How Phase 3 Trials Are Reshaping Perioperative MIBC Regimen Selection

Welcome to this Urology Times^® Insights program. In this segment, Roger Li, MD, a urologic oncologist in the Genitourinary Oncology Program at Moffitt Cancer Center in Tampa, Florida, discusses the phase 3 evidence reshaping perioperative care for muscle-invasive bladder cancer (MIBC).

Li explains that the move away from the traditional chemotherapy-based paradigm rests on efficacy, noting that the NIAGARA (NCT03732677), KEYNOTE-905 (NCT03924895), and KEYNOTE-B15 (NCT04700124) trials have produced unprecedented pathologic complete response (pCR), event-free survival (EFS), and overall survival (OS) results.

He describes NIAGARA, which added perioperative durvalumab (Imfinzi) to neoadjuvant gemcitabine-cisplatin, as transformative at the time of its reporting: the first trial to improve outcomes vs chemotherapy, by a degree similar to that reported more than 20 years ago in SWOG S8710. With little added toxicity, he says, it was readily adopted.

In KEYNOTE-905, Li highlights a pCR rate of just under 60% and low HRs for EFS and OS with perioperative enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda), calling adoption “a no-brainer” for cisplatin-ineligible patients whose only prior option was upfront radical cystectomy. He says KEYNOTE-B15 showed efficacy that superseded chemotherapy and, in indirect comparison, exceeded NIAGARA, making the enfortumab vedotin–pembrolizumab sandwich regimen today's standard of care regardless of cisplatin eligibility.

For VOLGA (NCT04960709), Li said he will be looking at EFS, OS, and pCR, and especially whether omitting adjuvant enfortumab vedotin, which lowers toxicity, affects long-term outcomes compared with KEYNOTE-B15. He also points to the correlation between circulating tumor DNA (ctDNA) and survival after cystectomy.

Finally, Li notes that many urologists still take cisplatin-ineligible patients to upfront cystectomy. He cites a multi-institutional study in which median OS for these patients was just over 1 year, adding that comorbidities mean systemic treatment may sometimes prolong life more than surgery alone.

In the next segment, Li explains where patients are lost between diagnosis and medical oncology and how referral relationships can shorten the time to treatment.