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WASHINGTON -- Approval of a PARP inhibitor for patients with advanced ovarian cancer should await results of an ongoing clinical trial that has the potential to answer questions about the drug's safety and efficacy, according to an FDA advisory committee that voted against accelerated approval.

The Oncologic Drugs Advisory Committee (ODAC) voted 11-2 to delay approval of the PARP inhibitor olaparib until more data become available. The ongoing SOLO-2 trial is limited to patients with germline BRCA mutations, the subgroup that derived the greatest benefit from olaparib. The trial will not finish patient accrual until the end of the year.

ODAC members seemed split on a second issue: whether the SOLO-2 trial should have a primary endpoint of overall survival, instead of progression-free survival (PFS), as currently stipulated in the design.

The FDA is not bound by the decisions of its advisory committees, but the agency has a history of making decisions consistent with the committees' recommendations.

Significant Problems

"There were some significant problems with the data that were being submitted," ODAC chair Mikkael Sekeres, MD, of the Cleveland Clinic, told 木瓜直播. "A couple of factors swayed my decision [to vote against immediate approval]. "There is a very real risk of secondary cancers in the patients who received the therapy. [The sponsor] reported that 2.2% of the patients they treated with olaparib developed acute myeloid leukemia or myelodysplastic syndrome. That's much higher than you would expect against population-matched controls."

"It's a high enough safety signal that, when you combine it with the number of patients who had an abnormal blood count that could have indicated either myelodysplastic syndrome or acute myeloid leukemia, gave me pause in voting to approve this drug."

A second key factor was the recognition that many of the patients in the trial ordinarily would have been receiving no therapy at all.

"This drug was being given in the maintenance setting," said Sekeres. "So, while they had a 7-month advantage in progression-free survival, they had no improvement in quality of life. A substantial number of the patients had side effects to the medication that lasted 2, 3, or 4 months. While the patients were living without progression, those were not symptom-free months."

"The totality of the data, the limited benefit, the side effects of the drug, the risk of secondary cancers, made me vote No because I wanted to see data from a much larger study, and I wanted to see these data mature to see if even more patients developed secondary cancers."

Key Influences

After 7 hours of data presentation and discussion, the ODAC decision hinged primarily on two factors: The request for approval was based on data from a subgroup analysis, not an intention-to-treat or per-protocol analysis involving all of the patients. Second, questions about the validity and applicability of the data intensified the focus on adverse events and quality of life, particularly olaparib's association with myelodysplastic syndrome and acute myeloid leukemia.

The so-called "Study 19" involved 265 patients with relapsed platinum-sensitive ovarian cancer. They were randomized to olaparib or placebo and followed until disease progression or death. The primary endpoint was PFS. The overall analysis showed a statistically significant reduction in the risk of progression or death in patients randomized to olaparib (HR 0.35, 95% I 0.25-0.49, P<0.001). However, a showed that patients with germline BRCA mutations derived even greater benefit, an 83% reduction in the risk of progression or death.

Study 19 data also showed that three patients developed MDS or AML, two of them in the olaparib arm, a rate higher than would have been expected in a control population, according to Sekeres.

In an effort to confirm the PFS benefit in the BRCA-mutated subgroup, drug sponsor AstraZeneca has launched the randomized, placebo-controlled SOLO-2 trial, which will evaluate olaparib maintenance therapy in patients with relapsed ovarian cancer associated with germline BRCA mutations.

ODAC originally was supposed to address the magnitude of PFS benefit in SOLO-2 that would warrant approval of olaparib. Instead, some members of the panel felt that overall survival should be the primary endpoint. The ensuing discussion produced no clear consensus.

"I think the drug has potential," said Sekeres. "It has activity in patients, and it makes biologic sense with its mechanism of action and the mechanism underlying BRCA and ovarian cancer. I guess we'll have to wait and see whether maintenance strategy is appropriate."

Need for Strong Data

The decision reflects the FDA's emphasis on strong phase III data to approve oncologic drugs for use in the maintenance setting, said Joyce Liu, MD, of Dana-Farber Cancer Institute in Boston.

"I believe that, in terms of the activity of olaparib, we have seen that this can be an active drug across a spectrum of patients with ovarian cancer, and potentially patients with other types of cancer as well," said Liu, who did not participate in the ODAC hearing. "However, how olaparib would compare with standard therapies in these populations has not yet been shown in clinical trials."

Discussion of ODAC's divergence from the question about magnitude of benefit in PFS should take into account the patient population, which consists of women who often have received multiple prior lines of therapy.

"In this group of women, the cancer is almost certain to recur again, and this is a population where a maintenance therapy with very low toxicities but which can effectively delay cancer recurrence certainly would be of interest," said Liu.

In response to the ODAC decision, AstraZeneca released a statement from executive vice president Briggs Morrisons.

"Patients with germline BRCA-mutated serous ovarian cancer have few options available to treat this disease. We are disappointed with today's recommendation, and strongly believe that olaparib has the potential to provide patients with relapsed BRCA-mutated ovarian cancer and their doctors with a much-needed treatment option. We look forward to continuing to work with the FDA as it evaluates the Advisory Committee recommendation and completes its review of the application. In the meantime, we are continuing with our phase III clinical program to evaluate the benefit of olaparib for this patient population. We aim to have completed this study by the end of 2015."

CORRECTION: This article, which was originally published June 25, 2014, at 6:43 p.m., has been corrected (June 26, 2014, at 11:45 a.m. ).

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