FDA claims AstraZeneca and Merck’s Lynparza works only in a subset of patients with prostate cancer

AstraZeneca’s Lynparza and Merck & Co.’s Lynparza have both claimed a wide trial success – and European approval – in prostate cancer. But the FDA still has reservations.

In documents that were published in advance of an advisory committee meeting by FDA staffers, they argue that Lynparza only has a favorable risk-benefit profile for patients with BRCA mutations in metastatic castration resistant prostate cancer (mCRPC).

The reviewers noted that those who do not have BRCA mutations would receive a “modest advantage and possible harm”. At this week’s advisory committee meeting, the agency will be looking to external advisors to confirm their stance.

If the FDA is able to follow through with their own analysis, Lynparza in combination with Johnson & Johnson Zytiga would be approved in a very limited setting. BRCA-mutant tumours account for only 10% to 15% all mCRPC.

The focus of the review is on data from phase 3 PROpel. The study showed that the Lynparza/Zytiga combination reduced the risk for disease progression or death in newly diagnosed mCRPC by 34% compared to Zytiga alone, regardless of the tumor mutation status. The interim analysis also revealed that the Lynparza treatment regimen showed a nonsignificant trend towards extending the lives of patients.

According to Jefferies analyst Peter Welford, based on the wide win, Lynparza’s potential sales in mCPRC are $1.8 billion.

The FDA deemed the PROpel study to have a “significant flaw” because it did not separate patients based on their biomarker status. The trial also did not include subgroup analyses prespecified based on mutations.

The FDA statisticians then pulled out their calculators to perform some post-hoc analyses. The FDA found that the 11% of trial participants with BRCA mutations seemed to be driving Lynparza’s benefits. Lynparza improved progression-free life expectancy by 76% in these patients and reduced the risk of dying by 70%.

The Lynparza/Zytiga combination only showed a 15% improvement in preventing progression among patients who were BRCA-negative, which accounted for 54% of PROpel’s participants. The FDA called the improvement “marginal.”

The FDA was alerted by a small, but worrying indication of potential harm. According to the FDA, patients receiving the Lynparza combination had a 6% higher risk of dying, as they lived on average 37 months compared to 38 months in the Zytiga group.

In the remaining patients who had an undetermined BRCA Status, but only tested positive on one of the two tests the FDA claimed that 90% of them were “truly negative”. The FDA combined these cases with confirmed BRCA negative cases and found that Lynparza provided a five-month increase in median progression free survival. However, there was almost no difference between overall survival.

AstraZeneca, Merck and their briefing documents claim that Lynparza’s efficacy in the larger non-BRCA group was “clinically significant,” but the FDA deems it “modest.” The FDA also considers Lynparza’s toxicity over a prolonged treatment period to be a factor in its review.

Lynparza’s FDA scrutiny is not a big surprise. The FDA raised concerns about the overall survival of non-BRCA mutant patients who were taking PARP inhibitors. This led GSK and Clovis Oncology, to restrict their approved indications.

AZ and Merck have withdrawn a Lynparza indication for late-line ovarian carcinoma due to worrying final patient survival results.

The FDA incorporated information into the current mCRPC evaluation from a study that compared Zejula with Zytiga, a combination therapy that was just approved by the European Commission under the name Akeega. J&J’s combination is only being approved in the U.S. based on results from a phase 3-trial named MAGNITUDE.

The FDA will be asking oncologists to weigh in at a meeting of its advisory committee scheduled for this Friday on whether Lynparza mCRPC should only be approved for BRCA-mutant diseases.