Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.

Abstract

BACKGROUND:

Olaparib (AZD2281) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that has shown antitumor activity in patients with high-grade serous ovarian cancer with or without BRCA1 or BRCA2 germline mutations.

METHODS:

We conducted a randomized, double-blind, placebo-controlled, phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen. Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines.

RESULTS:

Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Progression-free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75).

CONCLUSIONS:

Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.).

• Authors: Jonathan Ledermann, Philipp Harter, Charlie Gourley, Michael Friedlander, Ignace Vergote, Gordon Rustin, Clare Scott, Werner Meier, Ronnie Shapira-Frommer, Tamar Safra, Daniela Matei, Euan Macpherson, Claire Watkins, James Carmichael, Ursula Matulonis
• Journal: The New England journal of medicine (N Engl J Med) Vol. 366 Issue 15 Pg. 1382-92 (Apr 12 2012) ISSN: 1533-4406 [Electronic] United States
• PMID: 22452356 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Phthalazines
• Piperazines
• olaparib

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, therapeutic use)
• Disease-Free Survival
• Double-Blind Method
• Female
• Genes, BRCA1
• Genes, BRCA2
• Germ-Line Mutation
• Humans
• Kaplan-Meier Estimate
• Maintenance Chemotherapy
• Middle Aged
• Neoplasm Grading
• Neoplasm Recurrence, Local (drug therapy)
• Ovarian Neoplasms (drug therapy, mortality, pathology)
• Phthalazines (adverse effects, therapeutic use)
• Piperazines (adverse effects, therapeutic use)
• Young Adult