Dingwei Ye's research while affiliated with Shanghai Cancer Institute and other places

CRPC remains a significant challenge in prostate cancer research. We aimed to elucidate the role of gut microbiota and its specific mechanisms in CRPC using a multidisciplinary approach. We analyzed 16S rRNA sequencing data from mouse fecal samples, revealing substantial differences in gut microbiota composition between CRPC and castration-sensitive prostate cancer mice, particularly in Firmicutes and Bacteroidetes. Functional analysis suggested different bacteria may influence CRPC via the α-linolenic acid metabolism pathway. In vivo, experiments utilizing mouse models and fecal microbiota transplantation (FMT) demonstrated that FMT from healthy control mice could decelerate tumor growth in CRPC mice, reduce TNF-α levels, and inhibit the activation of the TLR4/MyD88/NF-κB signaling pathway. Transcriptome sequencing identified crucial genes and pathways, with rescue experiments confirming the gut microbiota’s role in modulating CRPC progression through the TLR4/MyD88/NF-κB pathway. The activation of this pathway by TNF-α has been corroborated by in vitro cell experiments, indicating its role in promoting prostate cancer cell proliferation, migration, and invasion while inhibiting apoptosis. Gut microbiota dysbiosis may promote CRPC development through TNF-α activation of the TLR4/MyD88/NF-κB signaling pathway, potentially linked to α-linolenic acid metabolism.

e16533 Background: For patients (pts) with recurrent or stage IV non-clear cell renal cancer (nccRCC),the medical treatment guidelines recommend the first choice to participate in clinical trials, or use TKI drugs such as sunitinib, and mTOR inhibitors such as everolimus. Anlotinib is a novel multi-target tyrosine kinase inhibitor (TKI). It’s antitumor targets include vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-kit. ALTER-UC-001 is a single-center, single-arm, phase II trial which evaluated the efficacy and tolerability of anlotinib plus everolimus as first-line therapy in pts with nccRCC (NCT05124431). Methods: Patients with advanced nccRCC and no prior systemic drug therapy for advanced disease were eligible for this trial; Eastern Cooperative Oncology Group (ECOG) performance status 0-1. The patients received 12mg anlotinib once daily on days 1-14 every 3 weeks by oral, and 5mg everolimus orally once daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall disease control rate (DCR), progression free survival (PFS), and over survival (OS). Adverse events will be monitored throughout the study and graded according to CTCAE V5.0. Results: Between Jan 2022 and Dec 2023, 24 pts were enrolled and received study treatment. The median age was 56 years old (range: 20 to 79 years). Nineteen pts (79.2%; 19/24) had a ECOG PS score of 1, and five pts (20.8%; 5/24) had a ECOG PS score of 0. All pts had not received prior treatment. In addition, 17 (70.8%) had received surgical treatment and 1 (4.2%) had received radiotherapy. The data cutoff was Dec 2023, with a median follow-up of 6.04 (range, 1.34-18.1) months.14 pts had the best overall response (unconfirmed) assessments which inferred the ORR of 57.1%(PR in 8 pts 95% CI, 29.6-81.2)and the DCR of 100% (PR in 8 pts and SD in 6 pts; 95% CI, 73.2-100). The median PFS has not reached. Any grades of adverse events (AEs) were observed in 91.7% (22/24) of pts, the most common of which were mucositis (29.1%), hypertension (25.0%) , creatinine increased(16.7%), proteinuria (16.7%) and glutamic-pyruvic transaminase increased (12.5%).Seven (29.1%) pts experienced grade 3 TRAEs, including hypertension (8.3%), proteinuria (8.3%), mucositis (4.2%), platelet count decreased (4.2%), creatinine increased (4.2%), chronic gastritis (4.2%) and bleeding (4.2%). No treatment-related deaths occurred. Three (12.5%) and two (8.3%) pts had suspension of treatment because of TRAEs caused by everolimus and anlotinib respectively. Conclusions: Anlotinib plus everolimus as first-line therapy is efficacious and safe for pts with advanced nccRCC. We will report more data in the future. Clinical trial information: NCT05124431 .

5001 Background: Oncogenic addiction to androgen receptor (AR) signaling drives mCRPC progression, highlighting the unmet need for novel treatment strategies to maximize AR-directed therapy. Preclinical evidence suggests a key role for CDK4/6 in sustained AR signaling, uncontrolled proliferation, and hormonal resistance in prostate cancer. Abemaciclib (ABEMA) is a potent CDK4/6 oral inhibitor that significantly augments the efficacy of endocrine therapy in hormonally driven (ER+) high-risk early-stage and metastatic breast cancer. ABEMA also showed single-agent activity in heavily pretreated mCRPC. Here, we report the primary results of CYCLONE 2, a Phase 3 study of ABEMA plus abiraterone (ABI) in pts with 1L mCRPC. Methods: CYCLONE 2 was a seamless Phase 2/3 adaptive trial with a dose-finding safety lead-in. Randomization to the ABEMA or placebo (PBO) plus ABI and predniso(lo)ne was stratified by prior docetaxel receipt for mHSPC, measurable disease, and radiographic progression at study entry. Primary endpoint was investigator-assessed radiographic progression-free survival (rPFS) per RECIST v1.1 and PCWG3. The study was powered at ~90%, assuming a HR of 0.55 for rPFS, at a cumulative 2-sided alpha level of 0.05. Results: Between Nov 2018 and Jul 2022, 393 pts were randomized. Baseline characteristics were balanced across arms. Primary endpoint of rPFS was not met (HR 0.829; 95% CI, 0.619–1.111; p=0.2123), medians were 21.96 months for the ABEMA plus ABI group vs 20.28 months for the PBO plus ABI group. rPFS by blinded independent central review was consistent with investigator assessment (HR 0.842; 95% CI, 0.611–1.160). OS was a gated secondary endpoint and not inferentially tested (HR 0.927; 95% CI, 0.669–1.285; 38.9% maturity). Other secondary endpoints included time to PSA progression (HR 0.637; 95% CI, 0.474–0.856), time to symptomatic progression (HR 0.768; 95% CI, 0.522–1.131), and time to worst pain progression (HR 0.935; 95% CI 0.665–1.314). The most common grade ≥3 adverse events (AEs) reported in the ABEMA plus ABI group were anemia (13.6% vs 4.3% in the PBO plus ABI group), neutropenia (12.6% vs 0.5%) and ALT increased (8.7% vs 6.5%). Discontinuations of all study treatments due to AEs were 13.1% vs 4.3% in ABEMA plus ABI vs PBO plus ABI groups, while discontinuations of ABEMA or PBO alone due to AEs were 5.8% vs 1.6%, respectively. Conclusions: In patients with mCRPC, adding abemaciclib to abiraterone did not significantly increase rPFS. While no OS detriment was observed, secondary endpoints were not meaningfully improved. Overall, the combination was well tolerated, and safety was consistent with the known profiles of the individual medicines. Clinical trial information: NCT03706365 Clinical trial information: NCT03706365 .

e14503 Background: HB0025 is a recombinant humanized bispecific molecule built on IgG1 that targets the human programmed death ligand 1 (PD-L1) (CD274) and vascular endothelial growth factor (VEGF, VEGF-A, VEGF165). In phase Ia, HB0025 monotherapy showed encouraging anti-tumor activity and safety profile in solid tumor. Herein, we aimed to explore safety and efficacy of HB0025 in advanced renal cell carcinoma pts that failed standard treatments. Methods: This ongoing, open-label, multicenter, phase 1/2 trial to evaluate the efficacy and safety of HB0025 monotherapy with 10mg/kg iv q2w for RCC pts. Response was evaluated by RECIST v.1.1 every 8 weeks. The primary endpoint was objective response-rate (ORR). Secondary endpoints included safety (CTCAE v.5.0), disease control rate (DCR), and progression free survival (PFS). Results: As of Dec 25, 2023, 17 (16M/1F) pts were enrolled and all received treatment. Median age was 58 y and 53% pts had intermediate/poor IMDC risk.6 pts were on treatment at data cutoff date. All pts had stage IV disease. 14 (82%) pts were clear cell renal cell carcinoma and the maximum duration of treatment was 7 months. 10 (59%) pts received ≥2 lines of previous systemic therapies and median follow up was 5.1 months. Among total the 15 pts having imaging tumor assessment by RECIST v1.1, 2 achieved partial responses (PR) and 9 achieved stable disease (SD) in Best of Response.1 subject who had received 2-line treatment with multiple metastases (including lung, bones, liver and adrenal gland) had achieved PR since the first tumor assessment, target lesion decreased by up to 52.1% from baseline. 1 subject who had received 2-line treatment with lung and lymph node metastasis had achieved PR since the first tumor assessment, target lesion decreased by up to 40.3% from baseline. Both two patients, duration of treatment was over 6 months and still in PR status when discontinued treatment. The ORR was 13.3% (95%CI: 1.7-40.5) and DCR was 73.3% (95%CI: 44.9-92.2). Median PFS was not reached. For all enrolled pts, 17 pts (100%) experienced a treatment related adverse events (TRAE). The most common TRAEs were proteinuria (58.8%, 10/17), hypoalbuminemia 6/9 (35.3%, 6/17), hypercholesterolemia (35.3%, 6/17), hyperuricemia (29.4%, 5/17). TRAEs ≥ grade 3 occurred in 6 (35.5%) patients and no death occurred. TRAE leading to discontinuation occurred in 3 (17.7%) pts. Conclusions: HB0025 10mg/kg monotherapy showed an acceptable safety profile and promising anti-tumor activity in prior multiple treated RCC, which supports further studies to explore the safety and efficacy of HB0025 as a monotherapy or in combination with other anti-tumor agents. HB0025 20mg/kg monotherapy study are currently ongoing. Clinical trial information: NCT06222125 .

Background The proposed trial is to examine the feasibility of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-guided cytoreduction plus apalutamide and androgen deprivation therapy (ADT) for newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) at oligometastatic state. Methods CHAMPION (NCT05717582) is an open-label, single-arm, phase II trial, planning to enroll newly diagnosed mHSPC cases with oligometastases (≤ 10 distant metastatic sites in conventional imaging). Patients will receive 6 cycles of apalutamide plus ADT. Patients with oligometastatic disease at PSMA PET/CT after 3 treatment cycles will receive cytoreductive radical prostatectomy. PSMA PET/CT-guided metastasis-directed external radiation therapy will be determined by the investigators. Apalutamide plus ADT will be continued for 2 weeks postoperatively. The primary endpoint is the proportion of patients with undetectable prostate-specific antigen (PSA), no disease progression, and no symptom deterioration after 6 cycles of apalutamide plus ADT. Secondary endpoints include the percentage of patients with PSA ≤ 0.2 ng/mL and oligometastases by the end of 3 treatment cycles, PSA response rate, and safety. Fleming’s two-stage group sequential design will be adopted in the study, where the null hypothesis is that the rate of patients with an undetectable PSA is ≤ 40% after 6 cycles of treatment, while the alternate hypothesis is an undetectable PSA of > 60%; with one-sided α = 0.05, power = 0.80, and an assumed dropout rate of 10%, the required number of patients for an effective analysis is 47. Enrolment in the study commenced in May 2023. Discussion The multi-modal therapy based on treatment response may improve the prognosis of newly diagnosed mHSPC patients with oligometastases. Trial registration The study is registered with Clinical Trials.Gov (NCT05717582). Registered on 8th February 2023.