FDA Advisors Question Benefit of Ovarian Cancer Drug Olaparib
Efficacy data obtained from small subgroup
Although the investigational ovarian cancer drug olaparib has shown an 83% reduction in the risk of disease progression, the FDA’s Oncologic Drugs Advisory Committee has questioned whether the result could be reproduced.
The panel’s report came 2 days ahead of a scheduled meeting that will discuss whether the benefits of olaparib outweigh its risks and whether further data are needed before an approval decision can be made. A new drug application was submitted to the FDA in February 2014.
Olaparib, which would have the brand name Lynparza if approved, is an oral inhibitor of polyadenosine 5'-diphosphoribose polymerase (PARP) activity. PARPs play a key role in cell repair.
The drug’s developer (AstraZeneca) is seeking accelerated approval of olaparib for the maintenance treatment of women with platinum-sensitive relapsed ovarian cancer (including fallopian tube or primary peritoneal cancer) with the germline BRCA (gBRCA) mutation who are in complete or partial response to platinum-based chemotherapy. The efficacy of olaparib for this indication is based on a subgroup analysis in a single efficacy trial (Study 19) in 96 patients with germline BRCA mutation (gBRCAm)-associated, platinum-sensitive ovarian cancer.
Study 19 was a multinational, randomized, double-blind, placebo-controlled trial of 265 patients with platinum-sensitive ovarian cancer who were in response to platinum-based chemotherapy. The patients were randomly assigned to receive either olaparib or placebo. Randomization was stratified by the time to disease progression from the completion of the penultimate platinum therapy (6 to 12 months vs. more than 12 months), by the objective response to the last platinum-containing regimen before enrollment (complete response vs. partial response), and the patient’s ethnic descent (Jewish vs. non-Jewish). The study’s primary efficacy endpoint was progression-free survival (PFS).
In the subgroup of 96 patients with gBRCAm-associated ovarian cancer, an 83% improvement in PFS was observed in olaparib-treated patients compared with those given placebo (11.2 months vs. 4.1 months, respectively).
The FDA’s advisors noted, however, that “the small sample size of gBRCAm patients and the retrospective identification of this patient population call into question the reliability of the estimation of a treatment effect.” Further, the committee said, “there are uncertainties related to the validity and the reproducibility of the magnitude of effect.”
According to the panel, the FDA has two options: 1) consider giving accelerated approval to olaparib now, or 2) wait for the results from an ongoing confirmatory trial (SOLO-2).
The randomized, double-blind, placebo-controlled SOLO-2 study is designed to assess the efficacy of olaparib maintenance monotherapy in patients with relapsed gBRCAm high-grade serous ovarian cancer (including patients with primary peritoneal and/or fallopian tube cancer) or high-grade endometrioid cancer who have responded to platinum-based chemotherapy. The study design largely mimics that of Study 19. Approximately 264 patients will be recruited.
The FDA is not obligated to follow the recommendations of its advisory panels, but it usually does so.