A PHASE 1B TRIAL OF MASOFANITEN (EPI-7386) IN PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC)

Abstract

Introduction

Masofaniten (EPI-7386) is a next generation aniten, a novel class of compounds designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain. Preclinical data supports disruption of AR regulated gene transcription, even in the presence of resistance mechanisms including ligand-binding domain point mutations and truncated splice variants, as a strategy to inhibit prostate cancer growth. In the Phase 1a dose-escalation study (NCT04421222), treatment with EPI-7386 monotherapy was safe, well tolerated up to a daily dose of 1200 mg (600 mg BID), achieved target clinical exposures and showed preliminary signals of antitumor activity in heavily pretreated mCRPC. We report here the results of the Phase 1b dose expansion first-in-human trial of EPI-7386 in mCRPC.

Methods

This Phase 1b, open-label, multicenter, dose expansion trial was designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of EPI-7386 in mCRPC patients (pts) progressing on standard of care treatment, including next generation antiandrogens. Two cohorts were tested, examining the 600 mg BID and 600 mg QD dosing regimens. Circulating Tumor DNA (ctDNA) samples were also collected in the study at baseline and at cycle 4 to characterize the tumor genomic profile and quantify molecular response.

Results

12 pts were enrolled in the 600 mg BID cohort (median follow up 12 months) and 12 in the 600 mg QD cohort (median follow up 8 months). Pts in both arms had a median of 2 (range 1-3) lines of prior therapy for mCRPC: 71% in both cohorts received abiraterone and at least one second generation AR inhibitor (enzalutamide, darolutamide or apalutamide). EPI-7386 was safe and well tolerated at both dosing schedules. The majority of related adverse events (AEs) were grade 1 (47%), and grade 2 (41%). AEs were consistent with AEs associated with second-generation antiandrogens (i.e. anemia, fatigue and hypertension), and no differences were observed between EPI-7386 600 mg QD and BID dosing. As expected, 600 mg BID dosing resulted in higher PK parameters at steady state, with a mean AUC_0-24 of 357,000 hr*ng/mL and a mean C_last of 14,500 ng/mL, in comparison to a mean AUC_0-24 of 246,000 hr*ng/mL and a mean C_last of 7,120 ng/mL for the 600 mg QD cohort. Both dosing regimens resulted in exposures in the range of those associated with antitumor activity in preclinical models. Evidence of antitumor activity was observed in ∼1/3 of the patients in both cohorts. Notably, genomic characterization of ctDNA samples showed, beside the expected alterations in the AR pathway (AR mutations, amplifications, structural rearrangements), additional molecular alterations associated with disease aggression and lineage plasticity (P53 mut, PTEN deletion, RB1 deletion).

Conclusions

Data from the Phase 1 dose expansion portion of the first-in-human study with EPI-7386 monotherapy confirmed the favorable safety and tolerability profile of the drug together with the achievement of clinically relevant exposures by both doses/regimens tested. Clinically relevant anti-tumor activity was observed in both arms in a small subset of patients displaying fewer molecular alterations outside of the AR pathway. Based on these observations, the clinical development of masofaniten is now focusing on its combination with other AR pathway inhibitors (NCT05075577; NCT05295927; NCT06312670) in earlier lines of treatment for mCRPC in combination with standard of care AR inhibitors.