Treatment of Metastatic Urothelial Carcinoma After Previous Cisplatin-based Chemotherapy for Localized Disease: A Retrospective Comparison of Different Chemotherapy Regimens.

BACKGROUND: Optimal chemotherapy for patients who received cisplatin for localized urothelial carcinoma (UC) and develop metastatic disease is unclear. We compared the efficacy of platinum-based (PBC) versus non-platinum-based (NPBC) first-line chemotherapy for metastasis. PATIENTS AND METHODS: Data were collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database of 3024 patients from 28 international academic centers from 2005 to 2012. Patient inclusion criteria included: (1) predominant UC; (2) any primary tumor site; (3) cT2-4, cN0-N2, cM0; (4) prior receipt of perioperative/radiation cisplatin-containing chemotherapy; and (5) receipt of cytotoxic chemotherapy in the first-line metastatic setting. Multivariate Cox proportional hazards models were used to show progression-free survival (PFS) and overall survival (OS) from the first day of chemotherapy for metastatic disease to date of censor. RESULTS: Eligibility criteria was met by 132 patients (n = 74 PBC; n = 58 NPBC). The median OS was 8.13 months (interquartile range, 4.87-16.64 months) and 8.77 months (interquartile range, 4.01-13.49 months) for PBC and NPBC, respectively. Neither OS (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.64-1.69; P = .87) nor PFS (HR, 0.86; 95% CI, 0.56-1.31; P = .48) differed for PBC versus NPBC. However, for patients who received chemotherapy more than a year after perioperative/radiation chemotherapy, OS was superior for PBC over NPBC (HR, 0.31; 95% CI, 0.10-0.92; P = .03). CONCLUSIONS: There is no significant outcome difference between PBC and NPBC in patients with metastatic UC who previously received cisplatin-based chemotherapy for localized disease. However, if over a year has elapsed, return to PBC is associated with superior OS.

ENERGIZE: a Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer.

Immune checkpoint inhibitors have revolutionized the treatment of patients with metastatic urothelial carcinoma. In cisplatin-eligible muscle-invasive bladder cancer (MIBC), cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy improves overall survival. Tumor PD-L1 expression increases in MIBC after NAC, suggesting potential synergy in combining PD1/PD-L1 inhibitors with NAC. IDO1 is overexpressed in bladder cancer and is associated with poor outcomes. Linrodostat mesylate (BMS-986205) - a selective, potent, oral IDO1 inhibitor - combined with nivolumab has demonstrated safety and preliminary evidence of clinical activity in metastatic urothelial carcinoma. Here, we discuss the rationale and trial design of the ENERGIZE, a Phase III trial investigating the efficacy of NAC in combination with nivolumab with or without linrodostat followed by postsurgery nivolumab or nivolumab with linrodostat in cisplatin-eligible patients with MIBC. Clinical trial registration number: NCT03661320.