Neoadjuvant Durvalumab Plus Chemotherapy Shows Promise in Upper Tract Urothelial Carcinoma

A phase II study investigating the use of neoadjuvant durvalumab in combination with chemotherapy has demonstrated encouraging pathologic response rates and a favorable safety profile for patients with high-risk, operable upper tract urothelial carcinoma (UTUC). The results, presented by Nadine Houde, MD, of Institut de Cancérologie du Gard at Montpellier University during the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, suggest that adding immunotherapy to neoadjuvant chemotherapy may improve treatment outcomes for patients with this aggressive malignancy.

Patients undergoing radical nephroureterectomy (RNU) for UTUC often face poor long-term outcomes, with high recurrence rates and limited postsurgical treatment options. Although platinum-based chemotherapy is a standard neoadjuvant approach, not all patients can tolerate cisplatin due to its nephrotoxicity. The addition of checkpoint inhibitors, such as durvalumab, has demonstrated survival benefits for patients with other urothelial cancers, prompting researchers to evaluate its role in the neoadjuvant setting for UTUC.

The trial was conducted at 10 centers in France and aimed to assess the efficacy and safety of combining durvalumab with platinum-based chemotherapy for patients with high-risk, nonmetastatic UTUC. The primary objective was to determine the rate of pathologic complete response (pCR), defined as the absence of residual tumor (ypT0) after surgery.

The trial enrolled 50 patients between 2021 and 2023, with a median age of 66 years (range, 38–79), and 58% were male. Most patients (90%) completed the planned four cycles of therapy, although a few required modifications, including switching from cisplatin to carboplatin due to toxicity. Patients were divided into two cohorts based on renal function: cohort 1 included 31 patients who received durvalumab with gemcitabine and cisplatin, and cohort 2 included 19 patients who received durvalumab with gemcitabine and carboplatin. All participants received treatment every three weeks for four cycles before RNU. The study’s primary endpoint was the pCR rate (ypT0), and secondary endpoints included the rate of non-infiltrative residual tumors, safety, and tolerability.

Among patients in cohort 1, 13% (4 of 31) achieved a pathologic complete response (ypT0), and in cohort 2, 5% (1 of 19) reached this benchmark. In addition, 65% of patients in cohort 1 and 42% in cohort 2 had only non-infiltrative residual disease at the time of surgery, indicating a significant tumor response to treatment.

In terms of safety, the combination of durvalumab with chemotherapy demonstrated a manageable toxicity profile, with no immune-related adverse events reported. The most common toxicities were hematologic, including grade 3 neutropenia in two patients, grade 4 neutropenia in one patient, grade 3 thrombocytopenia in one patient, and grade 3 anemia in one patient. Notably, the combination therapy did not increase surgical risk, supporting its feasibility for this patient population.

Implications and Future Directions

The study’s findings suggest that adding durvalumab to neoadjuvant chemotherapy, particularly cisplatin-based regimens, can induce significant pathologic responses in patients with UTUC while maintaining a manageable safety profile. The higher rate of non-infiltrative residual disease in the cisplatin-treated cohort suggests that platinum sensitivity may play a crucial role in determining response to immunotherapy combinations.

Given these promising results, researchers plan to validate these findings in a randomized phase III trial, iNDUCT-3, which will compare neoadjuvant chemotherapy alone with chemotherapy plus durvalumab in patients with high-risk localized UTUC.