ESSA Pharma‘s small molecule androgen receptor inhibitor, EPI-506 (ralaniten acetate), has shown a favorable safety and tolerability profile among end-stage prostate cancer patients enrolled in a Phase 1/2 trial, as well as promising preliminary efficacy in higher-dose cohorts.
Dr. Kim N. Chi, a prostate cancer expert at Vancouver’s BC Cancer Agency, gave a poster presentation at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting, held June 2-6 in Chicago.
The study is titled “Efficacy, safety, tolerability and pharmacokinetics of EPI-506 (ralaniten acetate), a novel inhibitor of androgen receptor (AR) N-terminal domain (NTD) inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC) progressing after enzalutamide and/or abiraterone.”
Phase 1 of the ongoing Phase 1/2 clinical trial (NCT02606123) evaluates the safety, pharmacology, dosing and anti-tumor activity of EPI-506 in 21 men with end-stage mCRPC, the lethal variant of the disease that develops even after castrate levels of testosterone. These patients had been unsuccessfully subjected to four or more prior therapies with Xtandi (enzalutamide) and/or Zytiga (abiraterone acetate), and had received a maximum of one line of chemotherapy.
The men self-administered oral doses of EPI-506 ranging from 80 mg to 2400 mg, with mean drug exposure of 87 days. Of the 21 men, 17 discontinued treatment, mainly due to progression of the disease. Three have undergone extended treatment (with a median of 286 days), after scaling up the EPI-506 dose. Importantly, researchers observed lower levels of PSA — a protein produced by prostate cells and a marker of prostate cancer — in four men taking more than 1280 mg.
Doses of EPI-506 up to 2400 mg were well tolerated and showed an acceptable safety profile. The most common adverse events were diarrhea and nausea. Anemia was the only severe adverse event observed in more than one patient, but was considered unrelated to EPI-506. Other adverse effects of the same magnitude were not unequivocally proven to be related to EPI-506 treatment.
Scientists also observed that EPI-506 doses of more than 2400 mg could reach the anticipated range to significantly inhibit tumor growth. Additional patients are still being enrolled to study a higher dose of 3600 mg.
“To see some indication of PSA responses in such a heavily treated patient population is encouraging,” Chi said in a press release. The scientist added that, given the current good safety and tolerability results of EPI-506, data from patients receiving higher doses are highly anticipated — but that new research efforts to develop therapies for prostate cancer, the second most common cancer in men, are greatly needed. “Despite the therapeutic advances made in recent years, prostate cancer patients eventually progress on these treatments, so finding new options to complement or follow these therapies is absolutely essential.”
EPI-506 is a first-in-class molecule that blocks a novel target in the androgen receptor, the N-terminal domain, which controls the receptor’s function. Current hormone therapies prevent androgen from binding the receptor, but cells often develop resistance through mutations in the receptor. By targeting the N-terminal domain, EPI-506 is believed to bypass these resistance mechanisms, targeting both the normal androgen receptor and its treatment-resistant variants.
“EPI-506 represents a novel approach to blocking the androgen pathway,” said Dr. David R. Parkinson, ESSA’s president and CEO. “We have observed signs of clinical activity at the higher doses in this analysis, which correlates with our preclinical modeling.”