An Open-label, Phase 1 Dose-finding Study of Single-agent IMU-935, a Novel RORγ/RORγt Inverse Agonist, in Patients...

Retinoic acid receptor-related orphan receptor gamma (RORγ) is frequently overexpressed in metastatic castration-resistant prostate cancer (mCRPC) and, together with retinoic acid-related orphan receptor gamma t (RORγt), can increase androgen receptor (AR) signalling and promote a proinflammatory tumour microenvironment.

In this phase 1 dose-finding study (NCT05124795), men with mCRPC received the oral RORγ/RORγt inverse agonist IMU-935 across three dose levels (150 mg, 300 mg, or 450 mg twice daily). The primary objective was to determine the recommended phase 2 dose according to a Bayesian optimal interval design. Key secondary endpoints included evaluation of pharmacokinetics and pharmacodynamics, as well as antitumour activity in terms of prostate-specific antigen (PSA), circulating tumour cells (CTCs), and responses according to Response Evaluation Criteria in Solid Tumours.

Eighteen men received IMU-935. No dose-limiting toxicities (DLTs) or any grade (G) ≥3 adverse events (AEs) were reported. The most common treatment-related AEs (TRAEs) were G1 nausea (n = 4; 22%) and G1 vomiting (n = 3; 17%). The only G2 TRAEs observed were anaemia (n = 2; 11%) and gastroesophageal reflux disease (n = 1; 6%). Overall, six men (33%) had a decrease in CTC level from ≥5 to <5 cells/7.5 ml, while one participant whose tumour had mismatch repair deficiency (MMRd) experienced a ≥50% decline in PSA and radiologically stable disease for >6 mo. The median time to PSA progression was 8 wk (range 2-36 wk), and median radiological progression-free survival was 11 wk (range 3.4-36 wk).

IMU-935 was well tolerated with no DLTs. One participant with MMRd mCRPC experienced a PSA response. Overall, however, robust antitumour activity was not observed in this molecularly unselected cohort.