ASCO GU 2023: Oral EPI-7386 in Patients with Metastatic Castration-Resistant Prostate Cancer

( The need for additional effective therapies for metastatic castration resistant prostate cancer (mCRPC) is omnipresent, particularly as therapies previously used in later lines or only in CRPC are now being deployed in earlier disease states. Among well-established mechanisms of resistance are alterations in the androgen receptor (AR), including mutations and copy number changes, which effect its activity and ligand independent signaling. EPI-7386 is an aniten, a class of compounds which can inhibitor AR activity by binding to the N-terminal domain (NTD) irrespective of resistance abrogation in the ligand binding domain that may otherwise make AR signaling inhibitors ineffective, as supported by preclinical data. Trial of this agent in a first-in-human study in heavily pre-treated patients with mCRPC was undertaken (NCT04221222), and preliminary data are reported here.

As reported by Dr. Russell Kent Pachynski and colleagues, this phase I, open-label, multicenter, dose-escalation study contained multiple parts, as follows:dosing regime.jpg

As illustrated above, daily and twice daily dosing in dose-escalation were completed in the Phase 1a. Patient demographics, with regard to prior therapies and sites of disease were also different between the dosing regimens, with no limitations on prior therapy number, prior receipt of chemotherapy, or sites of disease in the daily dosing group. Endpoints included safety and tolerability, evaluation of drug exposure, and antitumor activity (e.g., duration of treatment, changes in PSA or in rate of PSA doubling [PSADT], changes in circulating tumor DNA, and changes in radiographic disease burden).

31 patients enrolled in daily and 8 in the twice daily dosing cohort with evidence of more heavily pre-treated and lower performance status patients in the first group. In fact, the daily dosing group averaged a seven prior therapies (median, range 4-13). Prior exposures to AR pathway inhibitors (e.g., abiraterone acetate, enzalutamide) was observed in most patients, and is a setting where additional conventional AR-directed therapies would be expected to fail.parameters.jpg

In safety assessments, the authors report that EPI-7386 is well-tolerated with all treatment-related adverse events (TRAEs) of grade 1 or 2, with exception of one occurrance each of grade 3 hypertension and anemia. Both were later considered to be unlikely related to EPI-7386 administration. For doses greater than 400 mg daily, drug exposures were at or above those associated with antitumor activity in animal models. Elevation in serum triglycerides and LDL was observed with higher troughs of EPI-7386, but significantly only in patients who were not taking statins.


In efficacy analyses, the authors describe PSA changes, both declines in PSA and increases in PSA doubling times, corresponding to a presumed slowing of tumor growth. In the daily dosing, approximately 30% of patients remained on therapy for longer than 3 months, and of those who progressed prior to or at 12 weeks had baseline adverse parameters, including visceral metastases, neuron-specific enolase, prior chemotherapy exposure, or receipt of >3 prior lines of therapy for mCRPC. One subject, of these 31 remains on therapy at 1000 mg daily dose level. Twice daily dosing resulted in 5 of 8 patients continuing therapy for greater than 3 months. The 1b patient (600 mg BID) data appear immature.


As many patients had rapidly progressive disease (by PSADT), the authors described changes in PSA doubling time following initiation of therapy. Among the 25 patients who completed three cycles of treatment (12 weeks) without decrease in PSA, 10 showed a reduction in PSADT as shown below. Among nine patients with measurable nodal disease at baseline, 7 experienced radiographic decrease in disease burden, even in the absence of PSA decline.

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Seeking associations with response and resistance, the authors also profiled the ctDNA content of subjects treated on study. Common driver and disease-associated alterations were observed, and were stratified by time on therapy (> or ≤12 weeks) and responses (e.g., PSA changes, PSADT changes, radiographic changes). Presence of alterations in AR and its associated pathway (i.e., FOXA1, NCOA2, FOXP1) appear associated with greater likelihood of response to EPI-7386, consistent with the drug’s mechanism of action.


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In conclusion, the authors of the study state that EPI-7386 monotherapy is safe and well-tolerated, up to a total daily dose of 1200 mg with achievement of target clinical exposures. In addition, preliminary antitumor activity, enriched in those patients with disease driven by alterations in AR, was observed. The phase 1b dose expansion study is underway in a less heavily pre-treated population.

Presented by: Russell Kent Pachynski, MD, Washington University School of Medicine in St. Louis

Written by: Jones Nauseef, MD, PhD, Assistant Professor of Medicine within the Division of Hematology and Medical Oncology, Sandra and Edward Meyer Cancer Center, and Englander Institute for Precision Medicine Weill Cornell Medicine and Assistant Attending physician at NewYork-Presbyterian Hospital. @DrJonesNauseef on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.

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Oral EPI-7386 Monotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer - Russell Pachynski