Intravesical cretostimogene grenadenorepvec (CG0070) monotherapy demonstrated a high overall complete response rate in patients with high-risk, bacillus Calmette-Guérin (BCG)-naive non–muscle-invasive bladder cancer with carcinoma in situ, according to early results from Cohort A of the phase II CORE-008 trial. The findings, presented at the 26th Annual Meeting of the Society of Urologic Oncology (SUO), highlight a promising new treatment option in a disease space challenged by BCG shortages and the need for effective first-line alternatives.¹

Cretostimogene grenadenorepvec is a conditionally replicating oncolytic adenovirus designed with a dual mechanism of action: it selectively replicates in tumor cells with RB pathway dysfunction, leading to direct tumor cell lysis; and it expresses granulocyte-macrophage colony-stimulating factor to stimulate dendritic cell activation and prime tumor-specific immunity. This unique approach aims to elicit a potent antitumor response while being well tolerated.

Promising Impact in BCG-Naive Bladder Cancer

The study reported strong initial efficacy, with an 83.7% overall complete response rate at any time, coupled with an excellent safety and tolerability profile. These findings suggest cretostimogene grenadenorepvec could significantly impact the management of patients with high-risk non–muscle-invasive bladder cancer who have not yet received BCG.

“Intravesical cretostimogene grenadenorepvec monotherapy showed consistent efficacy, safety, and tolerability in [patients with BCG-naive high-risk non–muscle-invasive bladder cancer with carcinoma in situ],” said Trinity Bivalacqua, MD, PhD, Director of Urologic Oncology, and Co-Director of the Genitourinary Cancer Service Line at the Abramson Cancer Center, and Professor of Surgery at the Hospital of the University of Pennsylvania. “The optimized administration protocol appears equally as effective and tolerable as the original five-step approach, aligning well with current urology workflows for intravesical, bladder-sparing treatment without systemic toxicities.”

As Dr. Bivalacqua explained, high-risk non–muscle-invasive bladder cancer, particularly with carcinoma in situ, is a challenging condition with a high risk of recurrence and progression. Guidelines currently recommend intravesical BCG or radical cystectomy. While BCG demonstrates strong initial efficacy, historical data report over 50% of patients treated with it experiencing recurrence and 20% to 40% at risk for progression. Furthermore, approximately 70% of patients experience side effects from BCG, leading to treatment discontinuation.

“The ongoing BCG shortages exacerbate this problem, creating a critical unmet need for effective initial intravesical treatments for patients who are BCG-naive,” said Dr. Bivalacqua, who noted that radical cystectomy, while definitive, carries risks of postoperative complications and impacts quality of life.

CORE-008 Study Design

The CORE-008 study is a phase II, multi-cohort, multicenter trial evaluating cretostimogene grenadenorepvec in high-risk non–muscle-invasive bladder cancer. The data presented at the SUO meeting focused on Cohort A, which specifically enrolled patients classified as BCG-naive.

BCG-naive status was defined as no prior BCG intravesical treatment, BCG received more than 24 months ago, or a maximum of one to two doses within the past 24 months of current diagnosis. The presented results specifically pertain to patients with carcinoma in situ–only disease within this cohort. The primary endpoint for Cohort A was complete response at any time. The study allowed for reinduction at month 3 for patients with high-grade Ta and/or carcinoma in situ who experienced disease recurrence.

Patients were randomly assigned 1:1 to either the original five-step protocol (Arm 1), which included a series of bladder saline washes followed by dodecyl maltoside (DDM) and cretostimogene instillations, or an optimized two-step protocol (Arm 2), which streamlined the process to two steps inclusive of DDM followed by cretostimogene instillations. Cystoscopy and cytology were performed every 3 months, with mandatory mapping biopsies at 12 months. Computed tomography and magnetic resonance urography imaging were required every 6 months, and treatment was optional in year 3.

The patient demographics and baseline characteristics showed a well-balanced cohort. Of the 54 patients in the safety dataset, the majority were male (90.7%), White (92.6%), and older (88.8% were ≥ 65 years of age, with a median age of 73.5 years). All patients enrolled were from the United States. Eastern Cooperative Oncology Group (ECOG) performance status was 0 for 81.5% of patients and 1 for 18.5%. All patients had carcinoma in situ, with 44.4% having carcinoma in situ alone, 31.5% having carcinoma in situ with high-grade Ta, and 24.1% having carcinoma in situ with high-grade T1 disease. The majority (87.0%) had no prior BCG exposure.

High Initial Complete Response Rates With Favorable Safety Profile

Dr. Bivalacqua reported a high initial response rate, with an 83.7% overall complete response rate at any time in the carcinoma in situ–only cohort (n = 49 efficacy-evaluable patients). When stratified by administration protocol, the complete response rate was 79.2% (19 of 24 patients) for the original administration and 88.0% (22 of 25 patients) for the optimized administration, indicating similar efficacy between the two approaches. The median follow-up for the trial was 4.6 months.

No patients required radical cystectomy, and there were no treatment-related progressions to muscle-invasive bladder cancer or metastatic urothelial carcinoma. Three patients experienced non–muscle-invasive bladder cancer stage reclassification. The consistent treatment effect was observed across various patient subgroups, with no significant differences in complete response rates based on clinical factors such as age, sex, BCG history, prior adjuvant intravesical chemotherapy history, or ECOG performance status.

“The safety and tolerability profile was excellent, confirming cretostimogene grenadenorepvec as a well-tolerated therapy,” said Dr. Bivalacqua. “There were no grade 3 treatment-related adverse events, no serious treatment-related adverse events, no treatment-related discontinuations, and no deaths were reported.”

Fifty-three out of 54 patients (98.1%) completed all protocol-defined treatments. Common treatment-related adverse events (reported in > 10% of patients) included bladder spasm (24.1%), dysuria (20.4%), pollakiuria (14.8%), hematuria (14.8%), and fatigue (14.8%), all of which were grade 1 or 2.

“These promising results support the continued development of cretostimogene grenadenorepvec across [non–muscle-invasive bladder cancer] disease states, and additional treatment arms are planned for high-risk BCG-naive [non–muscle-invasive bladder cancer],” Dr. Bivalacqua concluded. “There is an ongoing shortage of BCG that we’ll hopefully be able to address in the future. In the meantime, we need to be considering additional intravesical agents for patients with high-risk non–muscle-invasive bladder cancer that have not been exposed to BCG.”

Disclosure: Dr. Bivalacqua reported financial interests with AUA Care Foundation, CG Oncology, Ferring Pharmaceuticals, UroGen, and Pfizer; and is the co-founder of OncoSTING, LLC.

Reference

1. Bivalacqua TJ: First results from CORE-008 cohort A: Phase 2 study of intravesical cretostimogene grenadenorepvec in patients with high-risk BCG-naïve NMIBC. 26th Annual Meeting of the Society of Urologic Oncology. Presented December 5, 2025.