A Study of Cediranib and Olaparib at Disease Worsening in Ovarian Cancer

This is a proof of concept study (a study to initially assess the benefit a new drug indication) of the combination of two investigational drugs cediranib and olaparib in patients with ovarian cancer whose cancer worsened despite previously receiving a poly (ADP-ribose) polymerase (PARP) inhibitor (such as olaparib). The purpose of this study is to find out whether taking cediranib and olaparib at the same time will be able to stop tumors from growing further or shrink it. Cediranib works by blocking (inhibiting) several specific proteins in cancer cells called the vascular endothelial growth factor (VEGF) receptors. These proteins are important in the formation of blood vessels to the tumor. It is believed that many tumors survive because the blood vessels on the tumors bring oxygen and nutrients to the cancer cells which enable them to grow. If the formation of the blood vessels is blocked, the tumor cells may die. Olaparib, works by blocking a protein called poly \[adenosine diphosphate-ribose\] polymerase (PARP). PARP is an important protein which tries to fix damaged deoxyribonucleic acid (DNA, molecules that contain important instructions for the development of cells). Many cancers are thought to develop from damaged DNA. By blocking PARP from fixing damaged DNA, the tumor cells may die. Adding cediranib to olaparib, and therefore blocking several different mechanisms for cancer growth, may stop tumor growth.

The recent changes in OC treatment with maintenance therapy raise the question of drug strategy at progression. It remains unclear what the best option for a patient relapsing during PARP inhibitor treatment would be. Findings from a retrospective study-and the first data available for treatment after a PARP inhibitor-have provided support for a lack of significant clinical cross-resistance between PARP inhibitor and platinum-based chemotherapy. However, based on a recent clinical trial, the addition of an anti-angiogenic to olaparib adds significant benefit. In a randomized phase II trial, cediranib with olaparib showed an objective response rate markedly higher in the combination arm (80%) than the olaparib single agent arm (48%) with a median PFS of 9.0 months for olaparib and 17.7 months for cediranib/olaparib (p=0.001). The overall rate of grade 3/4 toxicity was higher on the combination (70%) than on olaparib (7%). The main toxicities occurring were fatigue (27% cediranib/olaparib vs 7% olaparib), diarrhea (23% vs 0%), and hypertension (39% vs 0%). This is the first oral, non-chemotherapy-based combination treatment in the platinum-sensitive recurrent OC. Preclinically, PARP-inhibition has reported anti-angiogenic effects, where GPI 15427 (a potent PARP-1/2 inhibitor) inhibits in vivo angiogenesis in a matrigel plug assay. PARP-1 knockout mice also demonstrate decreased in vivo angiogenesis compared to control mice with wild-type PARP-1, supporting the notion that the observed anti-angiogenic effects are specific to anti-PARP activity. More recent work has demonstrated that HR can be suppressed by hypoxia through downregulation of HR repair proteins such as BRCA1 and RAD51 and that PARP inhibitor sensitivity is enhanced in hypoxic states. This information raises the hypothesis that PARP-inhibitors and anti-angiogenics may have synergistic effects. Furthermore, preclinical data demonstrated that hypoxia-mediated defects in DNA repair can lead to genetic instability and drive oncogenesis. Some patients with tumor expressing a 'mutator' phenotype due to the acquisition of repair-deficient cancer cells from an unfavourable tumour microenvironment could benefit from this combined approach. Based on evidence for targeting HRR and angiogenesis (two potential Achilles Heels in OC), we will evaluate the interest in adding cediranib to olaparib in patients relapsing after initial good response to olaparib treatment. This is a proof of concept study as we will assess the benefit of adding cediranib to olaparib at the time of disease progression under olaparib. As other PARP inhibitor are currently under investigations such as Rucaparib and ABT-888, with no data available regarding a rechallenge of PARP inhibitor beyond progression, we propose the combination cediranib and olaparib in the setting of disease progression under treatment with a PARP inhibitor such as olaparib.