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Rucaparib significantly improved investigator-assessed progression-free survival over placebo when used as maintenance treatment in newly diagnosed patients with advanced ovarian cancer following successful first-line treatment with platinum-based chemotherapy, according to top-line findings from the monotherapy arm of the phase 3 ATHENA trial.
Rucaparib (Rubraca) significantly improved investigator-assessed progression-free survival (PFS) over placebo when used as maintenance treatment in newly diagnosed patients with advanced ovarian cancer following successful first-line treatment with platinum-based chemotherapy, according to top-line findings from the monotherapy arm of the phase 3 ATHENA trial (GOG 3020/ENGOT-ov45; NCT03522246; ATHENA-MONO).1
In the homologous recombination deficiency (HRD)–positive population, the PARP inhibitor (n = 185) was found to achieve statistical significance over placebo (n = 49) regarding the primary end point of PFS, with a hazard ratio (HR) of 0.47 (95% CI, 0.31-0.72). The median PFS in the investigative and control arms was 28.7 months and 11.3 months, respectively (P = .0004).
In the intention-to-treat (ITT) population (n = 538), which was comprised of all patients randomized in the trial, the median PFS achieved with rucaparib (n = 427) was 20.2 months vs 9.2 months with placebo (n = 111), which was also found to be statistically significant (HR, 0.52; 95% CI, 0.40-0.68; P < .0001).
“While PARP inhibitors have shown efficacy as first-line maintenance treatment for patients with advanced ovarian cancer, questions still remain about the patient population that may benefit from their use,” Bradley J. Monk, MD, FACOG, FACS, at GOG Foundation, HonorHealth Research Institute, University of Arizona College of Medicine, Creighton University School of Medicine, stated in a press release. “The results of ATHENA-MONO address many of these unanswered questions and expands the opportunity for rucaparib for all patients regardless of biomarker status.”
The double-blind, placebo-controlled, phase 3 trial is comprised of 2 parts: ATHENA-MONO and ATHENA-COMBO.
To be eligible for enrollment, patients needed to be at least 18 years of age and have newly diagnosed, advanced, high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancer who have achieved a response following the completion of cytoreductive surgery and frontline platinum-based chemotherapy.2 Patients could not have previously received treatment for their disease other than the first-line platinum treatment.
Study participants were randomized 4:4:1:1 to the following arms: oral rucaparib plus intravenous (IV) nivolumab (nivolumab; arm A), oral rucaparib plus IV placebo (arm B), oral placebo plus IV nivolumab (arm C), and oral placebo plus IV placebo (arm D). Rucaparib was initiated at a starting dose of 600 mg twice daily, and nivolumab was started at a dose of 480 mg every 4 weeks.
The ATHENA-MONO portion of the research compared arm B with arm D to examine single-agent rucaparib compared with placebo in these patients. ATHENA-COMBO is comparing arm A with arm B of the trial to evaluate the efficacy of rucaparib/nivolumab vs single-agent rucaparib in this population. Although both portions share arm B, each comparison is independently powered.
The primary end point of the trial was investigator-assessed PFS per RECIST v1.1 criteria.
A total of 538 patients were enrolled to ATHENA-MONO. The primary efficacy analysis examined 2 prospectively-defined molecular subsets in a step-down manner: in those with HRD-positive, including BRCA-mutated tumors, as well as in the ITT population.
Additional data showed that in the exploratory HRD-negative subgroup, the median PFS with the PARP inhibitor (n = 189) was 12.1 months vs 9.1 months with placebo (n = 49; HR, 0.65; 95% CI, 0.45-0.95; P = .0284).
In another exploratory subgroup of patients who had BRCA-mutated tumors, the median PFS with rucaparib (n = 91) had not yet been reached per investigator assessment vs 14.7 months with placebo (n = 24), which translated to a HR of 0.40 (95% CI, 0.21-0.75; P = .0041).
Data proved to be consistent for those with germline BRCA mutations (n = 68), those with somatic BRCA mutations (n = 33), and those with unknown BRCA status (n = 14).
Regarding safety, the most frequent grade 3 or higher treatment-emergent toxicities experienced with rucaparib in ATHENA-MONO included anemia/decreased hemoglobin (28.7%), neutropenia (14.6%), alanine/aspartate aminotransferase increase (10.6%), and thrombocytopenia (7.1%). Treatment-emergent myelodysplastic syndrome/acute myeloid leukemia occurred in 0.2% of those who received rucaparib vs 0% of those who received placebo.
Treatment-emergent adverse effects resulted in discontinuation for 11.8% of those who received the PARP inhibitor and 5.5% of those who were given placebo.
“I believe the significant improvement in PFS demonstrated in the ATHENA-MONO trial underscores the importance of first-line maintenance therapy and the benefit that rucaparib can provide to women with advanced ovarian cancer irrespective of HRD status,” Rebecca S. Kristeleit, MD, PhD, of Guy’s and St. Thomas’ NHS Foundation Trust and lead ENGOT/NCRI National Cancer Research Institute investigator of ATHENA, added in the press release. “…The ATHENA-MONO study demonstrates the role of rucaparib monotherapy in the first-line maintenance treatment setting for advanced ovarian cancer.”
Based on the data to come out of the analysis, Clovis Oncology, Inc. shared plans to submit a supplement new drug application to the FDA seeking the approval of rucaparib in this patient population in the second quarter of 2022, and subsequently, a Type II Variation to the European Medicines Agency in the third quarter of 2022.