ORIC-101

Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.

P1, N=41, Terminated, ORIC Pharmaceuticals | Phase classification: P1b --> P1 | N=90 --> 41 | Trial completion date: Jun 2023 --> Dec 2023 | Active, not recruiting --> Terminated; IND Withdrawn

P1, N=83, Terminated, ORIC Pharmaceuticals | Phase classification: P1b --> P1 | N=174 --> 83 | Trial completion date: Jun 2023 --> Dec 2023 | Active, not recruiting --> Terminated; IND Withdrawn

To investigate the therapeutic potential for targeting this complex, we examined the effects of highly selective inhibitors of the GR ligand-binding pocket and found that GR antagonism with ORIC-101 suppressed FOXA1/GR target expression, activation of EGF signaling, entry into the S-phase, and attendant proliferation in vitro and in vivo...There is a need to identify novel druggable dependencies. We identify a subset of NSCLCs dependent on FOXA1-GR and sensitive to GR antagonism.

P1b, N=174, Active, not recruiting, ORIC Pharmaceuticals | Trial completion date: May 2022 --> Jun 2023 | Trial primary completion date: May 2022 --> Dec 2022

P1b, N=90, Active, not recruiting, ORIC Pharmaceuticals | Trial completion date: Dec 2022 --> Jun 2023

P1b, N=174, Active, not recruiting, Oric Pharmaceuticals | Recruiting --> Active, not recruiting

We tested three AKT inhibitors: the ATP-competitive inhibitors ipatasertib (GDC-0068) and capivasertib (AZD5363), in addition to the allosteric inhibitor MK2206, in CSS media and 10% FBS, with or without supplementation of the synthetic glucocorticoid, dexamethasone...In the AKTi plus enzalutamide setting, AKT inhibition did not block the enzalutamide-mediated GR upregulation in either PTEN-null or PTEN-wildtype cells.We next evaluated whether increased GR activity mediates resistance to the enzalutamide/AKTi doublet with ipatasertib or capivasertib, and whether this resistance can be reversed with ORIC-101...ORIC-101 was able to reverse these dexamethasone-induced effects, confirmed by reduced secreted PSA levels and cell number measured at end of study. These findings indicate that GR upregulation and activation, an established resistance mechanism for antiandrogens, may drive resistance when combined with an AKT inhibitor, and the GR antagonist ORIC-101 is able to overcome this resistance and restore antitumor activity.

P1b, N=174, Recruiting, Oric Pharmaceuticals | N=42 --> 174 | Trial completion date: Jan 2022 --> May 2022 | Trial primary completion date: Jan 2022 --> May 2022