A post hoc exploratory analysis of the phase III ARIEL3 study conducted in patients with platinum-sensitive, recurrent epithelial ovarian carcinoma (EOC) showed significant differences in quality-adjusted progression-free survival (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST), thus confirming the benefit of rucaparib versus placebo in all predefined study cohorts. Rucaparib provided significant benefits to patient health status even when accounting for toxicities; these benefits were observed in the intention-to-treat (ITT) population and irrespective of BRCA mutation status. Amit M. Oza of the Princess Margaret Cancer Centre, University Health Network and Sinai Health System, University of Toronto in Toronto, Ontario, Canada and colleagues reported on 24 August 2020 in the Journal of Clinical Oncology that taken together, their findings demonstrated that rucaparib extended PFS in the maintenance setting without detrimental effects on patient health status.
Although most women with EOC respond to first-line treatment, many experience relapse. Maintenance treatment with a targeted agent such as bevacizumab or a poly(ADP-ribose) polymerase (PARP) inhibitor has become the standard of care for patients with EOC after a response to chemotherapy. It is important to evaluate whether adding maintenance treatment to a patient’s therapeutic regimen prolongs survival at the expense of toxicities that compromise the patient’s overall health status.
In the ARIEL3 trial, the primary efficacy endpoint of investigator-assessed PFS was significantly improved with a PARP inhibitor, rucaparib maintenance treatment versus placebo in all 3 prespecified cohorts: patients with BRCA-mutated tumour (germline, somatic, or unknown origin), patients with a homologous recombination deficient (HRD) tumour (BRCA mutation plus BRCA wild-type/high loss of heterozygosity (LOH), and the ITT population. Based on the study results, rucaparib is approved for the maintenance treatment of adult patients with recurrent EOC, fallopian tube or primary peritoneal cancer who have a complete or partial response to platinum-based chemotherapy.
To further evaluate the clinical benefits of rucaparib maintenance treatment from a patient-centred perspective, the ARIEL3 investigators performed QA-PFS and Q-TWiST analyses. It is the first report of the Q-TWiST analysis for a PARP inhibitor in ovarian cancer and the first report of quality-adjusted outcomes for a PARP inhibitor that includes patients with ovarian cancer without a known deleterious BRCA mutation.
Patients completed the 3-level version of the EQ-5D questionnaire (EQ-5D-3L) at screening, on day 1 of each treatment cycle, at the treatment discontinuation visit, and at the 28-day follow-up visit. QA-PFS was calculated as PFS function x EQ-5D-3L index score function. Q-TWiST analyses were performed defining toxicity as the mean duration in which a patient experienced grade ≥3 treatment-emergent adverse events (TEAEs) or the mean duration in which a patient experienced grade ≥2 TEAEs of nausea, vomiting, fatigue, and asthenia. The visit cut-off was 15 April 2017.
Mean QA-PFS was significantly longer with rucaparib versus placebo in the ITT population (difference 6.28 months, 95% confidence interval [CI] 4.85 to 7.47 months), BRCA-mutated cohort (9.37 months, 95% CI 6.65 to 11.85 months), HRD cohort (7.93 months, 95% CI 5.93 to 9.53 months) and BRCA wild-type/LOH low patient subgroup (2.71 months, 95% CI 0.31 to 4.44 months).
With toxicity defined using grade ≥3 TEAEs, the difference in mean Q-TWiST for rucaparib versus placebo was 6.88 months (95% CI 5.71 to 8.23 months), 9.73 months (95% CI 7.10 to 11.94 months), 8.11 months (95% CI 6.36 to 9.49 months), and 3.35 months (95% CI 1.66 to 5.40 months) in the ITT population, BRCA-mutated cohort, HRD cohort, and BRCA wild-type/LOH low patient subgroup, respectively. Q-TWiST with toxicity defined using select grade ≥2 TEAEs also consistently favoured rucaparib.
The authors concluded that in their analyses, rucaparib provided significant benefits to patient health status even when accounting for toxicities, as demonstrated by QA-PFS and Q-TWiST analyses. These benefits were observed in the ITT population and in subgroups of patients with a BRCA-mutated tumour and those with a BRCA wild-type tumour. Across analysis groups, rucaparib maintenance treatment provided a significant benefit despite the impact of toxicities on patients’ health status, and patients treated with rucaparib had longer periods without clinically relevant symptoms compared with those receiving placebo. These findings demonstrated that rucaparib extended PFS in the maintenance setting without detrimental effects on patient health status.
The study was supported by Clovis Oncology.
Oza AM, Lorusso D, Aghajanian C, et al. Patient-Centered Outcomes in ARIEL3, a Phase III, Randomized, Placebo-Controlled Trial of Rucaparib Maintenance Treatment in Patients With Recurrent Ovarian Carcinoma. JCO; Published online 24 August 2020. DOI: 10.1200/JCO.19.03107.