The FDAâ€™s ODAC voted 11-2 against the accelerated approval of the PARP inhibitor olaparib as a maintenance therapy for women with platinum-sensitive relapsed ovarian cancer with germline BRCA mutations.
By voting no, the committee recommended waiting for results from the larger phase III SOLO-2 trial, which began enrolling in 2013. The primary endpoint of this study is progression-free survival (PFS) by RECIST criteria. Overall survival (OS) will remain a secondary endpoint, as was the case in earlier phase II trials.
In February 2014, the developer of the drug, AstraZeneca Pharmaceuticals, submitted a new drug application for accelerated approval based on a secondary analysis of a single phase II efficacy trial known as Study 19. In this analysis, treatment with olaparib reduced the risk of progression by 83% compared with placebo; however, OS was not significantly extended.
"This was a small dataset with no improvement in overall survival and no improvement in quality of life," advisory board member James E. Liebmann, MD, from the UMass Memorial Medical Center, said during the briefing. "The benefits demonstrated need to be borne out in a larger randomized trial, which we'll hopefully have soon."
In the ODAC hearing, advisory members were asked to define an appropriate magnitude of PFS benefit for approval and whether the primary endpoint of the SOLO-2 trial should be OS. Primarily the panelists believed that OS should be the endpoint used to approve new agents in the maintenance setting, with a PFS benefit being acceptable in some situations. Other committee members expressed concerns over the side effects and the rate of secondary acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) experienced with olaparib treatment.
In the phase II Study 19, 265 patients with platinum-sensitive ovarian cancer were randomized in a 1:1 ratio to receive either olaparib (n = 136) or placebo (n = 129). Olaparib was administered at 400 mg twice daily (BID); however, there was difficulty identifying whether this was the correct dose. For the phase III development program, olaparib is being administered at 300 mg BID.
In March 2012, data from this interim analysis were published inThe New England Journal of Medicineshowing an improvement in median PFS of 8.4 months with olaparib compared with 4.8 months with placebo (HR = 0.35; 95% CI, 0.25 - .049;P<.001) but no significant difference for OS. However, a preplanned subgroup analysis of a small portion of patients (36.6%) withBRCAmutations identified at the time showed a clear advantage for olaparib, causing renewed interest.
Based on this subgroup analysis,BRCAstatus was retrospectively identified for patients in the phase II trial. In total, germlineBRCAmutations were identified in 96 patients. When including somatic tumor mutations, 136 of the 265 patients (51%) were identified as positive for aBRCAmutation. Altogether,BRCAstatus was identified for 96% of trial participants. For patients specifically with germlineBRCAmutations, 53% of patients in the olaparib arm had received at least 2 prior therapies and 47% had received greater than 3 therapies, compared with 67% and 33%, respectively, in the placebo arm.
Results from this analysis suggested a greater clinical benefit in theBRCA-mutant population, but an OS analysis was confounded. For those with the mutation, PFS was 11.2 months compared with 4.1 months, for olaparib and placebo, respectively (HR = 0.17).
The OS findings between patients with germlineBRCAmutations and wild-typeBRCAwere similar, according to data presented at the 2013 ASCO Annual Meeting. Trial authors believe this similarity was due in part to 35% of patients with germline mutations on the placebo arm receiving a subsequent PARP inhibitor. However, when looking at all types ofBRCAmutations, the OS was 34.9 months with olaparib compared with 31.9 months for placebo (HR = 0.74; 95% CI, 0.46-1.19).
Grade 1/2 adverse events were frequent with olaparib while grade 3/4 adverse events were rare. The most common adverse events associated with olaparib were nausea, fatigue, abdominal pain, vomiting, diarrhea, and anemia. Additionally, patients treated with olaparib had higher rates of gastrointestinal events, anemia, neutropenia, fatigue, asthenia, infections, and respiratory disorders than patients treated with placebo. Three patients on olaparib (2.2%) were suspected of having MDS or AML, the FDA briefing documents noted. Overall, the FDA noted that of the 2618 patients treated with olaparib, there have been 21 cases of MDS and/or AML (0.8%) diagnosed, not including the three suspected cases from Study 19.
"I think it is important to emphasize that Study 19 was in a group of patients at high risk who had multiple numbers of treatment regimens, and who were going to face additional chemotherapy regimens for the rest of their life," Robert F. Ozols, MD, PhD, a retired ovarian cancer expert and consultant for AstraZeneca Pharmaceuticals, said during the briefing. "In this context, having an interval of longer than 6 months without cytotoxic chemotherapy is a true benefit."
While the FDA is not required to follow the recommendations of ODAC, historically, the federal agency often does. The FDA is scheduled to make a decision regarding the approval of maintenance olaparib on or before October 3, 2014.