How should ctDNA guide adjuvant therapy after perioperative EV?

The phase 3 VOLGA trial (NCT04960709), presented at the 2026 European Society for Medical Oncology Congress, tested perioperative durvalumab-based regimens with neoadjuvant-only enfortumab vedotin-ejfv (EV, Padcev) in patients with muscle-invasive bladder cancer who were ineligible for or declined cisplatin.¹ Both experimental arms gave 3 neoadjuvant cycles before surgery and no EV afterward; adjuvant durvalumab (Imfinzi), with a tremelimumab (Imjudo) dose in 1 arm, continued to complete 1 year, compared with surgery alone.²

The VOLGA data were among the topics in this Urology Times On Location filming hosted by Chandler Park, MD, MSc, FACP.

For Alexandra Drakaki, MD, PhD, the trial’s leading enroller, the key advantage was what patients avoided. After cystectomy, patients were still recovering and adapting to urinary changes, and omitting adjuvant EV spared them added neuropathy, hair loss, fatigue, and rash. Neuropathy often improved once EV stopped but could become permanent with continued dosing, and motor effects such as foot drop deserved as much attention as sensory symptoms.

“So giving less in the adjuvant doesn’t mean you’re compromising their care. And I think that’s a very important message that we need to pass on,” Drakaki said. She obtained circulating tumor DNA (ctDNA) at baseline and every 3 months, using conversion from positive to negative as a marker of treatment effect.

Guru P. Sonpavde, MD, called VOLGA positive, with HRs in the same range as EV plus pembrolizumab and less neuropathy, although he cautioned that cross-trial comparisons were hazardous. He continued to use EV plus pembrolizumab (Keytruda) in cisplatin-ineligible patients, citing what he considered more robust hazard ratios for event-free and overall survival. He omitted adjuvant EV for patients with a pathologic complete response (pCR) or treatment-limiting neuropathy but avoided routine omission, because complete responses in metastatic disease took longer to develop.

“There is some risk that if you omit the adjuvant EV routinely in everybody, you’re going to compromise some of the depth of response, especially in the non-pCR patients,” Sonpavde said.

Applying ctDNA after perioperative immunotherapy remained uncertain, because IMvigor011 (NCT04660344) data came from patients who had not received prior immunotherapy; the ongoing MODERN trial was expected to address ctDNA-guided adjuvant therapy. No biomarker—including molecular subtype, nectin-4 expression, or tumor mutational burden—yet justified withholding EV plus pembrolizumab. For variant histology with a urothelial component, Sonpavde would not deny EV plus pembrolizumab, although small cell neuroendocrine tumors warranted a platinum-based regimen with a checkpoint inhibitor, and plasmacytoid disease tended to spread along peritoneal and pleural surfaces, prompting his use of PET for baseline staging.

The negative ENERGIZE trial (NCT03661320) of nivolumab plus neoadjuvant chemotherapy, in which he participated, remained difficult to explain given a control-arm pCR rate similar to NIAGARA’s (NCT03732677), although its ctDNA findings were prognostic. He was most enthusiastic about V940, an individualized mRNA neoantigen therapy under study in a randomized phase 2 adjuvant trial with pembrolizumab.

REFERENCES

1. Powles T, Grande E, Simone G, et al. Perioperative durvalumab with or without tremelimumab plus neoadjuvant enfortumab vedotin in muscle-invasive bladder cancer: results from the phase 3 VOLGA trial. Presented at: European Society for Medical Oncology Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract LBA2. https://cslide.ctimeetingtech.com/esmo2026/attendee/confcal/show/session/346

2. Powles T, Grande E, Simone G, et al. Durvalumab, tremelimumab, and enfortumab vedotin in muscle-invasive bladder cancer. N Engl J Med. Published online October 24, 2026. Accessed October 24, 2026. https://www.nejm.org/doi/full/10.1056/NEJMoa2608323

3. Vulsteke C, Adra N, Danchaivijitr P, et al. Perioperative enfortumab vedotin and pembrolizumab in bladder cancer. N Engl J Med. 2026;394(13):1257-1269. doi:10.1056/NEJMoa2511674

4. Clarke H. Perioperative durvalumab plus enfortumab vedotin improves EFS in cisplatin-ineligible MIBC. Urology Times. May 14, 2026. Accessed October 26, 2026. https://www.urologytimes.com/view/perioperative-durvalumab-plus-enfortumab-vedotin-improves-efs-in-cisplatin-ineligible-mibc