A Phase II Clinical Trial of Cediranib and Olaparib Maintenance in Advanced Recurrent Cervical Cancer

Cervical cancer is the 4th most prevalent female cancer worldwide. In the UK there are around 3,207 new cases each year (2013) and 890 deaths (2012) (http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/cervical-cancer). It is the most common cancer in females under 35 with the majority of cases diagnosed in women aged 25-64. There is a large unmet need for active treatments in metastatic and recurrent cervical cancer patients. Although early-stage and locally advanced cancers may be cured with radical surgery, chemoradiotherapy or both, there are limited options for patients with metastatic disease or persistent/ recurrent disease after platinum-based chemoradiotherapy. Patients treated with chemotherapy for metastatic or relapsed cervical cancer respond poorly to conventional chemotherapy (overall response rate [ORR] of 30-35%) with a median overall survival of less than a year. The recent publication of a phase III randomised controlled trial GOG 240 demonstrating a 3.7 month improvement in median overall survival with the addition of bevacizumab to combination chemotherapy has offered some hope for these patients. The ORR and progression free survival (PFS) were also improved in patients receiving bevacizumab compared to those receiving chemotherapy alone. The advantage seen with bevacizumab persisted in some subsets of patients including those aged 48-56 years, and those with recurrent /persistent disease. Bevacizumab was also effective in patients who had undergone pelvic irradiation. This was the first time a targeted agent had significantly improved OS in gynaecological cancer.

High tumour angiogenesis is associated with poor survival when cervical cancer is treated with radiotherapy and high tumour vascularity is a significant prognostic factor independent of tumour radiosensitivity. A relationship between vascular endothelial growth factor (VEGF) expression and OS has been demonstrated in patients treated with radiotherapy, and a review of multiple biomarker studies in cervix cancer has highlighted the importance of VEGF as an adverse prognostic factor. Targeting VEGF in cervical cancer may potentially exploit the role of human papilloma virus (HPV, particularly subtypes 16 and 18) in the causation of cervical cancer. The role of HPV in oncogenesis relates to the E6 and E7 proteins, with the former promoting degradation of p53 while E7 inactivates retinoblastoma protein. Degradation of p53 may be responsible for activation of angiogenesis through production of VEGF and downregulation of a potent angiogenesis inhibitor, thrombospondin.

Cediranib is a highly potent inhibitor of the tyrosine kinase activity of VEGF receptors 1-3 (VEGFR 1-3.) The recently published CIRCCa study demonstrated an increased PFS, VEGF-R receptor inhibition and response rate with the addition of cediranib to carboplatin and paclitaxel chemotherapy. This was accompanied by a manageable increased toxicity (specifically diarrhoea and hypertension) with no detriment to QOL. The median PFS was 35weeks and 29 weeks in the cediranib and placebo arms respectively (HR 0.58 p= 0.032). Understanding which patients are most likely to derive benefit from these agents requires further evaluation as a priority.

Poly (ADP-ribose) polymerase (PARP) inhibitors including Olaparib may have potential activity in cancers deficient in DNA repair genes or signalling pathways that mitigate DNA repair. PARP inhibitors have demonstrated selectivity for cells harbouring homologous recombination (HR) deficiencies such as those with BRCA mutations. HR deficient cells are unable to maintain genomic integrity in the presence of large numbers of DNA DSBs and are therefore sensitive to PARP inhibition. The activity of PARP inhibitors in not limited to those with BRCA mutations and may demonstrate synthetic lethality in cancers deficient in other proteins mitigating DNA repair, such as those with mutations in Fanconi anaemia complementation group (FANC) proteins. Thus synthetic lethality may be more broadly applied to cancers with an impaired HR pathway.

It is well recognised that persistent genital infection with high risk strain(s) of HPV is necessary for the development of cervical cancer. Cells expressing high risk HPV oncoproteins (E6 and E7, see above) demonstrate increased levels of DNA damage and chromosomal instability, which may be a consequence of replicative stress; a process which is associated with a number of cancer-prone syndromes. There is also evidence that HPV oncoproteins inhibit the activation of DNA repair checkpoints, promote inappropriate DNA repair checkpoint recovery and inhibit the activation of DNA repair mechanisms.

Current therapeutic modalities for cervical cancer exploit the sensitivity of these tumours to DNA damaging agents such as ionising radiation and platinum chemotherapeutic agents. Poly (ADP-ribose) polymerase (PARP) inhibitors reduce the DNA repair capacity of cells and can induce synthetic lethality in cancers with underlying defects in DNA repair mechanisms such as BRCA mutations (Scott, Swisher, and Kaufmann 2015). The investigators therefore postulate that the action of HPV oncoproteins will lead to increase rates of DNA damage and reduced efficiency of DNA repair, leading in turn to increased susceptibility to PARP inhibitors.