EAU 2025: Localised MIBC: Evaluation of Complete Response Methods

(UroToday.com) The 2025 European Association of Urology (EAU) Annual Congress held in Madrid, Spain was host to a plenary session on organ-sparing paradigms in kidney and bladder cancer. Dr. Peter Black discussed whether current methods of complete response evaluation are adequate for appropriately selecting patients with muscle-invasive bladder cancer (MIBC) for bladder-sparing approaches.

Dr. Black emphasized that the current standard of care for MIBC remains morbid and de-intensification strategies are needed.

However, when considering de-intensification strategies involving active surveillance after neoadjuvant therapy (i.e., bladder-sparing approaches), there are two critical challenges:

Do we have the tools necessary to determine complete response accurately?
If we miss persistent disease, can we rescue these patients?

Current tools available for evaluating complete responses following neoadjuvant therapy, include cytology, CT chest/abdomen/pelvis, and a cystoscopy +/- TURBT:

To date, there are four trials evaluating bladder-sparing approaches for MIBC, of which three have been presented or published (RETAIN, HOOSIER, RETAIN 2):

RETAIN was a single arm, non-inferiority phase II trial (NCT02710734) that included cT2-T3N0M0 urothelial carcinoma patients who underwent neoadjuvant chemotherapy (NAC) with accelerated MVAC x 3 cycles. Pre-NAC TURBT specimens were sequenced for mutations in ATM, ERCC2, FANCC or RB1. Patients with ≥1 mutation and no clinical evidence of disease by restaging TUR, urine cytology and imaging post-NAC began pre-defined active surveillance. The remaining patients underwent bladder-directed therapy.

The trial design is summarized below:

Of the 70 patients in the intent-to-treat (ITT) population, 25 were found to be mutation-positive and had no residual disease. All these patients, including an additional 3 who were either mutation negative or had residual disease, proceeded to active surveillance (n=28). In the overall ITT cohort (n=70), the 2-year metastasis-free survival rate was 73%.

In the cohort of 25 mutation-positive patients who proceeded to active surveillance, 17 (68%) experienced a recurrence. 8 patients underwent a cystectomy (7 for MIBC, 4 N+). Nine patients (36%) developed metastases, of whom 8/9 first recurred in the bladder. To date, 12 (48%) are metastasis-free with an intact bladder (no radical cystectomy or radiotherapy).

HCRN GU 16-257 was a phase II trial of cisplatin-eligible cT2-T4aN0M0 urothelial bladder cancer patients who received 4 cycles of gemcitabine, cisplatin, plus nivolumab (RETAIN – chemotherapy alone) followed by clinical restaging including urine cytology, MRI/CT of the bladder, cystoscopy and bladder biopsies (no use of biomarkers). Patients achieving a complete CR (normal cytology, imaging, and cT0/Ta) were eligible to proceed without cystectomy and receive nivolumab every 2 weeks x 8 followed by surveillance. Patients not achieving a clinical complete response were recommended to undergo cystectomy.²

Among the 72 eligible patients, 33 (43%) had a clinical complete response. One patient opted for cystectomy, whereas 32 proceeded to surveillance and received 8 additional cycles of nivolumab.

At two-years follow-up, 97% of patients with a clinical complete response remained alive and free of metastases, and 72.2% were alive with an intact bladder.²

Notable differences between HCRN GU 16-257 and RETAIN included the following:

Biomarkers were used for the selection of patients for bladder-sparing approaches in RETAIN (ATM, RB1, FANCC, ERCC2), but not HCRN GU 16-257
Chemoimmunotherapy was used in HCRN GU 16-257 and patients received peri-operative nivolumab
Differences in clinical re-staging following neoadjuvant therapy

Dr. Black noted that the paradigm for bladder-sparing approaches is likely to evolve with the emergence of novel systemic therapy combination approaches, including perioperative durvalumab with neoadjuvant chemotherapy (NIAGARA)³ and enfortumab vedotin + pembrolizumab (EV-303, EV-304).

The next ‘wave’ of tools for determining complete response is likely to incorporate urinary tumor DNA (utDNA), circulating tumor DNA (ctDNA), and MRI (VI-RADS scoring system).

The prognostic utility of ctDNA has clearly been established. Following a radical cystectomy, ctDNA has a sensitivity of 94% and a specificity of 98% for identifying metastatic relapses. During NAC, ctDNA dynamics are independently associated with patient outcomes when adjusted for pathologic downstaging (HR: 4.7; p=0.029). For NAC-naïve patients, ctDNA is a prognostic predictor before (HR:3.4; p=0.0005) and after radical cystectomy (HR:17.8; p=0.0002).⁴

Dr. Black concluded by highlighting the NEO-BLAST trial, which is investigating neoadjuvant therapy for MIBC, incorporating ctDNA as part of the criteria to assess clinical complete response. Patients who achieve a complete response may proceed with local definitive treatment or surveillance instead of radical cystectomy.

Presented by: Peter Black, MD, Senior Research Scientist, Vancouver Prostate Centre, Professor, Department of Urologic Sciences, University of British Columbia, Vancouver Prostate Center

Written by: Rashid K. Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the European Association of Urology (EAU) 2025 Annual Meeting, Madrid, Spain, Fri, Mar 21 – Mon, Mar 24, 2025.

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