SILVER SPRING, MD—The Oncologic Drugs Advisory Committee (ODAC) of the U.S. Food and Drug Administration voted 11 to 2 in a meeting here against recommending accelerated approval of olaparib as oral maintenance monotherapy for women with relapsed platinum-sensitive ovarian cancer—including fallopian tube or primary peritoneal—who have the germline BRCA (gBRCA) mutation. Olaparib is a PARP (poly ADP ribose polymerase) inhibitor, which preferentially induces cell death in BRCA-deficient cells. As usual, the FDA does not have to follow ODAC's recommendations, but frequently does.
The Society of Gynecologic Oncology, patients, and patient advocates expressed disappointment with ODAC's recommendation, as did olaparib's manufacturer, AstraZeneca.
Briggs Morrison, MD, the company's Executive Vice President for Global Medicines Development and Chief Medical Officer, said in a statement, “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.” He said the company will continue its olaparib clinical trial development program, and pledged to work with the FDA to address its concerns.
In making their decision, ODAC committee members reviewed clinical data from a pivotal trial known as Study 19. That study of several hundred women demonstrated an 83 percent reduction in the risk of disease progression or death and a median improvement of 7.1 months in progression-free survival (PFS) for patients with gBRCA-mutated ovarian cancer taking olaparib as maintenance therapy. But data from Study 19 also raised questions about an increased risk of myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML), as well as questions about side effects, and statistical-design concerns about the validity and reproducibility of the magnitude of the benefit observed.
An important factor for voting ODAC members was that a larger global confirmatory trial of olaparib as maintenance monotherapy, SOLO-2, is now enrolling patients; results from SOLO-2, which will enroll only women with the gBRCA mutation and use a different oral formulation, are expected by the end of 2016.
Pazdur: ‘This Trial Has Problems...’
“This trial has problems... that's why we're having this discussion,” said Richard Pazdur, MD, Director of FDA's Office of Hematology & Oncology Products in the Office of New Drugs. “If we were dealing with a pristine clinical trial... we wouldn't be here,” he added, noting that the sponsor's New Drug Application for olaparib (which was filed in February), was “a very difficult application to discuss.”
He emphasized that the FDA is not against progression-free survival (rather than overall survival) as a primary endpoint in ovarian cancer trials—which was clearly a problem for some of the ODAC members. Pazdur said the FDA will work with AstraZeneca on the trial design of SOLO-2. He also asked AstraZeneca speakers about the drug company's philosophy on providing expanded access to olaparib. The company has such a program, but it is somewhat limited, said Hesham A. Abdullah, MD, MSc, RAC, AstraZeneca's Vice President for Global Regulatory Affairs in Oncology. “The best expanded access is regulatory approval,” he said.
“I think we need to take a deeper dive into cytopenias on this study,” said ODAC Chair Mikkael Sekeres, MD, MS, Director of the Leukemia Program and Chair of the Hematology/Oncology Pharmacy & Therapeutics Committee at the Cleveland Clinic's Taussig Cancer Institute, and OT's Clinical Advisory Editor for Hematology/Oncology.
Presiding at his final meeting as ODAC Chair, Sekeres said he was particularly concerned about the increased risk of MDS on Study 19, since MDS is underdiagnosed and some ovarian cancer patients put on olaparib as maintenance therapy could have undiagnosed MDS. He said he was also concerned about subjecting women on olaparib maintenance monotherapy to potential side effects such as nausea and vomiting, even though most nausea and vomiting in Study 19 was reported as mild.
He noted that the current standard of care is for platinum-sensitive ovarian cancer patients not to be treated until they relapse, at which time they would have another platinum-based chemotherapy treatment. For the majority of patients in Study 19, while their quality of life was no worse on olaparib than on placebo, it also did not change for the better.
Speaking in favor of the Accelerated Approval application for olaparib, Ursula A. Matulonis, MD, Medical Director and Program Leader of the Medical Gynecologic Oncology Program at Dana-Farber Cancer Institute, stressed that women with advanced ovarian cancer on olaparib maintenance therapy are “absolutely overjoyed” not to have to come into the clinic as frequently to have IV chemotherapy. “This is an overwhelmingly well-tolerated drug... patients want this drug now, and not to have to wait for it,” she said.
Ozols: ‘Meaningful PFS Increase’
Also speaking on behalf of approving olaparib, consultant Robert F. Ozols, MD, PhD, a pioneer in ovarian cancer research who formerly held positions at the National Cancer Institute and at Fox Chase Cancer Center, stressed that olaparib “capitalizes on ovarian cancer tumor biology,” thus leading to an acceptable toxicity profile in which “normal cells are less affected.” Ozols added, “Extending PFS by 7.1 months is meaningful, prolonging the chemotherapy-free interval.” He noted that “BRCA status allows patient selection sensitive to PARP inhibition.”
Voting for the accelerated approval application, temporary ODAC voting member Edward L. Trimble, MD, MPH, Director of NCI's Center for Global Health, said he was persuaded by the data on the prolonged disease-free interval. He added, “I support PFS as a primary endpoint, and so does the ovarian cancer advocacy community.”
The other person who voted for the New Drug Application was ODAC member Tito Fojo, MD, PhD, Program Director for Medical Oncology at NCI.
Disappointing to Many
Speaking on behalf of the Society of Gynecologic Oncology (SGO) during the public session of the ODAC meeting, G. Larry Maxwell, MD, FACOG, Col. (ret), Chair of the Department of Obstetrics and Gynecology at Inova Fairfax Hospital in Virginia, said, “SGO highly endorses this application.”
The data from Study 19 are “impressive” and olaparib maintenance therapy for gBRCA-mutated ovarian cancer patients represents “truly individualized therapy,” ushering in “personalized medicine for this patient population,” added Maxwell, who is also Professor in the Department of Obstetrics and Gynecology at Virginia Commonwealth University School of Medicine.
“We've waited 10 years just for this,” Lisa Schlager, Vice President for Community Affairs & Public Policy of FORCE (an advocacy group for people fighting hereditary breast and ovarian cancer), told OT.
In her formal presentation during the public session, Schlager said, “Women with BRCA-associated ovarian cancer cannot and should not have to wait another decade to have access to a PARP inhibitor. We ask that the FDA consider our community carefully when reviewing this drug application and grant approval to olaparib for maintenance therapy in ovarian cancer patients who are BRCA positive... How many more women will die or suffer the effects of advanced disease and chemotherapy while we are waiting for larger trials to be completed? Women fighting hereditary ovarian cancer do not have time to wait.”
Ovarian cancer survivor Nancy Long, a nurse practitioner who is Co-Chair of the Leadership Council for the Central Maryland Chapter of the National Ovarian Cancer Coalition (NOCC), stated during the public session, “Olaparib is one of the promising targeted drugs. I urge you to approve this drug. We cancer survivors are desperate for new drugs and treatments.”
And, in a letter sent to ODAC on behalf of the Ovarian Cancer National Alliance (OCNA), ovarian cancer survivor Kathleen S. Fallon said, “It is striking and disheartening to see that despite progress made in recent years, ovarian cancer continues to claim the lives of so many women.
“Furthermore, there are few FDA-approved medications for the treatment of ovarian cancer. ... To ensure that women have access to therapeutics necessary for their care, the Alliance advocates for the approval of every treatment and therapy that shows a benefit in fighting ovarian cancer, provided that benefit has been clearly documented through appropriate trials and review process.”