The randomized phase III MONALEESA-7 trial was the first trial to demonstrate a progression-free survival (PFS) benefit with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors plus endocrine therapy in premenopausal women with HR+, HER2− advanced breast cancer not previously treated with endocrine therapy in the advanced setting (see Figure; Lancet Oncol 2018;19(7):904-915).
In the phase III CDK4/6 inhibitor trials PALOMA-3 (palbociclib plus fulvestrant) and MONARCH 2 (abemaciclib plus fulvestrant), results in subsets of premenopausal women (~20% of the study population in both studies) provided preliminary evidence of efficacy in young women whose disease had been previously treated with endocrine therapy (Lancet Oncol 2016;17(4):425-439, J Clin Oncol 2017;35(25):2875-2884). However, no study has previously evaluated the efficacy of CDK4/6 inhibitors as initial endocrine therapy specifically in premenopausal women with HR+, HER2− advanced breast cancer.
In the MONALEESA-7 trial, a total of 672 pre/perimenopausal women with HR+, HER2− advanced breast cancer with no prior endocrine therapy for advanced disease were randomized to treatment with either the CDK4/6 inhibitor ribociclib plus endocrine therapy or placebo plus endocrine therapy. Additionally, all patients received the luteinizing hormone-releasing hormone agonist goserelin to suppress ovarian function. The endocrine therapy partner was either tamoxifen or a nonsteroidal aromatase inhibitor (NSAI). In the ribociclib plus endocrine therapy group, the risk of a PFS event (disease progression or death due to any cause) was reduced by 45 percent versus the endocrine therapy–only group. At the time of the data cutoff (median duration of follow-up was 19 months), the median PFS was 24 months in the ribociclib plus endocrine therapy group and 13 months in the endocrine therapy–only group (p<0.0001).
In addition to PFS benefits, the MONALEESA-7 trial demonstrated early and sustained tumor responses and improvements in health-related quality of life (HRQoL) in the ribociclib plus endocrine therapy group compared with that in the endocrine therapy–only group (Lancet Oncol 2018;19(7):904-915). In the ribociclib plus endocrine therapy group, 41 percent of patients had a complete or partial tumor response on study, with a 35 percent probability of response at 6 months. In comparison, 30 percent of patients in the endocrine therapy–only group had a complete or partial response; 6-month probability of response was 25 percent.
The overall response rate in the ribociclib plus endocrine therapy group was in the range of response rates historically observed with first-line chemotherapy (~40% in several studies; J Clin Oncol 2014;32(29):3307-3329), which is often the treatment of choice in patients for whom an early response is of greater importance than toxicity concerns (e.g., patients with rapidly progressive, immediately life-threatening disease; J Clin Oncol 2016;34(25):3069-3103). Tumor response rates are particularly relevant in premenopausal patients with breast cancer because of the propensity for patients <40 years of age at primary diagnosis to develop visceral metastases (Eur J Cancer 2014;50(10):1697-1705).
HRQoL benefits of ribociclib plus endocrine therapy included sustained clinically meaningful improvements in the European Organisation for Research and Treatment of Cancer Quality of Life Core 30 Questionnaire (EORTC QLQ-C30) pain score as early as 8 weeks in the ribociclib plus endocrine therapy group (Lancet Oncol 2018;19(7):904-915). Similarly, overall HRQoL scores were sustained for a longer duration of time in the ribociclib plus endocrine therapy group versus the endocrine therapy–only group. A significant benefit in the time to ≥10 percent deterioration in the EORTC QLQ-C30 overall score was reported for patients in the ribociclib plus endocrine therapy group (HR, 0.70 [95% confidence interval, 0.53-0.92]; p=0.004). These findings are particularly relevant in premenopausal patients because of the specific HRQoL challenges in this population, as discussed later in this article.
The safety profile of ribociclib plus endocrine therapy in the MONALEESA-7 trial was generally manageable and similar to that in reports including postmenopausal patients (N Engl J Med 2016;375(18):1738-1748, Lancet Oncol 2018;19(7):904-915). One notable observation was an apparent difference in corrected QT interval prolongation in the endocrine therapy subgroups. In both the ribociclib plus endocrine therapy and endocrine therapy–only groups, there was a higher percentage of patients with an increase in corrected QT interval using Fridericia's formula >60 ms from baseline in the tamoxifen subgroup compared with the NSAI subgroup. These findings are consistent with a recent report of increased corrected QT interval prolongation events in patients treated with tamoxifen in comparison to AIs (Heart 2018; doi:10.1136/heartjnl-2017-312934).
These results confirm, for the first time in a phase III trial, that the clinically significant benefits of ribociclib plus endocrine therapy observed in postmenopausal women with advanced breast cancer can also be achieved in premenopausal women with advanced breast cancer.
The results of the MONALEESA-7 trial are of particular interest because, although premenopausal women make up a substantial proportion of patients with advanced breast cancer, they often have been underrepresented or excluded from clinical trials (Clin Cancer Res 2017;23(11):2647-2654). Despite the recent availability of multiple targeted therapies that have been shown to prolong PFS in postmenopausal women with advanced breast cancer, the last randomized trial examining a new endocrine therapy or combination treatment specifically in premenopausal women was reported in 2000 (J Natl Cancer Inst 2000;92(11):903-911).
As we have discussed in a recently published review article, advanced breast cancer in premenopausal women presents distinct challenges compared with advanced breast cancer in postmenopausal women, complicating extrapolation of findings from postmenopausal to premenopausal women (Clin Cancer Res 2018; doi:10.1158/1078-0432.CCR-18-0162).
For example, premenopausal women with breast cancer often have a more aggressive disease biology than postmenopausal women, including advanced stage at diagnosis, higher tumor grades/larger tumor size, higher rate of aggressive disease subtypes, and a higher risk of recurrence (J Thorac Dis 2013;5(suppl 1):S2-S8, J Natl Compr Canc Netw 2017;15(10):1216-1223).
Young women with breast cancer also face unique QoL challenges with their diagnosis and treatment. Survey data show lower global QoL scores and lower emotional, social, and cognitive function scores in young women with breast cancer versus those in survivors of other cancers (Int J Cancer 2016;139(11):2415-2425). There also appear to be differences in symptoms experienced during treatment by young women with breast cancer compared with young women with other cancers, with young women with breast cancer reporting more fatigue and insomnia (Int J Cancer 2016;139(11):2415-2425).
Among patients with breast cancer, younger women report more distress from breast cancer and treatment than older women (Clin Breast Cancer 2014;14(2):e21-e31). The lower global QoL scores in younger women may partly arise from challenges associated with premature menopause, as well as body image problems and financial/day-to-day life concerns such caring for young children or career management (J Clin Oncol 2005;23(15):3322-3330, Psychooncology 2006;15(7):579-594, Am J Prev Med 2016;50(2):286-294).
Another consideration for the treatment of advanced breast cancer in premenopausal women is ovarian function suppression, a recommended component of endocrine therapy (required for AIs) in premenopausal women (J Clin Oncol 2016;34(25):3069-3103). This is often accomplished with gonadotropin-releasing hormone agonists, increasing the treatment burden and introducing additional adverse events related to premature menopause. Premenopausal women are also at risk of partial ovarian functional recovery while on an established dose of ovarian suppression medication (i.e., ovarian breakthrough; J Clin Oncol 2016;34(25):3069-3103). Currently, there is no way of predicting who is at risk for ovarian breakthrough, and there are no established guidelines on how frequently to assess hormone levels after ovarian suppression has been established.
The MONALEESA-7 trial is the first phase III randomized trial to demonstrate the efficacy and safety of a CDK4/6 inhibitor (ribociclib) in combination with endocrine therapy in premenopausal women with HR+, HER2− advanced breast cancer. The results from MONALEESA-7 provide the first level 1 evidence to validate the use of ribociclib in premenopausal women with advanced breast cancer who have not received prior endocrine therapy for advanced disease.
SARA HURVITZ, MD, is Assistant Professor of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine, UCLA, and Medical Director of the Clinical Research Unit, UCLA Jonsson Comprehensive Cancer Center. ADITYA BARDIA, MD, is Assistant Professor of Medicine, Department of Medicine, Harvard Medical School, and Attending Physician, Department of Medical Oncology, Massachusetts General Hospital Cancer Center.
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