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

• Published in: Clinical cancer research Vol. 28; no. 15; pp. 3214 - 3224
• Main Authors: Munster, Pamela N., Greenstein, Andrew E., Fleming, Gini F., Borazanci, Erkut, Sharma, Manish R., Custodio, Joseph M., Tudor, Iulia Cristina, Pashova, Hristina I., Shepherd, Stacie Peacock, Grauer, Andreas, Sachdev, Jasgit C.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 02.08.2022
• Subjects: Albumins; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Bridged-Ring Compounds; Clinical Trials: Targeted Therapy; Glucocorticoids - therapeutic use; Humans; Isoquinolines; Paclitaxel; Pancreatic Neoplasms - pathology; Pyrazoles; Pyridines; Receptors, Glucocorticoid; Taxoids - therapeutic use
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-21-4363

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 (GR) modulator relacorilant with taxanes can enhance antitumor activity. 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. In OVCAR5 cells, relacorilant reversed the deleterious effects of glucocorticoids on paclitaxel efficacy (P < 0.001). Compared with paclitaxel alone, relacorilant + paclitaxel reduced tumor growth and slowed time to progression in xenograft models (both P < 0.0001). 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 (≥16 weeks) with relacorilant + nab-paclitaxel and 28.6% (12/42) experienced longer duration of benefit than on prior taxane (up to 6.4×). The most common dose-limiting toxicity of the combination was neutropenia, which was manageable with prophylactic G-CSF. Clinical benefit with relacorilant + nab-paclitaxel was also associated with GR-regulated transcript-level changes in a panel of GR-controlled genes. The observed preclinical, clinical, and GR-specific pharmacodynamic responses 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.