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PURPOSE Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223 ) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% ( P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

5005 Background: Androgen receptor pathway inhibitors (ARPIs) may have distinct central nervous system (CNS) penetration and differential effects on cognition or quality of life (QOL). AFT-47, “ARACOG” is a prospective, randomized open-label phase 2 trial comparing objective and patient-reported cognitive and QOL outcomes between patients with metastatic hormone sensitive prostate cancer (mHSPC), metastatic castration-resistant prostate cancer (mCRPC) or non-metastatic castration-resistant prostate cancer (nmCRPC) treated with darolutamide (DAR) or enzalutamide (ENZ). Methods: Between 8/17/2021 and 3/11/2025, 111 pts were enrolled and randomized 1:1 to treatment with ENZ or DAR. CANTAB, a validated computer-based platform evaluating 5 cognitive domains (PALFAM-memory recall, SWM- spatial working memory, SSP-short-term visual memory, working memory, RVP-rapid visual processing, and OTSMCC- executive function), was performed at baseline, 12, 24, and 48 weeks. Crossover (Xover) was allowed at 12 or 24 weeks for significant pre-specified decline in cognitive testing or patient reported outcome measures (PROMs), or for CNS-associated adverse events, including falls. The primary endpoint was the percent change in the maximally changed cognitive domain (MCCD) from baseline to 24 weeks and was compared between groups with the Wilcoxon rank sum statistic. Patients crossing over prior to 24 weeks were evaluated at the time of Xover and analyzed with their randomized arm. Secondary endpoints included comparison of Xover rates. Results: Among 111 pts, 55 received DAR and 56 received ENZ; median age was 71, 83% White. 95 pts (48 DAR, 47 ENZ) were evaluable for the primary endpoint. Baseline CANTAB was similar between groups. Median cognitive change in MCCD between baseline and 24 weeks was -15.8% and -36.1% for the DAR and ENZ pts, respectively (p = 0.009) (Table). Individual cognitive domains suggest possible learning effect (increased scores) for DAR and are stable or show mild decline for ENZ treated patients at 24 weeks. 32 DAR (58%) and 33 ENZ (59%) participants were eligible for Xover by 24 weeks, and 23 pts crossed over by 24 weeks. All Xover was pts randomized to ENZ (crossed to DAR), with the most common causes being decline in objective (N = 14) or subjective (N = 11) cognitive testing. Conclusions: In this US randomized trial comparing DAR to ENZ, the primary endpoint of differential cognitive effects was met. ENZ showed significantly greater cognitive score decline than DAR at 24 weeks in the MCCD after treatment initiation. Learning effect was seen with DAR but not ENZ. Longer term follow-up of cognitive change and PROM analyses are ongoing. Clinical trial information: NCT04335682 . Percent change in maximally changed cognitive domain by treatment. DAR (N=48) ENZ (N=47) Wilcoxon Rank Sum Test Result CANTAB domain PALFAM SWM Degree of change -15.8 (-38.8, -2.6) -36.1 (-59.3, -16.7) P=0.009

4559 Background: Baseline QOL has been linked to survival in mRCC therapy clinical trials (Cella, 2024); however, there is a paucity of prospectively collected real-world QOL data across front-line management strategies. We used data from ODYSSEY to examine the relationship between baseline QOL and early death. Methods: ODYSSEY is a multi-site, prospective observational study of 468 US pts with mRCC. Pts must have mRCC (any histology); have no prior systemic therapy (ST) or be within 3 months of starting ST; and follow up at a PCORnet study site. Exclusion criteria include treatment for cancer except mRCC. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Early death was defined as death within 12 months post-enrollment. All pts with non-missing FKSI-19 or FKSI-DRS at enrollment were included. Cumulative event probabilities as a function of time were stratified by either < or ≥ median QoL value and plotted as a step function vs time since enrollment to create cumulative event curves. To determine association between QoL at enrollment and early death, separate Cox proportional hazards models (unadjusted and adjusted) for time-to-first-event as a function of baseline QoL were fit. The adjusted model controlled for the following baseline covariates: IMDC risk (favorable vs intermediate or poor), histology (clear cell vs non). Results: As of 1/5/26, 468 pts were enrolled; 425 had non-missing FKSI-19 or FKSI-DRS at enrollment (329 immediate ST, 96 deferred ST [DST]). ST included 129 IO-IO, 108 IO-TKI, 92 Other. DST included 57 Active Surveillance, 22 Local Therapy Planned, 17 Other/Missing. 209 and 190 pts have < median FKSI-19 (score = 59) and FKSI-DRS (score = 29), respectively; 216 and 235 pts have ≥ median FKSI-19 and FKSI-DRS, respectively. Those below the median have lower rates of nephrectomy, worse IMDC risk and KPS, shorter time since RCC diagnosis, and higher rates of bone metastasis (all p<0.05). Cumulative event probabilities for death at 12 months are 21% and 7% in those < and ≥ median baseline FKSI-19, respectively; and 21% and 7% in those < and ≥ median baseline FKSI-DRS, respectively. For FKSI-19, the unadjusted hazard ratio (HR) for early death is 0.55 (95% CI: 0.43 – 0.70; p<0.001) and adjusted HR is 0.65 (0.49 – 0.85; p = 0.002) per 1 SD higher score. For FKSI-DRS, the unadjusted HR for early death is 0.57 (95% CI: 0.46 – 0.71; p<0.001) and adjusted HR is 0.66 (0.51 – 0.86; p =0.002) per 1 SD higher score (higher score indicates better QOL). Conclusions: Across management strategies in our ODYSSEY cohort of systemic therapy naïve mRCC patients, better baseline QOL was associated with better survival. This is to our knowledge the largest reported real world mRCC cohort with prospectively collected PROs. Future analyses will focus on association of outcomes with longitudinal PROs. Clinical trial information: NCT04919122 .

TPS290 Background: Landmark randomized trials established the survival benefit of adding D to ADT in mCSPC. Building on this foundation, subsequent trials (PEACE-1 and ARASENS) demonstrated further survival improvements when androgen receptor pathway inhibitors (ARPI) were added to the ADT + D backbone. However, the independent contribution of D within the triplet regimen remains unclear given lack of prospective evaluation. Additionally, tumor suppressor gene (TSG) alterations involving TP53, PTEN, and RB1 are frequently observed in PC and are associated with aggressive biology and poor outcomes, providing an opportunity to enhance prognostic accuracy and optimize selection of candidates for treatment intensification. We hypothesize that adding D to ADT plus A will improve survival compared to ADT + A in mCSPC and stratification by TSG status may identify different treatment effects across molecular subgroups. Methods: ASPIRE is an open-label, two-arm, randomized phase 3 study to assess the benefit of D added to ADT plus A for patients with mCSPC. Eligible patients include those with confirmed adenocarcinoma of the prostate with evidence of distant metastatic disease on conventional imaging and are appropriate to receive D. Patients with metachronous low-volume disease or PSMA-PET only disease are excluded. Candidates must have next-generation sequencing (NGS) results from a CLIA-certified tissue test available for TSG status stratification at registration. Eligible patients will receive ADT plus A (240 mg PO daily) +/- D for up to 6 cycles until progression of disease by PCWG3/RECIST version 1.1 criteria. Prior therapy with ADT (with or without ARPI) initiated within 120 days before registration is permitted. The primary endpoint is overall survival (OS). Secondary endpoints include OS by TSG status; radiographic progression-free survival (rPFS); time to castration resistance; symptomatic skeletal event–free survival; time to worsening of disease-related symptoms (NCCN-FACT FPSI-17); safety and tolerability (CTCAE v5.0); PSA90 response at 6 weeks and 6 months; time to PSA progression; and objective response rate in patients with measurable disease. The study will enroll 1200 patients and is currently actively accruing patients. Clinical trial information: NCT06931340 .

476 Background: Lack of standardized reporting and collection of patient-reported outcomes (PROs) limits cross-trial comparisons of first-line IO-based regimens for mRCC. Prospectively collected real world data may fill this important knowledge gap. Pts with stable/improved QoL at 3 mo versus baseline have longer median OS than pts with worse/unobserved HRQoL versus baseline (Cella, 2024). Methods: ODYSSEY is a multi-site, prospective observational study of 468 US pts with mRCC. Pts must have mRCC (any histology), no prior systemic therapy (ST), and follow up at a PCORnet study site. Exclusion criteria include treatment for cancer except mRCC. Descriptive statistics are used to show PRO score changes from baseline. We evaluate longitudinal change from baseline in PRO scores using least squares mean (LSM). Minimally important differences (MID) are 3 points for FKSI-19 total score, 1 point for the FKSI-Disease Related Symptoms (DRS) subscale and 7 points for FACT-G. Higher score indicates better QOL. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Results: As of 10/1/25, 360 pts were managed with ST, including 266 pts on IO-based combinations: 35 cabozantinib + nivolumab (C+N), 49 lenvatinib + pembrolizumab (L+P), 40 axitinib + pembrolizumab (A+P), and 142 ipilimumab + nivolumab (I+N). Overall median follow-up is 12.1 mos (IQR 6, 24). Age, sex and race were similar across regimens. Prior nephrectomy (50%) was lower than in trials. C+N and L+P pts had less clear cell (56 and 65%) versus A+P and I+N pts (94 and 82%). A+P pts had more favorable IMDC risk (19%) and less poor risk (14%). Baseline QOL was variable across regimens, with L+P generally the lowest. Absolute changes in PROs from enrollment to mo 3 (early change) by regimen are shown in the Table. LSM change from baseline in FKSI-19 and FKSI-DRS favored IO-IO versus IO-TKI at 3 mos but not at 6 mos (not shown). Conclusions: While early change in PROs did not meet the MID threshold between the IO-TKI and I+N cohorts, different patterns of early change are apparent among specific IO-TKI regimens. IO-TKI regimens exhibited higher variation in early PRO change vs I+N. As the data matures, we will associate baseline PROs and early PRO changes with early death and other outcomes. Clinical trial information: NCT04919122 . 3 month change. Instrument C+N (N=35) L+P (N=49) A+P (N=40) All IO-TKI(N=124) I+N(N=142) FKSI-19, N (%) 26 (74) 33 (67) 33 (83) 92 (74) 104 (73) Mean (SD) -0.3 (11) 2.8 (13) -3.2 (12) -0.2 (12) 0.7 (10) Median (IQR) 1.4 (-7, 6) 5.0 (-7, 11) -1.0 (-14, 5) 1.4 (-10, 8) -0.3 (-5, 6) FKSI-DRS, N (%) 26 (74) 33 (67) 33 (83) 92 (74) 104 (73) Mean (SD) -0.8 (5) 1.5 (7) -1.8 (6) -0.3 (6) 0.8 (5) Median (IQR) -0.5 (-5, 3) 2.0 (-5, 5) -1.0 (-5, 3) 0.0 (-5, 4) 0.0 (-2, 4) FACT-G, N (%) 27 (77) 32 (65) 29 (73) 88 (71) 102 (72) Mean (SD) 2.1 (14) 5.2 (16) -3.5 (15) 1.4 (15) 0.3 (13) Median (IQR) 4.0 (-4, 10) 1.2 (-6, 13) -6.4 (-11, 4) 1.6 (-8, 10) 1.6 (-7, 8)

PURPOSE Previous studies suggest that SPOP mutations result in increased sensitivity to androgen receptor pathway inhibitors (ARPIs) but are limited by lack of granular data. We hypothesize that SPOP mutations are associated with improved outcomes across the spectrum of advanced prostate cancer (PC). METHODS Using the real-world clinicogenomic Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort database, we analyzed outcomes based on SPOP mutation status. The primary end point was overall survival (OS) from the diagnosis of metastatic disease. Secondary end points included real-world progression-free survival (PFS) and PSA90 response. RESULTS Among 2,097 patients with metastatic PC, 5.5% (N = 115) had SPOP -mutated tumors. Compared with SPOP wild-type, patients with SPOP mutations were older at diagnosis (median 65 v 63 years; P = .001) and had higher (≥8) Gleason sum (68% v 54%; P = .02), higher incidence of lung metastasis (17% v 6%; P = .001), and increased frequency of intraductal features (13% v 5%; P < .001). SPOP mutations were associated with improved PSA90 response with first ARPI exposure in the castrate-resistant setting (60% v 40.6%; OR, 2.20 [95% CI, 1.15 to 4.19]; P = .02) but not in the castrate-sensitive setting (78.9% v 71.5%; OR, 1.49 [95% CI, 0.66 to 3.37]; P = .43). Median PFS with first ARPI did not differ in SPOP- mutated versus wild-type group in both the castrate-sensitive (24.2 v 19.2 months; hazard ratio [HR], 0.80 [95% CI, 0.49 to 1.32]; P = .39) and castrate-resistant settings (15.0 v 12.4 months; HR, 0.81 [95% CI, 0.58 to 1.12]; P = .20). In multivariable analysis, SPOP mutations were associated with improved OS (HR, 0.65, P = .02). CONCLUSION SPOP mutations were associated with longer OS despite the presence of aggressive clinical features. The distinct clinical and molecular features of SPOP -mutated PC support its consideration as a unique molecular subtype with prognostic implications.

4516 Background: Ipilimumab/nivolumab (ipi/nivo) is a standard of care first-line treatment (tx) for patients (pts) with mccRCC; however, ideal timing of subsequent immunotherapy txs are not well defined. We performed an analysis of patients initially treated with ipi/nivo and subsequent cohort assignments on PDIGREE (A031704). Methods: The PDIGREE trial treated pts with IMDC intermediate/poor risk mccRCC with first-line ipi/nivo (Step 1) at NCTN sites (categorized as academic (A), academic regional (R), and community (C)). Subsequent management was based on iRECIST responses at 12 weeks: pts with complete response (CR) received 1-year nivo maintenance; pts with progressive disease (PD) received cabozantinib (cabo) monotherapy, pts with non-CR/non-PD were randomized to nivo with or without cabo (for primary endpoint of overall survival [OS], target sample size was 1175). Enrollment was held when the randomized sample target was reached. Pts with unresolved toxicity at week 22 were managed off protocol. Step 1 pt demographics, assignments into Step 2, and adverse event (AE) data are presented. Descriptive statistics were used, and cohorts were compared using a chi-square test. These data were released with DSMB approval and do not inform the primary OS endpoint (1EP). Results: From May 2019 to May 2024, 1111 pts were enrolled and treated with ipi/nivo. Pt characteristics included median age 64.0 years (range 29.0-86.0); 819 (73.7%) males; White (85.1%), Hispanic (10.4%), Black (4.2%), and American Indian/Native Hawaiian (1.3%); 849 (76.8%) intermediate risk/257 (23.2%) poor risk; 458 (41.2%) at Academic, 113 (10.2%) at Regional, and 540 (48.6%) at Community centers; and 603 (54.3%) with de novo metastases. 364 pts (33%) stopped tx in Step 1: 160 (44%) for AEs, 46 (13%) for PD/clinical PD/suspected PD, 42 (12%) withdrawals, 39 (11%) alternative txs, 37 (10%) deaths on the study, 12 (3%) other complicating disease, 8 (2%) MD decision and 19 (5%) other reasons. Of the 37 deaths, 15 (1.4%) grade 5 SAEs were reported, 6 of which were due to PD. Of 747 (67%) pts registered to Step 2 at 3 months, 9 (1.2%) achieved CR, and 141 (18.9%) pts were assigned to the PD cohort. 597 pts (80%) were randomized for the 1EP, notable with fewer pts with poor risk [(21 vs 27%, p = 0.01] and bone metastases [24.5% vs 34.2%, p = 0.0007] compared to Step 1 pts who discontinued tx. Gr 3/4 tx-related AEs in 314/1093 (29%) evaluable pts included diarrhea/colitis (8%), transaminase elevation (3%), rash (2%), adrenal insufficiency (2%), fatigue (2%), and hypophysitis (1%). Conclusions: The PDIGREE trial enrolled a representative US-based population with mccRCC. Step 1 pt characteristics and associated outcomes with induction ipi/nivo reveal new insights into the tolerability and tx response of 1L ipi/nivo. Clinical trial information: NCT03793166 .

4558 Background: In the past 7 years, 4 immuno-oncology (IO) based combinations have been approved for mRCC. However, QOL data on these combinations are limited to trials in which collection and reporting was not standardized, which further limits cross trial comparisons. Real-world QOL data with multiple treatment regimens are needed to understand how these regimens are tolerated in practice. Methods: ODYSSEY is a multi-site, prospective observational study of 500 US pts with mRCC. Pts must have mRCC (any histology), no prior ST, and follow up at a PCORnet study site. Exclusion criteria include treatment for cancer except mRCC. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Minimally important differences (MID) are 3 points for FKSI-19 total score, 1 point for the FKSI-Disease Related Symptoms (DRS) subscale and 7 points for FACT-G. Results: As of 1/6/25, 392 pts were enrolled of whom 299 were managed with ST. Of pts on ST, 114 were treated with IO-IO, 108 with IO-TKI, 33 with IO alone, 27 with Other, and 18 with TKI alone. Median follow up for all pts is 8.8 months (IQR 2.9, 16.2). IO-IO pts are median age 64 yrs, 81% male, 84% white, 56% prior nephrectomy, 84% clear cell; IO-TKI pts median age 66 yrs, 76% male, 92% white, 43% prior nephrectomy, 66% clear cell; IMDC risk profiles are similar. IO-IO pts are more likely to be KPS 100; whereas, IO-TKI pts have a higher median number of metastatic sites and are more likely to have bone or liver metastasis. With median follow-up of 6.0 (IQR 1.8, 14.9) and 8.8 months (4.5, 17.8) in the IO-IO and IO-TKI cohorts, 17 (15%) and 21 (19%) pts had died with a median time to death of 5.4 (2.5, 6.4) and 5.7 months (4.4, 12.8), respectively. 20 (18%) and 16 (15%) pts on IO-IO and IO-TKI had discontinued therapy at a median of 3.0 (IQR 2.0, 4.0) and 6.4 months (2.4, 13.0), respectively. Rates of discontinuation for disease progression and toxicity are similar. Baseline PROs for pts on ST are shown in the Table (higher score indicates better QOL), with RCT data for reference (NA, not assessed). Conclusions: In our prospective multi-center ODYSSEY study, we demonstrate that real world pts treated with contemporary ST have worse baseline QOL than those enrolled on pivotal RCTs. One-third of IO-IO and IO-TKI pts died or discontinued therapy within 6 months of initiation. Our data on real world vs RCT differences in baseline QOL may partially explain the limitations of current IO combination regimens in practice and support development of alternative treatment approaches. Instrument, Mean (SD) ODYSSEYIO-IO(N=114) CheckMate214(N=425) ODYSSEYIO-TKI(N=108) KEYNOTE426(N=402) CheckMate9ER(N=323) CLEAR(N=351) FKSI-19 total 56.0 (12.5) 60.1 (9.8) 53.8 (11.8) NA 58.7 (10.6) NA FKSI-DRS 27.5 (6.3) 30.7 (4.5) 27.0 (5.8) 32 (4.2) 30.2 (5.2) 31.3 (4.4) FACT-G 82.4 (16.7) 82.6 (15.0) 78.5 (16.0) NA NA NA

4553 Background: AS is a recognized strategy in select pts with mRCC to maximize QOL and delay potential toxicity of systemic therapy (ST); however, only 2 prospective studies of AS in mRCC have been published: only 1 with patient-reported outcomes (PRO) and none in the IO-TKI era. Methods: ODYSSEY is a prospective observational study of 500 US pts with mRCC. Eligible pts must have mRCC (any histology), no prior ST, age ≥19. Pts were excluded if treated for non-mRCC cancers or if not followed at a PCORnet study site. Pts completed QOL surveys at baseline, by phone every 3 months for 2 years and then every 6 months until end of follow up. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Minimally important differences (MID) are 3 points for FKSI-19 total score, 1 point for the FKSI-Disease Related Symptoms (DRS) subscale and 7 points for FACT-G. Here we report baseline pt characteristics in AS pts compared to ST pts, and baseline QOL differences between these cohorts. Results: As of 1/6/25, 392 pts were enrolled of whom 299 were managed with ST, and 93 pts deferred ST; of these, 53 pts (57%) were classified as AS. Pts on AS are median age 68 yrs, 66% male, 94% white, 81% clear cell, 50% favorable risk, 44% intermediate risk. Compared with ST pts, AS pts were more likely to have undergone nephrectomy (91% vs 53%), favorable risk profile (50% vs 15%), pancreatic metastasis (15% vs 5%), and longer time since RCC diagnosis (median 58 vs 3.3 months); and less likely to have bone, brain, or liver metastasis. After median 8.8 months follow-up (IQR 2.9, 16.2), 2 pts (4%) on AS had died compared with 45 pts (15%) on ST. One pt (2%) on AS started first-line therapy and 45 pts (15%) discontinued ST. Mean baseline QOL (FKSI-19 total, DRS and FACT-G) for AS and ST ODYSSEY pts is shown in the Table (higher score indicates better QOL), with RCT data for reference (NA, not assessed). ODYSSEY pts on AS had higher QOL for all measures compared with ODYSSEY pts on ST. FSKI-DRS was the same or lower for pts on AS compared to the pivotal trials, while ODYSSEY pts on ST had both lower FKSI-19 total and DRS. Conclusions: In our large prospective cohort from ODYSSEY, pts on AS had higher median QOL scores than pts on ST, but similar to those included in RCTs. These results suggest that some RCT pts could have benefitted from AS. Further follow up is needed to determine long term outcomes in pts on AS and how they respond to deferred ST. Clinical trial information: NCT04919122 . Instrument, Mean (SD) ODYSSEY AS (N=53) ODYSSEY ST (N=299) ODYSSEY Difference, AS vs ST (95% CI) CheckMate 214 (N=425) KEYNOTE 426 (N=402) CheckMate 9ER (N=323) CLEAR (N=351) FKSI-19 total 63.4 (9.2) 56.3 (12.5) 7.0(4.0, 10.1) 60.1 (9.8) NA 58.7 (10.6) NA FKSI-DRS 30.8 (4.2) 27.9 (6.0) 2.9(1.5, 4.7) 30.7 (4.5) 32 (4.2) 30.2 (5.2) 31.3 (4.4) FACT-G 87.9 (14.0) 82.4 (16.7) 5.6(1.1, 10.0) 82.6 (15.0) NA NA NA

4545 Background: The treatment landscape of front-line nccRCC has evolved with recent trials demonstrating the efficacy of combination systemic therapy. However, the efficacy of treatment after combination therapy is unknown. This study evaluates the efficacy of VEGF-based regimens in nccRCC patients (pts) previously treated with combination regimens. Methods: ORACLE is a real-world, multi-center, retrospective database that includes nccRCC patients that received combination systemic therapies (IO+IO, IO+VEGF and VEGF+ mTOR) in any line. Subsequent treatments were categorized as VEGF only regimens (cabozantinib vs other VEGF), IO+ VEGF and VEGF+ mTOR. The primary endpoint was objective response rate (ORR) assessed by investigator review using RECIST 1.1. Secondary endpoints included disease control rate (DCR), defined as the proportion of patients achieving complete or partial responses or stable disease, time to treatment progression (TTP), calculated from the date of VEGF-based initiation to progression or last follow-up using the Kaplan-Meier method. Differences between groups were estimated with the log-rank test, and categorical outcomes were compared with the chi-square test. Results: 105 pts who received VEGF – based regimens after combination therapy were included in the analysis. Baseline characteristics: median age: 59years, 71 % male, 58% white, 25% black, 87% ECOG 0-2. IMDC-risk categories included:21% favorable, 59% intermediate and 20% poor risk. Histology included papillary (40%), unclassified (32%), chromophobe (16%) and other rare subtypes (12%). Prior combination therapies included IO+IO: 62%, IO+ VEGF: 34% and VEGF+ mTORi:4%. 70% pts received combination therapy in the first line setting while the remainder received combination therapy in a second or later line. Outcomes with subsequent treatments are described in Table1. IMDC risk score correlated with TTP. Conclusions: Modest antitumor activity was observed with VEGF- based approaches in combination therapy refractory nccRCC. Optimal management of nccRCC remains an unmet need. Outcomes of nccRCC patients by treatment and histologic type. Outcomes per Treatment n ORR (%) DCR (%) mTTP (mo.) Cabozantinib 56 18 47 3.6 VEGF/mTOR 19 16 42 9.3 IO+VEGF 17 29 47 5.6 Other VEGF 13 15 46 5.5 Outcomes per Histology Papillary 42 19 43 6.5 Unclassified 33 21 42 6.1 Chromophobe 17 29 59 8.9 Other * 13 0 46 NR