Phase 1 Combination Study of the CHK1 Inhibitor Prexasertib and the PARP Inhibitor Olaparib in High-grade Serous Ovarian Cancer and Other Solid Tumors

Abstract

Purpose: Checkpoint kinase 1 (CHK1) plays a central role in the response to replication stress through modulation of cell-cycle checkpoints and homologous recombination (HR) repair. In BRCA-deficient cancers with de novo or acquired PARP inhibitor resistance, the addition of the CHK1 inhibitor prexasertib to the PARP inhibitor olaparib compromises replication fork stability, as well as HR proficiency, allowing for sensitization to PARP inhibition. Patients and Methods: This study followed a 3+3 design with a 7-day lead-in of olaparib alone, followed by 28-day cycles with prexasertib administered on days 1 and 15 in combination with an attenuated dose of olaparib on days 1–5 and 15–19. Pharmacokinetic blood samples were collected after olaparib alone and following combination therapy. Patients enrolled to the expansion phase of the study underwent paired tumor biopsies for pharmacodynamic (PD) assessments. Results: Twenty-nine patients were treated. DLTs included grade 3 neutropenia and grade 3 febrile neutropenia. The MTD/recommended phase 2 dose (RP2D) was prexasertib at 70 mg/m2 i.v. with olaparib at 100 mg by mouth twice daily. Most common treatment-related adverse events included leukopenia (83%), neutropenia (86%), thrombocytopenia (66%), and anemia (72%). Four of 18 patients with BRCA1-mutant, PARP inhibitor–resistant, high-grade serous ovarian cancer (HGSOC) achieved partial responses. Paired tumor biopsies demonstrated reduction in RAD51 foci and increased expression of γ-H2AX, pKAP1, and pRPA after combination exposure. Conclusions: Prexasertib combined with olaparib has preliminary clinical activity in BRCA-mutant patients with HGSOC who have previously progressed on a PARP inhibitor. PD analyses show that prexasertib compromises HR with evidence of induction of DNA damage and replication stress.

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

“…Based on pre-clinical work, inhibition of CHK1 sensitizes HR-proficient pancreatic cancer to chemotherapy and radiation [168,169]. The CHK1 inhibitor prexasertib combined with PARPi also shows activity in the treatment of patients with PARPi-resistant BRCA mutant ovarian cancer [170]. Although an early-phase trial failed to show the benefit of CHK1 inhibition in combination with gemcitabine for the treatment of patients with pancreatic cancer, in retrospect, the use of non-platinum chemotherapy limits conclusions about the effectiveness of CHK1 inhibition to induce HRD [171].…”

“…Although an early-phase trial failed to show the benefit of CHK1 inhibition in combination with gemcitabine for the treatment of patients with pancreatic cancer, in retrospect, the use of non-platinum chemotherapy limits conclusions about the effectiveness of CHK1 inhibition to induce HRD [171]. An ongoing challenge in pairing CHK1 inhibition with chemotherapy (e.g., FOLFIRINOX or gemcitabine cisplatin) or PARPi are the dose-limiting hematologic toxicities that emerge with combination therapy [170,172].…”

Perspectives on PARP Inhibitor Combinations for Ovarian Cancer

“…These characteristics are indeed observed when DNA repair is compromised due to deficient mismatch repair, a DNA repair mechanism that corrects mismatched base pairs, insertions, and deletions. However, different from what is observed with deficient mismatch repair/microsatellite instability, alterations in HR do not result in a considerable neoantigen load or high tumor burden ( 63 ). Genomic analysis shows that ovarian cancer usually exhibits less than 10 mutations per megabase ( 75 ).…”

“…Interestingly, most patients in the analysis were platinum-resistant. The safety of the combination of prexasertib and olaparib has been shown in a phase I trial ( 63 ), but additional studies are still needed to evaluate the efficacy of the combination.…”

Therapeutic Targeting of DNA Damage Response in Cancer

“…Grade 4 neutropenia was also very common (79%) but was mostly transient, with a median duration of 6 days, and resolved without growth-factor support [95]. Recent studies have also tested the combination of prexasertib with standard chemotherapy [98], olaparib [99], or anti-PD-L1 antibody [100]. In the olaparib-prexasertib combination study, 29 patients were enrolled, 18 of whom had BRCA1-mutant high-grade serous ovarian cancer resistant to prior PARP inhibitors.…”