Patient-Centered Outcomes in ARIEL3, a Phase III, Randomized, Placebo-Controlled Trial of Rucaparib Maintenance Treatment in Patients With Recurrent Ovarian Carcinoma

Abstract

Purpose: To investigate quality-adjusted progression-free survival (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST) in a post hoc exploratory analysis of the phase III ARIEL3 study of rucaparib maintenance treatment versus placebo.

Patients and methods: Patients with platinum-sensitive, recurrent ovarian carcinoma were randomly assigned to rucaparib (600 mg twice per day) or placebo. QA-PFS was calculated as progression-free survival function × the 3-level version of the EQ-5D questionnaire (EQ-5D-3L) index score function. Q-TWiST analyses were performed defining TOX 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. Q-TWiST was calculated as μTOX × TOX + TWiST, with μTOX calculated using EQ-5D-3L data.

Results: The visit cutoff was Apr 15, 2017. Mean QA-PFS was significantly longer with rucaparib versus placebo in the intent-to-treat (ITT) population (375 randomly assigned to rucaparib v 189 randomly assigned to placebo; difference, 6.28 months [95% CI, 4.85 to 7.47 months]); BRCA-mutant cohort (130 rucaparib v 66 placebo; 9.37 months [95% CI, 6.65 to 11.85 months]); homologous recombination deficient (HRD) cohort (236 rucaparib v 118 placebo; 7.93 months [95% CI, 5.93 to 9.53 months]); and BRCA wild-type/loss of heterozygosity (LOH) low patient subgroup (107 rucaparib v 54 placebo; 2.71 months [95% CI, 0.31 to 4.44 months]). With TOX defined using grade ≥ 3 TEAEs, the difference in mean Q-TWiST (rucaparib v 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-mutant cohort, HRD cohort, and BRCA wild-type/LOH low patient subgroup, respectively. Q-TWiST with TOX defined using select grade ≥ 2 TEAEs also consistently favored rucaparib.

Conclusion: The significant differences in QA-PFS and Q-TWiST confirm the benefit of rucaparib versus placebo in all predefined cohorts.

FIG 1.

Most frequent treatment-emergent adverse events (TEAEs; reported in ≥ 35% of patients) in ARIEL3. (*) Elevations were transient, self-limiting, and not associated with other signs of liver toxicity. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

FIG 2.

Quality-adjusted progression-free survival (QA-PFS) in the intent-to-treat population (A), BRCA-mutant cohort (B), homologous recombination deficient cohort (C), BRCA wild-type/loss of heterozygosity (LOH) high (D), BRCA wild-type/LOH low (E), and BRCA wild-type/LOH indeterminate (F) patient subgroups. Patients at-risk data are shown for the progression-free survival (PFS) analysis.

FIG 3.

Time without symptoms or toxicity (TWiST) analysis, with toxicity defined as all grade ≥ 3 treatment-emergent adverse events in the intent-to-treat population (A), BRCA-mutant cohort (B), homologous recombination deficient cohort (C), BRCA wild-type/loss of heterozygosity (LOH) high (D), BRCA wild-type/LOH low (E), and BRCA wild-type/LOH indeterminate (F) patient subgroups. PFS, progression-free survival. TOX, time with toxicity of treatment.

FIG A1.

Flowchart for calculation of quality-adjusted (QA) progression-free survival (PFS; QA-PFS).

FIG A2.

Flowchart for calculation of quality-adjusted time without symptoms or toxicity (TWiST; Q-TWiST). The mean time with symptoms of disease (REL state) was not included in these analyses because ARIEL3 OS data were not mature at the time of this analysis. AEs, adverse events; OS, overall survival; PFS, progression-free survival; TOX, time with toxicity of treatment.

FIG A3.

Quality-adjusted progression-free survival (QA-PFS) for the intent-to-treat population determined by multiplying the investigator-assessed progression-free survival (PFS) function (A) by the EQ-5D-3L index score function (B) to obtain a QA-PFS function (C). (*) EQ-5D-3L data were collected on day 1 of each 28-day treatment cycle. PFS, progression-free survival; QA-PFS, quality-adjusted progression-free survival.

FIG A4.

Time without symptoms or toxicity (TWiST) analysis with toxicity defined as grade ≥ 2 treatment-emergent adverse events of nausea, vomiting, fatigue, and asthenia only in the intent-to-treat population (A), BRCA-mutant cohort (B), homologous recombination deficient cohort (C), BRCA wild-type/loss of heterozygosity (LOH) high (D), BRCA wild-type/LOH low (E), and BRCA wild-type/LOH indeterminate (F) patient subgroups. TOX, time with toxicity of treatment.