AstraZeneca’s Olaparib Clears FDA For Later Therapy Line In Ovarian Cancer

AstraZeneca’s Lynparza was rejected as a maintenance therapy after second-line treatment by an FDA advisory committee, but landed accelerated approval for heavily pretreated relapsed patients, based on data not considered in the initial advisory committee review.

FDA has granted accelerated approval to AstraZeneca PLC’s Lynparza (olaparib) for a later line of therapy in BRCA-mutated ovarian cancer than the company sought in its original filing, having identified the area of unmet need as a potential route to approval after a negative panel review and solicited the company for additional data.

The agency announced accelerated approval of Lynparza in germline BRCA-mutated advanced ovarian cancer, along with the BRACnalysisCDx companion diagnostic developed by Myriad Genetics Inc. on Dec. 19. The drug is now indicated for use in patients who failed at least three prior lines of chemotherapy.

The approval came as a surprise, given that FDA’s Oncology Drugs Advisory Committee voted strongly against approval in June, citing concerns about the pivotal trial and safety, including the risk of developing acute myeloid leukemia and myelodysplastic syndromes (Also see "FDA Panel Crushes AstraZeneca’s Hopes For Olaparib Accelerated Approval" - Pink Sheet, 25 Jun, 2014.).

However, at that time, per the NDA, the committee was considering the drug in the maintenance setting, where risks of toxicities are more serious because patients would normally not be getting any treatment at all. The committee concluded it was best to wait for the ongoing Phase III SOLO-2 trial of olaparib as opposed to granting accelerated approval.

But after the meeting, AstraZeneca submitted an amendment to the filing, pushing the user fee date to Jan. 3. During a November investor meeting it said that it was confident of approval, though it did not comment on the details of the amendment (Also see "AstraZeneca Staking Its Growth On Oncology; Now It Needs Cancer Drugs" - Pink Sheet, 24 Nov, 2014.).

In its Dec. 19 statement about the approval, FDA explained: “In June, Lynparza was reviewed by the FDA’s Oncologic Drugs Advisory Committee for potential use as maintenance therapy (treatment given to keep cancer from returning). The committee advised the agency in a vote of 11 to 2 that the data did not support Lynparza’s accelerated approval for this use. After the meeting, the company submitted additional information supporting Lynparza’s use for a different use: in patients with gBRCAm-associated ovarian cancer who have received three or more chemotherapy treatments.”

AstraZeneca’s Jane Robertson, executive global clinical director for Lynparza, explained in an interview that the company kept in contact with FDA following the ODAC meeting and that the agency requested data for a different indication that it deemed to have high unmet need – relapsed patients who have had at least three prior chemotherapy treatments.

The company submitted data from a different study of 137 relapsed patients with germline BRCA-mutated advanced cancers. In that trial, the drug demonstrated a 34% overall response rate, including a 2% complete response and 32% partial response. Median duration of response in the trial was 7.9 months.

AstraZeneca also recently initiated the SOLO-3 study in this relapsed setting of BRCA-mutated ovarian cancer, which could serve as a confirmatory trial. However, the SOLO-2 study evaluating use as a maintenance therapy could also serve as a confirmatory trial for full approval, Robertson said.

FDA’s approval letter lists both confirmatory trials under the accelerated approval requirements. The PFS analysis of SOLO-2 is due in February 2016 and the final OS analysis in March 2019. The PFS analysis of SOLO-3 is due in June 2018 and the OS analysis in June 2020.

Post-marketing Requirements Deal With Safety

In addition to the confirmatory trials, FDA attached several post-marketing requirements and commitments to the approval. It is requiring the company to perform active surveillance to evaluate the risk of developing acute myeloid leukemia and myelodysplastic syndromes, with all cases analyzed and interim reports submitted on an annual basis.

Risks for secondary malignancies are cited in the warnings and precautions section of the labeling, but there is no boxed warning. “Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) occurred in patients exposed to Lynparza, and some cases were fatal,” the label states, advising that health care providers “monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if MDS/AML is confirmed.”

FDA also explains these risks in a medication guide for patients, advising “Lynparza may cause serious side effects that can lead to death,” including the bone marrow problems MDS or AML.”

“Symptoms of low blood cell counts,” such as weakness, weight loss and fever, are “common during treatment with Lynparza, but can be a sign of serious bone marrow problems, including MDS or AML.”

The agency is also requiring two Phase I clinical trials to assess serious risks for liver and kidney damage.

Major Win For AstraZeneca, Out Of A Failing Program

The Lynparza approval is the first clearance of a PARP inhibitor in the U.S. and is an important milestone for AstraZeneca in its bid to build oncology as a growth platform (Also see "AstraZeneca Staking Its Growth On Oncology; Now It Needs Cancer Drugs" - Pink Sheet, 24 Nov, 2014.). Lynparza was also approved as a maintenance therapy in BRCA-mutated advanced ovarian cancer in Europe on Dec. 18, following a recommendation for approval in October (Also see "European Backing For AstraZeneca’s Olaparib Bolsters Barriers To Pfizer" - Pink Sheet, 24 Oct, 2014.).

It is the second approval for ovarian cancer in recent weeks, however. Roche’s Avastin (bevacizumab) cleared FDA in November for platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan (Also see "Avastin Ovarian Cancer Approval Brings Some Clarity On PFS Endpoint" - Pink Sheet, 24 Nov, 2014.).

Ovarian cancer in the U.S.

• 2014: 21,980 new diagnoses, 14,270 deaths
• 10%-15% of all ovarian cancer has BRCA mutations

Source: NCI, FDA statement on Lynparza

Lynparza will be available to patients within weeks in the U.S., Robertson said. AstraZeneca did not disclose the exact price, but said that it will be “comparable to other oral cancer therapies.” Oral therapies launched in recent years typically cost around $10,000 per month.

The company will be offering patient assistance programs aimed at ensuring each patient pays no more than $50 per month out-of-pocket.

FDA’s Office of Hematology and Oncology Products Director Richard Pazdur described the drug as “an example of how a greater understanding of the underlying mechanisms of disease can lead to targeted, more personalized treatment,” in its announcement of the approval.

AstraZeneca had terminated development of olaparib in ovarian cancer in late 2011 after the drug failed to improve overall survival in a Phase II study. But following discoveries about the role of genetic mutations in ovarian cancer, the company announced the following year that it was re-evaluating the drug retrospectively in a subset with germline BRCA mutations. The company started Phase III trials in BRCA-positive patients in 2013 (Also see "AstraZeneca Back In The PARP Mix With Olaparib In Ovarian Cancer" - Pink Sheet, 4 Sep, 2013.).