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FDA argues AstraZeneca, Merck’s Lynparza only works in subset of prostate cancer patients

AstraZeneca and Merck & Co.’s Lynparza may have claimed a broad trial success—and European approval—in prostate cancer, but the FDA has its reservations.

In briefing documents published ahead an advisory committee meeting, FDA staffers argue that in metastatic castration-resistant prostate cancer (mCRPC), Lynparza has only showed a favorable benefit-risk profile in patients with BRCA mutations.

For those without BRCA mutations, the reviewers flagged a “modest benefit and possible harm.” At the advisory committee meeting this week, the agency is looking to its external advisers to corroborate that stance.

If the FDA follows through with its own analysis, Lynparza, used in combination with Johnson & Johnson’s Zytiga, would win a very limited approval in this cancer setting. BRCA-mutant tumors only account for 10% to 15% of all mCRPC cases.

The review centers around data from the phase 3 PROpel trial. In the study, the Lynparza-Zytiga combo cut the risk of disease progression or death by 34% over Zytiga alone in newly diagnosed mCRPC regardless of tumor mutation status. At the interim analysis, the Lynparza regimen also showed a non-significant trend toward extending patients’ lives.

Based on the broad win, Jefferies analyst Peter Welford has previously put Lynparza’s sales potential in mCPRC at $1.8 billion.

But in what the FDA labeled as a “significant design flaw,” the PROpel trial didn’t enroll patients into separate cohorts based on biomarker status. It also didn’t include prespecified subgroup analyses based on mutations.

So the FDA’s statisticians pulled out their calculators and performed some post hoc analyses. The agency found that those 11% of the trial participants who had BRCA mutations appeared to drive Lynparza’s benefit. In those patients, the Lynparza regimen improved progression-free survival by a whopping 76% and pared down the risk of death by 70%.

In contrast, in patients confirmed to be BRCA-negative—about 54% of the PROpel trial—those who received the Lynparza-Zytiga cocktail only performed 15% better at staving off progression. The FDA called this improvement “marginal.”

What really raised a red flag for the FDA is a small but concerning indication of possible harm. In the FDA’s analysis, the Lynparza combo was linked to a 6% increased risk of death as patients who got it lived a median 37 months, versus 38 months for the Zytiga arm.

For the rest of patients with an undetermined BRCA status who only tested positive in one of two tests, the FDA argued that over 90% were “truly negative.” The FDA combined them with confirmed BRCA-negative cases and found that Lynparza offered a five-month improvement in median progression-free survival but almost no difference in overall survival.

While AstraZeneca and Merck in their own briefing document argue that Lynparza’s showing in the bigger non-BRCA group is “clinically meaningful,” FDA considers the efficacy “modest.” And the added toxicity concerns for Lynparza over a long duration of treatment also factor into the FDA’s review.

The FDA’s detailed scrutiny on Lynparza shouldn’t come as a surprise. The agency previously raised concerns around overall survival for non-BRCA-mutant patients on PARP inhibitors, forcing GSK and Clovis Oncology to narrow their drugs’ approved indications.

AZ and Merck have withdrawn a Lynparza indication in late-line ovarian cancer because of worrisome final patient survival data.

In the current mCRPC review, the FDA also drew information from a study of a combination of J&J’s Zejula and Zytiga in a therapy that’s just been approved in Europe under the brand name Akeega. Based on findings from a phase 3 trial named MAGNITUDE, J&J is only pursuing a BRCA-mutant approval for its combo in the U.S.

At an advisory committee meeting scheduled for Friday, the FDA will ask oncology experts to opine on whether Lynparza’s mCRPC approval should also be limited to BRCA-mutant disease.