FDA Panel Votes Against Accelerated Approval for Olaparib

Larry Hand

June 26, 2014

The Oncologic Drugs Advisory Committee (ODAC) of the US Food and Drug Administration (FDA) has voted, by a wide margin, not to recommend accelerated approval for use of a targeted cancer drug in a subset of ovarian cancer patients.

Panel members voted 11 to 2 against the approval of olaparib (AstraZeneca) as a maintenance treatment for women with platinum-sensitive relapsed ovarian cancer who have a germline BRCA mutation and who have had a complete or partial response to platinum-based chemotherapy.

AstraZeneca was seeking the accelerated approval on the basis of a subgroup analysis from a phase 2 trial, which showed that olaparib lengthened the amount of time between chemotherapy and disease progression, as reported last year by Medscape Medical News.

Accelerated approval would have made the drug available to patients while AstraZeneca conducts the phase 3 SOLO2 trial to confirm the results, which should be completed by the end of 2015, according to company representatives. The ODAC panel recommended waiting until those results are available.

Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, acts through a DNA repair mechanism that blocks cancer cells but not regular cells. It has been under development for some time, but negative results from a previous trial of ovarian cancer led to the discontinuation of development. However, interest in the drug was revived when the phase 2 retrospective subgroup analysis showed a benefit in patients with the BRCA mutation.

That phase 2 trial involved patients with high-grade serous ovarian cancer, with or without germline gene mutations. Patients were randomized to olaparib 400 mg (8 × 50 mg capsules) twice a day or to placebo.

Overall, median progression-free survival was better with olaparib than with placebo (8.4 vs 4.8 months), and the risk reduction was 65% (P < .00001).

However, the difference in overall survival was not significant, and olaparib had no effect on quality of life during a maintenance period when the standard of care is no therapy.

In the subgroup analysis of patients with the mutated germline BRCA gene, progression-free survival was 7.1 months longer with olaparib than with placebo (11.2 vs 4.1 months); the reduction in risk was 83%. According to the AstraZeneca, an improvement of 6 months represents a significant clinical effect.

Panel members expressed concern about the way the subgroup results were obtained. The AstraZeneca researchers used a retroactive analysis of blood samples to obtain information on the mutation status of some patients, but blood samples were an option, not a requirement, so mutation status was not available for all patients.

Analyses of retrospective data are not typical for the advisory committee or the FDA, panel chair Mikkael Sekeres, MD, associate professor of medicine at the Taussig Cancer Institute at the Cleveland Clinic, told Medscape Medical News in a telephone interview. "We're used to seeing large prospective studies."

In addition, he said, panel members were concerned about a signal that some patients taking the drug were developing secondary cancers, myelodysplastic syndrome, or acute myeloid leukemia. FDA representatives presented data showing that the annual overall incidence of myelodysplastic syndrome is 0.0033% (3.3 per 100,000), whereas the incidence in the phase 2 study was 2.2% (1 suspected and 3 confirmed cases).

"While side effects on the whole were relatively minor, we're still talking about patients who had, for example, 2 and a half months of nausea or 3 months of abdominal pain" with the drug during the maintenance period, Dr. Sekeres told Medscape Medical News. "They were spending more time without progression, but a good portion of that time they were spending with side effects to a drug, when ordinarily they wouldn't have any side effects because they wouldn't be on any drug."

Panel members were also concerned about the treatment not improving quality of life, although AstraZeneca representatives pointed out that it did not worsen it.

And they expressed doubts about the reproducibility of the phase 2 results in the ongoing phase 3 study because the drug formulation has changed — from 8 × 50 mg twice a day to 2 × 300 mg twice a day. They question the bioequivalence of the 2 formulations.

During their meeting, the panel members also discussed the magnitude of treatment effect that could support eventual approval and whether progression-free survival should be replaced with overall survival as an end point. However, they did not reach consensus on either topic.

"It sounds like the company is going to have to sit down with the FDA and figure out whether they can still use progression-free survival as their end point, or whether they're going to have to change to overall survival," Dr. Sekeres told Medscape Medical News.

The survival issue is a trend in clinical trials. "The bar has moved over the past decade. It used to be that progression-free survival was an acceptable end point," he explained. "Now people are demanding more from drugs."

On a personal note, Dr. Sekeres, whose term on the advisory committee ended with this meeting, said he hopes the FDA will ask him back to committee meetings as an ad hoc member. The agency had already extended his 3-year term to 5 years.

The advisory committee members have disclosed no relevant financial relationships.

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