Data from the confirmatory phase 3 ARIEL3 trial of has been announced, in which rucaparib successfully achieved the primary endpoint of improved progression-free survival (PFS) by investigator review in each of the three populations studied.

ARIEL3 is a double-blind, placebo-controlled, phase 3 trial of rucaparib that enrolled 564 women with platinum-sensitive, high-grade ovarian, fallopian tube, or primary peritoneal cancer.

The primary efficacy analysis evaluated three prospectively defined molecular sub-groups in a step-down manner:

1. tumour BRCA mutant (tBRCAmut) patients, inclusive of germline and somatic mutations of BRCA;
2. HRD-positive patients, including BRCA-mutant patients and BRCA wild-type with high loss of heterozygosity, or LOH-high patients; and, finally,
3. the intent-to-treat population, or all patients treated in ARIEL3.

PFS was also improved in the rucaparib group compared with placebo by blinded independent central review (BICR), a key secondary endpoint.

The exploratory PFS endpoints were achieved by both investigator and independent review in the HRD-positive and HRD-negative subgroups of patients without a BRCA mutation.

Rucaparib has previously received accelerated approval by the FDA to treat BRCA mutant ovarian cancer, based on previous trial data in ARIEL2.

ARIEL3 patients with residual disease at study entry who were treated with rucaparib showed further reduction in tumour burden, including complete responses.

The most robust clinical outcomes were observed among ARIEL3 patients with a germline or somatic BRCA mutation (n=196).

By investigator review, the rucaparib arm successfully achieved statistical significance over the placebo arm for the primary endpoint of PFS with a hazard ratio of 0.23 (p<0.0001).

The median PFS for the tBRCAmut patients treated with rucaparib was 16.6 months vs. 5.4 months among those who received placebo.

By independent review (BICR), the rucaparib arm improved PFS over the placebo arm with a hazard ratio of 0.20 (p<0.0001). The median PFS for the tBRCAmut patients treated with rucaparib was 26.8 months vs. 5.4 months among those who received placebo.

The exploratory PFS endpoint was achieved in the 161 patients identified as BRCAwt and HRD negative.

By investigator review, the rucaparib arm successfully achieved its endpoint over the placebo arm for the primary endpoint of PFS with a hazard ratio of 0.58 (p=0.0049).

The median PFS for these patients treated with rucaparib was 6.7 months vs. 5.4 months for those who received placebo.

By independent review (BICR), the rucaparib arm improved PFS over the placebo arm with a hazard ratio of 0.47 (p=.0003). The median PFS for these patients treated with rucaparib was 8.2 months vs. 5.3 months for those who received placebo.

The most common (≥5%) treatment-emergent grade 3/4 adverse events (TEAEs) among all patients treated with rucaparib in the ARIEL3 study were anemia/decreased hemoglobin (19%), ALT/AST increase (11%), asthenia/fatigue (7%), neutropenia (7%), and thrombocytopenia (5%).

The discontinuation rate for TEAEs was 14% for rucaparib-treated patients and 2.6% for the placebo arm.

The rate of treatment-emergent myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) in the rucaparib arm was <1% (3/372), and no patients on the placebo arm experienced treatment-emergent MDS/AML.

“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, M.D., professor and vice chair, clinical research, in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center in Houston and the U.S. 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 tumour.”

“I first dosed a patient with rucaparib over five years ago, and these robust and exciting data are consistent with my experience,” said Professor Jonathan Ledermann, Professor of Medical Oncology, Director, Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, and European and ROW Principal Investigator for the ARIEL3 study. “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 tumour genetics. This is a very important step forward for women with advanced ovarian cancer.”

Based on these findings, Clovis Oncology plans to submit a supplemental New Drug Application (sNDA) within the next four months for a second-line and later maintenance treatment indication for all women with platinum-sensitive ovarian cancer who have responded to their most recent platinum therapy.

Source: BusinessWire