FDA Grants Fast Track Designation to ART6043/Olaparib in BRCA-Mutated, HER2– Breast Cancer

The FDA has granted fast track designation to ART6043 plus olaparib (Lynparza) for patients with germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer who have not received prior treatment with a PARP inhibitor, according to a press release from Artios Pharma Limited.¹

ART6043 is a potentially first-in-class DNA polymerase θ inhibitor. The agent is an orally bioavailable and a small-molecule inhibitor. DNA polymerase θ is an enzyme that is observed in cancer cells but mostly omitted in healthy cells. When adding olaparib to molecularly defined solid tumors, including those with BRCA mutation and PARP inhibitor resistance, the target engagement will be enhanced, and anti-tumor activity will be incurred while maintaining tolerability.

ART6043 plus olaparib was assessed in a phase 1/2a trial (NCT05898399) for patients with solid tumors who have DNA damage response pathways, including those with germline BRCA mutations in HER2-negative breast cancer.

“[Germline] BRCA-mutated HER2-negative breast cancer presents significant treatment challenges due to its frequently aggressive nature and high risk of recurrence, often due to BRCA reversions, with patients requiring intensive therapy,” Ian Smith, chief medical officer of Artios, said in the press release.¹ “In our ongoing phase 1/2a study, ART6043, in combination with olaparib, has shown encouraging clinical activity in the relevant genetic background, together with a favorable tolerability and pharmacology profile. These early results support ART6043 as a potential new targeted therapy capable of removing a cancer cell’s reliance on [polymerase θ] as a DNA repair mechanism to enhance anti-tumor activity in a well-defined patient population.”

At the European Society of Medical Oncology 2025 Congress, results from the phase 1/2a trial were presented.² Of the 19 patients enrolled in the ART6043 monotherapy arm, the median age was 58 years, and 37% had prior treatment with PARP therapy. In the ART6043 plus olaparib arm, 42 patients were enrolled, with the median age being 65.5 years, and 31% having prior treatment with PARP inhibitor. Of note, all patients were given a median of 4 prior therapies.

Additional results from the conference showed ART6043 demonstrating a benign tolerability profile as a monotherapy, and no additional toxicity when it was combined with olaparib. The oral once-daily dosing was supported by pharmacokinetic data as convenient, and there was no drug-drug interaction between ART6043 and olaparib. ART6043 pharmacodynamic data were enhanced with olaparib for those who had tumor regression.

“The first-in-class Polθ inhibitor, ART6043, represents a much-needed therapeutic option for patients with advanced, hard-to-treat cancers where resistance to existing treatments is a major clinical challenge,”Timothy A. Yap, MBBS, PhD, FRCP, Ransom Horne, Jr. Endowed Professor for Cancer Research, vice president and Head of Clinical Development in the Therapeutics Discovery Division, professor in the Department for Investigational Cancer Therapeutics (Phase I Program) and in the Department of Thoracic/Head and Neck Medical Oncology, at The University of Texas MD Anderson Cancer Center, and principal investigator of the study, said during the presentation.² “The initial clinical signals observed to date reinforce the potential of ART6043 to address this significant unmet need for patients who currently have limited treatment options. I look forward to the further evaluation of [polymerase θ] inhibition as additional clinical data become available.”

In part A of the trial, the primary end point was the number of patients with dose-limiting toxicities; in part B1, it was the number of patients with adverse effects; and in part B2, it was progression-free survival.³ Secondary end points included best overall response, objective response rate, disease control rate, duration of response, and change in tumor size.

Patients were eligible for treatment if they had discontinued all previous chemotherapeutic agents, non-hormonal targeted therapy, or investigational drugs at least 21 days or 5 half-lives, whichever is shorter; had resolution of all toxicities of prior therapy or surgical procedures; a performance status of 0 to 2; and adequate organ function.

Patients were excluded from treatment if they were pregnant, had myelodysplastic syndrome/acute myeloid leukemia, had ongoing interstitial lung disease or pneumonitis, had any gastrointestinal issues that could impact the absorption of the study treatment, or had brain metastases.

References

1. Artios receives U.S. FDA fast track designation for DNA polymerase Theta (Polθ) inhibitor ART6043 for treatment of gBRCA-mutated HER2-negative breast cancer. News release. February 23, 2026. Accessed February 24, 2026. https://tinyurl.com/yarwtkv9
2. Artios announces phase 1/2a data for DNA polymerase Theta inhibitor ART6043 at ESMO Congress 2025. News release. October 17, 2025. Accessed February 24, 2026. https://tinyurl.com/rbku993e
3. Study of ART6043 in advanced/​metastatic solid tumors patients. ClinicalTrials.gov. Updated October 15, 2025. Accessed February 24, 2026. https://tinyurl.com/6ar85wvr