FDA Grants Fast Track Designation to ETX-19477 in BRCA-Mutated HR+/HER2– Breast Cancer

The FDA has granted fast track designation to ETX-19477 for the treatment of adult patients with BRCA-mutated, hormone receptor (HR)–positive, HER2-negative unresectable or metastatic breast cancer.¹

ETX-19477 is an oral, potent, and selective inhibitor of poly(ADP-ribose) glycohydrolase (PARG), is being evaluated as monotherapy in the phase 1/2 ERADIC8 trial (NCT06395519), which is enrolling phase 2 cohorts of patients with BRCA-mutated ovarian cancer and BRCA-mutated HR-positive, HER2-negative breast cancer.

The designation was supported by preclinical findings and emerging clinical data from the ongoing ERADIC8 study. Initial results from the trial’s phase 1 dose-escalation portion presented at the 2026 ASCO Annual Meeting demonstrated that ETX-19477 monotherapy generated an objective response rate (ORR) of 57% and a disease control rate (DCR) of 100% among phase 2–eligible patients who were evaluable for response; the ORR was 40% in patients with ovarian cancer and 100% in patients with breast cancer.²

ETX-19477 was well tolerated at the go-forward dose levels of 190 mg to 300 mg twice daily, with grade 3 or higher neutropenia and anemia reported in 10% and 7% of patients, respectively; the most common treatment-emergent adverse effects across all doses (n = 53) were nausea (58%), vomiting (47%), and fatigue (42%).³ Investigators reported that ETX-19477 was associated with lower rates of hematologic toxicity than has been observed with PARP inhibitors.³

“For patients with advanced HR-positive/HER2-negative breast cancer, there is an urgent need for new treatment options that can delay disease progression,” Jeffrey Stafford, PhD, chief executive officer of 858 Therapeutics, stated in a news release.¹ “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.”

What is the mechanism of action of ETX-19477?

PARG is an enzyme that catalyzes the removal of poly-ADP-ribose (PAR) chains from proteins during the DNA damage response, a pathway that cancer cells rely on to repair the DNA breaks that accumulate under replication stress. According to 858 Therapeutics, depletion or inhibition of PARG increases the number of single- and double-strand DNA breaks and slows their repair. Under conditions of replication stress, it inhibits proliferation, arrests cells in the S or G2 phase of the cell cycle, and/or induces apoptosis. The company has described the replication stress response as a cancer-specific vulnerability that can be targeted with PARG inhibition, and it reported that ETX-19477 showed robust preclinical activity in mouse models of ovarian, breast, and gastric cancers.

How is the phase 1/2 ERADIC8 trial designed?

ERADIC8 is a 2-part, open-label, multicenter, non-randomized study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ETX-19477 across advanced solid tumors.^2,3 Eligible patients need to be 18 years of age or older with histologically or cytologically confirmed advanced (incurable recurrent, unresectable, or metastatic) solid tumors, excluding primary central nervous system tumors, that have progressed on or after, or were intolerant to, the most recent systemic therapy.³ Preferential enrollment consideration is given to patients with BRCA2 loss-of-function mutations. Additional requirements include measurable disease per RECIST 1.1 criteria and an ECOG performance status of 0 or 1.

In part 1, patients received oral ETX-19477 daily in a monotherapy dose-escalation phase that used a Bayesian optimal interval design, evaluating doses ranging from 80 mg once daily to 750 mg once daily and identifying recommended phase 2 expansion doses of 200 mg, 250 mg, and 300 mg twice daily.^2,3

The primary end point is safety and tolerability, including the frequency of dose-limiting toxicities and the maximum tolerated dose and/or recommended phase 2 dose.³ Secondary end points include pharmacokinetic parameters and preliminary antitumor activity measured by ORR, duration of response, and DCR per RECIST 1.1 criteria.

References

1. 858 Therapeutics announces FDA fast track designation for PARG inhibitor ETX-19477 for the treatment of patients with BRCA-mutated HR+/HER2- unresectable or metastatic breast cancer. News release. 858 Therapeutics. August 18, 2026. Accessed August 18, 2026. https://www.businesswire.com/news/home/20260818624165/en/858-Therapeutics-Announces-FDA-Fast-Track-Designation-for-PARG-Inhibitor-ETX-19477-for-the-Treatment-of-Patients-with-BRCA-Mutated-HRHER2--Unresectable-or-Metastatic-Breast-Cancer
2. Rosen E, Advani PP, Banda K, et al. First-in-human phase 1/2 study of ETX-19477, an oral, potent, and selective PARG inhibitor in patients with advanced solid tumors (ERADIC8). J Clin Oncol. 2026;44(suppl 16):3109. doi:10.1200/JCO.2026.44.16_suppl.3109
3. A study of PARG inhibitor ETX-19477 in patients with advanced solid malignancies (ERADIC8). ClinicalTrials.gov. Updated March 27, 2026. Accessed August 18, 2026. https://clinicaltrials.gov/study/NCT06395519