A phase I dose escalation study to determine the optimal biological dose of irosustat, an oral steroid sulfatase inhibitor, in postmenopausal women with estrogen receptor-positive breast cancer

Coombes, R. Charles; Cardoso, Fátima; Isambert, Nicolás; Lesimple, Thierry; Soulié, P; Peraire, Concepción; Fohanno, V.; Kornowski, Anne; Ali, Tauhid; Schmid, Peter

doi:10.1007/s10549-013-2597-8

Cited by 30 publications

(34 citation statements)

References 9 publications

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“…Two phase I studies have demonstrated irosustat to be well tolerated and provided evidence of clinical activity (Stanway et al 2006, Coombes et al 2013.…”

Section: Ar Antagonists and Androgen Biosynthesis Inhibitors In Er-pomentioning

confidence: 99%

Pushing estrogen receptor around in breast cancer

Lim

Tarulli

Portman

et al. 2016

Endocrine-Related Cancer

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The estrogen receptor-α (herein called ER) is a nuclear sex steroid receptor (SSR) that is expressed in approximately 75% of breast cancers. Therapies that modulate ER action have substantially improved the survival of patients with ER-positive breast cancer, but resistance to treatment still remains a major clinical problem. Treating resistant breast cancer requires co-targeting of ER and alternate signalling pathways that contribute to resistance to improve the efficacy and benefit of currently available treatments. Emerging data have shown that other SSRs may regulate the sites at which ER binds to DNA in ways that can powerfully suppress the oncogenic activity of ER in breast cancer. This includes the progesterone receptor (PR) that was recently shown to reprogram the ER DNA binding landscape towards genes associated with a favourable outcome. Another attractive candidate is the androgen receptor (AR), which is expressed in the majority of breast cancers and inhibits growth of the normal breast and ER-positive tumours when activated by ligand. These findings have led to the initiation of breast cancer clinical trials evaluating therapies that selectively harness the ability of SSRs to 'push' ER towards anti-tumorigenic activity. Our review will focus on the established and emerging clinical evidence for activating PR or AR in ER-positive breast cancer to inhibit the tumour growth-promoting functions of ER.

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“…Two phase I studies have demonstrated irosustat to be well tolerated and provided evidence of clinical activity (Stanway et al 2006, Coombes et al 2013.…”

Section: Ar Antagonists and Androgen Biosynthesis Inhibitors In Er-pomentioning

confidence: 99%

Pushing estrogen receptor around in breast cancer

Lim

Tarulli

Portman

et al. 2016

Endocrine-Related Cancer

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“…In prostate cancer cell lines, androgen deprivation up-regulates the OATPs, to facilitate enhanced uptake and release of steroid conjugates [57]. Sulfatase inhibitors have been tested for prostate, breast and endometrial cancers, but have not yet found efficacy as a monotherapy [58, 59]. Recent evidence suggests a gain-of-function mutation stabilizes type 1 3β-hydroxysteroid dehydrogenase and may represent a putative therapeutic target in CRPC [60].…”

Section: 11 Intratumoral Androgen Conversion and Akr1c3 Inhibitionmentioning

confidence: 99%

The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer

Tamae

Mostaghel

Montgomery

et al. 2015

Chemico-Biological Interactions

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Prostate cancer is the second leading cause of cancer death in the United States. Treatment of localized high-risk disease and de novo metastatic disease frequently leads to relapse. These metastatic castration resistant prostate cancers (mCRPC) claim a high mortality rate, despite the extended survival afforded by the growing armamentarium of androgen deprivation, radiation and immunotherapies. Here, we review two studies of neoadjuvant treatment of high-risk localized prostate cancer prior to prostatectomy, the total androgen pathway suppression (TAPS) trial and the neoadjuvant abiraterone acetate (AA) trial. These two trials assessed the efficacy of the non-specific P450c17 inhibitor, ketoconazole and the specific P450c17 inhibitor, AA, to inhibit tissue and serum androgen levels. Furthermore, a novel and validated stable isotope dilution liquid chromatography electrospray ionization selected reaction monitoring mass spectrometry assay was used to accurately quantify adrenal and gonadal androgens in circulation during the course of these trials. The adrenal androgens, Δ4-androstene-3,17-dione, dehydroepiandrosterone and dehydroepiandrosterone sulfate were significantly reduced in the patients receiving ketoconazole or AA compared to those who did not. However, in both trials, a significant amount of DHEA-S (~20 μg/dL) persists and thus may serve as a depot for intratumoral conversion to the potent androgen receptor ligands, testosterone (T) and 5α-dihydrotestosterone (DHT). The final step in conversion of Δ4-androstene-3,17-dione and 5α-androstanedione to T and DHT, respectively, is catalyzed by AKR1C3. We therefore present the case that in the context of the DHEA-S depot, P450c17 and AKR1C3 inhibition may be an effective combinatorial treatment strategy.

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“…This was a phase 2, multicenter, international, openlabel, randomized, 2-arm study of oral irosustat 40 mg/d (ie, the dose that was previously established in a phase 1, doseescalation study 21 ) versus oral megestrol acetate 160 mg/d. Participants were randomized 1:1 to receive either treatment until objective tumor progression, 2 years after the last patient was randomized (June 3, 2011), withdrawal, or death.…”

Section: Methodsmentioning

confidence: 99%

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

Pautier

Vergote²,

Joly³

et al. 2017

Int J Gynecol Cancer

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Objective: Advanced/metastatic or recurrent endometrial cancer has a poor prognosis. Malignant endometrial tissue has high steroid sulphatase (STS) activity. The aim of this study was to evaluate STS as a therapeutic target in patients with endometrial cancer. Methods: This was a phase 2, multicenter, international, open-label, randomized (1:1), 2-arm study of the STS inhibitor oral irosustat 40 mg/d versus oral megestrol acetate 160 mg/d in women with advanced/metastatic or recurrent estrogen receptorYpositive endometrial cancer. The primary end point was the proportion of patients without progression or death 6 months after start of treatment. Secondary end points included progression-free survival, time to progression, overall survival, and safety. Results: Seventy-one patients were treated (36 with irosustat, 35 with megestrol acetate). The study was prematurely stopped after futility analysis. Overall, 36.1% and 54.1% of patients receiving irosustat or megestrol acetate had not progressed or died at 6 months, respectively. There were no statistically significant differences between irosustat and megestrol acetate in response and overall survival rates. Irosustat patients had a median progression-free survival of 16 weeks (90% confidence interval, 9.0Y31.4) versus 40 weeks (90% confidence interval, 16.3Y64.0) in megestrol acetate patients. Treatment-related adverse events occurred in 20 (55.6%) and 13 (37.1%) patients receiving irosustat or megestrol, respectively. Most adverse events in both groups were grade 1 or 2. Conclusions: Although irosustat monotherapy did not attain a level of activity sufficient for further development in patients with advanced/recurrent endometrial cancer, this study confirms the activity of hormonal treatment (megestrol acetate) for this indication.

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A phase I dose escalation study to determine the optimal biological dose of irosustat, an oral steroid sulfatase inhibitor, in postmenopausal women with estrogen receptor-positive breast cancer

Cited by 30 publications

References 9 publications

Pushing estrogen receptor around in breast cancer

Pushing estrogen receptor around in breast cancer

The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer

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

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