For a study, researchers sought to know if increasing the anticancer activity achieved by using taxanes in conjunction with the selective glucocorticoid receptor (GR) modulator relacorilant was possible. It was determined whether or not relacorilant impacted the effectiveness of paclitaxel treatment in OVCAR5 cells cultured in vitro and in the MIA PaCa-2 xenograft. To identify the dose of relacorilant and nab-paclitaxel that should be administered in phase 2, a phase 1 trial was carried out with patients with advanced solid tumors. In OVCAR5 cells, relacorilant could completely counteract the detrimental effects of glucocorticoids on paclitaxel’s effectiveness (P<0.001). In xenograft models, the combination of relacorilant and paclitaxel resulted in significantly less tumor development and a significantly slower rate of progression (both of which were statistically significant at the P<0.0001 level). In the heavily pretreated phase 1 population [median (range) of prior regimens: 3 (1-8), the prior taxane in 75.3% (55/73], 33% (19/57) of response-evaluable patients achieved durable disease control (≥16 weeks) with relacorilant + nab-paclitaxel, and 28.6% (12/42) experienced a longer duration of a benefit than on prior taxane (up to 6.4 times). Neutropenia was the most prevalent dose-limiting hazard of the combination; however, it might be managed with prophylactic G-CSF. The clinical effect of relacorilant combined with nab-paclitaxel was also associated with GR-regulated alterations in the transcript levels of a panel of genes controlled by GR. The preclinical, clinical, and GR-specific pharmacodynamic studies showed that selective GR regulation with relacorilant combination with nab-paclitaxel might improve the response to chemotherapy and was well tolerated by patients. The effectiveness of this combination in treating tumors that were sensitive to taxanes was being researched further.

Source – aacrjournals.org/clincancerres/article/28/15/3214/707115/Overcoming-Taxane-Resistance-Preclinical-and-Phase