The European Commission has approved an expanded indication for single-agent rucaparib as a maintenance therapy in adult patients with platinum-sensitive, relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy, regardless of BRCA status.
Patrick J. Mahaffy
The European Commission has approved an expanded indication for single-agent rucaparib (Rubraca) as a maintenance therapy in adult patients with platinum-sensitive, relapsed, high-grade, epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy, regardless of BRCA status.1
The approval is based on results from the phase III ARIEL3 trial, in which rucaparib led to an investigator-assessed median progression-free survival (PFS) of 10.8 months versus 5.4 months with placebo across the entire study population (HR, 0.36; 95% CI, 0.30-0.45; P <.0001).2 Additionally, the overall response rate (ORR) with rucaparib was 18%, including 10 complete responses (CRs), compared with 8% and 1 CR with placebo. The FDA approved the PARP inhibitor in this setting in April 2018, also based on the ARIEL3 findings.
“This [European Commission] authorization of rucaparib is an important step in ensuring that it is available to all women who may potentially benefit, regardless of their BRCA status,” said Patrick J. Mahaffy, president and CEO of Clovis Oncology, the developer of rucaparib, in a press release. “We believe that access to maintenance treatment is extremely important for women with relapsed platinum-sensitive ovarian cancer, and we are pleased that rucaparib can now be an option for these women. As the only PARP inhibitor that has shown further tumor shrinkage as well as prolonged progression-free survival in this maintenance setting, we believe Rubraca represents an important step forward for women with advanced ovarian cancer.”
Results of the ARIEL3 study showed that, in 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 in this population was 16.6 months (95% CI, 13.4-22.9) versus 5.4 months with placebo (95% CI, 3.4-6.7; HR, 0.23; 95% CI, 0.16-0.34; P <.0001). 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).
In ARIEL3, 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), and 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 disease 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). Rucaparib was administered orally 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.
By blinded independent central review (BICR) in the BRCA-mutant group, which was a secondary endpoint, the median PFS with rucaparib was 26.8 months compared with 5.4 months for placebo (HR, 0.20; 95% CI, 0.13-0.32; 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.
Moreover, 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).
Regarding safety, 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.
Rucaparib previously had an indication in the European Union for adult patients with platinum-sensitive, relapsed or progressive, BRCA-mutated high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with 2 or more prior lines of platinum-based chemotherapy, and who are unable to tolerate further platinum-based chemotherapy.
Also in the press release, Clovis Oncology stated that it plans to initially launch rucaparib as a maintenance therapy in Germany by end of March 2019.