Neither study demonstrated a significant increase in overall survival. Women who did not receive bevacizumab maintenance therapy experienced no benefit from treatment.
No significant differences were observed between treatment groups. Bevacizumab was generally well tolerated. The gastrointestinal perforation rate with bevacizumab therapy ranged from 1% to 3%.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
When it is administered with initial chemotherapy and continued as maintenance therapy, bevacizumab leads to overall improvement in progression-free survival without a significant increase in overall survival.
We need additional studies to identify molecular markers that will predict the response to bevacizumab and other biologic treatments and determine whether any subgroup of patients will experience greater benefit from the addition of bevacizumab to standard chemotherapy regimens. The findings of such trials will allow us to better tailor treatment to each ovarian cancer patient.
Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382–1392.
Approximately 15% of epithelial ovarian cancers demonstrate a mutation in one of the BRCA genes, which function as an important component of DNA repair. Another 35% acquire a similar phenotype due to somatic mutations or silencing of the BRCA genes.
The poly ADP ribose polymerase (PARP) protein plays a role in the repair of single-strand breaks. Tumors with the mutated BRCA phenotype are particularly sensitive to PARP inhibitors8 because PARP inhibition leads to double-strand DNA breaks that cannot be repaired in BRCA mutated tumors.9
A recent phase II trial in recurrent ovarian cancer demonstrated a nearly twofold response rate to olaparib, a PARP inhibitor, among women who had a known BRCA mutation.10
Details of the trial
This study by Ledermann and colleagues was designed to determine the effect of olaparib in all women who have ovarian cancer. It was designed as a randomized, double-blind, phase II trial. Women who had recurrent ovarian, fallopian-tube, or primary peritoneal cancer who were sensitive to platinum and had an objective response to their most recent chemotherapy were randomly assigned to oral olaparib (twice daily dosing) or placebo until such time as disease progressed. The trial had 80% power to detect a 25% decrease in the risk of progression in the olaparib group, with an a less than 0.20.
Two hundred sixty-five women were allocated to each of the two treatment arms. Women treated with olaparib had a risk of recurrence or death that was 35% (95% CI, 25%–49%) the risk among women treated with placebo; they also had a median progression-free survival that was 4 months longer. This response was seen in women with and without BRCA mutations.
Overall, olaparib was well tolerated, although women randomized to the olaparib group had a higher rate of moderate to severe side effects, mostly due to a higher rate of nausea, vomiting, fatigue, and anemia.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
Maintenance therapy with oral olaparib significantly increases progression-free survival in women who have platinum-sensitive, recurrent ovarian cancer regardless of their BRCA-mutation status. No significant difference was seen in overall survival at an interim analysis.
Although olaparib is not FDA approved for treatment in patients, these results likely will renew interest in further studies to identify biomarkers to identify patients who are best suited for this treatment.
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