Advances in systemic therapies have improved survival in metastatic renal cell carcinoma (mRCC), leading to a growing population of long-term survivors who may receive both radiotherapy (RT) and tyrosine kinase inhibitors (TKIs) during their disease course. Both treatments induce vascular and mucosal toxicity, and their biological effects may overlap, increasing the risk of rare but life-threatening complications such as aorto-esophageal fistula (AEF). Herein, we present the case of a 47-year-old man with mRCC treated with nephrectomy and repeated pulmonary metastasectomies, followed by sunitinib, mediastinal stereotactic body radiotherapy (SBRT), and later cabozantinib for hepatic progression. Five years after thoracic RT and shortly after initiating cabozantinib, the patient developed massive hematemesis due to an AEF. Management included thoracic endovascular aortic repair (TEVAR), esophageal stenting, and prolonged antimicrobial therapy. Despite initial stabilization, recurrent fistulization and infections led to progressive deterioration and death 7 months later. This case underscores the catastrophic potential of RT-TKI interaction in long-term survivor patients. Sequential exposure can transform subclinical vascular injury into fatal outcomes. Risk stratification, nonconcurrent scheduling of RT and anti-VEGF therapy, and vigilant long-term monitoring are essential. Integration of multidisciplinary and palliative approaches is necessary to balance treatment efficacy with safety.

Prostate cancer represents the third leading cause of cancer-related mortality in the male population. Androgen deprivation therapy efficacy has been significantly enhanced by the addition of docetaxel chemotherapy and androgen receptor pathway inhibitors (ARPI), such as abiraterone, enzalutamide, apalutamide, and darolutamide. These agents have demonstrated improvements in both overall survival (OS) and progression-free survival (PFS). Nevertheless, a subset of patients eventually progresses to metastatic castration-resistant prostate cancer (mCRPC). The prostate-specific antigen (PSA) nadir, defined as the lowest PSA level achieved during therapy, has emerged as an early surrogate marker of treatment response and favorable prognosis. We conducted a meta-analysis to elucidate the prognostic value of the depth of PSA response in patients with metastatic metastatic hormone-sensitive prostate cancer (mHSPC) treated with ARPI or docetaxel. This is a reconstructed individual patient data (IPD) meta-analysis, in which prospective and retrospective clinical trials concerning patients with mHSPC who received first-line therapy with an ARPI or docetaxel were included. Prospective or retrospective studies on mHSPC patients with available data on the lowest value of PSA reached were included. IPD from the Kaplan–Meier curves of enrolled studies were obtained with the software IPDfromKM. Primary endpoints of the analysis were overall survival (OS) and progression-free survival (PFS) in patients who reached a PSA nadir ≤ 0.2 versus PSA nadir > 0.2. A total of 8 reports from 8 studies were included, collecting data from 1638 patients for the OS analysis and 1104 for the PFS analysis. In terms of median PFS (mPFS), the PSA nadir ≤ 0.2 arm had an advantage: mPFS not reached (NR) versus 12.1 months HR 0.19 (95

CONTEXT:With new treatment strategies approved in metastatic hormone-sensitive prostate cancer (mHSPC), heterogeneity across trials hinders the physicians' choice for first-line treatment. OBJECTIVE:We conducted a systematic review and network meta-analysis to assess the efficacy of currently approved treatments for mHSPC stratifying patients according to their disease burden (high- vs. low-volume as per CHAARTED criteria) and onset of metastatic disease (synchronous vs. metachronous). INTERVENTION:Eleven randomized controlled trials (RCTs) published until October 30, 2024 were included. Treatment regimens were grouped as triplets for combinations of docetaxel, androgen receptor pathway inhibitors (ARPIs) and androgen-deprivation therapy (ADT), separate doublets for docetaxel plus ADT, ARPI plus ADT, or monotherapy for ADT alone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Overall survival (OS) and radiographic progression-free survival (rPFS) outcomes were collected. OS as primary endpoint, and rPFS as secondary endpoint, were analyzed separately in high- and low-volume patients. Additional subgroup analyses accounted for timing of metastases categorized as high-volume/synchronous, high-volume/metachronous, low-volume/synchronous, and low-volume/metachronous disease. EVIDENCE SYNTHESIS:Triplet combinations prolonged significantly OS and rPFS in high-volume disease (P-score 0.99), and high-volume/synchronous disease (P-score 0.99). ARPI/ADT doublets performed best in low-volume patients (P-score 0.94), and low-volume/metachronous (P-score 0.99). In the high-volume/metachronous population, triplets, and doublets were equally effective. CONCLUSIONS:The results provide collective evidence for treatment selection based on disease volume and timing of metastasis with strongest survival benefits of triplets for high-volume/synchronous mHSPC patients and of ARPI doublets for low-volume disease.

425 Background: Artificial Intelligence can integrate clinic-pathological features, radiomics, genomic and transcriptomic analysis to define an optimal allocation strategy in first line treatment of metastatic renal cell carcinoma (mRCC). Methods: This is a multicenter Italian prospective translational study including patients (pts) with clear cell mRCC receiving first-line treatment as per investigator’s choice. Tumor tissue was collected at baseline, plasma samples and CT scan were collected at baseline and every 3 months until progression. Due to the short follow up, here we report the preliminary analysis of the radiomic features to identify signatures associated with Objective Response Rate (ORR). A subset of non-analytically correlated radiomic features was extracted from the selected regions of interest. This subset included first-order statistics, three-dimensional shape descriptors, and texture-based features. All features were computed on the original images using PyRadiomics v.3.1.0. The radiomic analysis pipeline consisted of feature variance filtering, multicollinearity reduction, data harmonization and standardization, and feature importance estimation through a Random Forest-based algorithm. Results: 100 pts were enrolled. For the radiomic analysis, 68 patients were included to ensure a more reliable data harmonization process and to improve the robustness of subsequent analyses. 18 (26%) received IO-IO, 38 (56%) received IO-TKI, 12 (18) received TKI monotherapy as first line treatment. According to IMDC score, 16(24%) were good risk, 39(57%) intermediate and 13(19%) poor. The most common site of metastasis were lung (55%, 38), bone (23%,16), nodes (20%, 14/68) and liver (13%, 9). In the overall population, ORR was 48% (33), 44% (18) in the IO-TKI group, 44% (8) in the IO-IO group and 42% (5) in the TKI group. The two most influential features identified by the Random Forest model were original_firstorder_Mean and original_glcm_Contrast (0.59 accuracy, 0.58 precision, 0.58 recall, 0.58 F1 score, 0.49 AUROC). Higher values of these features—reflecting increased tissue density and heterogeneity—were associated with a higher ORR. Conclusions: This preliminary analysis suggests that 2 radiomic signatures are associated with higher ORR and are promising as early biomarkers of response in mRCC. However, they do not appear to provide optimal predictive value when used alone, and should therefore be integrated with clinical, genomic, and transcriptomic data to refine predictive modeling. Acknowledgments: We thank AIRC (Associazione Italiana Ricerca sul Cancro) for the support received to conduct this trial. Clinical trial information: NCT05782400 .

Immune checkpoint inhibitor (ICI)–based combinations represent the standard first-line treatment for metastatic clear cell renal cell carcinoma (mRCC), although robust biomarkers for treatment selection remain undefined. We conducted a systematic review to identify biomarkers assessed in randomized clinical trials (RCTs) on first-line ICI-based regimens. Following PRISMA guidelines, we searched PubMed, Web of Science and Scopus (January 2018–October 2025) for phase III RCTs investigating first-line ICI-based therapies in mRCC with molecular or circulating biomarker analyses. Given heterogeneity across studies, a qualitative synthesis was performed. Sixteen reports were included. Biomarkers were assessed using immunohistochemistry, transcriptomics, genomic sequencing and blood analyses. PD-L1 expression did not reliably discriminate benefit across ICI-based combinations, although it revealed a negative prognostic influence with sunitinib and a potential predictive role for nivolumab-ipilimumab. Tumours with angiogenic signatures were consistently associated with improved outcomes, suggesting prognostic relevance, while derived limited additional benefit from ICIs. Immune-related signatures were associated with ICI response, whereas proliferation and MYC-related signatures identified disease with poor prognosis across treatments. Individual mutations (e.g. PBRM1, VHL, BAP1, PTEN) showed heterogeneous and mainly prognostic associations, whereas composite gene panels (e.g. rDM) may offer better predictive value. Circulating biomarkers, including inflammatory cytokines and KIM-1 dynamics, demonstrated promising prognostic and early predictive signals. No validated biomarker currently supports treatment selection among first-line ICI-based combinations in mRCC. Future research should prioritize adaptive, biomarker-guided trial designs integrating longitudinal multi-omic profiling and circulating biomarkers to generate clinical evidence and support personalized treatments.

681 Background: The therapeutic landscape of metastatic Urothelial Carcinoma (mUC) is rapidly evolving, alongside increasing opportunities to analyze molecular alteration and molecular classification. FGFR alteration (FGFRa) occur in about 15-20% of mUC patients. Data from randomized-controlled THOR trial demonstrated the clinical efficacy of erdafitinib, an FGFR 1-4inhibitor, in pretreated FGFR3/2a mUC. So, real-world data (RWD) on FGFRa patients remain an unmet need. Methods: SATURNO (NCT06235268) is an Italian, multicenter, prospective, non-interventional study enrolling all mUC patients managed at the participant institutions from Nov 2023 to Sept 2025. The Web National Registry includes patients with metastatic disease or with nodal involvement not suitable to surgery. Participating institutions were selected to adequately represent different geographical area. Results: A total of 237 patients were tested for FGFRa. Among them, 171 (72%) were FGFR3/2a and 66 (28%) were FGFR wild-type (WT). In the FGFR3/2a group, 134/171 (78%) were male and 37/171 (22%) were female; 165/171 (96%) had pure urothelial carcinoma histology. The most common metastatic sites were lung (61/171, 35%), liver (21/171, 12%), bone (41/171, 24%), and retroperitoneal lymph nodes (50/171, 29%). Compared with FGFR WT patients, older age was significantly associated with FGFR3/2a (OR 1.05, 95% CI 1.02–1.09, p = 0.003). Retroperitoneal lymph node involvement was less frequent among FGFR3/2a patients (29% vs 44%, OR 0.53, 95% CI 0.29–0.95, p = 0.033). FGFR3/2a tended to be more common in upper tract urothelial carcinomas (UTUC) compared with bladder tumors (23.4% vs 12.1%, OR 2.12, 95% CI 0.98–5.15, p = 0.073). FGFR3/2a patients were less likely to receive maintenance therapy (OR 0.36, 95% CI 0.19–0.65, p < 0.001). Among patients treated with platinum-based combinations (91/171, 53%), 41/91 (45%) FGFR3a patients received avelumab maintenance compared to 31/58 (53%) in the FGFR WT subgroup. Additionally, 26/91 (29%) FGFR3a patients had primary refractory disease to platinum-based therapy, compared with 14/58 (24%) among FGFR WT patients. Conclusions: RWD from this prospective registry show that FGFR3/2a is more common in older patients and, consistent with previous reports, tends to occur more frequently in UTUC. Retroperitoneal nodal involvement, usually associated with better prognosis, is less common in FGFR3/2a. FGFR3/2a are less likely to receive avelumab maintenance therapy due to primary progression to platinum-based combination. Acknowledgments: The IT infrastructure on which the urothelial tumor registry is based was developed thanks to the unconditional support of Gilead Sciences. Clinical trial information: NCT06235268 .

8536 Background: Low clinical trial accrual remains a critical barrier in oncology, driven by fragmented electronic health records (EHRs), limited trial awareness, and the substantial time required for manual eligibility screening. While large language models (LLMs) can extract clinical information from unstructured data, their probabilistic nature limits direct use for eligibility decisions that require protocol-level determinism and auditability. We developed a neuro-symbolic clinical trial matching platform that combines LLM-based information extraction with explicit rule-based eligibility reasoning, augmented by an uncertainty-aware triage strategy to safely integrate automation into real-world workflows. Methods: Unstructured EHRs were processed using a large language model (Llama 3.1–70B) to extract key clinical variables, which were normalized to a domain ontology. Trial eligibility was evaluated using deterministic inclusion and exclusion criteria encoded directly from full trial protocols, producing per-criterion explanations and an overall classification (eligible, not eligible, or indeterminate). A triage module quantified evidentiary completeness and logical consistency, categorizing cases into low-uncertainty confidence results suitable for automated screening, moderate and high-uncertainty cases requiring clinician review. Performance was assessed against clinician-validated ground truth in a real-world cohort of 107 patients, including advanced lung cancer patients and an independent genitourinary cancer validation cohort. Results: Among matchable patients (n = 79), the system achieved perfect Top-1 accuracy and Recall@3 of 1.00, with all eligible patients correctly identified within the top three trial recommendations. Thirty-nine patients (49%) were triaged as low-uncertainty and suitable for automated screening, while the remainder were appropriately flagged for clinician review. Among non-matchable patients (n = 28), no false-positive eligibility assignments were observed (false-positive rate 0.0). Triage correctly identified high-uncertainty cases, minimizing unsafe automation. In indeterminate cases (ground truth unknown, n = 6), the system deferred to manual review in two-thirds of cases, with zero unsafe automated classifications. Median end-to-end processing time was under one minute per patient. Conclusions: This neuro-symbolic, triage-aware approach enables transparent and deterministic clinical trial matching in oncology. By combining automated eligibility assessment with uncertainty-based triage, the system reduces manual screening burden while preserving clinician oversight, supporting scalable and trustworthy trial enrollment in real-world practice.

Background: Immune checkpoint inhibitors have revolutionized the treatment landscape for metastatic renal cell carcinoma (mRCC). However, some patients fail to experience durable benefits, especially those with bone metastases. Objective: This study aimed to evaluate the impact of bone-targeting agents (BTAs), specifically denosumab and zoledronic acid (ZA), on the clinical outcomes of patients with mRCC treated with nivolumab. Methods: This retrospective study analyzed data from the Meet-URO 15 trial on patients with mRCC who received nivolumab, categorizing them into BTA and non-BTA groups. Survival outcomes were assessed, with inverse probability of treatment weighting (IPTW) adjustment for confounding variables. Subsequently, the specific impact of different BTAs on the clinical outcomes was explored. Results: Of 203 mRCC patients with bone metastases, 38 received BTAs (BTA group) while 138 did not (non-BTA group). BTA treatment significantly improved the median progression-free survival (PFS) (291 vs. 117 days, p = 0.005) and overall survival (OS) (960 vs. 397 days, p = 0.008) compared with the non-BTA group, with a reduced risk of death (HR = 0.57, 95%CI = 0.34-0.95, p = 0.031) and progression or death (HR = 0.57, 95%CI = 0.35-0.92, p = 0.023) at multivariate analyses. IPTW adjustment confirmed these survival benefits, with a reduced risk of death (HR = 0.55-95%CI = 0.39-0.76, p < 0.001) and progression or death (HR = 0.58, 95%CI = 0.42-0.79, p < 0.001) in BTA patients. Furthermore, denosumab, compared with ZA and the non-BTA group, demonstrated superior OS (1,662 vs. 681 vs. 411 days, p < 0.001) and PFS (1,101 vs. 242 vs. 132 days, p < 0.001) in the same IPTW-adjusted population. Conclusion: This study suggests a potential beneficial impact of BTAs, especially denosumab, on the clinical outcomes after nivolumab therapy in mRCC patients with bone metastases. Prospective trials are needed to better define the impact of BTAs in these patients.

BACKGROUND:Androgen deprivation therapy (ADT) + androgen receptor pathway inhibitor (ARPI)  ± docetaxel represent the standard of care in patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, some patients still have early progression (EP). EMETPRO is a multicentric, retrospective registry of patients with EP mHSPC. METHODS:Patients with EP mHSPC were defined as patients who had progression ≤6 months under ADT+docetaxel or ADT + ARPI or ≤9 months from ADT monotherapy start. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS). RESULTS:Data from eligible patients treated between 2005 and 2023 were retrospectively collected. 201 (50%) patients received ADT monotherapy, while 124 (31%) and 76 (19%) received ADT+docetaxel and ADT + ARPI, respectively. 365 (91%) patients underwent first-line treatment for mCRPC-majority of the ADT monotherapy received ARPI (38%) or docetaxel (34%), whereas 69% of the ADT+docetaxel received ARPI and 62% of the ADT + ARPI received docetaxel. In the group of patients treated with ADT the median PFS was 6.8 months while the median OS was 26.4. In the group of patients treated with combination therapy the median PFS and OS was 4.9 and 18.6 months for patients who received docetaxel and 5.6 and 19.5 months for patients who received ARPI, respectively. Neither the first-line mCRPC treatment nor the genetic profiles were associated with survival outcomes. CONCLUSIONS:The results of our study suggest that patients with EP mHSPC are characterized by poor outcomes regardless of the type of treatment received at progression. The optimal first-line mCRPC therapy to use in these patients remains a crucial unmet clinical need.

473 Background: KEYNOTE-564 demonstrated that adjuvant pembrolizumab improves outcomes after nephrectomy for clear-cell renal cell carcinoma (RCC). Whether this benefit extends to non–clear cell RCC (nccRCC) remains uncertain. We evaluated the association between adjuvant pembrolizumab and outcomes in patients with nccRCC who underwent nephrectomy in a multicenter study. Methods: We conducted a retrospective multicenter cohort study at six international institutions. Eligible adults had nccRCC treated with nephrectomy and were classified by receipt of adjuvant pembrolizumab. The primary endpoints were disease-free survival (DFS), defined as the time from nephrectomy to the first radiographic or clinical recurrence, and overall survival (OS), defined as the time from diagnosis to death or last follow-up. Survival functions were estimated with the Kaplan–Meier method and compared between groups using the log-rank test. Estimates of median DFS and OS were calculated using the Kaplan–Meier method. Results: Patient characteristics are shown in Table 1. Among 90 patients, 15 (17%) received adjuvant pembrolizumab, and 75 (83%) were observed; age at diagnosis was 56.0 years (IQR 44.0–63.0; mean 52.9 ± 13.1) and 62.0 years (IQR 52.0–71.0; mean 59.6 ± 14.7) respectively. Recurrence occurred in 7/15 (46.7%) with pembrolizumab and 25/75 (44.6%) with observation. There was no significant difference in median DFS (p = 0.75) or OS (p = 0.89) between groups. Median DFS was 90.7 months (95% CI, 27.2–NR) with pembrolizumab vs 41.9 months (95% CI, 39.4–NR) with observation; median OS was not reached (95% CI, 65.1–NR) with pembrolizumab vs 52.4 months (95% CI, 44.4–NR) with observation. Conclusions: In this descriptive retrospective six-center cohort of nccRCC post-nephrectomy, adjuvant pembrolizumab did not demonstrate a DFS or OS advantage over observation. A larger multi-institutional cohort is in progress to refine effect estimates using richer clinical detail, with adjusted analyses and prespecified subgroup assessment. Baseline characteristics by treatment group. Characteristic Overall (n=90) Observation (n=75) Pembrolizumab (n=15) Sex (Male/Female), n (ratio) 58 / 32 (1.8:1) 48 / 27 (1.8:1) 10 / 5 (2:1) T1, n (%) 11 (12.2%) 10 (13.3%) 1 (6.7%) T2, n (%) 10 (11.1%) 10 (13.3%) 0 (0.0%) T3, n (%) 64 (71.1%) 52 (69.3%) 12 (80.0%) T4, n (%) 3 (3.3%) 2 (2.7%) 1 (6.7%) Papillary RCC, n (%) 41 (45.6%) 36 (48.0%) 5 (33.3%) Chromophobe RCC, n (%) 31 (34.4%) 27 (36.0%) 4 (26.7%) Unclassified RCC, n (%) 7 (7.8%) 6 (8.0%) 1 (6.7%) Xp11 translocation, n (%) 8 (8.9%) 4 (5.3%) 4 (26.7%)

PROpel (phase 3 randomized [1:1], double-blind trial: NCT03732820) met its primary endpoint, showing statistically significantly improved investigator-assessed radiographic progression-free survival (rPFS) with olaparib plus abiraterone versus placebo plus abiraterone in biomarker-unselected first-line metastatic castration-resistant prostate cancer (mCRPC; hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.54-0.81; p < 0.0001). Median overall survival (OS) was 42.1 mo with olaparib plus abiraterone, a 7.4-mo improvement versus placebo plus abiraterone. We report efficacy in patients with single homologous recombination repair gene mutations (HRRm). Before primary analysis, HRRm status was determined by aggregating tumor tissue (FoundationOne CDx) and circulating tumor DNA (FoundationOne Liquid CDx) assay results. Overall, 28.4% of patients had an HRRm, predominantly BRCA2 (7.3%), ATM (6.2%), and CDK12 (5.0%). HRs numerically favored olaparib plus abiraterone for rPFS (BRCA2, HR, 0.20; 95% CI, 0.08-0.44; ATM, HR, 0.55; 95% CI, 0.20-1.38; CDK12, HR, 0.51; 95% CI, 0.20-1.18) and OS (BRCA2, HR, 0.20; 95% CI, 0.07-0.48; ATM, HR, 0.79; 95% CI, 0.33-1.77; CDK12, HR, 0.57; 95% CI, 0.24-1.27). Other single-gene mutations were rare (<5 events in either arm), limiting interpretation. Findings support olaparib plus abiraterone as an important first-line option for patients with mCRPC. PREVIOUS PRESENTATION: Results were previously presented in part at the ASCO-GU 2024 congress, held on January 25-27, 2024: San Francisco, CA, USA.

BACKGROUND:Active surveillance (AS) is standard for early-stage prostate cancer, though intensive monitoring continues due to concerns about reclassification to Grade Group (GG) ⩾ 2. We hypothesized that simple and inexpensive clinical parameters could identify patients with indolent disease for whom less intensive monitoring is safe. METHODS:We analyzed upgrading to ISUP Grade Group (GG) ⩾ 2 in a large cohort of low-risk prostate cancer (PCa) patients on AS. We used mixed-effects logistic regression to develop a model predicting non-upgrading at the next follow-up biopsy, based on routine time-updated clinical-pathological variables. RESULTS:While annual reclassification persisted at a rate between 10.4% and 17.5% up to the 7th year, upgrades were predominantly GG2. Routine parameters powerfully stratified risk. Patients with a very unfavorable Prostate Specific Antigen (PSA) doubling time had a 40.5% upgrading rate versus 9.5% for those with a favorable value. The final model is based on baseline PSA density and number of positive cores, time-updated age and PSA doubling time category, detection of cancer in the last surveillance biopsy. The model showed moderate discrimination (0.73) in predicting non-upgrading. CONCLUSIONS:Many patients on AS have indolent disease but steady upgrading justifies monitoring. A model using simple, routine parameters and PSA doubling time can identify those at minimal risk of reclassification, enabling a safe reduction in biopsy intensity. This advocates for a risk-adaptive AS protocol, reserving advanced tools like MRI or biomarkers for the few higher-risk cases.

INTRODUCTION:The treatment landscape of metastatic hormone-sensitive prostate cancer (mHSPC) has changed substantially with the introduction of androgen receptor pathway inhibitors (ARPIs), which have improved survival outcomes and raised the threshold for demonstrating additional benefit from local interventions. In this setting, the role of local treatment of the primary tumor remains clinically relevant but requires reassessment, taking into account modern systemic intensification. AREAS COVERED:This expert opinion discusses the current role of local treatment of the primary tumor in mHSPC patients eligible for ARPIs therapy, focusing on prostate radiotherapy and surgery. It examines the evidence supporting radiotherapy in the androgen deprivation therapy era, the uncertainties emerging in the ARPI era, the implications for toxicity and local symptom control, and the rationale for ongoing trials evaluating local treatment in combination with contemporary systemic therapy. EXPERT OPINION:In the ARPI era, local treatment should be considered within an individualized, multidisciplinary framework rather than as an automatic standard for patients with mHSPC. Its main value may increasingly lie in preventing local progression and genitourinary complications in selected patients, while a definitive overall survival benefit on top of intensified systemic therapy remains unproven.

Purpose In the PROpel study (ClinicalTrials.gov identifier: NCT03732820), olaparib plus abiraterone demonstrated statistically significant radiographic progression-free survival benefit versus placebo plus abiraterone in a first-line metastatic castration-resistant prostate cancer (mCRPC) population unselected by homologous recombination repair gene mutation (HRRm) status. From PROpel, we report exploratory biomarker analyses assessing HRRm and BRCA1 and/or BRCA2 (BRCAm) status using tumor tissue and plasma-derived circulating tumor (ct) DNA. Methods Patients received (1:1) either olaparib (300 mg twice a day) or placebo in combination with abiraterone (1,000 mg once daily) plus prednisone/prednisolone (5 mg twice a day). Tumor tissue and ctDNA samples were analyzed using FoundationOne CDx and FoundationOne Liquid CDx tests, respectively. Biomarker results are presented by individual tests and as an aggregate analysis. Results HRRm status was obtained for 778 of 796 (98%) patients randomly assigned. Aggregating tumor tissue and ctDNA results, 226 patients were identified as having HRRm (including 85 BRCAm). In matched tumor tissue and ctDNA samples (n = 491), and using the tumor tissue result as the reference, high concordance was observed for HRRm (overall percent agreement, 85.1%; negative predictive value, 93.7%) and BRCAm status (overall percent agreement, 93.9%; negative predictive value, 97.3%), with low ctDNA fraction being a limiting factor in rare cases where discordance was observed. Based on the observed agreement, there was a potential incidence of 1% unidentified BRCAm in aggregated non-BRCAm patients (n = 693). Conclusion Aggregating tumor tissue and ctDNA analyses maximized the number of patients (98%) with known biomarker status in PROpel while limiting the number of potential false negatives. This represents the most comprehensive means for identifying biomarker-positive and biomarker-negative subgroups and demonstrates the complementary utility of ctDNA testing in mCRPC, particularly when tissue testing is unable to provide a clinically useful result.

We report on the randomized portion of the phase 2, open-label CheckMate 650 trial (NCT02985957), in which docetaxel-experienced, biologically male patients with chemotherapy-refractory metastatic castration-resistant prostate cancer were randomized 2:2:1:2 to nivolumab 3 mg /kg plus ipilimumab 1 mg /kg (n = 73), nivolumab 1 mg /kg plus ipilimumab 3 mg /kg (n = 74), ipilimumab 3 mg /kg (n = 38), or cabazitaxel (n = 74). Primary endpoints were objective response rate and radiographic progression-free survival; key secondary endpoints included overall survival, prostate-specific antigen response rate, and safety. This portion of CheckMate 650 was not designed to statistically compare between cohorts. Respectively, objective response rates (95% CI) were 9.3% (2.6-22.1), 19.5% (8.8-34.9), 4.5% (0.1-22.8), and 12.2% (4.1-26.2), and median radiographic progression-free survival (95% CI) was 3.9 (2.2-7.6), 4.2 (3.3-5.6), 3.5 (2.1-5.8), and 7.9 (5.6-9.3) months. Respective incidence of grade ≥3 treatment-related adverse events was 28.8%, 30.1%, 18.4%, and 34.7%. Preliminary post hoc biomarker analyses in patients who received treatment with any immunotherapy regimen (i.e., treated with either of the nivolumab plus ipilimumab regimens or with ipilimumab alone, n = 12) identified a transcriptional signature, derived from the most highly expressed genes across cell types within select perivascular immune niches (comprising CD31+ endothelial, CD14+HLA-DR+ myeloid, and CD4+ and CD8+ T cells), which was associated with prolonged overall survival. These results provide further evidence of antitumor activity with nivolumab plus ipilimumab in select patients with metastatic castration-resistant prostate cancer and nominate a candidate prognostic biomarker that warrants confirmation in future prospective clinical trials.

Integrating multi-modal patient data to support personalized medicine has gained a lot of interest across different health domains over the past decade. Addressing this challenge requires the development and implementation of an informed, evidence-based AI-driven decision-support system continuously maintained and updated to align with the latest clinical guidelines. A key challenge to ensure its real-life adoption lies in translating the outcomes of complex AI-driven data integration and modeling into a form easily understood by the clinical audience. To ensure explainability, knowledge graphs have emerged as data models integrating multi-omics data sources and representing them as interconnected networks. Knowledge graphs offer a framework which AI models can progressively refine, highlighting the most influential features and relationships facilitating transparency of complex interactions and interdependencies. In this perspective we present major components and challenges upon developing a knowledge-based explainable AI system. Additionally, we showcase a current effort undertaken by the Knowledge at the Tips of your Fingers (KATY) consortium to develop the infrastructure for an explainable system supporting best treatment decision for a renal cancer patient.

BACKGROUND AND OBJECTIVE:Management of metastatic renal cell carcinoma (mRCC) remains complex despite clinical guidelines. The aim of this Delphi study was to achieve consensus among RCC experts on the definition, diagnosis, and first-line treatments for mRCC. METHODS:Between May 2023 and April 2024, 14 experts from ten European countries completed two Delphi rounds of a 51-item questionnaire covering four topics: (1) oligometastatic RCC; (2) first-line treatment for metastatic clear-cell RCC; (3) treatment duration for metastatic clear-cell RCC; and (4) treatment of non-clear-cell RCC. Agreement was scored as absent/poor (<50%), fair (50-74%), or consensus (≥75%). KEY FINDINGS AND LIMITATIONS:Consensus was reached for 12 of 51 items (24%) in the first round and 25 of 49 items (51%) by the study end. Notably, 79% of experts defined oligometastatic RCC as five or fewer metastases and agreed that it typically does not require immediate systemic treatment. All experts (100%) emphasized the importance of clinical performance status in guiding treatment for metastatic clear-cell RCC, with 86% agreeing on additional factors such as International Society of Urological Pathology grade and sarcomatoid features. Nivolumab plus cabozantinib was favored for patients with brain or bone metastases (93% and 86% agreement, respectively), while there was fair agreement on pembrolizumab plus lenvatinib for patients with liver metastases. In addition, 71% supported stopping immune checkpoint inhibitors after 2 yr, while 86% agreed on the undefined duration of tyrosine kinase inhibitor therapy. CONCLUSIONS AND CLINICAL IMPLICATIONS:This Delphi study offers insights into mRCC management, and highlights the importance of multidisciplinary discussions for this challenging disease.

Adequate information about patients with bone metastases could increase adherence to treatment and reduce or delay skeletal and dental complications. Limited data are available on patient awareness, the degree of information received, and adherence to specific treatment for bone metastases. ROPI (Rete Oncologica Pazienti Italia) conducted an anonymous survey from 1 February to 31 August 2022 among patients with bone metastases from solid tumors to evaluate their level of information and adherence to specific treatments and dental evaluations. Questionnaires were administered by oncologists or nurses at participating cancer centers. Analysis of 351 questionnaires revealed that 75

Purpose:This real-world analysis described the characteristics and therapeutic management of patients with metastatic castration-resistant prostate cancer (mCRPC) in Italy before and after 2015, when androgen receptor signalling inhibitors (ARPI) entered clinical practice. Patients and Methods:An observational retrospective analysis was conducted using administrative healthcare databases from a pool of Italian Local Health Units, covering ~6.2 million residents. Adult men with ≥1 prescription of androgen deprivation therapy (ADT) from January 2011 to June 2022 were identified. mCRPC was proxied by treatment patterns-addition of docetaxel/cabazitaxel or ARPI to ADT-and confirmed by hospital discharge for metastasis. Patients were stratified according to their inclusion (date of the last inclusion criterion met): pre-2015 (2011-2014) and post-2015 (2015-2020). Results:Among 1890 mCRPC patients identified, 551 (29%) received ≥2 treatment lines. Chemotherapy (CHT) was the predominant first-line (1L) therapy in both cohorts [97.2% vs 82.9%], followed by ARPI [2.8% vs 17.1%]. In a 2020 sensitivity analysis (n=406), 1L therapy was ARPI in 76% and CHT in 24%. Among pre- and post-2015 patients, 29.4% and 31.6% received second-line (2L) therapy, mostly ARPI. Median OS from ADT initiation was 46.4 months (pre-2015) and 53.9 months (post-2015). In post-2015 patients, median OS from mCRPC index-date-reflecting the proxy-based diagnosis-was 14.2 months. Conclusion:In Italian clinical practice, CHT remains the most common 1L therapy though ARPI use has increased since 2015. While OS from ADT initiation has improved, survival from mCRPC diagnosis-based on proxies in administrative data-remains poor, underscoring an unmet clinical need. Differences in OS estimates depending on the starting point (ADT initiation vs mCRPC diagnosis) should be considered when interpreting results.