Updated 5-year Survival Results from PURE-01, a Phase 2 Study of Neoadjuvant Pembrolizumab Followed by Radical Cystectomy in Patients with Muscle-invasive Bladder Cancer - Beyond the Abstract
In this context of therapeutic intensification, improving survival must go hand in hand with preserving quality of life and treatment tolerability, including efforts to potentially reduce the central role of radical surgery in favor of bladder preservation strategies. The growing biological awareness that MIBC is not a single disease but rather a collection of distinct molecular entities makes it increasingly unrealistic to assume that one treatment strategy can fit all patients. Some individuals may derive profound benefit from specific systemic therapies, others may be undertreated, and others still may be exposed to unnecessary overtreatment.
The final analysis of PURE-01, a phase II, single-arm, single-center study that pioneered neoadjuvant ICIs in MIBC using three preoperative cycles of pembrolizumab in 155 patients, provides compelling evidence of the sustained efficacy of a low-toxicity, chemotherapy-free regimen. At a median follow-up exceeding five years, event-free survival and overall survival rates were 68% and 77%, respectively. Notably, patients with tumors classified as claudin-low achieved excellent outcomes. This molecular subtype, characterized by high immune-related signature expression, showed relapse-free and overall survival rates exceeding 90% at five years. Another key finding from PURE-01 is the robust association between pathological response and long-term survival. Pathological complete response (ypT0) or major response (ypT <2) were confirmed to be strong surrogates of systemic disease control, with approximately 90% of such patients alive at five years. In contrast, outcomes deteriorated markedly among non-responders, reinforcing the prognostic value of post-neoadjuvant pathological staging. The cumulative risk of recurrence in the overall population was relatively low (19% at five years) and dropped to approximately 5% among patients achieving complete response.
Two additional observations from PURE-01 deserve particular attention. First, eight patients refused radical cystectomy after neoadjuvant pembrolizumab and underwent repeat transurethral resection. Remarkably, seven of these patients remain alive and disease-free at long-term follow-up, with only one late relapse consisting of a solitary brain metastasis occurring more than six years after treatment. This suggests that, in selected patients, bladder-sparing strategies may be feasible, and initial signals in this direction have already emerged from phase II studies such as HCRN GU 16-257, RETAIN-1, and RETAIN-2. However, at present, bladder-preserving approaches remain investigational. Second, among the 31 relapses observed in the entire cohort, three occurred beyond five years after surgery, suggesting that patterns of recurrence following immunotherapy may differ from those historically seen after chemotherapy and may require prolonged surveillance strategies.
Placing PURE-01 in the current therapeutic landscape is inevitably complex. High-level evidence from randomized phase III trials cannot be directly compared with a single-center phase II experience. Nevertheless, PURE-01 demonstrates that a low-intensity, chemotherapy-free approach can achieve long-term survival outcomes comparable to more toxic regimens, at least in selected molecular subsets. This reinforces the urgent need for robust biomarker-driven strategies to individualize perioperative treatment in MIBC, with the ultimate goal of maximizing cure while minimizing unnecessary toxicity.
Written by: Valentina Tateo, MD, Genitourinary Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy
Read the Abstract