genetic testing for mPC patients can be a good guide for medication
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Level II of the guideline recommends the detection of mismatch repair related genes such as MSH2 and MSH6, as well as potential platinum-based treatments and PARP inhibitor sensitization molecular markers such as DNA repair genes
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Level III of the guideline recommends the detection of AR-V7, TP53, RB1, PTEN and other genes that have guiding significance for treatment selection and prognosis of prostate cancer
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In addition, in order to better guide clinical practice, the guidelines have clearly added recommendations for the types of samples that can be used for testing, including tumor tissue samples, plasma circulating tumor DNA (ctDNA) samples, and blood white blood cell samples
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Among them, tumor tissue samples and ctDNA can be used to find germline mutations and somatic mutations in tumors, while blood white blood cell samples can only find germline mutations.
However, for most mCRPC patients, there are many difficulties in obtaining tumor tissue samples, while plasma Samples can be obtained non-invasively and dynamically detected and monitored, while avoiding problems such as tumor tissue heterogeneity, which is a convenient and feasible technology
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At present, the biggest clinical concern for ctDNA technology is its consistency with the results of tissue samples
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Both the PROfound study and the TRITON 2/3 study announced at this year’s ASCO-GU conference showed that the consistency of the results of the tumor tissue and plasma ctDNA samples of mCRPC patients was more than 80%, and similar domestic studies also reached a consistency of 90%.
% Results
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Based on the above data, the guidelines recommend that mCRPC patients can be tested with plasma ctDNA samples when the tissue is not accessible or the test fails
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From the perspective of genetic counseling, the new guidelines recommend germline mutation testing for the following populations, including patients with limited-stage high-risk, very high-risk, locally advanced, and metastatic prostate cancer, patients with a positive family history of tumors, and patients with a family history of high-risk germline mutations (such as BRCA germline mutations, Lynch syndrome), intraductal carcinoma and ductal adenocarcinoma
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From the point of view of detection sites, genes such as homologous recombination repair genes, mismatch repair genes, and HOXB13 are highly correlated with an increased risk of prostate cancer.
Therefore, the guideline class I recommends the detection of these genes, and class II recommends the detection of other DNA repair-related genes
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In terms of "precision treatment", the new version of the guideline starts from the clinic and updates the drug recommendation and guidance strategy for mCRPC treatment
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The treatment plan for mCRPC in the old guideline is very complicated.
In addition to the traditional new endocrine therapy and chemotherapy, there are also PARP inhibitors, immunotherapy and other options to choose from.
As a result, the description of "first-line, second-line" in the old guideline is not enough to clearly indicate each plan Sequential relationship
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Therefore, in this update, CSCO draws on the description method of the National Comprehensive Cancer Network (NCCN) guidelines, and replaces the traditional first-line and second-line classification methods by whether or not they have received new endocrine therapy/chemotherapy in the past to provide clearer and more intuitive guidance Treatment of mCRPC patients at different stages
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For example, the updated guidelines recommend that patients be treated with docetaxel at level I (Class 1A evidence), at level I recommend olaparib for HRRm patients (level 1A evidence), and at level I recommend radium-223 treatment for patients with bone metastases ( Type 1A evidence)
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It is particularly noteworthy that, in this guideline update, China’s real-world data has been cited and referenced, and data from traditional clinical research has been expanded and filled
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For example, the guideline recommendation for olaparib, based on the reference to the phase III clinical study PROfound, also refers to a domestic real-world study: the study enrolled 43 patients with mCRPC, of ​​which 41 patients were treated with olapa With single-agent therapy, 2 patients were treated with olaparib combined with abiraterone, and the overall prostate-specific antigen (PSA) remission rate was 48.
8%
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Among them, 26 patients with HRRm gene mutation had a PSA remission rate of 57.
7%, and 17 patients with HRRm had a PSA remission rate of 35.
3%
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This update fills in the lack of Chinese population data in Phase III clinical studies by referring to domestic real-world data, and makes it easier for Chinese doctors to refer to in clinical practice
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In addition, olaparib has been approved for prostate cancer indication in China, becoming the first PARP inhibitor available on the market in the field of urinary tumors in China, officially opening the era of targeted therapy in the field of prostate cancer
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The approval of Olapali's prostate cancer indication coincides with the update of this guideline, which helps clinicians keep up with the times and make more reasonable treatment options in a timely manner based on the guideline
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Say goodbye to "first-line and second-line", the era of precision sequential treatment is coming to the medical world: this year's EAU guidelines have greatly updated the content of precision diagnosis and treatment.
Please introduce the highlights of this year's EAU guidelines in precision diagnosis and precision treatment.
, And please start from the guide update and look forward to the innovation direction of precision diagnosis and treatment of prostate cancer from an international perspective
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Professor Ye Dingwei: In terms of "precision diagnosis", the 2021 EAU guidelines further strengthen the application of genetic testing in the radical treatment of prostate cancer, mainly including the use of genetic testing for the classification and prognosis of prostate cancer, and improve the prognostic stratification of prostate cancer.
Accuracy
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The genomic profile is one of the decision-making factors for mCRPC treatment
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The expression used in the 2020 EAU guidelines on the timing of genetic testing is "as early as possible", especially during the initial diagnosis of castration resistance
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This year’s EAU guidelines further clarify and emphasize the need for prostate germline genetic testing: including metastatic prostate cancer, high-risk prostate cancer, and family history of prostate cancer patients younger than 60 years old, and family members who have died of prostate cancer.
, There are germline mutation carriers or patients with multiple malignant tumors in the family
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The 2020 EAU guidelines have reservations about the recommendation of genetic testing sites, and do not clearly state it
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This year’s EAU guidelines clarified that all mPC patients must undergo systematic genetic testing, and the detection sites include genes related to homologous recombination repair pathways and mismatch repair (MMR) genes
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In addition, the guidelines recommend high-risk and clinically indicated mPC patients to undergo germline BRCA1/2, ATM, and MMR testing
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Regarding the selection of test samples, the 2020 EAU guidelines have no priority recommendations for tissue biopsy, ctDNA, and fresh tissue biopsy of metastases, and they have reservations about the quality of the tissue
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This year’s EAU guidelines are aimed at systematic genetic testing of all mPC patients.
The first recommendation is to test metastatic tissue samples, followed by the primary tumor tissue samples, and ctDNA testing is also listed as an optional program
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At present, the U.
S.
Food and Drug Administration (FDA) has approved the Foundation One liquid biopsy kit, so this EAU guideline update adds ctDNA testing, which brings more convenient and faster testing methods to the clinic
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In terms of "precision treatment", this year's EAU guidelines have also undergone major updates on the treatment options for mCRPC patients, specifically focusing on the recommendation of PARP inhibitors and the recommendation of sequential therapy
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Based on the results of the TOPARP-A study of olaparib, the 2020 EAU guidelines recommend the use of PARP inhibitors for mCRPC patients after one endocrine therapy and docetaxel treatment
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This year, with the release of the PROfound data of the olaparib phase III clinical study, the 2021 EAU guidelines will add olaparib to the optional treatment plan for mCRPC (HRRm patients), and at the same time add PARP inhibitors to carry DNA repair gene mutations and past Both of the treatment options for mCRPC patients are strongly recommended
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The relevant content of PARP inhibitor application in the new version of the guide is a self-contained section, which introduces the PROfound study in detail and in a large space
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The PROfound study is the first phase III clinical study for precision treatment of prostate cancer so far
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The study first performed genetic testing on the patients.
According to the different HRR mutation genes of the patients, the patients were divided into two cohorts, cohort A was BRCA1/2 or ATM mutation patients, cohort B was the other 12 preselected HRR gene mutation patients, each The cohort randomly assigned patients to receive olaparib 300 mg and new endocrine therapy (cross-use of abiraterone or enzalutamide) at a 2:1 ratio
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The primary endpoint was radiographic progression-free survival cohort A (rPFS) period
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The results showed that the rPFS of the olaparib group in cohort A was up to 7.
4 months, which was significantly longer than the rPFS of the control group (3.
6 months) by nearly 4 months (Figure 1)
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And the just published overall survival (OS) data showed that the OS in the olaparib group in cohort A was 19.
1 months, which was nearly 5 months longer than the new endocrine therapy group (OS 14.
7 months) (Figure 2) [1]
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Figure 1 The results of rPFS in the cohort A olaparib group compared to the control group Figure 2 The OS results in the cohort A olaparib group compared to the control group It is worth noting that the 2021 EAU guidelines separately mentioned the benefits of the PROfound study cohort B Although no significant difference was observed in the Independent Central Neuroimaging Blind Evaluation (BICR), the researchers assessed that the olaparib group had a benefit, so the HRRm gene mutation was uniformly recommended as olaparib in the final recommendation.
Indications for the use of, there is no further stratification or grading
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In addition, for another approved PARP inhibitor, Lucaparib, the EAU guidelines briefly describe the results of its TRITON2 study
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In terms of final indications, the new EAU guidelines emphasize that olaparib is suitable for mCRPC patients who have failed a new endocrine therapy, and olaparib has been approved by the FDA for 14 HRRm gene mutations and BRCA mutations in Europe
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Lucapari is only approved for BRCA mutations in both the FDA and Europe, and it is suitable for mCRPC people who have undergone a new endocrine therapy and chemotherapy at the same time
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In addition, the new version of the EAU guidelines adds recommendations for sequential treatment of mCRPC phases
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For mCRPC patients who have not used chemotherapy, abiraterone sequential enzalutamide and other androgen receptor (AR)-targeted drugs will no longer be recommended, especially for the first AR-targeted drug with a short response time (Less than 12 months) and high-risk patients with rapid progress
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The AR sequential use of PARP inhibitors for mCRPC patients who carry harmful or suspected harmful germline or system HRR mutations has become a new recommendation in the guidelines, which is also based on the research data of PROfound
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In general, the 2021 EAU guidelines pay more attention to the full benefit for the treatment of mCRPC
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Nowadays, in the context of the emergence of more and more new drugs, how to better plan and manage the whole process is a major test for the clinic
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Combined with the recommendation of genetic testing, it is not difficult to see that the trend of using molecular typing as a treatment decision consideration is becoming more and more obvious.
In the future, it may no longer be a simple first-line and second-line method for classification, but based on different types of patients, making more accurate Sequential treatment
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Genetic testing runs through the diagnosis and treatment of patients, and dynamic monitoring helps treatment decision-making.
The medical community: The first PARP inhibitor olaparib in the field of prostate cancer in China was officially launched, which coincides with the update of two major domestic and foreign guidelines.
So what is the current clinical practice? What are the development directions for precision diagnosis and treatment? Professor Ye Dingwei: In the practice of precision treatment, the first direction is to assist in treatment decisions, prompt the clinic to make personalized diagnosis of patients in a timely manner, and classify patients through molecular classification to determine the subsequent diagnosis and treatment methods-which patients are suitable for active monitoring? Which patients need more aggressive treatment? In June 2021, Olapali's prostate cancer indications were officially approved, which officially opened the era of precision treatment of prostate cancer.
Combined with the precision diagnosis of genetic testing, precision diagnosis and treatment can be perfectly implemented in clinical practice
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The second direction is to expand the application of ctDNA to assist in the whole-process monitoring of diseases and the evaluation of tumor treatment efficacy
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After the tumor is resistant to a targeted drug, it can be repeatedly sampled and tested by liquid biopsy represented by ctDNA, enabling doctors to reassess the status of tumor driver genes at different stages of the patient’s disease and select new ones based on the results.
Of targeted drugs
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Therefore, in the future, the diagnosis of diseases will not be limited to the early pathological slice reading, but as the patient's course of disease progresses, real-time changes in gene levels will be grasped to make the next treatment more precise
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The third direction is to help the development of clinical scientific research, discover more tumor markers, and guide molecular targeted drugs
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Molecular targeted drugs are the cornerstone of precision medicine, and their high efficiency and safety make them have huge clinical application potential
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The "Management Measures and Guidelines for the Clinical Application of New Anti-tumor Drugs" promulgated by the National Health and Family Planning Commission in 2020 emphasizes the evidence-based use of drugs, that is, targeted drugs that require gene target testing must be tested by gene targets before use Detection
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Therefore, from the perspective of assisting treatment decision-making, it is necessary to discover more practical biomarkers in the future clinically, to have more in-depth research and mastery of the gene spectrum of disease driver genes, and to have a more macro and overall deployment of the whole process of disease management
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Expert profile Prof.
Ye Dingwei, Deputy Dean of the Department of Urology, Fudan University Cancer Hospital, Chief Expert of Urology MDT, Chief Expert, Shanghai Urological Oncology Institute, Director of Prostate Cancer Institute, Fudan University, Chinese Society of Clinical Oncology (CSCO) Prostate Cancer Committee Chairman CSCO Urothelial Carcinoma Special Committee Deputy Chairman CSCO Renal Cancer Special Committee Deputy Chairman and CSCO Immunotherapy Special Committee Deputy Chairman Chinese Anti-Cancer Association Urinary Male Reproductive Tumor Special Committee Chairman China Cancer Hospital Urology Chairman of the Cooperative Oncology Group (UCOG) Standing Director of the Chinese Anti-Cancer Association CSCO Standing Director of the Chinese Anti-Cancer Association Urinary and Male Reproductive Tumor Committee Prostate Cancer Group Leader NCCN Kidney Cancer Diagnosis and Treatment Guide China Edition Deputy Leader NCCN Prostate Cancer Member of the Asian Consensus Expert Committee on Diagnosis and Treatment of Kidney Cancer and Bladder Cancer Member of the Asian Consensus Expert Committee on Advanced Prostate Cancer Member of the Asian Consensus Expert Committee on Advanced Prostate Cancer ) Vice-President of the Asia-Pacific Society of Cryosurgery, Deputy Editor-in-Chief of Asian Journal of Andrology (AJA), Editorial Board Reference for Journal of Prostate Cancer and Prostate Disease (PCPD) and British International Journal of Urology (BJUI) 1.
de Bono J, Mateo J, Fizazi K, et al.
Olaparib for Metastatic Castration-Resistant Prostate Cancer.
N Engl J Med.
2020 May 28;382(22):2091-2102.
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