A new era of "combination therapy" for prostate cancer is here!

*Only for medical professionals to read and reference Professor Ye Dingwei's interpretation of the 2022 CSCO prostate cancer guidelines key points The 2022 Chinese Society of Clinical Oncology (CSCO) Guidelines Conference was held on April 23-24
.

During the period, Professor Ye Dingwei from Fudan University Affiliated Cancer Hospital gave a detailed interpretation of the updated main points of the "2022 CSCO Guidelines for the Diagnosis and Treatment of Prostate Cancer" (referred to as the "Guidelines")
.

Professor Ye Dingwei introduced: "This guideline update has three major characteristics: 1) Based on an international perspective, focusing on Chinese characteristics; 2) Paying attention to specific subtypes, with equal emphasis on precision and specification; 3) Combination therapy increases efficiency, and combination is better than sequential
.

" Medical Tumor Channel" is organized as follows for the readers
.

Feature 1: Based on an international perspective and focusing on Chinese characteristics, the revision of the 2022 guideline refers to the progress of international conferences such as EAJJ, NCCN, APCCC consensus, ESMO-Asia guideline, ASCO GU, and the latest literature in the field of prostate cancer at home and abroad
.

It is worth mentioning that Chinese scholars have participated in the compilation of international guidelines and consensus for the first time, and researches focusing on Chinese prostate cancer patients have also entered the international stage
.

Scholars from mainland China participated in the compilation and formulation of the St.
Gallen Consensus for Advanced Prostate Cancer (2021 APCCC) for the first time, discussing "triple therapy" in the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and prostate-specific membrane antigen (PSMA) in prostate cancer.
The role of diagnosis and treatment in the study, PARP inhibitors: molecular characteristics of tissues and blood, three hot issues were discussed.
Similarly, Professor Ye Dingwei and other mainland Chinese scholars also participated in the preparation and formulation of ESMO-Asia guidelines for the first time
.

The Chinese population research is once again going international, providing a reference for the diagnosis and treatment of prostate cancer in Asian countries
.

Feature 2: Emphasis on specific subtypes, precise specification and emphasis Professor Ye Dingwei said: "This "Guideline" update pays attention to the treatment of intraductal carcinoma and neuroendocrine differentiated carcinoma with poor prognosis, the standardized detection and treatment of HRR mutation patients, and the importance of The diagnostic and therapeutic value of PSMA in prostate cancer
.

” 1.
The correlation between germline mutations and prostate cancer risk in the Chinese population has been proven Correlations with Prostate Cancer Risk
.

In this study, 19 genomes were detected and analyzed in 1836 Chinese prostate cancer patients; the results showed that 89.
7% of the patients had a Gleason score of ≥8, and 65.
6% of the patients had metastases
.

In addition to BRCA2, Chinese men with germline pathogenic variants in MSH2 (15.
8-fold), PALB2 (5.
1-fold), or ATM (5.
3-fold) had a significantly increased risk of prostate cancer
.

2.
Pay attention to the diagnosis and treatment of intraductal carcinoma of the prostate (IDC-P) The positive rate of IDC-P in low-risk localized prostate cancer patients is low (2.
1%), and in intermediate-risk, high-risk, metastatic/recurrent prostate cancer The positive rate of IDC-P has gradually increased, especially in metastatic/recurrent prostate cancer, the incidence rate is as high as 56%; compared with negative patients, IDC-P positive patients have a higher proportion of germline DDR-related gene mutations (48% vs 12%) , suggesting that PARP inhibitors may be a treatment option for patients with IDC-P
.

In addition, the West China Hospital study demonstrated the importance of genetic testing for patients with advanced prostate cancer carrying IDC-P: the study included 170 patients with prostate cancer, of whom 47 were locally advanced patients who underwent local radical prostatectomy (RP).
, 46 patients with mHSPC, and 77 patients with castration-resistant prostate cancer (CRPC); the study showed that among 170 patients with prostate cancer, 124 (72.
9%) patients carried IDC-P
.

ctDNA-based genetic sequencing of all patients revealed that 803 somatic mutation genes were found in 94.
7% (161/170) of patients, of which 214 pathogenic mutations were found in 50.
0% (85/170) of patients; Compared with patients with IDC-P, IDC-P patients had a higher incidence of DNA damage repair (DDR) pathway gene mutations, including BRCA2, ATM, CDK12, CHEK2 and PALB2 (27.
4% vs 10.
9%; P=0.
038)
.

3.
Emphasis on the treatment of neuroendocrine differentiated carcinoma Professor Ye Dingwei said that patients with low PSA, large tumor burden, and poor or no response to endocrine therapy should be considered for neuroendocrine differentiated prostate cancer
.

The incidence of small cell/neuroendocrine differentiated prostate cancer in newly diagnosed patients is not high, but the degree of malignancy is extremely high; about 17% of the patients in biopsy samples of mCRPC metastases show the characteristics of small cell/neuroendocrine differentiated carcinoma; Patients with grade 5 are at high risk of developing neuroendocrine carcinoma
.

Regarding the follow-up diagnosis and treatment of neuroendocrine differentiated prostate cancer, Professor Ye Dingwei emphasized that secondary biopsy of metastatic lesions is recommended for further clarification; cytotoxic drug treatment (cisplatin/etoposide, etc.
) may be considered
.

4.
Prognosis of HRR-mutated prostate cancer is poor, and more attention should be paid to HRR gene testing.
Studies have shown that prostate cancer patients with HRR mutations often have poor prognosis and faster disease progression (prostate cancer-specific mortality in mutant vs non-mutated patients: 5.
0 years vs 16.
0 years; HR 2.
13; 95%CI 1.
24-3.
66; P=0.
006); the status of HRR testing in NCCN guidelines has been increasing year by year, and tumor HRR gene testing is recommended for all metastatic prostate cancer patients from 2020
.


.

5.
The emergence of PARP inhibitors provides a solution for HRR-mutated prostate cancer Olaparib alone can reduce BRCA in patients with HRR-mutated prostate cancer that has progressed on NHA (enzalutamide, apalutamide) therapy or ATM mutation patients had a 66% risk of imaging progression or death (HR 0.
34; P < 0.
001), and reduced the risk of imaging progression or death by 51% in all HRR mutation patients (HR 0.
49; P < 0.
001)
.

6.
PSMA plays an important role in the diagnosis and treatment of prostate cancer.
PSMA is a transmembrane protein that is highly expressed on the surface of prostate cancer cells.
important target for diagnosis and treatment
.

The application of PSMA has the following directions: preoperative staging/postoperative diagnosis of patients with biochemical recurrence New application of radionuclide therapy targeting PSMA: PSMA-guided prostate biopsy Superiority to conventional imaging and improved detection of clinically meaningful cancer with PSMA-guided prostate biopsy: a prospective randomized study, the proPSMA study, enrolled 302 patients with high-risk prostate cancer
.

The results showed that the accuracy of initial staging using PSMA PET/CT was better than that of conventional imaging (92% vs 65%); the method was fast (accurate detection and accurate puncture within 48 hours) and accurate (improved diagnostic accuracy by 27%).
, accessible (optional PSMA/PET and SPECT dual detection platform) three major advantages
.

In addition, PSMA radioligand therapy has also been shown to prolong overall survival (OS) in patients with mCRPC: the VISION study showed that patients who received ≥1 previous androgen receptor inhibitor, or received 1 or 2 taxanes PSAM-PET/CT-positive mCRPC patients (n=831)
.

Patients received standard treatment (SOC) + 177Lu-PSMA-617 or SOC alone; the results showed that compared with single SOC, SOC combined with 177Lu-PSMA-617 significantly prolonged the patient's OS (15.
3 months vs 11.
3 months; P < 0.
001)
.

Feature 3: Combination therapy is more effective, and combination is better than sequential treatment of mHSPC.
Since the advent of androgen deprivation therapy (ADT) in 2013, a variety of combination therapy has been tried in clinical practice in the past decade, including ADT combined with docetaxel.
Thalassa, abiraterone, primary tumor radiotherapy,
etc.

Today, the treatment of mHSPC has entered the era of triple therapy
.

Changes in the treatment of mHSPC 1.
The PEACE-1 study proves that ADT + abiraterone + docetaxel prolongs mHSPC OS: The PEACE-1 study is a combination of abiraterone/prednisone on the basis of standard treatment in mHSPC patients A study of pine and/or local radiotherapy; since docetaxel has become one of the standard treatments for mCSPC after 2015, ADT + docetaxel can be used in the late-stage SOC.
Of the 1173 patients who were finally enrolled, 710 had a SOC of ADT + docetaxel, 463 cases of SOC were treated with ADT alone; the results showed that ADT combined with abiraterone and docetaxel could significantly improve the OS of patients (5.
7 years vs 4.
7 years; HR=083; 95%CI 0.
69~0.
99 ; P=0.
034)
.

2.
The ARASENS study shows that ADT + dalotamide + docetaxel prolongs OS compared with standard treatment: The ARASENS study led by Professor Ye Dingwei is a randomized, double-blind, placebo-controlled Sichuan-phase Efficacy and safety of rostamide + docetaxel "triple combination" therapy in patients with mHSPC; the results showed that ADT + dalotamide + docetaxel combined treatment group could significantly reduce the risk of death in mHSPC (NE vs 48.
9 month; HR 0.
68; 95%CI 0.
57-0.
80; P<0.
001) mCRPC treatment revolution mCRPC has always been a difficult diagnosis and treatment in the field of prostate cancer
.

With the entry of docetaxel into the treatment of prostate cancer in 2004 and the addition of the PARP inhibitor olaparib in 2020, the prognosis of mCRPC patients has improved
.

With the continuous clinical exploration, the current combination therapy has shown greater clinical benefit in mCRPC patients, which opened the prelude to the combination therapy
.

Changes in mCRPC treatment 1.
The PROpel study found that olaparib plus abiraterone prolongs the survival of mCRPC patients: PROpel is a multicenter, randomized, double-blind phase III clinical study comparing olaparib combined with abiraterone and placebo Efficacy and safety of combined abiraterone in patients with mCRPC; the results showed that olaparib combined with abiraterone treatment group broke through rPFS for the first time for two years, reducing the risk of disease progression or death by 34%; and in all pre-specified subgroups The benefit of rPFS was observed in all groups, and both HRR mutation positive and negative patients benefited; Prof.
Ye Dingwei said that this study was emphasized in the "Guidelines"
.

2.
The PRESIDE study found that enzalutamide + docetaxel improved rPFS in patients with mCRPC: The PRESIDE study was a randomized, double-blind, placebo-controlled phase III study to explore the use of enzalutamide in patients with mCRPC.
The survival benefit and safety of enzalutamide combined with docetaxel showed that the PFS of the second-stage enzalutamide combined with chemotherapy group was significantly better than that of chemotherapy alone group (9.
53 months vs.
8.
28 months; HR=0.
72; 95%CI: 0.
53-0.
96; P=0.
027) Prof.
Dingwei Ye concluded: "Both mHSPC and mCRPC have entered a new era of 'combination
therapy
' All of these characteristics reflect the spirit of 'meeting challenges and following the trend'.
We hope that we will continue to conduct exploration and research in Chinese patients in the future, and develop new treatments for Chinese patients to improve the overall survival rate and 5-year survival rate
.

"Expert Profile Professor Ye Dingwei Director of the Institute of Prostate Tumors, Fudan University Director of the Shanghai Institute of Urologic Oncology Director of the Urology and Genital Oncology Committee of the China Anti-Cancer Association Executive Director of the China Anti-Cancer Association Executive Director of the Oncology Group of the Urology Branch of the Chinese Medical Association Chairperson-designate of the Asia Pacific Prostate Society (APPS)