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 .

Choriocarcinoma is a malignant neoplasia which develops from trophoblastic cells. In males it is rare and often associated with other non-seminomatous germ cell tumours of the testis. Choriocarcinoma often presents with metastatic disease and elevated βHCG levels. Usually, patients' symptoms are associated with the different metastatic sites and they can be severe or even life-threatening. Moreover, choriocarcinoma is chemosensitive and the administration of chemotherapy with curative intent may lead to tumour-lysis syndrome and the more specific choriocarcinoma syndrome (CS). Therefore, the treatment of metastatic choriocarcinoma is complex, involving both oncological therapy and the management of acute complications. This review explores choriocarcinoma in males, focusing on its clinical presentation, pathogenetic mechanisms, and treatment options, including investigational therapies. Additionally, we aim to highlight the severe complications of CS and discuss its management strategies.

Metastatic renal cell carcinoma remains clinically challenging because of heterogeneous outcomes and limited predictive biomarkers for immunotherapy. We performed an explainable machine learning analysis using data from the multicenter retrospective Meet-URO 15 study, including 571 patients with metastatic renal cell carcinoma treated with second-line or later nivolumab. Clinical and inflammatory variables were used to develop classification models for disease control rate, progression-free survival at 3 and 9 months, and overall survival at 6, 18 and 24 months, as well as survival models for continuous progression-free and overall survival. Model performance was assessed using weighted F1-score for classification and concordance index for survival analysis, with interpretability provided through Shapley additive explanations. The best classification performance was observed for 6-month overall survival using a support vector machine model combined with minimum redundancy maximum relevance feature selection, achieving an F1-score of 0.81 on the test set and 0.77 in external validation. In survival analysis, random survival forest achieved a test-set concordance index of 0.68 for overall survival. Inflammatory indices, IMDC score, hemoglobin, lymphocytes and platelets consistently emerged as relevant prognostic features. These findings support explainable machine learning as a transparent approach to refine outcome prediction in immunotherapy-treated metastatic renal cell carcinoma.

Background: Germline and somatic variants in DNA Damage Repair (DDR) genes are found in approximately one-fourth of patients with metastatic prostate cancer (PC). However, their precise prognostic role and predictive impact on standard therapies remain controversial. Methods: This retrospective, single-center study evaluated the prevalence of germline/somatic DDR aberrations in 287 eligible patients with metastatic prostate cancer (mPC), treated between 2017 and 2022. Clinical characteristics and treatment outcomes (PFS and OS) for chemotherapy (taxanes) or next-generation hormonal therapies (NHT) were compared between DDR-mutated (DDRmut) and wild-type (DDRwt) cohorts. Results: Sixty-three patients (21.9%) were DDRmut, with BRCA2 (12.5%), ATM (3.1%), and BRCA1 (1.39%) being the most common alterations. A family history of breast, ovarian, or prostate cancer strongly predicted DDRmut status (47.0% vs. 14.0%, p = 0.0001). Tissue samples remained evaluable for sequencing up to 180 months from collection. Overall baseline characteristics were similar between cohorts, and BRCA1/2- and ATM-mutated patients treated with first-line taxanes for mCRPC presented with non significantly highermedian OS compared to DDRwt patients (70 vs. 36 months; p = 0.30). On the contrary, the DDRmut subgroup showed a trend toward shorter PFS (12 vs. 18 months; p = 0.04) when treated with first-line NHT. No significant differences were observed with third-line Cabazitaxel. Conclusions: Formalin-fixed paraffin-embedded (FFPE) prostate tissue is highly reliable for DDR, possibly integrating novel liquid biopsy approaches for DDR evaluation. In a real-world setting, BRCA1/2 and ATM variants identify a distinct molecular subgroup that derives preferential survival benefit from first-line taxanes over standard hormonal intensification.

BACKGROUND:Nowadays, systemic treatment with immune-based combinations for metastatic renal cell carcinoma (mRCC) is the gold standard. However, the benefit of these treatments in patients aged ≥70 years is uncertain. Thus, we evaluate the effectiveness and safety of first-line immune-based combinations in elderly patients with mRCC. METHODS:We retrospectively collected data from mRCC patients who were treated with immune-based combinations in first-line setting at 75 hospitals from 23 countries. Patients were assessed for overall survival (OS), overall response rate (ORR) and severe adverse events (SAEs). The statistical analysis encompassed the Fisher's Exact Test, the Kaplan-Meier methodology, the log-rank test, as well as univariate and multivariate Cox proportional hazards regression models. RESULTS:Of the 1990 mRCC patients included in this analysis, 739 patients were aged ≥70 years. Median OS was 41 months for patients aged <70 years and 30.1 months in patients aged ≥71 years (P<0.001). The age was a prognostic factor in both univariate and multivariate analysis. There was no difference in ORR (52% versus 44%, P=0.262). There was no statistical difference in incidence SAEs as well as dose reductions or treatment discontinuation between elderly and young patients. CONCLUSIONS:This large real-world study with mRCC patients substantiates the effectiveness and safety of first-line immune-based combination treatments in elderly patients. Nonetheless, this population has a lower survival in comparison to younger patients.

Background: Although the relationship between androgen deprivation therapy (ADT) for prostate cancer (PC) and the biological mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unequivocally unclear, it is possible that exposure to the virus may influence PC evolution by altering TMPRSS2 expression. This study aims to evaluate the long-term oncological outcomes of patients with metastatic PC who were undergoing medical therapy at the time of contracting SARS-CoV-2 and who resumed/continued anticancer treatment after recovery. Methods: We retrospectively evaluated a consecutive series of 151 metastatic PC patients who developed SARS-CoV-2 infection while receiving one active systemic anticancer therapy (125 metastatic castration-resistant PC (mCRPC) patients and 26 metastatic hormone-sensitive PC (mHSPC) patients). We evaluated variables that influence the ability to maintain or resume the ongoing therapy. For the maintained/resumed therapies, we calculated the post-infection overall survival (piOS) and the overall survival (OS). Results: Of the patients, 12.6% died due to SARS-CoV-2 infection, 10.6% recovered from the infection but failed to maintain/resume the ongoing anticancer treatment, and the remaining 76.8% maintained/resumed the treatment after recovery. Hospitalization, duration of infection, and the type of ongoing anticancer agent influenced these treatment changes. In the cohort of mCRPC patients, the median piOS was 32 months, and the median OS was 67.8 months. The median piOS was not achieved in the cohort of mHSPC patients, while the median OS was 122 months. The outcomes of single anticancer agents were in line with those of pivotal trials. Conclusions: Although observed in a highly selected population of PC patients who survived SARS-CoV-2 infection and were able to resume/maintain anticancer therapy, the survival outcomes of this study appear to be in line with those reported in pivotal studies, and SARS-CoV-2 infection does not seem to have adversely affected long-term oncological outcomes.

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.

218 Background: DNA-damage-repair (DDR) gene alterations, particularly those involving BRCA1/2 genes, are clinically relevant in the management of mPC. Tumor tissue remains the standard DNA source for molecular profiling, but sample availability and quality of retrieved DNA are limiting factors. Liquid biopsy (LB), based on circulating free DNA (cfDNA), offers a minimally invasive alternative for real-time monitoring of DDR gene alterations, especially in consideration of clonal heterogeneity. Methods: We conducted a retrospective study at the Veneto Institute of Oncology including a random sample of 50 mPC patients (pts) previously tested for DDR alterations on tumor tissue: 25 DDR-mutated (DDRmut) and 25 DDR wild-type (DDRwt). cfDNA was extracted from plasma and analysed with amplicon-based NGS (BRCA1/2) and capture-based NGS (16 DDR genes). Mutations found at LB were classified according to IARC/ACMG-AMP guidelines. Clinical variables, genomic findings, and outcomes were compared between DDRmut and DDRwt pts. The study was approved by local Ethics Committee and all pts signed the informed consent. Results: Median age at diagnosis was 68 years; 64% had high Gleason score (GS, 8 to 10), 56% had high-volume metastatic (HV) disease at diagnosis. DDRmut pts had higher PSA at the time of LB (0.76 vs. 0.08 ng/mL; p=0.004), longer time to castration resistance (29 vs. 7 months; p=0.002), and more frequent family history of cancer (56% vs 30%; p=0.044). Median cfDNA concentration was 5.27 ng/mL, higher in GS 8 to 10 vs 6 to 7 (5.57 vs. 4.51 ng/mL; p<0.001). No correlation was found with disease volume or PSA levels. cfDNA quantity and quality were adequate for NGS testing in all DDRmut and 18 DDRwt pts. LB detected the same DDR variants previously reported in tumor tissue analysis in 20/25 DDRmut pts. LB revealed six previously unknown DDR variants in 18 evaluable DDRwt pts involving BRCA2 gene (3pts, 2 Likely Pathogenic, 1 Not Present), ATM (2 pts, both Not Present) RAD51B (2 pts, both Not Present), and BRIP1 (1 pt, Not Present), with 2 pts bearing 2 concomitant variants. Median VAF ranged from 0.5 to 3.8%. All 6 pts had positive family history for tumors related to DDR mutations and were being treated with ARPi (androgen receptor pathway inhibitor) with undetectable or declining PSA. Overall concordance with archival tissue was 79% (κ=0.41). Conclusions: In this mPC cohort, cfDNA concentration correlated with Gleason score rather than PSA levels. LB demonstrated moderate concordance with tissue-based DDR profiling and revealed previously undetected but likely pathogenetic variants even in patients with biochemical response.. These findings support the potential role of LB in longitudinal monitoring of DDR alterations; however, methodological standardization and prospective validation are required before routine clinical implementation.

BACKGROUND:Germ cell tumors (GCTs) are highly curable, yet a subset of patients with metastatic disease experience early death (ED) soon after starting first-line chemotherapy. These patients are underrepresented in trials, and risk factors remain unclear. METHODS:We performed a retrospective multicenter cohort study including adults ( ≥ 18 years) with metastatic GCT who died within 3 months of completing their last cycle of first-line chemotherapy. Primary outcomes were cause and timing of death; secondary endpoints included clinical predictors of acute respiratory failure (ARF) and very early death ( ≤ 30 days). RESULTS:Among 102 patients (1.7% of treated cases), 69.6% had non-seminoma, 83.3% testicular primaries, and 67.6% poor-risk disease. Median time to death was 28 days (range, 2-179). Leading causes were ARF (34.1%), disease progression (16.7%), septic shock (15.7%), hemorrhage (12.7%), and cardiovascular events (4.0%). ARF correlated with > 50% lung involvement, dyspnoea, and haemoptysis, but not choriocarcinoma histology or bleomycin use. Mostly, ED (51%) was associated with liver metastases, massive lung involvement, β-hCG > 50,000 mIU/mL, ECOG 2-3, elevated neutrophil/lymphocyte ratio, and need for intensive care (all P < 0.05). CONCLUSIONS:Early death in metastatic GCT, though rare, remains a critical clinical issue. Early identification, adapted induction regimens, and optimized supportive care may help prevent avoidable mortality.

Circulating analytes in cancer patients capture tumor-related signals. We profiled matched extracellular vesicle (EV) total RNA and cell-free DNA (cfDNA) from the same plasma aliquots of chemo-naive metastatic castration-resistant prostate cancer (mCRPC) patients treated with Enzalutamide (n=54 patients, n=119 longitudinal samples; NCT06981377 ) at four Italian clinical centers and interrogated data from >10,000 cancer patients' and healthy individuals' samples. Transcript integrity analysis identified coding and non-coding species with fragmentation patterns varying across RNA biotypes. EV-RNA data deconvolution revealed signal from immune populations, including fractions classified as CD4+ T cells, whose abundance increased with disease progression in plasma EVs and mCRPC tissues. By leveraging tissue data-informed mining, we established a novel prostate cancer-related EV-RNA signature that resulted in an independent predictor of poor prognosis and captured tumor microenvironment-derived signals. Integrating EV-RNA and ctDNA information improved patient stratification for progression-free survival. These findings suggest a multifaceted role for plasma EVs as a source of cancer biomarkers.

Neoadjuvant cisplatin-based chemotherapy (NAC) confers a survival benefit in muscle-invasive bladder cancer (MIBC), however a relevant proportion of patients experience early disease recurrence following radical cystectomy. We conducted a multicenter observational study to evaluate clinical, pathological, and laboratory factors associated with early recurrence defined as disease-free survival [DFS] ≤ 12 months in patients with MIBC treated with neoadjuvant cisplatin plus gemcitabine followed by radical cystectomy. Early recurrence was significantly associated with aggressive pathological features, including higher ypT stage, nodal involvement, lymphovascular invasion, and lower rates of pathological complete response. Patients experiencing early recurrence predominantly presented with systemic dissemination and had significantly shorter DFS and overall survival (OS). Variant histology and the presence of post-treatment lymphovascular invasion were independently associated with early recurrence. Early recurrence after NAC identifies a subgroup of patients with aggressive clinicopathological features and poorer oncological outcomes, highlighting the need for improved postoperative risk stratification and novel perioperative treatment strategies.

INTRODUCTION:The incidence of renal cell carcinoma (RCC) increases with age, yet older patients (≥70 years) are underrepresented in clinical trials. Evidence on the efficacy of immune checkpoint inhibitors (ICIs) and on reliable prognostic tools for this population remains limited. We aimed to evaluate the effectiveness of nivolumab-based immunotherapy in older patients with metastatic RCC (mRCC) and assess the prognostic accuracy of the International Metastatic RCC Database Consortium (IMDC) and Meet-URO scores. MATERIALS AND METHODS:This multicenter study included 889 patients with mRCC treated with nivolumab alone or in combination with ipilimumab, using data from the Meet-URO 15 study and the Italian Expanded Access Program. Progression-free survival (PFS), overall survival (OS), and prognostic factors were analyzed by age group (<70 and ≥ 70 years) using Kaplan-Meier curves and multivariate models. RESULTS:Median OS and PFS were similar between younger and older patients (mOS: 23.5 vs. 25.1 months, HR: 1.02, p = 0.82; mPFS: 6.28 vs. 7.82 months, HR: 0.93, p = 0.40). The Meet-URO score outperformed the IMDC score in prognostic accuracy (p < 0.001), particularly in older patients. Non-clear cell histology was linked to shorter PFS (HR: 1.37, p = 0.05), while prior nephrectomy improved OS (HR: 0.55, p = 0.001). Limitations include the retrospective design and treatment heterogeneity. Prospective validation is needed. DISCUSSION:In this large real-world cohort, outcomes in older patients with mRCC receiving nivolumab-based immunotherapy were comparable to those in younger patients. The Meet-URO score improved prognostic stratification and supported clinical decision-making.

AIM:Androgen receptor signaling inhibitors (ARSI) demonstrated to be efficacious as first-line therapy for mCRPC. The present real-world study aimed to identify the characteristics of the long-term responders (LTR) patients to first-line ARSI. METHODS:We retrospectively reviewed a consecutive series of 622 mCRPC patients treated with one ARSI as first line. Patients received standard doses of abiraterone (1000 mg daily plus prednisone 10 mg daily) or enzalutamide (160 mg daily) until progression. Patients with an ARSI exposure ≥ 36 months were considered as LTR. RESULTS:We identified 99 LTR patients who were compared to 523 no-LTR patients. At the multivariable analysis, LTR patients showed younger age (p < 0.0001), longer time to mCRPC (p < 0.0001), higher baseline levels of hemoglobin (p = 0.007), lower baseline PSA levels (p = 0.03), longer PSA doubling time (p = 0.03), low number of bone metastases (p = 0.01), and receivedenzalutamide (p = 0.01). The median overall survival (OS) of LTR was 78.2 months (95% CI 72.3-84.1 months) vs 27.7 months of no-LTR (95% CI 25.9-29.6 months). CONCLUSIONS:Several clinical and biological factors allow to identify those patients with higher probability of becoming LTR to ARSI in first-line mCRPC setting.

511 Background: Local therapy for managing metastatic sites may be a beneficial frontline approach for patients with mRCC. However, existing data are limited to retrospective studies involving patients treated mainly with tyrosine kinase inhibitors (TKIs). This study aims to characterize the initial LT approach prior to the initiation of immuno-TKI combinations. Methods: ProPaxi is a prospective observational study that enrolled pts treated with the Pembrolizumab/Axitinib (Paxi) combination as first-line therapy. We conducted a retrospective analysis of pts characteristics and outcomes when LT was used as a frontline approach. Results: From December 2020 to September 2023 ProPaxi study enrolled 170 pts, of whome 56 (33%) received LT as frontline therapeutic approach. The majority had clear-cell histology (86%). Approximately half of pts (46%) had synchronous metastasis and nephrectomy was performed in 60% of cases. Stratifying by IMDC criteria at the time of the start of systemic treatment, 11 pts (20%) were classified as favorable-risk, 32(59%) as intermediate-risk, and 12 (21%) as poor-risk. Additionally, around half of pts (52%) had time-to-treatment start longer than 1 year as prognostic factors; this was the only prognostic factor in 18% of cases. Bone was the most commonly treated metastatic site, accounting for 50% of cases, followed by the lung (14%) and brain (13%). The types of LT administered were as follows: radiotherapy (46%), surgery (43%), and other (11%). The objectives of treatment included: pain control (30%), curative treatment for local complications (29%), prevention of local complications (29%), and achieving complete response or delaying systemic treatment (30%). In one-fifth of patients (21%), there were multiple objectives for the local therapy. Radiotherapy was the most frequently used treatment for pain control, applied in 94% of cases. For managing local complications, surgery and radiotherapy were also common, accounting for 31% and 38%, respectively. Both treatments were equally utilized (38%) for the prevention of local complications. Surgery was the predominant approach for achieving complete response or delaying systemic treatment, used in 88% of cases. The mean time from metastasis diagnosis to treatment start was 7.9 months (95% CI: 4.1–11.2) for patients who received LT versus 2.5 months (95% CI: 1.9–3.1) for those who did not (p < 0.001). No significant differences were observed in progression-free survival (PFS) or overall survival (OS). Conclusions: This analysis describes for the first time the current approach to implementing LT for the management of mRCC. Thus, LT emerges as a valid and established option even in the era of immuno-TKI combinations. The objective of therapy appears to be the key factor in determining the choice of treatment in clinical practice.

Pembrolizumab has demonstrated efficacy in improving disease-free survival (DFS) and overall survival (OS) as adjuvant therapy in clear cell renal cell carcinoma (ccRCC) at a higher risk of recurrence. However, real-world data on its effectiveness and safety remain limited. This study evaluates DFS, OS and severe adverse events (SAEs) associated with adjuvant pembrolizumab in a multicenter international cohort. This retrospective analysis included 311 ccRCC patients treated with adjuvant pembrolizumab across 40 hospitals in 12 countries from the ARON-1 dataset. Eligible patients had histologically confirmed ccRCC with high relapse risk and received up to 17 cycles of pembrolizumab. The primary objective was DFS, with OS and safety as secondary objectives. Kaplan–Meier survival estimates, Cox proportional hazards models and log-rank tests were used for statistical analysis. At a median follow-up of 15.4-month, 2-year OS and DFS rates were 95