In the previous episode, we explored the clinical rationale and technical safeguards behind the expanded enrollment criteria of HOPE-02/03. In this installment, we place HOPE-02 within the broader landscape of perioperative and bladder-preservation research in muscle-invasive bladder cancer (MIBC) to better understand its position among contemporary global studies.In the era of chemo-immunotherapy combinations, three major studies have emerged, each representing a distinctly different therapeutic philosophy. Together with the INDI-BLADE study specifically highlighted by Professor Shen Yali during the program, these trials form a fascinating four-way comparison. Each pursues a different direction, while HOPE-02 appears to occupy a unique middle ground.
Expert Perspectives
Professor Zhang Peng:
“We want to show that neoadjuvant therapy itself can help identify the ideal candidates for bladder preservation. If a patient develops progressive disease, early surgery should still be strongly recommended.”
Professor Shen Yali:
“If radiotherapy is part of the strategy, then the focus should not be obsessing over cCR. What truly matters is bladder-intact event-free survival and overall survival.”
Professor Zhang Ruiyun:
“Four studies, four philosophies. HOPE-02 follows a uniquely balanced Chinese approach — finding radiotherapy as the middle ground between radical surgery and simple observation.”
Four Studies, Four Therapeutic Philosophies
If perioperative MIBC research in the chemo-immunotherapy era were viewed as a spectrum, these four studies would occupy distinct positions across it.
NIAGARA: The Most Conservative and Surgery-Centered Strategy
The NIAGARA trial combined gemcitabine-cisplatin (GC) chemotherapy with durvalumab as neoadjuvant therapy, followed by adjuvant durvalumab after radical cystectomy. Every patient was required to undergo radical bladder removal. Only cN0-1 patients were eligible, while cN+ patients were excluded.
The study demonstrated an event-free survival hazard ratio of 0.68, an overall survival hazard ratio of 0.75, and a pathological complete response (pCR) rate of 43%.
The core philosophy of NIAGARA is therapeutic intensification without changing the central role of surgery. It sought to improve surgical outcomes but did not attempt to identify patients who might safely avoid surgery altogether.
RETAIN-02: The Most Aggressive Organ-Preservation Strategy
RETAIN-02 adopted the opposite philosophy. Patients received nivolumab combined with dose-dense MVAC chemotherapy, followed by DDR gene sequencing evaluation involving ATM, RB1, and ERCC2 mutations together with TURBT assessment.
Patients who were DDR-positive and achieved clinical complete response (cCR) entered active surveillance without radiotherapy or additional local treatment.
Only cN0 patients were enrolled.
Results presented at ASCO GU 2026 showed that among 23 patients entering active surveillance, 12 experienced recurrence. Two-year metastasis-free survival approached 80%, yet ctDNA positivity was detected in only two patients, suggesting that neither DDR status nor ctDNA negativity reliably predicted durable local control.
RETAIN-02 represents a “subtraction strategy” — attempting to identify patients who might safely omit all local therapy. However, the stability and reproducibility of this approach remain uncertain.
INDI-BLADE: The Closest Comparator to HOPE
Professor Shen Yali specifically discussed the INDI-BLADE study, published in Nature Medicine in March 2025.
This study utilized induction dual immunotherapy with CTLA-4 and PD-1 inhibitors, followed by trimodality bladder-preservation therapy incorporating radiotherapy and chemotherapy.
The study enrolled cN0-N2 patients, with more than 60% classified as cT3 disease. Two-year bladder event-free survival approached 70%, while overall survival outcomes were similar to those reported in HOPE-02/03.
Professor Shen commented:
“INDI-BLADE is truly a radiotherapy-centered TMT strategy following induction therapy. It completely moved away from using cCR as the primary endpoint and instead focused directly on bladder-intact event-free survival. Every time I see this study, it feels very familiar to me.”
HOPE-02: A Dynamic Middle-Ground Strategy
HOPE-02 combined GC chemotherapy with tislelizumab as neoadjuvant therapy. Patients without progressive disease then proceeded to sequential radiotherapy as a bladder-preservation strategy.
Unlike the other studies, HOPE-02 enrolled the highest-risk population: cT2-4b and N0-3 disease.
Its reported outcomes included a three-year bladder-intact disease-free survival rate of 76% and a three-year overall survival rate of 81%.
The philosophy of HOPE-02 is dynamic balance. Patients first undergo response-based selection through neoadjuvant therapy. Those with progression are directed toward surgery, while non-progressive patients receive radiotherapy as a local control “safety net.” The strategy avoids both extremes — neither abandoning local therapy entirely nor insisting that every patient undergo cystectomy.
Why Was the Bar Higher for HOPE-02 Than for Any Other Study?
Professor Zhang Ruiyun emphasized that NIAGARA enrolled only cN0-1 patients, RETAIN-02 enrolled exclusively cN0 patients, while HOPE-02 included cN0-3 disease, including cN2-3 patients.
This means the HOPE-02 population was fundamentally higher risk than those in competing trials.
Despite this, HOPE-02 achieved an 81% three-year overall survival rate with four years of follow-up, making it highly distinctive among contemporary bladder-preservation studies.
Although direct cross-trial comparisons remain imperfect, these outcomes strongly suggest that the traditional boundaries of bladder preservation deserve re-evaluation.
Professor Zhang Peng: Neoadjuvant Therapy Is Itself a Selection Tool
Professor Zhang summarized the core clinical message of HOPE-02:
“HOPE-02 and HOPE-03 are fundamentally different from traditional TMT. Whether using chemo-immunotherapy or ADC-immunotherapy combinations, four cycles of neoadjuvant treatment already help identify the subgroup most suitable for bladder preservation. Patients with progressive disease should still be encouraged to undergo early surgery.”
Regarding the ongoing debate between cCR and pCR, he acknowledged the limitations directly:
“One of the biggest controversies today is that cCR does not necessarily equal pCR. Without performing radical cystectomy, we cannot truly confirm pCR. That’s why we explored urine-based and blood-based assessments. In HOPE-02 and HOPE-03, we eventually added sequential radiotherapy precisely to avoid the risks associated with simply observing patients after drug therapy alone, as in the RETAIN strategy, because recurrence rates remain relatively high.”
This concept — using neoadjuvant treatment response itself to identify candidates for organ preservation — represents the central hypothesis proposed by the HOPE series.
Distant Metastasis Remains the Major Challenge
In the data presented at ASCO GU 2025, only four progression events occurred in HOPE-02: one intravesical Tis recurrence and three distant metastases.
An important question emerged: were these distant metastases concentrated among the cN+ subgroup?
Professor Zhang responded candidly:
“These patients were all relatively advanced at baseline. Whether treated with radical surgery after neoadjuvant therapy or comprehensive combined therapy, their prognosis remains difficult. Given that only four events occurred during follow-up, I personally consider the results acceptable.”
Although the small number of events prevents meaningful subgroup analysis, the findings suggest that even after strong chemo-immunotherapy and radiotherapy achieve local control, systemic disease eradication in cN+ patients remains an unresolved challenge.
The impressive 81% three-year overall survival achieved in HOPE-02 was built upon a chemo-immunotherapy plus radiotherapy framework. However, for cN+ patients, future studies may need to explore even more intensive systemic strategies.
Key Takeaways
In the chemo-immunotherapy era, NIAGARA, RETAIN-02, INDI-BLADE, and HOPE-02 represent four distinct clinical philosophies ranging from mandatory surgery to pure observation.
HOPE-02 achieved an 81% three-year overall survival rate despite enrolling the highest-risk population, including cN+ patients, suggesting that the boundaries of bladder preservation deserve reconsideration.
Neoadjuvant therapy itself functions as a biological selection tool: patients with progressive disease proceed to surgery, while non-progressive patients receive sequential radiotherapy for bladder preservation.
Clinical complete response does not equal pathological complete response, but sequential radiotherapy may compensate for the uncertainty of cCR assessment by providing a local control safety net.
Distant metastasis remains the primary mode of treatment failure, particularly among cN+ patients, highlighting the need for stronger systemic therapeutic strategies in future HOPE-series investigations.
