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 

 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.”

®, 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.

: 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?

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].

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. 

. 2023;42(suppl 4):141. doi:10.1200/JCO.2024.42.4_suppl.141

Articles

Christos Kyriakopoulos, MD, discusses key phase 1 results from the ongoing evaluation of masofaniten and enzalutamide in patients with mCRPC.

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

Dr Kyriakopoulos on the Initial Activity and Safety of Masofaniten Plus Enzalutamide in mCRPC

Christos Kyriakopoulos, MD, medical oncologist, associate professor, Department of Medicine, Division of Hematology, Medical Oncology and Palliative Care, the University of Wisconsin School of Medicine and Public Health, discusses initial safety, pharmacokinetic, and efficacy findings with the addition of masofaniten (EPI-7386) to enzalutamide (Xtandi) in metastatic castration-resistant prostate cancer (mCRPC).

A multicenter phase 1/2 trial (NCT05075577) evaluated patients with mCRPC who had not been previously exposed to second-generation anti-androgen therapy. In the phase 1 dose equilibrium portion, patients were randomly assigned to received either 1 of 4 escalating doses of enzalutamide at 120 mg or 160 mg and masofaniten at 600 mg every day or twice a day. Primary end points included safety and pharmacokinetics.

 showed that the combination therapy was safe and tolerable, with primarily low-grade AEs and a safety profile consistent with that of enzalutamide monotherapy, Kyriakopoulos reports. The most frequently observed AEs attributed to masofaniten were related to androgen receptor inhibition and gastrointestinal tract irritation. One grade 3 dose-limiting toxicity of maculopapular rash was observed at dose level 4, and the patient discontinued study treatment. However, no serious AEs were observed, Kyriakopoulos adds. The recommended phase 2 dose of enzalutamide was established as the full approved dose of enzalutamide at 160 mg per day and 600 mg of masofaniten twice a day to compensate for the reduction in exposure caused by enzalutamide, he states.

Notably, a high percentage of patients treated with masofaniten plus enzalutamide achieved significant declines in PSA levels regardless of the starting PSA levels, Kyriakopoulos continues. At a median follow-up of 11.1 months, 81% of patients experienced a decline greater than 90% and 60% achieved PSA90 within 90 days, Kyriakopoulos details. Additionally, 88% of patients achieved a 50% reduction of PSA from baseline (PSA50), and 56% achieved a PSA level less than 0.2 ng/ml, he says. Data on disease progression and other efficacy findings were still immature at the time of analysis, Kyriakopoulos notes.

A total of 13 patients are still on treatment, Kyriakopoulos continues. Reasons for treatment discontinuation included disease progression (n = 3), development of a non-cancer related brain abscesses (n = 1) , and non-cancer related death (n = 1), Kyriakopoulos says. Notably, the latter 2 patients had reached PSA50, Kyriakopoulos states.

The phase 2 portion of the study is actively enrolling patients from this population at multiple sites across the United States, Canada, and Australia.

Videos

Christos Kyriakopoulos, MD, discusses data from a phase 1/2 study of masofaniten plus enzalutamide in metastatic castration-resistant prostate cancer.
 

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 

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. 

. 2023;34(suppl 2):S982-S983. doi:10.1016/j.annonc.2023.09.2761

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.

Masofaniten Plus Enzalutamide Demonstrates Safety and Durable Responses in mCRPC 

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.

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.


The emergence of a novel class of compounds, known as anitens, potentially offers clinicians the ability to elongate responses for patients with metastatic castration-resistant prostate cancer (mCRPC), with the first-in-class N-terminal domain androgen receptor (AR) inhibitor masofaniten (EPI-7386) showing promise as it moves to the phase 2 portion of a phase 1/2 trial (NCT05075577).

By targeting the N-terminal domain of the AR, masofaniten blocks transcription regardless of AR resistance mechanisms driven by the ligand-binding domain. Following the demonstration of promising preliminary activity in the phase 1 dose-equilibration portion of the trial in combination with the AR inhibitor enzalutamide (Xtandi), the recommended phase 2 dose (RP2D) of masofaniten was determined and the phase 2 portion of the study is enrolling patients with mCRPC (

 In combination, the agents have shown the ability to produce a deeper blockade of the AR pathway and cause increased antitumor activity.

“We’re hopeful that masofaniten will be positioned as a chemotherapy-sparing treatment option for patients who have developed resistance to other androgen receptor pathway inhibitors and androgen deprivation therapy,” Andrew Laccetti, MD, MS, a genitourinary oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and Montvale, New Jersey, said in an interview with 

. “Targeting patients [who] have AR-centered resistance mechanisms [is key]; masofaniten may be a means to help overcome this resistance and provide a tool to further support cancer control through an AR-blocking approach.”

Findings from the phase 1 dose optimization portion of the multicenter, open-label trial, which were presented at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium, showed that masofaniten in combination with enzalutamide was well tolerated; preliminary activity was observed. Patients were treated in 4 cohorts: cohort 1 received oral masofaniten at a dose of 600 mg once daily and oral enzalutamide at 120 mg once daily; cohort 2 was treated with masofaniten 800 mg once daily and enzalutamide 120 mg once daily; cohort 3 received masofaniten 600 mg twice daily with enzalutamide at 120 mg once daily; and cohort 4 was given masofaniten 600 mg twice daily with enzalutamide 160 mg once daily.

An announcement from ESSA Pharma in September 2023 noted that the RP2D has been determined as masofaniten 600 mg twice daily combined with enzalutamide 160 mg once daily based on data from cohort 4 of the phase 1 portion of the trial. Updated results from the phase 1 portion of the trial will be shared at the European Society for Medical Oncology Congress 2023.

Cohorts 1 and 2 of Phase 1 Demonstrate Early Activity

Of patients enrolled in cohort 1 (n = 3) and cohort 2 (n = 4), 1 patient discontinued treatment with masofaniten and enzalutamide after a single cycle of therapy due to treatment with a CYP3A4/5 inhibitor causing decreased exposure to the study drugs; this patient was not included in the efficacy-evaluable population.

 “It’s important to recognize the combination was delivered in patients [who] were AR inhibitor naïve,” Laccetti said. “In that effect, we do anticipate a very high response rate to enzalutamide monotherapy. Nevertheless, the response rate is encouraging and does support further exploration of the combination in a randomized fashion.”

Data from the cohorts revealed that of the 6 evaluable patients, 5 experienced rapid and deep reductions in prostate-specific antigen (PSA) levels, with a PSA decrease of greater than 90% from baseline recorded. Additionally, 4 of the 6 patients (67%) experienced a PSA of less than 0.2 ng/mL irrespective of whether they previously received chemotherapy, which 5 of the 7 patients enrolled in cohorts 1 and 2 did. Most patients (83%) experienced a decrease in PSA levels of more than 50% from baseline (PSA50), and the median baseline PSA level was 2.7 ng/mL (range, 1.8-1209.0).

“There is evidence to support [the notion] that the combination has some rational efficacy, suggesting that we’re observing greater treatment efficacy with enzalutamide and masofaniten compared with either agent alone,” Laccetti said. “We’re interested to examine this postulate in a human population, but understanding that 2 mechanistically different AR antagonists, one acting at the ligand-binding domain and one at the end terminal domain, may create an environment in which we’re performing a deeper AR antagonism and hopefully a delay or diminishment of potential resistance mechanisms can occur.”

The phase 1 portion of the trial also examined drug-drug interactions with a 7-day run-in phase with masofaniten alone at the beginning of cycle 1 for each dose level; enzalutamide was given on day 1 of cycle 1.

 “We’ve observed in the first portion of the study that there is an interplay between the 2 drugs,” Laccetti explained. “We initially had hypothesized that there may be an increase in serum concentration of enzalutamide in combination with masofaniten through interactions with cytochrome P450 enzymes, specifically seeing masofaniten as a potential inhibitor of drug metabolism for enzalutamide. To date, we have not observed this effect.”

The phase 1 portion found that masofaniten did not have a significant effect on enzalutamide exposure, allowing enzalutamide to be safely administered at a full dose of 160 mg; however, enzalutamide significantly reduced the exposure of masofaniten, which investigators hypothesized may be through induction of CYP3A. Investigators noted that the reduction of masofaniten exposure can be compensated for with twice-daily dosing of the agent.

“The initial dose of 120 mg of enzalutamide will be increased to the standard dosing of 160 mg [in the phase 2 portion of the trial], understanding that that interplay has not yet been observed,” Laccetti said. “We have seen that enzalutamide does function as an inducer of cytochrome P450 enzymes that effectively metabolize masofaniten; this will in fact lead to lower concentrations of masofaniten in the combination. However, all tested doses with patients to date, although lower than what the monotherapy pharmacokinetics might be, have fallen within a concentration that we expect masofaniten to be an effective drug in preclinical modeling.”

Masofaniten Displays Tolerable Safety Profile 

Masofaniten monotherapy was well tolerated up to a dose of 1200 mg total daily, with 600 mg given twice daily, according to findings from a first-in-human phase 1 trial (NCT04421222). The most common grade 1 and grade 2 treatment-related adverse effects (TRAEs) reported in patients with mCRPC (n = 45) included nausea (15.5% and 4.4%, respectively), fatigue (8.8% and 11.1%), diarrhea (8.8% and 4.4%), anemia (8.8% and 2.2%), increased aspartate aminotransferase (4.4% and 0.0%), and hot flush (0.0% and 8.8%). One patient experienced grade 3 hypertension and another experienced grade 3 anemia; however, these occurrences were considered unlikely to be related to masofaniten.

“Masofaniten has proven to be an extremely tolerable drug at essentially all dose levels that have been investigated, with [AEs] that are very similar to those of other AR antagonists and androgen deprivation therapy in general,” Laccetti said.“[AEs] such as fatigue and hot flashes have been observed, and a minority of patients have gastrointestinal AEs such as diarrhea, but in general, the experience of patients has been very similar to [that of those who received] androgen deprivation therapy or other AR pathway inhibitors to date.”

Additionally, early data from cohorts 1 and 2 of the phase 1/2 trial examining masofaniten plus enzalutamide demonstrated that the combination had a safety profile consistent with other second-generation antiandrogen agents. No dose-limiting toxicities were observed. The only serious AE was with a single case of myocardial infarction; however, it was unrelated to masofaniten treatment. The most common grade 1 and 2 TRAEs experienced by patients in the safety population (n = 7) were nausea, fatigue, hot flush, hypertension, and hypertriglyceridemia, with each AE occurring in 2 patients. No grade 3 TRAEs were reported.

The phase 2 portion of the study will enroll patients with progressive mCRPC, with a primary end point of 12-week PSA50 rate. Additional inclusion criteria include an ECOG performance status of 0 or 1 and patients must be naïve to second-generation antiandrogen agents.

“Barriers to enrollment [to phase 2] include the designation that patients enrolled in the combination trial must be naïve to receiving a second-generation antiandrogen [agent] such as abiraterone acetate [Zytiga], enzalutamide, or apalutamide [Erleada],” Laccetti noted. “This practice pattern is somewhat incongruent with how we care for patients with castration-sensitive metastatic prostate cancer in the United States, understanding the majority of patients do receive one of these agents in the castration-sensitive setting. There have been discussions and there is consideration to expand enrollment in our phase 2 portion. However, planning to that capacity has yet to be determined definitively.” Further, the trial prohibits the prior use of strong inhibitors of CYP2C8, strong inducers of CYP3A, and narrow therapeutic index sensitive CYP2C8 or sensitive substrates for CYP3A and CYP2B6.

Laccetti AL, Chatta GS, Iannotti N, et al. Phase 1/2 study of EPI-7386 in combination with enzalutamide (enz) compared with enz alone in subjects with metastatic castration-resistant prostate cancer (mCRPC). 

. 2023;41(suppl 6):179. doi:10.1200/JCO.2023.41.6_suppl.179

EPI-7386 in combination with enzalutamide compared with enzalutamide alone in subjects with mCRPC. ClinicalTrials.gov. Updated March 6, 2023. Accessed October 9, 2023. https://clinicaltrials.gov/ct2/show/NCT05075577

ESSA Pharma announces initiation of phase 2 study evaluating masofaniten (EPI-7386) in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer. News release. ESSA Pharma. September 18, 2023. Accessed October 10, 2023. bit.ly/3Qbv5RN

Pachynski RK, Iannotti N, Laccetti AL, et al. Oral EPI-7386 in patients with metastatic castration-resistant prostate cancer. 

. 2023;41(suppl 6):177. doi:10.1200/JCO.2023.41.6_suppl.177

The emergence of a novel class of compounds, known as anitens, potentially offers clinicians the ability to elongate responses for patients with metastatic castration-resistant prostate cancer, with the first-in-class N-terminal domain androgen receptor inhibitor masofaniten showing promise as it moves to the phase 2 portion of a phase 1/2 trial.

Research Efforts Are Underway in the Prostate Cancer Paradigm | Supplements and Featured Publications

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

Dr Kyriakopoulos on the Initial Activity and Safety of Masofaniten Plus Enzalutamide in mCRPC

Masofaniten Plus Enzalutamide Demonstrates Safety and Durable Responses in mCRPC

Dr Laccetti on PSA Responses With Masofaniten Plus Enzalutamide in mCRPC

Dr Laccetti on the Use of Masofaniten Monotherapy in mCRPC

Next-Generation Aniten Masofaniten Gains Momentum in mCRPC