An FDA advisory panel on Wednesday recommended that the agency require AstraZeneca to gather more data about olaparib’s benefit for patients before deciding on an application filed earlier this year—threatening to derail the accelerated approval sought by the pharma giant for the ovarian cancer candidate.

FDA's Oncologic Drugs Advisory Committee (ODAC) voted 11–2 to recommend that the agency postpone a decision on approving olaparib until AstraZeneca can present results next year from the Phase III SOLO-2 trial. The FDA is not bound by the committee’s recommendation, but typically follows the advice of its advisory panels.

SOLO-2 is designed to assess efficacy of olaparib as a maintenance monotherapy in relapsed germline BRCA mutation (gBRCAm) high-grade serous ovarian cancer (HGSOC) patients (including patients with primary peritoneal and/or fallopian tube cancer) or high-grade endometrioid cancer who have responded following platinum-based chemotherapy. SOLO-2’s primary endpoint is progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, with overall survival (OS) a secondary endpoint.

AstraZeneca has cited an analysis of results from a single Phase II trial (“Study 19”) showing an 83% reduction in the risk of progression or death—as well as a seven-month median improvement in maintenance PFS for a subgroup patients who had the BRCA mutation. The analysis identified 51% of Study 19 patients (136) with either a germline or somatic tumor BRCA mutation. Median PFS in patients with the mutation was 11.2 months vs. 4.1 months with placebo.

The further look followed a 2012 interim analysis of Study 19’s 265 patients with platinum-sensitive ovarian cancer. The interim analysis showed a closer variance in median PFS—8.4 months with olaparib, 4.8 months with placebo.

But a staff report prepared for ODAC questioned the size of the reanalysis study sample and whether the results looked better because the control arm underperformed. The report also cited concerns about the risk of myelodysplastic syndrome/acute myeloid leukemia and the side effects reported by patients in Study 19, such as nausea, fatigue, vomiting, and anemia.

“There are uncertainties related to the validity and the reproducibility of the magnitude of effect seen in [the study], and there are risks associated with olaparib therapy,” the staff report concluded.

Olaparib is an oral inhibitor of polyadenosine 5'-diphosphoribose polymerases (PARP). AstraZeneca filed its NDA for olaparib approval in February. Three months later, FDA granted the company a six-month priority review rather than the standard 10-month review, and set October 3 as its Prescription Drug User Fee Act (PDUFA) target date for a decision.

Solo-2 is unlikely to produce first results before 2015; the trial is set to conclude in 2016. AstraZeneca is counting on olaoparib to deliver as much as a projected $2 billion in annual sales—and help rebuild its pipeline in oncology, one of the company’s three core therapeutic areas.

AstraZeneca revived olaparib shortly after current CEO Pascal Soriot took office in 2012. A year earlier, Soriot’s predecessor David Brennan suspended development of the compound, following a failed clinical study. Soriot and executives opted for the retrospective analysis, and tried last year but failed to win a breakthrough drug designation from the FDA.

The ODAC recommendation is likely to raise more questions about the value of AstraZeneca’s pipeline compounds just weeks after the company beat back several takeover offers from Pfizer, the last of which was for £69 billion ($117.2 billion) before throwing in the towel last month.

Earlier this month, during the American Society of Clinical Oncology (ASCO) annual meeting in Chicago, AstraZeneca trumpeted positive Phase II results of olaparib with cediranib in patients with platinum-sensitive high-grade serous ovarian cancer. The combination—which in the study nearly doubled the progression-free survival of patients—“has the potential to replace chemotherapy,” Briggs Morrison, AstraZeneca’s evp and CMO, said in a June 3 press release. 

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