A phase II study, RETAIN 1, revealed that biomarker-driven treatment for muscle-invasive bladder cancer (MIBC) resulted in a 2-year metastasis-free survival (MFS) rate above 70%. While the trial narrowly missed its prespecified statistical endpoint, the results suggest a promising avenue for bladder preservation in select patients. The research, led by Daniel Geynisman, MD, of Fox Chase Cancer Center, was published in the Journal of Clinical Oncology.
RETAIN 1 Trial Details
The RETAIN 1 trial enrolled 70 patients with newly diagnosed cT2-3N0M0 MIBC, all of whom received cisplatin-based neoadjuvant chemotherapy (NAC). Tumor specimens were sequenced for mutations of interest prior to NAC. Patients with at least one mutation who achieved cT0 status after NAC were assigned to active surveillance. The primary endpoint was MFS at 2 years from the first dose of NAC.
Key Findings
Median MFS was 72.9% in the study population. Among patients assigned to active surveillance based on tumor genomics, the 2-year MFS was 76%. After a median follow-up of 40 months, nearly half of the patients on active surveillance remained metastasis-free with an intact bladder. Genomic analysis showed that 33 (47%) patients had at least one mutation and achieved cT0 status after NAC, with 25 (36%) opting for active surveillance.
Eight patients in the active surveillance group remained metastasis-free during follow-up, while 17 experienced some form of non-metastatic recurrence, treated with various modalities. At the last follow-up, 12 (48%) of the 25 patients remained metastasis-free with an intact and non-irradiated bladder. The 2-year overall survival (OS) was 84.3% in all patients.
Clinical Significance
Cisplatin-based NAC followed by cystectomy has been a standard of care for MIBC. However, a significant proportion of patients achieve pathologic complete response (pCR) after NAC, which is associated with favorable long-term survival. Cystectomy carries risks of complications and the need for urinary diversion. Identifying patients who achieve pCR before cystectomy could spare them the procedure without compromising oncologic outcomes.
"So [in] 12 of 70 patients, we were able to preserve their bladder without radiation, without surgery, even though they had muscle-invasive bladder cancer," said Geynisman. "That's really the key point. If you look at the 2-year metastasis-free survival and overall survival, it is totally on par with large trials that mandated surgery. So we're getting the same ultimate endpoint, it seems, but we're helping people preserve their bladder."
Biomarkers and Treatment Response
Previous research has indicated that genomic mutations in DNA repair pathways predict response to cisplatin-based chemotherapy. Specifically, mutations in ATM, RB1, FANCC, and ERCC2 are associated with pathologic response or pCR and predict improved progression-free and overall survival.
Future Directions
Recommendations from a recent international consensus conference aim to refine biomarker-guided treatment strategies post-NAC, potentially including immunotherapy and incorporating circulating tumor DNA and MRI to improve patient selection for active surveillance.
