Next-Generation Aniten Masofaniten Gains Momentum in mCRPC

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).¹

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 (FIGURE).^1-3 In combination, the agents have shown the ability to produce a deeper blockade of the AR pathway and cause increased antitumor activity.¹

“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 OncologyLive^®. “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.^1,3

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 2023.³

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.¹ “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.”

Pharmacokinetic Evaluation Reveals Drug-Drug Interactions

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 1.¹ “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.¹

“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.⁴

“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.¹

Phase 2 Begins Enrollment

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.^1,2

“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 CYP2B6.²

References

1. 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). J Clin Oncol. 2023;41(suppl 6):179. doi:10.1200/JCO.2023.41.6_suppl.179
2. 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
3. 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
4. Pachynski RK, Iannotti N, Laccetti AL, et al. Oral EPI-7386 in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2023;41(suppl 6):177. doi:10.1200/JCO.2023.41.6_suppl.177