According to a recent press release, Artios Pharma has begun dosing patients in a global Phase 2 clinical trial evaluating its investigational DNA polymerase theta (Polθ) inhibitor, ART6043, in combination with the PARP inhibitor olaparib for patients with germline BRCA-mutated (gBRCAm), HER2-negative breast cancer.
The randomized study, known as POLKA (NCT05898399), will enroll approximately 80 patients with locally advanced or metastatic disease. Participants are being assigned to receive either ART6043 plus olaparib or olaparib alone, with progression-free survival as the primary endpoint. Secondary measures include overall response rate, overall survival, and assessment of BRCA mutation reversion.
ART6043 is designed to target Polθ, a DNA repair enzyme overexpressed in many cancers but largely absent in healthy tissue. By inhibiting this pathway (specifically microhomology-mediated end joining) the drug aims to exploit tumor reliance on error-prone DNA repair mechanisms and enhance the efficacy of PARP inhibition. Investigators also hope the combination may help delay or overcome resistance commonly observed with PARP inhibitors.
The trial builds on earlier Phase 1/2a findings that indicated a favorable safety profile, predictable pharmacokinetics and pharmacodynamics, and early signs of clinical activity for the ART6043-olaparib combination. These data were previously presented at the 2025 European Society for Medical Oncology (ESMO) Congress.
The development program has received additional regulatory support, with the combination therapy granted Fast Track designation by the U.S. Food and Drug Administration in February 2026 for this patient population.
PARP inhibitors are well established in the treatment of HER2-negative breast cancer, particularly in patients with BRCA mutations. However, therapeutic resistance remains a significant clinical challenge, driving interest in combination strategies that target complementary DNA repair pathways. Polθ inhibition represents a novel approach within the broader field of DNA damage response (DDR) therapeutics.
Artios is positioning ART6043 as a potential first-in-class therapy within this emerging category. The company’s broader pipeline focuses on DDR-targeted treatments, including additional investigational agents aimed at disrupting cancer cell survival mechanisms through synthetic lethality and replication stress.
Results from the POLKA trial will help determine whether the addition of ART6043 can improve outcomes compared with current PARP inhibitor monotherapy in this genetically defined subset of breast cancer patients.
