Figure 1 from ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Nab-Paclitaxel in Patients with Advanced Solid Tumors

GR antagonism by ORIC-101 overcomes taxane resistance in preclinical models. A and B, Effect of ORIC-101 on dexamethasone-induced chemoprotection in vitro as measured by (A) caspase 3/7 apoptosis assays and (B) colony formation assays, in three TNBC lines (HCC1806, MDA-MB-231, Hs578T), three PDAC lines (BxPC3, SW1990, PSN1), and ovarian cancer line COV362. Veh: vehicle; Dex: 30 nmol/L dexamethasone; 101: 0.5 μmol/L ORIC-101; Chemo = 100 nmol/L paclitaxel + 100 nmol/L gemcitabine; PTX = 100 nmol/L paclitaxel; DTX = 100 nmol/L docetaxel; Gem = 100 nmol/L gemcitabine. A, The caspase activities of Veh were assigned as 1, and the values for other conditions were relative to Veh. One representative experiment with three biological repeats is shown (mean ± SEM). *, P < 0.05; **, P < 0.01; ***, P < 0.001 by one-way ANOVA using Tukey’s test to correct for multiple comparisons. B, One representative experiment with three biological repeats is shown. Numbers in white indicate the percentage of confluency quantitated by Celigo S. C, Effect of ORIC-101 on paclitaxel response in taxane-naïve HCC1806 TNBC xenografts in cortisol-treated mice. Mice were treated with paclitaxel 20 mg/kg by intraperitoneal injection every 3 days for a total of eight cycles (20 mg/kg, IP, Q3D × 8), cortisol (100 mg/L in drinking water, ad libitum) or ORIC-101 75 mg/kg by oral administration twice daily (75 mg/kg, PO, BID) starting on day 0 for the duration of the study. Arrowheads indicate PTX dosing days. Data are displayed as mean ± SEM. D and E, Effect of ORIC-101 in paclitaxel-relapsed HCC1806 TNBC xenografts in cortisol-treated mice. D, Animals were dosed with paclitaxel (15 mg/kg, IP, Q3Dx5) as indicated by the black arrowheads or ORIC-101 (150 mg/kg, PO, QD) as indicated by gray line. n = 15 in each group. Data is displayed as mean ± SEM. E, PFS, defined as the time elapsed between treatment initiation of the second cycle of paclitaxel and tumor progression or death from any cause, as a percentage of all animals in each cohort. A Kaplan–Meier plot was constructed to show the percentage of animals remaining in the study following treatment (P < 0.0001 by log-rank test). F, Overall survival, defined as the time elapsed between treatment initiation of the second cycle of paclitaxel and death from any cause as a percentage of all animals in each cohort, was not significantly different between the cohorts (by log-rank test).