ICON 9-an international phase III randomized study to evaluate the efficacy of maintenance therapy with olaparib and cediranib or olaparib alone in patients with relapsed platinum-sensitive ovarian cancer following a response to platinum-based chemotherap

Two novel biological agents-cediranib targeting angiogenesis, and olaparib targeting DNA repair processes-have individually led to an improvement in ovarian cancer control. The aim of ICON9 is to investigate the combination of cediranib and olaparib maintenance in recurrent ovarian cancer following platinum-based therapy. To assess the efficacy of maintenance treatment with olaparib in combination with cediranib compared with olaparib alone following a response to platinum-based chemotherapy in women with platinum-sensitive ovarian, fallopian tube or peritoneal cancer during first relapse. Maintenance therapy with cediranib and olaparib in combination is associated with improved patient outcomes compared with olaparib alone. International phase III randomized controlled trial. Following a response to platinum-based chemotherapy patients are randomized 1:1 to either oral olaparib and cediranib (intervention arm) or oral olaparib alone (control arm). Patients with a known diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, progressing more than 6 months after first-line platinum-based chemotherapy, who have responded to second-line platinum-based chemotherapy. Progression-free and overall survival. Co-primary endpoints to be assessed using a fixed-sequence gatekeeping approach: (1) progression-free survival, all patients; (2) progression-free survival, BRCA wild type; (3) overall survival, all patients; (4) overall survival, BRCA wild type. 618 patients will be recruited. Accrual is expected to be completed in 2024 with presentation of results in 2025. ClinicalTrials.gov: NCT03278717.

Elyashiv O ，Ledermann J ，Parmar G ，Farrelly L ，Counsell N ，Feeney A ，El-Khouly F ，Macdonald I ，Neto A ，Arthur-Darkwa E ，Burnett E ，Jayson GC ，Mileshkin L ，Gourley C ，Nicum S ... -  《-》

DUETTE: a phase II randomized, multicenter study to investigate the efficacy and tolerability of a second maintenance treatment in patients with platinum-sensitive relapsed epithelial ovarian cancer, who have previously received poly(ADP-ribose) polymeras

With the success of poly(ADP-ribose) polymerase (PARP) inhibitor therapy in the first-line and second-line treatment settings, a new patient population is emerging with platinum-sensitive relapsed ovarian cancer, who have previously received a PARP inhibitor in the maintenance setting and for whom no second maintenance standard of care exists. DUETTE (NCT04239014) will evaluate the combination of ceralasertib (a potent, selective inhibitor of the serine/threonine kinase ataxia telangiectasia and Rad3-related protein (ATR) + olaparib, or olaparib monotherapy, compared with placebo, in this patient population of unmet need. The primary objective is to assess the efficacy of ceralasertib + olaparib combination, and olaparib monotherapy, compared with placebo, as second maintenance therapy in platinum-sensitive relapsed ovarian cancer. This study will test the hypothesis that ceralasertib + olaparib, or olaparib monotherapy, is tolerable, and effective at prolonging progression-free survival compared with placebo. This is a phase II, multicenter study where patients will be randomized in a 1:1:1 ratio to receive either (Arm 1) ceralasertib + olaparib, (Arm 2) olaparib monotherapy, or (Arm 3) placebo. The olaparib and placebo arms will be double-blinded, whereas the ceralasertib + olaparib arm will be open label. Patients will be stratified according to BRCA status, and response to platinum-based chemotherapy. Eligible patients will have histologically diagnosed high-grade epithelial ovarian cancer, with platinum-sensitive relapse on, or after, completion of at least 6 months of any prior PARP inhibitor maintenance therapy (a minimum of 12 months is required if the patient received PARP inhibitor maintenance following first-line chemotherapy). If the prior PARP inhibitor used was olaparib then patients must have received treatment without significant toxicity or the need for a permanent dose reduction. Disease relapse in the second-line or third-line setting is allowed. Patients who have received secondary debulking surgery are potentially eligible if they meet all other inclusion criteria. The primary endpoint is progression-free survival determined by blinded independent central review according to RECIST 1.1, with sensitivity analysis of progression-free survival using investigator assessments according to RECIST 1.1. 192 patients. December 2022. NCT04239014.

McMullen M ，Karakasis K ，Loembe B ，Dean E ，Parr G ，Oza AM ... -  《-》

Cediranib and Olaparib Combination Compared With Cediranib or Olaparib Alone, or Chemotherapy in Platinum-Resistant or Primary Platinum-Refractory Ovarian Cancer: NRG-GY005.

Lee JM ，Brady MF ，Miller A ，Moore RG ，MacKay H ，McNally L ，Lea J ，Street D ，Lheureux S ，McDonald ME ，Duska LR ，Cantuaria G ，Kavecansky J ，Leath CA 3rd ，Powell M ，Cadungog MG ，Rose PG ，Kim YM ，Huang HQ ，Provencher M ，Wenzel LB ，Bookman MA ，Kohn EC ，Secord AA ... -  《-》

Olaparib beyond progression compared with platinum chemotherapy after secondary cytoreductive surgery in patients with recurrent ovarian cancer: phase III randomized, open-label MITO 35b study, a project of the MITO-MANGO groups.

Poly (ADP-ribose) polymerase inhibitors have transformed the management landscape for patients with ovarian cancer, demonstrating remarkable improvements in progression-free survival and overall survival. Unfortunately, most relapses are due to an acquired mechanism of resistance to these agents. We hypothesize that secondary cytoreductive surgery, removing resistant clones, might help to overcome the development of resistance to poly (ADP-ribose) polymerase inhibitors, prolonging their therapeutic effect. To determine the efficacy of olaparib beyond progression compared with standard platinum-based chemotherapy in patients with recurrent ovarian cancer progressed during or after poly (ADP-ribose) polymerase inhibitor maintenance therapy after secondary cytoreductive surgery. Olaparib administered beyond progression is more effective in increasing progression-free survival and progression-free survival 2 compared with second-line platinum-based chemotherapy in patients after secondary cytoreductive surgery. Phase III, randomized, open-label, multicenter trial. Eligible patients will be randomized in a 1:1 ratio to receive olaparib or platinum-based chemotherapy of the investigator's choice. Eligible patients must have high-grade serous or endometrioid ovarian cancer progressed during or after first-line poly (ADP-ribose) polymerase inhibitor maintenance therapy and must have undergone secondary cytoreductive surgery. The dual primary endpoints will include progression-free survival and progression-free survival 2. Progression-free survival is defined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as the time between randomization and progression or death from any cause. Progression-free survival 2 is defined by the investigator using RECIST version 1.1 as the time frame from randomization to the second progression or death from any cause after subsequent treatment. Approximately 200 patients will be enrolled in this study. Enrollment will be completed in 2024. Results will be presented in 2026. EudraCT 2021-000245-41 NCT05255471.

Schettino C ，Musacchio L ，Bartoletti M ，Chiodini P ，Arenare L ，Baldassarre G ，Califano D ，Capoluongo E ，Costi MP ，D'Incalci M ，Marchini S ，Mezzanzanica D ，Normanno N ，Scala S ，Greggi S ，Perrone F ，Pignata S ... -  《-》

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 c

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. 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). (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. 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. 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. The primary endpoint is investigator-assessed progression-free survival by Response Evaluation Criteria in Solid Tumors v1.1. Approximately 1000 patients have been enrolled and randomized. 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. This trial is registered at clinicaltrials.gov (NCT03522246).

Monk BJ ，Coleman RL ，Fujiwara K ，Wilson MK ，Oza AM ，Oaknin A ，O'Malley DM ，Lorusso D ，Westin SN ，Safra T ，Herzog TJ ，Marmé F ，N Eskander R ，Lin KK ，Shih D ，Goble S ，Grechko N ，Hume S ，Maloney L ，McNeish IA ，Kristeleit RS ... -  《-》