BAYOU: Phase II study of efficacy and safety of durvalumab plus olaparib as first-line therapy in cisplatin-ineligible patients (pts) with stage iv urothelial cancer (UC)

Abstract

Background: UC is platinum‐responsive and hypothesized to be sensitive to targeted DNA‐damaging agents such as PARP inhibitors (PARPi). Cisplatin (cis)‐ineligible pts with metastatic/unresectable primary UC have limited effective treatment options. Immune checkpoint blockade may increase the proportion of pts that respond to PARPi. Durvalumab is a selective, high‐affinity, engineered, human IgG1 monoclonal Ab that blocks PD‐L1 binding to PD‐1 and CD80. In UC, the combination of olaparib (a PARPi) + durvalumab may broaden the therapeutic effect of monotherapy given their different mechanisms of action, with potentially enhanced benefit for pts with metastatic/unresectable UC and DNA repair deficiencies (mutations in homologous recombination repair genes [HRRm]). Trial design: BAYOU is a double‐blind, randomized, placebo‐controlled, multicenter phase 2 study designed to assess the efficacy and safety of durvalumab + olaparib vs durvalumab +placebo in cis‐ineligible pts with stage IV UC. Adult pts (≥18 years) who are cis‐ineligible with histologically/cytologically confirmed unresectable stage IV UC,WHOperformance status 0‐2, and with known HRRm status will be enrolled. Pts with active/prior autoimmune disorders, brain metastases, prior PARPi/immune therapy, current/prior immunosuppressive agents, non‐UC invasive malignancies, and concomitant use of strong CYP3A inhibitors/inducers are excluded. All pts will be randomized (1:1) to durvalumab (1500 mg intravenous, every 4 weeks)+ placebo or durvalumab +olaparib (tablet) until disease progression. Olaparib dose will be 300 mg twice daily in pts with CrCl 50 mL/min and 200 mg twice daily in pts with CrCl ≥31 to≤50 mL/min. The primary endpoint is progression‐free survival in HRRm patients (investigator assessed, RECIST v1.1). Secondary endpoints are overall survival (OS), duration of response, objective response rate, proportion of pts alive and progression free at 6 months, and OS at 18 months. Safety, pharmacokinetics, and immunogenicity will also be assessed. The trial is currently enrolling pts.