Masofaniten Plus Enzalutamide Shows Safety With Potentially Durable PSA Decreases in mCRPC

Christos Kyriakopoulos, MD

Early data from a phase 1/2 trial (NCT05075577) indicate that oral masofaniten (EPI-7386) in combination with enzalutamide (Xtandi) is safe, well tolerated, and may result in rapid, durable prostate-specific antigen (PSA) decreases in patients with metastatic castration-resistant prostate cancer (mCRPC), according to Christos Kyriakopoulos, MD.

Results from the dose-escalation portion of the study were presented at the 2024 Genitourinary Cancers Symposium and indicated that with regard to safety, the most frequent adverse effects (AEs) experienced with the doublet were low grade and related to androgen receptor inhibition or gastrointestinal (GI) tract irritation. The AEs were consistent with prior data reported with enzalutamide monotherapy. No treatment-related serious AEs were observed. Moreover, the recommended phase 2 dose (RP2D) of enzalutamide was determined to be the full approved dose of 160 mg per day plus 600 mg of masofaniten twice daily to partially compensate for the drop in exposure caused by masofaniten’s interaction with enzalutamide.

Regarding PSA responses, 81% of patients (n = 16) treated with masofaniten plus enzalutamide at any dose level achieved a PSA decline greater than 90% (PSA90); 60% of patients achieved PSA90 in 90 days. Eighty-eight percent of patients achieved PSA50, and 56% achieved a PSA of less than 0.2 ng/mL. PSA responses were observed independently from starting PSA levels.

Efficacy data on disease progression are still maturing. Additionally, the phase 2 portion of the study is currently open to enrollment at approximately 25 sites in the United States, Canada, and Australia, with planned expansion to European sites.

“These results look very promising [compared with] historical data from the [phase 2] ENZA-P study [NCT04419402], as well as the [phase 3] AFFIRM [NCT00974311] and PREVAIL [NCT01212991] trials,” said Kyriakopoulous, who is a medical oncologist and an associate professor in the Department of Medicine, Division of Hematology, Medical Oncology and Palliative Care at the University of Wisconsin School of Medicine and Public Health. “Even though those were phase 3 studies and included much larger numbers of patients, [the PSA data] we have so far [with] the combination compare favorably with [what has been seen with] enzalutamide alone.”

In an interview with OncLive®, Kyriakopoulous expanded on phase 1 results from the ongoing evaluation of masofaniten and enzalutamide in mCRPC and detailed the ongoing phase 2 portion of the study that is further evaluating the efficacy of the doublet vs enzalutamide monotherapy in this population.

OncLive: What was the rationale for adding masofaniten to enzalutamide for use in patients with prostate cancer, and how might their mechanisms of action be synergistic?

Kyriakopoulos: Masofaniten is a novel hormonal therapy that binds to the N terminal domain of androgen receptors [ARs]. It doesn’t bind to the ligand-binding domain where testosterone binds, as well as like other drugs such as enzalutamide, apalutamide [Erleada], or darolutamide [Nubeqa]. The idea [of administering these agents in combination] is to attack the AR from 2 different directions. Because of the location where masofaniten binds, its action does not depend on splice variants or other mutations that might be present at the ligand-binding domain. With deeper suppression of the [AR pathway], we can [potentially] have better outcomes in patients with prostate cancer.

What is known about the drug-drug interactions between masofaniten and enzalutamide? How were these accounted for in the study design?

This [presentation featured] phase 1 results from an ongoing phase 1/2 study combining masofaniten with enzalutamide. The first step was to conduct the dose escalation. It appears that there were some drug-drug interactions between these drugs. Enzalutamide seems to induce the enzyme that metabolizes masofaniten. On the other hand, masofaniten blocks the enzyme that metabolizes enzalutamide.

The concern was that the concomitant use of the 2 drugs would decrease the plasma levels of masofaniten and increase the plasma levels of enzalutamide. For that reason, the study was designed to include 4 cohorts. For the first 3 cohorts, the starting dose for enzalutamide was lower than what we use in the clinic at 120 mg a day. We used escalating doses of masofaniten starting at 600 mg, going up to 800 mg daily, and then 600 mg twice a day. For cohort 4, we also increased the dose of enzalutamide to 160 mg daily, which is the standard dose, plus the 600-mg twice daily dose of masofaniten.

What patient population was evaluated in the study?

Most of the patients were considered high risk based on the ENZA-P study presented at the 2023 ASCO Annual Meeting. Interestingly, 44% of the patients who participated in that study had previously received docetaxel for castration-sensitive disease. Still, the results that we found in the phase 1 portion of the study look very promising.

Could you expand on the key safety and pharmacokinetic findings that were presented at the meeting?

[Across] all dose levels of masofaniten, it appears that concomitant use of the 2 drugs didn’t [substantially] affect the plasma levels of enzalutamide, whereas enzalutamide did decrease the levels of masofaniten. However, at the highest twice-daily 600-mg dose, the plasma levels of masofaniten were clinically relevant and clinically active. For that reason, the RP2D for the combination is the full dose of enzalutamide at 160 mg daily plus 600 mg twice a day for masofaniten.

In terms of safety, only 1 DLT was observed at dose level 4, and that was grade 3 maculopapular rash. Eventually, the patient came off the study, even though they had a very good response. The rest of the AEs that we noticed are similar to what we expect from the use of enzalutamide. There were some GI-related AEs, which were probably related to masofaniten. Overall, the combination was well tolerated.

What efficacy data have been seen with this combination so far?

The treatment of these patients is ongoing. However, we do have some preliminary efficacy data for PSA [responses]. It appears that PSA50 was [achieved] in 88% of patients, PSA90 [was seen] in 81% of patients, and PSA levels of less than 0.2 ng/mL [were achieved in] 56% of cases. [Of] the initial 18 patients who participated in the study, 13 are still on treatment.

Of the 5 patients who eventually discontinued the study, 3 of them came off study because of disease progression and were refractory to hormonal therapy. One came off study because of a brain abscess, and the last patient [experienced non-cancer]–related [death]. [Both of those] patients [were previously] responding to the treatment.

Regarding next steps, please describe the design and objective of the phase 2 portion of this research.

The phase 2 part of the study is ongoing. The study is open at approximately 25 sites in the United States, Australia, and Europe. The study [is randomly assigning] patients to masofaniten plus enzalutamide vs enzalutamide alone [in a] 2:1 ratio. We’re looking at [several] efficacy variables, such as the proportion of patients with PSA50 at week 12, the proportion of patients with PSA90 at weeks 12 and 24, and time to PSA progression per the Prostate Cancer Clinical Trials Working Group 3 criteria. We are assessing other variables, such as overall response rate and time to radiographic progression, as well.

What is your take-home message to colleagues about this research?

The [data we have on] PSA responses look very promising. Putting things into context, the phase 1 portion of the ongoing study only enrolled 18 patients. [However], if we look at the PSA results [from this study] compared with [those from] ENZA-p, as well as the AFFIRM and PREVAIL trials, [the data] seem [encouraging].

Reference

Kyriakopoulos C, Chatta GS, Laccetti AL, et al. Phase 1/2 trial of oral EPI-7386 (masofaniten) in combination with enzalutamide (Enz) compared to Enz alone in patients with metastatic castration-resistant prostate cancer (mCRPC): Phase 1 (P1) results and phase 2 (P2) design. J Clin Oncol. 2023;42(suppl 4):141. doi:10.1200/JCO.2024.42.4_suppl.141