Analyzing Risks vs. Benefits of Adding Ribociclib or Abemaciclib for Advanced Breast Cancer

Patients with estrogen receptor-positive metastatic breast cancer frequently respond to endocrine therapy (ET), either alone or combined with targeted agents. This approach can help reduce tumor burden and alleviate symptoms, often with fewer side effects and lower toxicity compared to chemotherapy. 

Moreover, newer ETs seem to extend disease progression and possibly improve survival rates compared to older treatments. The chosen treatment focuses on stabilizing or reducing disease burden while minimizing side effects, and it is continued until either intolerable toxicities arise or the disease progresses. 

Notably, the development of new medications that offer survival benefits alongside ET has been both promising and practical in clinical settings. However, choosing between these new agents presents challenges, and several key considerations must be highlighted.

Optimal First-Line Therapy For Advanced Breast Cancer: Aromatase Inhibitor + CDK 4/6 inhibitor

In postmenopausal women with hormone receptor-positive breast cancer, combining the aromatase inhibitor (AI) letrozole with CDK 4/6 inhibitors (palbociclib, ribociclib, or abemaciclib) has shown enhanced progression-free survival (PFS) compared to AI treatment alone. These combinations have received approval from the US Food and Drug Administration (FDA) for this use. Additionally, the combination of ribociclib with an AI has demonstrated overall survival (OS) benefits. 

A meta-analysis of nine randomized trials involving over 5000 postmenopausal patients further revealed that adding CDK 4/6 inhibitors to endocrine therapy (ET) improved OS (hazard ratio [HR] 1.33, 95% CI 1.19-1.48), though it also raised the risks of neutropenia, leukopenia, and diarrhea. Notably, CDK 4/6 inhibitors have yet to be directly compared in clinical trials.

Choosing Between Ribociclib and Abemaciclib

There is ongoing debate regarding the selection of CDK 4/6 inhibitors. Both ribociclib and abemaciclib are considered valid options, with the decision largely influenced by their efficacy and toxicity profiles. Ribociclib is more frequently associated with higher rates of neutropenia, while abemaciclib is more commonly linked to diarrhea.

Ribociclib also has a higher incidence of liver function test abnormalities and can cause QTc prolongation, which may make it less suitable for certain patients, such as those already on QTc-prolonging medications.

Ribociclib has shown an overall survival (OS) benefit when combined with an AI or AI plus ovarian function suppression, as demonstrated in the MONALEESA-2 trial (64 months versus 51 months, HR 0.76, 95% CI 0.63-0.93) and the MONALEESA-7 trial (58 months versus 48 months, HR 0.76, 95% CI 0.61-0.96). 

Preclinical studies have shown that ribociclib and abemaciclib are four- and five-times more selective for CDK 4 over CDK 6, respectively, while abemaciclib also targets a broader range of CDKs, including cyclin B–CDK1, cyclin A/E–CDK2, and cyclin T–CDK9. These findings suggest potential differences between the two CDK 4/6 inhibitors. Despite this, all the two agents are considered valid treatment options.

Tolerability Consideration: The Key to Treatment Choices

CDK 4/6 inhibitors can lead to a substantial symptom burden that may affect tolerability and diminish patients’ health-related quality of life. The expected side effects of the agent associated with the patient profile should be a significant driver in the decision between the two agents. 

“It has to be a very motivated population,” Dr. Heather McArthur, the clinical director of breast cancer at UT Southwestern in Dallas, Texas, tells SurvivorNet Conenct. “…The intervention for abemaciclib is a two-year course of medication taken daily. The vast majority of patients who take abemaciclib have diarrhea, particularly within the first two months.”

In this scenario, Dr. McArthur also shares that the first two months of abemaciclib is the most aggressive period of therapy, and it can be tremendously uncomfortable for patients — leading to discontinuation.   

In a pooled analysis of clinical trials, over 70% of older patients had their treatment dose reduced, and more than 15% discontinued treatment. Tolerability is a critical factor for CDK 4/6 inhibitors, particularly since treatment duration can extend beyond two years, especially when used in the first-line setting. However, no head-to-head study comparing CDK4/6 options exists to observe the differential effects of these agents directly

Interestingly, a prior study compared the patient-reported quality of life (QoL) between the MONALEESA-2 and MONARCH-3 trials using a matching-adjusted indirect comparison. Patients in the ribociclib and placebo arms of MONALEESA-2 were matched with those in the abemaciclib and placebo arms of MONARCH-3. The time to sustained deterioration (TTSD) significantly favored ribociclib in terms of appetite loss (HR 0.46, 95% CI [0.27, 0.81]), fatigue (HR 0.63, 95% CI [0.41, 0.96]), and diarrhea (HR 0.42, 95% CI [0.23, 0.79]). TTSD did not favor abemaciclib compared to ribociclib on any functional or symptom scale. 

“With ribociclib, again, it’s three years on top of the hormone therapy that’s already planned. So there has to be a willingness to be compliant with that additional medication. And it requires EKG monitoring, it can lead to QTC prolongation. So for the first two months, we do routine EKGs, and so that requires additional visits by patients that wouldn’t be standard of care if they’re receiving hormone therapy alone,” Dr. McArthur explains. 

There is no universal solution when it comes to choosing the most suitable CDK 4/6 inhibitor for patients, as no genomic biomarker has yet been identified to predict response, highlighting the need for further research. In the meantime, factors like toxicity profiles, cost, and quality of life (QoL) considerations play a key role in decision-making. Current data suggests that patients on ribociclib combined with an AI may experience better symptom-related QoL compared to those on abemaciclib with an AI. The introduction of CDK inhibitors has significantly improved the treatment landscape for hormone receptor–positive metastatic breast cancer, and the potential for future advancements is promising.