HR+ HER2- Breast Cancer
Extending Overall Survival in HR+/HER2- Advanced Breast Cancer
There have been major advances that prolong the survival of patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer. The addition of CDK4/6 inhibitors to the backbone of endocrine therapy is one such advance.
The 3 available CDK4/6 inhibitors (ie, palbociclib, ribociclib, and abemaciclib) have been widely used to treat metastatic HR+/HER2- breast cancer over the last 5 to 8 years in the first- and second-line settings and, more recently, in the adjuvant setting (abemaciclib). While these drugs were initially used interchangeably based on similar improvements in PFS of approximately 12 to 14 months, they differ in terms of their effects on OS. Whereas there were consistent OS improvements seen with ribociclib in the MONALEESA-2, -3, and -7 trials and with abemaciclib in the MONARCH 2 trial, no OS advantage was seen with palbociclib in any of the PALOMA trials. An interim analysis from MONARCH 3 evaluating abemaciclib in the first-line, metastatic, HR+ setting demonstrated a more than 12-month improvement in OS, but this did not reach statistical significance. Finally, the lack of improvement in OS in the metastatic setting seen with palbociclib seems to correlate with the lack of an invasive disease-free survival benefit in the adjuvant setting.
It is unknown why the PFS benefit of palbociclib does not translate to improved OS in the metastatic setting, nor why palbociclib did not improve invasive disease-free survival in the adjuvant setting. Because the primary goal of therapy in the metastatic setting is to improve patient survival, we are beginning to see a transition toward greater use of ribociclib and abemaciclib.
The choice of therapy between ribociclib and abemaciclib is primarily based on their toxicity profiles. The primary toxicity seen with abemaciclib is diarrhea, and, in my experience, this tends to be a bigger issue with older patients. So, I may be more inclined to consider ribociclib over abemaciclib in older patients. Either agent could be used in younger patients.
The 3 available CDK4/6 inhibitors have been shown to generally produce similar improvement in PFS when added to first- or second-line endocrine therapy for metastatic HR+/HER2- breast cancer, whereas survival benefits were observed only with ribociclib and abemaciclib, but not with palbociclib. The addition of abemaciclib and ribociclib has also been shown to reduce recurrence rates when added to adjuvant endocrine therapy in patients with high-risk operable breast cancer, whereas similar benefits were not observed with palbociclib. The totality of the data suggests that there are clinically relevant differences in the effectiveness of these agents, although the explanation for these differences is currently not apparent.
Palbociclib was the first CDK4/6 inhibitor to be approved by the US Food and Drug Administration, and clinicians became familiar and comfortable with using it because it was quite well tolerated. However, because of the lack of improvement in OS in trials with palbociclib compared with the other CDK4/6 inhibitors, clinicians have shifted away from using palbociclib to using ribociclib and abemaciclib in most scenarios. Nonetheless, palbociclib may be a very acceptable option in older women with comorbidities because it is usually better tolerated than the other agents.
The introduction of CDK4/6 inhibitors has led to significantly improved clinical outcomes for patients with HR+/HER2- advanced breast cancer. As noted by my colleagues, while all 3 approved CDK4/6 agents are all associated with a statistically significant improvement in PFS vs placebo, only ribociclib and abemaciclib have shown significant improvements in OS. While OS was a secondary end point in these trials, it is considered a strong clinical end point from a regulatory standpoint and an important end point for patients. As a clinician who practices evidence-based medicine, I am more inclined to select a drug that shows an OS advantage.
The best thing about CDK4/6 inhibitors is that they are taken orally, which delays the time until intravenous chemotherapy. Chemotherapy significantly reduces patient quality of life, and it requires significant time in the infusion center and time to come in for blood work. Although, like chemotherapy, CDK4/6 inhibitors cause neutropenia, they differ in that very few patients on CDK4/6 inhibitors develop febrile neutropenia. When selecting a CDK4/6 inhibitor, it is important to consider toxicities that are unique to the different agents. Abemaciclib is associated with more gastrointestinal toxicity (eg, diarrhea), and ribociclib has a risk of QTc prolongation, which is important if patients are on concomitant QTc-prolonging medication. The selection of a CDK4/6 inhibitor should also take into consideration a patient’s comorbidities, as this will impact drug tolerability and adherence.
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