Amid death risk fears, Clovis pulls Rubraca in 3rd-line ovarian cancer as PARP player plugs away at earlier setting

A death risk signal has taken a toll on Clovis Oncology’s already lagging ovarian cancer drug, Rubraca. The company has taken FDA's hint, withdrawing the med in a late-line setting, but it remains undeterred in newly diagnosed patients despite an FDA warning.

Clovis is voluntarily pulling the U.S. approval for Rubraca in BRCA-mutated ovarian cancer after at least two prior chemotherapies, the company said in a securities filing (PDF) Thursday. The U.S. market withdrawal started a week ago, on June 10, and Clovis is also making a similar request with European authorities, it added.

The third-line indication represents “a very small portion” of the company’s total sales in the two territories, Clovis said. While other Rubraca indications remain in place, Clovis acknowledged the removal could hurt sales in those settings as well. In the U.S., Rubraca is also approved as a second-line maintenance treatment for patients with recurrent ovarian cancer who respond to chemo, and it’s allowed for previously treated BRCA-mutant, metastatic castration-resistant prostate cancer.

Clovis made up its mind after discussing with the FDA data from the Ariel4 postmarketing trial. As Clovis previously reported, the study linked Rubraca to an increased risk of death over chemo in patients with third- or later-line ovarian cancer despite the Clovis drug showing a benefit in stalling disease progression.

The company noted that the death risk problem stemmed from a group of patients with platinum-resistant disease. In the platinum-sensitive group, the drug’s death risk was similar to that of chemo.

Ariel4 is the only randomized phase 3 trial of a PARP inhibitor in advanced ovarian cancer that included both platinum-resistant and -sensitive patients, according to Clovis. AstraZeneca and Merck & Co.’s market-leading PARP drug, Lynparza, actually showed the same patient survival results in the platinum-sensitive-only Solo-3 trial.

While Clovis argued the imbalance in patient subgroup outcomes and subsequent treatments complicated the survival analysis in Ariel4, the company did warn back in May that the unflattering patient survival data may lead to market withdrawals in the U.S. and EU. Now, rather than getting into a tug of war with the FDA, Clovis is voluntarily pulling the indication.

Data from Ariel4 might not be the only update that could hurt Rubraca’s sales. In Thursday’s filing, Clovis simultaneously unveiled overall survival results from the phase 3 Ariel3 trial. Back in 2018, a tumor progression analysis of Ariel3 got Rubraca the second-line maintenance ovarian cancer nod regardless of the tumor’s biomarker status and converted the original accelerated approval for the third-line setting into a full approval.

In the new update, Clovis said Rubraca pared down the risk of death by 16.8%—which wasn’t statistically significant—over placebo in BRCA-mutant patients. But in the bigger homologous recombination deficiency (HRD) population and in all-trialed patients—including HRD-negative people—basically no difference in death risk was observed.

By comparison, Lynparza as a second-line maintenance treatment reduced the risk of death by 26% in BRCA-mutant patients in the phase 3 Solo-2 trial, prolonging the median overall survival by 12.9 months. In another phase 2 trial dubbed Study 19, Lynparza cut the risk of death by 27% in patients with any BRCA status, although it didn’t carry statistical significance because of the trial design.

As updated data from those later-line indications failed to impress, Clovis has also hit an FDA roadblock in its effort to move Rubraca into the frontline maintenance setting, where Lynparza and GSK’s Zejula are both available.

Despite strong data showing Rubraca could reduce the risk of disease progression or death from the phase 3 Athena-Mono trial, the FDA asked Clovis not to file for a frontline maintenance nod until getting more mature overall survival data. But the data will take another two years to collect, Clovis said.

After seeing the death risk in Ariel4, the FDA is “looking to ensure that there is no decrement,” Clovis CEO Patrick Mahaffy told Fierce Pharma a few days ago at the American Society of Clinical Oncology annual meeting.

Nevertheless, Clovis is still preparing for a submission, the company said in Thursday’s filing. It noted that the agency has accepted a request for another meeting to discuss a potential application. The FDA has warned about holding an advisory committee meeting if Clovis filed based on the current data.