TPS1165 Background: Microhomology-mediated end joining (MMEJ) repair of DNA double-strand breaks is reliant on DNA polymerase theta (Polθ). ART6043 inhibits Polθ and hence MMEJ without affecting other forms of DNA double-strand break repair (DSBR) such as homologous recombination (HR) and non-homologous end joining (NHEJ). MMEJ becomes essential for tumor survival in patients with germline BRCA1/2 mutations being treated with poly adenosine diphosphate ribose polymerase (PARP) inhibitors. Polθ inhibition is therefore a powerful strategy to target HR-deficient cancers by potentiating the DNA damage induced by PARP inhibition. Combination of Polθ inhibition with PARP inhibition may also delay or prevent emergence of PARP inhibitor resistance through circumvention of MMEJ-mediated BRCA1/2 gene reversions that restore HR activity. The restricted expression profile of the POLQ gene in normal tissues compared with tumor tissues predicts a high therapeutic index for combining Polθ inhibition with DNA damaging agents without synergistic toxicity. Data from 61 pts dosed in the ART6043 dose escalation as monotherapy and in combination with the PARP inhibitor, olaparib, in a tumor agnostic population were presented at ESMO 2025 (Yap et al 2025). These data showed that ART6043 was well-tolerated alone and with the approved dose of olaparib; good ART6043 exposure with no evidence of drug-drug interaction with olaparib; pharmacodynamic engagement as monotherapy and enhanced with olaparib and promising signals of anti-tumor activity for the combination of ART6043 + olaparib. These data support a randomized expansion of ART6043 + olaparib compared to olaparib alone to demonstrate the first proof of concept for Polθ inhibition in HR-deficient cancers. Methods: In this expansion to study NCT05898399, approximately 80 pts with locally advanced or metastatic HER2 negative breast cancer with a germline BRCA1/2 mutation will be randomized to ART6043 + olaparib vs olaparib (stratified by use of prior platinum). Patients must have received prior chemotherapy and no or ≤1 month of prior PARP inhibitor. Patients with hormone receptor positive breast cancer should have been treated with prior endocrine therapy. Patients in the investigational arm will receive ART6043 600 mg once daily with olaparib 300 mg twice daily. Patients on the olaparib-alone arm may cross over to receive ART6043 + olaparib on progression. Key objectives include preliminary efficacy (progression-free survival, objective response rate etc), safety and tolerability. Cell free DNA samples will be collected to assess stratification biomarkers, response and compare the occurrence of resistance mechanisms (eg BRCA reversion) between the two arms. Enrollment will continue until Q4-2027. Clinical trial information: NCT05898399 .
Robson et al. (Thu,) studied this question.