Elsevier

The Lancet Oncology

Volume 15, Issue 11, October 2014, Pages 1207-1214
The Lancet Oncology

Articles
Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study

https://doi.org/10.1016/S1470-2045(14)70391-2Get rights and content

Summary

Background

Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer.

Methods

In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648.

Findings

Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7–not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7–16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23–0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none).

Interpretation

Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy.

Funding

American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.

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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