New Maintenance Therapy for Ovarian Cancer Seeks FDA Approval

Patrick J. Mahaffy

The pharmaceutical company Clovis Oncology filed a supplemental new drug application (sNDA) to the FDA for their drug Rubraca (rucaparib) to be used as maintenance therapy for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

The sNDA is based on findings from the phase 3 ARIEL3 trial, in which maintenance Rubraca — a PARP inhibitor – improved median progression-free survival (PFS) by 11.2 months compared with placebo for patients with BRCA-mutant platinum-sensitive ovarian cancer.

For patients with germline or somatic BRCA mutations, there was a 77 percent reduction in the risk of progression or death with Rubraca versus placebo. Moreover, the median PFS with Rubraca was 16.6 months compared with 5.4 months for placebo. Similar PFS benefits were observed in patients with BRCA wild-type tumors and those with homologous recombination deficiency (HRD) or low to high loss of heterozygosity (LOH).

“The submission of the sNDA for rucaparib in the ovarian cancer maintenance setting just four months after we reported topline results marks an important milestone that brings Clovis closer to our ultimate goal of making rucaparib available to a broader population of women with advanced ovarian cancer,” Patrick J. Mahaffy, president and CEO of Clovis Oncology, said in a statement. “We believe that the ARIEL3 results demonstrate the potential of rucaparib to provide a new, much-needed therapeutic option for women with advanced ovarian cancer.”

In the ARIEL3 trial, patients with platinum-sensitive, high-grade ovarian, fallopian tube or primary peritoneal cancer were randomized in a 2-1 ratio to receive Rubraca or placebo. Endpoints were prospectively assessed across three cohorts. In the first, patients had BRCA-positive tumors, including both germline and somatic alterations (196 patients). In the second group, patients were HRD-positive, which could include BRCA-mutant or wild-type with a high LOH (354 patients). A third group assessed all-comers in the intent-to-treat population (564 patients).

All enrolled patients had received two or more prior platinum-based therapies, and continued to have platinum-sensitive ovarian cancer (defined as progression in at least six months on their last platinum-based therapy). Oral Rubraca was administered at 600 mg twice daily. In the BRCA-mutant group, 130 patients received Rubraca and 66 got placebo. In the HRD group, 236 got Rubraca and 118 received placebo. The intent-to-treat group contained those with BRCA-mutant and wild-type tumors and those with high, indeterminate and low genomic LOH.

In the BRCA-mutant group, by blinded independent central review (BICR), which was a secondary endpoint, the median PFS with Rubraca was 26.8 months compared with 5.4 months for placebo. The objective response rate (ORR) was 38 percent for Rubraca versus 9 percent with placebo. There were seven complete responses (CR) with the PARP inhibitor and none for placebo.

In the HRD group, the investigator assessed PFS was 13.6 versus 5.4 months for Rubraca and placebo, respectively. In the BICR assessment, the median PFS was 22.9 months with the PARP inhibitor versus 5.5 months with placebo. The ORRs were 27 percent (10 CRs) and 12 percent (0 CRs) for Rubraca and placebo, respectively.

In the intent-to-treat group, for Rubraca and placebo, respectively, the PFS was 10.8 versus 5.4 months by investigator assessment and 13.7 versus 5.4 months by BICR. The ORR with Rubraca was 18 percent (10 CRs) versus 8 percent with placebo (1 CR).

An exploratory analysis looked at outcomes specifically in those with BRCA wild-type tumors with LOH high (158 patients) and low status (161 patients). In the LOH high group, the median PFS was 9.7 months with Rubraca versus 5.4 months with placebo. In the LOH low group, the medians were 6.7 and 5.4 months for Rubraca and placebo, respectively. By BICR, for Rubraca and placebo, respectively, the medians were 11.1 versus 5.6 months for the LOH high group and 8.2 versus 5.3 months for the LOH low group.

The most common grade 3 or higher treatment-emergent adverse events (TEAEs) with Rubraca were anemia/decreased hemoglobin (19 percent), increase in ALT/AST (10 percent), neutropenia (7 percent), asthenia/fatigue (7 percent), thrombocytopenia (5 percent), vomiting (4 percent) and nausea (4 percent). TEAEs led to treatment discontinuation for 13.4 percent of patients in the Rubraca arm versus 1.6 percent for placebo. Three patients developed treatment-emergent myelodysplastic syndrome/acute myeloid leukemia with Rubraca versus none for placebo.

Rubraca was initially approved by the FDA in December 2016 as a monotherapy for patients with ovarian cancer with a deleterious BRCA mutation following prior treatment with two or more chemotherapies.