Enfortumab Vedotin Plus Pembrolizumab Reshapes the Perioperative MIBC Paradigm
Representative trial: KEYNOTE-B15/EV-304 — Phase 3 results presented at ASCO GU 2026
The KEYNOTE-B15/EV-304 trial delivered what may be the most practice-changing readout of the meeting, directly challenging the established neoadjuvant chemotherapy paradigm in cisplatin-eligible muscle-invasive bladder cancer (MIBC).
Perioperative enfortumab vedotin plus pembrolizumab (EVP) demonstrated superiority over neoadjuvant cisplatin-based chemotherapy in cisplatin-eligible MIBC Cancer News
The regimen pairs four neoadjuvant cycles of EV-pembrolizumab with five cycles of adjuvant EV and thirteen cycles of adjuvant pembrolizumab, compared against standard GEMCIS chemotherapy GU Oncology Now
EV-pembrolizumab is already FDA-approved for cisplatin-ineligible patients; this trial extends the evidence base into the larger cisplatin-eligible population GU Oncology Now
The result reframes the traditional decision tree, which previously hinged first on cystectomy candidacy and then on cisplatin eligibility, toward an ADC-immunotherapy-first algorithm.
Novel Nectin-4 ADC Shows Activity After Enfortumab Vedotin Progression
Representative trial: NEXUS-01 (NCT06465069) — Phase 1 first-in-human results presented at ASCO 2026
With EV-based therapy now front-line standard, the post-EV treatment gap has become one of the field’s most pressing unmet needs — and a new Nectin-4-directed ADC offers an early answer.
LY4052031, an investigational Nectin-4 antibody-drug conjugate built around a topoisomerase I inhibitor payload, produced confirmed responses in one-third of patients with metastatic urothelial carcinoma who had progressed on prior EV-based therapy Targeted Oncology
Among 36 evaluable patients with prior EV exposure and intact CYP2D6 function, the overall response rate was 33%, the disease control rate was 75%, and the median duration of response was 7.4 months, with 67% of responses ongoing at data cutoff Targeted Oncology
This represents one of the first targeted options to show meaningful activity specifically in the post-EV setting, a population with few standardized options
HER2-Directed ADC Disitamab Vedotin Expands the Biomarker-Selected Treatment Landscape
Representative trial: RC48G001 — Phase 2 results presented at ASCO GU 2026
Disitamab vedotin’s data reinforce HER2 expression as an actionable biomarker in advanced urothelial carcinoma, an agent not yet approved in the U.S. but with a substantial international evidence base.
RC48G001, a phase 2 study of disitamab vedotin in HER2-expressing previously treated advanced urothelial carcinoma, was discussed alongside KEYNOTE-B15 as one of the two pivotal urothelial abstracts of the meeting UroToday
Disitamab vedotin is a HER2-directed ADC not yet approved in the United States for bladder cancer, although substantial supporting data have accumulated internationally GU Oncology Now
The data add to a growing case for routine HER2 testing in advanced urothelial carcinoma as ADC sequencing strategies mature
Bladder-Sparing Approaches Gain Ground with Immunotherapy-Based Induction Regimens
Representative trials: Indi-Blade (Phase 2) and SAKK 06/19 — Presented at ASCO GU 2026 and ASCO 2026
Two complementary studies strengthened the case for organ-sparing strategies in MIBC, an area of growing interest as systemic therapy options improve.
The phase 2 Indi-Blade trial evaluated induction ipilimumab plus nivolumab followed by consolidating chemoradiotherapy as a bladder-sparing approach in stage II/III urothelial carcinoma UroToday
In the SAKK 06/19 trial, intravesical recombinant BCG combined with chemoimmunotherapy achieved a pathological complete response rate of 68%, compared with a null hypothesis benchmark of 53% Oncology News Central
While the trial is relatively small and the confidence intervals around the pathological CR rate are not tight, the result falls outside the range previously observed with chemotherapy alone Oncology News Central
Together these data suggest immunotherapy-based induction may meaningfully expand the pool of patients eligible for bladder preservation
ctDNA Moves Toward Practical Use in Postoperative Surveillance and Treatment Selection
Representative studies: pT0 study ctDNA analysis; FGFR3 liquid biopsy detection — ASCO GU 2026; cost-effectiveness analyses.
Circulating tumor DNA (ctDNA) is emerging as a tool with near-term clinical applicability in both surveillance after cystectomy and treatment selection in advanced disease.
Circulating tumor DNA analysis from the prospective pT0 study examined systematic endoscopic evaluation in patients undergoing radical cystectomy for bladder cancer.
A separate analysis focused on detecting FGFR3 genomic alterations in liquid biopsies from patients with clinically advanced urothelial bladder cancer, supporting non-invasive identification of patients eligible for FGFR-targeted therapy UroToday
A prospective multicenter study analyzed plasma samples from patients with metastatic urothelial carcinoma to gauge the clinical effect of ctDNA testing, while a parallel analysis assessed the cost-effectiveness of ctDNA-guided therapy in the postoperative muscle-invasive settin.
These complementary efforts position ctDNA as a candidate companion diagnostic for both perioperative escalation/de-escalation decisions and post-EV treatment selection
Combination Immunotherapy Strategies in Advanced Urothelial Carcinoma Show Mixed Results
Representative trial: KEYMAKER-U04 Substudy 04B — Phase 1/2 results presented at ASCO GU 2026.
Not every combination strategy moved the needle — KEYMAKER-U04 provided an important negative-but-informative result regarding checkpoint combination intensification on top of the EVP backbone.
The KEYMAKER-U04 Substudy 04B phase I/II study compared standard EVP against EV combined with co-formulated anti-LAG-3 (favezelimab) plus pembrolizumab, and EV combined with co-formulated anti-TIGIT (vibostolimab) plus pembrolizumab Cancer News
Objective response rates were similar across the three arms, with the highest at 68% for EV plus favezelimab/pembrolizumab versus 64% for standard EVP — not a statistically significant improvement Cancer News
Median duration of response was also similar across arms, indicating that addition of anti-LAG-3 or anti-TIGIT did not improve upon EVP efficacy Cancer News
The result reinforces EVP as the frontline backbone to beat, while redirecting combination strategy efforts toward novel ADC payloads (as in NEXUS-01) rather than additional checkpoint targets.
Cabozantinib Shows Early Activity in Refractory Germ Cell Tumors
Representative commentary: ASCO GU 2026 Kidney Cancer and Germ Cell Tumor
Testicular germ cell tumors remain a small but important area of unmet need in refractory disease, and early signals with repurposed TKIs are drawing renewed attention.
Early cabozantinib activity was reported in refractory germ cell tumors, an area with very limited systemic options after standard cisplatin-based regimens fail GU Oncology Now
While data remain preliminary, the signal supports further exploration of TKI-based salvage strategies in this rare, young-adult-predominant population. This represents one of the few active investigational threads in refractory testicular cancer presented this cycle
EXECUTIVE OUTLOOK
ASCO GU and ASCO 2026 crystallized a urothelial cancer landscape defined by three converging forces: ADC-immunotherapy combinations displacing chemotherapy as the perioperative backbone for muscle-invasive disease, a rapidly diversifying ADC pipeline (Nectin-4, HER2, and novel payloads) addressing the post-EV treatment gap, and ctDNA maturing from a research tool into a practical instrument for surveillance and treatment selection. The most consequential near-term question is not whether ADC-based regimens outperform chemotherapy — that case now appears settled — but how to sequence an increasingly crowded ADC landscape, and which biomarkers (HER2, FGFR3, ctDNA dynamics) will determine that sequence for individual patients.
