First-line maintenance of rucaparib improves PFS in ovarian cancer, regardless of HRD status
Rucaparib (Rubraca) significantly improved progression-free survival (PFS) when used as first-line maintenance therapy for patients with ovarian cancer who have responded to platinum-based chemotherapy , regardless of the status of the homologous recombination deficiency (HRD), according to the results of the ATHENA study -Essai MONO (NCT03522246), presented to the 2022 Annual Meeting of the American Society for Clinical Oncology (ASCO).
Results in the intent-to-treat (ITT) population showed a median PFS of 20.2 months (95% CI, 15.2-24.7) in the rucaparib arm and 9.2 months (95% CI %, 8.3-12.2) in the placebo arm (HR, 0.52; 95% CI: 0.40-0.68; log-rank P <.0001 the secondary pfs endpoint by blinded independent central radiological review showed a median of months ci in rucaparib arm and arm. placebo log-rank>P <.0001>
“Patients with measurable disease at baseline have additional tumor shrinkage with rucaparib. [Additionally]the safety profile of rucaparib is consistent with previous studies,” Bradley J. Monk, MD, FACS, FACOG, Professor, Division of Gynecologic Oncology, University of Arizona College of Medicine, Medical Director of the Gynecologic Program of the US Oncology Research Network, and principal investigator of this study, said during the presentation.
Overall, the ATHENA trial was split into 2 analyzes of studies after randomization based on treatment regimens. Patients with newly diagnosed stage III-IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who completed doublet first-line chemotherapy were randomized in a 4:4 ratio. :1:1 in one of the four treatment groups. Patients must have achieved a complete response (CR) or a partial response (PR) assessed by the investigator, have undergone cytoreductive surgery, have an ECOG performance status of 0 or 1 and have had no previous treatment for ovarian cancer.
In ATHENA, patients were randomized to either arm A with oral rucaparib 600 mg twice daily plus intravenous (IV) nivolumab (Opdivo) 480 mg; arm B with IV placebo and rucaparib; arm C with oral placebo and nivolumab; or arm D consisting of an intravenous and oral placebo regimen. Patients were treated for 24 months or until radiographic progression, unacceptable toxicity, or other reasons for discontinuation. ATHENA-MONO included arms B (n=400) and D (n=100), and were reported at 2022 ASCO. ATHENA-COMBO will include arms A (n=400) and B (n=400). The primary endpoint of the entire trial is investigator-assessed PFS.
“Arm C, which is nivolumab only, will not be analyzed. In ATHENA-MONO, rucaparib is the investigational arm, and in ATHENA-COMBO, the combination of rucaparib plus nivolumab is the investigational arm, and rucaparib plus placebo is the control arm,” Monk said.
A hierarchical tapered design was developed for the primary endpoint, which first assessed PFS as a function of HRD status in individuals with BRCA mutant and loss of heterozygosity (LOH) – high, BRCA wild-type disease. Since diet met with statistical significance in this group, then the study would narrow down to an ITT analysis. At 90% power at a two-sided significance level of 0.025, predicted HR values were 0.45 for those with HRD and 0.60 for those in the ITT population.
In the HRD group, the median investigator-assessed PFS was 28.7 months (95% CI, 23.0 – not reached) versus 11.3 months (95% CI, 9.1-22.1 HR, 0.47, 95% CI, 0.31-0.72; P = .0004). Median PFS by BICR was NR (95% CI, 28.7-NR) versus 9.9 months (95% CI, 6.5-NR; HR, 0.44; 95% CI, 0, 28-0.70; P = .0004).
In the exploratory, investigator-assessed PFS subgroup analysis, rucaparib continued to demonstrate increased benefit over placebo regardless of the presence of a BRCA mutation (HR, 0.40; 95% CI, 0.21-0.75), high LOH disease (HR, 0.58; 95% CI, 0.33-1.01) or HRD negativity (HR , 0.65; 95% CI, 0.45-0.95). Data were similar in subgroups assessed by BICR.
The investigator-assessed objective response rate (ORR) in the HRD population was 58.8% (95% CI, 32.9% versus 81.6%) in the rucaparib arm versus 20.0% (CI at 95%, 0.5%-71.6%) in the placebo arm, both composed exclusively of PR, with a median duration of response (DOR) of 16.7 months versus 5.5 months, respectively. In the ITT population, the ORR in the rucaparib arm was 48.8% (95% CI, 32.9%-64.9%) versus 9.1% (95% CI, 0.2%-41 .3%) in the placebo arm, with 1 CR in the rucaparib arm group and the rest of the responses being PRs. The corresponding median DOR between the groups was 22.1 months and 5.5 months.
At least 1 adverse reaction (AE) of grade 3 or higher was reported in 60.5% of patients in the rucaparib group versus 22.7% in the placebo group, with treatment interruptions or dose reductions following AEs treatment-emergent (TEAE) occurring in 63.8% and 21.8%, respectively. The most common Grade 3 or higher adverse reactions with rucaparib compared to placebo were anemia or increased hemoglobin (28.7% vs. 0%, respectively), neutropenia or decreased number of neutrophils (14.6% versus 0.9%), and increased alanine aminotransferase or aspartate aminotransferase (10.6%). % versus 0.9%).
Patients did not show significant changes in bilirubin or increased levels of drug-induced liver toxicity. Additionally, through month 12, 70% of patients continued to receive at least 500 mg rucaparib twice daily, more than 80% of the initial dose.
Of the 425 patients treated in the rucaparib arm versus 110 in the placebo group, 12.4% versus 9.9%, respectively, were still on treatment as of the data cut-off date of March 23, 2022, and 63.5% versus 80 .2% discontinued treatment before 2 years due to disease progression (41.0% vs 64.9%), AE (12.6% vs 5.4%), withdrawal of consent (4.9% vs 2.7%), clinical progression (3.3% vs 5.4%), or other reasons (1.6% vs 1.8%) . The median duration of treatment was 14.7 months (95% CI, 0.1-32.7) in the rucaparib group and 9.9 months (95% CI, 0.9-25.9) in the placebo group, with a median duration of follow-up of 26.1 months (95% CI, 25.8-26.9) versus 26.2 (95% CI, 24.0-27.7).
In the HRD population, patient characteristics included a median age of 57 years in the rucaparib group versus 59 years in the placebo group, whiteness in 74.1% and 71.4%, ECOG performance status of 0 in 71.4% and 79.6% and stage III disease in 73.5% and 63.3%, respectively. Cancer types included epithelial ovary (82.7% vs 79.6%), fallopian tube (11.4% vs 10.2%) and primary peritoneum (5.9% vs 10.2% ). Primary surgery was performed in 56.2% of patients in the rucaparib arm and 55.1% in the placebo arm, 74.1% vs 71.4% had no residual disease, 50.8% vs 51.0 % were BRCA wild-type/high LOH, and 9.2% versus 10.2% had measurable disease at baseline.
In the ITT populations, the median age in the rucaparib and placebo arms was 61 years, Caucasian in 76.8% vs. 78.4%, ECOG performance score of 0 in 69.1% vs. 68.5 % and stage III disease in 75.6% versus 70.3%, respectively. Cancer types included epithelial ovary (78.7% vs 76.6%), fallopian tube (11.7% vs 16.2%) and primary peritoneum (9.6% vs 7.2% ). Primary surgery was performed in 48.9% of patients in the rucaparib arm vs 48.6% in the placebo group and no residual disease was found in 75.4% vs 73.9%. Patients in the rucaparib vs. placebo arms had a positive HRD, BRCA wild type/elevated LOH status at rates of 22.0% vs 22.5%, HRD negative in 44.3% vs 44.1%, with unknown HRD in 12.4% vs 11.7%. Additionally, measurable disease at baseline was observed in 9.6% of patients in the rucaparib group and 9.9% of patients in the placebo group.
Monk BJ, Parkinson C, Lim MC, et al. ATHENA–MONO (GOG-3020/ENGOT-ov45): randomized, double-blind, phase 3 trial evaluating rucaparib monotherapy versus placebo as maintenance treatment after response to first-line chemotherapy containing platinum in ovarian cancer. J Clin Oncol. 2022;40(supplement 17):LBA5500. doi: 10.1200/JCO.2022.40.17_suppl.LBA5500