ESMO 2017: Rucaparib Shows Clinical Benefit as Maintenance Therapy in Patients with Recurrent Ovarian Cancer

Rucaparib delayed disease recurrence in the ITT population and across subgroups in ARIEL3 study

Women with platinum-sensitive, recurrent, high-grade ovarian, fallopian tube, or primary peritoneal cancer who took the PARP inhibitor rucaparib as a maintenance therapy demonstrated improved progression-free survival (PFS) compared to placebo in the randomised phase III ARIEL3 trial, according to findings presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain. 

Jonathan Ledermann, Professor of Medical Oncology at UCL Cancer Institute and UCL Hospitals, London, UK presented findings from the double-blind, multinational phase III ARIEL3 trial (NCT01968213), which tested rucaparib as a maintenance therapy compared to placebo in women with high-grade ovarian, fallopian tube, or primary peritoneal cancer following aresponse to platinum-based chemotherapy. The women had platinum-sensitive disease defined as disease progression 6 or more months after penultimate platinum.

Enroled patients had received ≥2 prior platinum-based therapies and had achieved a complete or partial response per RECIST v1.1 or by Gynaecologic Cancer InterGroup CA-125 criteria to the most recent platinum therapy. All patients were required to have CA-125 less than the upper limit of normal.

The 564 patients were randomised in a 2 to 1 ratio to receive 600 mg of rucaparib twice daily or placebo; a total of 375 patients were treated with rucaparib and 189 received placebo.  

The primary efficacy analysis evaluated investigator-assessed PFS as the primary endpoint in 3 prospectively-defined nested subgroups in a step-down manner. The nested subgroups were: BRCA mutant with either a deleterious germline or somatic BRCA mutation, homologous recombination deficient (HRD) comprising either BRCA mutant or BRCA wild-type/loss of heterozygosity (LOH) high, and the intent-to-treat (ITT) population. PFS as assessed by blinded independent central review was a key secondary endpoint and LOH status in patients with BRCA wild-type ovarian cancer was an exploratory endpoint.

PFS was improved across all subgroups with rucaparib over placebo

Investigators found that maintenance treatment with rucaparib resulted in longer PFS for the ITT population, as well as in patients with tumours with HRD, and patients with BRCA-mutant tumours, including both germline and somatic mutations.

Rucaparib-Shows-Clinical-Benefit-As-Maintenance-Therapy-In-Patients-With-Recurrent-Ovarian-Cancer

Kaplan-Meier estimates of investigator-assessed progression-free survival in the rucaparib and placebo arms for patients with a BRCA-mutant carcinoma (A), patients with an HRD carcinoma (B), and the intent-to-treat population (C). Visit cut-off date: 15 April 2017. CI=confidence interval. HR=hazard ratio. HRD=homologous recombination deficient.

© Jonathan Ledermann. 

Median PFS favoured rucaparib at 10.8 months versus 5.4 months in the intent-to-treat population, according to investigator review, hazard ratio [HR] 0.36 (p < 0.0001). By independent review, rucaparib improved PFS by 8.3 months over placebo, HR 0.35 (p < 0.0001).

In the HRD subgroup, including both patients with BRCA-mutant tumours and patients with wild-type/LOH high tumours, median PFS by investigator review was 13.6 months with rucaparib versus 5.4 months with placebo, HR 0.32 (p < 0.0001) and median PFS by independent review was 22.9 months versus 5.5 months, respectively, HR 0.34 (p < 0.0001).

The BRCA mutant subgroup demonstrated median PFS of 16.6 months in the rucaparib arm versus 5.4 months with placebo by investigator review, HR 0.23 (p < 0.0001). The PFS advantage associated with rucaparib was more pronounced by independent review where median PFS was 26.8 months versus 5.4 months, respectively, HR 0.20 (p < 0.0001).

PFS difference was least pronounced in patients with BRCA wild-type and LOH low tumours

Regarding the exploratory endpoint of LOH status in patients with BRCA wild-type ovarian cancer, these patients showed the least benefit from rucaparib; by investigator review patients with BRCA wild-type/LOH-high tumours had median PFS of 9.7 months with rucaparib versus 5.4 months with placebo, HR 0.44 (p < 0.0001) and median PFS by independent review was 11.1 months versus 5.6 months, respectively, HR 0.55 (p = 0.0.0135).
 
The subgroup of patients with BRCA wild-type/LOH low tumours showed the poorest median PFS with rucaparib of 6.7 versus 5.4 months with placebo by investigator review, HR 0.58 (p = 0.0049) and median PFS by independent review was 8.2 months versus 5.3 months, respectively, HR 0.47 (p = 0.0003).

The most common grade 3 or higher treatment-emergent adverse events (AEs) with rucaparib or placebo were anaemia, which occurred in 18.8% and 0.5%, and alanine/aspartate aminotransferase increase in 10.5% and 0% of patients, respectively.

Discontinuation of study drug due to treatment-emergent AEs (excluding disease progression) occurred in 13.4% and 1.6% of rucaparib and placebo patients and 1.6% and 1.1% of patients died due to AEs (including disease progression), respectively.

Conclusions

The authors concluded that rucaparib significantly improved PFS compared to placebo in all primary analysis groups of patients with platinum-sensitive, recurrent ovarian cancer.

Improvement in PFS, albeit less, was observed in non-nested subgroups of patients with BRCA wild-type ovarian cancer with both LOH-high and LOH-low tumours.

Sandro Pignata of the National Cancer Institute of Naples, Fondazione G Pascale, Naples, Italy who discussed the study results, said that rucaparib is another option as maintenance therapy in platinum sensitive patients responding to platinum. There are clear signs of activity also in BRCA wild-type patients. LOH is not able to separate unresponsive patients.

Disclosure

This trial was sponsored by Clovis Oncology, Inc.

Reference

LBA40_PR – Ledermann J, 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).