524MO Glucocorticoid receptor expression and activity in a phase II ovarian cancer trial of the glucocorticoid receptor modulator relacorilant in combination with nab-paclitaxel

Lorusso, D.; Greenstein, Andrew E.; Wadekar, Subhagya A.; Tudor, Iulia Cristina; Hunt, Hazel; Guyer, B.

doi:10.1016/j.annonc.2022.07.652

Cited by 3 publications

(4 citation statements)

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“…Although patients treated with paclitaxel-carboplatin had a longer overall survival (30 months versus 25 months) and PFS (15 months versus 10 months) when compared to paclitaxel-ifosfamide, these differences were not statistically significant. 101 A high glucocorticoid receptor (GR) expression can identify patients who are less likely to derive benefit from nab-paclitaxel 102 and given the high expression of GR in OCS, 103 it may have a role as a biomarker for this patient population. These high GR levels may also mean that the GR modulator relacorilant could be beneficial in the treatment of OSC patients with recurrent disease.…”

Section: Chemotherapymentioning

confidence: 99%

Disparity in the era of personalized medicine for epithelial ovarian cancer

Devlin

Miller

2023

Ther Adv Med Oncol

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The treatment of high-grade serous ovarian cancer and high-grade endometrioid ovarian cancer has seen significant improvements in recent years, with BRCA1/2 and homologous recombination status guiding a personalized approach which has resulted in improved patient outcomes. However, for other epithelial ovarian cancer subtypes, first-line treatment remains unchanged from the platinum–paclitaxel trials of the early 2000s. In this review, we explore novel therapeutic approaches being adopted in the treatment of clear cell, mucinous, carcinosarcoma and low-grade serous ovarian cancer and the biological rational behind them. We discuss why such disparities exist, the challenges faced in conducting dedicated trials in these rarer histologies and look towards new approaches being adopted to overcome them.

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Section: Chemotherapymentioning

confidence: 99%

Disparity in the era of personalized medicine for epithelial ovarian cancer

Devlin

Miller

2023

Ther Adv Med Oncol

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“…The primary PFS analysis, after 11.1 months of median follow-up, confirmed a statistically significant benefit of 1.8 months for intermittent RELA plus nab-paclitaxel arm versus nab-paclitaxel alone (5.6 vs. 3.8 months) [ 98 ] . In addition, an updated survival analysis at 22.5 months of median follow-up showed a median OS of 13.9 months in the intermittent RELA arm compared with 12.2 months in the nab-paclitaxel arm, with low TGF-β1 levels found to be predictive of longer OS [ 99 ]. Treatment benefit was mainly observed among patients with high tumor GR expression who most benefited from adding RELA to nab-paclitaxel treatment (ORR = 40.4% vs. 18.8%).…”

Section: Glucocorticoid Receptor As a Potential Target For A Therapeu...mentioning

confidence: 99%

“…Treatment benefit was mainly observed among patients with high tumor GR expression who most benefited from adding RELA to nab-paclitaxel treatment (ORR = 40.4% vs. 18.8%). In addition, continuous or intermittent RELA administration resulted in significant suppression of canonical GR target genes expression such as SGK1, phosphatidylinositol-4,5-Bisphosphate 3-Kinase catalytic subunit gamma (PIK3CG), and glycogen synthase kinase 3 beta (GSK3B) compared to the nab-paclitaxel arm treatment, thus suggesting pleiotropic activity of GR antagonist [ 98 , 99 ]. Regarding the safety profile, the most frequent grade ≥ 3 adverse events were neutropenia and anemia peripheral sensory neuropathy in the intermittent RELA arm [ 98 , 99 ].…”

Section: Glucocorticoid Receptor As a Potential Target For A Therapeu...mentioning

confidence: 99%

“…In addition, continuous or intermittent RELA administration resulted in significant suppression of canonical GR target genes expression such as SGK1, phosphatidylinositol-4,5-Bisphosphate 3-Kinase catalytic subunit gamma (PIK3CG), and glycogen synthase kinase 3 beta (GSK3B) compared to the nab-paclitaxel arm treatment, thus suggesting pleiotropic activity of GR antagonist [ 98 , 99 ]. Regarding the safety profile, the most frequent grade ≥ 3 adverse events were neutropenia and anemia peripheral sensory neuropathy in the intermittent RELA arm [ 98 , 99 ]. A phase III randomized trial (ROSELLA, NCT05257408) is currently evaluating the intermittent RELA plus nab-paclitaxel schedule vs. investigator’s choice of chemotherapy in platinum-resistant or refractory HGSOC who had received up to 1–3 prior lines of chemotherapy and at least one platinum-based regimen [ 100 ] ( Table 2 ).…”

Section: Glucocorticoid Receptor As a Potential Target For A Therapeu...mentioning

confidence: 99%

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Glucocorticoid Receptor and Ovarian Cancer: From Biology to Therapeutic Intervention

et al. 2023

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Ovarian cancer (OC) is the leading cause of death from gynecological malignancies worldwide. Fortunately, recent advances in OC biology and the discovery of novel therapeutic targets have led to the development of novel therapeutic agents that may improve the outcome of OC patients. The glucocorticoid receptor (GR) is a ligand-dependent transcriptional factor known for its role in body stress reactions, energy homeostasis and immune regulation. Notably, evidence suggests that GR may play a relevant role in tumor progression and may affect treatment response. In cell culture models, administration of low levels of glucocorticoids (GCs) suppresses OC growth and metastasis. Conversely, high GR expression has been associated with poor prognostic features and long-term outcomes in patients with OC. Moreover, both preclinical and clinical data have shown that GR activation impairs the effectiveness of chemotherapy by inducing the apoptotic pathways and cell differentiation. In this narrative review, we summarize data related to the function and role of GR in OC. To this aim, we reorganized the controversial and fragmented data regarding GR activity in OC and herein describe its potential use as a prognostic and predictive biomarker. Moreover, we explored the interplay between GR and BRCA expression and reviewed the latest therapeutic strategies such as non-selective GR antagonists and selective GR modulators to enhance chemotherapy sensitivity, and to finally provide new treatment options in OC patients.

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A Review of the Latest Advancements in Ovarian Cancer Care Featured at ESMO 2022

Scott¹

2023

EMJ Oncol

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Ovarian cancer is the seventh most commonly diagnosed cancer among females and the most lethal gynaecologic malignancy globally because of its vague presentation, insidious nature, recurrence, and drug resistance. There is a pressing need to improve survival and quality of life in patients with ovarian cancer in the context of rising global incidence, high risk of relapse, and poor prognosis. Presentations at the European Society for Medical Oncology (ESMO) Congress 2022 from 9th–13th September in Paris, France, showed the breadth and depth of research in ovarian cancer, including a first look at the highly anticipated data from Phase III studies on the impact on overall survival (OS) of poly(ADP-ribose) polymerase (PARP) inhibitors as first-line maintenance therapy. Clinically meaningful OS benefit was shown with olaparib at 5 years’ follow-up in PAOLA-1 and at 7 years’ follow-up in SOLO1. These positive results are a breakthrough in ovarian cancer treatment and are an important indicator that improvements in progression-free survival (PFS) may translate into OS benefits. Studies in which PARP inhibitors showed clinically meaningful efficacy, but OS data remain immature, include PRIMA, in which niraparib as a first-line maintenance therapy maintained clinically significant improvement in progression-free survival at 3.5 years’ follow-up. Research into chemotherapy resistance using a glucocorticoid receptor modulator in combination with nab-paclitaxel as part of second-line treatment showed that glucocorticoid receptor modulation can improve the efficacy of chemotherapy. Pre-clinical and early phase clinical studies are investigating a range of approaches for the treatment of ovarian cancer such as development of a chimeric antigen receptor T cell therapy, combination of a PARP inhibitor and an immune checkpoint inhibitor, and a bispecific antibody. Developments in these areas are awaited with interest. There is considerable focus on biomarkers for prognosis and progression in ovarian cancer, including research on breast related cancer antigen and homologous recombination deficiency testing, cancer antigen 125 (CA125) decline, and circulating tumour DNA (ctDNA); however, wider genetic testing, improved education of physicians on the importance of testing, and increased access to testing are recommended to optimise treatment and disease prevention. The research in ovarian cancer presented at ESMO 2022 marks important progress in this field.

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524MO Glucocorticoid receptor expression and activity in a phase II ovarian cancer trial of the glucocorticoid receptor modulator relacorilant in combination with nab-paclitaxel

Cited by 3 publications

References 0 publications

Disparity in the era of personalized medicine for epithelial ovarian cancer

Disparity in the era of personalized medicine for epithelial ovarian cancer

Glucocorticoid Receptor and Ovarian Cancer: From Biology to Therapeutic Intervention

A Review of the Latest Advancements in Ovarian Cancer Care Featured at ESMO 2022

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