A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45)

Abstract

Purpose: ATHENA (ClinicalTrials.gov identifier: NCT03522246) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA-MONO comparison of rucaparib versus placebo.

Methods: Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population.

Results: As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%).

Conclusion: Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.

FIG 1.

CONSORT diagram of patients. BRCA, BRCA1 or BRCA2; HRD, homologous recombination deficiency; ITT, intent-to-treat; LOH, loss of heterozygosity.

FIG 2.

PFS by investigator in the (A) homologous recombination deficiency population and (B) intent-to-treat population and PFS by BICR for the same populations (C and D, respectively). For BICR analyses, nominal P values, not adjusted for multiplicity, are shown. BICR, blinded independent central review; HR, hazard ratio; NR, not reached; PFS, progression-free survival.

FIG 3.

Investigator-assessed PFS in subgroups in the ITT population. The vertical gray band corresponds to the 95% CI of the ITT population. ^aExcludes patients with unknown race. ^bOne rucaparib-treated patient had an ECOG PS of 1 at screening and 2 at cycle 1 day 1. BRCA, BRCA1 or BRCA2; CA-125, cancer antigen 125; CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; HRD, homologous recombination deficiency; ITT, intent-to-treat; LOH, loss of heterozygosity; PFS, progression-free survival; PR, partial response.

FIG 4.

PFS by investigator in (A) patients with BRCA-mutant tumors, (B) patients with BRCA wild-type/LOH high tumors, and (C) patients in the homologous recombination deficiency-negative subgroup (BRCA wild-type/LOH low tumors). BRCA, BRCA1 or BRCA2; HR, hazard ratio; LOH, loss of heterozygosity; NR, not reached; PFS, progression-free survival.

FIG A1.

Plots of the log of the cumulative hazard for PFS by investigator in (A) the homologous recombination-deficiency population and (B) the intent-to-treat population and PFS by blinded independent central review for the same populations (C and D, respectively). PFS, progression-free survival.

FIG A2.

PFS by blinded independent central review in (A) patients with BRCA-mutant tumors, (B) patients with BRCA wild-type/LOH high tumors, and (C) patients in the homologous recombination deficiency-negative subgroup (BRCA wild-type/LOH low tumors). BRCA, BRCA1 or BRCA2; HR, hazard ratio; LOH, loss of heterozygosity; NR, not reached; PFS, progression-free survival.

FIG A3.

Duration of RECIST response in the (A) homologous recombination deficiency population and (B) intent-to-treat population. NR, not reached.

FIG A4.

Changes from baseline in (A) ALT and (B) AST. Horizontal dotted lines in graphs represent the upper and lower limits of normal for each laboratory parameter.

FIG A5.

Change from baseline in Functional Assessment of Cancer Therapy—Ovarian Trial Outcome Index score in the intent-to-treat population.