Already teetering on the brink, Clovis Oncology was dealt another blow by the FDA.
The U.S. regulator is asking Clovis to limit Rubraca’s use for the second-line maintenance treatment of ovarian cancer to patients whose tumors have BRCA mutations, the company said (PDF) Wednesday, citing a Monday teleconference with the FDA. The drug’s current label allows it to treat patients with recurrent ovarian cancer who’ve responded to chemo regardless of their BRCA biomarker status.
If Clovis doesn't revise the indication voluntarily, the FDA threatened to gather an advisory committee meeting to review the matter, Clovis said. The company said it’s "currently evaluating FDA’s request."
Restricting Rubraca’s indication would be nearly a death sentence for Clovis. In a securities filing last week, Colorado-based Clovis warned investors of a possible imminent bankruptcy amid back-to-back regulatory setbacks for Rubraca, including a recent withdrawal of the drug’s late-line ovarian cancer indication.
In the filing, Clovis noted that “a substantial portion” of Rubraca’s revenue currently comes from the second-line ovarian cancer maintenance setting. A narrowed approval could cause a “significant impact” on Clovis’ top line, the company warned.
The FDA’s concerns stem from patient survival findings from the phase 3 ARIEL3 trial, which previously supported Rubraca’s second-line nod in 2018 by showing a tumor progression benefit over placebo. But new data presented at this year’s International Gynecologic Cancer Society congress flashed a life expectancy red light.
In patients without BRCA mutations and with high level of a genetic abnormality called loss of heterozygosity, Rubraca showed a 28% higher risk of death than placebo. And non-BRCA-mutant patients with low loss of heterozygosity who took Rubraca had a 15% increased risk of death compared with those on placebo.
The FDA is pressuring Clovis after it successfully strong-armed GSK to trim the non-BRCA-mutant portion of Zejula’s second-line maintenance ovarian cancer indication. Similar to Rubraca’s ARIEL3 study, Zejula’s phase 3 NOVA trial also raised an overall survival problem for that patient group. If the FDA can bend a Big Pharma company to its will, it’s hard to imagine little Clovis can overcome the agency's pressure.
GSK’s restriction and Clovis’ announcement still leave AstraZeneca and Merck & Co.’s Lynparza unaccounted for in this round of FDA scrutiny targeting PARP inhibitors. AstraZeneca didn’t reply to a Fierce Pharma inquiry about whether the FDA has sent a similar request for Lynparza.
While Lynparza’s own clinical data in the second-line maintenance setting didn’t show an overall survival problem, the drug doesn’t have phase 3 results for the non-BRCA-mutant population. That portion of the Lynparza approval was based on a phase 2 trial coded Study 19. In that study's non-BRCA-mutant subgroup comprised of about 120 patients, Lynparza cut the risk of death by 16% over placebo.
In the fourth-line ovarian cancer indication, AZ and Merck had previously yielded to the FDA’s request, joining Clovis and GSK in pulling their PARP inhibitor’s nod.