As the risk of death was observed to be on the rise, PARP inhibitors for pretreated ovarian cancer have been withdrawn by three oncology drugmakers
This largely unnoticed decision has been the voluntary pulling of Merck and AstraZeneca’s Lynparza’s approval for BRCA-mutated ovarian cancer patients with a minimum of three previous lines of chemo.
After observing a possibly harmful effect on the survival of patients in the phase III trial, both companies requested a voluntary withdrawal of their accelerated approval. The approval was the first one granted to Lynparza back in 2014, eight years ago. The Food and Drug Administration (FDA) did not waste any time signing off on the alteration.
This move of fourth-line ovarian cancer drug withdrawal by the companies is after a similar pullout was made in June by Clovis Oncology for the third-line ovarian cancer drug Rubraca. Just last week GSK’s removal request was accepted for Zejula, which is for highly pretreated ovarian cancer as well.
In the case of Zejula and Lynparza, the pullout will not affect the sales by a significant margin as the drugs have mostly been shifted to earlier settings of treatment. This mainly includes first-line maintenance for recently diagnosed patients who have gone through a round of chemo and responded to it.
An advisory committee meeting has been scheduled by the FDA to evaluate the latest patient survival results from the phase III ENGOT-OV16/NOVA trial. That trial was the reason Zejula won FDA approval as a second-line maintenance treatment.
As for Clovis, it is in the direst situation in comparison. FDA has asked for more patient survival data for Clovis’ new application of its drug Rubraca to the first-line maintenance setting. This data could take a couple of years to mature.
The FDA has also threatened to keep an advisory committee meeting to evaluate the application solely on the first-line results already at hand following the late-line pulling of the drug. This could prove to be bad for Rubraca.
These withdrawals are a direct result of PARP inhibitors showing a higher death risk in their trials, despite showing the capability of slowing the progression of the tumor.
The confirmatory phase III trial of Lynparza, SOLO3, showed a 33% rise in the death risk compared to chemo in patients who had gone through three lines of chemotherapy earlier. In a bigger trial population that also involved patients with only two therapies before, the risk of death was alike between the drug and chemotherapy.
For Clovis’ Rubraca, the ARIEL4 trial demonstrated a 31.3% higher risk of death than chemo in patients with at least two prior lines of chemotherapy. The results seemed to be driven by a few patients with tumors that were platinum-resistant.
In a long-term follow-up of nearly half a decade, patients who had non-BRCA-mutated cancer and got Zejula seemed to live less than those who got chemo. For BRCA mutated cancer patients, the drug prolonged their lives by a median of two months to a little less than 44 months, which was not deemed statistically significant.