Single-center phase 2 trial of risk-enabled therapy after neoadjuvant chemotherapy for muscle-invasive bladder cancer

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Mutations in DNA damage repair genes are associated with pathologic downstaging after NAC. The phase 2 RETAIN 1 study at Fox Chase Cancer Center (Philadelphia, PA) evaluated the hypothesis that a combination of biomarker selection and clinical staging would identify patients for cystectomy-sparing active surveillance (AS). The study included patients with cT2-T3N0M0 MIBC, who underwent NAC with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMC). Pre-NAC bladder tumor specimens were sequenced for mutations in ATM, ERCC2, FANCC, and RB1. Patients with at least one mutation and cT0 post-NAC began AS. Among 70 patients, 25 began per-protocol AS. The 2-year metastasis-free survival (MFS) rate was 72.9% among all patients, not reaching the primary end point. The MFS 76.0% (95% CI 54.2-88.4) in the AS group and 71.1% (55.5-82.1) in the remaining patients. With a median follow-up of 40 months, in the AS group 48% were metastasis-free with an intact bladder. The 2-year overall survival rate was 88.0% (95% CI 67.3-96.0) in the AS group and 82.2 (67.6-90.7) in the not-AS group. The authors conclude that patients with MIBC treated with AMVAC followed by a risk-adapted approach to local consolidation achieved a 2-year MFS rate of 72.9%; 17% of all patients and 48% of the AS group avoided cystectomy without metastatic disease.