Dr Laccetti on PSA Responses With Masofaniten Plus Enzalutamide in mCRPC

Andrew Laccetti, MD, MS, assistant attending physician, Memorial Sloan Kettering Cancer Center, discusses phase 1 findings from a phase 1/2 trial (NCT05075577) investigating masofaniten (EPI-7386) in combination with enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC), which were presented at the 2023 ESMO Congress.

This trial enrolled 18 patients with mCRPC who were treated with androgen deprivation therapy and were naive to second-generation anti–androgen receptor therapy. Patients in the first three dose-equilibration cohorts received enzalutamide at 120 mg daily in combination with masofaniten at 600 mg daily, 800 mg daily, or 600 mg twice daily. The fourth cohort received enzalutamide at 160 mg once daily plus masofaniten at 600 mg twice daily.

Across 16 evaluable patients, 88% achieved a prostate-specific antigen (PSA) response of over 50%, and 69% achieved a PSA response of over 90%. These PSA responses typically occurred within the first 3 months of treatment, Laccetti says.

The pharmacokinetics between enzalutamide and masofaniten observed in this trial disproved 1 hypothesis and confirmed another, Laccetti emphasizes. Investigators hypothesized that adding masofaniten, a CYP2C8 inhibitor, to enzalutamide would increase enzalutamide metabolism, Laccetti explains. However, masofaniten did not affect enzalutamide metabolism, which led to the initiation of the fourth trial cohort, in which patients received enzalutamide at the full dose of 160 mg daily, Laccetti notes.

Conversely, as hypothesized, enzalutamide, a CYP inducer, decreased masofaniten metabolism, according to Laccetti. However, the masofaniten concentrations were preserved within the expected therapeutic range across all cohorts, Laccetti says. Furthermore, twice-daily masofaniten dosing resulted in a favorable maintenance of minimum masofaniten concentration, allowing for effective exposure to the agent despite its pharmacokinetic interaction with enzalutamide, Laccetti explains.

Preclinical data and biological rationales indicate that using masofaniten as an end-terminal androgen receptor (AR) antagonist in combination with ligand-binding domain drugs, such as enzalutamide, can result in a deeper suppression of AR signaling, greater antitumor activity, and a delay in the development of AR-mediated resistance mechanisms compared with enzalutamide alone, Laccetti notes. Masofaniten and enzalutamide can be safely administered in combination, and the twice-daily dosing schedule for masofaniten can overcome the pharmacokinetic effect of enzalutamide on masofaniten, Laccetti concludes.

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