Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.

European urology. 2021 Dec 18 [Epub ahead of print]

Anirban P Mitra, Vikram M Narayan, Sharada Mokkapati, Tanner Miest, Stephen A Boorjian, Mehrdad Alemozaffar, Badrinath R Konety, Neal D Shore, Leonard G Gomella, Ashish M Kamat, Trinity J Bivalacqua, Jeffrey S Montgomery, Seth P Lerner, J Erik Busby, Michael Poch, Paul L Crispen, Gary D Steinberg, Anne K Schuckman, Tracy M Downs, Robert S Svatek, Joseph Mashni, Brian R Lane, Thomas J Guzzo, Gennady Bratslavsky, Lawrence I Karsh, Michael E Woods, Gordon A Brown, Daniel Canter, Adam Luchey, Yair Lotan, Tracey Krupski, Brant A Inman, Michael B Williams, Michael S Cookson, Kirk A Keegan, Gerald L Andriole, Alexander I Sankin, Alan Boyd, Michael A O'Donnell, Richard Philipson, Seppo Ylä-Herttuala, David Sawutz, Nigel R Parker, David J McConkey, Colin P N Dinney

Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Urology, Mayo Clinic, Rochester, MN, USA., Department of Urology, Kaiser Permanente Los Angeles, Los Angeles, CA, USA., Department of Urology, Rush Medical College, Chicago, IL, USA., Carolina Urologic Research Center, Myrtle Beach, SC, USA., Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA., Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA., Department of Urology, University of Michigan, Ann Arbor, MI, USA., Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA., Department of Surgery, Prisma Health, University of South Carolina School of Medicine at Greenville, Greenville, SC, USA., Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Department of Urology, University of Florida, Gainesville, FL, USA., Department of Urology, New York University Langone Health, New York, NY, USA., Institute of Urology, University of Southern California, Los Angeles, CA, USA., Department of Urology, University of Wisconsin, Madison, WI, USA., Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Department of Surgical Oncology, Banner MD Anderson Cancer Center, Gilbert, AZ, USA., Division of Urology, Spectrum Health, Michigan State University College of Human Medicine, Grand Rapids, MI, USA., Division of Urology, University of Pennsylvania, Philadelphia, PA, USA., Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA., The Urology Center of Colorado, Denver, CO, USA., Department of Urology, Loyola University, Maywood, IL, USA., New Jersey Urology, Bloomfield, NJ, USA., Georgia Urology, Atlanta, GA, USA., Department of Urology, West Virginia University Cancer Institute, Morgantown, WV, USA., Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Department of Urology, University of Virginia, Charlottesville, VA, USA., Division of Urology, Department of Surgery, Duke University, Durham, NC, USA., Urology of Virginia, Virginia Beach, VA, USA., Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Department of Urology, Vanderbilt University Medical Center, Nashville, TN, USA., Division of Urologic Surgery, Department of Surgery, Washington University School of Medicine in St Louis, St Louis, MO, USA., Department of Urology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, USA., Boyd Consultants Ltd, Crewe, UK., Department of Urology, University of Iowa, Iowa City, IA, USA., Trizell Ltd, Chinnor, UK., AI Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland., FKD Therapies Oy, Kuopio, Finland., Department of Urology, Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD, USA., Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: .