European OK for Olaparib in Ovarian Cancer

Zosia Chustecka

Disclosures

October 24, 2014

A first-in-class drug, olaparib (Lynparza, AstraZeneca), has been recommended for approval for use in certain patients with advanced ovarian cancer by the European Medicines Agency (EMA). This is a first step; this recommendation will now be considered by the European Commission for the adoption of a decision on an EU-wide marketing authorization.

The positive opinion is a stark contrast to the reaction in the United States, where the drug was recently turned down. In June, a US Food and Drug Administration (FDA) advisory committee recommended against approval for its use in ovarian cancer, with a vote of 11 to 2, as reported by Medscape Medical News.

Olaparib acts as an inhibitor of the enzyme poly(ADP-ribose) polymerase (PARP), and is the first of this class of drugs to get close to approval. In fact, olaparib was itself at one point dropped from development.

PARP inhibitors have been studied in several types of cancer, as well as in cardiovascular and neurodegenerative disorders. The EMA explains that PARP enzymes "help to repair damaged DNA, including in tumor cells. If they are blocked, damaged DNA in a tumor cell cannot be repaired, and the tumor cell dies as a result. As a consequence, this medicine is expected to reduce tumor size or slow its growth."

The European Committee for Medicinal Products for Human Use (CHMP) recommended approval of olaparib for use as monotherapy for the maintenance treatment of adult patients with relapsed platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer with BRCA mutations who have already responded to platinum-based chemotherapy.

Olaparib is the first drug against ovarian cancer that specifically targets tumors that carry a mutation of the BRCA gene, it notes.

The product has orphan drug designation, and the EMA provided protocol assistance to the applicant during the development of the medicine, it adds.

The positive opinion from the CHMP is based on the results of a phase 2 pivotal study in patients with ovarian cancer with BRCA mutation who had received two or more previous platinum-containing regimens.

The summary-of-opinion document does not give any further details about the clinical data, but the manufacturer does in its press release.

The company said that the positive opinion was based on a subgroup analysis of phase 2 trial data (recently published in the Lancet Oncology). "The study showed that olaparib maintenance therapy significantly prolonged progression-free survival compared with placebo in patients with BRCA-mutated ovarian cancer (median, 11.2 vs 4.3 months; hazard ratio, 0.18; 95% confidence interval, 0.10 - 0.31; P < .0001). The most common adverse events associated with olaparib monotherapy to date were generally mild to moderate, and included nausea, vomiting, fatigue, and anemia," it said.

These are exactly the same data that were recently considered and rejected by the FDA advisory committee in its June 2014 meeting.

In fact, when the original results from this phase 2 trial (for all 265 patients, regardless of BRCA status) were published back in 2012 in the New England Journal of Medicine, the company said that it was dropping olaparib from further development for ovarian cancer.

However, interest in the drug was revived when a retrospective subgroup analysis of these phase 2 data showed a benefit in patients with the BRCA mutation. The company then changed its mind and submitted an application for accelerated approval of olaparib in BRCA ovarian cancer to the FDA, which was considered at the recent meeting.

As previously reported by Medscape Medical News, at that meeting, the advisory committee heard that the overall results from the phase 2 trial showed that median progression-free survival was better with olaparib than with placebo (8.4 vs 4.8 months), and the risk reduction was 65% (P < .00001). However, the difference in overall survival was not significant, and olaparib had no effect on quality of life during a maintenance period when the standard of care is no therapy.

The company then presented a subgroup analysis of patients with the mutated germline BRCA gene, which showed that median progression-free survival was 7.1 months longer with olaparib than with placebo (11.2 vs 4.1 months); the reduction in risk was 83%. According to the AstraZeneca, an improvement of 6 months represents a significant clinical effect.

However, advisory committee members expressed concern about the way the subgroup results were obtained. The AstraZeneca researchers used a retroactive analysis of blood samples to obtain information on the mutation status of some patients, but blood samples were an option, not a requirement, so mutation status was not available for all patients.

Analyses of retrospective data are not typical for the advisory committee or the FDA, panel chair Mikkael Sekeres, MD, associate professor of medicine at the Taussig Cancer Institute at the Cleveland Clinic, told Medscape Medical News at the time. "We're used to seeing large prospective studies."

In addition, he said, panel members were concerned about a signal that some patients taking the drug were developing secondary cancers, myelodysplastic syndrome, or acute myeloid leukemia. FDA representatives presented data showing that the annual overall incidence of myelodysplastic syndrome is 0.0033% (3.3 per 100,000), whereas the incidence in the phase 2 study was 2.2% (1 suspected and 3 confirmed cases).

"While side effects on the whole were relatively minor, we're still talking about patients who had, for example, 2 and a half months of nausea or 3 months of abdominal pain" with the drug during the maintenance period, Dr Sekeres told Medscape Medical News. "They were spending more time without progression, but a good portion of that time they were spending with side effects to a drug, when ordinarily they wouldn't have any side effects because they wouldn't be on any drug."

Phase 3 Trial is Ongoing

A phase 3 trial of olaparib in BRCA ovarian cancer is currently in progress, with results are expected in 2015. The FDA advisory committee decided to wait to see those results, and recommended against accelerated approval based on the subgroup analysis. However, they also noted that a different dosing of olaparib was being used: the phase 2 trial had used a dosing of 8 × 50 mg twice a day, while the phase 3 trial is now using 2 × 300 mg twice a day. This raises questions about whether the two regimens are bioequivalent, they said.

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