PURPOSE: This study aims to describe genomic characteristics of patients with metastatic prostate cancer (mPC). PATIENTS AND METHODS: This study is a retrospective, multicenter cohort study of patients with mPC and reports on genomic testing. Patients were included from 12 academic centers in five countries. RESULTS: A total of 349 patients with PC were included in this study. Most patients (209, 59.9%) were de novo metastatic. Genomic analysis was performed in 233 (66.6%) patients in the metastatic castration-resistant prostate cancer (mCRPC) setting, and only 115 (32.8%) patients had a tumor evaluation in the metastatic hormone sensitive prostate cancer scenario. The evaluation of somatic and/or germline mutations was performed through multigene panel analyses in 290 (83.09%) patients, and next-generation sequencing of BRCA1 and BRCA2 genes was performed in 59 (16.91%) patients. Analyzing the mCRPC subgroup, with a median follow-up of 15.6 months (IQR, 14-19.06), the median progression-free survival (PFS) was not reached (NR) and the PFS at 16 months was 58.7% (95% CI, 50.8 to 67.8). When comparing patients with BRCA mutations with those who are not BRCA -mutated in the mCRPC scenario, the median PFS was NR (95% CI, 14 to NR) and 26.3 months (95% CI, 16.7 to 36.5; P = .2), respectively. Two of six patients with BRCA mutations were treated with targeted therapies (poly-ADP-ribose polymerase inhibitors). CONCLUSION: Our study, to the best of our knowledge, represents one of the larger data sets for somatic testing in patients with PC in Latin America (LATAM). It adds valuable information to the growing body of knowledge about the genomic landscape of advanced PC in real-world daily practice scenarios in LATAM countries, which are not always well-represented in large-scale randomized clinical trials.

Attrition rates for patients with mRCC are not well characterized in the era of immunoncology (IO)-based combinations. This study aims to quantify real-world attrition rates by line of therapy, analyze associated clinical predictors, and describe treatment sequencing across multiple international centers. IMDC data for patients with mRCC who received first line Nivolumab + Ipilimumab (IO-IO) or IO- Vascular Endothelial Growth Factor receptor targeted therapy (VEGFR TT) (IO-VE) were included. Clinical and pathologic characteristics and outcomes were extracted. Chi-square tests were used to compare categorical variables between patients who received second line and those who did not. A logistic regression model was used to assess predictors of second line therapy initiation. A total of 1411 patients were identified, of whom 995 patients were treated with first line IO-IO and 434 with IO-VE. Of them, 935 (704 first line IO-IO and 231 first line IO-VE) stopped first line and were suitable for second line therapy. Reasons for stopping first line included progressive disease (PD) in 41.1%, toxicity in 24.4%, death in 3.9%, complete response in 1.5% and other in 28.3%. Among second line suitable patients, 544 (58.2%) started any second line whereas 391 (41.8%) did not. Patients who stopped first line for PD were more likely to initiate second line than those who stopped for other reasons (57.9% vs. 17.6%, P < .00001). Patients who received second line were more likely to have clear-cell histology (77.2% vs. 66.8%, P = .04), without sarcomatoid features (57.2 vs. 44.8%, P = .02), a Karnofsky performance score (KPS) of 80 or higher (80.1 vs. 73.9%, P = .01), and bone metastases (39.0 vs. 28.1%, P = .0009). (Table 2). After adjusting for IMDC criteria, only age and reason for stopping first line remained significant predictors of receiving second line therapy. Among 353 patients who stopped second line, 199 (56.4%, overall 21.3%) started third line therapy. Of the 139 patients who stopped third line, 80 (57.6%, overall 8.6%) started fourth line therapy. In this real-world analysis, we found that just over half of suitable patients received the subsequent line of therapy post first line. We were able to identify age and reason for stopping first line as predictors of second line therapy initiation.

Importance: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk criteria stratify metastatic renal cell carcinoma (mRCC) into favorable, intermediate, and poor risk groups, but heterogeneity within the favorable risk category remains poorly understood. Objective: To evaluate a proposed very favorable subgroup (tier 1: Karnofsky Performance Status ≥90%; diagnosis to treatment ≥3 years; and no brain, liver, and bone metastases) and characterize its molecular and clinical features. Design, Setting, and Participants: This retrospective cohort study analyzed IMDC data, from January 2015 to September 2024, of patients with favorable risk mRCC (tier 1 and tier 2 [favorable and not tier 1]). Molecular profiling leveraged IMmotion151 (A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma) trial data with whole-exome sequencing, RNA sequencing, and programmed cell death ligand 1 immunohistochemistry. Exposures: Systemic standard of care treatments for mRCC, which include vascular endothelial growth factor receptor targeted therapy (VEGF-TT [sunitinib or pazopanib]), immune-oncology–VEGF (IO-VE [pembrolizumab and axitinib, pembrolizumab and lenvatinib, nivolumab and cabozantinib, or avelumab and axitinib]), and 2 IO (IO-IO [ipilimumab and nivolumab]) regimens. Main Outcomes and Measures: The primary end point of this study was overall survival (OS) at 2 years of the favorable risk group and in the tier 1 and tier 2 subgroups with the different treatment options. Secondary end points included time to next treatment, treatment duration, and overall response rate. Outcomes were compared across treatment types: VEGF-TT, IO-VE, and IO-IO. Results: Among 641 patients with favorable risk mRCC (median [IQR] age, 65 [58-71] years; 475 males [74.1%]), 176 (27.5%) were in tier 1, and 465 (72.5%) were in tier 2. Those in tier 1 met criteria for a very favorable subgroup, characterized by similar age and treatment distribution but lower rates of sarcomatoid features; more patients with only 1 metastatic site; and an absence of brain, bone, and liver metastases compared with patients in tier 2 with favorable risk. Patients in tier 1 showed a median OS of 79.1 (95% CI, 73.7 to not reached) months vs 54.5 (95% CI 45.5-67.7) months in tier 2 ( P < .001) and distinct molecular features: high polybromo-1 alterations (64.7%), low BRCA1 -associated protein 1 alterations (8.8%), and programmed cell death ligand 1 positivity (21.9%); transcriptomics revealed less immune-infiltrated tumors (8.5% immunogenic clusters) than in the other subgroups. Clinically, IO-IO underperformed in tier 1, with a 2-year OS of 73.1% (95% CI, 49.1%-97.1%) vs 89.1% (95% CI, 79.0%-99.2%) with IO-VE and 92.4% (95% CI, 86.5%-98.3%) for VEGF-TT (IO-IO hazard ratio, 3.64 [95% CI, 1.49-9.06]; P = .005), and a lower overall response rate (26.3% vs 63.3% in IO-VE and 57.0% in VEGF-TT). Conclusions and Relevance: In this cohort study, the very favorable risk subgroup had a less immunogenic molecular profile and superior outcomes from VEGF-containing regimens (VEGF-TT and IO-VE) compared with the favorable risk group. The IO-IO combination showed significantly worse survival in this population, suggesting that VEGF inhibition remains essential for optimal outcomes.

Background: Enfortumab vedotin plus pembrolizumab (EVP) is the standard first-line treatment for locally advanced or metastatic urothelial carcinoma (la/mUC); however, real-world toxicity patterns, timing of onset, and prognostic significance of treatment-related adverse events (AEs) remain incompletely characterized. Methods: We conducted a retrospective, multicenter analysis of 60 la/mUC patients treated with first-line EVP in Alberta, Canada (September 2024–January 2026). Treatment related toxicities, time to AE onset, dose modifications, and treatment discontinuation were assessed. Progression-free survival (PFS) and overall survival (OS) were analyzed. Results: The median age was 69 years, 82% of patients were male, and 80% had metastatic disease at treatment initiation. Histology was pure urothelial in 82% and mixed in 18%. Median follow-up was 10.3 months, and the median number of EV and pembrolizumab cycles was seven and eight, respectively. Rash (63%), fatigue (57%), and peripheral neuropathy (47%) were the most common adverse events, with median onset at 17, 29, and 90 days, respectively. Dose reductions occurred in 62%, dose delays in 43%, and treatment discontinuation in 38%. An initial enfortumab vedotin dose of 1.25 mg/kg was associated with improved PFS (HR 0.30, 95% CI 0.13–0.68; p = 0.004) and OS (HR 0.32, 95% CI 0.10–0.97; p = 0.044) compared with 1.0 mg/kg. Neuropathy was associated with improved PFS (HR 0.32, 95% CI 0.14–0.73; p = 0.007) and OS (HR 0.24, 95% CI 0.07–0.87; p = 0.029), while rash was associated with improved OS (HR 0.31, 95% CI 0.11–0.91; p = 0.032). Conclusions: EVP was associated with frequent treatment-related adverse events requiring dose modifications, and the development of rash and peripheral neuropathy was associated with favorable survival outcomes.

Background: Cabozantinib is approved as a subsequent therapy for patients with metastatic renal cell carcinoma (mRCC) based on the METEOR trial. However, only 5% of patients in this trial received prior immunotherapy. Objective: Analyze the effectiveness of Cabozantinib in the second-line setting after different first-line treatments. Methods: This retrospective study analyzed patients with mRCC who received second-line Cabozantinib between 2010 and 2023, using the International mRCC Database Consortium (IMDC). Patients were grouped by prior therapy and IMDC risk category. We assessed overall response rate (ORR), time to next treatment (TTNT), treatment duration (TD), and overall survival (OS). Results: Among 603 patients (mean age 59 years), 31.5% had received IO-IO regimens, 24.5% IO-TKI combinations, and 34.3% TKI monotherapy as initial therapy. At Cabozantinib start, 13.8% were favorable-risk, 49.1% intermediate-risk, and 16.7% poor-risk per IMDC. The ORR for the overall cohort was 25.7%; median TTNT was 10.1 months; median TD was 8.9 months; and median OS was 19.0 months. Efficacy outcomes were consistent across first-line treatment groups. Conclusion: This real-world analysis supports the effectiveness of Cabozantinib in the second-line setting, including among patients previously treated with immune checkpoint inhibitors. Prior treatment type did not significantly affect Cabozantinib outcomes.