Olaparib is indicated
as maintenance therapy for people with BRCA-mutated high-grade serous
epithelial ovarian, fallopian tube or primary peritoneal cancer. It is a poly
(ADP-ribose) polymerase (PARP) inhibitor. In normal cells, DNA repair during
cell division involves BRCA1 and BRCA2 proteins. In people who have mutations
in BRCA1 and BRCA2 genes, DNA repair is mediated through alternative pathways
and involves PARP enzymes. As olaparib inhibits PARP enzymes, it prevents DNA
repair and causes the cancer cells to die.
Olaparib (400 mg twice
daily) has been compared to placebo in a phase II trial.1 The study enrolled
265 women with platinum-sensitive relapsed serous ovarian cancer with or
without BRCA1 or 2 germline or somatic mutations. Patients must have previously
had a complete or partial response to platinum-containing chemotherapy and at
least two previous platinum regimens.
Progression-free
survival was significantly longer with olaparib compared with placebo (8.4
months vs 4.8 months) but there was no significant difference in overall
survival (29.7 months vs 29.9 months).1 In a subgroup of 136 women with a BRCA
mutation, progression-free survival was 11.2 months with olaparib and 4.3
months with placebo.2 In an analysis of this subgroup, overall survival was
34.9 months in the olaparib arm and 30.2 months in the placebo arm. The
difference was not statistically significant.3
The most common adverse
events with olaparib included nausea (68.4% of patients), fatigue (48.5%),
vomiting (31.6%), diarrhoea (22.8%), headache (18.4%), decreased appetite
(18.4%), abdominal pain (17.6%), anaemia (16.9%), dyspepsia (16.2%) and
dysgeusia (14%). These events were serious (grade 3 or 4) in some patients.
Treatment-related events that led to permanent discontinuation with olaparib
included palpitations and myalgia, erythematous rash and nausea.1
Haematological toxicity
was common with olaparib and one patient in the trial died of haemorrhagic
stroke associated with thrombocytopenia. Blood counts should be measured before
starting treatment and then monthly for the first year of treatment.
Olaparib is genotoxic
and should not be used during pregnancy. Taking it during lactation is also not
recommended, although it is not known if the drug is excreted in breast milk.
Following oral
administration, olaparib is rapidly absorbed and peak plasma concentrations are
reached after 1–3 hours. As food slows absorption, capsules should be taken at
least an hour after eating and two hours before the next meal. Olaparib is
mainly metabolised by cytochrome P450 (CYP) 3A4 so concomitant use of potent
CYP3A4 inducers or inhibitors, including grapefruit and Seville oranges, should
be avoided.
Olaparib prolonged
progression-free survival by 6.9 months in women with BRCA mutant-positive
high-grade serous ovarian cancer. Overall survival was also slightly longer
with olaparib than with placebo, although this difference was not statistically
significant. Patients must have a confirmed BRCA1 or 2 mutation before starting
treatment and have already had at least two courses of platinum-containing
chemotherapy.