Patients had to have measurable disease and willing to undergo tumour biopsy. Given the pilot nature of this study, patients with platinum-resistant, platinum-refractory or platinum-sensitive ovarian tumours were included. Central review of ER or pathology was not required. Patients were eligible if they had biopsy-proven, relapsed and measurable ER-positive ovarian, fallopian tube or primary peritoneal carcinomas (OCs) or relapsed ER-positive EC had not been previously treated with ribociclib or AIs and had an Eastern Cooperative Oncology Group performance status between 0 and 2. This investigator-initiated concomitant phase II clinical trial (separate trials for OC and EC) was sponsored by Novartis and performed at Mayo Clinic in Rochester in Minnesota, Phoenix in Arizona and Jacksonville in Florida. 20 Given these findings, we decided to explore if the possibility that combination ribociclib and letrozole could improve outcomes against relapsed OR-positive OC and EC. 19 An unpublished report of a phase II trial of palbociclib and letrozole in OC, showed a PFS of 3.7 months and a Partial Remission (PR) rate of 4% with 60% stable disease. 16–18 In addition, a patient with refractory high-grade serous OC with a homozygous CDKN2 deletion had a significant response to palbociclib and letrozole lasting over 12 months. 15 CDK inhibitors (palbociclib, ribociclib and abemaciclib) have been developed and shown on clinical trials to significantly prolong PFS (palbociclib, ribociclib and abemaciclib) and overall survival (OS) (ribociclib and abemaciclib) when combined with AIs or fulvestrant in the treatment of metastatic ER-positive breast cancer, leading to approval by the Food and Drug Administration. Alterations in cell cycle checkpoint regulation occur in nearly all malignancies 14 and contribute to endocrine therapy resistance in breast cancer. In conjunction with cyclin D1 binding partner, a combination of CDK 4/6 and cyclin D1 holoenzyme acts on critical cell cycle checkpoints that allow cell cycle progression. Cyclin-dependent kinase (CDK) 4 and 6 are important downstream targets of OR. Strategies to improve the efficacy of AIs in metastatic breast cancer have been extensively studied. 3 The activity of these agents might be higher in patients with ER-positive tumours and those without previous exposure to tamoxifen. ![]() 11 In OC, a phase II study of letrozole in 60 patients showed that only 20% were progression-free and still on trial at 12 weeks. 3–13 A Gynecologic Oncology Group trial of anastrozole in chemotherapy-naïve EC showed median progression-free survival (PFS) of 1 month and a 9% response rate. Despite the high prevalence of ER expression, limited clinical activity of single-agent AIs have been reported in at least two phase II trials in EC and eight phase II clinical trials in OC. 1 2 Treatment with aromatase inhibitors (AIs) is an acceptable option included in the National Comprehensive Cancer Network treatment guidelines for relapsed OC or EC. Oestrogen receptor (ER) positivity is present in 38% to 60% of all ovarian cancers (OCs) and up to 80% of all endometrial cancers (ECs).
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