Olaparib in Ovarian Cancer: Parsing the Data

Maurie Markman, MD


June 25, 2012

Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer

Ledermann J, Harter P, Gourley C, et al
N Engl J Med. 2012;366:1382-1392


A multinational group of researchers evaluated olaparib, an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, as maintenance therapy for in a phase 2 trial of 265 patients with high-grade serous ovarian cancer who had entered a second (or later) remission after complete or partial response to platinum-based chemotherapy. Patients were randomly assigned to receive either olaparib (400 mg twice a day) or placebo.

The primary study endpoint, progression-free survival, was substantially improved in the olaparib treatment population (median, 8.4 months vs 4.8 months; hazard ratio, 0.35; P <.001). Olaparib was generally well tolerated, with most side effects (nausea, anemia, and fatigue) being only grade 1 or 2 in severity. In a preliminary analysis of overall survival, which was a secondary endpoint, there was no difference observed between the 2 study arms (hazard ratio, 0.94; P = .75).


Previous phase 2 trials demonstrated objective response rates of 30%-40% for single-agent olaparib in the second-line management of epithelial ovarian cancer in patients with a documented germline BRCA1 or BRCA2 mutation.[1,2] However, because only 5%-15% of patients with ovarian cancer have such a germline mutation, it may be difficult to conduct a randomized trial with a sufficient number of participants to document a survival benefit. In fact, a randomized phase 2 study that compared single-agent olaparib with single-agent pegylated liposomal doxorubicin as second-line treatment for ovarian cancer in patients with BRCA mutations failed to demonstrate a difference in outcome between the study arms.[3] The current trial expands the cohort by including patients with the "BRCAness" gene expression profile, which has been shown to correlate with responsiveness to platinum-based drugs.[4]

Nevertheless, despite showing substantial improvement in progression-free survival with olaparib, the study failed to reveal an improvement in overall survival. This is not surprising, because the use of clinically active drugs after progression in this trial will almost certainly favor outcomes in patients in the placebo arm. This does not mean that patients in the experimental arm did not benefit, but rather that subsequent therapy makes it very difficult, if not impossible, to demonstrate a statistically significant effect of a prior treatment on overall survival -- especially in a setting in which multiple active strategies are available.

Since publication of these data, AstraZeneca announced that it would not continue to develop olaparib as maintenance therapy in patients with high-grade serous ovarian cancer.[5] Thus, although olaparib clearly has important biological and clinical activity in a subset of patients with ovarian cancer, the next step in the development of this novel agent remains uncertain.



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