A Phase II Multicenter Randomized Open-Label Study of Oral Steroid Sulphatase (STS) Inhibitor Irosustat (BN83495) Versus Megestrol Acetate (MA) in Women with Advanced/Recurrent Endometrial Cancer (EC)

ABSTRACT Background Despite the progress in the diagnosis and therapy of early EC, advanced (metastatic) or recurrent EC remains an incurable disease. Irosustat (also known as BN83495, STX64 and 667-coumate) is a selective irreversible STS inhibitor developed for the treatment of hormone-dependent tumors. Objective: A phase II, randomized, open-label study was designed to explore the safety and efficacy of irosustat as a single agent in advanced/recurrent EC. Methods Post-menopausal women with histologically verified estrogen and/or progesterone receptor-positive EC (defined as ≥10% positive cells in primary tumor or metastasis), with recurrent/advanced disease, at least one measurable target lesion, life expectancy ≥6 months, not eligible for surgery or radiotherapy and no prior systemic treatment for EC (except adjuvant chemotherapy if completed ≥1 year before randomization) were randomized 1:1 to daily oral irosustat 40 mg or MA 160 mg. The primary endpoint was the percentage of patients alive without progression after 6 months of treatment. Blinded central review of responses (evaluated using RECIST 1.0) was performed. Secondary endpoints included progression-free survival (PFS), time to progression, overall survival, quality of life and safety. Results 73 patients were enrolled in 11 European countries, 36 were randomized to irosustat and 37 to MA. Median age was 68 years (range 37-85 years). Treatment-related severe toxicities (grade 3-4) were symptomatic hyponatremia, asthenia, dry skin and worsening of hypertension for irosustat (n = 1) and pulmonary embolism (n = 3, 1 led to death) and hyperglycemia with MA. Conclusion This study demonstrates clinical benefit of hormonal treatment (irosustat and MA) in selected patients with advanced/recurrent EC with a different toxicity profile. Irosustat(n = 36) Megestrol acetate(n = 37) Alive without progression at 6 months n (%) 13 (36.1) 21 (56.8) Response (CR + PR) n (%) 4 (11.1) 12 (32.4) Stable disease n (%) 17 (47.2) 12 (32.4) Median PFS (weeks) [90% CI] 16 [9-34] 32 [16-63] Disclosure P. Pautier: Author is an advisory board member for Roche and Ipsen. F. Joly Lobbedez: Author is an advisory board member for Sanofi, Roche, Novartis, Janssen, Ferring, Pfizer. No conflit of interest with Ipsen or BN83495. N. Reed: Consultancy fees and lecturing for Novartis, Roche, AZ, Johnson and Johnson, Otsuka. All other authors have declared no conflicts of interest.