Treatments Emerging to Combat Endocrine Resistance in ER+ Breast Cancer

Heather Han, MD

Most patients with ER-positive breast cancer will develop resistance to treatment with endocrine therapy, said Heather Han, MD, which makes understanding causes of resistance an important area of study.

CDK 4/6 inhibitors have emerged as a potential tool for overcoming endocrine resistance. The efficacy is similar for the 3 CDK4/6 inhibitors approved for the treatment of patients with metastatic breast cancer, as they have all demonstrated improvement in progression-free survival (PFS) in the first- and second-line settings.

Abemaciclib (Verzenio) joined palbociclib (Ibrance) and ribociclib (Kisqali) as the third CDK 4/6 inhibitor for patients with hormone receptor (HR)-positive, HER2-negative breast cancer. Most recently, abemaciclib was approved by the FDA in February 2018 for use in the frontline setting in combination with an aromatase inhibitor (AI), based on results from the phase III MONARCH 3 trial. This study showed that the the addition of abemaciclib to anastrozole or letrozole reduced the risk of progression or death by 46% compared with a nonsteroidal AI alone.

Han said the next step with the CDK 4/6 agents will be combination approaches, including with PD-1/PD-L1 inhibitors, as early research suggests CDK 4/6 inhibitors increase tumor immunogenicity, likely enhancing the impact of immune checkpoint agents.

OncLive: Please provide an overview of your presentation on ER-positive breast cancer.

In an interview during the 2018 with OncLive^® State of the Science Summit^TM on Breast Cancer, Han, research director, medical oncologist, Department of Breast Oncology, Moffitt Cancer Center, discussed emerging approaches for combating endocrine resistance in patients with ER-positive breast cancer.Han: In my presentation, I discussed hormone therapy and the main mechanisms of endocrine resistance. HR-positive breast cancer is the most common subtype of breast cancer. The main treatment is endocrine therapy, but unfortunately resistance is universal to endocrine therapies. Patients end up having recurrence and progressive disease. Understanding the mechanism of endocrine resistance is critical in order for us to find targeted therapy to try and overcome the resistance.

Can you elaborate on these mechanisms of resistance?

What percentage of patients develop resistance?

What are some combination approaches being explored?

Can you specify the differences between the different CDK 4/6 inhibitors?

I reviewed some of the mechanisms that have been identified in recent studies, so we can see what is FDA approved for use in routine clinical practice along with ongoing new therapies and novel combinations for these patients. I also reviewed attempts to identify the predicative markers for targeted therapies that have been studied. Many genetic and epigenetic alterations have been identified to explain the mechanisms to endocrine resistance. For example, a reduction or loss of ER expression explains some of the required resistance to endocrine therapy. Also, cell cycle regulation and deregulation have been the important mechanisms of endocrine resistance—not to mention to the cell itself and its interaction to the microenvironment, extracellular metrics, and immune cells.In the metastatic setting, resistance to endocrine therapy is universal for patients with ER-positive breast cancer. Most patients end up developing resistance to endocrine therapy throughout their courses of therapy. That is why it is very important to understand this resistance mechanism—to find potential targets and reverse this resistance. The approved agents that we are using in this setting include an mTOR inhibitor, such as everolimus (Afinitor), and 3 approved CDK 4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib. These are approved agents, but there are also many ongoing studies investigating new agents being studied in this subset, such as including PI3K inhibitors. Specifically, combinations with PI3K inhibitors, CDK 4/6 inhibitors, and new checkpoint inhibitors are actively being investigated. Some of the results show promising efficacy. Published and presented data suggest that efficacy across the 3 different agents are similar and are significantly improving PFS in the first- and second-line settings. However, what we have seen is that the toxicity of the 3 agents is slightly different. For example, abemaciclib has more diarrhea, gastrointestinal toxicities, and fatigue. Ribociclib and palbociclib have similar toxicities with neutropenia.

How do you choose one CDK 4/6 inhibitor over another?

Are there any regimens that you are interested in that are being investigated currently?

Also, one of the differences is that abemaciclib has been approved to be used as a single agent at 200 mg of continuous dosing because it was demonstrated that it has single-agent activity based on the MONARCH 1 trial. This is slightly different from the other 2 inhibitors, which had less single-agent activity when studied in early phases. The dosing is also different. Ribociclib and palbociclib have to be used on a 3-weeks-on/1-week-off schedule, due to neutropenia being the main toxicity issue. However, abemaciclib can be used continuously at either 150 mg twice daily in combination with endocrine therapy or as a single agent at 200 mg twice daily.I would choose the agent based on the individual patient, because toxicity profiles are different even though they have [similar] efficacy. It depends on what comorbidities a patient has. Out of the 3 agents, I have to choose which one will work best based on a patient’s individual circumstances, as there isn’t data to say that one agent would be better than the other.We are currently investigating what to give a patient after they progress on a CDK 4/6 inhibitor, whether it is in the first- or second-line setting. There are many other agents to choose from. For example, when you are choosing a second-line treatment following endocrine therapy, do you continue to use a CDK 4/6 inhibitor? Is using a different agent in this setting going to make a difference? We don't know these answers, so some of the clinical trials are interesting.

Although these data aren't yet released, is it likely to have an impact on combinations?

Would you like to highlight anything else?

There are randomized trials where patients are receiving endocrine therapy alone versus switching to a different agent or combinations with continued CDK 4/6 inhibitors and immunotherapy. There is an ongoing trial evaluating palbociclib after CDK 4/6 inhibitors and endocrine therapies. Some of the trials will address those questions that we have day-to-day in the clinic. We have been using palbociclib or other CDK 4/6 inhibitors for years, but now we have patients progressing on that treatment—so we need answers.Yes. Single-agent PD-1/PD-L1 inhibitors for patients with ER-positive metastatic breast cancer have not seen activity compared with other subsets of breast cancer. However, there is a lot of data on how to make these nonimmunogenic tumors potentially immunogenic and more responsive. A lot of that is with combinations of CDK 4/6 or MEK inhibitors. Those are being studied to make immunotherapy more effective in this patient population. I hope that one day we will be able to make a difference.One thing that I would like to emphasize is to continue clinical trials for patients who potentially progress after endocrine therapy with or without CDK 4/6 inhibitors. There are a lot of ongoing trials evaluating new combinations, whether it is targeted therapy combinations, immunotherapy combinations, or other novel combinations. I can't emphasize enough to consider clinical trials to help us answer these questions.

Di Leo A, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for patients with HR+/HER2- advanced breast cancer. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 236O_PR.