Physician discussion of GU trials, October 23–25

Physician posts on X, October 23–25.

The eleven most-discussed trials are covered below.

Bladder cancer

VOLGA: durvalumab + 3 cycles of neoadjuvant EV, cisplatin-ineligible MIBC

Phase 3, N=695, cisplatin-ineligible or refusing. Durvalumab + EV vs control: EFS HR 0.51 (95% CI 0.38–0.67), 24-month EFS 64% vs 45%. OS HR 0.58 (0.40–0.83), 24-month OS 78% vs 69%. pCR 45% vs 10% (local review). The triplet arm with tremelimumab: EFS HR 0.61 (0.47–0.80); OS HR 0.77 (0.54–1.07), not significant. Grade 3–4 AEs of any cause 64% (durvalumab + EV), 70% (triplet), 44% (control). (ESMO 2026 LBA2, Tom Powles; data cutoff Mar 2, 2026) Investigational. FDA granted Priority Review to durvalumab + EV on September 25, 2026. (KOL Pulse VOLGA page)

Physicians favored the doublet. The debate was the triplet’s added toxicity and how much EV is needed, since VOLGA gave no adjuvant EV.

Presenter first, then agreement and debate

Tom Powles @tompowles1

GU oncologist; VOLGA presenter · Oct 24

VOLGA explored short periods of EV (3 cycles) with duvalumab in muscle invasive bladder cancer #ESMO26 @NEJM. Results showed EVD was associated with better EFS + OS vs cystectomy alone (0.51 and 0.58 respectively). pCR 40-45% with ctDNA clearance rates of 60%. High rates of adjuvant IO therapy uptake and low rates of neuropathy suggest potential advantages of this approach which focuses the ADC in the neoadjuvant phase. It’s likely to be attractive for patients.

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Shilpa Gupta @shilpaonc

GU oncologist, Cleveland Clinic · Oct 24

Kudos @tompowles1 on a fantastic #VOLGA presidential @ #ESMO26 👏 Less is More! • Cis-inelig MIBC, 25% were cis refusers
• D+EV x3 → RC → adj D x9 (NO adj EV)
• EFS HR 0.51 
• OS HR 0.58 
• pCR 45 vs 10%
• G3-4 TRAE 30%, 
• neuropathy only 18% 
• imAEs 33% (G3-4 11%)
• GHS/QoL maintained post-RC • Treme ↑tox (G3-4 42%, 5 deaths), NO OS gain. My take: it's not just about chasing bigger numbers. Tox matters too, especially when OS is achieved. Need to discuss the pros and cons with patients. Less PN and skin tox, and fewer G3+ immune AEs than more cycles and that's a win for patients ! 🙌 @Uromigos @OncoAlert @brian_rini @LosUromigos @drenriquegrande

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Karine Tawagi MD @DrKarineTawagi

GU oncologist · Oct 24

💫#VOLGA: Durva + EV in cis-ineligible, like #EV303 but NO adjuvant EV here ⬆️ 2-year EFS (HR 0.51), OS (HR 0.58) & pCR (45% vs 10%) Triplet arm OS not significant & ⬆️ tox Less robust #s then EVP but how much benefit does adjuvant EV add? Can we use ctDNA/pCR to ⬇️? #ESMO26 https://t.co/UruMRqJPnI

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KEYNOTE-866 and ENERGIZE: two negative Phase 3 trials of PD-1 + cisplatin chemotherapy

Both trials added a PD-1 inhibitor to neoadjuvant gemcitabine-cisplatin, continued after cystectomy, in cisplatin-eligible MIBC. KEYNOTE-866 (pembrolizumab, N=907): EFS HR 0.88 (95% CI 0.71–1.10), one-sided P=0.1366, not significant. OS HR 1.00 (0.79–1.27). pCR 44.4% vs 35.8%; OS and pCR were not formally tested. (ESMO 2026 4735O, Jens Bedke; data cutoff Jan 26, 2026) ENERGIZE (nivolumab, N=653): EFS HR 0.94 (0.72–1.24), P=0.6697. pCR 39.1% vs 29.6%, not significant after multiplicity adjustment. Both co-primary endpoints were missed. (ESMO 2026 4736O, Andrea Necchi; median follow-up 54.5 months) Neither regimen is approved for MIBC. NIAGARA, with durvalumab on the same chemotherapy backbone, was positive.

Physicians noted that higher pCR did not translate into EFS. Explanations offered for the difference from NIAGARA included control-arm outcomes, trial populations and the need for biomarker selection.

Why NIAGARA and not these two?

Shilpa Gupta @shilpaonc

GU oncologist, Cleveland Clinic · Oct 23

Bravo @AndreaNecchi on a superb presentation of ENERGIZE trial at @myESMO #ESMO26 ! 👏 Ph3, n=653 cis-eligible MIBC: neoadj GC + nivo → adj nivo vs GC alone. Median f/u 54.5 mo. 🔹 pCR 39.1% vs 29.6%: not dig
🔹 EFS HR 0.94: co-primaries not met
🔹 OS HR 0.88 👉Negative trial, but the ctDNA data are a key message: detectable ctDNA at baseline and after NAC strongly prognostic for worse EFS & OS. Selecting patients by ctDNA, rather than adding IO for all, is where the field is heading! Great to see this build on our Ph2 BLASST-1. Despite the negative result, it's very practice-informing. Proud to be a part of this effort! @CleClinicMD @caseccc @CleClinicUro @sonpavde @MattGalsky @MichvdHeijden @Uromigos @Annals_Oncology @tompowles1

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Toni Choueiri, MD @DrChoueiri

chief of GU cancers, Dana-Farber · Oct 23

Negative Ph.III KEYNOTE-866 by #DrJensBedke: perioperative pembrolizumab + neoadjuvant Gem/Cis vs placebo + Gem/Cis in cis-eligible MIBC. EFS HR 0.88 (95% CI 0.71-1.10), p=0.137. pCR 44.4% vs 35.8%; OS HR 1.00. Higher pCR did not translate into EFS benefit. #ESMO26 #BladderCancer @myESMO @OncoAlert

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Tian Zhang, MD, MHS, FASCO (@tiansterzhangmd.bsky) @TiansterZhang

GU oncologist, UT Southwestern · Oct 23

Nice comparison chart @tompowles1 — control cohorts in the #ENERGYZE & #Keynote866 trials both did much better than #NIAGARA control cohort… some may have had access to adjuvant IO to contribute to EFS? #ESMO26 @myESMO @OncoAlert https://t.co/K6ubio90xc

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David H Aggen, MD PhD @Dr_Aggen

GU oncologist, MSK · Oct 23

ENERGIZE: Another negative perioperative IO trial in MIBC. Nivo + GC → cystectomy → nivo failed to improve EFS (HR 0.94, p=0.67). OS HR 0.88. Notably, split-dose cisplatin was allowed and 77% had cT2 disease. Again, excellent outcomes in the control arm. #ESMO26 @OncoAlert https://t.co/9g4zjz7Nq7

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KEYNOTE-B15 / EV-304: ctDNA from the approved perioperative EV + pembrolizumab regimen

Exploratory ctDNA analysis (Signatera) presented by Jonathan Chatzkel. ctDNA clearance from baseline to surgery 82.1% vs 66.7% with EV + pembrolizumab vs gemcitabine-cisplatin. ctDNA-positive after surgery 4.8% vs 13.5%. pCR 72.4% vs 43.7% in patients ctDNA-negative before surgery, and 3.7% vs 2.2% in those still ctDNA-positive. ctDNA-positive status was associated with worse EFS in both arms. (ESMO 2026 Abstract 4734O and slides; discussant slide for pCR by ctDNA; data cutoff Oct 27, 2025) ctDNA is not validated to guide treatment. Perioperative EV + pembrolizumab has been FDA approved for MIBC since July 10, 2026, based on the trial’s EFS and OS results. (KOL Pulse KEYNOTE-B15 page)

Physicians agreed ctDNA is prognostic. The open question is whether ctDNA and pCR can guide de-escalation, including adjuvant EV and bladder sparing.

KEYNOTE-905 / EV-303: what pembrolizumab alone adds, in an ad hoc three-arm analysis

Ad hoc analysis of 255 cisplatin-ineligible or cisplatin-declining patients randomized concurrently to EV + pembrolizumab (n=85), pembrolizumab alone (n=83) or cystectomy alone (n=87). 24-month EFS 75.8%, 55.8% and 41.0%. EFS HR vs cystectomy alone 0.40 (95% CI 0.25–0.65) for EV + pembrolizumab and 0.71 (0.47–1.07) for pembrolizumab alone. OS HR 0.48 (0.29–0.80) and 0.76 (0.48–1.20). pCR 58.8%, 25.3% and 10.3%. All comparisons were descriptive, not prespecified hypothesis tests. (ESMO 2026 4733O slides, Anders Ullén; data cutoff Jun 6, 2025) Perioperative EV + pembrolizumab has been FDA approved since November 21, 2025, based on the primary two-arm analysis. Perioperative pembrolizumab alone is not approved for MIBC. (KOL Pulse KEYNOTE-905 page)

Physicians read the result as support for both drugs. The questions were which patients need EV on top of pembrolizumab, and how much toxicity the added EV brings.

Kidney cancer

XmAb819: an ENPP3 × CD3 T-cell engager in heavily pretreated clear cell RCC

Phase 1 study (XmAb819-01, NCT05433142) of XmAb819, a bispecific T-cell engager that targets ENPP3, in patients with relapsed or refractory clear cell RCC after a checkpoint inhibitor and a VEGFR TKI. Sumanta K. Pal of City of Hope presented the data in the October 25 GU proffered paper session, and Manuela Schmidinger discussed it. XmAb819 is investigational. Source: XmAb819 presentation, ESMO 2026 program.

Physicians, including the LITESPARK-011 presenter, called the activity promising in heavily pretreated disease and pointed to ENPP3 as a new target in RCC. The caveat they raised: these are Phase 1 data, and randomized trials are needed. Pal’s own posts, quoted below, are on LITESPARK-011 and LITESPARK-012.

LITESPARK-011 final analysis: belzutifan + lenvatinib vs cabozantinib after PD-1/PD-L1 therapy

Phase 3, N=747, presented by Daniel Heng (3587O) and published at the same time in Annals of Oncology. Overall survival, a dual primary endpoint, was not statistically significant: median 33.7 vs 28.6 months, HR 0.85 (95% CI 0.70–1.03), one-sided P=0.04689 against a prespecified boundary of 0.0223. PFS by blinded central review: median 14.8 vs 10.8 months, HR 0.74 (0.62–0.88), not formally re-tested at this analysis. ORR 53.1% vs 40.2%; median duration of response 22.0 vs 11.9 months. Grade 3 or higher adverse events 85.4% vs 83.0%. (ESMO 2026 3587O / Annals of Oncology, final analysis; data cutoff Feb 2, 2026) PFS was statistically significant at the first interim analysis: median 14.6 vs 10.6 months, HR 0.74 (0.61–0.89), one-sided p=0.00095. (FDA label; first interim analysis (IA1), data cutoff Jun 26, 2024) The FDA approved belzutifan + lenvatinib on September 24, 2026 for adults with advanced RCC with a clear cell component after a PD-1 or PD-L1 inhibitor, based on PFS and ORR. No overall survival benefit has been demonstrated. (KOL Pulse LITESPARK-011 page)

Physicians agreed the PFS and response benefit held up and that OS missed significance. The debate was whether the combination should displace single-agent therapy after immunotherapy, given lenvatinib tolerability and cardiac toxicity.

LITESPARK-012: adding belzutifan or CTLA-4 blockade to first-line pembrolizumab + lenvatinib

Phase 3, three arms, in previously untreated advanced clear cell RCC: pembrolizumab + lenvatinib with belzutifan, or with quavonlimab (an anti-CTLA-4 antibody) coformulated with pembrolizumab, vs pembrolizumab + lenvatinib. Toni Choueiri presented the trial (3586O), with a concurrent publication in Annals of Oncology. Neither triplet improved PFS or OS over pembrolizumab + lenvatinib, and more patients stopped treatment because of adverse events on the triplets. Both triplets are investigational; pembrolizumab + lenvatinib, the control arm, is an FDA-approved first-line regimen. Source: 3586O abstract, ESMO 2026 program.

Physicians read the trial as a limit on stacking current drug classes. Explanations offered included toxicity reducing the dose intensity of the doublet and a strong control arm; others asked which patients, if any, need CTLA-4 blockade.

Prostate cancer

DASL-HiCaP: darolutamide added to ADT and radiation in very high-risk localized prostate cancer

Phase 3, placebo-controlled trial (ANZUP1801) presented by Tamim Niazi in Presidential Symposium I (LBA4), with Silke Gillessen as discussant. The presented result was an interim analysis; the trial reported a metastasis-free survival benefit with darolutamide. Darolutamide is investigational in this setting. Source: LBA4 abstract, ESMO 2026 program.

The US lead investigator called it a new standard of care. Others focused on patient selection, nodal disease and what the abstract did not report about radiation.

PROTEUS substudy: perioperative apalutamide + ADT vs prostatectomy alone

Open-label substudy, randomized 1:3, N=408: apalutamide + ADT around radical prostatectomy and pelvic lymph node dissection (n=102) vs surgery alone (n=306), in high-risk localized or locally advanced disease. EFS HR 0.38 (95% CI 0.26–0.55), P<0.0001; 36-month EFS 63.0% vs 41.4%; median EFS 19.1 months with surgery alone. Metastasis-free survival, a secondary endpoint: HR 0.49 (0.26–0.90), nominal P=0.0193. Time to first subsequent therapy HR 0.29 (0.20–0.43), nominal. (ESMO 2026 LBA53 slides, Alberto Briganti; clinical cutoff Jul 13, 2026) The substudy is separate from the double-blind PROTEUS main trial presented at ASCO 2026. Perioperative apalutamide is investigational; apalutamide is FDA approved in nmCRPC and mCSPC. (KOL Pulse PROTEUS page)

Physicians saw the substudy as addressing a criticism of the main trial, which had no surgery-alone control. One physician reported that the discussant, Nicholas van As, concluded longer follow-up is needed before changing practice.

JNJ-6143: a first-in-class oral AR-targeted RIPTAC in mCRPC

Phase 1 dose-escalation study presented by Benjamin Garmezy (2216O) in heavily pretreated metastatic castration-resistant prostate cancer. JNJ-6143 is investigational. Source: 2216O abstract, ESMO 2026 program.

Physicians highlighted the new mechanism and activity across molecular subgroups, with the caveat that these are Phase 1 data.

New mechanism; early data

Katy Beckermann @katy_beckermann

GU medical oncologist · Oct 24

JNJ-6143, first-in-class oral AR-BRD4 RIPTAC, phase 1 mCRPC: a wide window between efficacy and safety. n=105, doses 12.5 to 150 mg. 📈 50 mg daily: PSA50 77%, PSA90 48%, confirmed ORR 69%, after a median 4 prior lines 📊 PSA declines seen from 12.5 to 150 mg. 66% of all patients still on drug 🔍 At 50 mg: 58% any-grade TRAEs, no serious TRAEs. Median DOR 11.0 months, CI 5.9 to NE Activity across a 12-fold dose range. Phase 2 is open at 50 mg. Congrats to @BGarmezy on the presentation and all the investigators. #ESMO26 #ProstateCancer #mCRPC #GUonc

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Tian Zhang, MD, MHS, FASCO (@tiansterzhangmd.bsky) @TiansterZhang

GU oncologist, UT Southwestern · Oct 24

@BGarmezy with 1st report of an AR RIPTAC - JNJ-6143 in metastatic castration resistant #prostatecancer showing good PSA responses across aggressive molecular subtypes, median duration 11 months. New mechanism to degrade androgen receptor is active! @oncoalert #ESMO26 @myESMO https://t.co/ejTYkqTkgw

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Tomas Pokrivcak, MD, PhD @pokrivcak

oncologist, Masaryk Memorial Cancer Institute · Oct 24

Promising #ESMO2026 data for JNJ-6143, a first-in-class oral RIPTAC in heavily pretreated #mCRPC. PSA50 77% | PSA90 48% | ORR 69% Encouraging activity, including in high-risk molecular subgroups. Early phase I, but one to watch. #ProstateCancer https://t.co/59WZYQMAQ9

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Also discussed

PEACE-1 long-term OS (posts), TROPHY-U-01 (posts), CAPItello-281 (posts) and PE-PE, pembrolizumab after metastasis-directed therapy in oligometastatic RCC, presented on October 25 by Roberto Iacovelli (posts).

KEYNOTE-564: Toni Choueiri presented the final protocol-prespecified analysis of adjuvant pembrolizumab vs placebo in clear cell RCC on October 25 (3589RO). Physicians pointed to the durability of the benefit. KEYNOTE-564 trial page.

KOL Voices: the top GU physicians at ESMO 2026

The ten GU physicians at the top of the ESMO 2026 Top KOLs leaderboard. One line from each, verbatim and linked, with the trial it is about.

1. 1. Toni Choueiri, MD chief of GU cancers, Dana-Farber · 121.9K impressions, 51 posts
   on KEYNOTE-866 → “Higher pCR did not translate into EFS benefit.”
2. 2. Tom Powles GU oncologist; VOLGA presenter · 94.9K impressions, 25 posts
   on VOLGA → “More is not always better.”
3. 3. Yüksel Ürün GU oncologist, Ankara University · 42.8K impressions, 44 posts
   on KEYNOTE-905 / EV-303 → “KEYNOTE-905: pembro alone raises a question worth testing. Who might safely need less?”
4. 4. Zach Klaassen urologic oncologist · 30.5K impressions, 28 posts
   on DASL-HiCaP → “Differences in BL risk and pt selection may explain variation in treatment effects for STAMPEDE M0, ENZARAD, DASL-HiCaP”
5. 5. Enrique Grande medical oncologist, Quironsalud Madrid · 26.6K impressions, 9 posts
   on VOLGA → “Perioperative Durvalumab plus EV showed statistically significant and clinically meaningful improvements in event-free survival and overall survival in muscle-invasive bladder cancer in the Phase III VOLGA trial.”
6. 6. Markus Eckstein uropathologist, Erlangen · 25.2K impressions, 6 posts
   on KEYNOTE-905 / EV-303 → “Equal rates, unequal consequences.”
7. 7. Dra. María Natalia Gandur Quiroga GU oncologist, Instituto Roffo · 24.8K impressions, 57 posts
   on KEYNOTE-866 → “A higher pathological response rate is encouraging, but it is not enough to redefine a standard of care.”
8. 8. Shilpa Gupta GU oncologist, Cleveland Clinic · 20.6K impressions, 14 posts
   on VOLGA → “Tox matters too, especially when OS is achieved.”
9. 9. David H Aggen, MD PhD GU oncologist, MSK · 16.9K impressions, 21 posts
   on ENERGIZE → “ENERGIZE: Another negative perioperative IO trial in MIBC.”
10. 10. Julian Chavarriaga urologic oncologist · 14.8K impressions, 24 posts
    on KEYNOTE-905 / EV-303 → “The efficacy gradient suggests both EV and pembrolizumab contribute to the combination's activity, with substantially greater benefit from EV+P.”

What’s yet to come

GU sessions still ahead. Times are Madrid time.

October 26–27

• Mon Oct 26, 08:30-10:00 (Madrid) · Educational: How to optimise care for patients receiving prostate cancer systemic therapy, Bilbao Auditorium - Hall 3. Optimising therapy for locally advanced prostate cancer 08:30; Personalised systemic therapy for mHSPC 08:55; Management of mCRPC 09:20. Speakers: Barbara Jereczek-Fossa; Aurelius G. Omlin; Deborah Mukherji.
• Mon Oct 26, 10:15-11:00 (Madrid) · Challenge your expert: Challenges in the management of neuro-endocrine and small cell prostate cancer, Granada Auditorium - Hall 4. Presentation by expert 10:15; discussion 10:35. Speakers: Himisha Beltran; chair Ravindran Kanesvaran.
• Mon Oct 26, 10:15-11:30 (Madrid) · Multidisciplinary: Response-based adaptive strategies in primary metastatic kidney cancer, Leon Auditorium - Hall 4. Image-guided strategy 10:20; What to do with the primary in extreme responders 10:40; Timing and optimal local treatment for metastatic disease 11:00. Speakers: Viktor Grünwald; Geraldine Pignot; Shankar Siva.
• Mon Oct 26, 14:45-16:00 (Madrid) · Multidisciplinary: Optimal multidisciplinary management of penile cancer, Cordoba Auditorium - Hall 4. Surgery 14:50; adjuvant chemotherapy 15:10; radiation therapy 15:20; distant recurrence 15:40. Speakers: Maarten Albersen; Fernando C. Maluf; Angela U. Pathmanathan.
• Tue Oct 27, 09:00-13:00 (Madrid) · Scientific Congress Highlights 1, Almeria Auditorium - Hall 9. GU prostate, penile and testis 09:20-09:40; GU renal and urothelial 09:40-10:00. Speakers: Christopher J Sweeney; Bernadett E. Szabados.

Regulatory: durvalumab + EV from VOLGA is under FDA Priority Review. (KOL Pulse VOLGA page) Physician posts on new GU readouts are added to the ESMO 2026 trials page through October 27.

Related ESMO 2026 pages

• ESMO 2026 GU slide library
• ESMO 2026 trials: all physician posts by trial
• ESMO 2026 conference page
• Trial pages: VOLGA · KEYNOTE-866 · ENERGIZE · KEYNOTE-B15 · KEYNOTE-905 · PROTEUS · DASL-HiCaP · NIAGARA · LITESPARK-011 · LITESPARK-012 · KEYNOTE-564 · CAPItello-281

FAQ

Which GU cancer trials did physicians discuss most at ESMO 2026?

By physician posts on X from October 23 to 25, the most-discussed GU trials were VOLGA, KEYNOTE-866, DASL-HiCaP, KEYNOTE-905, KEYNOTE-B15, ENERGIZE, LITESPARK-012, PROTEUS, LITESPARK-011, XmAb819 and JNJ-6143.

What did VOLGA show?

In cisplatin-ineligible or cisplatin-refusing MIBC, perioperative durvalumab plus 3 cycles of neoadjuvant enfortumab vedotin improved EFS (HR 0.51, 95% CI 0.38-0.67) and OS (HR 0.58, 0.40-0.83) vs control (ESMO 2026 LBA2, data cutoff Mar 2, 2026). It is investigational and under FDA Priority Review.

Why were KEYNOTE-866 and ENERGIZE negative?

Both added a PD-1 inhibitor to neoadjuvant gemcitabine-cisplatin and missed EFS (HR 0.88 and 0.94) despite higher pCR. Physicians on X pointed to control-arm outcomes, trial populations and biomarker selection. These are cross-trial observations, not head-to-head results.

What did the KEYNOTE-905 three-arm analysis add?

In an ad hoc, descriptive analysis of 255 concurrently randomized patients, EFS HR vs cystectomy alone was 0.40 with EV plus pembrolizumab and 0.71 with pembrolizumab alone (ESMO 2026 4733O, data cutoff Jun 6, 2025). Pembrolizumab alone is not approved for MIBC.

What did the LITESPARK-011 final analysis show?

Belzutifan plus lenvatinib did not significantly improve overall survival vs cabozantinib after PD-1/PD-L1 therapy: HR 0.85 (95% CI 0.70-1.03), one-sided P=0.04689 vs a boundary of 0.0223 (ESMO 2026 3587O, final analysis, data cutoff Feb 2, 2026). PFS (HR 0.74) and response benefits were maintained. The combination has been FDA approved since September 24, 2026, based on PFS and ORR.

What are XmAb819 and LITESPARK-012?

XmAb819 is an investigational ENPP3 x CD3 T-cell engager; Sumanta K. Pal presented Phase 1 data in heavily pretreated clear cell RCC. LITESPARK-012 is a Phase 3 trial in which adding belzutifan or quavonlimab to first-line pembrolizumab plus lenvatinib did not improve PFS or OS. Both triplets are investigational.

Is perioperative apalutamide approved for localized prostate cancer?

No. The PROTEUS substudy showed EFS HR 0.38 (95% CI 0.26-0.55) vs prostatectomy alone (ESMO 2026 LBA53), but perioperative use is investigational. Apalutamide is FDA approved in nmCRPC and mCSPC.