Maintenance therapy with the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib led to a significant improvement in progression-free survival compared with placebo in patients with newly diagnosed advanced ovarian cancer who responded to first-line platinum-based chemotherapy. The progression-free survival benefit of maintenance rucaparib was consistent in all patient subgroups in the final analysis of the phase III ATHENA-MONO trial, according to a presentation at the 2022 ASCO Annual Meeting.1,2
“Despite the long history of PARP inhibitor use in ovarian cancer, the optimal first-line maintenance strategy for newly diagnosed, advanced ovarian cancer has not been elucidated. This study showed that patients with measurable disease at baseline have further tumor reduction with rucaparib. [Additionally], the rucaparib safety profile is consistent with prior studies,” said lead author Bradley J. Monk, MD, Professor at the University of Arizona College of Medicine, and Director, Principal Investigator, Community Research Development, HonorHealth Research Institute.
This study showed that patients with measurable disease at baseline have further tumor reduction with rucaparib. [Additionally], the rucaparib safety profile is consistent with prior studies.— Bradley J. Monk, MD
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Key Findings
Progression-free survival was extended with maintenance rucaparib vs placebo in both homologous recombination deficient (HRD)-positive and HRD-negative populations. However, the magnitude of benefit was greater for patients with HRD-positive disease. Median follow-up was 26.1 months.
The HRD cohort included pooled patients with BRCA mutation or wild-type BRCA and high loss of heterozygosity. In this group, median investigator-assessed progression-free survival was 28.7 months with rucaparib vs 11.3 months with placebo (P = .0004). On blinded independent central review, median progression-free survival was not reached vs 9.9 months, respectively (P = .0004).
In the intention-to-treat population, median progression-free survival was 20.2 months in the rucaparib arm vs 9.2 months in the placebo arm (P < .0001). The secondary endpoint of progression-free survival by blinded-independent central radiology review showed a median progression-free survival of 25.9 months in the rucaparib arm vs 9.1 months in the placebo arm (P < .0001). In the HRD-negative population, median progression-free survival was 12.1 months with rucaparib vs 9.1 months with placebo.
“The magnitude of benefit based on molecular characteristics showed that rucaparib was of greater benefit in the HRD-positive patients than in the intent-to-treat analysis,” he added.
Study Methodology
ATHENA was an international, randomized, double-blind, phase III trial in all comers evaluating maintenance rucaparib therapy in 1,000 patients, consisting of two independent comparisons: ATHENA-MONO and ATHENA-COMBO. Both parts of the study shared a rucaparib arm. In ATHENA-MONO, rucaparib was the experimental arm. Results of ATHENA-COMBO will be reported at a later date.
Dr. Monk presented mature results of ATHENA-MONO, which included 535 patients with newly diagnosed, stage III or IV high-grade primary peritoneal, fallopian tube, or epithelial ovarian cancer who were platinum-sensitive. Patients were randomly assigned to maintenance rucaparib or placebo and were stratified according to HRD status, disease status postchemotherapy, and timing of surgery. The study was conducted at 200 sites in 24 countries from 2018 to 2020.
In ATHENA-MONO, 425 women were randomly assigned to receive oral rucaparib at 600 mg twice daily plus intravenous placebo, and 110 women were randomly assigned to receive placebo. Treatment was continued for 2 years or until disease progression or unacceptable toxicity.
Baseline characteristics were mainly similar between the two treatment arms in both the HRD subset analysis and in the intention-to-treat analysis. The primary endpoint was investigator-assessed progression-free survival in the HRD subset, who all had loss-of-heterozygosity–high disease. If the analysis showed statistical significance for rucaparib vs placebo, then an intention-to-treat analysis of progression-free survival was performed.
“A blinded independent committee review analysis is a stand-alone secondary endpoint outside of the step-down analysis of progression-free survival,” Dr. Monk explained.
Additional Results
In an investigator-assessed progression-free survival exploratory subgroup analysis, rucaparib continued to show increased benefit compared with placebo, regardless of the presence of a BRCA mutation, loss-of-heterozygosity–high disease, or HRD-negative disease.
“Everyone benefits in all subgroups. The greatest benefit was seen in the highest-risk patients—that is, those with residual disease after six cycles of a platinum doublet, stage IV disease, and persistently elevated CA-125 after six doses of chemotherapy,” he told listeners. “Ten percent of patients had persistent disease and continued to respond to rucaparib, both in the HRD subset and the intention-to-treat analysis.” Results were similar in the analysis by blinded independent central review.
Investigator-assessed objective response rate in the HRD population was 58.8% in the rucaparib arm vs 20.0% in the placebo arm and were mostly partial responses in both treatment arms. Median duration of response was 16.7 months with rucaparib vs 5.5 months with placebo.
Everyone benefits [from rucaparib maintenance] in all subgroups. The greatest benefit was seen in the highest-risk patients….— Bradley J. Monk, MD
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In the intention-to-treat population, the objective response rate was 48.8% in the rucaparib arm vs 9.1% in the placebo arm. One complete response was observed in the rucaparib arm and none in the placebo arm. Median duration of response was 22.1 months and 5.5 months, respectively.
The median duration of treatment was 14.7 months in the rucaparib group and 9.9 months in the placebo arm. Median duration of follow-up was 26 months in both arms. The per-protocol 2-year treatment was completed by 23.7% of the rucaparib arm and 9% of the placebo arm.
Reasons for premature discontinuation of treatment included disease progression (41% vs 64.9%, respectively), adverse events (12.6% vs 5.4%), withdrawal of consent (4.9% vs 2.7%), or clinical disease progression (3.3% vs 5.4%).
“I think there is a therapeutic window for PARP inhibition. Dose intensity matters. Throughout the study, 70% of patients on rucaparib were maintained on a dose of more than 500 mg through month 12.” Dr. Monk commented on the “substantial dose flexibility of rucaparib, having four doses of 600, 500, 400, or 300 mg. There was no dose optimization needed in the study per se. We started every patient on 600 mg and did not reduce the dose based on age and/or body weight.”
Safety Profile
Almost all patients—even those receiving placebo—had at least one treatment-emergent adverse event: 96.7% with rucaparib and 92.7% with placebo. Myelodysplastic syndrome or acute myeloid leukemia was observed in two patients in the rucaparib group and none in the placebo group.
At least one grade 3 or higher adverse effect was reported in 60.5% of patients in the rucaparib group vs 22.7% in the placebo group. Treatment interruptions or dose reductions due to treatment-emergent adverse events occurred in 63.8% and 21.8% of patients, respectively. The most common grade 3 or higher adverse events observed with rucaparib vs placebo were anemia or increased hemoglobin (28.7% vs 0%), neutropenia or neutrophil count decrease (14.6% vs 0.9%), and increased levels of alanine aminotransferase or aspartate aminotransferase (10.6% vs 0.9%).
No significant changes in bilirubin or increased levels of drug-induced liver toxicity were observed in the rucaparib-treated group. Additionally, 70% of patients continued to receive at least 500 mg of rucaparib twice daily through month 12, which was more than 80% of the starting dose.
Two deaths were reported in the rucaparib-treated group and none in the placebo arm.
“Quality of life matters. These patients were carefully monitored for quality of life, and quality of life was stable,” said Dr. Monk.
DISCLOSURE: The study was funded by Clovis Oncology, Inc. Dr. Monk has served as a consultant or advisor to Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Clovis Oncology Inc., Eisai, Genmab/Seattle Genomics, GOG Foundation, Immunogen, Iovance Biotherapeutics, Merck, Mersana, Myriad Pharmaceuticals, Pfizer, Puma Biotechnology, Regeneron, Roche/Genentech, Tesaro/GSK, Vascular Biogenics, Gradalis, Karyopharm Therapeutics, EMD Serono/Merck, Gradalis, US Oncology, Novartis, Pieris Pharmaceuticals, and OncoC4; served on a speakers bureau for Roche/Genentech, AstraZeneca, Clovis Oncology, Eisai, Tesaro/GSK, and Merck; and received research funding from Novartis, Amgen, Genentech, Lilly, Janssen, Array BioPharma, Tesaro, Morphotek, Pfizer, Advaxis, AstraZeneca, Immunogen, Regeneron, and NuCana.
REFERENCES
1. Monk BJ, Parkinson C, Lim MC, et al: ATHENA–MONO (GOG-3020/ENGOT-ov45): A randomized, double-blind, phase 3 trial evaluating rucaparib monotherapy versus placebo as maintenance treatment following response to first-line platinum-based chemotherapy in ovarian cancer. 2022 ASCO Annual Meeting. Abstract LBA5500. Presented June 6, 2022.
2. Monk BJ, Parkinson C, Lim MC, et al: 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). J Clin Oncol. June 6, 2022 (early release online).
