Landmark Studies Show Clear Overall Survival Benefit for CDK4/6 Inhibitors in Advanced Breast Cancer

Get Permission

CDK4/6 inhibitors clearly improve overall survival in advanced breast cancer, as this prized endpoint was robustly demonstrated in two landmark phase III trials reported at the European Society for Medical Oncology (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

Dennis J. Slamon, MD, PhD

Dennis J. Slamon, MD, PhD

George Sledge, MD

George Sledge, MD

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 universally shown with the three approved CDK4/6 inhibitors, overall survival benefit had not been firmly established.

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.


  • The phase III MONALEESA-3 trial 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 essentially all patient subsets.
  • Experts say these trial data qualify CDK4/6 inhibitors for front-line use in patients with advanced breast cancer.

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.

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

Huge Clinical Impact Expected

Dr. Slamon 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.”

“The new standard of care in the first-line setting should be a CDK4/6 inhibitor. The data are highly meaningful clinically and are going to make a huge impact in how we treat metastatic breast cancer.”
— Nadia Harbeck, MD, PhD

Tweet this quote

Nadia Harbeck, MD, PhD, of the Ludwig Maximilian University in Munich, commented at a press briefing, “We were always struggling with whether to give these drugs in the first- or second-line setting. Now we see there is a first-line survival benefit. The new standard of care in the first-line setting should be a CDK4/6 inhibitor together with endocrine therapy. The data are highly meaningful clinically, and I think they’re going to make a huge impact in how we treat metastatic breast cancer.”


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 (500 mg intramuscularly on day 1 of each 28-day cycle, with an additional dose on day 15 of cycle 1).

“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.

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).

Additionally, 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 months vs 9.3 months, respectively (HR = 0.536; P < .0001). At 36 months, 29.9% of the albemaciclib 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).”

“This survival benefit [in MONARCH 2] is consistent across subgroups, including patients with poor prognostic factors such as visceral metastasis and primary endocrine therapy resistance.”
— George Sledge, MD

Tweet this quote

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.

Is One Better Than Another?

Both investigators emphasized that ribociclib and abemaciclib appear to confer similar benefits. “One thing that impresses us from a scientific endpoint is the consistency in hazard ratios across trials…. From a primary efficacy endpoint, I don’t think we have anything to tell us that one drug is superior to any other, although there are clear differences in toxicities among the agents that may favor one over another in a particular clinical situation,” Dr. Sledge 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. Harbeck disclosed relevant relationships with AstraZeneca, Lilly, Novartis, and Pfizer.


1. Slamon DJ, Neven P, Chia S, 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, Toi M, Neven P, 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, Toi M, Neven P, 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: A randomized clinical trial. JAMA Oncol. September 29, 2019 (early release online).

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

Related Articles

Expert Point of View: Sibylle Loibl, MD, and Nadia Harbeck, MD, PhD