(UroToday.com) The 2025 GU ASCO annual meeting featured a urothelial carcinoma trials in progress session and a presentation by Dr. Trinity Bivalacqua discussing CORE-008, a phase 2, multi-arm, multi-cohort, open-label study to evaluate intravesical cretostimogene grenadenorepvec in participants with high-risk non-muscle invasive bladder cancer. Treatment for patients with high-risk non-muscle invasive bladder cancer consists of TURBT followed by intravesical BCG. Despite high initial response rates, over 50% of patients will recur and 20-40% are at risk for progression. Treatment of high-risk non-muscle invasive bladder cancer is challenged by the BCG shortage, thus there exists a need for clinically effective, well-tolerated, and readily available treatment options for patients with high-risk non-muscle invasive bladder cancer. Cretostimogene grenadenorepvec is an oncolytic immunotherapy with a dual mechanism of action. It selectively replicates and lyses bladder cancer cells with Rb-E2F pathway alterations. The subsequent release of virus- and tumor- specific antigens initiate antitumor immune activation amplified by the GM-CSF transgene, a potent cytokine:
Cretostimogene received both Fast Track and Breakthrough Therapy Designations by the US FDA for the BCG-unresponsive high-risk non-muscle invasive bladder cancer with CIS indication. Given the strength of these data, the CORE-008 clinical trial was developed as a phase 2, multi-arm, multi-cohort trial to further evaluate the safety and efficacy of cretostimogene in patients with high-risk non-muscle invasive bladder cancer.
Eligibility criteria include pathologic confirmation of high-risk non-muscle invasive bladder cancer as defined by the AUA Guidelines. Cohort A (BCG-naive) is comprised of CIS +/- HG Ta/T1 participants who have not received prior BCG. Cohort B (BCG-exposed) will consist of CIS +/- HG Ta/T1 or papillary-only patients who have received prior BCG, and recurred either immediately after induction therapy (BCG-resistant) or recurred at a delayed time point, after adequate or inadequate BCG:
Intravesical cretostimogene will be instilled in combination with n-dodecyl-β-D-maltoside (DDM), an excipient, that enhances adenoviral delivery, for six weekly doses during the induction phase, followed by three weekly maintenance cycles quarterly through month 12, then every six months through month 36:
Cystoscopy and cytology will be performed every 3 months, with a mandatory biopsy at week 51. A CT or MRU will be performed every 6 months. Re-induction is allowed for patients with HG Ta and/or CIS at month 3 and treatment is optional in year 3. The primary endpoint for the CIS population is complete response at any time, and high-grade event-free survival is the primary endpoint for papillary-only participants. Secondary endpoints will include:
- Duration of response
- All-cause event-free survival
- Bladder cancer specific survival
- Radical cystectomy free survival
- Safety
Exploratory outcome measures include health-related quality of life, overall survival, and biomarker assessments. Additional high-risk non-muscle invasive bladder cancer cohorts are under development. Multiple clinical sites have been identified and Cohort B has received collaborative support from the Society of Urologic Oncology-Clinical Trials Consortium. Dr. Bivalacqua provided several key takeaways:
- CORE-008 is a phase 2, multi-arm, multi-cohort trial evaluating cretostimogene in patients with high risk NMIBC who are BCG-naïve or BCG-exposed
- Cretostimogene is an oncolytic immunotherapy with dual mechanism of action, with postulated innate to adaptive immune switching
- This is a potentially effective, well tolerated, and durable regimen, which easily fits within the existing clinical work flow
Presented by Trinity Bivalacqua, MD, Department of Urology, Hospitals of the University of Pennsylvania, Philadelphia, PA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.