AstraZeneca, Merck withdraw Lynparza's late-line ovarian cancer nod amid PARP inhibitor death concerns

Increased risks of death have led three groups of oncology drugmakers to withdraw their PARP inhibitors in heavily pretreated ovarian cancer patients.

In a decision that has largely flown under the radar, AstraZeneca and Merck & Co. have started pulling (PDF) Lynparza’s approval in BRCA-mutated advanced ovarian cancer patients who have received at least three prior lines of chemotherapy.

After seeing a potential “detrimental effect” on patient survival from a confirmatory phase 3 trial, the companies in August asked to voluntarily withdraw their accelerated approval—which became Lynparza’s first licensure back in 2014—and the FDA quickly signed off (PDF) on the change.

AZ and Merck’s Lynparza withdrawal in fourth-line ovarian cancer followed a similar move by Clovis Oncology in June for Rubraca in third-line ovarian cancer. The FDA last week also agreed to GSK’s request to remove Zejula in heavily pretreated ovarian cancer patients whose cancer has homologous recombination deficiency (HRD).

For Lynparza and Zejula, the withdrawals likely won’t cause much of a sales impact given that the drugs have largely moved into earlier treatment settings, notably as first-line maintenance therapies in newly diagnosed patients who have responded to a round of chemotherapy. Thanks to the first-line maintenance nod, as well as a recent FDA green light for postsurgery treatment of BRCA-mutated, HER2-negative high-risk breast cancer, Lynparza sales for AZ jumped 20% at constant currencies to $673 million in the second quarter.

As for Zejula, the FDA recently scheduled an advisory committee meeting to review updated patient survival data from the phase 3 ENGOT-OV16/NOVA trial. That trial enabled Zejula to win an FDA approval as a second-line maintenance treatment for patients with recurrent ovarian cancer who have responded to chemo.

Clovis is in the worst situation among the drugmakers. For its new application to move Rubraca into the all-important first-line maintenance setting of ovarian cancer, the FDA has demanded additional patient survival data that could take two years to mature.   

Further, the agency has threatened to hold an advisory committee to review the application based on existing first-line clinical results against the backdrop of the late-line withdrawal. That could portend bad news for the med’s place in the treatment landscape. 

The pulling of the indications comes after the PARP inhibitors showed an increased risk of death in their clinical trials, even though they have demonstrated an ability to slow tumor progression.

In Lynparza’s case, the confirmatory phase 3 trial, SOLO3, linked the AZ-Merck drug to a 33% increase in risk of death compared with chemo in ovarian cancer patients who had previously tried at least three lines of prior chemo. In a broader trial population that also included patients who had received two prior therapies, the death risks were similar between Lynparza and chemo.

Similarly, in the ARIEL4 trial, Clovis’ Rubraca also showed an increased 31.3% risk of death over chemo in patients who had already received two or more lines of chemo. The poor performance appeared to be driven by a group of patients with platinum-resistant tumors.

After a long-term follow-up of about five years, patients with non-BRCA-mutated tumors who got Zejula appeared to live shorter than those in the chemo group did. In patients with BRCA mutations, Zejula extended patients’ lives by a median two months to 43.6 months, a benefit that wasn’t statistically significant.