Lymph node metastasis as a favorable prognostic factor in metastatic urothelial carcinoma with histological variants treated with pembrolizumab: a retrospective multicentric study (YUSHIMA study-04).

[BACKGROUND] Histological variants (HV) are associated with aggressiveness in urothelial carcinoma (UC). Although immune checkpoint inhibitor (ICI) therapy has improved the prognosis of patients with metastatic UC with HV (HV-UC), the factors determining the prognosis of these patients following ICI therapy remain unclear.

[METHODS] The present, retrospective, multicentric study (YUSHIMA study-04) included patients with histologically confirmed metastatic UC who received pembrolizumab as a second-line or later therapy between January 2018 and June 2023. The primary endpoint was the assessment of differences in prognostic factors of progression-free survival (PFS) and overall survival (OS) in patients with HV-UC and those with pure UC (pUC).

[RESULTS] The study cohort consisted of 61 and 331 patients with HV-UC and pUC, respectively, having comparable PFS and OS. The presence of lymph node metastasis (LNM) was independently associated with longer PFS (multivariable hazard ratio [mHR]: 0.35; P = .02) and OS (mHR: 0.25; P = .002) in the HV-UC group but was not in the pUC group (univariate HR: 1.10; P = .54 and HR: 1.05; P = .76, respectively). When the prognosis of the groups was compared by LNM status, a subpopulation of patients without LNM in the HV-UC group had significantly shorter PFS (P = .003) and OS (P = .008).

[CONCLUSIONS] The presence of LNM may be a HV-UC-specific prognostic factor of a favorable outcome in patients with mUC receiving pembrolizumab as second-line or later therapy.