Robert L. Coleman, MD
Clovis Oncology, the manufacturer of the PARP inhibitor, announced the results today in a press release. The company expects to deliver expanded results at a medical meeting later this year.
Investigators found that treatment with rucaparib resulted in longer PFS for the intent-to-treat population (N = 564), as well as patients positive for homologous recombination deficiency (HRD; n = 354) and those with BRCA mutant tumors, including germline and somatic mutations of BRCA (n = 196). The HRD-positive population included BRCA-mutant patients and BRCA wild-type with high loss of heterozygosity (LOH-high) patients.
“Based on these encouraging data, it is clear that rucaparib demonstrates a clinically meaningful impact in delaying disease recurrence in women in this trial with advanced ovarian cancer,” said Robert L. Coleman, MD, vice chair of clinical research in the department of Gynecologic Oncology and Reproductive Medicine at the University of Texas MD Anderson Cancer Center and the US principal investigator for the ARIEL3 study.
“The PFS and safety results achieved in this study are particularly promising, because they suggest women are able to stay on rucaparib for a prolonged period of time while gaining benefit. It is also clinically significant that rucaparib not only sustained the most recent response to platinum, but in some patients also enhanced that response, including the elimination of residual tumor,” added Coleman.
ARIEL3 is a double-blind, multinational phase III trial of rucaparib in women with platinum-sensitive, high-grade ovarian, fallopian tube, or primary peritoneal cancer. Patients were randomized in a 2:1 ratio to receive 600 mg of rucaparib twice daily or placebo. The primary efficacy analysis evaluated 3 prospectively-defined molecular subgroups in a step-down manner.
Median PFS favored rucaparib at 10.8 months versus 5.4 months (HR, 0.36; P <.0001) in the intent-to-treat population, according to investigator review. By independent review, rucaparib improved PFS by 8.3 months (13.7 vs 5.4; HR, 0.35; P<.0001).
By investigator review, median PFS was 16.6 months in the rucaparib arm versus 5.4 months with placebo (HR, 0.23; P<.0001). The PFS advantage associated with rucaparib was even more pronounced by independent review, 26.8 months versus 5.4 months (HR, 0.20; P < .0001).
Investigators said the results were consistent for the germline BRCA (n = 130) and somatic BRCA (n = 56) populations.
In HRD-positive patients, including patients with a germline or somatic BRCA mutation and those with BRCA wild-type tumors, rucaparib was associated with a statistically significant improvement in median PFS compared with placebo (13.6 months vs 5.4 months; HR, 0.32; P <.0001), by investigator review. Median PFS in the experimental arm was 22.9 months compared with 5.5 months with placebo (HR, 0.34; P <.0001) as assessed by independent review.
Investigators also analyzed experimental endpoints for PFS in BRCA wild-type/HRD-positive and BRCA wild-type/HRD-negative subgroups.
In the BRCA wild-type/HRD-positive group, 158 patients achieved PFS. By investigator review, median PFS was 9.7 months in the rucaparib arm compared with 5.4 months with placebo (HR, 0.44; P <.0001). PFS also favored the rucaparib arm by independent review (11.1 months vs 5.6 months; HR, 0.55; P = .014).
In the wild-type/HRD-negative subgroup, 161 patients achieved PFS. By investigator review, median PFS was 6.7 months for the experimental arm compared with 5.4 months with placebo (HR, 0.58; P = .0049). By independent review, median PFS was 8.2 months versus 5.3 months favoring the rucaparib arm (HR, 0.47; P = .0003).
Investigators found that 37% of patients in the study had measurable disease at baseline, making them evaluable for response. Among that group, the response rate was 38%, with a complete response rate of 18% in the experimental arm, double the complete response rate observed in the phase II ARIEL2 trial.
The response rate was 9% with no complete responses for patients assigned to placebo.
The most common (≥5%) treatment-emergent grade 3/4 adverse events among all patients treated with rucaparib were anemia/decreased hemoglobin (19%), ALT/AST increase (11%), asthenia/fatigue (7%), neutropenia (7%), and thrombocytopenia (5%).
The discontinuation rate was 14% for the rucaparib arm compared with 2.6% for the placebo arm. The rate of treatment-emergent myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) was <1% in the rucaparib arm was. No patient assigned to placebo experienced treatment-emergent MDS/AML.
“These results show that rucaparib has the potential to provide an enduring and important clinical benefit in women with advanced ovarian cancer, irrespective of their tumor genetics,” Jonathan Ledermann, MD, FRCP, director of Cancer Research UK and European and ROW principal investigator for the study, said in a release. “This is a very important step forward for women with advanced ovarian cancer.”
Based on results from ARIEL2, the FDA granted an accelerated approval to rucaparib in December 2016 as a treatment for patients with BRCA-positive advanced ovarian cancer who have received at least 2 prior lines of chemotherapy.
Clovis plans to submit a supplemental new drug application to the FDA later this year for rucaparib as a second line or later maintenance treatment in ovarian cancer based on the ARIEL3 results.
Clovis Oncology’s rucaparib significantly improved progression-free survival in all ovarian cancer patient populations studied in phase 3 ARIEL3 maintenance treatment trial [press release]. Boulder, Colo. Clovis Oncology. June 18, 2017. Available at: http://www.enhancedonlinenews.com/news/eon/20170619005377/en