There are few bladder-sparing treatment options for high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer that are effective and have a manageable adverse event profile. Cretostimogene grenadenorepvec (hereafter, cretostimogene) is an oncolytic immunotherapy with dual mechanisms of action—it replicates in and lyses cancer cells with retinoblastoma–E2F pathway alterations and amplifies the immune response. We evaluated the response and safety/tolerability of cretostimogene in patients with high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer.
BOND-003 Cohort C is a single-arm, international, phase 3 study done in 41 centres (community practices and academic centres) located in North America, Asia, and Australia. Sites were selected through a study team-led qualification process that evaluated feasibility, protocol alignment, operational capabilities, and regulatory readiness, as applicable. We enrolled patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0–2 and pathologically confirmed, high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer with carcinoma in situ, with or without resected high-grade Ta or T1 disease. Patients received intravesical cretostimogene (1 × 1012 viral particles per 0·8 mL per week) as 6-week induction followed by maintenance; re-induction was permitted for persistent disease at 3 months. The primary endpoint was centrally confirmed complete response at any time in patients who received at least one dose of cretostimogene and completed the 3-month assessment; safety was assessed in those who received at least one dose of cretostimogene. This trial is registered with ClinicalTrials.gov (NCT04452591) and is ongoing.
Between Oct 9, 2020, and Aug 3, 2023, 165 patients were assessed for eligibility; 115 patients were enrolled in the study and 112 received cretostimogene. 83 (74%) were male and 29 (26%) were female; median age was 74·0 years (IQR 68·5–79·5). As of June 23, 2025, after a median follow-up of 25·8 months (IQR 22·1–33·1), complete response at any time was observed in 83 (75% [95% CI 66·3–83·2]) of 110 patients. 71 (63%) of 112 patients had at least one treatment-related adverse event, the most common being bladder spasm in 28 (25%) patients, pollakiuria in 25 (22%) patients, and micturition urgency in 23 (21%) patients; there were no grade 3 or 4 treatment-related adverse events and no treatment-related discontinuations or deaths. Two (2%) patients had serious treatment-related adverse events (one non-infective cystitis and one urinary bladder haemorrhage, both grade 2).
Cretostimogene showed clinically meaningful anti-tumour response, with an adverse event profile characterised predominantly by low-grade, transient events. Cretostimogene shows promise as an innovative bladder-sparing treatment for high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer with carcinoma in situ.
CG Oncology
Commentary by Dr. Elisabeth Grobet-Jeandin
Beyond BCG unresponsiveness: The promise of oncolytic immunotherapy in non-muscle-invasive bladder cancer
The management of high-risk BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) remains a highly challenging scenario for urologists. Despite its substantial morbidity and potential impact on health-related quality of life (HRQoL), radical cystectomy (RC) is still the most oncologically effective option and the gold-standard treatment according to the EAU guidelines [1]. As many patients are unwilling or unfit to undergo surgery, several bladder-sparing agents have recently been evaluated in this setting, but none has emerged as a standard of care. Cretostimogene grenadenorepvec, investigated in the phase III single-arm BOND-003 Cohort C trial [2], is an oncolytic adenovirus that selectively replicates in and lyses tumor cells, while expressing GM-CSF to enhance the anti-tumour immune response.
In this international multicentre study, 112 patients with BCG-unresponsive carcinoma in situ (CIS), with or without high-grade Ta/T1 disease, were enrolled. The population included heavily pre-treated patients, with a median of 12 prior BCG instillations, and almost half (47%) had undergone at least one additional NMIBC-directed therapy. As in most trials in this setting, there was no control arm. Randomising patients between RC and a bladder-sparing strategy is notoriously difficult, previously illustrated by the SPARE trial which was closed early due to poor accrual [3]. Therefore, following results do not allow a direct comparison with the standard of care.
Nevertheless, the results are compelling. The trial met its primary endpoint, with a complete response (CR) at any time in 75% of patients, well above the prespecified 20% benchmark. Responses were durable: CR rates were 46% at 12 months and 42% at 24 months. Among responders, 64.2% and 60.1% remained disease-free at 12 and 24 months, respectively, with a median duration of response of 27.9 months. Cystectomy-free survival reached 89% at 12 months and 81% at 24 months, and progression to muscle-invasive disease was rare (four patients). Of the 18 patients who ultimately underwent RC, 83% had NMIBC or pT0 on final pathology, suggesting that the window for salvage RC was preserved in most cases. Tolerability also appeared favourable. Treatment-related adverse events occurred in 63% of patients, but all were grade 1-2, mainly bladder spasm (25%), pollakiuria (22%) and urgency (21%). The median time to resolution was one day, and there were no treatment-related discontinuations.
Beyond oncological efficacy and tolerability, preserving the bladder is undoubtedly an attractive goal, but at what cost? Heavily pre-treated bladders may be associated with storage and voiding dysfunction, and intravesical treatments require considerable patient commitment to both treatment and follow-up. As HRQoL data were not reported in this initial publication, the impact of this strategy on patients’ daily lives remains an open question.
Overall, BOND-003 Cohort C positions cretostimogene as a promising, well-tolerated bladder-sparing option for a difficult-to-treat population. Forthcoming HRQoL and long-term analyses will be key to defining its place in this rapidly evolving treatment landscape.
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