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Biomarker-driven treatment for muscle-invasive bladder cancer (MIBC) led to a 2-year metastasis-free survival (MFS) rate that exceeded 70% in a phase II study, but failed to meet prespecified statistical constraints for a positive trial.

Median MFS was 72.9% for 70 patients, but the lower range of the confidence the intervals for that value was 62.8% versus a prespecified 64%. Patients assigned to active surveillance on the basis of tumor genomics had a 2-year MFS of 76%. After a median follow-up of 40 months almost half of patients on active surveillance remained metastasis free with an intact bladder, reported Daniel Geynisman, MD, of Fox Chase Cancer Center in Philadelphia, and colleagues in the .

Though the study missed the prespecified statistical boundaries, the biomarker-guided strategy showed enough promise to continue evaluating the approach to help more patients delay or avoid cystectomy, Geynisman said.

"The trial was negative but it was literally negative by about one patient, so we barely missed our primary endpoint of 2-year metastasis-free survival, which we set at a very conservative value," Geynisman told 番茄社区app. "It easily could have been set differently and it would have been a positive trial."

"But I think that the real key is we're sort of pioneering an approach of allowing patients with muscle-invasive bladder cancer to preserve their bladders if they have an excellent response [to neoadjuvant therapy]," he noted. "This is where the field is trying to go, and this is one of the first trials to do so."

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy has been a longstanding standard of care for MIBC. However, prospective studies have consistently shown that 35-40% of patients achieve pathologic complete response (pCR) after NAC, and pCR has a well-established association with favorable long-term survival.

Cystectomy carries a risk of serious postoperative complications and the need for life-altering urinary diversion, Geynisman's group noted. If pCR could be predicted before cystectomy, a subset of patients might be spared the procedure or chemoradiotherapy (CRT) without compromising oncologic outcomes.

Retrospective series have shown that select patients without clinical evidence of urothelial carcinoma after NAC and who decline cystectomy have a disease-specific survival of about 90% and a rate exceeding 70%. Collaborative work by Geynisman and colleagues have shown that genomic mutations in DNA repair pathways predict response to cisplatin-based chemotherapy. Specifically, mutations in one or more of , and are associated with pathologic response or pCR at the time of cystectomy and predict improved progression-free (PFS) and overall survival (OS).

To evaluate biomarker-guided therapy after NAC for MIBC, investigators designed the phase II RETAIN 1 trial. They enrolled 70 patients with newly diagnosed cT2-3N0M0 MIBC, all of whom received cisplatin-based NAC. Prior to NAC, tumor specimens were sequenced for mutations of interest, and patients with at least one mutation, and who were cT0 after NAC, were assigned to active surveillance. All other patients were counseled to undergo cystectomy, CRT, or intravesical therapy.

The primary endpoint was MFS at 2 years from the first dose of NAC in the intention-to-treat population. Key secondary endpoints included cancer recurrence in the active surveillance cohort, OS, toxicity, and proportion of patients requiring cystectomy.

Genomic analysis results showed that 33 (47%) patients had at least one mutation and achieved cT0 status after NAC, and 25 (36%) of them opted for active surveillance. The remaining 37 patients had no mutation of interest. Two opted for active surveillance off protocol after achieving cT0 status with NAC.

Eight patients in the active surveillance group remained metastasis free during follow-up, and 17 had some form of non-metastatic recurrence, which was treated with intravesical therapy in four cases, CRT in two, cystectomy in eight, and/or systemic therapy in seven. At last follow-up, 12 (48%) of the 25 patients remained metastasis free with an intact and non-irradiated bladder. The 2-year OS was 84.3% in all patients, 88% in the active surveillance subgroup, and 82.2% in the remaining patients.

Investigators did not observe any statistically significant associations between the presence of specific mutations and MFS or recurrence. They also saw no significant association between pathogenic or variant of unknown significance mutation status and recurrence.

"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."

At a recent international consensus conference, leaders in the field established guidelines for moving forward with trials that use biomarker-guided treatment strategies post-NAC, said Geynisman Recommendations, which will be published in the near future, are aimed at refining the approach, potentially including immunotherapy after chemotherapy or in combination and incorporating circulating tumor DNA and MRI to "home in on and select the best of the best, so we don't have people on active surveillance who have microscopic disease," he said.

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