ART6043, a Promising DNA Polymerase Theta Inhibitor for the Treatment of gBRCA-mutated HER2-Negative Breast Cancer Receives Fast Track Designation

The U.S. Food and Drug Administration (FDA) has granted a Fast Track designation to a new class of DNA Damage Response (DDR) medicines to deliver meaningful survival benefits for patients with breast cancer. The investigational drug, ART6043, is a potentially first-in-class selective, orally bioavailable small-molecule inhibitor of DNA polymerase theta (Polθ), a DNA repair enzyme preferentially expressed in cancer cells but virtually absent in most healthy tissues.[1]

The investigational drug, developed by Artios Pharma, is used in combination with the PARP inhibitor olaparib (AstraZeneca and Merck & Co/MSD) for the treatment of adult patients with germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer who have not received prior treatment with a PARP inhibitor.

By inhibiting Polθ, ART6043 targets microhomology-mediated end joining (MMEJ) to exploit tumor dependence on error-prone DNA repair, with broad rationale for use as monotherapy and in combination with PARP inhibition and other DNA‑damaging modalities.*

Cancer cells rely on Polθ as a backup DNA repair mechanism to survive when their primary homologous recombination (HR) DNA repair pathway is defective or when they acquire resistance to DNA-damaging therapies such as PARP inhibitors. By blocking Polθ, ART6043 is designed to shut down this alternative repair route, rendering tumors unable to effectively repair DNA damage and thereby enhancing anti-tumor activity.

Resistance to PARP inhibitors
“Breast cancer remains the second leading cause of cancer death in women in the United States. Granting of U.S. Fast Track designation is an important recognition of ART6043’s clinical profile to treat gBRCAm HER2-negative breast cancer and supports our mission to rapidly deliver potential first-in-class therapies to patients who have limited treatment options,” noted Mike Andriole, Chief Executive Officer of Artios.

“Importantly, breast cancer patients with a BRCA mutation often develop resistance to treatment with a PARP inhibitor alone. There remains a significant need to improve clinical outcomes and rates of survival through inhibition of Polθ (DNA polymerase Theta).”

Fast Track
The Fast Track designation was granted based on data from the ongoing, first-in-human, Phase 1/2a study (NCT05898399), evaluating ART6043 in combination with olaparib in patients with advanced solid tumors harboring mutations in DDR pathways, including gBRCAm HER2-negative breast cancer. [1]

In data presented at the European Society for Medical Oncology (ESMO) Congress, held October 17 – 21, 2025, in Berlin, Germany, ART6043 demonstrated an attractive tolerability profile, expected PK/PD activity, and promising clinical signals.

“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,” commentedTimothy A. Yap, Principal Investigator of the study at the time of the presentation.

“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 Polθ inhibition as additional clinical data become available,” Yao added.

Significant challenges
“gBRCA-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,” explained Ian Smith, Chief Medical Officer of Artios.

“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 Polθ as a DNA repair mechanism to enhance anti-tumor activity in a well-defined patient population,” Smith added.

“Our experiments to date with ART6043 have been rationally designed following our team’s pioneering work with the industry’s first PARP inhibitor and recognizing that inhibition of Polθ may enhance the cancer cell killing effects of PARP inhibition and overcome key mechanisms of resistance to improve survival in these patients,” added Graeme Smith, Chief Scientific Officer of Artios.

Expedite development
The FDA’s Fast Track program is designed to facilitate the development and expedite the review of investigational drugs that demonstrate the potential to address unmet medical needs in serious or life-threatening conditions. Product candidates with Fast Track designation are eligible for priority review and accelerated approval if relevant criteria are met. This designation will enable Artios to interact more frequently and earlier with the FDA to discuss ART6043’s development path.

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Note:* Artios’ differentiated approach is to evaluate ART6043 with olaparib in molecularly defined solid tumors, including settings with BRCA variants and PARP inhibitor resistance, to enhance target engagement and anti-tumor activity while maintaining tolerability.

Clinical trials
Study of ART6043 in Advanced/​Metastatic Solid Tumors Patients – ClinicalTrials.gov ID NCT05898399

Highlights of Prescribing Information
Olaparib (AstraZeneca and Merck & Co/MSD)[Prescribing Information]

Reference
[1] Yap TA, Lakhani N, Barve M, Hamilton EP, Bashir B, Mackay K, Skelton S, Harrop BJ, Little N, Langford G, Menon S, Baxter C, Pentony MM, Dickinson P, Martin N, Smith GC, Barriga S, Headley D, Smith IC, Ulahannan S; 924MO First data disclosure of the first-in-class DNA polymerase theta inhibitor, ART6043, as monotherapy and in combination with olaparib, in patients with molecularly-selected advanced solid tumors. Annals of Oncology, Volume 36, S566 – S567

Featured image licensed under the Unsplash+ license. Used with permission.

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