FDA Approves Maintenance Rucaparib for Ovarian Cancer

The FDA has approved rucaparib (Rubraca) tablets for use as a maintenance treatment for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, according to Clovis Oncology, the manufacturer of the PARP inhibitor.

The approval is based on findings from the phase III ARIEL3 trial, in which the median progression-free survival (PFS) in the overall study population was 10.8 month with maintenance rucaparib versus 5.4 months with placebo. The overall response rate (ORR) with rucaparib was 18% (10 complete responses [CRs]) versus 8% with placebo (1 CR).

For patients with germline or somatic BRCA mutations, there was a 77% reduction in the risk of progression or death with rucaparib versus placebo (HR, 0.23; 95% CI, 0.16-0.34; P <.0001). Moreover, the median PFS with rucaparib was 16.6 months (95% CI, 13.4-22.9) compared with 5.4 months for placebo (95% CI, 3.4-6.7). 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).

“Rubraca provided statistically-significant improvement in PFS versus placebo to all patients, regardless of BRCA mutation status,” Robert L. Coleman, MD, Professor & Executive Director, Cancer Network Research, Ann Rife Cox Chair in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine at University of Texas MD Anderson Cancer Center in Houston and one of the principal investigators in the ARIEL3 clinical trial program, said in a statement.

“Both the efficacy and safety results from the ARIEL3 study reinforce the important role of Rubraca in the treatment of recurrent ovarian cancer and expands the treatment options for patients and physicians battling this disease,” added Coleman.

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 rucaparib (n = 375) or placebo (n = 189). Endpoints were prospectively assessed across 3 cohorts. In the first, patients had BRCA-positive tumors, including both germline and somatic alterations (n = 196). In the second group, patients were HRD-positive, which could include BRCA-mutant or wild-type with a high LOH (n = 354). A third group assessed all-comers in the intent-to-treat population (n = 564).

All enrolled patients had received ≥2 prior platinum-based therapies, and continued to have platinum-sensitive ovarian cancer (defined as progression in ≥6 months on their last platinum-based therapy). Oral rucaparib was administered at 600 mg twice daily. In the BRCA-mutant group, 130 patients received rucaparib and 66 got placebo. In the HRD group, 236 got rucaparib 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 rucaparib was 26.8 months compared with 5.4 months for placebo (HR, 0.20; P <.0001). The ORR was 38% for rucaparib versus 9% with placebo. There were 7 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 rucaparib and placebo, respectively (HR, 0.32; P <.0001). In the BICR assessment, the median PFS was 22.9 months with the PARP inhibitor versus 5.5 months with placebo (HR, 0.34; P <.0001). The ORRs were 27% (10 CRs) and 12% (0 CRs) for rucaparib and placebo, respectively.

An exploratory analysis looked at outcomes specifically in those with BRCA wild-type tumors with LOH high (n = 158) and low status (n = 161). In the LOH high group, the median PFS was 9.7 months with rucaparib versus 5.4 months with placebo (HR, 0.44; P <.0001). In the LOH low group, the medians were 6.7 and 5.4 months for rucaparib and placebo, respectively (HR, 0.58; P = .0049). By BICR, for rucaparib and placebo, respectively, the medians were 11.1 versus 5.6 months for the LOH high group (HR, 0.55; P = .0135) and 8.2 versus 5.3 months for the LOH low group (HR, 0.47; P = .0003).

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

Ledermann J, Oza AM, Lorusso D, et al. ARIEL3: a phase 3, randomised, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma (OC). Presented at: 2017 ESMO Congress; September 8-12; Madrid, Spain. Abstract LBA40_PR.

In addition to the maintenance approval, the FDA has also converted rucaparib's previous accelerated approval into a full approval for use as a monotherapy for the treatment of patients with ovarian cancer with a deleterious BRCA mutation following prior treatment with 2 or more chemotherapies.