EXTRA-PC: A phase II trial of masofaniten (EPI-7386) and enzalutamide with androgen deprivation therapy (ADT) for patients with metastatic hormone-sensitive prostate cancer (mHSPC).

148 Background: Masofaniten is a next-generation aniten which showed promising activity and safety in patients with metastatic castrate-resistant prostate cancer (mCRPC) (NCT05075577). Anitens are a family of oral N-terminal domain (NTD) inhibitors of the androgen receptor (AR). They may help overcome AR resistance mechanisms at the ligand-binding domain (LBD), which is the binding site of currently approved androgen receptor pathway inhibitors (ARPIs) such as enzalutamide, apalutamide, and darolutamide. The addition of an aniten to an ARPI and ADT may improve outcomes for patients with mHSPC over ARPI and ADT alone. Methods: In this investigator-initiated, phase II, single-institution trial, patients with treatment-naïve mHSPC were enrolled in a Simon 2-stage study design to receive the combination of masofaniten 600 mg BID and enzalutamide 160 mg daily with ADT. The primary endpoints included undetectable PSA (PSA <0.2 ng/mL) at 6 months, PSA progression-free survival (PFS), and radiographic PFS. The secondary endpoints were treatment-emergent adverse events and pharmacokinetics. The study was designed to enroll 35 patients (13 patients in stage 1, then 22 patients in stage 2). The trial would move to stage 2 if 9 or more subjects achieved an undetectable PSA at 6 months. Results: All 13 patients who were screened were enrolled into stage 1. Five were African American, and eight were Caucasian. Eleven patients had de novo metastatic disease. Median age was 68 years (range 52-75) at time of enrollment. Metastatic sites included lymph node (100%) and bone (85%). No patients had visceral metastases. Median PSA at time of enrollment was ng/mL (range 0.23-171.87), and 62% had a Gleason grade group 4-5. Median follow up time was 9.9 months (range 7.7-13.6). Ten of 13 patients (77%) achieved a PSA <0.2 ng/mL at 6 months, achieving the threshold to enroll to stage 2. Median time on masofaniten was 3.0 months (range 0.7-5.1). Two patients (16%) developed grade ≥3 adverse events (AEs) of neutropenia that were unrelated to the study drug. There were no serious treatment-related AEs. One patient had radiographic progression to mCRPC at 6.7 months and died of disease progression at 7.7 months. The remaining 12 patients are alive with no PSA or radiographic progression at the time of data cutoff. Based on the results of the mCRPC study (NCT05075577), further development of masofaniten was terminated by the sponsor. Thus, this study was closed prior to expansion to stage 2, and pharmacokinetics were not performed. Patients who were still on masofaniten discontinued the study drug and continued enzalutamide and ADT. Conclusions: The triplet combination of masofaniten, enzalutamide, and ADT for mHSPC did show efficacy and had an acceptable safety profile. Dual inhibition of the NTD and LBD of the AR is feasible in this setting. Clinical trial information: NCT06312670 .