ArticlesCombination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study
Introduction
Ovarian cancer is the leading cause of death from gynaecological malignancy in the USA, with about 22 000 new diagnoses and 14 000 deaths per year.1 Although response rates to initial treatment are high, most patients will relapse.2 New therapeutic directions that increase cure rate, prolong life, and do so in the most tolerable fashion are needed; targeted therapeutics could fill that need.
Poly(ADP-ribose) polymerase (PARP) inhibitors are a promising class of drugs that show activity against ovarian cancer. Inhibition of PARP by these drugs leads to the accumulation of double-stranded DNA breaks that cannot be accurately repaired, resulting in synthetic lethality in cells that are deficient in homologous recombination.3, 4 Homologous recombination deficiency has been described in up to 50% of patients with high-grade serous ovarian cancers, with about 17% of newly diagnosed women having deleterious germline BRCA1/2 mutations (henceforth, BRCA describes germline status unless otherwise specified) or other defects in the homologous recombination pathway.5, 6 Clinical development of PARP inhibition in ovarian cancer is thus of particular interest.
Olaparib is a potent, orally available PARP inhibitor, with documented activity against active disease in BRCA mutation-associated ovarian cancer and breast cancer in phase 17, 8 and phase 2 studies.9, 10, 11 Activity has been shown in wild-type BRCA1/2 ovarian cancer, with a response of 24%.10 Additionally, benefit was shown in a randomised phase 2 study of olaparib versus placebo administered as maintenance therapy after completion of platinum-based chemotherapy in women with platinum-sensitive high-grade serous ovarian cancers.12 Median progression-free survival (PFS) was 4·8 months in the placebo group and was 8·4 months in the olaparib group in the whole unselected trial cohort (hazard ratio [HR] 0·35, p=0·001).12 This difference was more striking in a group including patients with mutated BRCA and those with somatic BRCA1/2 mutations, in which median PFS was 4·3 months in the placebo group and was 11·2 months in the olaparib group (HR 0·18, p<0·0001).13
Angiogenesis inhibitors are active in recurrent ovarian cancer.14, 15 Cediranib is an oral ATP-competitive tyrosine kinase inhibitor of VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3 that has produced a 17% response rate in relapsed ovarian cancer.16 Ledermann and colleagues17 reported a phase 3 study in women with platinum-sensitive recurrent ovarian cancer in which the combination of cediranib with platinum-based chemotherapy followed by cediranib maintenance therapy significantly increased PFS and overall survival compared with platinum-based chemotherapy alone.
Angiogenesis inhibitors combined with PARP inhibitors have shown at least additive effects in preclinical studies. In-vivo antiangiogenic activity has been recorded with PARP inhibitors and in PARP-1 knockout mice.18 Downregulation of homologous recombination repair genes, such as BRCA1 and RAD51, occurs with hypoxia, with enhancement of PARP inhibitor sensitivity in the hypoxic setting.19, 20 VEGFR3 inhibition results in downregulation of both BRCA1 and BRCA2 in cancer cells.21 We recorded preclinical synergy between olaparib and cediranib in inhibition of ovarian cancer cell invasion and microvascular endothelial cell tube formation in vitro (unpublished data). Cediranib plus olaparib showed activity against recurrent ovarian cancer in our phase 1 dose-finding trial, which yielded an objective response rate of 44%.22
In this study, we assessed the efficacy and toxicity of the cediranib plus olaparib compared with olaparib alone in platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancers.
Section snippets
Study design and participants
This study was a randomised, open-label, phase 2 trial. We recruited patients from nine participating US academic medical centres. Eligible patients were aged 18 years or older, had Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, an estimated life expectancy of 6 months or longer, and recurrent high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients with mutated BRCA and any high-grade histology were eligible. Patients
Results
Between Oct 26, 2011, and June 3, 2013, 90 patients were enrolled to the study; 46 were randomly allocated to olaparib monotherapy and 44 to cediranib plus olaparib (figure 1). Treatment groups were balanced across baseline characteristics, although 29 (63%) of 46 patients in the olaparib monotherapy group had received more than one previous line of therapy compared with 18 (41%) of 44 patients in the combination therapy group (table 1). 47 women carried BRCA mutations.
Interim analysis was done
Discussion
To our knowledge, we report the first phase 2 study to assess the efficacy of a combination of a PARP inhibitor and an anti-angiogenic drug (panel). Cediranib plus olaparib improved median PFS and the proportion of patients with an objective response compared with olaparib monotherapy in women with platinum-sensitive high-grade serous or endometrioid ovarian cancers. These results suggest that the combination of a PARP inhibitor and an anti-angiogenic drug could be synergistic and have
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