First-Line Approaches for HR+ Metastatic Breast Cancer

Gabriel N. Hortobagyi, MD, FACP: The CDK4/6 inhibitors have been a major addition to our treatment of hormone receptor–positive primary breast cancer. At this point, we select treatments for this group of patients, based essentially on the expression of estrogen and progesterone receptors and the lack of expression or normal expression of HER2 [human epidermal growth factor receptor 2]. During the development of CDK4/6 inhibitors, there was a major effort expended in identifying biomarkers to enrich the population. We don’t have a good biomarker that identifies patients who will have a greater or smaller probability of response to a CDK4/6 inhibitor. For patients with metastatic breast cancer who have tumors that express hormone receptors and have a normal expression of HER2, a CDK4/6 inhibitor combined with endocrine therapy is the treatment of choice.

We have 3 CDK4/6 inhibitors available in North America and much of the Western world: ribociclib, palbociclib, and abemaciclib. The 3 CDK4/6 inhibitors were developed almost simultaneously, and all 3 have demonstrated similar efficacy in second- and third-line therapy of hormone receptor–positive HER2- metastatic breast cancer. The safety profiles of ribociclib and palbociclib are very similar. Abemaciclib is slightly different with less myelosuppression and somewhat more diarrhea characterizing its safety profile. Most North American physicians would choose either inhibitor as their first choice and perhaps reserve abemaciclib for somewhat later utilization. More recently, we’ve had clinical trials reporting on first-line therapy of hormone receptor–positive HER2- metastatic breast cancer showing that the 3 CDK4/6 inhibitors have a similar and highly significant effect on prolonging progression-free survival. More recently, the first of the 3, ribociclib, has been reported to show equally highly significant and clinically relevant prolongation of overall survival. That’s where we stand today.

The selection of endocrine partners for CDK4/6 inhibitors is relatively simple. We have 3 highly selective aromatase inhibitors available that have a somewhat equivalent therapeutic ratio or efficacy and safety profile; therefore, any of the 3 would provide an appropriate partner to the CDK4/6 inhibitors. Fulvestrant is a selective estrogen receptor down regulator that was initially partnered with the CDK4/6 inhibitors in the second and third lines after progression on aromatase inhibitor–based therapy and showed a similar highly significant advantage in progression-free survival and overall survival in those trials in which it was the endocrine backbone. More recently, additional randomized trials included fulvestrant as the endocrine partner in first-line therapy. The same therapeutic effect was observed with fulvestrant and with aromatase inhibitors as an endocrine backbone. One could say that it’s equally appropriate to choose either an aromatase inhibitor or fulvestrant as an endocrine partner for a CDK4/6 inhibitor in first- or second-line therapy depending on the prior endocrine therapy utilized. Having said that, some patients will prefer total oral therapy, while others will prefer an intramuscular administration of a drug once a month. It becomes a question more of patient preference than of medical evidence.

Sara A. Hurvitz, MD: In a patient with hormone receptor–positive advanced breast cancer who’s being treated initially in the frontline setting, I almost always recommend a CDK4/6 inhibitor–based therapy in combination with hormonal therapy. The decision among the 3 CDK4/6 inhibitors is a bit tricky because we have 3 available that show strikingly similar objective response rates and strikingly similar hazard ratios when it comes to progression-free survival.

However, we are beginning to see some differences among the 3 agents that may help us select among them. For example, there are differences in toxicity profiles. Abemaciclib is associated with more GI [gastrointestinal] toxicity and a lower rate of neutropenia. However, it also has associated with it a rate of venous thromboembolic events of around 4%. Ribociclib and palbociclib have higher rates of neutropenia, typically nonfebrile but still a more significant rate of neutropenia. With ribociclib, 1 has to watch the ECGs [electrocardiogram] for QTC prolongation and keep in mind concomitant medications.

We’re also beginning to see some differences in the survival benefits associated with these. We have survival benefits associated with ribociclib in the frontline setting from the MONALEESA-7 clinical trial. And then more recently, from the MONALEESA-2 clinical trial. We’re still waiting for survival benefits to be reported from the MONARCH 3 and PALOMA-2 trials. We’ll have to see if those trials end up showing a significant improvement in survival when it comes to those agents.

For now, I talk to a patient about the different regimens available and select the endocrine therapy based on what they’d received previously. If they’d recently been on an Agilent aromatase inhibitor, I’ll almost likely recommend fulvestrant as the endocrine partner. In some cases, I’ll suggest fulvestrant, even in a patient who is endocrine therapy-naïve, if they prefer not to have to take more pills. It’s a patient discussion regarding adverse-effect profiles: the benefits we’ve seen from each of them, the dosing regimen, and recent therapies that the patient has been on for their breast cancer.

Transcript edited for clarity.