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Olaparib, a PARP inhibitor, in patients with BRCA mutated Platinum-sensitive relapsed serous ovarian cancer


A retrospective subgroup analysis of a phase II study ( Study 19 ) has shown the effect that an investigational drug, Olaparib, has on progression-free survival ( PFS ) compared with placebo in Platinum-sensitive relapsed serous ovarian cancer patients with BRCA mutations.

Study 19 was a randomized, double-blinded phase II clinical trial evaluating the efficacy and safety of Olaparib 400mg twice daily maintenance therapy compared with placebo in 265 Platinum-sensitive, relapsed, high grade serous ovarian cancer patients who had received two or more previous Platinum regimens and who were in a partial or complete response following their last Platinum-containing regimen.
The primary endpoint was progression-free survival.

Results from the full study population, first presented at American Society of Clinical Oncology ( ASCO ) 2011 and later published in the New England Journal of Medicine ( NEJM ) in 2012, showed that Olaparib maintenance therapy significantly extended progression-free survival compared with placebo ( hazard ratio, HR=0.35; P less than 0.001, median PFS 8.4 vs 4.8 months ), however an interim overall survival ( OS ) analysis did not detect a benefit for Olaparib compared with placebo ( HR=0.94; P less than 0.75 ).

The initial pre-planned subgroup analysis of progression-free survival and overall survival in patients with a BRCA mutation suggested an improved outcome compared to the overall study population. However, mutation status was known for only a minority of patients in the study ( 36.6% ) at that time and additional biomarker work was therefore conducted to further investigate this signal. BRCA mutation status was subsequently determined for patients from either blood samples ( taken pre-randomization ) and/or archival tumor samples and BRCA mutation status was eventually documented for 254 ( 96% ) of the 265 patients in Study 19 confirming that 136 ( 51% ) patients in the study had a BRCA mutation ( BRCAm ).

Retrospective results, in the total BRCAm population showed that Olaparib maintenance therapy prolonged progression-free survival compared with placebo ( HR=0.18; p less than 0.00001, median PFS 11.2 vs 4.3 months ). This result was statistically significant.
A second interim analysis of overall survival for Olaparib ( 58% maturity ) in the BRCAm group did not demonstrate a statistical significant difference between the two arms. A numerical advantage on the Olaparib arm compared with placebo was observed ( HR=0.74; p=0.21; median OS 34.9 mo vs 31.9 mo ).
23% of the BRCAm patients who received placebo ( 14/62 ) subsequently received a PARP inhibitor, potentially confounding the overall survival data in this subgroup.

The most common adverse reactions occurring more frequently in the BRCAm patients treating with olaparib were low grade nausea, fatigue, vomiting and anemia, similar to those seen in patients without BRCA mutations.

The statistically significant seven month difference in progression-free survival in the subgroup of patients with a BRCA mutation supports the hypothesis that a personalized therapeutic approach based on BRCA mutation status could preferentially benefit this patient population.
BRCA are human genes that belong to a type of genes known as tumor suppressors. Mutation of these genes has been linked to hereditary breast and ovarian cancer and a woman's risk of developing breast and/or ovarian cancer is greatly increased if she inherits a BRCA1 or BRCA2 mutation. Only 15% of ovarian cancers are found before the cancer has spread outside the ovary. Despite advances in treatment and diagnosis, for patients with ovarian cancer that has spread beyond the ovary, the 5-year survival rate is well below 50%.

Olaparib is an innovative, potential first-in-class oral poly ADP ribose polymerase ( PARP ) inhibitor that has been shown in pre-clinical models to exploit DNA repair pathway deficiencies to preferentially kill cancer cells. This mode of action gives Olaparib the potential for activity in a range of tumor types with DNA repair deficiencies. ( Xagena )

Source: AstraZeneca, 2013

XagenaMedicine_2013



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