UPDATED: FDA experts spurn AstraZeneca's pitch for ovarian cancer drug olaparib

AstraZeneca's ($AZN) top investigators took their best case for an accelerated approval of the failed cancer drug olaparib to the FDA's panel of outside experts on Wednesday, and they lost.

Dr. Richard Pazdur

The panel voted 11 to 2 against an early approval, concluding that there were too many troubling questions about potential side effects of the drug as well as uncertainties about the sliver of efficacy data demonstrating an improvement on progression-free survival. It's not over yet, though. AstraZeneca is conducting a confirmatory Phase III study of the PARP inhibitor, dubbed SOLO-2. And the R&D group will need to report clear signs of a benefit to get this drug to the U.S. market. 

"This trial has problems," noted FDA cancer chief Richard Pazdur during the panel discussion. If investigators had "pristine evidence of a 7-month advantage in PFS, we wouldn't be here." It was the panel's job to consider if there were other clinical benefits that warrant an early approval for this drug as a maintenance therapy.

The general consensus was that AstraZeneca--which pegged peak sales potential for this drug at $2 billion--failed at that task.

AZ CEO Pascal Soriot

AstraZeneca's team faced a stiff challenge. Olaparib had already failed a study for ovarian cancer--overall survival in the olaparib arm was 34.9 months compared to 31.9 months for placebo--and was later shelved, spurring a $285 million writeoff. But the new turnaround team that took charge under CEO Pascal Soriot wanted to take a second shot, pegging their argument on a retrospective analysis of the data showing a distinct progression-free survival benefit for a group of patients with germline BRCA mutations.

The stakes were high. A win here would have helped make the case that AstraZeneca under new management was far more competent when it comes to drug development and new product approvals, an argument it made successfully just weeks ago when it beat back Pfizer's ($PFE) $120 billion takeover bid. A loss raised the specter of past failures and an uncertain and risky future. And for Bernstein's Tim Anderson, who discounted the market potential of this drug, the rejection raises the odds a bit that Pfizer will make another run at the company.

"The rejection by ODAC comes at a critical time because failed R&D efforts may make AZN shareholders more inclined to push AZN into PFE's arms," Anderson noted after the vote came in. "Is the olaparib ruling a major setback for AZN that will materially change how investors think about AZN?  No, but every bit of slippage at the company probably does tilt the balance slightly more in favor of a future PFE+AZN tie-up." 

Inside the FDA, regulators were distinctly downbeat about the regulatory package filed for this drug. The FDA internal review out earlier this week questioned whether the conclusions AstraZeneca reached could have been skewed by a very small group of patients delivering signs of a false benefit due to an "underperforming" control arm in the study. And given the potential side effects, the agency wanted the reviewers to consider whether AstraZeneca should wait on more definitive data before marketing a drug that could just be adding to patients' woes.

Today the agency and panelists zeroed in on a handful of lethal cases of myelodysplastic syndrome and acute myeloid leukemia suffered by patients in the study. These patients were already well advanced when they were given olaparib, raising the possibility that prior drugs may have triggered their deaths. The company suggested a variety of ways to reduce the risk associated with accelerated approval and laid out plans to set up an early-alert system if they won accelerated approval. After the vote, AstraZeneca EVP Briggs Morrison voiced the company's disappointment at the setback. 

"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," Morrison said in a statement. "We look forward to continuing to work with the FDA as it evaluates the Advisory Committee recommendation and completes its review of the application. In the meantime, we are continuing with our Phase III clinical programme to evaluate the benefit of olaparib for this patient population. We aim to have completed this study by the end of 2015."

The FDA doesn't have to accept the advice of its panel, but given the internal negative review and the overwhelming panel vote against AstraZeneca, its chances are slim to none. According to clincialtrials.gov, the SOLO-2 study is slated to wrap in the summer of 2016.

PARP inhibitors for cancer have spurred some considerable excitement in the cancer field, but there have been some notable setbacks. Sanofi in particular had to take an embarrassing writeoff for iniparib last year following a key trial failure. 

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