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FDA Advisors Seek More Data on Ovarian Cancer Drug Olaparib

Committee votes against accelerated approval

The FDA’s Oncologic Drugs Advisory Committee voted 11 to 2 to await further clinical data before acting on AstraZeneca’s olaparib as a maintenance treatment for certain women with ovarian cancer.

Current evidence from clinical studies does not support an accelerated approval for use of olaparib as a maintenance treatment for women with platinum-sensitive relapsed ovarian cancer who have the germline BRCA (gBRCA) mutation and are in complete or partial response to platinum-based chemotherapy, the committee said. The FDA is not bound by its committees’ advice, but often follows it.

The FDA granted priority review status for the olaparib new drug application (NDA) in April and set a Prescription Drug User Fee Act (PDUFA) action date of October 3, 2014. AstraZeneca said it expects to complete its phase III clinical program to evaluate the benefit of olaparib for this patient population by the end of 2015.

The NDA filing was based on a subgroup analysis of phase II data from a randomized, double-blind, placebo-controlled trial that evaluated olaparib versus placebo as maintenance treatment in platinum-sensitive relapsed serous ovarian cancer patients who had received previous treatment with at least two platinum regimens and were in a maintained partial or complete response following their last platinum regimen. The study met its primary endpoint of progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors guidelines. A predefined subgroup analysis was conducted in patients who have germline BRCA mutations.

However, an FDA briefing document prepared for the committee meeting questioned whether the results from the subgroup analysis (a seven-month improvement in median PFS and a hazard ratio of 0.17) demonstrated a favorable risk–benefit profile. The small sample size and retrospective identification of the patient population “call into question the reliability of the estimation of treatment effect,” the FDA staff wrote.

The phase III SOLO program, designed to evaluate olaparib’s efficacy and safety as a maintenance monotherapy in ovarian cancer patients who have a BRCA mutation who are in complete or partial response following platinum-based chemotherapy in the relapsed setting, is under way. However, the FDA briefing document speculated that the study design could detect “a statistically significant but potentially clinically insignificant improvement in PFS.”

Olaparib is a potential first-in-class oral poly ADP ribose polymerase (PARP) inhibitor that exploits tumor DNA repair pathway deficiencies to selectively induce cancer cell death. PARP is a key enzyme in one of the DNA repair pathways in human cells. Inhibition of PARP results in a build-up of DNA damage in the cell, requiring repair via an alternative pathway called homologous recombination repair (HR). Cancer cells that already have a HR pathway deficiency (HRD) are limited in their ability to repair their DNA, causing them to die. HRD is associated with a range of tumor types, in particular with breast and ovarian cancers.

The FDA noted that grade 1 and 2 adverse effects were frequent with olaparib use, but grade 3 or 4 events were rare.

Sources: AstraZeneca; June 25, 2014; FDA; June 24, 2014.

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