FDA Rules Hamper Novel Ovarian Cancer Drugs

J. Tate Thigpen, MD

The FDA’s rules for approving new drugs for the treatment of women with ovarian cancer pose frustrating problems for researchers developing novel agents and for clinicians seeking to improve outcomes for their patients, according to leading oncologists.

Those sentiments surfaced in interviews during the 9th International Symposium on Ovarian Cancer and Gynecologic Malignancies,® a one-day meeting that Physicians’ Education Resource, LLC (PER®) hosted October 5 in Philadelphia, where various strategies for treating patients and novel therapies under study were discussed.

Although there are several promising new agents in the pipeline, experts fear that a new drug for advanced ovarian cancer will not gain approval in the United States unless the FDA accepts evidence of progression-free survival (PFS) as a primary outcome measure in clinical trials, rather than the “gold standard” of overall survival (OS).

The multiple lines of therapy that patients with recurrent ovarian cancer receive make it difficult to obtain a clear comparison of the OS impact of a novel therapy versus a standard treatment, said J. Tate Thigpen, MD, director of the Division of Medical Oncology at the University of Mississippi School of Medicine in Jackson, one of the course directors of the conference.

“In our studies, we cannot control for what the patient gets after the patient progresses on the study therapy,” said Thigpen. “The patient essentially comes off study and is followed for survival. You start introducing then, at random if you will, additional lines of treatment. In the case of ovarian cancer, that may go up to as many as eight or 10 lines of therapy.”

Thigpen, who has played a leadership role in the Gynecologic Oncology Group (GOG), has long been a proponent of considering PFS as an acceptable endpoint for clinical trials in ovarian cancer, particularly for first-line therapy in advanced disease and in recurrent/persistent disease.^1,2 He contended that large trials have confirmed that PFS provides clinical benefit to patients and is a surrogate for OS.¹

If the FDA does not recognize PFS as a valid endpoint in ovarian cancer trials, new drug approvals for the disease will remain stalled while patients continue to be treated upon recurrence primarily with cytotoxic agents. “It is going to be very difficult to get a new drug approved, or to get the pharmaceutical industry to invest in evaluating new drugs in ovarian cancer, if they know that the odds of their being able to get the drug approved based on an overall survival endpoint is just by chance alone,” said Thigpen.

PFS Definitions Disputed

In recent years, the use of PFS (and time-to-progression [TTP]) as a primary endpoint in phase III randomized clinical trials has increased dramatically, from 0% in 1975-1984 to 26% in 2005-2007, according to an analysis of four eras of reports concerning breast, colorectal, and non-small cell lung cancers published in the Journal of Clinical Oncology.³ And, the FDA has been willing to approve oncology drugs based on PFS, with 23% of new drug approval indications from 2005-2007 and 29% of approvals from 2000-2010 based on trials with PFS or TTP endpoints.³

In ovarian cancer, the question of how to assess PFS in patients emerged as a major point of contention when the FDA convened a workshop on clinical trial endpoints for the malignancy in 2006.¹

The optimal use of CA-125 values to evaluate whether a patient’s disease has progressed and how such assay results should be incorporated into clinical trials were disputed. In addition, some panelists believed that PFS assessments are susceptible to bias because of their timing during the course of a trial. “The point that the FDA makes is they do not believe that progression-free survival can be assessed accurately in ovarian cancer, because it is an intra-abdominal disease process,” said Thigpen in the interview. “We believe that the literature shows that PFS can be measured consistently in ovarian cancer and is the optimal endpoint for ovarian cancer.”

Issues concerning the FDA’s views on PFS as a clinical trial endpoint go beyond ovarian cancer, noted Maurie Markman, MD, senior vice president for Clinical Affairs and national director for Medical Oncology at Cancer Treatment Centers of America, who also served as a symposium director.

“Progression-free survival in a phase III randomized trial or well-designed randomized phase II trial with adequate differences in hazard ratios should be unequivocally acceptable for approval of an agent within weeks of the data being reported,” said Markman.

Indeed, concerns about defining PFS pervade investigations into novel therapies across many tumor types, prompting the FDA’s Oncologic Drugs Advisory Committee to hold a meeting in July 2012 solely to discuss related issues.⁴ Specifically, the panel considered whether an independent audit of investigator assessment of PFS in a random sample of patients instead of an independent review of all patients would help streamline clinical trials and improve the accuracy of collected data. Historically, the agency has required an independent radiologic review of scans to confirm local evaluation of investigator assessment.

Targeted Agents Stalled

In ovarian cancer, however, the clinical trial endpoint question is particularly pressing. Although novel and targeted therapies have been approved in a growing range of malignancies, FDA-approved drugs and regimens in ovarian cancer are comprised of chemotherapies, according to the National Cancer Institute.⁵

As a result, many of the therapies used to treat patients with recurrent disease are not specifically indicated for ovarian cancer. Hormonal therapies and the antiangiogenic agent bevacizumab are considered acceptable recurrence therapies based on clinical trials results under the National Comprehensive Cancer Network guidelines (Table).⁶

When it comes to bevacizumab, off-label use based on PFS clinical trial findings has created a “patchwork arrangement” in which insurance coverage varies from state to state and from one specific disease setting to another, said Michael J. Birrer, MD, PhD, a professor at Harvard Medical School and director of Gynecologic Medical Oncology at Massachusetts General Hospital.

Table. Therapies for Recurrent Ovarian Cancer, NCCN Guidelines Versus FDA Approvals

National Comprehensive Cancer Network (NCCN) guidelines include the above therapies as acceptable for recurrent ovarian cancer either alone or in combination, based on clinical trial evidence. Only highlighted therapies are FDA-approved for ovarian cancer.

“I think FDA approval would provide a very strong framework to recommend both to patients and physicians when they should get the drug, but we don’t have that,” said Birrer, who also was a course director at the PER symposium.

Development of another targeted therapy, the PARP inhibitor olaparib, was nearly sidelined in ovarian cancer after a phase II trial failed to demonstrate an overall survival benefit as a maintenance therapy.

AstraZeneca announced in December 2011 that it would discontinue its olaparib development program, but subsequently revived its clinical efforts after a subgroup analysis showed strong activity in patients with BRCA-mutated tumors. Two phase III clinical trials are now moving forward with PFS as the primary endpoint—as measured by radiologic scans performed at baseline and then every 12 weeks and evaluated by blinded independent central review using modified RECIST data.

Data Accepted Elsewhere

While the FDA wrestles with clinical trial endpoints, results that may not be acceptable for a new drug approval in the United States are finding acceptance in other countries.

In November, Japanese regulators approved bevacizumab for the treatment of ovarian cancer based mainly on the results of the phase III GOG- 0218 study, according to Chugai Pharmaceutical Co, Ltd, which is part of the Roche Group. The study, conducted partly in the United States, demonstrated a median PFS of 14.1 months for patients with stage III/IV disease who took prolonged bevacizumab plus chemotherapy upfront and as maintenance therapy versus 10.3 months for chemotherapy alone.⁶

Bevacizumab is now approved as front-line therapy for ovarian cancer in 110 countries, including 26 European Union countries, said Chugai.

In a similar vein, the European Medicines Agency has agreed to consider marketing authorization for olaparib as a maintenance treatment for patients with BRCA-mutated, platinum-sensitive relapsed ovarian cancer based on phase II clinical trial results, according to AstraZeneca.

References

1. Ovarian cancer endpoints workshop, April 26, 2006, meeting summary. US Food and Drug Administration website, Cancer Drug Approval Endpoints section. www.FDA.gov. Updated August 26, 2013. Accessed December 3, 2013.
2. Stuart GCE, Kitchener H, Bacon M, et al. 2010 Gynecologic Cancer InterGroup (GCIG) Consensus Statement on Clinical Trials in Ovarian Cancer: report from the Fourth Ovarian Cancer Consensus Conference. Int J Gynecol Cancer. 2011;21(4): 750-755.
3. Booth CM, Eisenhauer EA. Progression-free survival: meaningful or simply measurable? J Clin Oncol. 2012;30(10):1030-1033.
4. FDA briefing information, progression-free survival in non-hematologic malignancies, for the July 24, 2012 meeting of the Oncologic Drugs Advisory Committee. US Food and Drug Administration website. www.FDA.gov. Updated July 10, 2012. Accessed December 3, 2013.
5. Drugs approved for ovarian cancer. National Cancer Institute website. www.cancer.gov. Updated August 16, 2013. Accessed December 3, 2013.
6. 6. Ovarian cancer including fallopian tube cancer and primary peritoneal cancer version 2.2013. NCCN Clinical Practice Guidelines in Oncology. www.nccn.com. Updated June 13, 2013. Accessed December 3, 2013.
7. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-2483.