Repare Therapeutics (RPTX) Study Update summary

Study background and rationale

• Lunresertib (PKMYT1 inhibitor) and camonsertib (ATR inhibitor) combination targets gynecologic tumors with specific biomarkers (Cyclin E1, PPP2R1A, FBXW7), leveraging synthetic lethal biology for precision oncology therapies.

• Preclinical and animal data showed strong synergy and complete tumor regressions, supporting clinical development.

• The MYTHIC trial, initiated in 2021, focused on endometrial cancer (EC) and platinum-resistant ovarian cancer (PROC), both with high unmet needs and poor prognosis.

• Regulatory support and alignment with FDA and EMA, including accelerated approval options, have been secured for pivotal phase III trials.

• Proof of concept achieved in both EC and PROC, enabling registrational trial planning.

Patient population and unmet need

• EC is the only gynecologic cancer with rising incidence and mortality, now surpassing ovarian cancer in annual deaths.

• High-risk patients with adverse genomic profiles (CCNE1, FBXW7, PPP2R1A) have significantly worse outcomes.

• No approved second-line therapy exists for EC after ICI and chemotherapy; PROC patients face poor prognosis with limited options.

• Biomarker-driven selection is critical for optimal patient outcomes.

• The MYTHIC trial enrolled over 50 heavily pretreated, biomarker-positive patients with EC and PROC.

Clinical trial design and patient population

• 51 evaluable patients enrolled in the gynecologic cancer expansion cohort; 27 with EC, 24 with PROC.

• EC cohort: median age 67, 60% had ≥3 prior therapies, 85% had p53 mutations, all had prior platinum regimens.

• PROC cohort: >50% received treatment as fourth-line or later, nearly half had prior PARP inhibitors, all had p53 mutations.

• Tumor biomarker profiles included high rates of p53 mutations and specific gene alterations (CCNE1, FBXW7, PPP2R1A).

• Patients were heavily pretreated, with most receiving the combination as fourth-line therapy or beyond.