MONALEESA-3, MONARCH 2: CDK4/6 Inhibitors Plus Fulvestrant Benefit Survival in Advanced Breast Cancer

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CDK4/6 inhibitors improve overall survival in advanced breast cancer, according to results of two important phase III trials reported at the ESMO Congress 2019. Dennis J. Slamon, MD, PhD, of the University of California, Los Angeles Women’s Cancer Research Program, presented the findings from the MONALEESA-3 trial,1 and George Sledge, MD, of Stanford University Medical Center, presented the findings from the MONARCH 2 trial.2

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have been widely incorporated into the care of women with advanced hormone receptor–positive, HER2-negative breast cancer. Although progression-free survival benefits have been shown with the three approved CDK4/6 inhibitors, overall survival benefit had not been firmly established.

George Sledge, MD, FASCO (left), of Stanford University Medical Center, and Dennis J. Slamon, MD, PhD (right), of the University of California, Los Angeles Women’s Cancer Research Program, presented findings from the MONARCH 2 and MONALEESA-3 trials, respectively.

The treatment landscape has changed in both the first- and second-line settings, experts say, based on the results presented at ESMO’s Presidential Symposium for ribociclib in MONALEESA-3 and for abemaciclib in MONARCH 2. Both drugs were given with fulvestrant and yielded statistically significant differences in multiple endpoints, compared with fulvestrant plus placebo.

MONALEESA-3 evaluated ribociclib in the first- and second-line settings in postmenopausal patients. MONARCH 2’s population included both postmenopausal (80%) and premenopausal (20%) women who received abemaciclib as second-line therapy. In both studies, overall survival was a key secondary endpoint, and progression-free survival was the primary endpoint.

Key Findings

In MONALEESA-3, with ribociclib/fulvestrant, the median overall survival was not reached but was 40.0 months for placebo/fulvestrant, a 28% risk reduction.1 In the early-relapse/second-line setting, the combination led to a median survival benefit of 7.7 months, a 27% reduction in risk, according to Dr. Slamon. He shared his own impression of the findings from the two studies: “I had the good fortune to work with many of you [in the audience] in testing targeted therapy with [trastuzumab], and I think the results we are seeing today are as exciting as we saw back in those days.”

In MONARCH 2, abemaciclib plus fulvestrant led to a median 9.4-month overall survival benefit in patients who experienced disease progression with prior endocrine therapy, a 24% reduction in risk, according to Dr. Sledge.2 The results were simultaneously published in JAMA Oncology.3


In the previous MONALEESA-7 trial, ribociclib plus endocrine therapy significantly improved overall survival vs endocrine therapy alone, in premenopausal advanced breast cancer (hazard ratio [HR] = 0.71; P = .00973).4 The -MONALEESA-3 trial has now shown a similar benefit in 726 postmenopausal patients randomly assigned to ribociclib (600 mg daily for 3 weeks on, 1 week off) plus fulvestrant intramuscular injection.

“What was somewhat unique in this study was that essentially half of the patients were getting their therapy in the first-line setting. In other words, they had not received any treatment for metastatic breast cancer, and they were being compared with those who were getting fulvestrant alone in the same setting,” Dr. Slamon said.

At a median follow-up of 39.4 months, the median overall survival was not reached in the ribociclib arm and was 40.0 months with placebo (HR = 0.724; P = .00455), Dr. Slamon reported, He noted that benefits were observed “regardless of whether the patient received treatment in the front-line setting or subsequently.” The advantage was consistent across patient subgroups.


  • MONALEESA-3 evaluated ribociclib/fulvestrant in 726 postmenopausal patients in the first- and second-line settings.
  • MONARCH 2 evaluated abemaciclib/fulvestrant in 669 postmenopausal and peri/premenopausal patients in the first- and second-line settings.
  • Significant improvements in overall survival were demonstrated in both treatment settings and in all patient subsets.

The updated progression-free survival, for the ribociclib vs placebo arms, respectively, was 20.6 vs 12.8 months (HR = 0.587; 95% confidence interval [CI] = 0.488–0.705). By line of treatment, in the first-line setting, this was 33.6 and 19.2 months (HR = 0.546; 95% CI = 0.415–0.718) and in the second-line setting, 14.6 and 9.1 months, respectively (HR = 0.571; 95% CI = 0.443–0.737).

Second disease progression was prolonged with ribociclib/fulvestrant by a median of 10.4 months, a 23% reduction in risk. The median time to first chemotherapy was not reached with the combination and was 29.5 months with fulvestrant alone (HR = 0.696; 95% CI = 0.551–0.879).

A landmark analysis of overall survival at 3 and 4 years showed respective survival rates of 67.0% and 57.8% with ribociclib/fulvestrant compared with 58.2% and 45.9% for fulvestrant alone. “What is interesting about the MONALEESA-3 data is that we have not yet reached the median survival in the experimental arm. Patients are continuing on treatment, and we don’t know how far up that curve will go. That is certainly good for the patients,” Dr. Slamon commented.


In the MONARCH 2 trial, the investigators randomly assigned 669 pre/perimenopausal or postmenopausal patients with tumors resistant to endocrine therapy to receive continuous abemaciclib (150 mg twice daily) plus fulvestrant (500 mg administered intramuscularly on days 1, 15, 29, and once monthly thereafter) or placebo/fulvestrant. All patients had relapsed on neoadjuvant endocrine therapy or within 1 year (or during) endocrine treatment in the adjuvant setting or had experienced disease progression on front-line endocrine therapy for advanced disease. Patients had no prior chemotherapy for advanced disease and no more than one prior line of endocrine therapy.

At a median follow-up of 47.7 months, the median overall survival with abemaciclib/fulvestrant was 46.7 months, compared with 37.3 months for placebo/fulvestrant (HR = 0.757; P = .0137), an absolute improvement of almost 10 months. This difference was shown despite a crossover rate of 17% on the control arm, vs 6% on the abemaciclib arm, Dr. Sledge reported.

In the updated analysis of progression-free survival, the median was 16.9 vs 9.3 months, respectively (HR = 0.536; P < .0001). At 36 months, 29.9% of the abemaciclib arm was progression-free vs 10.1% of the placebo arm, “three times as many patients,” he noted.

“The addition of abemaciclib to fulvestrant provided a statistically significant overall survival improvement in patients with hormone receptor–positive, HER2-negative breast cancer who had experienced disease progression on prior endocrine therapy,” Dr. Sledge said. “This survival benefit is consistent across subgroups, including, interestingly, patients with poor prognostic factors such as visceral metastasis (HR = 0.675) and primary endocrine therapy resistance (HR = 0.686).”

In an exploratory analysis, abemaciclib significantly delayed the receipt of subsequent chemotherapy from 22.1 months to 50.2 months (HR = 0.625; P < .0001). At the median 47.7-month follow-up, 17% of patients on abemaciclib remain on treatment, compared with 4% of those on placebo. Abemaciclib/fulvestrant also showed a statistically significant improvement in median chemotherapy-free survival compared with fulvestrant/placebo at 25.5 months and 18.2 months, respectively (HR = 0.638; 95% CI = 0.527–0.773). In the published study, the investigators further reported that the time to second disease progression was prolonged by a median of 2.5 months, a 33% improvement.

Safety profiles in both studies were consistent with observations from previous clinical trials, both investigators reported.

Trials Not to Be Compared, but Results of Each Significant

Sibylle Loibl, MD, of the University of Frankfurt, commented as a formal discussant of -MONALEESA-3 and MONARCH 2. “It’s great to see overall survival in the first- and second-line metastatic breast cancer settings. We haven’t seen that in many years,” she said. Dr. Loibl devoted a good portion of her formal discussion to describing the features of and differences between the individual trials. Primarily,

Sibylle Loibl, MD

Sibylle Loibl, MD

their populations are different in the extent of pretreatment (and lack thereof), menopausal status, relapse profile, and definitions of endocrine resistance, for example. Their “special characteristics” are sufficient enough to discourage comparisons of their results, she emphasized. “These patient populations are significantly different; therefore, we cannot and should not compare the individual data.”

Differences aside, however, Dr. Loibl applauded the findings of these trials: Significant improvements in progression-free survival, in both the first and second lines, have now translated into overall survival improvements. “Outcomes improve irrespetive of pretreatment, menopausal status, endocrine sensitivity, and site of metastasis. That’s good for our patients,” she said. 

DISCLOSURE: Dr. Slamon has served as a consultant or advisor to Eli Lilly and Novartis; received travel funding from Biomarin, Novartis, and Pfizer; served on the board of directors for Biomarin; has held stock or ownership interests in Amgen, Merck, Pfizer, and Vertex; and received research funding from Novartis and Pfizer. Dr. Sledge has served as a consultant for Syndax, Symphogen, and Verseau Therapeutics; served on the board of directors for Tessa Therapeutics; and received travel funds or research support from Eli Lilly and Pfizer. Dr. Loibl has received honoraria from Prime and Chugai and numerous institutional research grants.


1. Slamon DJ, et al: Overall survival results of the phase III MONALEESA-3 trial of postmenopausal patients with hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer treated with fulvestrant ± ribociclib. ESMO Congress 2019. Abstract LBA7_PR. Presented September 29, 2019.

2. Sledge GW Jr, et al: MONARCH 2: Overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2– advanced breast cancer. ESMO Congress 2019. Abstract LBA6_PR. Presented September 29, 2019.

3. Sledge GW Jr, et al: The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy–MONARCH 2. JAMA Oncol. September 29, 2019 (early release online).

4. Hurvitz SA, et al: Phase III MONALEESA-7 trial of premenopausal patients with HR+/HER2− advanced breast cancer treated with endocrine therapy ± ribociclib. 2019 ASCO Annual Meeting. Abstract LBA1008. Presented June 4, 2019.