Lactate-induced IL8 expression in macrophages is dependent on MCT-1-mediated lactate transport.

Immune cell infiltration in ccRCC with high versus low IL8+ TAMs infiltration.

BackgroundWe evaluated whether pseudocapsule status, alone and in combination with pathological parameters, could serve as a prognostic marker in human renal cell carcinoma (RCC).MethodsWe retrospectively analyzed 1560 patients with RCC who underwent surgery at a single institution between 2007 and 2012. The patients were randomly assigned to training (n=780) and validation (n=780) cohorts. Pseudocapsule status was classified as grade 0 (intact pseudocapsule without breakthrough), grade 1 (pseudocapsule invasion), and grade 2 (pseudocapsule breakthrough or absence). A pseudocapsule-pathological parameter score (PPS) was constructed by integrating pseudocapsule status with pathological type, Fuhrman grade, nuclear necrosis, sarcomatoid transformation, microvascular infiltration, Eastern Cooperative Oncology Group performance status score, and tumor-node-metastasis stage. The scores were categorized as low, intermediate, and high. Overall survival and relapse-free survival were evaluated using Kaplan–Meier and Cox regression analyses.ResultsAmong the 1560 patients, 529 had grade 0 pseudocapsules, 701 had grade 1 pseudocapsules, and 330 had grade 2 pseudocapsules. The Kaplan–Meier curves revealed better overall survival in patients with grade 0 pseudocapsules than those with grades 1 and 2. Multivariate analyses identified grade 2 pseudocapsule status as an independent predictor of worse overall survival (hazard ratio 3.94, 95% confidence interval 2.09–7.43, p < 0.001) and relapse-free survival (hazard ratio 2.87, 95% confidence interval 1.72–4.81, p < 0.001) in the training cohort. The validation cohort showed similar findings (overall survival: hazard ratio 2.64, 95% confidence interval 1.55–4.49, p < 0.001; relapse-free survival: hazard ratio 2.92, 95% confidence interval 1.81–4.71, p < 0.001). In addition, the PPS was independently associated with overall survival. Compared with the low PPS group, the high PPS group showed significantly worse prognosis in both cohorts (training: hazard ratio 33.58, 95% confidence interval 15.52–72.67, p < 0.001; validation: hazard ratio 18.10, 95% confidence interval 9.35–35.03, p < 0.001).ConclusionsPseudocapsule status demonstrated good prognostic implications in RCC. Furthermore, the new PPS system, which combines pseudocapsule status with established pathological parameters, may better predict patient prognosis.

Higher IL8+ TAMs infiltration is associated with an increased incidence of tumor necrosis.

Purpose: Immune checkpoint blockade (ICB) has revolutionized clear-cell renal cell carcinoma (ccRCC) therapy, yet resistance remains common. Tumor-associated macrophages (TAM) shape the tumor-immune interface and contribute to ICB resistance. Although IL8 (CXCL8) was known as a chemokine involved in tumor progression, the role of IL8+ TAMs in ccRCC remains poorly defined. In this study, we aimed to define the clinical and functional relevance of IL8+ TAMs in ccRCC.Experimental Design: Two in-house and four external RCC cohorts, encompassing more than 1,400 patients, were analyzed to determine the clinical relevance of IL8+ TAMs. Immunofluorescence and IHC were applied to quantify IL8+ TAM infiltration. Mass/flow cytometry and multiomics were used to define their phenotype, metabolic profile, and immune interactions. Ex vivo tumor cultures were performed to test IL8 blockade and combination with anti-PD-1 therapy.Results: High IL8+ TAM infiltration was consistently associated with ICB resistance. Transcriptomic analyses revealed that IL8+ TAMs adopt a glycolysis-associated metabolic program and are responsive to lactate, which directly promotes IL8 expression. Phenotypically, IL8+ TAMs exhibited an immunosuppressive and chemotactic profile that correlated with CD8+ T-cell dysfunction and regulatory T-cell accumulation. Importantly, ex vivo IL8 blockade alleviated CD8+ T-cell exhaustion and synergized with PD-1 inhibition to enhance antitumor immune responses.Conclusions: IL8+ TAMs represent a metabolically reprogrammed and immunosuppressive subset driving ICB resistance in ccRCC. Targeting IL8 may overcome resistance and enhance immunotherapy efficacy.

Immune checkpoint blockade (ICB) based therapy improved clinical outcomes in clear cell renal cell carcinoma (ccRCC), yet prognosis remains dismal in patients with advanced disease, especially those with sarcomatoid differentiation. Tumor-associated macrophages (TAMs), abundantly infiltrating in the tumor immune microenvironment (TIME), emerge as regulators of tumor evolution and immune evasion. This study aims to characterize the clinical relevance, functional phenotypes, and therapeutic vulnerability of FN1+ TAMs. We performed an integrated analysis across five cohorts to assess the clinical relevance of FN1+ TAMs infiltration in ccRCC. Single-cell and spatial transcriptomics analyses characterized the transcriptomic profiles and spatial distribution of FN1+ TAMs. Flow cytometry analysis further quantified the phenotype of FN1+ TAMs and associated CD8+ T cells features. Ex vivo functional assays using patient-derived tumors assessed the efficacy of FN1 blockade, as well as combination with PD-1 blockade. FN1+ TAMs preferentially enriched in tumors with sarcomatoid differentiation and correlated with epithelial-mesenchymal transition (EMT) signatures. High infiltration of FN1+ TAMs related to immunotherapy resistance and inferior survival outcomes in ccRCC. FN1+ TAMs exhibited an M2-polarized immunosuppressive phenotype and were associated with CD8+ T cells dysfunction. FN1 blockade reversed EMT-associated transcriptional programs, reduced immunosuppressive molecule expression in macrophages, and restored CD8+ T cells effector function. Combination therapy targeting FN1 and PD-1 synergistically enhanced T cell cytotoxicity and tumor cell apoptosis. FN1+ TAMs, enriched in sarcomatoid-differentiated ccRCC, mediate immune suppression and confer resistance to immunotherapy. FN1 blockade remodels the TIME, promotes tumor apoptosis, and represents a potential therapeutic strategy in ccRCC.

Higher IL8 expression level is associated with worse ICB response in ccRCC.

422 Background: Despite recent advancements, non-clear cell renal cell carcinoma (nccRCC) remains a significant therapeutic challenge with poor prognosis. Innovative therapeutic strategies are urgently needed. We previously reported promising anti-tumor activity of the combination of fruquintinib (small-molecule VEGFR inhibitor) and serplulimab (anti–PD-1 antibody) as first-line therapy in metastatic or unresectable nccRCC patients (pts). Here, we present the updated efficacy and safety data. Methods: This study was designed to enroll 39 treatment-naïve pts (aged 18–80 years, ECOG performance status 0–1) with metastatic or unresectable nccRCC. All pts received fruquintinib (5 mg QD, orally, 2 weeks on/1 week off) plus serplulimab (4.5 mg/kg, IV, Q3W). The primary endpoint was progression-free survival (PFS) per RECIST 1.1, while secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Results: As of September 30th, 2025, 38 pts were enrolled across 3 centers. The median age was 53.5 years (range 19–78), with 68.4% being male; 44.7% had an ECOG performance status of 1. Histological subtypes included papillary (50.0%), unclassified (18.4%), fumarate hydratase-deficient (13.2%), TFE3-rearranged (7.9%), chromophobe (5.3%) and rare variants (5.2%). Sarcomatoid features were observed in 5 pts. The most frequent metastatic sites were lymph nodes (52.6%), lungs (34.2%), peritoneum (34.2%). With a median follow-up of 10 months (95% CI: 9.2–15.9) for PFS, the median PFS was not reached, and the 9-month PFS rate was 87.3%. Among the 36 efficacy evaluable pts, 1 achieved complete response, 18 achieved partial response and 16 had stable disease, yielding an ORR of 52.8% (95% CI: 36.5–69.1) and a DCR of 97.2% (95% CI: 85.5–99.9). Three pts experienced rapid progression (progressing within 4 months in this study), all with sarcomatoid differentiation. 94.7% pts experienced at least one treatment-related adverse event (TRAE) of any grade, with the most common (≥15%) TRAEs were rash (28.9%), proteinuria (26.3%), hypertension (26.3%), hypothyroidism (21.1%), increased ALT or AST (21.1% each), fever (18.4%) and increased blood creatinine (15.8%). The majority of these events were grade 1 or 2, except for one pt who experienced a grade 3 increased AST. No serious adverse events (SAEs) or adverse events leading to permanent discontinuation of medication were observed during the study period, and no TRAEs resulting in death were reported. Conclusions: The combination of fruquintinib and serplulimab showed promising anti-tumor activity with acceptable tolerability as first-line treatment for metastatic or unresectable nccRCC. This novel combination therapy has the potential to become a valuable therapeutic option for this challenging disease. Clinical trial information: NCT05831891 .

Background:Over the past decade, the prognosis of patients with metastatic renal cell carcinoma (mRCC) has significantly improved owing to the development of anti-angiogenic targeted drugs such as sunitinib, pazopanib, and sorafenib. However, biomarkers that can identify patients with mRCC who may rapidly develop drug resistance are still lacking. Approximately 25% of patients experience rapid disease progression [progression-free survival (PFS) ≤3 months]. Currently, there is a lack of effective noninvasive biomarkers to identify resistant patients prior to treatment. This study aimed to identify plasma biomarkers associated with therapeutic resistance and develop a predictive model for clinical decision-making. Methods:Plasma proteomic analysis was conducted in 159 patients with mRCC treated with targeted therapy. Patients were divided into training and validation cohorts. Candidate protein biomarkers were initially screened using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and further validated using enzyme-linked immunosorbent assay (ELISA). A predictive nomogram was subsequently developed using logistic regression analysis and assessed for discrimination and calibration performance. Immunohistochemistry (IHC) was performed to compare protein expression levels in corresponding tumor tissue samples. Results:Four plasma proteins-chitotriosidase-1 (CHIT1), interleukin-6 receptor (IL-6R), neuronal cell adhesion molecule (NRCAM), and ecto-5'-nucleotidase (NT5E)-were identified as significant predictors of intrinsic resistance. The nomogram incorporating these biomarkers exhibited a high predictive accuracy, with a concordance index (C-index) of 0.956 and 0.869 for the training and validation cohorts, respectively. Notably, while the plasma concentrations of these proteins were significantly elevated in resistant patients, their expression levels in tumor tissues showed no significant differences, underscoring their utility as circulating, noninvasive biomarkers. Conclusions:We developed and validated a plasma protein-based nomogram to predict mRCC resistance to targeted therapy. The four identified biomarkers allow noninvasive identification of high-risk patients and offer a practical tool for early clinical stratification. This model may assist clinicians in avoiding ineffective treatment and optimizing therapeutic strategies for patients with mRCC.

The non-invasive assessment of renal masses remains a critical challenge in urologic oncology, where diagnostic uncertainty frequently causes overtreatment. Here, we develop RenalCLIP, a vision-language foundation model for precision oncology in kidney cancer. Utilizing 27,866 computed tomography scans from 8809 patients across diverse multi-center cohorts, we employ a two-stage pre-training strategy to align domain-specific visual and textual representations. RenalCLIP achieves enhanced performance and generalizability across ten core clinical tasks, spanning anatomical assessment, diagnostic classification, and survival prediction, significantly outperforming state-of-the-art general-purpose foundation models. Furthermore, RenalCLIP demonstrates strong data efficiency in diagnostic classification, achieving peak baseline performance using only 20% of the training data. The model also exhibits robust zero-shot diagnostic capabilities, effective image-text retrieval, and high-quality medical report generation. Our findings establish RenalCLIP as a powerful, generalizable tool to enhance diagnostic precision, refine prognostic stratification, and personalize the management of renal masses.

Overview of patient cohorts included in the study.

Abstract Background 177Lu-PSMA-617 is a radioligand therapy targeting cells expressing prostate-specific membrane antigen (PSMA). The pharmacokinetics, dosimetry, and safety of 177Lu-PSMA-617 in participants with metastatic castration-resistant prostate cancer are described previously. In this study, we describe the blood pharmacokinetics behavior, biodistribution, and dosimetry of 177Lu-PSMA-617 to support its clinical use in Chinese participants. Results Nine participants were infused with 177Lu-PSMA-617 (range: 6985.6–8036.0 MBq). The geometric (Geo)-mean blood terminal half-life was 52.6 h, corresponding to an effective half-life of approximately 40 h. The Geo-mean maximum blood concentration of 11.3 ng/mL was achieved at a median time of 0.217 h post administration. The Geo-mean volume of distribution and clearance were 123 L and 1.62 L/h, respectively. The lacrimal glands received the highest absorbed dose of 3.1 mGy/MBq (Geo-coefficient of variation, 93.7%), followed by the thyroid, kidneys, and salivary glands. The Geo-mean whole-body effective dose was 890 mSv (Geo-coefficient of variation, 112.4%). Conclusions The blood pharmacokinetics and organ dosimetry of 177Lu-PSMA-617 in Chinese participants with progressive metastatic castration-resistant prostate cancer were consistent with those previously reported. The cumulative absorbed dose, corresponding to six cycles of treatment, was consistent with published literature. This analysis was conducted as part of a phase II study registered as NCT05670106 at ClinicalTrials.gov on November 7, 2022.

Metastatic castration-resistant prostate cancer (mCRPC) after treatment with docetaxel and androgen receptor signaling inhibitors (ARSIs) has limited treatment options. Although enzalutamide has shown activity after abiraterone and docetaxel, robust evidence from randomized phase III trials is lacking. Deutenzalutamide, a novel derivative with slower metabolism and improved pharmacokinetics, may offer enhanced safety and efficacy. This phase III, double-blind trial conducted at 36 centers in China enrolled patients whose disease progressed on or who were intolerant to abiraterone and docetaxel, or who were ineligible for docetaxel. Patients were randomized (2:1) to receive deutenzalutamide 80 mg once daily or placebo until progression or unacceptable toxicity; the primary endpoint was radiographic progression-free survival (rPFS). Of 417 patients (276 deutenzalutamide; 141 placebo), all had previously received abiraterone, and 68% had also received docetaxel. Deutenzalutamide significantly improved rPFS (HR, 0.58; P = 0.0001), reducing the risk of progression by 42%. Although the initial OS analysis was not significant (HR, 0.95), sensitivity analyses adjusting for subsequent therapies showed significant OS benefits (HR, 0.65-0.73). Treatment-related grade 3 or higher adverse events occurred in 22.3% of patients treated with deutenzalutamide, compared with 15.0% with placebo. The most common treatment-related adverse event was anemia, reported at any grade in 21.2% versus 17.9%, with grade 3/4 anemia in 6.6% versus 2.9%, respectively. Notably, no seizures or falls were reported. In summary, deutenzalutamide significantly prolonged rPFS and, after adjustment, showed a potential OS benefit with a favorable safety profile, supporting its promise as a new treatment option for mCRPC. Clinical trial registration: NCT03851640.

IL8+ TAMs signature correlates with CD8+ T cell dysfunction.

4626 Background: SHR-1501, an IL-15 agonist fusion protein composing of a humanized antibody Fc region fused with IL-15 and IL-15Rα sushi domain, demonstrated promising efficacy, well tolerance, and acceptable safety in alone or in combination with BCG in patients with BCG-naive and BCG-unresponsive high-risk NMIBC ( ASCO 2025 ). Here, we report the updated results of this phase 1/2 study (NCT05410730). Methods: In the dose-escalation phase 1a and 1b parts, SHR-1501 monotherapy (200, 400, and 600 μg) or SHR-1501 (600 μg) in combination with BCG (120 mg) was administered to patients with high-risk NMIBC. In the phase 2 part, patients with BCG-naive NMIBC (cohort A), BCG-unresponsive NMIBC carcinoma in situ (CIS; cohort B), and BCG-unresponsive high-grade Ta/T1 NMIBC without CIS (cohort C) were enrolled to receive SHR-1501 (600 μg) plus BCG (120 mg). During the induction phase, all patients received weekly intravesical study treatment for 6 weeks. In the maintenance phase, instillations were administered weekly for three weeks at months 3, 6, 12, 18, and 24 following the initial induction dose. Primary endpoints were dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase 2 dose in phase 1a and 1b parts; and was complete response (CR) rate for cohort B and 12-mo disease-free survival (DFS) rate for cohorts A and C in phase 2 part. Results: As of Oct 31, 2025, 112 patients were enrolled (n=8 in phase 1a; n=6 in phase 1b; n=30, 25, and 43 in cohorts A, B, and C in phase 2). The median follow-up duration was 23.0 months (range 3.5-25.6) in patients with BCG-naive NMIBC, 6.5 months (range 2.6-21.2) in patients with BCG-unresponsive NMIBC CIS, and 13.5 months (range 2.5-23.1) in patients with BCG-unresponsive high-grade Ta/T1 NMIBC without CIS. In cohort B, the overall CR rate was 80.0% (20/25), the median DFS was 12.0 months (95% CI 6.0-NR). The 12-mo DFS rate was 90.3% (95% CI, 72.8-96.8) in patients with BCG-naive NMIBC and 62.7% (95% CI, 44.9-76.1) in patients with BCG-unresponsive high-grade Ta/T1 NMIBC without CIS. The 18-mo DFS rates were 90.3% (95% CI, 72.8-96.8) and 58.2% (95% CI, 39.6-72.9), respectively. Treatment-related adverse events (TRAEs) and grade 3 TRAEs occurred in 90 (86.5%) and 19 (18.3%) of 104 patients with SHR-1501 + BCG. The most common TRAEs were urinary tract infection (62.5%) and pollakiuria (35.6%). No TRAEs led to death. Conclusions: This updated analysis confirms the promising efficacy and manageable safety profile of SHR-1501 monotherapy or in combination with BCG in BCG-naive and BCG-unresponsive high-risk NMIBC patients. Two randomized, controlled phase 3 trials are underway in both BCG-unresponsive and BCG-naïve, high-risk NMIBC populations, with the recommended dose of 600 μg SHR-1501 plus BCG. Clinical trial information: NCT05410730 .

Clear cell renal cell carcinoma (ccRCC) represents one of the most prevalent malignancies worldwide, characterized by high incidence and mortality rates. It is characterized by mitochondrial dysfunction with enhanced Warburg effect. In this study, we identify the sortilin-related receptor 1 (SORL1) as a regulator of ccRCC progression and a potential molecular target for oxidative phosphorylation inhibition. The present evidence demonstrates that SORL1 promotes the ubiquitin-mediated degradation of C-MYC via TRIM22, which is associated with the downregulation of ACO2 and IDH2 and a consequent suppression of oxidative phosphorylation capacity. Molecular investigations further indicated that Cefoperazone could bind to SORL1 and increase its protein level, exerting the SORL1-triggering function. Targeting delivery Cefoperazone exhibits unexpected anti-tumor performances in ccRCC. Collectively, our findings establish SORL1 as a tumor suppressor in ccRCC and highlight its potential as a therapeutic target in advancing ccRCC clinical treatment strategies.

4533 Background: The multicenter randomized phase 2/3 FRUSICA-2 trial (NCT05522231) demonstrated that fruquintinib plus sintilimab (F+S) significantly improved progression-free survival (PFS) (22.2 months vs 6.9 months) and objective response rate (ORR) (60.5% vs 24.3%) by blinded independent central review (BIRC) assessment compared to axitinib or everolimus (A/E) in Chinese patients (pts) with advanced renal cell carcinoma (aRCC) who had failed prior tyrosine kinase inhibitor therapy (Ye D, et al; 2025 ESMO). Considering that baseline tumor burden may correlate with efficacy outcome, we present the results of a relevant post-hoc subgroup analysis. Methods: Overall, 234 eligible pts were 1:1 randomized to receive either F+S or A/E. The primary efficacy endpoint was PFS assessed by BIRC per RECIST 1.1; secondary endpoints included investigator-assessed PFS, ORR, disease control rate, duration of response, time to response, and overall survival. This subgroup analysis evaluated BIRC-assessed PFS and ORR across subgroups defined by the number of target lesions (TLs) and metastatic sites (METs) at baseline. Results: At baseline, 79, 79, 32 and 44 pts had 1, 2, 3 and ≥4 TL(s), respectively. Metastatic disease was present in 117 (98.3%) pts in F+S arm and 110 (95.7%) pts in A/E arm, with a higher proportion of pts in F+S arm (88, 73.9%) having ≥3 METs than in A/E arm (67, 58.3%). By the data cut-off date of Feb 17, 2025, median follow-up for PFS was 16.6 months. As summarized in the table, F+S demonstrated superior PFS versus A/E across all subgroups, with unstratified hazard ratios (HRs) ranged from 0.28 to 0.50, as well as consistently longer median PFS. Similarly, improvements in ORR were observed across subgroups with odds ratios (ORs) ranged 2.46~7.22. Notably, in F+ S arm, fewer baseline TLs and METs appeared to correlate with longer median PFS, though such trend was not observed for ORR. Conclusions: Consistent with the primary analysis, F+S showed superior efficacy compared to A/E in terms of PFS and ORR in the second-line treatment of aRCC, regardless of the amount of baseline TLs or METs. Clinical trial information: NCT05522231 . Subgroup(F+S v A/E) 1 TL(38 v 41) 2 TLs(38 v 41) 3 TLs(16 v 16) ≥4 TLs(27 v 17) 1 MET(29 v 43) 2 METs(39 v 28) ≥3 METs(49 v 39) PFS, HR (95% CI) a 0.39 (0.20, 0.76) 0.33 (0.17, 0.66) 0.43 (0.17, 1.10) 0.28 (0.12, 0.62) 0.28 (0.13, 0.60) 0.50 (0.24, 1.04) 0.31 (0.18, 0.545) Median PFS, months b 24.9 vs 8.3 22.2 vs 6.9 15.3 vs 4.2 13.8 vs 6.9 24.9 vs 8.3 22.2 vs 8.3 NE vs 4.2 ORR, OR (95% CI) c 3.95 (1.35, 11.91) 4.65 (1.63, 13.43) 7.22 (1.17, 52.78) 5.53 (1.21, 28.76) 7.18 (2.22, 23.84) 2.46 (0.81, 7.76) 6.12 (2.13, 18.44) ORR, % 52.6 vs 22.0 65.8 vs 29.3 62.5 vs 18.8 63.0 vs 23.5 65.5 vs 20.9 53.8 vs 32.1 61.2 vs 20.5 NE, not estimable. a Based on an unstratified Cox proportional risk model. b Estimated using Kaplan-Meier method. c Exact 95% CI for OR was calculated using Cochran-Mantel-Haenszel method.

5047 Background: The development and progression of prostate cancer are regulated by steroid hormones. HSK46575 Tablet is a novel oral small-molecule inhibitor of cytochrome P450 11A1 (CYP11A1), which can block the production of all downstream steroid hormones and their precursors, thereby reducing the activation of the androgen receptor (AR) signaling pathway and inhibiting tumor progression. Herein, we report the safety and efficacy of HSK46575 in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: This multicenter, open - label Phase I clinical trial had two parts: Phase Ia (dose escalation and expansion) and Phase Ib (dose optimization). Eligible patients were mCRPC patients who failed at least one NHA treatment and either failed, were intolerant to, or refused at least one line of chemotherapy. Phase Ia's dose escalation used a "3 + 3" design to explore four doses (3 mg, 10 mg, 30 mg, 60 mg), and dose expansion was done at 30 mg due to good safety and preliminary efficacy.The primary endpoints were safety and the recommended Phase II dose (RP2D). Results: As of November 4, 2025, 27 subjects were enrolled, with a median follow-up of 3.7 months and a median age of 68 years (range: 51-82 years). Among them, 15 (55.6%) had AR ligand -binding domain (AR-LBD) mutations, and 12 (44.4%) had received taxane-based chemotherapy before. No dose-limiting toxicities were observed in any dose group. Treatment-related adverse events (TRAEs) occurred in 18 subjects (66.7%), most of which were Grade 1-2. The most common TRAEs were alanine aminotransferase elevation (18.5%), sinus bradycardia (11.1%), and nausea (11.1%).No adverse events leading to permanent treatment discontinuation or death were observed. Prostate-specific antigen (PSA) assessment was available for 26 subjects, with PSA response rates confirmed after at least 3 weeks. The PSA 30 and PSA 50 response rates were 42.3% and 34.6% in the total population, 71.4% and 57.1% in AR-LBD mutant subjects (n = 14), and 75% and 58.3% in the 30 mg dose group with AR-LBD mutations (n = 12). The PSA 50 response rate was 12.5% (1/8) in the 30 mg dose group with AR-LBD wild-type. Fourteen subjects were eligible for soft tissue assessment, 8 of whom had AR-LBD mutations. One partial response (PR) was seen during treatment in an AR-LBD mutant patient in the 30 mg dose group, leading to an objective response rate (ORR) of 14.3% in this population. . The radiographic progression-free survival (rPFS) has not been reached. The 6-month rPFS rates were 67.5% in the total population and 76.2% in the AR - LBD mutation population. Conclusions: HSK46575 shows a manageable safety profile and preliminary antitumor activity, especially in the population with AR - LBD mutations. These findings support further exploration in the mCRPC population. Clinical trial information: NCT07007910 .