乌鸦传媒

AUSTIN, Texas -- Patients with relapsed, platinum-sensitive ovarian cancer had almost a twofold improvement in progression-free survival (PFS) with PARP-inhibitor maintenance therapy, investigators reported.

Median PFS increased from 4.8 months with placebo to 8.4 months with olaparib (AZD2281). A planned subgroup analysis showed a consistent benefit similar to the overall difference.

Adverse events were more common with olaparib, but most events were grade 1 or 2 severity, according to data presented here at the Society of Gynecologic Oncology meeting.

The improvement in PFS has yet to translate into a survival advantage, as patients in both groups have a median overall survival of about 30 months.

"It's important to point out that this is an immature interim survival analysis," said Jonathan Ledermann, MD, of University College London. "It was done when the data were 38% mature, that is, 38% of the population had died. We will do a final survival analysis when the data reach 60% maturity."

The final analysis could prove to be moot, as AstraZeneca has stopped clinical development of olaparib as maintenance therapy for ovarian cancer. In a statement released in December, company officials said an analysis of the data indicated that the trial was unlikely to show a survival advantage.

Published simultaneously online in the New England Journal of Medicine, the results remained largely unchanged from those reported at the 2011 meeting of the American Society of Clinical Oncology.

About 80% of patients with newly diagnosed ovarian cancer respond to platinum-based chemotherapy. However, most patients relapse, and responses to subsequent therapies tend to be of shorter duration compared with the initial response.

About 15% of epithelial ovarian cancers have homologous repair deficiency arising from BRCA1/2 mutations. As many as 50% of high-grade serous ovarian tumors are deficient in the homologous repair enzyme as a result of germline or acquired BRCA1/2 mutations or defects in the homologous repair pathway, according to the introduction of the journal article.

Silencing or abnormal function of genes in BRCA1/2-related pathways has given rise to a so-called "BRCAness" phenotype, a term referencing the similarity to inherent mutations in BRCA1/2.

Microarray analysis of serous ovarian tumors has revealed a BRCAness gene-expression profile that appears to predict responsiveness to platinum chemotherapy and inhibitors of poly(adenosine diphosphate [ADP]-ribose) polymerase, or PARP, authors of the journal article continued.

Olaparib has demonstrated potent lethality in BRCA1/2-deficient tumor cell lines. A phase II study of of patients with high-grade serous ovarian cancer, single-agent olaparib resulted in a response rate 41% in patients with BRCA1/2 mutations and 24% in those without mutations.

The favorable clinical and preclinical data provided the basis for a randomized trial of olaparib maintenance therapy in patients with relapsed, platinum-sensitive, high-grade serous ovarian cancer.

Eligibility criteria included a history of at least two courses of platinum-based chemotherapy, the most recent of which had resulted in an objective response. Additionally, pretreatment measurements of the CA-125 cancer antigen had to be within the upper limit of normal.

Within 8 weeks after the last dose of platinum-based chemotherapy, investigators randomized 264 patients to daily olaparib or placebo and followed them until disease progression, death, or discontinuation. The primary endpoint was PFS.

At the planned interim analysis, the results showed a significant improvement in PFS in the olaparib arm (HR 0.35, P<0.001). Median overall survival did not differ between the groups (29.7 months with olaparib versus 29.9 months with placebo).

Whether assessed by change in tumor size or CA-125 levels, an identical hazard ratio emerged in favor of the olaparib arm.

Almost all patients had one or more adverse events. Olaparib-treated patients had a higher incidence of nausea, fatigue, vomiting, and anemia. About a third of patients in the olaparib arm had grade 3-4 adverse events compared with 20.3% in the placebo group. No unexpected adverse events occurred in either treatment group.

Symptom and quality-of-life scores did not differ between the groups.

Discussion that followed the presentation included speculation about olaparib's future. Ledermann and Robert Coleman, MD, of the University of Texas MD Anderson Cancer Center in Houston, said production problems contributed to the decision to suspend clinical development of the drug.

Coleman, who moderated the session that included Ledermann's presentation, said the problems related to the transition of olaparib from a capsule to a tablet formulation. He and Ledermann were optimistic that clinical development would resume if the manufacturing issues can be resolved.