Overcoming Taxane Resistance: Preclinical and Phase 1 Studies of Relacorilant, a Selective Glucocorticoid Receptor Modulator, with Nab-Paclitaxel in Solid Tumors

Abstract

Purpose: Chemotherapy resistance remains a major problem in many solid tumors, including breast, ovarian, and pancreatic cancer. Glucocorticoids are one potential driver of chemotherapy resistance as they can mediate tumor progression via induction of cell-survival pathways. We investigated whether combining the selective glucocorticoid receptor modulator relacorilant with taxanes can enhance anti-tumor activity. Experimental Design: The effect of relacorilant on paclitaxel efficacy was assessed in OVCAR5 cells in vitro and in the MIA PaCa-2 xenograft. A phase 1 study of patients with advanced solid tumors was conducted to determine the recommended phase 2 dose of relacorilant + nab-paclitaxel. Results: In OVCAR5 cells, relacorilant reversed the deleterious effects of glucocorticoids on paclitaxel efficacy (P<.001). Compared to paclitaxel alone, relacorilant+paclitaxel reduced tumor growth and slowed time to progression in xenograft models (both P<.0001). In the heavily pretreated phase 1 population (median [range] of prior regimens: 3 [1-8], prior taxane in 75.3% [55/73]), 33% (19/57) of response-evaluable patients achieved durable disease control ({greater than or equal to}16 weeks) with relacorilant+nab-paclitaxel and 28.6% (12/42) experienced longer duration of benefit than on prior taxane (up to 6.4x). The most common dose-limiting toxicity of the combination was neutropenia, which was manageable with prophylactic granulocyte-colony stimulating factor. Clinical benefit with relacorilant+nab-paclitaxel was also associated with GR-regulated transcript-level changes in a panel of GR-controlled genes. Conclusions: Preclinical, clinical, and GR-specific pharmacodynamic responses observed demonstrate that selective GR modulation with relacorilant combined with nab-paclitaxel may promote chemotherapy response and is tolerable. Further evaluation of this combination in tumor types responsive to taxanes is ongoing.

Glucocorticoid Receptor and β-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance

“…While PC3-DR and DU145-DR cells are AR negative, the contribution of other BET bromodomain-regulated proteins should be considered. Future studies with more selective GR modulators, such as relacolirant, currently in clinical trials to determine its effectiveness in promoting taxane responses in solid tumors [ 78 ], should shed additional mechanistic insights into the contribution of GR to taxane resistance.…”

Genetically Engineered Human Pituitary Corticotroph Tumor Organoids Exhibit Divergent Responses To Glucocorticoid Receptor Modulators

“…Relacorilant may also induce PitNET apoptosis independently of SSTR activation ( Supplemental Figure 8 ). In support of this notion, studies in several cancers that are driven by the dysregulation of these receptors, including leukemia, breast, prostate, lung and ovarian cancers, show promise of targeting the GR as a strategy for combination treatment [52, 53]. In addition, relacorilant induces apoptosis in vitro using pancreatic and ovarian cancer cell lines [54].…”

Treatment of Ovarian Cancer Beyond PARP Inhibition: Current and Future Options

“…GRs are abundantly expressed on OC cells and high expression is associated with poor outcomes [ 154 ]. Relacorilant is a selective modulator of GRs, which compete with cortisol and can reverse the cortisol-induced chemotherapy resistance in multiple solid tumours [ 155 ]. In a phase II, randomized study, recurrent PROC patients were randomized to nab-paclitaxel alone or nab-paclitaxel with intermittent (150 mg/day the day before, of, and after nab-paclitaxel administration) or a continuous schedule of relacorilant (100 mg daily).…”