858 Therapeutics' PARG Inhibitor ETX-19477 Shows 57% ORR in BRCA-Mutated Ovarian and Breast Cancer, Earns FDA Fast Track Designation
核心洞察
ETX-19477, an oral PARG (搜索) inhibitor, demonstrated a 57% objective response rate in a Phase 2-eligible subset of BRCA-mutated ovarian and HR+/HER2- breast cancer (搜索) patients (n=7).
Durable RECIST responses were observed in both tumor types, providing the first clinical proof-of-concept for PARG (搜索) inhibition in ovarian and breast cancer.
The drug was generally well tolerated with low rates of hematologic toxicity, supporting continued monotherapy and future combination development.
858 Therapeutics (搜索) announced preliminary safety and efficacy data from its ongoing first-in-human Phase 1/2 trial of the PARG (搜索) inhibitor ETX-19477, alongside a U.S. FDA Fast Track designation for the candidate in BRCA-mutated HR+/HER2- unresectable or metastatic breast cancer. The clinical data were released in an ASCO abstract ahead of a poster presentation at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, scheduled for Saturday, May 30, 2026.
The ASCO abstract includes clinical data from 45 patients enrolled in the Phase 1a/b dose escalation and expansion portions of the study. The poster presentation features an expanded dataset of 53 patients, including seven patients who meet the eligibility criteria for the ongoing Phase 2 expansion cohorts in BRCA-mutated ovarian cancer (搜索) and HR+/HER2- breast cancer (搜索).
Clinical Efficacy in the Phase 2-Eligible Subset
In the Phase 2-eligible subset, ETX-19477 demonstrated robust antitumor activity with a 57% objective response rate (n=7). The eligibility criteria limit prior therapy to no more than five lines for ovarian cancer and no more than two lines for breast cancer. Durable RECIST responses were observed in both tumor types, providing what the company describes as the first clinical proof-of-concept for PARG (搜索) inhibition in ovarian and breast cancer patients.
"These data represent an important clinical milestone for ETX-19477 and for the emerging field of PARG (搜索) inhibition," said Jeffrey A. Stafford, CEO of 858 Therapeutics (搜索). "We are encouraged by the clinical efficacy and RECIST responses observed to date, in both ovarian and breast cancer patients. These treatment outcomes, together with the robust PK-PD relationship established during dose escalation, support the continued development of ETX-19477, including combination approaches that can meaningfully expand the patient populations treatable with ETX-19477."
Safety Profile
ETX-19477 was generally well tolerated, with low rates of hematologic toxicity observed to date. The favorable safety profile supports further monotherapy development as well as future combination strategies.
Mechanism of Action
Poly(ADP-ribose) glycohydrolase (PARG (搜索)) is an enzyme that catalyzes the removal of poly-ADP-ribose (PAR) chains from proteins during the DNA damage response. PARG inhibition leads to selective cell death in tumors with underlying replication fork defects, including BRCA-mutated tumors, through a mechanism distinct from PARP inhibition. ETX-19477 is an oral, potent, and selective PARG inhibitor that is efficacious in preclinical mouse models of ovarian, breast, and gastric cancers.
FDA Fast Track Designation
In August 2026, the U.S. Food and Drug Administration granted Fast Track designation to ETX-19477 for the treatment of adult patients with BRCA-mutated, hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), unresectable or metastatic breast cancer.
"For patients with advanced HR+/HER2- breast cancer (搜索), there is an urgent need for new treatment options that can delay disease progression," said Jeffrey Stafford, Ph.D., CEO of 858 Therapeutics (搜索). "We are pleased that the FDA has granted Fast Track designation to ETX-19477 and are committed to working closely with the agency to accelerate its development. The designation was supported by preclinical findings and emerging clinical data from our ongoing Phase 1/2 trial, including evidence of antitumor activity."
FDA Fast Track status is designed to facilitate the development and expedite the review of new therapies intended to treat serious conditions with unmet medical need. Under the designation, the ETX-19477 development program gains access to more frequent interactions with the FDA and may be eligible for accelerated approval and/or priority review if certain criteria are met.
Ongoing Clinical Development
858 Therapeutics (搜索) is actively enrolling patients in Phase 2 monotherapy expansion cohorts, with a focus on BRCA-mutated ovarian and breast cancer. The ongoing Phase 1/2, open-label, multicenter study in patients with advanced solid tumors is designed to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity. Additional details on the ETX-19477 clinical program are available on clinicaltrials.gov (NCT06395519).
The ASCO poster presentation (Abstract Number 3109) is titled "First-in-human phase 1/2 study of ETX-19477, an oral, potent, and selective PARG (搜索) inhibitor, in patients with advanced solid tumors (ERADIC8)" and will be presented by Ezra Rosen, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center, New York, NY, in the Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology session.