Targeted therapy for DNA damage response and homologous recombination repair defects: The Olaparib Combinations trial

Background: Mutations in genes encoding proteins involved the DNA damage response (DDR) occur in up to 20% of patients with cancer. It is unknown whether poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors, alone or in combination with ATR or AKT inhibitors, have histology-agnostic clinical efficacy in tumors with DDR mutations or PI3K/AKT pathway mutations, respectively. Methods: The Olaparib Combinations (OLAPCO) trial enrolled patients in treatment arms based on next-generation sequencing results. In cohorts 1 and 2, patients with tumors harboring DDR mutations received either the PARP inhibitor olaparib or olaparib and the ATR inhibitor ceralasertib. In cohort 3, patients with tumors with PI3K-AKT pathway alterations or ARID1A mutations received olaparib and capivasertib. The primary end point was overall response rate (ORR) at 16 weeks assessed by the Response Evaluation Criteria in Solid Tumors, version 1.1. Results: Sixty-six patients were treated, including 26 on olaparib monotherapy, 24 on olaparib and ceralasertib, and 16 on olaparib and capivasertib. Among all patients treated, the ORR was 6.1% and the clinical benefit rate was 31.2% with a median duration of benefit (DoB) of 11 months. Among seven patients with platinum- and PARP inhibitor-resistant high-grade ovarian serous cancer in the olaparib and ceralasertib arm, one had a partial response and four had stable disease with a median DoB of 10 months. No unexpected toxicities were observed. Conclusion: The study failed to meet its primary end point of ORR. DDR and homologous recombination repair defects are not consistently actionable with olaparib as monotherapy or in combination with other targeted therapies in a histology-agnostic manner.