Efficacy and safety of LY01005 versus goserelin implant in Chinese patients with prostate cancer: A multicenter, randomized, open-label, phase III, non-inferiority trial / 中华医学杂志(英文版)

BACKGROUND@#LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer.@*METHODS@#We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels.@*RESULTS@#On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]).@*CONCLUSION@#LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile.@*TRIAL REGISTRATION@#ClinicalTrials.gov, NCT04563936.

Analysis and interpretation of genetic testing results from 124 patients(age ≤60 years old)with upper tract urothelial carcinoma / 中华泌尿外科杂志

Objective:To analyze germline pathogenic mutations in patients with upper tract urothelial carcinoma(age≤60 years old), and to explore the clinicopathological characteristics of germline pathogenic mutation carriers.Methods:The data of 124 patients (age≤60 years old) with upper tract urothelial carcinoma who underwent germline genetic testing at Fudan University Shanghai Cancer Center from September 2008 to February 2023 were retrospectively analyzed. There were 86 males and 38 females, and the median age was 55.0(49.8, 58.0)years old. The primary tumors were located in the renal pelvis in 81 cases (65.3%), the ureter in 34 cases (27.4%), and both in 9 cases (7.3%). There were 13 patients (10.5%) with low-grade UTUC and only 8 patients (6.5%) with carcinoma in situ. Twelve patients (9.7%) had a history of bladder cancer and 12 (9.7%) had a history of malignancy other than bladder cancer. Whole gene exome sequencing or target region sequencing was performed to explore germline mutations associated with patients with UTUC. The germline genetic testing data were interpreted in accordance with the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP)2015 edition guideline to clarify the germline pathogenic mutation rate and elucidate the clinicopathological characteristics of germline pathogenic mutation carriers. Germline pathogenic mutation rates were further compared with those of healthy East Asian populations to analyze germline mutations associated with the risk of carcinogenesis in UTUC.Results:In this study, 31 germline pathogenic mutations were detected in 28 (22.6%) of 124 patients with UTUC. There were no statistically significant differences in age [54.0 (47.0, 58.0) years old vs. 56.0 (50.8, 58.0) years old], gender (male/female: 21/7 vs. 65/31), history of bladder cancer (0 vs. 12/96), T-stage (T 3-4: 12/28 vs. 41/96), and proportion of histologic high-level (26/28 vs. 85/96) between patients with and without germline pathogenic mutations ( P>0.05). The 31 germline pathogenic mutations were located in 22 genes, including BRCA2 (4, 12.9%), MSH2 (3, 9.7%), RAD54L (2, 6.5%), BRCA1 (2, 6.5%), BRIP1 (2, 6.5%), NOTCH3 (2, 6.5%), XRCC2 (1, 3.2%), VEGFA (1, 3.2%), TBX3 (1, 3.2%), RET (1, 3.2%), PRKN (1, 3.2%), PALB2 (1, 3.2%), NTRK1 (1, 3.2%), NCOA3 (1, 3.2%), MSH6 (1, 3.2%), LRP1B (1, 3.2%), KMT2D (1, 3.2%), KMT2A (1, 3.2%), FANCA (1, 3.2%), BARD1 (1, 3.2%), ARID1A (1, 3.2%), and AR (1, 3.2%). The germline pathogenic mutation rates of 124 patients were compared with those of the healthy East Asian population. The results showed that germline pathogenic mutations in BRCA2 ( OR = 11.9, 95% CI 3.8 - 37.7, P<0.001), MSH2 ( OR = 11.9, 95% CI 3.2-44.5, P<0.001), RAD54L ( OR=14.2, 95% CI 2.7-73.8, P=0.002) and BRCA1 ( OR=11.8, 95% CI 2.4-59.1, P=0.003) genes significantly increase the risk of developing UTUC. Conclusions:The rate of germline pathogenic mutations in ≤60 years old UTUC patients in this study was 22.6%, and germline pathogenic mutations carrying germline BRCA2, MSH2, RAD54L or BRCA1 genes significantly increased the risk of developing UTUC.

2023 ESMO express: research on changing clinical practice for prostate cancer / 中华泌尿外科杂志

The 2023 European Society for Medical Oncology (ESMO) was held recently. In this conference, numbers of cutting-edge studies were discussed and published including advances in diagnosis and treatment, especially in prostate cancer. Studies that may influence clinical treatment decisions were summarized in this article, including timing of radiotherapy after radical prostatectomy, Enzalutamide in biochemically recurrent prostate cancer, predictive factors of novel hormonal therapies in metastatic hormone-sensitive prostate cancer, and the value of osteoprotective agent. The purpose of this article was to help clinicians make better clinical decisions.

Mismatch repair gene germline mutations in patients with prostate cancer / 浙江大学学报·医学版

OBJECTIVES@#To investigate the prevalence of pathogenic germline mutations of mismatch repair (MMR) genes in prostate cancer patients and its relationship with clinicopathological characteristics.@*METHODS@#Germline sequencing data of 855 prostate cancer patients admitted in Fudan University Shanghai Cancer Center from 2018 to 2022 were retrospectively analyzed. The pathogenicity of mutations was assessed according to the American College of Medical Genetics and Genomics (ACMG) standard guideline, Clinvar and Intervar databases. The clinicopathological characteristics and responses to castration treatment were compared among patients with MMR gene mutation (MMR+ group), patients with DNA damage repair (DDR) gene germline pathogenic mutation without MMR gene (DDR+MMR－ group) and patients without DDR gene germline pathogenic mutation (DDR－ group).@*RESULTS@#Thirteen (1.52%) MMR+ patients were identified in 855 prostate cancer patients, including 1 case with MLH1 gene mutation, 6 cases with MSH2 gene mutation, 4 cases with MSH6 gene mutation and 2 cases with PMS2 gene mutation. 105 (11.9%) patients were identified as DDR gene positive (except MMR gene), and 737 (86.2%) patients were DDR gene negative. Compared with DDR－ group, MMR+ group had lower age of onset (P<0.05) and initial prostate-specific antigen (PSA) (P<0.01), while no significant differences were found between the two groups in Gleason score and TMN staging (both P>0.05). The median time to castration resistance was 8 months (95%CI: 6 months-not achieved), 16 months (95%CI: 12-32 months) and 24 months (95%CI: 21-27 months) for MMR+ group, DDR+MMR－ group and DDR－ group, respectively. The time to castration resistance in MMR+ group was significantly shorter than that in DDR+MMR－ group and DDR－ group (both P<0.01), while there was no significant difference between DDR+MMR－ group and DDR－ group (P>0.05).@*CONCLUSIONS@#MMR gene mutation testing is recommended for prostate cancer patients with early onset, low initial PSA, metastasis or early resistance to castration therapy.

Clinical analysis of prostate targeted biopsy guided by multiparametric magnetic resonance imaging and 68Ga-PSMA PET/CT image fusion / 中华泌尿外科杂志

Objective:To explore clinical value of prostate target biopsy guided by multiparametric magnetic resonance imaging (mpMRI) and 68Ga-labeled prostate specific membrane antigen ligand imaging positron emission tomography/X-ray computed tomography ( 68Ga-PSMA PET/CT) image fusion. Methods:The data of 50 patients admitted to Fudan University Shanghai Cancer Center from January 2021 to February 2022 who underwent mpMRI and 68Ga-PSMA PET/CT to guide prostate biopsy were retrospectively analyzed. The median age was 70 (63-79) years, the median serum tPSA value was 8.1 (6.8-83.0) ng/ml, and the prostate volume was 45.5 (30-80) ml. 36 cases were positive by mpMRI, including PI-RADS score 3 in 5 cases, 4 score in 19 cases, 5 score in 12 cases. 32 cases were positive by 68Ga-PSMA PET/CT examination, of which 30 cases were double positive and the fusion of both imaging techniques was positive, referred to as PET/CT-MRI. The patient's mpMRI and 68Ga-PSMA PET/CT images were imported into the MIM fusion software, and the outline of the prostate and the target area were outlined respectively. When PET/CT and MRI double positive cases were biopsied, the two images were alternately fused, calibrated and locked with the real-time prostate ultrasound interface(PET/CT-MRI). Single-positive cases were guided by positive images to complete targeted biopsy, and 12-needle systematic biopsies were completed after targeted biopsy and double-negative cases. The advantages of targeted biopsy and systematic biopsy was evaluated, and the diagnostic performance (sensitivity, specificity, positive predictive value, and negative predictive value) was analyzed. Results:Among the 50 biopsy patients in this group, 31 (62%) had prostate cancer, of which 22 (44%) were CsPCa. There was no significant difference in the detection rate of prostate cancer between targeted biopsy and systematic biopsy [78.9% (30/38) and 62.0% (31/50), P=0.088], and there was no significant difference in the detection rate of CsPCa [57.9% (22/38) and 40.0% (20/50), P=0.096]. The positive rate of the biopsy needles number was significantly different [86.3% (69/80) and 19.0% (114/ 600), P<0.001]. The detection rates of prostate cancer in mpMRI positive, PET/CT positive and PET/CT-MRI positive cases were 83.3% (30/36), 90.6% (29/32) and 96.6% (29/30) respectively, the detection rates of CsPCa were 61.1% (22/36), 68.8% (22/32) and 73.3% (22/30) respectively.The sensitivity, specificity, positive predictive value and negative predictive value of mpMRI in the diagnosis of prostate cancer were 96.8%(30/31), 68.4%(13/19), 83.3%(30/36)and 92.9%(13/14), respectively.Those values in 68Ga-PSMA PET/CT were 93.5%(29/31), 84.2%(16/19), 90.6%(29/32)and 88.9%(16/18), respectively.Those values in PET/CT-MRI were 93.8%(29/31), 94.7%(18/19), 96.7%(29/30)and 90.0%(18/20), respectively. The above four indicators of mpMRI diagnosis of CsPCa were 100.0%(22/22), 50.0%(14/28), 61.1%(22/36)and 100.0%(14/14), respectively.Those indicators in 68Ga-PSMA PET/CT were 100.0%(22/22), 64.3%(18/28), 68.8%(22/32)and 100.0%(18/18), respectively.Those indicators in PET/CT-MRI was 100.0%(22/22), 71.4%(20/28), 73.2%(22/30)and 100.0%(20/20), respectively. The detection efficiency of PET/CT-MRI was better than that of mpMRI (Kappa value was 0.737, P=0.031). Conclusions:PET/CT-MRI image fusion-guided targeted prostate biopsy can effectively improve the detection efficiency of prostate cancer and clinically significant prostate cancer, and increase the positive rate.

Analysis and interpretation of genetic testing results from 249 Chinese high to very-high risk non-metastatic prostate cancer patients / 中华泌尿外科杂志

Objective:To analyze germline genetic testing in Chinese high-to very-high-risk non-metastatic prostate cancer patients.Methods:This study included 249 Chinese patients with high- to very-high-risk non-metastatic prostate cancer for germline genetic testing, in Fudan University Shanghai Cancer Center, West China Hospital and Cancer Center of Sun Yat-sen University, from January 2018 to December 2022. High risk and very-high risk are termed according to National Comprehensive Cancer Network (NCCN) Prostate Cancer Guideline (2022 V1). The mean age of the patients was (66.7±9.2) years old and median PSA level was 28.50 (ranging 2.43 - 1481.11) ng/ml. Within these 249 patients, 84 (33.7%) were T 1-2, 98 (39.3%) were T 3-4, while 67 (26.9%) were unclear in T stage. Additionally, 51 patients (20.5%) were classified into International Society of Urological Pathology(ISUP) grade group 1-3 group and 198 patients (79.5%) were in ISUP 4-5 group. Focusing on 16 genetic susceptibility genes for prostate cancer, we interpret the germline genetic testing data in accordance with the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guideline, clarify the germline pathogenic mutation rate and elucidate the clinicopathological characteristics of germline pathogenic mutation carriers. Results:Among Chinese high-to very-high-risk non-metastatic prostate cancer patients, 7.2% (18/249) had germline pathogenic mutations. Patients with mutations had a significantly higher proportion of first-degree relatives with a history of malignancy than those without mutations (50% vs. 13%, P<0.001), but there was no difference in age of onset [(68.2±9.3)years vs. (66.6±9.2) years], PSA level (median: 40.68 ng/ml vs. 28.00 ng/ml), T stage [T 3-4: 38.9%(7/18)vs. 39.4%(91/231)] and ISUP grade [group 4-5: 88.9%(16/18) vs. 78.8%(182/231)]. Germline pathogenic mutations were observed in BRCA2 (7 patients, 38.9%), MSH2 (3 patients, 16.7%), PALB2 (2 patients, 11.1%), ATM (2 patients, 11.1%), RAD51C (1 patient, 5.6%), PMS2 (1 patient, 5.6%), MSH6 (1 patient, 5.6%) and HOXB13 (1 patient, 5.6%). By comparing with normal controls of East-Asian population, germline pathogenic mutations in BRCA2 ( OR=11.1, 95% CI 4.8-25.6, P<0.001) and MSH2 ( OR= 43.5, 95% CI 8.5-200.0, P<0.001) can significantly increase the risk of developing high- to very-high-risk prostate cancer in Chinese males. Conclusions:This study identified a germline pathogenic mutation rate of 7.2% in 249 Chinese patients with high- or very-high-risk non-metastatic prostate cancer. Carrying germline BRCA2 or MSH2 pathogenic mutations can significantly increase the risk of high- or very-high-risk prostate cancer in Chinese men.

Study of gonadotropin-releasing hormone antagonist in management of hormonal sensitive prostate cancer / 中华泌尿外科杂志

Objective:To explore the value of gonadotropin-releasing hormone (GnRH) antagonist in prostate cancer management.Methods:We retrospectively analyzed the data of 92 consecutive hormonal sensitive prostate cancer (HSPC) patients treated with GnRH antagonist from Jan 2019 to March 2022 in Fudan University Shanghai Cancer Center. The median (IQR) age at diagnosis was 70(65-76)years old. Median(IQR) serum prostate-specific antigen (PSA) level before treatment was 98.30 (32.50-436.75)ng/ml. The median (IQR) testosterone level was 12.30(1.51-18.44)nmol/L. Twenty-six(28.3%)cases were in M 0 stage, while 66(71.7%) were in M 1 stage at diagnosis. There were 67(72.8%)cases in ≥T 3 stage, and 54(58.7%)cases in N 1 stage.The Gleason score of 80(87.0%)cases was ≥8.The second generation androgen inhibitor was used in 58(63.0%)cases, and 21(22.8%)cases had specific gene mutation. Patients received a subcutaneously 240mg Degarelix in the first 28 days and 80 mg Degarelix following every 28 days. The pre-injection and 3 months post injection PSA and testosterone (T) level were collected. According to the proportion of patients with the largest decrease in PSA, the patients were divided into high response group (PSA decrease ≥99% after 3 months of use of Degarelix) and low response group (PSA decrease <99% after 3 months of use of Degarelix). Univariate and multivariate logistic analysis were used to analyze the risk factors affecting the treatment response of Degarelix. Results:Among the 92 prostate cancer patients, after 3 months Degarelix treatment, the median PSA value decreased to 0.64ng/ ml ( P <0.001), and the median testosterone value decreased to 0.45nmol/L ( P <0.001). After treatment, there were 48 cases in the high reaction group and 44 cases in the low reaction group. Before treatment, the median PSA in the high-response group was 100.00(67.11-444.25) ng/ml, higher than 88.50 (9.91-582.25) ng/ml in the low-response group, but not statistically significant ( P=0.077). The median testosterone level in the high response group was 13.82 (7.53-19.43) nmol/L, which was significantly higher than that in the low response group [4.61 (0.75-16.12) nmol/L, P =0.030]. After treatment, the median PSA in the high-response group was 0.22 (0.09-0.82) ng/ml, significantly lower than that in the low-response group [3.22 (0.19-15.88) ng/ ml, P<0.001]. The median testosterone value of the high reaction group was 0.40 (0.09-0.80) nmol/L and that of the low reaction group was 0.45 (0.02-0.65) nmol/L, which showed no significant difference ( P =0.826), and both reached the level of castration (<1.7nmol/L). Univariate analysis showed that age ≤ 65 years old was a good prognostic factor ( OR=0.333, 95% CI 0.119-0.810, P =0.017); T stage ( P =0.540), N stage ( P =0.363), M stage ( P =0.660), Gleason score ( P =0.834), application of second-generation antiandrogens ( P=0.238) and gene mutation ( P =0.525) were not related to Degarelix hyperresponsiveness. In multivariate analysis, age was the only independent favorite prognostic factors( OR=0.913, 95% CI 0.847-0.983, P=0.016). Conclusions:In the real world, GnRH antagonists significantly reduced the levels of testosterone and PSA in HSPC patients after 3 months of treatment regardless of TNM stage, Gleason score, and the second generation androgen inhibitor using.

Efficacy and safety of radium-223 in 48 patients with bone metastatic castration resistant prostate cancer / 中华泌尿外科杂志

Objective:To observe the efficacy and safety of radium-223 in metastatic castration resistant prostate cancer (mCRPC) with bone metastasis.Methods:The clinical data of 48 patients with mCRPC treated with radium-223(55 kBq/kg, once every 4 weeks, planned to use for 6 cycles)from February 2021 to May 2022 were analyzed retrospectively. All patients had symptomatic bone metastasis without visceral metastasis, which the number of bone metastasis was more than one site.They were all classified as IVb stage. The average age was 70.5 (ranging 49-90) years. The median PSA was 44.70(ranging 0.15-1 864.00) ng/ml. The median ALP was 162 (ranging 43-1 589) U/L. The median time from mCRPC diagnosis to radium-223 use was 10 (ranging 3-47) months. 9, 18 and 11 patients had received first-line, second-line and third-line treatment for mCRPC before enrollment respectively, 10 patients had received at least fourth-line treatment. 38 (79.1%), 31 (64.5%), 30 (62.5%) and 7 (14.6%) patients had used abiraterone, enzalutamide, docetaxel and olaparib before enrollment. The probability of PSA level decrease >30%, ALP level decrease >30%, symptom improvement rate, median overall survival (OS), as well as the occurrence of treatment-related adverse reactions and the reasons for withdraw treatment were analyzed.Results:The median follow-up time was 8 (ranging 1-16) months. 11 patients completed all 6 courses of treatment. The median number of completed courses was 4 (ranging 1-6). 27 patients (56.2%) received radium-223 and bone protection drugs (Bisphosphate/ Denosumab). PSA decreased by >30% was recorded in 10 patients (20.8%) and ALP decreased by >30% was recorded in 25 patients (52.1%). 23 cases (47.9%) reported bone pain relief during treatment. Among the 9 patients who had received first-line of mCRPC previously, 6 cases (66%) had relief of bone pain symptoms, and 4 cases (44%) had a decrease of PSA >30%. Among the 18 patients who had previously received second-line mCRPC treatment, 11 cases (61%) had relief of bone pain symptoms, and 4 cases (22%) had a decrease of PSA >30%. Among the 21 patients who had received third-line or more mCRPC treatment in the past, 6 (28.5%) had symptom relief, and 2 (9.5%) had PSA decrease >30%. The median overall survival (OS) was not reached, and the OS was estimated to be 12.5 months using the Kaplan-Meier method. The most common hematological adverse effects were thrombocytopenia (15 cases, 31.2%; grade 3 in 6 cases and grade 4 in 0), followed by leucopenia (11 cases, 22.9%; grade 3 in 4 cases and grade 4 in 1 case) and anemia (8 cases, 16.7%; grade 3 in 3 cases and grade 4 in 0). Non-hematological adverse reactions included fever in 1 case (2.1%), constipation in 4 cases (8.3%), nausea and vomiting in 10 cases (20.8%), diarrhea in 7 cases (14.6%), dizziness in 1 case (2.1%) and fatigue in 11 cases (22.9%). Seven cases were discontinued due to intolerable adverse reactions (median 2 courses), 14 cases were discontinued due to disease progression or death (median 2 courses), and 5 cases were discontinued due to other reasons (median 1 course).Conclusions:Radium-223 has a good performance in symptom control for mCRPC patients who have previously received first-line or second-line therapy. Due to the high incidence of hematological adverse reactions, more attention should be paid to the changes of hemogram during the treatment, and timely treatment should be carried out to improve the drug tolerance of patients.

Prostate cancer with homologous recombination repair gene mutations and PARP inhibitors: clinical progress / 中华泌尿外科杂志

DNA damage repair gene mutations are prevalent in advanced prostate cancer. Among these, mutations in homologous recombination repair genes could impair the ability of cell to restore the DNA double-strand break, which can be exploited by Poly-ADP-ribose polymerase (PARP) inhibitors through synthetic lethality and result in cell death. The phase Ⅲ study " PROfound" showed that the PAPR inhibitor Olaparib could significantly improve the survival of patients with homologous recombination repair gene mutations compared with novel hormone agents, starting the era of targeted, precise and individualized treatment based on genetic profile detection for prostate cancer treatment.

Where are the future directions in prostate cancer diagnosis and treatment in Asia / 中华泌尿外科杂志

Prostate cancer is the most common solid malignant tumor among men in Western countries. While the incidence of prostate cancer is relatively low in Asia. In recent years, the incidence of prostate cancer in Asia is growing rapidly due to the development of social and economic level, popularization of people's health awareness and technological progress of health medicine in Asian countries. However, the uneven level of economic, social, human and medical aspects in Asian countries has also brought some difficulties and challenges to the standardized diagnosis and treatment of prostate cancer. Based on the Asian population, combined with the characteristics of Asian countries, this paper will explore the future directions of prostate cancer diagnosis and treatment in Asia from the development of prostate cancer diagnosis and treatment in China.