(UroToday.com) The 2023 Society of Urologic Oncology (SUO) annual meeting held in Washington, D.C. between November 28th and December 1st, 2023, was host to a poster/abstract session. Dr. Sandip Prasad presented the results of the recently published phase 3 ATLAS trial comparing primary chemoablation with UGN 102 ± TURBT versus TURBT monotherapy in patients with low-grade, intermediate-risk non-muscle invasive bladder cancer (NMIBC).
Patients with low-grade, intermediate-risk NMIBC are at low risk of disease progression; however, disease recurrence is common and occurs in >50% of patients requiring repeated TURBT. This procedure commonly requires general anesthesia, utilizes healthcare resources, and may increase patient morbidity and mortality. Furthermore, while clinical guidelines recommend adjuvant therapy in the post-TURBT setting to reduce disease recurrence and, potentially, disease progression, compliance with such practices remains low. As such, there is a clear need for primary non-surgical chemoablative treatment options for such patients with low-grade, intermediate-risk NMIBC.
UGN-102 is an investigational drug consisting of mitomycin-C combined with a proprietary reverse thermal hydrogel used to reconstitute mitomycin prior to instillation. The reverse thermal properties of UGN-102 allow for the local administration of mitomycin as a liquid in a cooled state, with subsequent conversion to a semi-solid gel depot at body temperature post-instillation. The gel slowly disintegrates and is subsequently eliminated by voiding, allowing for the sustained release of mitomycin over four to six hours. The prolonged exposure of tumor cells to mitomycin is hypothesized to improve chemoablation compared with aqueous preparations of the drug. This drug is administered intravesically once weekly for 6 weeks.
In the phase 2b, open-label, single-arm, multicenter OPTIMA II trial of UGN-102 primary chemoablation in patients with biopsy-proven low-grade intermediate-risk NMIBC, UGN-102 was associated with a 65% complete response rate at 3 months, with 61% of patients remaining disease-free 12 months following treatment initiation.1 Patients who completed OPTIMA II and participated in a rollover study had a 24.4-month median duration of response.2
ATLAS is a prospective, phase 3, randomized, open-label trial that randomized patients with newly diagnosed or recurrent low-grade, intermediate risk NMIBC in a 1:1 fashion to either UGN-102 +/- TURBT or TURBT alone (no adjuvant therapy). Eligible patients were those diagnosed via cold cup biopsy, with visible tumor left in situ, and had a voiding cytology negative for high-grade disease. Intermediate-risk disease was defined as having one or two of the following three risk factors:
- Presence of multiple tumors
- Solitary tumor >3 cm
- Recurrence (≥1 occurrence of low-grade NMIBC within one year of the qualifying diagnosis)
Patients in the UGN-102 arm of ATLAS received six weekly intravesical instillations. Patients in this arm with a complete response at 3 months received no further treatment, whereas those with residual low-grade disease in either treatment arm underwent a TURBT for any remaining lesions. The primary study endpoint was disease-free survival, defined as the time from randomization until treatment failure or death. Secondary endpoints included:
- Complete response rate at 3 months
- Duration of response up to 24 months for patients who achieved a complete response at 3 months
- Incidence of adverse events
Of note, following enrollment of 282 of the planned 632 study participants, further study enrollment was suspended early by the sponsor to pursue an alternative development strategy for UGN-102 for the treatment of bladder cancer. Patients who had consented at the time of trial termination were permitted to continue, but follow-up was discontinued once the last patient had been followed for 15 months after treatment initiation.
Among the 282 patients, 142 and 140 were randomized to UGN-102 +/- TURBT and primary TURBT, respectively. The median patient age was 68 years, and approximately 42% of patients had recurrent disease, with 29% having recurrence within the year prior to study enrollment. Multifocal disease was present in 63% of patients, and 45% had evidence of tumors >3 cm. Of the 142 patients randomized to UGN-102, 132 (96%) completed all six instillations.
At the first disease assessment 3 months post-treatment initiation, a complete response was observed in:
- UGN-102 +/- TURBT arm: 65% (95% CI: 56 – 73%)
- TURBT alone arm: 64% (95% CI: 55 – 72%)
Disease progression at the 3-months assessment was noted in 12 UGN-102 patients and 9 TURBT patients. Among patients with residual low-grade disease at the 3-month assessment, 24/26 treated with UGN-102 and 18/22 treated with primary TURBT underwent a TURBT. Disease-free survival 15 months after randomization was estimated to be 72% for patients in the UGN-102 ± TURBT arm and 50% for patients in the TURBT monotherapy arm, with a hazard ratio of 0.45:
Among patients achieving a complete response at the 3-month assessment, the estimated 12-months maintained response was 80% following induction treatment with UGN-102 and 68% following primary TURBT, with a hazard ratio of 0.46:
Treatment-related adverse events occurred more commonly in the UGN-102 arm (39% versus 11%), with serious events in 8.7% and 5.3%, respectively (none related to treatment per investigator assessment). The most frequent adverse events in the UGN-102 +/- TURBT arm were dysuria (30%), micturition urgency (18%), nocturia (18%), and pollakiuria (16%). Patient-reported symptoms, functioning, and quality of life (assessed via the EORTC-QLQ-NMIBC24) were either improved or not worsened in both arms.
Dr. Prasad concluded that primary, non-surgical chemoablation with UGN-102 for the management of low-grade, intermediate-risk NMIBC offers a potential therapeutic alternative to TURBT monotherapy and warrants further investigation.
Presented by: Sandip M. Prasad, MD, MPHil, Atlantic Health System, Morristown, NJ
Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 Society of Urologic Oncology (SUO) Annual Meeting, Washington, D.C., Tues, Nov 28 – Fri, Dec 1, 2023.
References:
- Chevli KK, Shore ND, Trainer A, et al. Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A Phase 2b, Open-Label, Single-Arm Trial. J Urol 2022; 207(1):61-9.
- Prasad SM, Huang WC, Shore ND, et al. Treatment of Low-grade Intermediate-risk Nonmuscle-invasive Bladder Cancer With UGN-102 ± Transurethral Resection of Bladder Tumor Compared to Transurethral Resection of Bladder Tumor Monotherapy: A Randomized, Controlled, Phase 3 Trial (ATLAS). J Urol 2023; 101097JU0000000000003645.