HAO Wenzhe1, CHEN Dong1, LU Ningning2, HAN Sujun1, SI Zhannan1, YANG Feiya1, LI Wenzhuo1, SONG Gang1, XING Nianzeng1(1. Department of Urology, National Cancer Center/National Clinical Research Center for Oncology/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021;2. Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Oncology/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021)
Corresponding authors: Song Gang, Xing Nianzeng
E-mail:[email protected]
Professor Xing Nianzeng
Chief physician, professor, doctoral/postdoctoral supervisor, vice president of the National Cancer Center/Cancer Hospital of the Chinese Academy of Medical Sciences, deputy to the National People's Congress, and president of the Urology Branch of the Chinese Medical Doctor Association. He has undertaken 20 national/provincial and ministerial projects such as key projects of the Ministry of Science and Technology, National Natural Sciences, and innovative projects of the Academy of Medical Sciences, and published more than 370 papers in Adv Mater, Nat Commun, Cancer Commun, APSB and other journals, including more than 120 SCI papers, published 18 monographs, founded UroPrecision academic journal, and led the formulation of more than 10 national standards, diagnosis and treatment standards, industry guidelines and expert consensus. He has won 12 provincial and ministerial science and technology progress awards. He has won the "Wu Yang Medical Pharmacy Award" and the first Innovation Contribution Award of the World Chinese Urological Association. He has won the honorary titles of "Millions of Talents Project" national talent, "Young and Middle-aged Experts with Outstanding Contributions" of the state and the National Health Commission, and Beijing Science and Technology Leading Talent.
Song Gang
Associate Professor, Deputy Chief Physician, Master Supervisor, and Deputy Director of the Department of Urology at the National Cancer Center/Cancer Hospital of the Chinese Academy of Medical Sciences, and Deputy Director of the Department of Urology at Langfang Campus. Specializing in accurate diagnosis and robotic/laparoscopic treatment of tumors of the urinary male genital system. He is currently the executive editor-in-chief of UroPrecision magazine, the secretary of the Youth Committee of the Urology Branch of the Chinese Medical Doctor Association, the member of the Youth Committee of the Urology Branch of the Beijing Medical Association, and the member of the Youth Committee of the Urogenital Tumor Branch of the Beijing Anti-Cancer Association. Editor-in-chief of "Precise Diagnosis and Treatment of Prostate" and "Precise Diagnosis and Treatment of Bladder Cancer". He won the first prize of the Science and Technology Progress Award of the Beijing Science and Technology Award (the first completer), won 1 invention patent, 4 utility model patents, and undertook 1 national key research and development project.
Lu Ningning
Deputy Chief Physician of the Department of Radiation Oncology, National Cancer Center/Cancer Hospital of Chinese Academy of Medical Sciences, specializing in radiotherapy of urological tumors, proficient in new technologies such as magnetic resonance accelerator and hypofractionated radiotherapy. Clinical fellow at Princess Margaret Cancer Center in Canada for one year.
Han Sujun
Professor and Deputy Chief Physician of the Department of Urology, National Cancer Center/Cancer Hospital of Chinese Academy of Medical Sciences, Vice Chairman of the Youth Committee of the Urology Branch of the Chinese Medical Doctor Association, Member of the Prostate Cancer Quality Control Expert Committee of the National Cancer Quality Control Center, Member of the Urology Professional Committee of the National Health Technology Promotion, Inheritance and Application Project, Youth Member and Secretary of the Urogenital Tumor Professional Committee of the Beijing Anti-Cancer Association. Member of Beijing Oncology Society, member and secretary of Urology Oncology Professional Committee of Beijing Oncology Society.
Chen Dong
Department of Urology, National Cancer Center/Cancer Hospital of Chinese Academy of Medical Sciences, Capital Medical University-University of Rochester, USA, M.D., under the supervision of Professor Xing Nianzeng, a well-known expert in urology. At present, he is the secretary of the prostate cancer cooperation group of the Urology Branch of the Chinese Medical Doctor Association, and a member of the Urologic Oncology Youth Committee of the Beijing Cancer Prevention and Control Society. He presided over 1 youth project of the National Natural Science Foundation of China, and was selected for the young talent lifting project of Beijing Association for Science and Technology. He is the first/co-first author of more than 10 SCI papers such as JECCR and CANCER LETT, serves as a young editorial board member of SCI journals such as iMeta and Phenomics, and serves as a reviewer for more than 10 SCI journals such as Cell Death & Disease, Journal of Endourology, and Cancer MedICIsne.
Yang Feiya
Deputy Chief Physician of the Department of Urology, National Cancer Center/Cancer Hospital of Chinese Academy of Medical Sciences, M.D., under the supervision of Professor Xing Nianzeng, 2018 Beijing Outstanding Talent. He is good at the comprehensive diagnosis and treatment of urological tumors, especially minimally invasive surgeries such as robotics and laparoscopy, including resection of difficult and recurrent tumors. He served as the secretary of the Urologic Oncology Committee of the Beijing Oncology Society, and presided over or participated in scientific research projects such as the Hope Marathon, the National Key R&D Program, the National Natural Science Program, and the Beijing Initiative. At present, more than 70 articles have been published, of which more than 40 are included in SCI. He has participated in the compilation of 9 books. He has won many awards from the Ministry of Education and Beijing Science and Technology Progress Award.
Shishan-nan
Attending physician of the Department of Urology, National Cancer Center/Cancer Hospital of Chinese Academy of Medical Sciences, undergraduate and graduate students at Hebei Medical University from 2014 to 2022. In 2020 and 2022, he won the first-class scholarship at the university level. In May 2021, he was awarded the title of "Provincial Outstanding Student Cadre" in Hebei Province. In 2021, he was awarded the National Scholarship.
Hao Wenzhe
Master of Urology, National Cancer Center/Cancer Hospital of Chinese Academy of Medical Sciences. In 2020, he won the title of "Three Good Students" at the school level. In 2020 and 2022, he was awarded the university-level scientific research special scholarship.
Li Wenzhu
Master of Urology, National Cancer Center/Cancer Hospital of Chinese Academy of Medical Sciences.
Prostate cancer (PC) is the most common malignant tumor in the male genitourinary system, ranking second in the incidence of all malignant tumors in men worldwide. Although the incidence of PC in China is lower than that in Europe and the United States, the incidence and mortality rate of PC are increasing year by year with the aging of the population, the change of dietary habits and the improvement of diagnostic technology. In terms of treatment, Hood technology, robot-assisted single-port radical PC resection and radioguided surgery have improved the prognosis of patients, endocrine therapy has shown good clinical benefits in patients of different strata, immunotherapy has provided new ideas for PC treatment, and new radiotherapy technologies such as magnetic resonance have been increasingly used in the treatment of PC. However, there is still an urgent need to explore new ways of diagnosis and treatment. This article will review the progress in the diagnosis and treatment of PC in 2023, aiming to provide more options for clinical treatment decisions of PC.
【Keywords】prostate cancer, surgical treatment, endocrine therapy, targeted therapy, immunotherapy, radiation therapy
Prostate cancer (PC) is the most common malignant tumor of the male genitourinary system in the world, and its incidence ranks first among male cancer patients in the United States. In terms of diagnosis, with the release of the expert consensus on targeted puncture of the prostate, the application of targeted puncture in the diagnosis of PC has been further promoted, and the use of artificial intelligence to evaluate tumors and predict the efficacy has also become one of the important directions of future research. In terms of treatment, Hood technology, robot-assisted single-port radical prostatectomy and radiation-guided surgery have greatly improved the prognosis and quality of life of patients. Triple intensive regimens in endocrine therapy, as well as combination therapy with polyadenosine diphosphate ribase polymerase inhibitors or radionuclides, have shown good clinical benefit in patients of different strata. The development of novel androgen receptor inhibitors and the clinical study of 177Lu-PSMA-617 have promoted the development of PC-targeted therapy. The initial success of two clinical studies, the BXCL701 of programmed cell death protein 1 combined with innate immune activators in immunotherapy, and the chimeric antigen receptor T lymphocyte immunotherapy targeting 4-1BB co-stimulation of prostate stem cell antigen, provide new ideas for the immunotherapy of PC. The new technology of adaptive hypofractionated radiotherapy based on magnetic resonance accelerator developed by the team of the National Cancer Center has been increasingly used in the treatment of PC, and stereotactic radiosurgery has become a preferred option in addition to localized PC surgery. Based on this, this article mainly analyzes the diagnosis of PC in 2023 and limited-time PC, hormone-sensitive prostate cancer (HSPC), castration-resistant prostate cancer (CRPC) from seven aspects: diagnosis, surgical treatment, endocrine therapy, targeted therapy, immunotherapy, radiotherapy (referred to as radiotherapy), and basic research Treatment progress was reviewed and summarized.
1. PC diagnosis
1.1 Clinical diagnosis of PC
Most patients with PC are found by prostate-specific antigen (PSA) screening, and a small number are found by digital rectal examination (DRE) or electroresection of the prostatic hyperplasia. Currently, the gold standard for the diagnosis of PC is prostate biopsy pathology.
1.2 Digital rectal examination
PC usually originates from the peripheral zone of the prostate, and 18%~21% of PCs are found due to the abnormality of DRE alone. The positive rate of digital prostate examination is low, and PSA examination should be cooperated.
1.3 PC tumor markers
1.3.1 PSA There are many factors that cause PSA to rise, including prostatic hyperplasia, prostatitis, PC, ejaculation, catheterization, cystoscopy, DRE and prostate puncture. The normal value of total PSA is 0~4ng/ml, and the probability of PC in Chinese men is about 25% when PSA is between 4~10ng/ml, and when PSA is > 10ng/ml, further prostate puncture is required to confirm the diagnosis. The use of PSA for population-based screening in men aged 55~69 years has been recognized.
1.3.2 Free PSA (fPSA)In patients with PSA < 10 ng/ml, a lower fPSA to total PSA ratio (%fPSA) is associated with an increased risk of PC. A uniform %fPSA threshold has not yet been established, and different studies can avoid 20%~65% of the first biopsy using a threshold of 14%~28%. Compared with PC antigen, 3% fPSA was a better predictor of a positive biopsy on the second and third repeat biopsies, but not on the first repeat biopsy.
1.4 经直肠前列腺超声（transrectal ultras-ound ，TRUS）
TRUS has low specificity for the diagnosis of PC, and the typical manifestation of TRUS in PC is a hypoechoic nodule located in the peripheral zone, and transrectal contrast-enhanced ultrasound can better show the microvascular system in the prostate tissue, which improves the sensitivity and specificity of PC diagnosis.
1.5 磁共振成像（magnetic resonance imaging，MRI）
MRI provides T staging and can provide surgical techniques for nerve preservation and extensive resection of the underlying extraprostatic extension. Multiparametric MRI (mpMRI) of the prostate has become a mandatory option for the initial evaluation of patients with clinical suspicion of PC who have not undergone biopsy. The Prostate Imaging Reporting and Data System Version 2.1 is a joint initiative and framework for prostate MRI acquisition and reporting that aims to standardize techniques and interpretation across centers. By integrating advanced mpMRI methods into the diagnostic process of PC, the current challenges of screening based on serum PSA levels can be addressed, such as increased false-positive rates, inability to detect clinically significant PC by random biopsy, multifocal and molecular heterogeneity of PC, etc. The standard method for diagnosing PC is TRUS-guided systematic prostate biopsy, but it is subject to sampling error and often fails to detect clinically significant PC. mpMRI not only improves the detection of clinically significant prostate cancer (csPC), but also helps to reduce unnecessary biopsies due to its high negative predictive value. IN ADDITION, NON-CARTESIAN IMAGE ACQUISITION AND COMPRESSION SENSING TECHNIQUES ENABLE FASTER MRI ACQUISITION AND CAN BE USED FOR QUANTITATIVE MRI METHODS SUCH AS DYNAMIC CONTRAST-ENHANCED MRI (DCE-MRI). With the increasing importance of the role of prebiopsy mpMRI in the evaluation of PC, there is a growing need for innovative MRI methods that can improve PC grading, detect csPC, and guide biopsy. To meet these needs, in addition to conventional T1-weighted, T2-weighted, DCE-MRI, diffuse magnetic resonance imaging, and magnetic resonance spectroscopy, several new MRI methods have been developed, such as restriction spectrum imaging, vascular imaging, restricted diffusion methods for extracellular and tumor cell counting, hybrid multidimensional MRI, luminal water imaging, and MRI fingerprinting to better characterize the disease.
1.6 Nuclide bone scintigraphy
Bone is the most common distant metastasis site of PC, whole-body nuclear bone scan is the most commonly used method for clinical evaluation of bone metastasis, bone metastases can be detected 3~6 months earlier than conventional X-ray plain films, and the positive rate of bone scan is affected by factors such as PSA level, clinical stage and grouping of the International Society of Urological Pathology of Oncology. Suspicious bone lesions that cannot be diagnosed by bone scan should be combined with clinical factors and other imaging tests.
1.7 正电子发射断层成像/计算机断层成像(positron emission tomogt-
aphy/compyted tomography，PET/CT）
Prostate-specific membrane antigen (PSMA) is a membrane glycoprotein that is 100~1000 times more expressed on PC cells than the normal prostate. Compared with mpMRI, PSMA PET/CT has higher sensitivity and better positive and negative predictive values. It is also specific for the detection of intermediate- and high-risk primary PC. In patients with pelvic lymph nodes or distant metastases, PSMA PET/CT is 92% accurate, 27% higher than 65% for conventional imaging. The sensitivity (38%vs. 85%) and specificity (91%vs. 98%) of conventional imaging were found to be lower compared with PSMA PET/CT.
1.8 Prostate needle biopsy
Prostate needle biopsy is the gold standard for diagnosing PC. Indications for prostate puncture: (1) prostate suspicious nodule on digital rectal examination, any PSA value, (2) TRUS or MRI suspicious lesion, any PSA value, (3) PSA >10ng/ml, any fPSA and PSA density (PSAD) value, (4) PSA 4~10ng/ml, abnormal f/t PSA value and/or PSAD value. Ultrasound-guided prostate biopsy is the standard needle method, mainly ultrasound-guided transrectal needle biopsy and ultrasound-guided transperineal needle biopsy. The detection rate of the latter was similar to that of PC, while the detection rate of the latter was higher for csPC, the former had a low detection rate and a high incidence of infection complications for anterior and apical prostatic tumors, while the latter increased the detection rate of anterior and apical prostatic tumors and had a low complication rate. Therefore, ultrasound-guided transperineal biopsy is more recommended in clinical diagnosis and treatment.
Targeted needle biopsy of prostate under direct guidance of mpMRI is to obtain tissue samples directly under the guidance of mpMRI imaging, which can accurately locate and detect small lesions in real time, and can be directly guided by the rectum and directly guided by the perineum, which has the advantage of low missed diagnosis rate (6%~10%). Prostate targeted biopsy (TB) has a higher diagnostic yield of csPC than traditional systematic biopsy (SB). Focusing on the current controversial indications and treatment strategies for prostate TB, the National Cancer Center/Cancer Hospital of the Chinese Academy of Medical Sciences invited well-known urology experts and imaging experts in the field of PC in China to hold the "Panjiayuan Consensus Conference". The experts focused on 10 focus areas: imaging selection, indications for TB, transperineal and transrectal needle biopsy, TB pathway, TB versus SB, TB technology, TB needles per lesion, SB needle count, free-arm TB and future TB for prostate disease diagnosis. An expert panel of 25 urologists and 2 radiologists from China voted anonymously on 14 pre-identified questions based on clinical practice experience and the latest research results. Consensus opinion can help clinicians determine biopsy timing and strategy in the context of limited guidelines. The consensus conference also discussed the future development of prostate disease diagnostic technologies, including TB and SB combination therapy, TB technology, biopsy needle count, free-arm TB and PSMA PET/CT. This expert consensus is the first international expert consensus in the field of prostate TB, which has been published in the inaugural issue of UroPrecision magazine in 2023.
2. PC surgical treatment
Traditional prostatectomy is the most common surgical modality and aims to completely remove the patient's prostate. In the past, open surgery was the main surgical method, requiring a large abdominal incision. However, with the introduction of laparoscopic and robotic-assisted surgical techniques, laparoscopic prostatectomy and robotic-assisted prostatectomy are gradually becoming more popular options. Compared with the traditional open retropubic radical prostatectomy, this procedure can not only effectively reduce the physical trauma to the patient, but also improve the surgical efficiency, greatly reduce the intraoperative blood loss of the patient, and enable the patient to recover better after surgery. Robot-assisted laparoscopic radical PC resection is a new type of treatment for PC in developed countries in Europe and the United States, and its treatment effect is more accurate than laparoscopic radical PC resection, especially to reduce the physical damage to patients. Research data show that when performing robot-assisted laparoscopic PC radical resection on patients, three-dimensional imaging technology can be used to enable doctors to more accurately separate the patient's urethral sphincter and prostate tip, which can well prevent damage to the urethral sphincter and reduce the patient's bleeding.
Tumor control, urinary control, and recovery of sexual function are the three criteria for quality control after radical resection of anterior PC. To this end, surgeons have tried many new techniques to promote postoperative functional recovery, including the Vatikuti Institute prostatectomy (VIP), which was first proposed by Menon in the United States. Compared with the standard nerve-sparing interfascial technique, the VIP procedure can not only preserve the neurovascular bundle behind the prostate, but also preserve the prostatic fascia on the prostatic side, and retain the fascial tissue around the prostate to a greater extent, which is conducive to the recovery of postoperative function. As the technology evolves, another technique has also caught the attention of urologists – the Hood technique. The Hood technique only needs a limited free fat layer on the surface of the anterior bladder wall to establish the surgical operation space, unlike the VIP that needs to completely expose the posterior pubic Retzius space, so as to preserve the integrity of the suspension support structures around the posterior pubic urethra to the greatest extent.
In recent years, with the advancement of science and technology, there are more possibilities for the development of PC surgical treatment, in order to improve the prognosis and quality of life of patients. In 2008, single-port laparoscopic PC radical resection was performed for the first time. After 2009, robot-assisted radical PC resection was gradually carried out and better results were obtained. With the increasing number of robotic surgery cases reported, robotic-assisted single-port prostate surgery is receiving more and more attention. A recent study showed that single-port laparoscopic radical prostatectomy was associated with a favorable safety profile, with less postoperative pain, better aesthetic incisions, and faster recovery compared to traditional multi-port laparoscopy, while the functional and oncology outcomes were comparable between the two groups.
Radio-guided surgery (RGS) targeting PSMA is a kind of surgery-assisted technology, which is a bridge between preoperative image information and surgical decision-making, which can improve the identification and removal efficiency of metastatic lymph nodes during surgery, and has been widely used in foreign trials in recent years. In 2015, Schottelius et al. performed the first targeted PSMA-RGS using 111In-PSMAI&T, in which a surgeon performed the operation in an open environment with a γ-ray probe in hand. With the popularization of the minimally invasive concept, a large number of PC surgeries have been performed in a laparoscopic environment, and PSMA-RGS has gradually shifted to the use of laparoscopic γ-ray probes.
As a tumor disease that is extremely harmful to men's health, life safety and life dignity, PC needs to be effectively treated as soon as possible after diagnosis. Surgery is a common treatment for the disease, and it is also a treatment with more definite efficacy. With the continuous exploration, improvement and optimization of these different PC surgical methods, the quality of life of PC patients will continue to improve in the future.
3. PC endocrine therapy
In the past few years, new endocrine therapy (NHA) has become an important cornerstone of PC drug therapy, whether it is metastatic hormone-sensitive PC (mHSPC) stage or CRPC stage, and there are sufficient drug application data. The research related to the new endocrine therapy for PC disclosed in 2023 mainly focuses on androgen-deprivation therapy (ADT) combined with NHA + chemotherapy or programmed death-1 (PD-1) inhibitors or polyadenosine diphosphate ribose inhibitors polymerase inhibitor (PARPI) or radionuclides.
3.1 Endocrine therapy for mHSPC
3.1.1 ADT + NHA + chemotherapy [docetaxel (DOC)] The ARASENS study is a randomized, double-blind, placebo-controlled, phase III study to evaluate the efficacy and safety of ADT and DOC in combination with darolutamide versus ADT and DOC in combination with placebo in patients with mHSPC who are candidates for DOC chemotherapy. In 2022, the median overall survival (OS) time of the primary endpoint of the study was disclosed for the first time, and the risk of death was significantly reduced by 32.5% in the intensive treatment group combined with darolutamide compared with the control group (not reached: 48.9 months, HR=0.68, 95%CI 0.57~0.80, P<0.001). 2023 American Society of Clinical Oncology-Genitourinary Symposium
tem, SCO-GU) was stratified by tumor burden at the annual meeting, updating the median OS time data for the primary endpoint. In this study, intensive treatment showed that the median OS duration was prolonged in patients with high tumor burden (HR=0.69, 95%CI 0.57~0.82), high-risk (HR=0.71, 95%CI 0.58~0.86) and low-risk (HR=0.62, 95%CI 0.42~0.90), but the median OS time of patients with low tumor burden did not benefit from intensive therapy (HR=0.68, 95%CI 0.41~1.13). The study's key secondary endpoints, such as time to pain progression and time to first symptomatic bone event, also showed a benefit in the intensive treatment group (patients with low tumor burden compared to patients with high tumor burden). At the same time, safety analysis showed an increase in the incidence of grade 3 adverse reactions > intensive treatment group.
The PEACE-1 study is a multi-arm, multi-stage study to evaluate whether the application of new therapies in combination with standard of care (SOC) for mHSPC can further improve efficacy. THE SOC SET IN THE STUDY WENT THROUGH THREE PHASES OF CHANGE: ADT ALONE AS A SOC FROM 2013 TO 2015, DOC WAS ALLOWED FROM 2015 TO 2017, AND DOC WAS FORCED AS PART OF THE SOC AFTER 2017 (LATITUDE AND STAMPEDE STUDIES WERE PUBLISHED).
Results from the previously disclosed PEACE-1 study showed that ADT+DOC+abiraterone (ABI) (+prednisone) improved median OS time (3.47 years versus 5.14 years) and reduced the risk of death by 28% in patients with high tumor burden compared with ADT+DOC treatment, but no benefit was observed in patients with low tumor burden. The results of the PEACE-1 study published by ASCO-GU in 2023 showed that the ADT+DOC+ABI (+prednisone) augmentation regimen had a significant effect on median radiographic progression-free surv-
ival, rPFS) and median OS time decreased with age. Therefore, the benefits of ADT+NHA+DOC intensive therapy regimen are mainly in people with high tumor burden and relatively young (< 70 years), while for patients with low tumor burden and advanced age (≥70), the survival benefit is not large, and there may be more adverse effects.
Both the ARASENS and PEACE-1 studies suggest that compared with ADT+DOC and ADT+DOC+NHA, intensive therapy can benefit from high tumor burden, while patients with low tumor burden cannot benefit from intensive therapy. Multiple meta-analyses have also shown that intensive therapy with ADT+NHA+DOC may be more appropriate for high tumor burden, and ADT+NHA+DOC is not superior to ADT+NHA dual therapy and has higher toxicity for low tumor burden. The 2023 guidelines from the National Comprehensive Cancer Network (NCCN) recommend intensive therapy only in mHSPCs with high tumor burden and who are suitable for or tolerant chemotherapy.
The PEACE-1 study presented at the 2023 ASCO Annual Meeting showed that SOC+ABI (+prednisone) + radiation therapy (RT) prolonged rPFS (HR=) in metastatic castration-resistant prostate cancer (mCSPC) populations with low tumor burden metastatic castration-resistant prostate cancer (mCSPC). 0.65, 95%CI 0.36~1.19, P=0.02), RT combined with ABI (+ prednisone) + ADT intensive therapy could improve rPFS and median castration resistance free-survival (CRFS) in mHSPC with low tumor burden Although OS did not improve, PEACE-1 was the first study to suggest that RT had the ability to reduce the occurrence of serious genitourinary-related events, regardless of tumor burden. Triple therapy [ADT + ABI (+ prednisone) + RT] can be used as standard of care for patients with mHSPC with low tumor burden.
The exploration of mHSPC treatment regimens has evolved from the previous ADT monotherapy, combined androgen blockade (CAB) regimen, ADT + chemotherapy or novel endocrine two-drug combination therapy to ADT + NHA + chemotherapy triple intensification regimen. Results from the ARASENS study, the PEACE-1 study, and meta-analysis showed that compared with ADT+DOC, the patients with mHSPC with high tumor burden and suitable for or tolerant of DOC chemotherapy were mainly those who benefited from the intensive treatment regimen of ADT+DOC. However, there is still controversy as to whether the augmentation regimen is superior to the ADT+NHA duplex regimen. For mHSPCs with low tumor burden, ADT+NHA+RT regimens are a better choice.
3.1.2 ADT+NHA+PD-1 inhibitors The KEYNOTE-991 trial showed that the addition of pembrolizumab to enzalutamide + ADT did not significantly improve rPFS in patients with mHSPC, and the frequency of treatment-related adverse events of any grade and grade ≥3 was higher in the intensive treatment group, so it was discontinued in the first prespecified interim analysis. Treatment of mHSPC with ADT+NHA+PD-1 inhibitors did not result in a survival benefit.
3.1.3 Relationship between NHA treatment and deep remission and survival benefit of PSA The results of the 2023 updated ARASENS study, the TITAN study, and the CHART study all found that NHA (darolutamide, apalutamide, revilutamide) regimen combined with ADT therapy can cause a more rapid and large decline in PSA, and a large response to PSA is associated with survival benefit. PSA response is again supported by the fact that PSA response is one of the important prognostic indicators for patients with mHSPC.
3.2 Endocrine therapy for metastatic CRPC (mCRPC).
3.2.1 Results previously published in the ADT+NHA+PARPI PROpel (NCT03732820) study showed that first-line treatment with ABI (+prednisone) + olaparib significantly extended the median rPFS time in patients with mCRPC (24.8 months versus 16.6 months, HR=0.66, 95%) compared with placebo + ABI (+prednisone) The CI was 0.54~0.81, P<0.001), and patients could benefit from this PARPI combination therapy regardless of their homologous recombination repair mutation (HRRm) status. In the ABI (+prednisone)+olaparib group, a median OS time benefit trend was observed (42.1 months versus 34.7 months, HR=0.81, P>0.05). Exploratory analysis of biomarker subgroups showed a clear benefit of olaparib plus ABI (+ prednisone) on the median rPFS time and median OS time in patients with mCRPC with breast cancer susceptibility gene mutation (BRCAm). 2023 European Society for Medical Oncology (European Society for Medical oncology (ESMO) presented data from the non-BRCAm subgroup in the PROpel study: olaparib + ABI (+ prednisone) treatment resulted in a significant median rPFS time benefit in non-BRCAm patients compared with placebo + ABI (+ prednisone), with a median rPFS time of 24.1 months versus 19.0 months (HR=0.76, 95% The CI was 0.61~0.94), and the blinded independent center assessment was 27.6 months to 16.6 months (HR=0.72, 95%CI 0.58~0.90). The treatment of olaparib combined with ABI (+ prednisone) showed a certain trend of median OS time benefit (39.6 months vs. 38.0 months, HR=0.91, 95%CI 0.73~1.13).
The TALAPRO-2 study is another clinical trial investigating PARPI (talazoparib) and a novel androgen receptor inhibitor (enzalutamide) in patients with mCRPC, using a combination model at the beginning of the first line. The results of this study showed that compared with placebo plus enzalutamide, the median rPFS time of patients in the taprazoparib plus enzalutamide group was significantly longer in the HRRm cohort, and compared with the non-BRCAm (HR=0.68, 95%CI 0.46~1.02, P=0.060), the median rPFS time of BRCAm patients was more beneficial (HR=0.20, 95%CI 0.11~0.36, P<0.0001). Although the median OS time data were not complete, there was a trend of benefit in HRRm patients (HR=0.69, 95%CI 0.46~1.03, P=0.068); no new safety issues were found, and anemia was the most common grade 3 and 4 adverse reactions.
The MAGNITUDE study is a prospective, international, multicenter, randomized, double-blind phase III clinical trial to evaluate the efficacy and safety of niraparib (NIRA) in combination with ABI (+prednisone) versus ABI (+prednisone) in the first-line treatment of mCRPC. The results, published in 2022, showed that NIRA in combination with ABI (+ prednisone) as first-line therapy could significantly improve median rPFS time and other clinical outcomes in patients with mCRPC harboring HRRm. Results after a median follow-up of 35.9 months were presented at the 2023 ESMO Annual Meeting: median OS time in the NIRA+ABI (+prednisone) group was better in the BRCA+ group than in the placebo + ABI (+prednisone) group (30.4 months: 28.6 months, HR=0.788, 95% CI was 0.554~1.120), and preset multivariate analysis showed that the median OS time benefit was more significant in the NIRA+ABI (+prednisone) group (HR=0.663, 95% The CI was 0.464~0.947), and the NIRA+ABI (+prednisone) group was significantly improved in other secondary endpoints, such as time to symptom progression (HR=0.562, P=0.0056) and time to cytotoxic chemotherapy (HR=0.598, P=0.0192).
3.2.2 ADT + NHA + chemotherapy (cabazitaxel) Enzalutamide combined with cabazitaxel in patients with mCRPC (n=37) (n=37) The results of the phase I and II studies showed that the median rPFS time was 22.2 months, the median OS time was 25.1 months, and the objective response rate (objecti-
ve response rate，ORR）为50%。
3.2.3 ADT + NHA + radionuclide ERA-223 is a randomized, double-blind, placebo-controlled phase III clinical study in patients with mCRPC, in which 806 patients were randomly assigned to receive 223Ra in combination with ABI (+ prednisone or prednisone) or placebo in combination with ABI (+ prednisone or prednisone). The study, which was unblinded early on November 17, 2017 (because the 223Ra group had a higher number of fractures and deaths than the placebo group in an unplanned interim analysis), showed that the 223Ra + ABI (+ prednisone or prednisone) treatment group did not improve median OS time (33.3 months versus 30.7 months, HR=1.195) and had a higher incidence of clinical fractures compared with the control group. Based on the results of the ERA-223 study, a similar study in the future called for mandatory use of osteoprotectants.
The REASSURE (NCT02141438) study, a global, prospective, single-arm observational, real-world study evaluating 223Ra in the treatment of mCRPC, showed no new safety signals or increased fracture risk in the treatment of mCRPC with 223Ra plus enzalutamide, and a significantly longer median OS time in the 223Ra plus enzalutamide group compared with the crossover and overall population. An international multicenter, randomized phase III study (PEACE III, NCT02194842) is underway to investigate the safety of 223Ra in combination with enzalutamide.
3.2.4 ADT+NHA+PD-1 inhibitors
The randomized phase III KEYNOTE-641 study (NCT03834493) showed that ADT + enzalutamide + pembrolizumab did not improve median OS time in patients with mCRPC compared with ADT + enzalutamide (24.7 months versus 27.3 months, HR=1.04, P=0.66), and there was no significant benefit in median rPFS and median event-free survival. The combination of immune checkpoint inhibitors and NHA still needs to explore more suitable populations.
In summary, from the perspective of the whole process management of patients with advanced PC, screening a more suitable stratified population, better combination of existing drugs (ADT+NHA), and arranging troops can make patients achieve longer survival benefits.
4. PC targeted therapy
The VISION study enabled 177Lu-PSMA-617 to become the first U.S. Food And Drug Administration (FDA)-approved targeted radioligand therapy for the treatment of mCRPC. Based on the data from the VISION study, 177Lu-PSMA-617 received Breakthrough Therapy Designation from the U.S. FDA in 2021 and was officially launched in the U.S. and Europe in 2022. NCCN guidelines recommend the use of 177Lu-PSMA-617 in combination with standard therapy (category 1 evidence) for patients who have failed both prior neocrine therapy and DOC chemotherapy with positive PSMA. The 2022 Chinese Society of Clinical Oncology (CSCO) guidelines added 177Lu-PSMA-617 in combination with standard therapy (category 2B evidence). The PSMAfore (NCT04689828) study further advanced the indication to test the efficacy and safety of 177Lu-PSMA-617 in chemotherapy-naïve patients with mCRPC. The study included inhibitors in the first-line androgen receptor pathway inhibitor, ARPI) is suitable for replacement ARPI treatment of mCRPC patients with at least 1 PSMA-positive lesion without exclusionary PSMA-negative lesions, subjects randomized 1:1 to receive 177Lu-PSMA-617 or ARPI replacement therapy, patients who are randomized to the ARPI treatment group after central review of imaging progression can be crossed over to the 177Lu-PSMA-617 treatment group, the study endpoint includes median rPFS time, Median OS time (key secondary endpoints), etc. The results of this study showed that the median rPFS time in the 177Lu-PSMA-617 and ARPI groups was 12.02 months and 5.59 months, respectively (HR=0.43, 95%CI 0.33~0.54), and there was a significant benefit in the 177Lu-PSMA-617 group, with an ORR of 50.7% and 14.9% in the two groups, respectively, and the complete response rate in the 177Lu-PSMA-617 group was as high as 21.1%. The analysis of other study endpoints such as PSA level, time to symptomatic skeletal events, health-related quality of life, and time to pain progression all showed that 177Lu-PSMA-617 had better treatment performance, and 177Lu-PSMA-617 had a stronger safety profile, with a lower incidence of grade 3~4 adverse events (33.9%∶43.1%) and serious adverse events (20.3%∶28.0%) than those in the ARPI group. PSMAfore studies have shown that radioligand therapy plays a positive role in improving patient survival, as well as improving quality of life through tumor control. The importance of the PSMAfore study lies in the fact that it has demonstrated that radioligand therapy can also be significantly beneficial in patients with CRPC who are not treated with chemotherapy, and has a good application prospect.
A phase II ENZA-p study explored the use of enzalutamide ±177Lu-PSMA-617 in the first-line treatment of mCRPC, with a median PSA progression-free survival (PSA progression-free) for the primary endpoint survival, PSA-PFS) time analysis showed that the median PSA-PFS of the enzalutamide +177Lu-PSMA-617 treatment group was significantly better than that of the enzalutamide monotherapy group (13 months: 7.8 months, HR=0.43, 95%CI 0.29~0.63, P=0.00001), and the treatment of enzalutamide combined with 177Lu-PSMA-617 was also longer, reducing the risk of imaging progression or death by 33%; Compared with enzalutamide alone, enzalutamide in combination with 177Lu-PSMA-617 had a higher PSA50 response rate (93%vs. 68%) and PSA90 response rate (78%vs. 37%). In addition, 177Lu-PSMA-617 is being extensively explored in different disease stages and treatment lines for PC. The PSMAddition study aims to verify the efficacy and safety of 177Lu-PSMA-617 in mHSPC, and is expected to broaden the scope of benefits to hormone-sensitive patients, rather than castration-resistant patients, bringing more treatment options and better survival outcomes to more PC patients.
5. PC immunotherapy
Whether it's ADT, or newly developed drugs such as enallutamide and ABI, most patients develop drug resistance. In contrast, immunotherapy focuses on restoring and strengthening a patient's immune system, and its superior efficacy over other drug treatments has been demonstrated in a variety of cancers. For PC, investigators are looking for and evaluating new immunotherapies and hopefully find effective treatment strategies.
5.1 免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）
In the phase III. KEYNOTE-921 study (NCT03834506), the efficacy and safety of pembrolizumab + DOC (n=515) and placebo + DOC (n=515) in patients with mCRPC who had received NHA were evaluated, with median rPFS time of 8.6 and 8.3 months (HR=0.85, 95%CI 0.71~1.01, P=0.0335), median OS time of 19.6, At 19.0 months (HR=0.92, 95%CI 0.78~1.09, P=0.1677), the incidence of treatment-related adverse events (TRAEs) was 94.6% and 94.9%, respectively. This clinical trial suggests that the addition of pembrolizumab to DOC does not provide significant benefit in patients with mCRPC who have received prior NHA therapy, but it does not result in a significant increase in TRAEs.
The efficacy and safety of pembrolizumab + olaparib or NHA in patients with mCRPC who have failed chemotherapy were evaluated in the phase III KEYLYNK-010 study (NCT03834519). The results of the study showed that the median rPFS time was 4.4 months (95%CI 4.2 months~6.0 months) and 15.8 months (95%CI 14.6 months~17.0 months) in the pembrolizumab + olaparib treatment group, and the median rPFS time was 4.2 months (95%CI 4.0 months~6.1 months) and 14.6 months (95% %) and 14.6 months (95% %) in the NHA treatment group, and the median rPFS time was 14.6 months (95% The CI was 12.6 months ~ 17.3 months), there was no significant difference between the two treatment groups (all P>0.05), the ORR of the pembrolizumab + olaparib group was higher than that of the NHA group (16.8%vs. 5.9%, P<0.05), and TRAEs occurred in 34.6% and 9.0% of the participants, respectively, and there were no clinically meaningful changes in health-related quality of life and disease-related symptom scores compared with baseline in the two groups (all P>0.05).
The CheckMate 650 study (NCT02985957) is a clinical study evaluating PD-1 inhibitors in combination with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, and nivolumab + ipilimumab treatment improves PSA remission rates compared with ipilimumab monotherapy. Although the dual immunity therapy of PD-1 inhibitors in combination with CTLA-4 inhibitors has shown a certain degree of clinical benefit in patients with mCRPC, due to the obvious > grade 3 TRAEs and higher discontinuation rates, it should be carefully selected in clinical use by weighing the clinical benefit and drug toxicity.
In addition, a phase II.a clinical trial (NCT03910660) enrolled 32 patients with mCRPC with features of small-cell neuroendocrine cancer (SCNC) who were treated with pembrolizumab in addition to oral innate immune activators BXCL701 and demonstrated good treatment tolerance (the main TRAEs were hypotension, fever, fatigue) and considerable antitumor activity; 5 of 25 evaluable patients achieved partial response (PR) with an ORR of 20% and a composite response rate of 25%; responders were patients with low microsatellite stability and/or tumor mutational burden who had a poor monotherapy response to PD-1 inhibitors; 11% of 27 patients with evaluable PSA had at least a 50% reduction in PSA from baseline; In 4 patients with evaluable circulating tumor cells (CTCs), the CTC response rate was 25%. Therefore BXCL701 combination with pembrolizumab has anti-tumor effects on neuroendocrine PC with a manageable safety profile.
5.2 T淋巴细胞衔接体及双特异的T淋巴细胞接合器（bispecific T-cell engager，BiTE）
Xaluritamig (AMG509) is a novel bispecific bispecific prostate epithelial antigen of the prostate 1 (STEAP1) xCD3 XmAb 2+1 T lymphocyte redirecting bispecific antibody designed to redirect T lymphocytes to kill STEAP1-expressing PC cells. Kelly et al. performed AMG509 monotherapy dose exploration in mCRPC patients for the first time, and the results showed that different degrees of TRAEs were observed in 97 patients, of which the incidence of grade ≥3 TRAEs was 52.6%; The response rate of PSA50 was 49% and the ORR was 24%, showing better therapeutic effect (59% and 41%) at the target dose ≥ 0.75mg, and the preliminary pharmacokinetic analysis showed that the drug dose increased proportionally with the degree of exposure, and the average terminal half-life was about 3~4d. In the future, more in-depth research will be conducted on AMG509 drug, which is expected to become a new treatment option for patients with mCRPC.
Tarlatamab (AMG757) is an extended, bispecific antibody with a median half-life of 9.8 days, which redirects CD3+ T lymphocytes to kill cells expressing δ-like ligand 3 (DLL3), exhibiting potent and long-lasting antitumor activity. Clinical trials (NCT04702737) of AMG757 in patients with primary SCNC and treatment-evoked SCNC are ongoing, and the first objective response observed to date was achieved in a patient with primary SCNC. The patient had previously undergone prostatectomy but subsequently developed a new soft tissue mass at the junction of the right ureter and iliac vessels, and the tumor shrank by >30% within 10 months of AMG757 treatment, and PR was consistently confirmed. Overall, these results suggest that DLL3 can be identified as a therapeutic target for SCNC, and DLL3-targeted BiTE immunotherapy has significant antitumor activity in this aggressive PC subtype.
JNJ-63898081 (JNJ-081) is a bispecific antibody against PSMA and CD3, and the results of phase I clinical trial showed that all 39 patients experienced ≥1 TRAEs, and 4 patients observed dose-limiting toxicity; cytokine release syndrome syndrome, CRS) and infusion-related reactions can be administered subcutaneously and gradually increase the dose from high doses to achieve PR, anti-drug antibody responses were observed in 19 patients, and the therapeutic dose > 30 μg/kg can cause a temporary decrease in PSA.
5.3 嵌合抗原受体T细胞免疫疗法（chimeric antigen receptor T-cell immunotherapy, CAR-T）
Following the announcement of the results (NCT03089203) of the first human Phase I clinical trial of CART-PSMA-TGFβRDN in 2022, the results of several other αβT lymphocyte-based CAR-T products are also forthcoming (NCT02744287, NCT04249947, NCT03089203, NCT02744287, NCT03873805). Dorff et al. announced that CAR-T therapy targeting 4-1BB co-stimulation using prostate stem cell antigen (CAR-T therapy) for the treatment of mCRPC patients who had failed at least one line of ARPI-targeted therapy showed that 79% of the 14 patients had 80% of tumor cells expressing >2+ PSCA, and after using the chemotherapy dose of modified lymphodepletion (LD), all patients did not experience dose-limiting toxicity, and the best efficacy was stable disease; 60% CAR-T amplification can last up to 28 days, and CTC reduction in bone marrow and peripheral blood occurs at the same time as PSA decline. These results indicated that CAR-T exhibited anti-tumor activity in patients with mCRPC, and reducing the dose of LD chemotherapy could improve toxicity.
In 2023, there will be many breakthroughs in the preclinical research of CAR-T for PC, using cutting-edge γδT lymphocytes to make CAR-T targeting PSCA, significantly reducing the diameter of mouse tumors. For patients with PC bone metastasis, targeted treatment can be carried out, and the combination of zoledronic acid can not only kill tumor cells but also protect the bone health of patients with bone metastasis. STEAP1-targeting CAR-T combined with interleukin 12 (IL-12) immunotherapy and STEAP2-targeting dnTGFβRII-loaded CAR-T have achieved promising results in preclinical studies. In addition, B7-H3-targeting CAR-T therapy may become a new PC immunotherapy strategy.
5.4 PC vaccines
Human telomerase reverse transcriptase (hTERT) vaccine in combination with androgen deprivation therapy and radiotherapy in patients with primary metastatic PC. The results of the phase II clinical trial (NCT01784913) showed that 9 of the 22 patients survived, with a median time to PSA progression of 21 months, a median OS time of 62 months, and a median specific survival time of 84 months. Therefore, hTERT vaccination may have a clinical benefit in a subset of men with mHSPC receiving ADT and radiotherapy.
The results of the phase II clinical trial (NCT03600350) of DNA vaccine (pTVG-HP) and nivolumab in non-mHSPC showed that no patients achieved complete remission of PSA, 21% of patients experienced PSA reduction of >50%, median rPFS time was not reached, and 47% of patients experienced immune-related adverse events (irAEs); CT shows that treatment elicits an anti-tumor response at a single tumor site, but new lesions continue to appear over time. In conclusion, the combination of pTVG-HP and nivolumab is safe and immunoactive, prolongs disease progression but does not eradicate the disease.
A phase II, double-blind randomized controlled trial showed that PROSTVAC did not cause a more favorable peripheral T lymphocyte response in patients with topical PC compared with controls, and there was no difference in clinicopathologic effects. In addition, a multicenter randomized clinical trial (NCT00450463) showed that the combination of fluoramide + PROSTVAC failed to improve the prognosis of non-mCRPC in men compared with fluoramide alone.
PF-06753512 completed a phase I clinical trial (NCT02616185) in patients with PC, and the results showed that 91 patients were treated with dose escalation (38 cases of mCRPC) and dose expansion (35 cases of biochemical recurrence of prostate cancer, 18 cases of mCRPC), with TRAEs and irAEs of 70.3% and 42.9%, respectively, and ORR of 5.6% (95%CI 1.2%~15.4%) in patients with mCRPC ), the median rPFS time was 5.6 months (95% CI 3.5 months ~ not reached), the PSA50 rate was 25.7% in patients with biochemical recurrence of prostate cancer, and the median duration of PSA response in cohorts 5B-prostate cancer biochemical recurrence and 1B-prostate cancer biochemical recurrence was 3.9 months (95% CI 1.9 months~4.2 months) and 10.1 months (95% CI was 6.9 months ~ 28.8 months), and overall, the response of antigen-specific T lymphocytes to PSMA was 88.0%, 84.0% to PSA, and 80.0% to PSCA. The PF-06753512 study demonstrated a similar safety profile to other ICIs combination trials, with significant TRAEs in some patients with biochemical recurrence of prostate cancer. Stimulates antigen-specific immunity in all cohorts and produces modest antitumor activity in patients with biochemical recurrence of prostate cancer without ADT.
In conclusion, a considerable number of studies have been conducted on PC immunotherapy, ranging from ICIs monotherapy to combination therapy, but have not been shown to have the same efficacy as other tumors. Current findings are more favoured towards screening for possible stratification or predictors to assess the subset of patients who may benefit. BXCL701 clinical studies suggest that the combination of existing PC treatment regimens and immune-activating drugs may be an important direction for PC immunotherapy in the future. In addition, although there are few clinical studies of CAR-T for the treatment of PC in 2023, the clinical studies in 2022 and the preclinical studies in 2023 have shown considerable efficacy and controllable toxicity, so CAR-T is also a direction that cannot be ignored in the future of PC immunotherapy, and PC is expected to become the first solid cancer to be approved by the FDA for the use of CAR-T.
6. PC radiotherapy
6.1 Radical radiotherapy for PC with limited limit
6.1.1 Advances in radiotherapy technology The 15-year follow-up results of the ProtecT study further confirmed that for localized early-to-mid-stage PC, the efficacy of radiotherapy and surgery was similar, and the TRAEs were different, with a 15-year PC mortality rate of about 2% and a distant metastasis probability of about 5% in both groups. The PACE-A study is the first clinical trial to investigate the efficacy of stereotactic body radiotherapy (SBRT) versus surgery in localized PC, without ADT in all patients. The results of this study showed that compared with the surgical treatment group, SBRT significantly improved the score of sexual dysfunction (57.5:29.3, P<0.001) and significantly improved the symptoms of urinary incontinence (4.5%vs. 46.9%, P≤0.001), but the incidence of intestinal TRAEs was high. As a milestone in radiotherapy, MRI-guided precision radiotherapy has shown preliminary results with lower TRAEs in clinical practice. The MIRAGE study included 156 patients who were randomly assigned to magnetic resonance guided radiation therapy (MRgRT) and computed tomography guided radiation therapy (CTgRT), and the results showed that the MRgRT group had a grade 2 ≥ urology compared with the CTgRT group (24.4% vs. 43.4% , P=0.01) and intestinal (0%∶10.5%, P=0.003) acute TRAEs were significantly reduced, and the patient-reported 1-month ≥-15 International Prostate Status Score (6.8%∶19.4%, P=0.01) and the patient-reported 1-month ≥ 12-point extended prostate cancer composite index were both low (25%∶50%, P=0.01). The team of Professor Lu Ningning, Li Yexiong and Xing Nianzeng from the Cancer Hospital of the Chinese Academy of Medical Sciences carried out the first adaptive hypofractionated radiotherapy PC based on magnetic resonance accelerator in Chinese mainland, acute TRAEs were rare in all patients, dosimetry analysis showed that the dose of online adaptive radiotherapy was reliable, and the standard process of shape adaptive radiotherapy PC was summarized.
With the maturity of precision radiotherapy technology, hypofractionated radiotherapy with 36.25 Gy in 5 fractions or 42.7 Gy in 7 fractions has also been written into major guidelines (NCCN, ASTRO, ASCO, AUA, SUO, ESTRO, RANZCR), and has become one of the recommended treatment modes for patients with limited-stage low-intermediate-high-risk PC.
6.1.2 Research progress in combination with endocrine therapy There has been controversy about whether endocrine therapy is necessary and optimal for patients with limited intermediate-risk PC. RTOG0815 study included 1492 patients with intermediate-risk PC (T2b~T2c stage, Gleason score 7 or PSA >10ng/ml and ≤20ng/ml) with a median follow-up of 6.3 years, the results showed that on the basis of high-dose radiotherapy, although the addition of secretion therapy within 6 months reduced the metastasis rate (3.1%∶0.6%, P<0.001), PC mortality (0.9%∶0%, P=0.007) and PSA failure probability (14%∶8%) , P<0.001), but the 5-year OS rate was similar between the two groups (90%vs. 91%, P=0.22). Therefore, clinical decision-making requires a trade-off between drug toxicity and clinical benefit. Meta-analyses of the only two randomized controlled trials (RCTs) in the world showed that early radiotherapy combined with adjuvant ADT had fewer distant metastases (12% and 18% at 15 years, P = 0.04) and biochemical failure (33% and 43% at 15 years) and biochemical failure (33% and 43%, respectively) than the neoadjuvant ADT + delayed radiotherapy model , P=0.002), while the two groups had similar late TRAEs. This suggests that neoadjuvant ADT does not reduce TRAEs, so it is important not to delay the start of radiotherapy in patients at intermediate and high risk of localization.
Meta-analysis of 10,000 patients in 12 RCTs spanning 60 years in > 10,000 patients showed that the addition of ADT to curative radiotherapy in limited intermediate- and high-risk patients improved metastasis-free survival (MFS), OS time, according to the different risk stratification of NCCN, ADT will reduce 1 distant metastasis at 10 years for every 8~18 patients treated, MFS and OS time can also be improved when adjuvant ADT is extended from 4~6 months to 18 months, for NCCN high-risk patients, adjuvant ADT will reduce 1 distant metastasis at 10 years for every 10 patients treated, and prolonging the time of neoadjuvant ADT (from 3~4 months to 6~9 months) can not improve any survival. However, the study included a patient population spanning more than 60 years, during which the level of diagnosis and advances in radiotherapy technology could potentially influence the conclusions: for example, less than 20% (1018/5136) of patients who were analysed with or without ADT (≥74 Gy) were analysed, 74% (2688/3657) of patients were at high risk (2688/3657) were analysed with prolonged adjuvant ADT, while only 22% (≥856/ 3774), and there was no significant difference in the benefit of prolonged adjuvant ADT in the high-dose radiotherapy subgroup (P=0.200). Another meta-analysis of three recent RCTs in limited high-risk patients also showed that it was possible to achieve the best time to distant metastasis-free survival (DMFS) with only 12 months of ADT when given a higher dose of prostate (external beam radiation plus brachytherapy boost), while external beam radiation alone required > 18 months of ADT even ≥ 74 Gy. Based on precision radiotherapy technologies such as magnetic resonance accelerators, the hypofractionated irradiation of 36.25~40.0 Gy in 5 fractions is equivalent to 74~88 Gy (α/β=3) or even 90~108.6 Gy (α/β=1.5) in the future.
6.1.3 Research progress on the comparison of radiotherapy and surgery for localized high-risk PC SPCG-15 is currently the only international RCT on the efficacy of surgery and radiotherapy in patients with localized high-risk PC, and it is a multicenter study from Northern Europe. Enrollment criteria for the study: ≤ 75 years old, T3~T4 stage (DRE or MRI showed obvious extraprostatic invasion), and ≥ Gleason3+4, N0M0, and PSA <100 ng/ml, PET/CT is allowed to participate in staging. The patients in the study were randomly divided into the experimental group (surgery + extended lymph node dissection, no neoadjuvant or adjuvant endocrine dissection, the surgical group included obturator, internal iliac/external/total to the ureter across the external iliac artery, which can be adjuvant or salvage radiotherapy, and endocrine therapy can be added during radiotherapy) and control group (radiotherapy plus neoadjuvant 3 months + adjuvant 21 months of endocrine therapy), and the primary endpoint event was PC-specific survival. Enrollment was originally scheduled to be completed in 2022, but only 600 patients > enrolled as of 2022, and preliminary analysis showed that the clinical characteristics of the two groups matched, but it took an extended time to complete the enrollment.
6.2 局限期PC术后放疗
6.2.1 Indications for postoperative radiotherapy The three RCTs of RADICALS-RT, GETUG-AFU 17 and RAVES all preliminarily showed that under the premise of no ADT before or after surgery, for patients with PSA < 0.1~0.2ng/ml after R1 but PSA can wait for PSA to rise to 0.1~0.2ng/ml and start early salvage. At a median follow-up of 8 years, the 10-year DMFS rates in the adjuvant radiotherapy group and the early salvage radiotherapy group were 93% and 90% (HR=0.68, 95%CI 0.43~1.07, P=0.095), and OS rates were 88% and 87% (HR=0.98, 95%CI 0.67~1.44, P=0.92).
However, the above three RCTs were mainly intermediate-risk patients, and only about 20% or lower of patients with Gleason score 8~10 or T3~T4 were included. A meta-analysis of patients with more pathologic prognostic factors by D'Amico et al. showed that patients with Gleason score of 8~10 and T3~T4 (P=0.02) or N1 (P=0.04) were more likely to benefit from postoperative adjuvant radiotherapy, and for these patients, planned adjuvant radiotherapy after surgery could reduce all-cause mortality.
Therefore, if the patient intends to decide whether to receive early salvage radiotherapy according to the trend of PSA after surgery, he should avoid preoperative or postoperative ADT therapy, closely observe PSA during follow-up, and actively undergo early salvage radiotherapy when PSA reaches 0.1ng/ml, but if the patient's pathology suggests more adverse prognostic factors, such as T3~T4 stage with Gleason score of 8~10 or N1 stage, adjuvant radiotherapy should be given as soon as possible after the recovery of urinary continence.
6.2.2 Postoperative radiotherapy dose There are two RCTs on postoperative radiotherapy dose, both of which have recently published results. One of the studies included 144 patients with PC with pT3~T4 stage, R1 or postoperative biochemical failure (PSA>0.2ng/ml), and the results showed that there was no significant difference in efficacy between the 66 Gy and 72 Gy groups, but the 72 Gy group had a significant increase in 7-year biochemical progression-free survival (bPFS) time in patients with Gleason score 8~10 and multiple positive margins (30.2%) ∶66.5%, P=0.012 and 57.5%∶92.5%, P=0.037), but only 55 cases had a Gleason score of 8~10 in the whole group, and only 60 cases had positive multiple margins. Another RCT, SAKK09/10, included 350 patients with biochemical failure after radical prostatectomy (RP) who were randomly assigned to 64 Gy and 70 Gy radiotherapy groups with a median follow-up of 6.2 years, with 62% and 61% of the 6-year biochemical progression-free rates in the two groups, respectively, while other patients with clinical recurrence-free survival, time to salvage hormone therapy, and OS were similar, and there were no significant differences in advanced TRAEs and quality of life between the two groups. Comparing the two RCTs, there were some differences in the characteristics of the included patients: about 88% of the patients in the SAKK09/10 study underwent extensive lymph node dissection (5 in both left and right pelvic regions for median lymph node dissection), and only about 40% of patients had T3a~Tb stage (no T4 patients), while less than 10% of patients in the first study underwent pelvic lymph node dissection (the exact number of dissections was unknown), and about 70% of patients with T3a~T4 stage. Differences in the clinical characteristics of these enrolled patients may affect the final efficacy.
Although the number of patients enrolled in the above two studies was not large, and the data on the susceptibility of patients with Gleason score of 8~10 or positive margins in the first study was not a preset subgroup analysis, these two studies showed that the conventional fractionated postoperative radiotherapy dose of 64~66 Gy was sufficient for most patients after RP, especially some patients with higher risk and more pathological adverse factors may benefit from postoperative incremental radiotherapy, but more data support is still needed.
6.2.3 Whether pelvic irradiation is required for postoperative radiotherapy In the NRG, RTOG0534 and SPPORT studies, patients after RP were randomly divided into prostate bed radiotherapy (PBRT) alone, PBRT+short-course ADT and PBRT+short-course ADT+pelvic prophylaxis, with a median follow-up of 8.2 years and 5-year PFS rates of 70.9% (95%CI 67.0%~74.9%) and 81.3%, respectively (95% CI 78.0%~84.6%) and 87.4% (95% CI 84.7%~90.2%) (3 groups were different from 1 group before), and the other 3 groups were similar except for the 3 groups with slightly higher grade ≥2 advanced hematology and bone marrow suppression than the 2 groups. This is also the first time in the world that pelvic prophylaxis plus short-term endocrine is superior to tumor bed irradiation alone. It should be noted that about half of the patients in the SPPORT study were staged ≥ T3, about half of the surgeries were R1 resection, and about one-third of the patients did not undergo surgical management of pelvic lymph nodes during surgery. According to the definition of early and late salvage in the RADICALS-RT study, at least half of the patients with late salvage (median PSA was 0.3~0.4ng/ml), and 55% of patients had a PSA doubling time of < 1 year. These suggest that this patient group is more likely to benefit from pelvic prophylaxis and endocrine therapy.
The PROPER study is a patient with postoperative pathology suggesting N1 stage (1~4 lymph node metastasis), randomly divided into prostate bed irradiation only or prostate bed + pelvic irradiation, both groups were given ADT for 2 years, unfortunately the study was terminated due to too slow enrollment, and the median follow-up data of 64 patients in the final enrollment for nearly 3 years showed that the 3-year bPFS of the two groups was 79% and 92% respectively (P=0.08).
6.3 M1 stage PC radiotherapy with oligometastases
6.3.1 Radiotherapy for primary PC with oligometastatic M1 A randomized cohort in the STAMPEDE series of studies confirmed that radiotherapy for primary PC, for patients with M1 PC with oligometastases, radiotherapy for the primary lesion improved the 3-year OS rate (73%vs. 81%, P=0.007). The latest results of PEACE-1 were also reported at the 2023 ESMO Annual Conference. The study was a 2X2 study design, in which 1 173 patients were randomly divided into standard of care (SOC), SOC+ABI (+prednisone), SOC+radiotherapy, and SOC+radiotherapy+ABI (+prednisone). For about 500 patients with low metastatic burden, the addition of radiotherapy to SOC+ABI (+ prednisone) significantly improved rPFS (median rPFS time was 4.4 years and 7.5 years, respectively, P=0.002), but did not improve OS time (P=0.21). However, the addition of radiotherapy significantly reduced the incidence of urinary TRAEs in both the low and high metastatic burden groups, presumably due to the delay in the progression of local lesions caused by radiotherapy to control the primary lesion. In addition, the updated results of STAMPEDE were also shared at the 2023 ESMO Annual Meeting, and after a median follow-up >of 5 years, the addition of radiotherapy to the primary lesion in the low metastatic burden group not only significantly improved the OS rate (P<0.001), but also reduced the incidence of upper urinary tract obstruction events requiring intervention (3%∶5%, P=0.0017). Therefore, patients with oligometastatic M1 PC should be treated aggressively with radiotherapy to the primary lesion, which can not only improve the OS rate, but also reduce the probability of local symptoms due to the progression of the primary lesion.
6.3.2 Radiotherapy for M1 PC metastases with oligometastases In the SABR-COMET randomized phase II study, 99 patients (including 16 PC) who were treated with stereotactic ablative radiotherapy (SABR) for oligometastatic lesions increased the 5-year OS rate in the radiotherapy group from 17.7% to 42.3% after a median follow-up of 51 months (P=0.006), the latest updated 8-year follow-up results still maintained the advantage of OS rate in the radiotherapy group (27.2% in the radiotherapy group and 13.6% in the control group, P=0.008), and there was no significant difference in quality of life between the two groups, but fewer patients in the SABR group required chemotherapy (33.3% vs. 54.6%, P=0.043). The SABR-COMET 3 study (1~3 oligometastatic RCTs) and the SABR-COMET 10 study (4~10 oligometastatic RCTs) are ongoing. Although there is still a lack of articles that only include patients with oligometastatic PC, the long-term follow-up results of the SABR-COMET study for patients with oligometastatic patients who were enrolled in radiotherapy for all metastases suggest that hypofractionated radiotherapy for patients with oligometastatic PC should be performed as early as possible.
7. Basic research
7.1 Endocrine therapy and targeted therapy
Exploring the mechanism of drug resistance, establishing predictive biomarkers, finding new therapeutic targets, and combining drugs are important directions for basic research on endocrine therapy and targeted therapy. At present, drug resistance to endocrine therapy is mainly caused by androgen receptor (AR) splice variants, AR amplification or overexpression, AR mutations and activation of bypass signaling pathways, etc., and a deep understanding of the mechanism of drug resistance is helpful for further drug development.
Gankyrin, also known as non-ATPase proteasome 26S subunit 10, is highly expressed in many tumor tissues, and studies have shown that Gankyrin is highly expressed in many tumor tissues.
The O/AR/HMGB1/IL-6/STAT3 positive feedback signal transduction pathway promotes the transition from HSPC to CRPC and resistance to ADT. In patients with CRPC resistant to enzalutamide, programmed cell death ligand 1 (PD-L1) expression was up-regulated, cytotoxic T lymphocytes were significantly reduced, and IL-6 levels were significantly increased. Therefore, targeting or blocking the above positive feedback signal transduction pathways may alleviate ADT resistance, and IL-6 is also expected to be a marker for predicting the sensitivity of ADT treatment. It was found that apolipoprotein B mRNA-editing enzyme catalytic polypepti-
de-likeprotein (APOBEC) family has been implicated in >70% of human cancer mutations, and the SYNCRIP gene is an endogenous molecule that inhibits APOBEC-driven mutations in PC. SYNCRIP deficiency is an intracellular mechanism that promotes APOBEC-driven mutations, thereby increasing tumor mutational burden and heterogeneity, and driving the development of resistance to AR-targeted therapies. This study demonstrates that SYNCRIP can be used as an early biomarker to predict patients at risk of AR-targeted resistance due to ectopic APOBEC-driven mutations. Ring finger protein 19a (RNF19A) is a novel PC driver that is amplified and expressed at high frequency in PC. Clinically, higher RNF19A levels were positively correlated with Gleason score and castration resistance. Targeting AR, HIF1A-RNF19A-TRIP13 signaling axis, would be another option for the diagnosis and treatment of PC.
At present, there are no antagonists targeting the rest of AR sites on the market except for the ligand binding pocket, and in order to overcome the resistance of current targeted AR drugs, it is of great clinical value to develop antagonists that act on new sites and have new structures. A study confirmed that the dimer interface point (DIP) of the AR ligand binding domain (LBD) is a new potential binding site for drug molecules, and on this basis, a new potential AR antagonist M17-B15 was discovered by using computer-aided drug design technology. In mouse experiments, the drug showed superior tumor growth inhibition activity to enzalutamide. In addition to AR, there are many nuclear receptors in the nuclear receptor family with DIP sites, which is also a new opportunity for future targeted therapy research. In addition, mutations at different sites at the AR-LBD dimer interface will have different effects on cell proliferation and anti-androgen therapy, so it has become a hot topic in the field of PC therapy to link the type of AR mutation in patients with PC subtypes and optimize the treatment regimen.
Neuroendocrine PC generally occurs in the advanced stage of disease progression after ADT resistance, and although platinum-based chemotherapy drugs combined with etoposide are the recommended first-line treatments, the median OS time is only 10.5 months. Single-cell RNA sequencing and bioinformatics analysis were performed on the needle biopsies obtained from 6 cases of CRPC (2 of which were pathologically confirmed to be neuroendocrine PC), combined with the published PC datasets, it was finally determined that ELAV-like RNA-binding protein 3 is a key oncogenic driver for the initiation and maintenance of neuroendocrine differentiation in PC, providing a new therapeutic target for this type of PC.
7.2 Immunotherapy
Due to the "cold" immune microenvironment of PC, the search for novel immune checkpoints and the exploration of methods to enhance immunity have become the focus of immunotherapy research. recombinant macrophage receptor with collagenous structu-
re, MARCO) is a novel immune checkpoint expressed on tumor-associated macrophages, and it has been found that the high expression of MARCO is associated with poor OS rate of PC, and the expression level of MARCO is positively correlated with CD80, CD86 and leukocyte-associated immunoglobulin-like receptor 1 in most cancers, and gene set enrichment analysis revealed that MARCO is associated with TNF/NFkB, KRAS, PI3K/AKT/ There is a significant correlation between the mTOR pathway, so MARCO has the potential to be an emerging biomarker and a new target for tumor immunotherapy in the future. Neuropilin-2 (NRP2), as a receptor for vascular endothelial growth factor (VEGF), is a powerful target for regulating anti-tumor immunotherapy for PC. Related studies have revealed that the use of mouse-specific anti-NRP2 monoclonal antibody to inhibit the binding of VEGF to NRP2 can reduce the PD-L1 expression of tumor cells, enhance immune cell infiltration, and ultimately lead to tumor cell necrosis and tumor regression. This study provides a solid foundation for conducting clinical trials of NRP2 monoclonal antibodies in PC. Metallothionein 1G (MT1G) regulates the tumor microenvironment by modulating immune cell infiltration and inhibiting immunosuppressive factors, and studies have shown a significant correlation between MT1G expression levels and response to ICIs in PC patients. This finding not only provides a marker for predicting the therapeutic effect of ICIs, but also explores its potential to increase the sensitivity of ICIs treatment. In addition, Lu et al. found that Pygopus family PHD finger 2 (PYGO2) inhibited the infiltration of cytotoxic T lymphocytes in tumors and inhibited their activity by upregulating the Sp1/Kit/Ido1 signaling pathway. Knockout of the PYGO2 gene or the use of small molecule inhibitors significantly increased the responsiveness of mice to immunotherapy. In some experiments, PYGO2 inhibitors have been combined with immunotherapy to achieve a 100% cure of mouse PC. This study provides a theoretical basis for the clinical trial of PYGO2 inhibitors, and also provides a new idea for enhancing the effect of immunotherapy in PC.
In addition to traditional immunotherapy, innovative immunotherapy options are also being explored. Natural killer (NK) cells can recognize and remove cancerous cells in the body, and have the effect of tumor immunotherapy. The Department of Urology, Cancer Hospital, Chinese Academy of Medical Sciences has explored the latest research progress on the use of NK cells expanded in human peripheral blood to control the growth of PC in animal models of CRPC, and the results show that reinfusion of NK cells can effectively inhibit the tumor growth rate of CRPC, and its killing effect gradually increases with the increase of the proportion of NK cells. This study provides experimental support for the application of NK cells in the treatment of PC. STEAP1 and STEAP2 were highly expressed in PC but low in normal tissues. CAR-T targeting STEAP1 exhibits significant delay in tumor progression, reduced tumor mutational burden, and prolonged survival in animal models of PC. CBD-IL-12 can reverse the immunosuppressive tumor microenvironment to a pro-inflammatory state, and bind to STEAP1 CAR-T is beneficial to reshape the PC tumor microenvironment, enhance antigen processing and presentation, and promote epitope diffusion by using host immunity. The study of the antitumor effect of CAR-T loaded with dominantly inactivated TGFβ type II receptor (dnTGFβRII.) targeting STEAP2 in PC showed that dnTGFβRII. CAR-T always maintained >90% cell killing activity, and at the same time produced a large number of cytokines, and there was no significant change in body weight in each treatment group. In addition to its high lethality to orthotopic tumors, it still has certain anti-tumor ability in the microenvironment of bone metastatic tumors. In addition, B7-H3 was highly expressed in the tissues of PC patients, and its expression level was positively correlated with tumor aggressiveness, metastasis and disease recurrence, and the construction of B7-H3-targeting CAR-T with B7-H3 and CD28 as synergistic stimulation receptors caused significant anti-tumor activity in both in vitro and in vivo experiments, but the safety and efficacy of B7-H3 CAR-T in PC patients need to be further explored.
8. Discussion
In terms of PC endocrine therapy, researchers are trying to improve the efficacy of combination therapy based on ADT therapy. mHSPC has evolved from a monotherapy or a two-agent regimen to a triple intensive regimen of ADT + NHA + chemotherapy or radiotherapy. Multiple studies have demonstrated that ADT combined with NHA therapy can cause a rapid, large decline in PSA, which can lead to greater survival benefits. The combination of DOC or RT on the basis of ADT+NHA was selected to stratify mHSPC patients according to tumor burden and patient age, so as to better improve OS rate and reduce the probability of local symptoms due to primary progression. A major advance in endocrine therapy for patients with mCRPC is the combination therapy with radionuclides, and 223RA plus enzalutamide significantly prolongs median OS time without increasing fracture risk, which is significantly better than 223RA plus ABI (+ prednisone or prednisone). With the approval of PARPI olaparib for the treatment of advanced PC in China, the molecular targeted therapy for PC in China has begun. The ADT+NHA+PARPI regimen has been supported by sufficient evidence-based medical evidence in mCRPC patients, among which ABI (+ prednisone) combined with olaparib has certain clinical benefits for patients with BRCA mutation and non-BRCA mutation, and enzalutamide combined with talazoparib and ABI (+ prednisone) combined with NIRA have achieved considerable therapeutic effects on patients with mCRPC with biochemical recurrence of prostate cancer with A mutation and HRR mutation under the premise of ensuring safety。 From the current research, it can be seen that the efficacy of endocrine therapy is sufficiently certain, and researchers continue to try to combine other treatment regimens on the basis of ADT, such as immunotherapy, AR antagonists, chemotherapy, etc., in order to further improve the efficacy. However, there is not enough evidence-based medical evidence to provide new guidance for clinical decision-making, and further research is still needed.
The VISION study and the PSMAfore study demonstrated that 177Lu-PSMA-617 alone demonstrated good anti-tumor activity and an excellent safety profile in patients with mCRPC who failed chemotherapy or were not treated with chemotherapy, and that the combination of 177Lu-PSMA-617 and enzalutamide showed higher clinical benefit than enzalutamide alone. At present, in order to further expand the indication of 177Lu-PSMA-617, the PSMAddition study is validating the efficacy and safety of this drug in mHSPC, which is intended to bring more treatment options and survival benefits to PC patients. In addition, the PI3K-AKT signaling pathway, AKT inhibitors, and new AR inhibitors are also under development, and with the deepening of the exploration of the molecular mechanism of PC, there will be more targeted drugs and their combinations for the treatment of PC in the future, accelerating the development of PC therapy from the endocrine era to the targeted era.
Due to the "cold" immune microenvironment of PC, the therapeutic effect of immunotherapy in PC was not ideal, mainly due to the weak immunogenicity of tumors, the small number of infiltrating immune cells, and the immune depletion of immune cells caused by various immunosuppressive factors. How to improve the effect of PC immunotherapy has been explored in many aspects. Immunosuppressants have not achieved satisfactory results in combination with endocrine therapy, chemotherapy or dual immunotherapy, and many clinical studies of immunosuppressants have been terminated because the primary endpoint has not been met. However, the success of the clinical study of the immunosuppressant penbrolizumab combined with oral innate immune activators BXCL701 neuroendocrine PC provides a new idea for the immunotherapy of PC. In addition, there is a need for more accurate classification of patients with PC to screen out patients who are highly sensitive to immunotherapy. AMG509, AMG757 and JNJ-081 have been studied in three BiTE clinical studies, all of which have shown significant anti-tumor activity, which is expected to be a new treatment option for patients with mCRPC or SCNC PC. In recent years, the research on CAR-T in PC has gradually increased, and clinical studies are also being carried out gradually. Three clinical studies of CAR-PSMA-TGFβRDN, P-PSMA-101 and PSCA-targeting 4-1BB co-stimulated CAR-T have been successful, and their efficacy is better than most other immunotherapy regimens. This also indicates that the application of CAR-T in the PC field should be one of the important directions in the future. With the development of more and more complex cell therapies, there are still many problems to be solved in clinical application, such as the mode of administration, the amount of cells transfused, and whether continuous infusion is required for patients with high tumor burden. The widespread distribution of PSMA in healthy tissues may contribute to the development of CRS, and although it is less reported in current clinical studies, it is likely to increase as more products initiate clinical studies. Although PSCA is highly expressed in primary PC and PC metastases, it should still be noted that it is also expressed in normal tissues such as bladder, kidney, stomach, and brain, which will affect its application. PC vaccine is also an important part of immunotherapy, among which Sipuleucel-T, as a monocyte-based cancer vaccine, is currently the only PC therapeutic vaccine approved by the US FDA. Therefore, determining the PC component and its immune microenvironment status can enhance the accuracy of disease prognosis assessment, eliminate different responses to PC immunotherapy, and support individualized treatment for patients.
Although the efficacy of radiotherapy is similar to that of surgery for confined early-to-mid-term PC, two new technologies, MRgRT and adaptive hypofractionated radiotherapy based on magnetic resonance accelerator developed by the Cancer Hospital of the Chinese Academy of Medical Sciences, have shown lower TRAEs in the treatment of PC. As one of the recommended treatment modalities for patients with limited-stage low-intermediate-high-risk PC, hypofractionated radiotherapy, combined with more accurate diagnostic techniques, may further shorten the optimal duration of ADT in the future. At present, only one clinical study in limited, high-risk patients supports this hypothesis, so more data are needed to support it. For intermediate- and high-risk patients with limited stage, early radiotherapy combined with adjuvant ADT is more likely to result in greater survival benefit. Except for high-risk patients who should be given adjuvant radiotherapy as soon as possible after limited-stage PC, whether patients should undergo radiotherapy should be flexibly selected according to the level of PSA, and if salvage radiotherapy is planned after surgery, ADT therapy should be avoided before or after surgery, and postoperative pelvic prophylaxis irradiation is more likely to benefit patients from treatment. For M1 PC with oligometastases, both primary and metastases should be treated early and aggressively.
For patients with mHSPC, the purpose of treatment is to improve the quality of life of patients on the one hand, and to avoid or slow down the development of mHSPC into mCRPC on the other hand, which requires precise and individualized treatment plans for existing clinical treatments. To achieve this goal, researchers need to conduct a comprehensive assessment of the patient before treatment, from the examination of primary lesions and metastatic lesions, to the assessment of whether there are underlying diseases and family history, and accurately determine the grade, stage and tumor burden of the tumor. Therefore, the use of machine learning and artificial intelligence to evaluate tumors and predict their efficacy has gradually become one of the important directions of future research. For example, a phase III clinical study of STAMPEDE attempted to use an artificial intelligence model to predict the prognosis of PC patients after treatment with zoledronic acid in combination with ADT (±DOC).
9. Summary
In 2023, researchers will have a more comprehensive understanding of the application of TB of PC in diagnosis, and surgical methods and surgical skills are also constantly improving and improving, and endocrine therapy combined with chemotherapy, immunotherapy, targeted therapy, and radiotherapy will become the main non-surgical treatment methods in the future. With the deepening of PC molecular typing and immune microenvironment research, more and more targeted drugs and immunotherapy drugs have entered clinical research, and more accurate diagnosis and stratification of patients will become the focus of clinical treatment selection. It is believed that in the near future, PC treatment will gradually develop towards combination, individualization and precision. Looking forward to a bigger breakthrough in the PC field in 2024.