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Maintenance rucaparib extends PFS in recurrent ovarian cancer
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MADRID — Maintenance therapy with rucaparib significantly extended PFS compared with placebo among women with platinum-sensitive recurrent ovarian cancer, according to results of the randomized phase 3 ARIEL3 study presented at the European Society for Medical Oncology Congress.
Researchers observed the benefit among women with BRCA-mutant disease, as well as those who did not have BRCA mutations or homologous recombination deficiency.
This suggests rucaparib (Rubraca, Clovis Oncology) can offer a clinically meaningful, enduring benefit to women with advanced ovarian cancer regardless of tumor genetics, principal investigator Jonathan A. Ledermann, BSc, MD, FRCP, told HemOnc Today.
“Although patients with a BRCA mutation had a better outcome, from a scientific point of view, we can conclude that rucaparib is active in all patients with platinum-sensitive, high-grade ovarian cancer,” Ledermann, professor of medical oncology at UCL Cancer Institute and director of the Cancer Research UK and UCL Clinical Trials Centre, said in an interview. “Whether someone makes a decision to use it in one subgroup or another is more of a clinical decision, or even one payers will have to make.”
Rucaparib, the first PARP inhibitor approved by the FDA, has demonstrated antitumor activity in BRCA-mutant or BRCA wild-type/genomic loss of heterozygosity (LOH) high-associated ovarian cancer. The FDA granted accelerated approval last year to the agent as monotherapy for women with BRCA-associated ovarian cancer who received two or more prior chemotherapies.
In ARIEL3, Ledermann and colleagues evaluated rucaparib vs. placebo as maintenance treatment for women with recurrent platinum-sensitive ovarian cancer.
The analysis included 564 women who received at least two prior platinum-based therapies whose disease progressed at least 6 months after their penultimate platinum regimen and achieved a response per RECIST to their most recent platinum regimen.
Researchers randomly assigned women 2:1 to oral rucaparib 600 mg twice daily (n = 375) or placebo (n = 189).
Investigator-assessed PFS in three groups — those with BRCA-mutant disease (n = 196), defined as deleterious germline or somatic BRCA mutation; those with homologous recombination-deficient disease (n = 354), defined as BRCA mutant or BRCA wild-type/LOH high; and the intent-to-treat population — served as the primary endpoint.
PFS by blinded independent central review served as a key secondary endpoint. Outcomes by LOH status among patients with BRCA wild-type disease served as an exploratory endpoint.
Results of the primary analysis showed rucaparib significantly extended median PFS by investigator review among women with BRCA-mutant disease (16.6 months vs. 5.4 months; HR = 0.23; 95% CI, 0.16-0.34), among those with homologous recombination-deficient disease (13.6 months vs. 5.4 months; HR = 0.32; 95% CI, 0.24-0.42) and among the intent-to-treat population (10.8 months vs. 5.4 months; HR = 0.37; 95% CI, 0.3-0.45).
PFS assessment by blinded independent central review revealed similar benefits for women with BRCA-mutant disease (26.8 months vs. 5.4 months; HR = 0.2; 95% CI, 0.13-0.32), those with homologous recombination-deficient disease (22.9 months vs. 5.5 months; HR = 0.34; 95% CI, 0.24-0.47) and the intent-to-treat population (13.7 months vs. 5.4 months; HR = 0.35; 95% CI, 0.28-0.45).
Exploratory analyses included 319 women, 158 of whom had BRCA wild-type/LOH-high disease and 161 of whom had BRCA wild-type/LOH-low disease.
Results showed rucaparib extended median PFS in the BRCA wild-type/LOH-high group as determined by investigator review (9.7 months vs. 5.4 months; HR = 0.44; P < .0001) and blinded independent central review (11.1 months vs. 5.6 months; HR = 0.55; P = .0135).
Women with BRCA wild-type/LOH-low disease also achieved longer median PFS with rucaparib as determined by investigator review (6.7 months vs. 5.4 months; HR = 0.58; P = .0049) and blinded independent central review (8.2 months vs. 5.3 months; HR = 0.47; P = .0003).
Although all patients in the trial had responded to their most recent platinum regimen, many only achieved partial responses. Among this group, the percentage who demonstrated further response during ARIEL3 was significantly higher with rucaparib than placebo. Researchers observed this outcome in the BRCA-positive group and the intent-to-treat population.
“Some of that is a carryover effect of chemotherapy,” Ledermann told HemOnc Today. “However, this indicates that rucaparib is not only acting in a maintenance fashion to delay progression, but it’s actually further reducing the tumor burden.”
OS data are not yet mature. However, the PFS results are strong enough to support regulatory consideration for use of rucaparib in women who do not have BRCA mutations, Ledermann said.
“This was a well-constructed randomized clinical trial,” Ledermann said. “There is no doubt about the endpoint analysis and the magnitude of benefit that we see across all of these subgroups, particularly the intent-to-treat population.”
Rucaparib’s safety profile appeared consistent with that observed in prior studies. The number of symptomatic side effects was relatively small, Ledermann said.
The most common grade 3 or higher treatment-emergent adverse events included anemia (18.8% for rucaparib vs. 0.5% for placebo) and increased alanine/aspartate aminotransferase levels (10.5% vs. 0%).
More than half (54.6%) of patients assigned rucaparib required dose reduction.
“This is not unusual, because we know from other PARP inhibitors that you have to tailor the dose to the patient,” Ledermann said.
At data cutoff, 13.4% of women assigned rucaparib and 1.6% of those assigned placebo had discontinued treatment due to adverse events, excluding disease progression. A comparable percentage of women in both groups died to due adverse events, including disease progression (1.6% for rucaparib vs. 1.1% for placebo). – by Mark Leiser
Reference:
Ledermann J, et al. Abstract LBA40_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.
Disclosures: Clovis Oncology funded this study. Ledermann reports an advisory role with Clovis Oncology. Please see the abstract for a list of all other researchers’ relevant financial disclosures.