abstract:
Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial - The Lancet Oncology
This trial is ongoing and is registered
with
ClinicalTrials.gov, number
NCT00753545.
Summary
Background
In
patients with platinum-sensitive recurrent serous ovarian cancer,
maintenance monotherapy with the PARP inhibitor olaparib significantly
improves progression-free survival versus placebo. We assessed the
effect of maintenance olaparib on overall survival in patients with
platinum-sensitive recurrent serous ovarian cancer, including those with
BRCA1 and
BRCA2 mutations (
BRCAm).
Methods
In
this randomised, placebo-controlled, double-blind,
phase 2 trial
involving 82 sites across 16 countries, patients with platinum-sensitive
recurrent serous ovarian cancer who had received two or more courses of
platinum-based chemotherapy and had responded to their latest regimen
were randomly assigned (1:1) using a computer-generated sequence to
receive oral maintenance olaparib (as capsules; 400 mg twice a day) or a
matching placebo by an interactive voice response system. Patients were
stratified by ancestry, time to progression on penultimate platinum,
and response to most recent platinum. Patients and investigators were
masked to treatment assignment by the use of unique identifiers
generated during randomisation.
The primary endpoint of the trial was
progression-free survival. In this
updated analysis, we present data for
overall survival, a secondary endpoint, from the third data analysis
after more than
5 years' follow-up (intention-to-treat population). We
did the updated overall survival analysis, described in this Article at
77% data maturity, using a two-sided α of 0·95%. As the study was not
powered to assess overall survival, this analysis should be regarded as
descriptive and the p values are nominal.
We analysed randomly assigned
patients for overall survival and all patients who received at least one
dose of treatment for safety. This trial is ongoing and is registered
with
ClinicalTrials.gov, number
NCT00753545.
Findings
Between
Aug 28, 2008, and Feb 9, 2010, 265 patients were randomly assigned to
olaparib (n=136) or placebo (n=129). 136 patients had deleterious
BRCAm.
The data cutoff for this analysis was Sept 30, 2015. An overall
survival advantage was seen with maintenance olaparib versus placebo in
all patients (hazard ratio [HR] 0·73 [95% CI 0·55–0·96]; nominal
p=0·025, which did not meet the required threshold for statistical
significance [p<0·0095];
median overall survival was 29·8 months [95%
CI 26·9–35·7] for those treated with olaparib vs 27·8 months [24·9–33·7] for those treated with placebo), and in patients with
BRCAm (HR 0·62 [95% CI 0·41–0·94] nominal p=0·025;
34·9 months [95% CI 29·2–54·6] vs 30·2 months [23·1–40·7]). The overall survival data in patients with
BRCA wild-type were HR 0·83 (95% CI 0·55–1·24, nominal p=0·37; 24·5 months [19·8–35·0] for those treated with olaparib
vs 26·6 months [23·1–32·5] for those treated with placebo). 11 (15%) of 74 patients with
BRCAm
received maintenance olaparib for 5 years or more. Overall, common
grade 3 or worse adverse events in the olaparib and placebo groups were
fatigue (11 [8%] of 136 patients
vs four [3%] of 128) and anaemia (eight [6%]
vs
one [1%]). 30 (22%) of 136 patients in the olaparib group and
11 (9%)
of 128 patients in the placebo group reported serious adverse events. In
patients treated for 2 years or more, adverse events in the olaparib
and placebo groups included low-grade nausea (24 [75%] of 32 patients
vs two [40%] of five), fatigue (18 [56%] of 32
vs two [40%] of five), vomiting (12 [38%] of 32
vs zero), and anaemia (eight [25%] of 32
vs one [20%] of five); generally, events were initially reported during the first 2 years of treatment.
Interpretation
Despite not reaching statistical significance, patients with
BRCA-mutated
platinum-sensitive recurrent serous ovarian cancer receiving olaparib
maintenance monotherapy after platinum-based chemotherapy appeared to
have longer overall survival, supporting the reported progression-free
survival benefit. Clinically useful long-term exposure to olaparib was
seen with no new safety signals. Taken together, these data support both
the long-term clinical benefit and tolerability of maintenance olaparib
in patients with
BRCA-mutated platinum-sensitive recurrent serous ovarian cancer.
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