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 

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.

Editor's Note: Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.

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Andrew Laccetti, MD, MS, discusses phase 1 findings from a phase 1/2 trial investigating masofaniten in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer. 

Dr Laccetti on the Use of Masofaniten Monotherapy in mCRPC

Andrew Laccetti, MD, MS, medical oncologist, assistant attending, Genitourinary Medical Oncology, Memorial Sloan Kettering Cancer Center, discusses results from a phase 1 trial (NCT04421222) of masofaniten (EPI-7386) monotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC) and highlights the rationale for launching a phase 1/2 study (NCT05075577) evaluating masofaniten in combination with enzalutamide (Xtandi) vs enzalutamide alone in this patient population.

The single-arm, first-in-human, phase 1 trial with masofaniten monotherapy has been discussed at prior medical meetings, Laccetti begins. This study aimed to determine the ideal monotherapy dosage for the agent and assess its safety, toxicity, and initial efficacy. In the trial, this agent was highly tolerable across all tested dose levels, with adverse effects (AEs) largely resembling those of other androgen receptor (AR) antagonists and androgen deprivation therapy (ADT), Laccetti explains. These include AEs such as fatigue and hot flashes. Although a minority of patients experienced gastrointestinal AEs such as diarrhea, the overall safety profile of masofaniten closely aligns with that of ADT and other AR pathway inhibitors, he notes.

Accordingly, oncologists remain optimistic regarding the continued tolerability of masofaniten, Laccetti continues. Specific patient groups have experienced early indications of positive responses, fueling the ongoing investigation of the agent and its use in a broader patient population, he emphasizes.

Furthermore, the phase 1/2 trial investigating the combination of masofaniten and enzalutamide represents another significant step in human clinical research, Laccetti continues. Preclinical evidence strongly supports the idea that this combination could offer enhanced treatment efficacy compared with that elicited by either agent alone, he says, noting that these data are from preclinical studies and require further exploration in human trials. The rationale behind this investigation is that this approach may delay or reduce the development of resistance mechanisms, he explains. The primary goal of the combination study is to establish the safety of using masofaniten and enzalutamide together and determine the recommended dosage for both after considering the potential for pharmacokinetic interactions between these 2 drugs, Laccetti concludes.

Andrew Laccetti, MD, MS, discusses results from a phase 1 trial of masofaniten monotherapy in patients with metastatic castration-resistant prostate cancer and highlights the rationale for launching a phase 1/2 study evaluating masofaniten in combination with enzalutamide vs enzalutamide alone in this patient population.


Andrew Laccetti, MD, MS

Articles

Dr Laccetti on PSA Responses With Masofaniten Plus Enzalutamide in mCRPC

Dr Laccetti on the Use of Masofaniten Monotherapy in mCRPC