Repare Therapeutics Inc. has commenced its Phase I POLAR clinical trial, marking the first patient dosed with RP-3467, a Polθ ATPase inhibitor, as a potential therapeutic intervention for a spectrum of advanced solid tumors. This open-label, multicenter, dose-escalation study is designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and initial clinical activity of RP-3467, both as a monotherapy and in combination with olaparib, a PARP inhibitor.
The POLAR trial (NCT06560632) aims to enroll approximately 52 adult patients with molecularly selected advanced solid tumors, including those with locally advanced or metastatic epithelial ovarian cancer, metastatic breast cancer, metastatic castration-resistant prostate cancer, or pancreatic adenocarcinoma. The primary objective is to determine the safety and tolerability of RP-3467, alone and in combination with olaparib, and to establish a preliminary recommended Phase II dose for the combination therapy.
Rationale for RP-3467 Development
RP-3467 is designed to inhibit Polθ ATPase, an enzyme involved in DNA repair. Preclinical studies have demonstrated compelling results, particularly in combination with PARP inhibitors like olaparib. According to Maria Koehler, MD, PhD, Executive Vice President and Chief Medical Officer of Repare, this combination has shown "complete and durable tumor regressions" in preclinical models, with no additive toxicities. The rationale behind this approach is to mitigate PARP inhibitor resistance, a significant challenge in cancer treatment.
Potential Clinical Impact
The combination of RP-3467 and olaparib holds promise for improving patient outcomes by addressing PARP inhibitor resistance, a critical unmet medical need in oncology. PARP inhibitors are effective in treating cancers with deficiencies in DNA repair pathways, such as BRCA-mutated tumors. However, resistance to these agents often develops, limiting their long-term efficacy. RP-3467 may restore sensitivity to PARP inhibitors by targeting an alternative DNA repair pathway.
Expanding Therapeutic Horizons
Beyond PARP inhibitors, Repare is also exploring the potential of RP-3467 in combination with radioligand therapy and chemotherapy-bearing antibody-drug conjugates (ADCs). Preclinical data suggest that RP-3467 could enhance the efficacy and reduce the toxicity of these treatment modalities, opening new avenues for cancer therapy.
Trial Design and Objectives
The Phase I POLAR trial is a dose-escalation study, meaning that the dose of RP-3467 will be gradually increased to determine the maximum tolerated dose (MTD) and the recommended Phase II dose (RP2D). The trial will assess the safety and tolerability of RP-3467, both as a monotherapy and in combination with olaparib. Secondary endpoints include pharmacokinetic and pharmacodynamic assessments, as well as preliminary evaluations of clinical activity.
About Repare Therapeutics
Repare Therapeutics is a clinical-stage precision oncology company focused on discovering and developing novel therapeutics using its proprietary synthetic lethality approach. The company's SNIPRx® platform enables the systematic discovery of highly targeted cancer therapies focused on genomic instability, including DNA damage repair. Repare's pipeline includes multiple clinical-stage programs, including lunresertib (RP-6306), camonsertib (RP-3500), RP-1664, and RP-3467.
