A Phase 2, Randomized, Open-Label Study of Irosustat Versus Megestrol Acetate in Advanced Endometrial Cancer

Pautier, Patricia; Vergote, Ignace; Joly, Florence; Melichar, Bohuslav; Kutarska, E.; Hall, G. D.; Lisyanskaya, Alla; Reed, Nicholas; Oaknin, Ana; Ostapenko, Valerijus; Zvirbule, Zanete; Chetaille, Eric; Agnes, Geniaux; Shoaib, Muhammad; Green, John A.

doi:10.1097/igc.0000000000000862

Cited by 35 publications

(37 citation statements)

References 34 publications

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“…STS inhibitors have been considered as novel anticancer agents where phase II clinical study has already been performed in ER-positive advanced/recurrent EC, however with no convincing results for STS inhibitor irosustat vs. progestin megestrol acetate (Pautier et al, 2017) with the progression free survival of 16 and 32 weeks, respectively. STS inhibitor thus performed worse as compared to the current medical treatment for recurrent EC.…”

Section: Discussionmentioning

confidence: 99%

The Significance of the Sulfatase Pathway for Local Estrogen Formation in Endometrial Cancer

et al. 2017

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Endometrial cancer (EC) is the most common estrogen-dependent gynecological malignancy in the developed World. To investigate the local formation of estradiol (E2), we first measured the concentrations of the steroid precursor androstenedione (A-dione) and the most potent estrogen, E2, and we evaluated the metabolism of A-dione, estrone-sulfate (E1-S), and estrone (E1) in cancerous and adjacent control endometrium. Furthermore, we studied expression of the key genes for estradiol formation via the aromatase and sulfatase pathways. A-dione and E2 were detected in cancerous and adjacent control endometrium. In cancerous endometrium, A-dione was metabolized to testosterone, and no E2 was formed. Both, E1-S and E1 were metabolized to E2, with increased levels of E2 seen in cancerous tissue. There was no significant difference in expression of the key genes of the aromatase (CYP19A1) and the sulfatase (STS, HSD17B1, HSD17B2) pathways in cancerous endometrium compared to adjacent control tissue. The mRNA levels of CYP19A1 and HSD17B1 were low, and HSD17B14, which promotes inactivation of E2, was significantly down-regulated in cancerous endometrium, especially in patients with lymphovascular invasion. At the protein level, there were no differences in the levels of STS and HSD17B2 between cancerous and adjacent control tissue by Western blotting, and immunohistochemistry revealed intense staining for STS and HSD17B2, and weak staining for SULT1E1 and HSD17B1 in cancerous tissue. Our data demonstrate that in cancerous endometrium, E2 is formed from E1-S via the sulfatase pathway, and not from A-dione via the aromatase pathway.

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Section: Discussionmentioning

confidence: 99%

The Significance of the Sulfatase Pathway for Local Estrogen Formation in Endometrial Cancer

et al. 2017

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“…Accessed on date: February 2018) and a phase II trial started 2016 ( http://adisinsight.springer.com/drugs/800041929 ) . ∧ NSCLC: non-small cell lung cancer ∧∧ LAM: lymphangioleiomyomatosis 1 Perez Carrion et al ( 1994 ), 2 Arnold and Einspanier ( 2013 ), 3 Delvoux et al ( 2014 ), 4 Konings et al ( 2017 ), 5 Järvensivu et al ( 2018 ), 6 Husen et al ( 2006 ), 7 Saloniemi et al ( 2010 ), 8 Gargano et al ( 2015 ), 9 Soubhye et al ( 2015 ) 10 Day et al ( 2013 ), 11 Wang et al ( 2017 ), 12 BroŽic et al ( 2011 ), 13 Kikuchi et al ( 2014 ), 14 Purohit and Foster ( 2012 ), 15 Pautier et al ( 2017 ), 16 Palmieri et al ( 2017a ), 17 Palmieri et al ( 2017b ), 18 Pohl et al ( 2014 ), 19 Ma et al ( 2004 ), 20 Rose et al ( 2000 ), 21 Lindemann et al ( 2014 ), 22 Slomovitz et al ( 2015 ), 23 NCT00932152; 25 Lu et al ( 2017 ) . …”

Section: Drug Developmentmentioning

confidence: 99%

“…More recently, there is a re-emerging interest in developing novel intracrine drugs. A number of compounds are in their clinical phases, like STS inhibitors (Maltais and Poirier, 2011 ; Woo et al, 2011 ; Purohit and Foster, 2012 ; Pohl et al, 2014 ; Pautier et al, 2017 ) or inhibitors of AKR1C3/17βHSD5, which are of particular interest because this enzyme has crucial role in androgen/estrogen and prostaglandin biosynthesis (Penning, 2017 ). Bayer's AKR1C3/17βHSD5 inhibitor BAY 1128688 has a modified estrogen core, it interferes with both pathways, and is in phase II clinical trial for endometriosis (Bothe et al, 2017 ).…”

Section: Drug Developmentmentioning

confidence: 99%

“…STS inhibitors showed promising results in a mouse subcutaneous model of EC, with decreased tumor growth by 48–67% (Foster et al, 2008b ). However, a phase II trial on advanced stage EC was stopped because of the absence of added benefit compared with progestogen treatment (Purohit and Foster, 2012 ; Pautier et al, 2017 ).…”

Section: Intracrinology In Peripheral Tissuesmentioning

confidence: 99%

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Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

et al. 2018

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Our understanding of the intracrine (or local) regulation of estrogen and other steroid synthesis and degradation expanded in the last decades, also thanks to recent technological advances in chromatography mass-spectrometry. Estrogen responsive tissues and organs are not passive receivers of the pool of steroids present in the blood but they can actively modify the intra-tissue steroid concentrations. This allows fine-tuning the exposure of responsive tissues and organs to estrogens and other steroids in order to best respond to the physiological needs of each specific organ. Deviations in such intracrine control can lead to unbalanced steroid hormone exposure and disturbances. Through a systematic bibliographic search on the expression of the intracrine enzymes in various tissues, this review gives an up-to-date view of the intracrine estrogen metabolisms, and to a lesser extent that of progestogens and androgens, in the lower female genital tract, including the physiological control of endometrial functions, receptivity, menopausal status and related pathological conditions. An overview of the intracrine regulation in extra gynecological tissues such as the lungs, gastrointestinal tract, brain, colon and bone is given. Current therapeutic approaches aimed at interfering with these metabolisms and future perspectives are discussed.

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“…Moreover, a phase 3 trial comparing zoptarelin to doxorubicin also failed to improve the overall survival (OS) of patients with advanced endometrial cancer [6]. Several other clinical trials of both targeted therapies and chemotherapeutic regimens have also demonstrated disappointing outcomes in advanced and recurrent endometrial carcinoma, underscoring the challenging nature of this disease [7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Second-line lenvatinib in patients with recurrent endometrial cancer

Vergote

Powell

Teneriello

et al. 2020

Gynecologic Oncology

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Objective. This study assessed the efficacy of lenvatinib, a multitargeted tyrosine kinase inhibitor, as secondline therapy in patients with unresectable endometrial cancer. The primary end point was the objective response rate (ORR) as assessed by independent radiologic review (IRR). Secondary end points included median progression-free survival (PFS), overall survival (OS), and clinical benefit rate. Exploratory end points examined the association of baseline levels of plasma biomarkers (50 circulating cytokine and/or angiogenic factors measured by immunoassays) with efficacy outcomes. Methods. An international, open-label, single-arm, multicenter, phase 2 trial was conducted. Eligible patients had histologically confirmed unresectable endometrial cancer that relapsed after 1 prior systemic platinumbased chemotherapy. Patients received once-daily oral lenvatinib 24 mg in a 28-day dosing cycle. Results. There were 133 patients in the study. By IRR, 19 patients had a confirmed objective response for an ORR of 14.3% (95% CI: 8.8-21.4). Durable stable disease (≥23 weeks) was observed in 31 patients (23.3%) and the clinical benefit rate was 37.6% (95% CI: 29.3-46.4). Median PFS was 5.6 months (95% CI: 3.7-6.3), and median OS was 10.6 months (95% CI: 8.9-14.9). The most common (any grade) treatment-related adverse events were fatigue/asthenia (48%), hypertension (49%), nausea/vomiting (32%), decreased appetite (32%), and diarrhea (31%). Lower baseline levels of angiopoietin-2 were associated with longer PFS, OS, and a higher ORR. Conclusions. Patients with recurrent endometrial cancer treated with second-line lenvatinib experienced modest antitumor activity and treatment was generally well tolerated, with a safety profile consistent with previous studies.

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A Phase 2, Randomized, Open-Label Study of Irosustat Versus Megestrol Acetate in Advanced Endometrial Cancer

Cited by 35 publications

References 34 publications

The Significance of the Sulfatase Pathway for Local Estrogen Formation in Endometrial Cancer

The Significance of the Sulfatase Pathway for Local Estrogen Formation in Endometrial Cancer

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

Second-line lenvatinib in patients with recurrent endometrial cancer

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