Merck and AstraZeneca are seeking broad approval for Lynparza in mCRPC regardless of BRCA status.
Pictured: Front of FDA headquarters/Grandbrothers/Adobe Stock
In briefing documents published ahead of the Oncologic Drugs Advisory Committee (ODAC) meeting, FDA staffers argued that Merck and AstraZeneca’s Lynparza (olaparib) is effective in only a subset of patients with metastatic castration-resistant prostate cancer (mCRPC).
The pharma partners seek to broaden the indication of their PARP inhibitor in combination with Johnson & Johnson’s Zytiga (abiraterone) and prednisone or prednisolone. The combination is designed to be a first-line therapy in adult mCRPC patients, regardless of BRCA mutation status.
In their supplemental New Drug Application (sNDA), which the FDA accepted in August 2022, Merck and AstraZeneca backed Lynparza’s FDA bid with data from the Phase III PROpel study. Patients treated with the Lynparza regimen saw a 34% drop in the risk of progression or death, as compared with a corresponding placebo-based combination regimen.
Moreover, median progression-free survival (PFS) in the Lynparza arm was 24.8 months, as opposed to only 16.6 months in placebo comparators.
At the time, the FDA awarded the sNDA its Priority Review designation, but a few months later, in December 2022, the regulator announced it needed more time to review the sNDA and pushed back the target action date by three months.
In March, the FDA indicated it would convene ODAC to discuss the merits of Merck’s and AstraZeneca’s sNDA for Lynparza and assess the drug’s risk-benefit profile in the proposed indication. The meeting is set for Friday.
Merck and AstraZeneca inked their global strategic oncology partnership for Lynparza in 2017.
The FDA’s Concerns
In its briefing package for the ODAC, the FDA zeroed in on what it called PROpel’s “significant design flaw.”
Because the pharma partners were aiming for the broad applicability of Lynparza in this indication, the randomized Phase III study enrolled an intention-to-treat (ITT) population that did not assess patients for BRCA or HRR mutation status. PROpel also did not include pre-specified analyses based on these mutation subgroups.
“However, because of the design issues noted previously, the ITT in PROpel represents a heterogeneous population, which complicates interpretability and applicability of overall trial results to unselected patients with mCRPC,” the FDA wrote.
In the regulator’s post hoc analyses, it found that the significant radiographic PFS (rPFS) benefits of the Lynparza regimen could be “heavily attributed” to its effects in the small subgroup of participants carrying the BRCA mutation. These patients comprised only 11% of the ITT population.
In contrast, Lynparza had a “marginal” benefit in patients without this genetic hallmark who made up more than half of the ITT population. Treatment with the Lynparza regimen in this subgroup improved rPFS by a non-significant 15% and led to only five more rPFS months.
Moreover, patients in the Lynparza arm saw a nominal 6% increase in the likelihood of death from any cause.
“FDA is thus concerned about the risk:benefit tradeoff and potential OS detriment in patients with tumor BRCA mutation,” FDA staffers wrote in the briefing document.
Tristan Manalac is an independent science writer based in metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com
