Based on findings from the phase III ARIEL3 trial, the European Medicines Agency’s Committee for Medicinal Products for Human Use has issued a positive opinion recommending an expanded approval for single-agent rucaparib as a maintenance treatment for 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.
Jonathan Ledermann MD, FRCP
Based on findings from the phase III ARIEL3 trial, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending an expanded approval for single-agent rucaparib (Rubraca) as a maintenance treatment for 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.
Rucaparib is currently approved in the EU 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. The European Commission is expected to make its decision on the expanded approval in the first quarter of 2019.
In the ARIEL3 trial, treatment with rucaparib led to a median progression-free survival (PFS) of 10.8 months compared with 5.4 months with placebo across the overall study population. 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 data.
“The CHMP recommendation represents an important step forward for women with recurrent ovarian cancer, for whom additional treatment options are needed. The ARIEL3 trial demonstrated rucaparib to be effective across all patient types, regardless of theirBRCAmutation status, and is the only PARP-inhibitor trial in which independent radiological review reported a median progression-free survival of more than 1 year across the entire population studied,” lead ARIEL3 investigator of the non-US sites, Jonathan Ledermann, MD, said in a statement.
“The meaningful efficacy data and tolerable safety profile offers women diagnosed with relapsed ovarian cancer a new therapy option,” added Ledermann, a professor of Medical Oncology, UCL Cancer Institute and UCL Hospitals, London, United Kingdom.
Results of the ARIEL3 study showed that, in patients with germline or somaticBRCAmutations, 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). Similar PFS benefits were observed in patients withBRCAwild-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 hadBRCA-positive tumors, including both germline and somatic alterations (n = 196). In the second group, patients were HRD-positive, which could includeBRCA-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 theBRCA-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 withBRCA-mutant and wild-type tumors and those with high, indeterminate, and low genomic LOH.
By blinded independent central review (BICR) in theBRCA-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;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 withBRCAwild-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.
“We are pleased that the CHMP recognizes the clinical relevance of rucaparib in the maintenance treatment setting for European women with relapsed platinum-sensitive ovarian cancer,” Patrick J. Mahaffy, president and CEO of Clovis Oncology, said in a statement.
“This brings us a step closer to delivering on our commitment to ensure that women who may benefit from treatment with rucaparib have the opportunity to do so. We seek to make ovarian cancer an actively managed disease, rather than one that is treated and then wait for recurrence. Rucaparib’s clinical benefit in the maintenance treatment setting is supported by the pivotal ARIEL3 study, which showed that Rubraca provided benefit in all ovarian cancer patient populations studied,” added Mahaffy.
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.