FDA’s approval of AstraZeneca PLC’s ovarian cancer drug Lynparza (olaparib) reflects the different prisms through which the agency views benefit/risk in the relapse and maintenance settings.

It also shows an agency – and particularly an oncology review division – willing to go the extra mile to save a novel drug seemingly doomed to receive a “complete response” letter for the originally proposed maintenance indication. Instead, the oncology office urged AstraZeneca to submit data for a different patient population – highly pre-treated, relapsed subjects for whom there is an unmet need.

It was also the second saving grace for the first-in-class PARP inhibitor. AstraZeneca had shelved the drug in 2011 after a review of Phase II data suggested there wouldn’t be much impact on overall survival, but olaparib was revived by the identification that there might be better effect in patients with BRCA mutations ([A#14130904002]).

FDA “requested that we analyze the data for olaparib in patients who had had at least three prior lines of chemotherapy,” AstraZeneca’s Robertson said.

FDA granted accelerated approval to olaparib Dec. 19 for ovarian cancer patients whose tumors express a deleterious germline BRCA mutation and who have already received three or more lines of chemotherapy. The agency also approved a companion diagnostic, Myriad Genetics Inc.’s BRACAnalysis CDx, for use in conjunction with the drug ([A#14141219004]).

Yet, this fourth-line setting was not the indication publicly vetted by the agency’s Oncologic Drugs Advisory Committee at a June meeting. The application under review at that time sought accelerated approval for maintenance treatment of patients with relapsed ovarian cancer with germline BRCA mutation who have responded to platinum-based chemotherapy.

Based upon the committee discussion and FDA analyses released at that time, it appeared that the proposed maintenance indication was in trouble on both efficacy and safety grounds. It seemed likely that the advisory committee’s recommendation against accelerated approval would be followed by a “complete response” letter by the original Oct. 3 user fee date.

FDA To AstraZeneca: Look At Relapse Setting

However, subsequent to the advisory committee meeting FDA requested AstraZeneca go back and analyze data on use in heavily pre-treated, relapse patients – a request that ultimately may have saved the application from a first-cycle rejection.

In an interview, Jane Robertson, AstraZeneca’s executive global clinical director for Lynparza, said the agency “requested that we analyze the data for olaparib in patients who had had at least three prior lines of chemotherapy and when olaparib was given at the time of relapse, not as a maintenance treatment but as a line therapy in its own right.”

AstraZeneca submitted a major amendment to the application with the data in fourth-line use on July 24, one month after the advisory committee meeting. That submission extended the review clock by three months, and FDA’s accelerated approval came two weeks ahead of the reset PDUFA date of Jan. 3.

While AstraZeneca may not have gotten the maintenance claim it wanted – an indication recently approved in the European Union – it did manage to get olaparib on the U.S. market, where it can be used on- or off-label as practitioners see fit.

All eyes now will be on the two confirmatory studies AstraZeneca must run to convert its accelerated approval into a full approval, or else face the prospect of market withdrawal.

‘Better Than What Would Be Expected’

Olaparib’s accelerated approval was based a single-arm, open-label trial (Study 42) in patients with deleterious or suspected deleterious gBRCAm advanced cancers.

The study recruited patients with breast, ovarian, prostate, pancreatic and other tumor types with gBRCA mutations. Of 193 patients with ovarian cancer in the trial, 137 had received three or more prior lines of chemotherapy.

The objective response rate among these 137 patients was 34%, with 2% achieving complete response and 32% having a partial response. The median duration of response was 7.9 months.

In a Dec. 16 summary review, Division of Oncology Products 1 Acting Director Amna Ibrahim quoted the primary clinical review as stating: “The observed response rate of 34% in the patients with gBRCAm-associated ovarian cancer who have received three lines of chemotherapy is better than what would be expected of available therapy and represents an improvement on a surrogate endpoint that is reasonably likely to predict clinical benefit.”

In addition, durable response rate “is an established endpoint in heavily pre-treated cancer patients as it is able to isolate the antitumor effect,” Ibrahim said.

In a Dec. 19 memo, Office of Hematology and Oncology Products Director Richard Pazdur noted that the primary efficacy results in Study 42 were supported by a pooled analysis from other trials of patients with gBRCAm-associated ovarian cancer who had received three or more prior lines of chemotherapy.

While Study 42 accounted for the lion’s share of the patients in this pooled analysis, 68 patients in five other trials also met these criteria. The overall response rate across the six trials was 31%, with a median duration of response of 7.8 months.

Maintenance Study Provides Support, But Not Standalone Claim

The progression-free survival results in the gBRCAm subgroup of patients in a Phase II maintenance trial (Study 19) also provided support for olaparib’s efficacy in the fourth-line setting, Pazdur said.

Study 19 was a double-blind, placebo-controlled trial assessing PFS in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who were in partial or complete response to their last platinum-containing regimen. The Phase II trial was the basis for AstraZeneca’s original request for a maintenance indication, and it was the focus of the advisory committee’s attention at the June meeting.

In contrast, there were almost no data presented from Study 42 to the committee.

In the primary analysis of 265 patients in Study 19, olaparib was associated with a 65% PFS improvement and a median benefit of 3.6 months. However, a pre-planned PFS analysis in the known gBRCAm subpopulation suggested a differential improvement in this patient subgroup.

AstraZeneca retrospectively identified a total of 96 patents with deleterious gBRCAm in the trial. In this subgroup, olaparib was associated with an 83% reduced risk of disease progression or death, which translated into a median advantage of 7.1 months over placebo.

However, the retrospective identification and small sample size of the gBRCAm population raised questions for some panelists – and FDA itself – about the reliability and validity of the PFS results ([A#14140623001]). The committee voted 11-2 against granting accelerated approval for a maintenance claim now and said the agency should wait for results from the confirmatory SOLO-2 trial ([A#14140625004]).

Same Safety Issues, But Different Result

Advisory committee members also were troubled by olaparib’s toxicities in the maintenance setting, with its open-ended treatment window, especially because AstraZeneca and its experts had positioned the drug as a “holiday” from chemotherapy. Safety concerns ranged from mild events that lasted for many weeks, such as nausea, to secondary cancers such as myelodysplastic syndromes and acute myeloid leukemia.

Olaparib’s toxicities and the context of use specific to the maintenance setting led some panelists to urge that FDA require an overall survival benefit or demonstration of improved quality of life in SOLO-2.

In a particularly prescient comment, committee chairman and Cleveland Clinic hematologist Mikkael Sekeres suggested that relapse would be a more appropriate setting for olaparib than maintenance given the drug’s toxicities and the risk for secondary cancers ([A#00140630012]).

The committee’s discussions prompted a comment by Pazdur at the meeting’s close affirming the use of a PFS endpoint to support approval in ovarian cancer but noting that FDA would expect a larger magnitude of benefit for a maintenance claim than in an advanced disease setting.

In her summary review of the fourth-line indication, Ibrahim said the serious risk of secondary myelodysplastic syndromes and acute myeloid leukemia was deemed acceptable “considering the poor therapeutic options available to this population.”

Confirmatory Trials

As a condition of accelerated approval, AstraZeneca must submit PFS and overall survival analyses from both the SOLO-2 trial in the maintenance setting and the SOLO-3 trial in relapsed ovarian cancer. AstraZeneca’s Robertson said either study could serve as a confirmatory trial for full approval.

The 440-patient SOLO-2 trial is fully enrolled; an interim PFS analysis must be submitted to FDA by February 2016, with the final overall survival analysis due by March 2019, the agency’s approval letter states.

SOLO-3 is scheduled to begin enrolling in January; an interim PFS analysis is due in June 2018 and the final overall survival analysis in June 2020.

At the advisory committee meeting, AstraZeneca representatives pledged that if olaparib received accelerated approval for a maintenance indication and the SOLO-2 trial failed to demonstrate a magnitude of benefit on par with that seen in the Study 19 gBRCAm patient subgroup, it would voluntarily withdraw the drug from the market Also see "AstraZeneca Takes “Anti-Avastin” Pledge On Accelerated Approval Withdrawal" - Pink Sheet, 30 June, 2014..

When asked if AstraZeneca would voluntarily withdraw the fourth-line indication if the SOLO trials fail to confirm the magnitude of benefit seen in Study 42, a company spokeswoman said, “If not confirmatory in nature, AstraZeneca will consequently abide by the results and take the necessary actions, which could include withdrawal of the NDA.”

While AstraZeneca failed to gain the maintenance indication in the U.S., its data proved more persuasive with European regulators ([A#14141024001]).

On Dec. 18, the European Commission granted marketing authorization for maintenance treatment of patients with platinum-sensitive relapsed BRCA-mutated, high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete response or partial response to platinum-based chemotherapy.

Emily Hayes (emily.hayes@citeline.com) contributed to this story.

Lynparza Approval Shows Benefit/Risk Contrast In Maintenance, Relapse Settings

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