Masofaniten Plus Enzalutamide Demonstrates Safety and Durable Responses in mCRPC

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Masofaniten administered in combination with enzalutamide (Xtandi) was tolerable, pharmacokinetically active, and led to a decrease in prostate-specific antigen levels at the recommended phase 2 dose in patients with metastatic castration-resistant prostate cancer.

Andrew Laccetti, MD, MS

Andrew Laccetti, MD, MS

Masofaniten (formerly EPI-7386) administered in combination with enzalutamide (Xtandi) was tolerable, pharmacokinetically active, and led to a decrease in prostate-specific antigen (PSA) levels at the recommended phase 2 dose (RP2D) in patients with metastatic castration-resistant prostate cancer (mCRPC), according to findings from a phase 1/2 trial (NCT05075577) presented during the 2023 ESMO Congress.

Initial findings from the first 4 cohorts in the dose escalation phase showed that 88% of evaluable patients treated with the combination (n = 16) achieved PSA50 (decrease of 50% or greater from baseline), while 69% achieved PSA90 (decrease of 90% or greater from baseline). Additionally, 63% of patients achieved PSA90 in less than 90 days, and 56%

experienced a reduction in PSA to less than 0.2 ng/mL. Notably, investigators did not observe an association between responses to the combination and prior chemotherapy exposure in the 6 patients who were previously treated with docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC).

Moreover, administration of 600 mg of masofaniten twice daily plus 160 mg of enzalutamide daily produced a consistent reduction of PSA levels across all cohorts. Of the 6 evaluable patients treated with the recommended phase 2 combination dose, 5 experienced a PSA reduction independent from baseline levels, although 2 patients have not yet reached the 3-month follow up.

“The combination of masofaniten and enzalutamide at all doses tested is safe and well-tolerated…,” Andrew Laccetti, MD, MS, lead study author and genitourinary oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and colleagues wrote in a poster presentation of the data. “Based on the totality of the safety and pharmacokinetic data from the phase 1 portion of the study, the RP2D [recommended phase 2 dose] is 600 mg of twice-daily masofaniten plus 160 mg of once-daily enzalutamide.”

In-vitro studies have shown that masofaniten has a strong inhibitory effect on CYP2C8, the main enzyme responsible for the breakdown of enzalutamide. Consequently, administration of masofaniten alongside enzalutamide may elevate the blood concentration of enzalutamide. Notably, enzalutamide’s ability to stimulate the enzyme CYP3A4, which is involved in masofaniten metabolism, could potentially reduce plasma levels of masofaniten, thereby necessitating dose adjustments.

Based on these data, investigators sought to assess the pharmacokinetics and safety of masofaniten combined with enzalutamide in this population, and to establish the RPD2 for both agents.

This multi-center, open-label, 2-part study consisted of a phase 1 dose-equilibration portion followed by a phase 2 open-label randomized study. Patients with mCRPC who were previously treated with androgen deprivation therapy and were naïve to second-generation antiandrogens were enrolled. Prior exposure to docetaxel in the mHSPC setting was allowed.

Patients received treatment at 1 of 4 dose levels during a 28-day cycle: a 600 mg dose of once daily masofaniten and 120 mg of enzalutamide, a daily 800 mg dose of masofaniten and 120 mg of enzalutamide, a twice daily dose of 600 mg of masofaniten and 120 mg of enzalutamide, and a twice daily 600 mg dose of masofaniten and 160 mg of enzalutamide.

A 7-day run-in phase with masofaniten monotherapy was conducted to assess potential drug-drug interactions and determine pharmacokinetic parameters at steady state for each dose level. Masofaniten was administered at the start of cycle 1, and enzalutamide was then introduced at day 1 of cycle 1. Pharmacokinetic parameters were assessed at day 7 and 28 and compared with published data. After cycle 1, the combination was administered continuously.

At the time of data cutoff, a total of 18 patients were enrolled onto the study. Of these, 3 patients were enrolled in cohort 1, 4 were each enrolled in cohorts 2 and 3, and 7 were enrolled in cohort 4. All were evaluable for safety, and 16 patients were evaluable for efficacy. Notably, 2 of the 3 patients enrolled in cohort 1 escalated to the cohort 2 dose of masofaniten after 9 cycles. Additionally, 2 patients from cohort 2 underwent dose escalation to cohort 3 after 8 to 10 cycles.

Regarding baseline characteristics, the median age of patients was 70 (range, 68-73), 73.5 (range, 61-86), 72.0 (range, 60-75), and 75.0 years (range, 65-89). All patients in cohort 1 had an ECOG performance status of 1, followed by 50% of patients in both cohorts 2 and 3, and 28.6% of patients in cohort 4. Bone-only disease was observed in 33.3%, 100.0%, 75.0%, and 14.3% of those in cohorts 1, 2, 3, and 4, respectively. The highest percentage of patients previously exposed to chemotherapy was in cohort 2 (75.0%) followed by cohort 1 (66.6%), cohort 4 (28.6%), and cohort 3 (25.0%). Median baseline PSA level was 24.9 ng/mL (range, 2.6-26.4) in cohort 1, 2.54 ng/mL (range, 1.84-12.09) in cohort 2 , 2.13 ng/mL (range, 1.35-20.6) in cohort 3, and 13.5 ng/mL (range, 1.18-5.65) in cohort 4.

Among the patients with non-measurable disease (n = 13), 11 achieved stable disease (SD) with the combination and 2 experienced progressive disease (PD). Two patients were not deemed efficacy evaluable due to insufficient drug exposure. Two patients with measurable disease (n = 5) achieved a partial response, 2 achieved SD and 1 experienced PD.

Assessment of pharmacokinetic data revealed that masofaniten did not influence enzalutamide exposure, indicating that the full 160 mg dose of enzalutamide can be utilized in the combination. As expected, enzalutamide was found to significantly reduce masofaniten exposure. Similar effects were observed with the daily 160 mg dose and the 120 mg dose of enzalutamide. However, twice-daily dosing of 600 mg of masofaniten was found to maintain active levels of the drug, thereby compensating for this decrease.

A total of 5 patients discontinued treatment due to disease progression (n = 3), brain abscess not related to treatment (n = 1), or non-cancer related death (n = 1). The most frequently observed adverse effects (AEs) with the combination were low grade, related to androgen receptor inhibition or gastrointestinal tract irritation, and consistent with the safety data for enzalutamide monotherapy. Notably, one grade 3 rash was observed in cohort 4 during the dose-limiting toxicity period; this AE was determined to most likely be treatment related. The patient went on to discontinue treatment due to disease progression with liver metastasis.

Other common, low-grade treatment-emergent AEs included hypertriglyceridemia (grade 1, 27.8%; grade 2, 11.1%), fatigue (16.7%; 11.1%), diarrhea (16.7%; 5.6%), dizziness (16.7%; 0.0%), nausea (11.1%; 5.6%), rash (11.1%; 0.0%) hot flashes (5.6%; 5.6%) hypertension (0.0%; 11.1%), memory impairment (11.1%; 0.0%), weight loss (11.1%; 0.0%), alopecia (5.6%; 0.0%), alanine aminotransferase increase (5.6%; 0.0%), aspartate aminotransferase increase (0.0%; 5.6%), cough (5.6%; 0.0%), dysuria (5.6%; 0.0%), edema (5.6%; 0.0%), gait disturbance (5.6%; 0.0%), headache (5.6%; 0.0%), increased lactate dehydrogenase levels (5.6%; 0.0%), lymphocyte decrease (0.0%; 5.6%), paresthesia (5.6%; 0.0%), and vomiting (5.6%; 0.0%).

These findings support the continued investigation of masofaniten and enzalutamide, and the randomized phase 2 portion of the study is currently ongoing.


Laccetti A, Chatta G, Kyriakopoulos C, et al. Phase I/II trial of oral EPI-7386 in combination with enzalutamide (enz) compared to enz alone in metastatic castration-resistant prostate cancer (mCRPC) subjects: current phase I (PI) results. Ann Oncol. 2023;34(suppl 2):S982-S983. doi:10.1016/j.annonc.2023.09.2761

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