Phase 1 Combination Study of the CHK1 inhibitor prexasertib, and the PARP inhibitor olaparib, in high-grade serous ovarian cancer and other solid tumors
Mené sur 29 patientes atteintes d'une tumeur séreuse de l'ovaire de haut grade ou d'une autre tumeur solide présentant une mutation BRCA, cet essai de phase I évalue la dose maximale tolérée du prexasertib (un inhibiteur de CHK1) en combinaison avec l'olaparib, et analyse ses caractéristiques pharmacodynamiques
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. Experimental Design: 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 (pts) enrolled to the expansion phase of the study underwent paired tumor biopsies for pharmacodynamic (PD) assessments. Results: Twenty-nine pts were treated. DLTs included Gr 3 neutropenia and Gr 3 febrile neutropenia. The MTD/RP2D was prexasertib at 70mg/m2 IV with olaparib at 100 mg PO BID. Most common treatment-related AEs included leukopenia (83%), neutropenia (86%), thrombocytopenia (66%) and anemia (72%). Four of 18 pts with BRCA1-mutant, PARP inhibitor-resistant, high-grade serous ovarian cancer (HGSOC) achieved PRs. Paired tumor biopsies demonstrated reduction in RAD51 foci and increased expression of g-H2AX, pKAP1 and pRPA after combination exposure. Conclusions: Prexasertib combined with olaparib has preliminary clinical activity in pts with BRCA-mutant 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.