Undeterred by FDA warning, desperate Clovis seeks Rubraca nod in front-line ovarian cancer

The FDA has been flashing the red light at Clovis Oncology’s bid to move struggling ovarian cancer med Rubraca to earlier treatment lines, but the biotech has decided to press on anyway.

Clovis has submitted an application to the FDA and European Medicines Agency, seeking approvals for Rubraca as a first-line maintenance treatment for ovarian cancer patients who have responded to a round of chemotherapy, the company said Tuesday.

The Colorado drugmaker made the move despite the FDA demanding more mature patient survival data from the phase 3 ATHENA-MONO trial. The FDA can’t stop Clovis from filing for approval but warned that it will pore over the application at an advisory committee meeting.

Clovis didn’t really have much choice. Rubraca, the company’s only marketed product, is verging on becoming commercially irrelevant amid tough competition from two Big Pharma-managed PARP inhibitors, AstraZeneca and Merck’s Lynparza and GSK’s Zejula, both of which are approved in the first-line maintenance ovarian cancer setting.

With dwindling sales from Rubraca, Clovis only had $94.6 million in cash as of end of June and only up to $9.8 million available to draw from a Sixth Street Partners agreement to fund Rubraca’s ATHENA clinical program.

Based on Clovis’ current cash position and revenue estimates for Rubraca, “the company will need to raise additional capital in the near term in order to fund our operating plan” and continue as a functioning business beyond February 2023, Chief Financial Officer Daniel Muehl told investors during a conference call last month.

Rubraca is currently available as a second-line maintenance treatment for patients with recurrent ovarian cancer who respond to chemo. With Lynparza and Zejula having established themselves as the standard of care in the first-line setting, the second-line patient pool is shrinking.

To make things worse, Clovis is pulling Rubraca’s third-line ovarian cancer indications in the U.S. and EU markets. The withdrawals came after the confirmatory ARIEL4 trial showed that patients with heavily pretreated BRCA-mutated ovarian cancer might live shorter on Rubraca than on chemo.

Clovis has noted that patients with platinum-resistant disease were driving the negative outcome for Rubraca. In those patients, taking Rubraca was linked to a 51.1% increased risk of death, according to data presented at the ongoing European Society for Medical Oncology congress 2022. In platinum-sensitive patients, the death risk was roughly similar between the two treatments.

Besides, nearly 70% of chemo patients subsequently took Rubraca following disease progression in ARIEL4. Excluding those crossover patients, Rubraca cut the risk of death by 58% in the trial, though the data don’t bear statistical rigor.

Still, after seeing the ARIEL4 outcome, the FDA apparently wants further evidence that Rubraca doesn’t hurt patients’ life expectancy in the front-line maintenance setting. As Clovis has previously disclosed, the FDA wants to see at least 50% of the pre-specified number of deaths from the ATHENA-MONO trial. When the company unveiled the trial had hit its primary goal of stalling disease progression or death in March, only 25% of the pre-specified deaths had occurred. Waiting for those additional death events would take another two years by Clovis’ estimates.

“We believe the compelling [progression-free survival] results, the primary endpoint of the ATHENA-MONO trial, are strongly supportive of an approval and reinforce the potential of Rubraca as an important new first-line maintenance treatment for ovarian cancer,” Clovis CEO Patrick Mahaffy said in a statement Tuesday.

In ATHENA-MONO, Rubraca cut the risk of disease progression or death by 48% over placebo in patients regardless of their homologous recombination deficiency (HRD) status. And that broad population is what Clovis is gunning for right now. Previously, Lynparza got its first-line maintenance approval in HRD-positive patients and Zejula in the broad population both based on progression-free survival data.