ESMO 2025: DISCUS: A Phase II Study Comparing 3 Versus 6 Cycles of Platinum-Based Chemotherapy Prior to Maintenance Avelumab in Advanced Urothelial Cancer

(UroToday.com) The 2025 ESMO annual meeting featured a urothelial carcinoma proffered paper session and a presentation by Dr. Enrique Grande discussing DISCUS, a phase 2 study comparing 3 versus 6 cycles of platinum-based chemotherapy prior to maintenance avelumab in advanced urothelial cancer. Enfortumab vedotin + pembrolizumab has become the new standard first-line regimen in advanced urothelial carcinoma.¹ However, platinum-based chemotherapy remains widely used worldwide.

Historically, longer platinum-based chemotherapy exposure was thought to improve objective response rate, progression-free survival, and overall survival, but this has never been proven in prospective trials. Maintenance avelumab significantly prolongs survival in patients with benefit from induction platinum-based chemotherapy.² Whether fewer cycles could preserve efficacy while improving tolerability and quality of life is being investigated in the DISCUS trial.

Patients with previously untreated advanced urothelial carcinoma were randomized 1:1 to receive 3 or 6 cycles of gemcitabine/cisplatin or gemcitabine/carboplatin, followed by maintenance avelumab. The dual primary endpoints were patient-reported outcomes (EORTC QLQ-C30 GHS/quality of life scale score; change in quality of life at cycle 6 of treatment versus baseline) and overall survival. Secondary endpoints included additional patient-reported outcomes analysis, progression-free survival, and safety. The trial design for DISCUS is as follows:

At ESMO 2025, Dr. Grande and colleagues presented the final patient-reported outcomes analysis and interim overall survival.

From a statistical analysis standpoint, a sample size of 224 evaluable patients (112/arm) was needed to detect a 9-point quality of life difference (alpha = 0.1, power = 80%). Planned analyses include a patient-reported outcome/interim overall survival analysis at 224 patients, and a final overall survival after 224 events in ~320 patients.

The time point collection of quality of life questionnaires is as follows: 

By August 25, 2025, a total of 267 patients were randomized (133 to the 3-cycle arm, 134 to the 6-cycle arm), with balanced baseline characteristics:

Overall, 42% received cisplatin/gemcitabine, and 78% and 40% of patients completed 3 and 6 cycles, respectively, as allocated. There were 74% of patients that received avelumab in the 3-cycle arm versus 56% in the 6-cycle arm. The mean quality of life change between baseline and cycle 6 was 0.0 (95% CI: -5.9, 5.2) in the 3 cycle arm versus -8.5 (95% CI: -14.1, -2.9) in the 6 cycle arm, with a clinically significant difference favoring the 3 cycle arm (+8.5 points, 95% CI: 0.7–16.3; p = 0.016):

Improvement in patient-reported outcomes scores was observed in 41% (3 cycles) versus 24% (6-cycle arm) of patients:

The mean change in global health status/quality of life based on EORTC QLQ-C30 over time from cycle 3 is highlighted in the following figure:

There was no difference between the groups for time to deterioration in global health status/quality of life based on EORTC QLQ-C30 (HR 0.81, 95% CI 0.46-1.43):

The median overall survival was 18.9 months in both arms (HR 1.15, 95% CI 0.72–1.86; p = 0.56):

The overall response rate was 24% in the 3-cycle arm versus 27% in the 6-cycle arm, with no significant difference between groups. The median progression-free survival was 8.0 months (95% CI 6.7–11.9) versus 9.0 months (95% CI 6.9–12.7), HR 1.05 (95% CI 0.73–1.53; p = 0.79), with the following figure highlighting progression-free survival by platinum-based chemotherapy regimen: 

Finally, grade 3–4 treatment-related adverse events occurred in 11.9% (the 3-cycle arm) versus 15.7% (the 6-cycle arm):

Dr. Grande concluded his presentation discussing DISCUS with the following take-home points:

• DISCUS achieved its patient-focused primary endpoint, showing improved patient-reported outcomes with shorter periods of platinum-based chemotherapy prior to maintenance avelumab
• The median progression-free survival in the 3-cycle arm and 6-cycle arm was 8 months versus 9 months, with a median overall survival of 18.9 months in both arms. 3 cycles of chemotherapy were not superior to 6 cycles, and non-inferiority cannot be claimed due to design limitations
• More patients in the 3-cycle arms went on to maintenance avelumab, which may facilitate long-term efficacy
• DISCUS highlights the feasibility of exploring shorter periods of systemic therapy in metastatic urothelial carcinoma, which is relevant in the era of antibody drug conjugate therapy in metastatic urothelial carcinoma and beyond

Presented by: Enrique Grande, MD, PhD, MSc, Associated Professor at Universidad Francisco de Vitoria, Quirónsalud Madrid, Madrid, Spain; Adjunct Professor , University of Texas, MD Anderson Cancer Center, Houston, TX

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 European Society of Medical Oncology (ESMO) Annual Meeting, Berlin, Germany, Fri, Oct 17 – Tues, Oct 2

References:

1. Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. doi: 10.1056/NEJMoa2312117. PMID: 38446675.
2. Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. doi: 10.1056/NEJMoa2002788. Epub 2020 Sep 18. PMID: 32945632.