ATHENA (GOG-3020/ENGOT-ov45): a randomized, phase III trial to evaluate rucaparib as monotherapy (ATHENA-MONO) and rucaparib in combination with nivolumab (ATHENA-COMBO) as maintenance treatment following frontline platinum-based chemotherapy in ovarian cancer

Abstract

Background: The optimal treatment strategy for women with newly diagnosed ovarian cancer has yet to be determined. Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated substantial improvement in progression-free survival as monotherapy maintenance treatment in the frontline setting versus active surveillance. Furthermore, preclinical and early clinical studies have shown that PARP inhibitors and immune checkpoint inhibitors have synergistic antitumor activity and may provide an additional therapeutic option for patients in this population.

Primary objectives: In women with newly diagnosed ovarian, fallopian tube, or peritoneal cancer, we wish to assess the efficacy of frontline maintenance treatment with the PARP inhibitor rucaparib versus placebo following response to platinum-based chemotherapy (ATHENA-MONO), and to assess the combination of rucaparib plus nivolumab (a programmed death receptor 1 (PD-1)-blocking monoclonal antibody) versus rucaparib alone (ATHENA-COMBO).

Study hypothesis: (1) Maintenance therapy with rucaparib monotherapy may extend progression-free survival following standard treatment for ovarian cancer in the frontline setting. (2) The combination of nivolumab plus rucaparib may extend progression-free survival following standard treatment for ovarian cancer in the frontline setting compared with rucaparib alone.

Trial design: ATHENA is an international, randomized, double-blind, phase III trial consisting of two independent comparisons (ATHENA-MONO and ATHENA-COMBO) in patients with newly diagnosed platinum-sensitive ovarian cancer. Patients are randomized 4:4:1:1 to the following: oral rucaparib+ intravenous nivolumab (arm A); oral rucaparib + intravenous placebo (arm B); oral placebo+ intravenous nivolumab (arm C); and oral placebo + intravenous placebo (arm D). The starting dose of rucaparib is 600 mg orally twice a day and nivolumab 480 mg intravenously every 4 weeks. ATHENA-MONO compares arm B with arm D to evaluate rucaparib monotherapy versus placebo, and ATHENA-COMBO evaluates arm A versus arm B to investigate the effects of rucaparib and nivolumab in combination versus rucaparib monotherapy. ATHENA-MONO and ATHENA-COMBO share a common treatment arm (arm B) but each comparison is independently powered.

Major inclusion/exclusion criteria: Patients ≥18 years of age with newly diagnosed advanced, high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancer who have achieved a response after completion of cytoreductive surgery and initial platinum-based chemotherapy are enrolled. No other prior treatment for ovarian cancer, other than the frontline platinum regimen, is permitted.

Primary endpoint: The primary endpoint is investigator-assessed progression-free survival by Response Evaluation Criteria in Solid Tumors v1.1.

Sample size: Approximately 1000 patients have been enrolled and randomized.

Estimated dates for completing accrual and presenting results: The trial completed accrual in 2020. While dependent on event rates, primary results of ATHENA-MONO are anticipated in early 2022 and results of ATHENA-COMBO are anticipated to mature at a later date.

Trial registration: This trial is registered at clinicaltrials.gov (NCT03522246).

Keywords: BRCA1 protein; BRCA2 protein; homologous recombination; ovarian neoplasms.

Conflict of interest statement

Competing interests: BJM has served as a consultant and received honoraria from Clovis Oncology, Aravive, AstraZeneca, Easai, Elevar, Genetics, Genmab/Seattle, GOG Foundation, Gradalis, ImmunoGen, Karyopharm, McKesson, Merck, Mersana, Myriad, Novocure, Pfizer, Roche/Genentech, Sorrento, Tesaro/GSK, and VBL outside the submitted work. RLC reports grants from Clovis Oncology, AstraZeneca, Genmab, Janssen, Merck, and Roche/Genentech; and has served as a consultant for Clovis Oncology, Agenus, AstraZeneca, Genmab, GSK, Janssen, OncoQuest, Roche/Genentech, and Regeneron outside the submitted work. KF has received institutional funding from Clovis Oncology during the conduct of the study; and received traveling support from Clovis Oncology outside the submitted work. AMO has received an institutional grant from AstraZeneca; served on data safety monitoring boards or advisory boards (uncompensated) for AstraZeneca and GSK; served on steering committees (uncompensated) for Clovis Oncology and AstraZeneca; and served as a principal investigator on investigator-initiated trials for Clovis Oncology, AstraZeneca, and GSK. DMO has served as a consultant for Clovis Oncology, Abbvie, Agenus, Ambry, Amgen, Arquer Diagnostics, AstraZeneca, Eisai, Elevar, Genentech/Roche, GOG Foundation, Immunogen, InxMed, Iovance Biotherapeutics, Janssen/J&J, Merck, Mersana, Myriad Genetics, Novartis, Novocure, Regeneron, Roche Diagnostics MSA, Rubis, SDP Oncology (BBI), SeaGen, Sorrento, Takeda, Tarveda, Tesaro/GSK, and Toray; and has received research support from Clovis Oncology, Abbvie, Agenus, Ajinomoto, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Cerulean Pharma, Eisai, EMD Serono, Ergomed, Genentech/Roche, GenMab, GOG Foundation, Immunogen, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, Janssen/J&J, Ludwig Cancer Research, Merck, Mersana, New Mexico Cancer Care Alliance, Novocure, PRA International, Regeneron, SDP Oncology (BBI), SeaGen, Serono, Stemcentrx, Tesaro/GSK, TRACON Pharmaceuticals, VentiRx, and Yale University outside the submitted work. DL has received institutional funding for trial development from Clovis Oncology during the conduct of the study; and has received research grants from Clovis Oncology; served on advisory boards for Clovis Oncology, AstraZeneca, GSK, Merck Sharp & Dohme, and PharmaMar outside the submitted work. SNW has received institutional funding and served as a consultant for Clovis Oncology during the conduct of the study; received institutional funding from Clovis Oncology, AstraZeneca, Bayer, Bio-Path, Cotinga Pharmaceuticals, GSK/Tesaro, Mereo, NIH, Novartis, and Roche/Genentech; served as a consultant for Clovis Oncology, Agenus, AstraZeneca, Eisai, GSK/Tesaro, Merck, Novartis, Pfizer, Roche/Genentech, and Zentalis; and is involved in an unpaid leadership or fiduciary role for GOG Foundation Board of Directors, Houston Gynecology and Obstetrical Society, NOCC – National Ovarian Cancer Coalition Advisory Board, OVARCOME Leadership Council, and Society of Gynecologic Oncology Board of Directors outside the submitted work. TJH has served on advisory boards for Clovis Oncology, Aravive, AstraZeneca, Caris, Elsai, GSK, Johnson & Johnson, Merck, and Roche Genentech; and has served as a consultant for Abbvie outside the submitted work. FM reports personal fees from Amgen, AstraZeneca, Celegene, CureVac, Eisai, GenomicHealth, Gilead/Immunomedics, GSK, Janssen-Cilag, MSD, Myriad, Novartis, Pfizer, Pierre-Fabre, PharmaMar, Roche, Tesaro, and Seagen outside the submitted work. RNE has served as a consultant for Clovis Oncology, AstraZeneca, Daiich Sankyo, Eisai, GSK, Merck, and Seagen; and received honoraria from AstraZeneca and Myriad outside the submitted work. IAM has served on advisory boards for Clovis Oncology, AstraZeneca, Roche, Takeda, and Tesaro; and received institutional funding from AstraZeneca outside the submitted work. RSK has served on data safety monitoring boards or advisory boards for Clovis Oncology, Basilea, Eisai, GSK, iTeos Therapeutics, Roche, Sotio, and Tesaro; and is involved in a leadership or fiduciary role for MHRA OHEAG. KKL, DS, SG, NG, SH, and LM are employees of Clovis Oncology and may own stock or have stock options in that company. All authors received writing support from Clovis Oncology during the conduct of the study.

© IGCS and ESGO 2021. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.

Figures

Figure 1

Study schema and analysis plan. Starting dose of rucaparib is 600 mg orally twice a day and nivolumab 480 mg intravenously every 4 weeks. BRCA, BRCA1 or BRCA2; CA-125, cancer antigen 125; CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenous; LOH, loss of heterozygosity; PO, by mouth; PR, partial response; R0, total cytoreduction; RECIST, Response Evaluation Criteria in Solid Tumors.