Introduction and Context
The Advanced Urologic Cancer Consensus Conference (AUC3) 2025 convened 51 multidisciplinary experts to produce a timely, practice‑focused consensus on management of renal cell carcinoma (RCC) and urinary tract cancers (UTCs). Rapid approvals and shifting indications over recent years—adjuvant immune checkpoint inhibitors (ICIs) in RCC, perioperative chemo‑immunotherapy in bladder cancer, and enfortumab vedotin plus pembrolizumab (EV+pembro) as a new frontline standard in metastatic urothelial carcinoma (UC)—have created complex sequencing questions that randomized trials have not fully answered. AUC3 used a modified Delphi process with pre‑ and post‑meeting voting to identify areas of strong agreement, nuanced recommendations and important gaps in evidence (McKay et al., AUC3 2025).1
Why AUC3 matters now
– New agents and expanded indications have created regionally variable access and significant decision complexity.
– Clinicians face daily questions about perioperative use of ICI, how to sequence ICI/TKI/antibody‑drug conjugates, and how to treat histologic variants and vulnerable populations.
– AUC3 aims to translate evolving trial data into pragmatic guidance while highlighting uncertainties that require prospective study.
Primary source: McKay RR et al., “Advanced Urologic Cancer Consensus Conference (AUC3) 2025,” CA: A Cancer Journal for Clinicians (2026).1
New Guideline Highlights — Top Takeaways
– Strong consensus: recommend adjuvant pembrolizumab for many high‑risk resected RCC cases that align with KEYNOTE‑564 criteria and closely related high‑risk presentations (pT3–pT4 any grade, pTxN1, pT2 grade 4, or fully resected metastatic disease within 1 year).4
– Strong consensus: EV+pembro is the preferred frontline systemic regimen for metastatic urothelial carcinoma where available; platinum‑based chemotherapy remains the recommended option after progression for biomarker‑negative patients.10
– For RCC after progression on frontline ICI+VEGFR‑TKI or dual ICI: consensus favors switching to single‑agent VEGFR‑TKI (cabozantinib commonly preferred).17–19
– Important practice notes: routine PD‑L1 testing is not recommended to determine frontline therapy choice in ccRCC; ctDNA is not yet established to guide adjuvant decisions for RCC; germline testing recommended for young, bilateral, or familial RCC presentations.
Updated Recommendations and Key Changes from Prior Practice
Table (summary): major AUC3 2025 updates vs prior/established guidance
– Adjuvant RCC: AUC3 endorses broader use of pembrolizumab in patients meeting high‑risk features, clarifying support for node‑positive disease and pT3b/pT4 tumors—extending the practical interpretation of KEYNOTE‑564 survival data.4
– Metastatic UC frontline: AUC3 elevates EV+pembro to preferred first‑line standard (where available), reflecting EV‑302/EV+pembro results and changing prior platinum → maintenance paradigms.10
– Sequencing in RCC: clarified preference for VEGFR‑TKI monotherapy after progression on ICI‑containing frontline regimens, aligning with CONTACT‑03, TiNivo‑2, and real‑world practice shifts.17,18
– Variant histology: AUC3 underscores the need for exact pathologic nomenclature, routine somatic profiling in metastatic variant RCC, and tailored therapy rather than extrapolation from ccRCC data.
Evidence driving updates
– KEYNOTE‑564 demonstrated DFS and later OS benefit of adjuvant pembrolizumab in high‑risk resected RCC; AUC3 applies these findings pragmatically to surgical scenarios beyond trial inclusion when recurrence risk is similarly high.4
– EV + pembrolizumab phase 3 data influenced the strong endorsement of EV+pembro in frontline metastatic UC.10
– Trials of post‑ICI strategies (CONTACT‑03, TiNivo‑2) showed constrained benefit of ICI re‑challenge after certain progressions, steering experts toward TKI‑based approaches in many contexts.17,18
Topic‑by‑Topic Recommendations
(here we distill the AUC3 consensus into practical, clinician‑oriented recommendations)
1) Locally advanced RCC — perioperative and adjuvant
Primary recommendations
– Adjuvant pembrolizumab (one year) is recommended for:
– pT3b/pT3c/pT4 of any grade;
– pTxN1 disease;
– pT2 tumors with grade 4 histology;
– resected metastatic (M1 NED) disease within 1 year of nephrectomy (panel consensus supportive). (Strong consensus in many scenarios: >90% agreement for several categories).4
– Consider adjuvant therapy for positive surgical margins in clinically high‑risk disease.
Practical caveats
– pT3a, grade 1–2: panel divided — personalized risk assessment advised; discuss potential modest absolute benefit vs toxicity and patient preferences.
– Routine post‑op ctDNA not endorsed to drive adjuvant decisions in RCC; a negative ctDNA should not withhold adjuvant therapy.11,12
– Germline testing: recommend for patients ≤45 years at diagnosis, bilateral/multifocal tumors, or with first‑degree relatives with RCC.
2) Surgery, biopsy and staging
– Routine preoperative biopsy is not recommended for fit patients undergoing nephrectomy for cT3N0M0 masses (majority opposed to routine biopsy).
– Restaging imaging (chest/abdomen/pelvis) before adjuvant therapy is strongly recommended to exclude occult metastatic disease.
– Brain imaging in asymptomatic, high‑risk patients: practice varied; consider on a case‑by‑case basis.
3) Frontline systemic therapy for metastatic RCC
– ICI+VEGFR‑TKI combinations and dual ICI (ipilimumab+nivolumab) remain both reasonable options; selection should be individualized based on disease kinetics, patient comorbidity, and goals of care.5–8
– In rapidly progressive/symptomatic disease, preference is for ICI+VEGFR‑TKI given higher objective response rates and rapid tumor control. (Strong consensus).5–7
– PD‑L1 testing is not to be used routinely to select frontline therapy in ccRCC (100% consensus).
– Very favorable‑risk patients (long interval to systemic therapy, KPS >80, absence of visceral/bone/brain metastases) may be managed more conservatively; individualized approach supported.
4) Sequencing after frontline failure in RCC
– After progression on ICI+VEGFR‑TKI or dual ICI: single‑agent VEGFR‑TKI (cabozantinib commonly favored) is preferred. (Strong panel consensus).17–19
– If primary progression on ICI+VEGFR‑TKI: consider switching to lenvatinib + everolimus in selected patients where rapid salvage responses are needed (panel majority).19
– Belzutifan (HIF‑2α inhibitor): placement uncertain; commonly chosen in later lines after multiple prior therapies but some experts consider earlier use—monitor anemia and hypoxia closely.20
5) Variant histology RCC
– Insist on precise histologic designation (eg, papillary, chromophobe, collecting duct). Experts advocated routine pathology re‑review and somatic genomic profiling in metastatic variant histologies.
– Histology‑specific preferences: platinum chemotherapy for collecting duct and renal medullary carcinoma (strong consensus); lenvatinib‑based combinations favored for some non‑clear cell subtypes; avoid automatic extrapolation of adjuvant pembrolizumab from ccRCC to papillary RCC.13
6) Non‑muscle‑invasive bladder cancer (NMIBC)
– Low‑risk NMIBC surveillance duration remains variable; no consensus on stopping time. Use individualized risk stratification.
– Intermediate‑risk NMIBC: both BCG and single‑agent intravesical chemotherapy are accepted; BCG shortages warrant consideration of alternate intravesical regimens or gemcitabine‑docetaxel in many practices.
– BCG‑unresponsive CIS: intravesical gemcitabine‑docetaxel commonly preferred; systemic pembrolizumab usage is variable among experts; selection should prioritize endpoints such as recurrence‑free survival and cystectomy‑free survival.
7) Muscle‑invasive bladder cancer and locally advanced UC
– For localized MIBC with adequate renal function: neoadjuvant cisplatin‑based chemotherapy remains standard; neoadjuvant gemcitabine/cisplatin + durvalumab is increasingly used (practice split in AUC3).9
– In patients with hydronephrosis and elevated creatinine, decompress (stent or nephrostomy) to facilitate cisplatin use; split‑dose cisplatin may be offered for CrCl 40–60 mL/min (strong consensus).
– cN‑positive UC (LN‑positive): experts favor initial systemic therapy (EV+pembro commonly chosen) for cN1–cN3 followed by surgical consolidation in selected patients; cN3 particularly favored EV+pembro pre‑consolidation.10
8) Frontline and post‑frontline therapy for metastatic urothelial carcinoma
– First line (cisplatin‑eligible or not): EV + pembrolizumab endorsed as the new preferred frontline where available (strong consensus).10
– In regions without access to EV+pembro: cisplatin‑gemcitabine + nivolumab is an established alternative (consensus).26
– After progression on EV+pembro: for biomarker‑negative patients, return to platinum doublet chemotherapy if platinum‑naïve (consensus); post‑platinum, EV monotherapy or biomarker‑directed targeted agents such as erdafitinib (FGFR3) or trastuzumab deruxtecan (HER2) are considered based on molecular profile. Heterogeneity remains for sequencing of erdafitinib vs T‑DXd and the role of sacituzumab govitecan.10
9) Biomarker and ctDNA use
– Next‑generation sequencing (NGS) is recommended to identify actionable targets (FGFR3, HER2, ERBB2, Nectin‑4 expression not yet strictly predictive) but should not delay initiation of frontline therapy (strong consensus).22
– Plasma ctDNA for MRD currently has limited, non‑standardized application in RCC and UC; AUC3 cautioned against using ctDNA alone to decide adjuvant therapy in RCC or UC.
10) Special populations
– Age alone should not preclude EV+pembro; dose modifications may be individualized. Elderly and dialysis patients were broadly considered eligible for EV+pembro with close monitoring.
– Diabetes and uncontrolled hyperglycemia: most experts would not withhold EV for moderately elevated HbA1c but would optimize glycemic control and involve endocrinology.
Expert Commentary, Consensus Strengths and Controversies
What the experts agreed on
– Clear, strong recommendations in several high‑impact areas: adjuvant pembrolizumab for defined high‑risk RCC; EV+pembro as frontline for metastatic UC where available; VEGFR‑TKI monotherapy after progression on ICI‑containing regimens in RCC.
– Need for precise histologic classification and somatic profiling in variant RCC and metastatic UC variants.
Key controversies and unsettled questions
– The optimal choice among ICI+VEGFR‑TKI combinations in RCC (no head‑to‑head data; preferences split between nivolumab+cabo and pembrolizumab+lenvatinib).
– Best sequencing of targeted agents (erdafitinib, trastuzumab deruxtecan, sacituzumab govitecan) after EV+pembro, and prioritization in dual‑biomarker (HER2+/FGFR3+) cases.
– Role of ctDNA to guide adjuvant therapy—an active area of research but not yet practice‑defining according to AUC3.
Panel insights on clinical application
– Use clinical and pathologic risk plus patient preferences to determine adjuvant therapy in borderline cases; engage in shared decision‑making emphasizing potential absolute benefits and ICI toxicities.
– For metastatic UC, check NGS/IHC early to anticipate targeted options, but do not delay starting effective systemic therapy while awaiting results.
– Maintain multidisciplinary care (urology, medical oncology, radiation oncology, pathology) for variant histologies and locally advanced disease decisions.
Practical Implications for Clinicians
– Standardize pre‑adjuvant restaging imaging to exclude occult spread prior to adjuvant pembrolizumab in RCC.
– For RCC patients who meet KEYNOTE‑564‑like high‑risk features, discuss adjuvant pembrolizumab as part of routine post‑nephrectomy care.
– In UC, consider EV+pembro frontline where available; for patients progressing on EV+pembro and who are platinum‑naïve, prioritize platinum doublet chemotherapy.
– Institute early molecular profiling for metastatic UC and variant RCC; use results to guide second‑line targeted choices but not to delay initial systemic therapy.
– In older or comorbid patients, tailor dosing and monitor toxicities closely—AUC3 supports treatment for fit older adults, not excluding on basis of age alone.
Patient Vignette — Applying AUC3 in Clinic
Case: “Mr. James Miller,” a 64‑year‑old man underwent radical nephrectomy for pT3bN0 clear‑cell RCC. Pathology shows grade 3. Postop imaging is negative. Per AUC3, Mr. Miller meets criteria for adjuvant pembrolizumab and should be counseled on potential benefits (improved DFS and OS in KEYNOTE‑564) versus risk of immune‑related toxicity. If he had pT3a, grade 1–2 disease, AUC3 would recommend individualized discussion and shared decision making given divided expert opinion.4
Research Priorities Identified by AUC3
– Head‑to‑head comparisons among ICI+VEGFR‑TKI regimens in RCC to define best regimen selection.
– Trials defining sequencing after EV+pembro in UC, including randomized studies comparing T‑DXd, erdafitinib, sacituzumab govitecan, and chemotherapy in biomarker‑selected populations.
– Prospective MRD/ctDNA studies to validate a role in adjuvant therapy decisions in RCC and UC (ongoing interest from AUC3 panel).22
– Better biomarkers predictive of response to belzutifan and other novel agents in RCC.
Limitations and How to Use These Recommendations
– AUC3 is an expert consensus generated by a North American/European‑centric panel with majority medical oncology representation; local resource availability and regulatory approvals will affect applicability.
– Recommendations should complement, not replace, guideline documents from societies (eg, NCCN, ESMO) and multidisciplinary tumor board decisions.
– When evidence is lacking or consensus absent, clinicians should prioritize enrollment in clinical trials where feasible.
Conclusions
AUC3 2025 synthesizes contemporary trial evidence and expert experience into pragmatic recommendations for complex decision points in RCC and UTC management. The conference provides clear guidance in areas with strong data (adjuvant pembrolizumab in high‑risk RCC, EV+pembro frontline UC, VEGFR‑TKI after ICI‑containing RCC regimens) and identifies important uncertainties that should shape trial design and real‑world research. Clinicians should integrate these consensus recommendations with individual patient factors, molecular profiling, and multidisciplinary input to optimize outcomes.
References
1. McKay RR, Pal S, Xie W, et al. Advanced Urologic Cancer Consensus Conference (AUC3) 2025: Expert consensus on the management of renal cell and urinary tract cancers. CA Cancer J Clin. 2026 Jan‑Feb;76(1):e70052. doi:10.3322/caac.70052.
4. Choueiri TK, Tomczak P, Park SH, et al. Overall survival with adjuvant pembrolizumab in renal‑cell carcinoma. N Engl J Med. 2024;390(15):1359‑1371. doi:10.1056/NEJMoa2312695.
5. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib for advanced RCC. N Engl J Med. 2021;384:829‑841. doi:10.1056/NEJMoa2026982.
6. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib + pembrolizumab or everolimus for advanced RCC. N Engl J Med. 2021;384:1289‑1300. doi:10.1056/NEJMoa2035716.
7. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab + ipilimumab vs sunitinib in advanced RCC. N Engl J Med. 2018;378:1277‑1290. doi:10.1056/NEJMoa1712126.
9. Powles T, Catto JWF, Galsky MD, et al. Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med. 2024;391:1773‑1786. doi:10.1056/NEJMoa2408154.
10. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390:875‑888. doi:10.1056/NEJMoa2312117.
17. Pal SK, Albiges L, Tomczak P, et al. CONTACT‑03: atezolizumab + cabozantinib vs cabozantinib in RCC after prior ICI. Lancet. 2023;402:185‑195. doi:10.1016/S0140‑6736(23)00922‑4.
18. Choueiri TK, Albiges L, Barthelemy P, et al. TiNivo‑2: tivozanib + nivolumab vs tivozanib in RCC post‑ICI. Lancet. 2024;404:1309‑1320. doi:10.1016/S0140‑6736(24)01758‑6.
19. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and combination in metastatic RCC. Lancet Oncol. 2015;16:1473‑1482. doi:10.1016/S1470‑2045(15)00290‑9.
20. Choueiri TK, Powles T, Peltola K, et al. Belzutifan vs everolimus for advanced RCC. N Engl J Med. 2024;391:710‑721. doi:10.1056/NEJMoa2313906.
22. Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. 2021;595:432‑437. doi:10.1038/s41586‑021‑03642‑9.
24. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab vs placebo in MIBC. N Engl J Med. 2021;384:2102‑2114. doi:10.1056/NEJMoa2034442.
26. van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab + gemcitabine‑cisplatin in advanced UC. N Engl J Med. 2023;389:1778‑1789. doi:10.1056/NEJMoa2309863.
(For a complete citation list and supplemental tables of the AUC3 voting results, see McKay et al. AUC3 2025.)
