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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 .

TPS277 Background: Recent advances in genomic sequencing have deepened our understanding of the molecular complexity of metastatic castration-resistant prostate cancer (mCRPC), revealing multiple actionable alterations that now inform biomarker-driven treatment strategies. Accordingly, germline and somatic tumor profiling is recommended for all patients with mCRPC. Beyond DNA aberrations, gene expression profiling can uncover additional therapeutic targets and pathway activations. The phase 2 PREDICT trial is leveraging both DNA and RNA alterations to guide rationally designed, biomarker-based therapeutic approaches for patients with mCRPC. Methods: This multi-center, multi-arm, biomarker-driven phase 2 umbrella trial is evaluating rationally selected therapies for patients with metastatic castration-resistant prostate cancer (mCRPC). The primary endpoint is objective response rate in patients with measurable disease, with secondary endpoints including radiographic progression-free survival, PSA response, time to first symptomatic skeletal event, overall survival, safety, and correlative biomarker analyses. Eligible patients must have progressive mCRPC of any histology, prior treatment with an androgen receptor pathway inhibitor (ARPI), and either prior or declined taxane chemotherapy, with both measurable and non-measurable disease permitted. Enrollment requires standard-of-care next-generation DNA sequencing from tissue or circulating tumor DNA performed in a CLIA-certified laboratory, and RNA-based allocation will use the CLIA-certified Caris MI Tumor Seek assay (whole exome and whole transcriptome sequencing) on tissue obtained within 12 months of study entry, with a real-time molecular tumor board reviewing results to confirm arm assignment. Patients with RB1 loss (DNA), an RB functional loss signature (RNA), or an NEPC signature (RNA) will receive the EZH1/2 inhibitor valemetostat; those with ≥2 of 3 tumor suppressor gene alterations (TP53, RB1, PTEN), FANC alterations (DNA), or SLFN11 overexpression (RNA) will receive cabazitaxel plus carboplatin; and those without study-defined alterations will receive physician’s choice of cabazitaxel, ARPI, or 177Lu-PSMA-617. The design permits incorporation of additional biomarker-defined arms, and up to 158 patients per arm (64 with measurable and 94 with non-measurable disease) will be accrued under a Simon two-stage minimax design, providing a one-sided type I error of 0.05 if the true response rate is 0.20 and 90% power if the response rate is 0.37 (Clinical trial information: NCT06632977). Clinical trial information: NCT06632977 .

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)

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

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature, and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more . PURPOSE To provide evidence-based recommendations for patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS An Expert Panel including patient representation completed a systematic review of the evidence and made recommendations. RESULTS Depending upon prior treatment received, androgen receptor pathway inhibitors (ARPIs: enzalutamide, abiraterone with prednisone), poly(ADP-ribose) polymerase inhibitors (PARPi), chemotherapeutic agents (docetaxel, cabazitaxel), radiopharmaceuticals (radium 223, 177 Lu-prostate-specific membrane antigen [PSMA]-617), and sipuleucel-T have demonstrated an overall survival (OS) benefit for patients with mCRPC. For patients with BRCA1 / 2 alterations who did not receive prior ARPI, the combination of PARPi and ARPI (talazoparib + enzalutamide, olaparib and/or niraparib + abiraterone) has shown clinical benefit. For patients with BRCA1 / 2 alterations who received prior ARPI or ARPI followed by docetaxel, olaparib showed OS benefit. In select patients with microsatellite instability-high/mismatch repair-deficient, pembrolizumab showed clinical efficacy. RECOMMENDATIONS Prior systemic therapy for castration-sensitive prostate cancer will determine subsequent therapy used for mCRPC. Continue androgen-deprivation therapy for patients with mCRPC indefinitely. Early adoption of somatic genetic testing and palliative care is recommended. Patients with mCRPC and bony metastases should receive a bone-protective agent. The panel recommends the combination of ARPI with PARPi in patients with BRCA1 / 2 alterations who did not receive prior ARPI. For patients who received prior ARPI, the panel recommends docetaxel chemotherapy. The panel recommends 177 Lu-PSMA-617 or cabazitaxel chemotherapy for patients who receive prior ARPI and docetaxel chemotherapy. For patients with BRCA1 / 2 alterations who received prior ARPI, the panel recommends PARPi monotherapy. Radium 223 is recommended for patients with symptomatic bone–only disease. Evidence for optimal sequencing for mCRPC regimens is lacking. Additional information is available at www.asco.org/genitourinary-cancer-guidelines .

4574 Background: Mutations of COMPASS-related proteins KMT2D, KMT2C, and KDM6A are observed in 66% of advanced urothelial carcinomas (UC). In vivo, the administration of tazemetostat, an enzymatic EZH2 inhibitor (EZH2i), reduced tumor burden and enhanced the immune response in animal models of UC. We hypothesized that tazemetostat might improve response to immunotherapy in advanced UC. Methods: ETCTN 10183 (NCT03854474) is a multicenter pilot study evaluating the safety and efficacy of tazemetostat 800 mg BID+ pembrolizumab 200 mg given every three weeks for up to two years in patients (pts) with platinum-refractory (Arm A) or cisplatin/chemo-ineligible advanced UC (Arm B). The primary objective was to identify the recommended phase two dose (RP2D) of tazemetostat in combination with pembrolizumab. Secondary objectives included safety, response rate, and progression-free survival. Translational objectives included determining tumor mutational burden in COMPASS-related genes, tumor subtyping, TCR clonality, T cell infiltration, and PDL-1 expression. Results: There were no dose-limiting toxicities in the safety lead-in phase (n=6 pts), and the RP2D for tazemetostat was established at 800 mg BID. Baseline characteristics for Arm A N=12, Arm B N=13: 72% males; 96% white, 4% Black; 88% ECOG PS 0-1; 88% had bladder primary, 20% Stage III, 72% stage IV; 80% had visceral or bone metastases. The median number of cycles was 5 in Arm A (range 1-35) and 4 in Arm B (range 2-12). Treatment related G3/4 adverse events (AEs) were observed in 8 patients, most common were anemia and lymphopenia (n=2 each). Treatment related G1/2 AEs included nausea (n=6); skin and subcutaneous tissue disorders (n=3); anemia, lymphopenia, and thrombocytopenia (n=2 each). Among evaluable patients (n=10 in each arm), partial response rate was: Arm A 30%, Arm B 20%; stable disease: Arm A 30%, Arm B 30%; and progressive disease: Arm A 30%, Arm B 20%. 8 pts were on study treatment for ≥ 9 cycles (5 in Arm A, 3 in Arm B). All pts are off protocol treatment. Median progression-free survival was 3.06 (95% CI: 1.38-7.75) months for Arm A and 3.02 (95%CI: 2.4-5.65) for Arm B. Conclusions: Tazemetostat 800 mg BID and pembrolizumab combination is feasible and well-tolerated in patients with advanced UC. In this pilot study, improvement in efficacy relative to historical controls of pembrolizumab alone appears to be modest. Response in tumors with COMPASS-related mutations and EZH2 activity will be evaluated. Clinical trial information: NCT03854474 .

385 Background: Tyrosine kinase inhibitors (TKI) and immuno-oncology (IO) agents alone or in combination have revolutionized the landscape of management for untreated metastatic renal cell carcinoma (mRCC). Baseline quality of life (QOL) outside of interventional clinical trials and rationale for management decisions in mRCC are poorly understood. Methods: In this prospective observational study of 800 mRCC pts in the US, pts must: have a diagnosis of mRCC (any histology) with no prior systemic therapy (ST) for mRCC; be age ≥19 at informed consent; be able to comply with completion of PROs. Exclusion criteria include being treated for active malignancy other than mRCC or not intending to follow up at a study site within PCORnet. Pts undergo consent and baseline assessments by the study site team, with subsequent follow up by the central coordinating center. The primary objective is to determine distinct patterns of change in QOL and symptom burden of mRCC pts. A key secondary objective is to identify patterns of clinical management in the real world setting of mRCC across treatment regimens. Minimally important differences are defined as 3- and 7-points for FKSI-19 and FACT-G respectively. ClinicalTrials.gov ID: NCT04919122. Results: As of 9/1/2023, 173 pts have been enrolled (126 ST, 47 no ST [NST]): 75% male, 87% white, 73% clear cell, 52% intermediate risk and 47% poor risk. 47% had radical nephrectomy and 22% another solid tumor. ST pts as compared to NST pts were more likely to be poor risk (52% vs 16%); but differences in baseline pain were not significant. Of ST pts, 44 were treated with IO-IO (ipilimumab + nivolumab), 50 with IO-TKI (cabozantinib + nivolumab 38%, axitinib + pembrolizumab 38%, lenvatinib + pembrolizumab 24%) and 32 other (IO alone 34%, TKI alone 31%, investigational drug 25%). Reasons for NST included active surveillance (AS, 50%), other (21%), local therapy (13%). Mean differences between ST and NST for baseline FKSI-19 and FACT-G were 5.7 (95% CI: 1.2 – 10.2) and 3.3 (-2.6 – 9.3). There were no differences in pain or PROs between IO-IO and IO-TKI pts. Mean differences in FKSI-19 and FACT-G between AS vs IO-IO were 10.6 (4.8 – 16.4) and 8.6 (1.1 – 16.0); and vs IO-TKI were 11.0 (4.9 – 17.0) and 10.3 (3.5 – 17.1). On physician surveys, primary reasons for treatment selection were (in order of % selected): complete response (CR), prolonged survival (OS), prognostic factors (Px), treatment-free interval for IO-IO; versus delaying progression (PFS), OS, CR, Px for IO-TKI. Conclusions: Our data suggest differences in baseline QoL in pts treated with ST vs NST, as well as AS vs IO-IO or IO-TKI, in the real world. Reasons for selection of ST regimen differed among combination regimen classes. Completion of ODYSSEY will clarify baseline and longitudinal differences in pain and PROs among management strategies and give novel insights into the rationale for real world management of untreated pts with mRCC. Clinical trial information: NCT04919122 .