J Bellmunt1, B J Eigl2, E Senkus3, Y Loriot4, P Twardowski5, D Castellano6, N Blais7, S S Sridhar8, C N Sternberg9, M Retz10, S Pal5, B Blumenstein11, C Jacobs12, P S Stewart12, D P Petrylak13. 1. Department of Medical Oncology, Hospital del Mar-IMIM, Barcelona, Spain; and Dana Farber Cancer Institute/Harvard Medical School, Boston. Electronic address: joaquim_bellmunt@dfci.harvard.edu. 2. British Columbia Cancer Agency, Vancouver, Canada. 3. Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland. 4. Medical Oncolgy, Centre Hospitalier Universitaire, Institut Gustave Roussy, Villejuif, France. 5. Medical Oncology, City of Hope National Medical Center, Duarte, USA. 6. Medical Oncology Department, Hospital Universitario 12 de Octubre (CiberOnc), Madrid, Spain. 7. Department of Medicine, Centre Hospitalier Universitaire de Montréal, Hospital Notre-Dame, Montreal. 8. Medical Oncology, Princess Margaret Hospital, Toronto, Canada. 9. Department of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy. 10. Department of Urology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. 11. Trial Architecture Consulting, Washington. 12. OncoGenex Pharmaceuticals Inc., Bothell. 13. Department of Medical Oncology, Yale University School of Medicine, New Haven, USA.
Abstract
BACKGROUND: Five-year survival of patients with inoperable, advanced urothelial carcinoma treated with the first-line chemotherapy is 5%-15%. We assessed whether the Hsp27 inhibitor apatorsen combined with gemcitabine plus cisplatin (GC) could improve overall survival (OS) in these patients. PATIENTS AND METHODS: This placebo-controlled, double-blind, phase II trial randomized 183 untreated urothelial carcinoma patients (North America and Europe) to receive GC plus either placebo (N = 62), 600 mg apatorsen (N = 60), or 1000 mg apatorsen (N = 61). In the experimental arm, treatment included loading doses of apatorsen followed by up to six cycles of apatorsen plus GC. Patients receiving at least four cycles could continue apatorsen monotherapy as maintenance until progression or unacceptable toxicity. The primary end point was OS. RESULTS: OS was not significantly improved in the single or combined 600- or 1000-mg apatorsen arms versus placebo [hazard ratio (HR), 0.86 and 0.90, respectively]. Exploratory study of specific statistical modeling showed a trend for improved survival in patients with baseline poor prognostic features treated with 600 mg apatorsen compared with placebo (HR = 0.72). Landmark analysis of serum Hsp27 (sHsp27) levels showed a trend toward survival benefit for poor-prognosis patients in 600- and 1000-mg apatorsen arms who achieved lower area under the curve sHsp27 levels, compared with the placebo arm (HR = 0.45 and 0.62, respectively). Higher baseline circulating tumor cells (≥5 cells/7.5 ml) was observed in patients with poor prognosis in correlation with poor survival. Treatment-emergent adverse events were manageable and more common in both apatorsen-treatment arms. CONCLUSIONS: Even though apatorsen combined with standard chemotherapy did not demonstrate a survival benefit in the overall study population, patients with poor prognostic features might benefit from this combination. Serum Hsp27 levels may act as a biomarker to predict treatment outcome. Further exploration of apatorsen in poor-risk patients is warranted.
BACKGROUND: Five-year survival of patients with inoperable, advanced urothelial carcinoma treated with the first-line chemotherapy is 5%-15%. We assessed whether the Hsp27 inhibitor apatorsen combined with gemcitabine plus cisplatin (GC) could improve overall survival (OS) in these patients. PATIENTS AND METHODS: This placebo-controlled, double-blind, phase II trial randomized 183 untreated urothelial carcinoma patients (North America and Europe) to receive GC plus either placebo (N = 62), 600 mg apatorsen (N = 60), or 1000 mg apatorsen (N = 61). In the experimental arm, treatment included loading doses of apatorsen followed by up to six cycles of apatorsen plus GC. Patients receiving at least four cycles could continue apatorsen monotherapy as maintenance until progression or unacceptable toxicity. The primary end point was OS. RESULTS: OS was not significantly improved in the single or combined 600- or 1000-mg apatorsen arms versus placebo [hazard ratio (HR), 0.86 and 0.90, respectively]. Exploratory study of specific statistical modeling showed a trend for improved survival in patients with baseline poor prognostic features treated with 600 mg apatorsen compared with placebo (HR = 0.72). Landmark analysis of serum Hsp27 (sHsp27) levels showed a trend toward survival benefit for poor-prognosis patients in 600- and 1000-mg apatorsen arms who achieved lower area under the curve sHsp27 levels, compared with the placebo arm (HR = 0.45 and 0.62, respectively). Higher baseline circulating tumor cells (≥5 cells/7.5 ml) was observed in patients with poor prognosis in correlation with poor survival. Treatment-emergent adverse events were manageable and more common in both apatorsen-treatment arms. CONCLUSIONS: Even though apatorsen combined with standard chemotherapy did not demonstrate a survival benefit in the overall study population, patients with poor prognostic features might benefit from this combination. Serum Hsp27 levels may act as a biomarker to predict treatment outcome. Further exploration of apatorsen in poor-risk patients is warranted.
Authors: Leila Jahangiri; Tala Ishola; Perla Pucci; Ricky M Trigg; Joao Pereira; John A Williams; Megan L Cavanagh; Georgios V Gkoutos; Loukia Tsaprouni; Suzanne D Turner Journal: Cancers (Basel) Date: 2021-03-11 Impact factor: 6.639