Testimony of Dr. Anna E. Mazzucco to FDA advisory committee on olaparib

June 25, 2014

Thank you for the opportunity to speak today on behalf of the Cancer Prevention and Treatment Fund. My name is Dr. Anna Mazzucco, and after completing my Ph.D. in Cell and Developmental Biology from Harvard Medical School I conducted research at the National Cancer Institute. I speak from those perspectives today.

Our nonprofit organization conducts research, scrutinizes data in the research literature, and then explains the evidence of risks and benefits to patients and providers.  Our president is on the Board of Directors of the Alliance for a Stronger FDA, which is a nonprofit dedicated to increasing the resources that the FDA needs to do its job.  Our organization does not accept funding from pharmaceutical companies, and therefore I have no conflicts of interest.

Maintenance therapy for ovarian cancer patients is vital to extending the recovery time between chemotherapeutic regimens and preserving the efficacy of those agents.  Under consideration today is whether there is sufficient evidence at this time to approve olaparib for a maintenance therapy indication for platinum-sensitive high-grade relapsed serous ovarian cancer.

The goal of maintenance therapy is to extend the time between therapeutic intervals with an optimal risk-benefit ratio.  Otherwise, these patients would not be taking any medication during this time and need this period to recover before additional chemotherapy is needed.  Therefore safety, efficacy, and quality-of-life measures are defining features of maintenance therapy.

Afterreviewing the study evidence, we have three major concerns about olaparib, which were also raised by the FDA.

Firstly, we are concerned about the reliability of the progression-free survival benefit of olaparib, especially since there was no improvement in overall survival during Study 19.

Secondly, we are concerned about the safety profile of olaparib in the context of maintenance therapy. Olaparib-treated patients were almost twice as likely to experience a serious adverse event, in addition to the potentially elevated occurrence of myelodysplastic syndrome orAML.

Lastly, we are concerned that there is not enough evidence of efficacy and low toxicity to ensure that use of olaparib will not compromise patient response to subsequent therapy, which is critical to successful maintenance therapy.

Previous studies of first-line therapy for ovarian cancer suggested that progression-free survival can be predictive of overall survival.  However, a recent paper by the Society of Gynecologic Oncology cautioned against extrapolation of progression-free survival to presumed overall survival benefit in the context of prolonged post-progression survival and multiple lines of treatment.

I’m sure we all agree with the FDA that overall survival is clearly the most significant efficacy measure.  Progression-free survival may only be an acceptable efficacy endpoint when certain criteria are met.  These criteria include low toxicity and efficacy which is both truly predictive of clinically significant benefit and is of robust magnitude, in this particular case, an extension of progression-free survival by six months or more.

Given these stipulations, the seven month extension of progression-free survival in gBRCAm patients may meet a minimal efficacy threshold, but there are strong concerns about the reliability of this observed effect.  In the exploratory analysis conducted by the FDA within the placebo arm, the gBRCAwt/vus population unexpectedly had a superior progression-free survival outcome when compared to the gBRCAm population.  This suggests that the placebo-treated gBRCAm population may have “underperformed”, meaning that the progression-free survival improvement observed in the gBRCAm population may be overestimated.  The SOLO-2 trial currently underway is powered to precisely detect changes in the hazard ratio.  That data is critical to clarifying the potential progression-free survival benefit of olaparib due to this uncertainty.

While the patient-reported FACT-O quality-of-life measures did not indicate detriment, there were significantly increased adverse events with olaparib treatment, including a 2-fold increase in nausea, a 4-fold increase in anemia, a 2-fold increased incidence of various infections, and a near 2-fold increase in gastrointestinal disorders.

As the FDA stated, the patient-reported measures may not capture all possible negative effects of olaparib treatment, and any reported improvements could also reflect cessation of previous platinum treatments.

In addition, approximately four times as many patients in the olaparib-treated arm versus the placebo-treated arm underwent dose reductions, and about six times as many underwent dose interruptions due to adverse events.  Many adverse events also lasted longer in the olaparib-treated arm. There were ten adverse event categories which lasted more than a month longer for olaparib-treated patients, including abdominal, joint, musculoskeletal pain and nausea.  For these reasons, we are concerned that olaparib does not meet the low toxicity and quality-of-life parameters that are essential in the maintenance therapy setting.

The ongoing phase III SOLO-2 trial has the potential to clarify the potential progression-free survival benefit of olaparib, in addition to providing an additional analysis of overall survival and quality-of-life measures.

The results of SOLO-2 are needed In order to be able to guarantee patients an effective maintenance therapy that is not likely to jeopardize their quality-of-life and overall prognosis.  Therefore, we urge the committee to delay approval of olaparib until sufficient evidence has been provided.