The Road Beyond Frontline CDK4/6 Inhibitors in HR+/HER2– Metastatic Breast Cancer Examines Combinations


Erin Frances Cobain, MD, highlights the current role of endocrine therapy and CDK4/6 inhibitors in HR-positive, HER2-negative metastatic breast cancer.

Erin Frances Cobain, MD

Erin Frances Cobain, MD

Selecting optimal second- and third-line therapies for patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer involves careful consideration of patients’ disease characteristics and responses to prior lines of therapy, according to Erin Frances Cobain, MD. 

The oral selective estrogen receptor degrader (SERD) elacestrant (Orserdu) was FDA approved in 2023 for patients with ER-positive, HER2-negative advanced or metastatic breast cancer harboring an ESR1 mutation who experienced progressive disease (PD) following at least 1 line of endocrine therapy. This regulatory decision was supported by findings from the phase 3 EMERALD trial (NCT03778931), in which elacestrant elicited a median progression-free survival (PFS) of 3.8 months (95% CI, 2.2-7.3) in the efficacy population (n = 115) compared with 1.9 months (95% CI, 1.9-2.1) in those who received fulvestrant (Faslodex) or an aromatase inhibitor (AI; n = 113).1

Regarding the use of CDK4/6 inhibitors in the second-line setting and beyond, in the phase 2 MAINTAIN trial (NCT02632045) patients with HR-positive, HER2-negative metastatic disease who had progressed on prior endocrine therapy and a CDK4/6 inhibitor received switched endocrine therapy from what they had received prior to random assignment in combination with ribociclib (Kisqali) or placebo. Patients achieved a median PFS of 5.29 months (95% CI, 3.02-8.12) with switched endocrine therapy plus ribociclib vs 2.76 months with switched endocrine therapy plus placebo (95% CI, 2.66-3.25; HR, 0.57; 95% CI, 0.39-0.85; P = .006).2

“Would I consider using a CDK4/6 inhibitor after a prior CDK4/6 inhibitor based on the available data we have? It’s a consideration, but not [a choice I am making] as my go-to in the second-line treatment setting,” Cobain said in an interview with OncLive® following an Institutional Perspectives in Cancer (IPC) webinar on breast cancer, which she chaired. Cobain is an assistant professor and codirector of the Breast Cancer Clinical Research Team at the University of Michigan Rogel Cancer Center in Ann Arbor.

In the interview, Cobain highlighted key points from her presentation, including the current role of endocrine therapy in patients with HR-positive, HER2-negative metastatic breast cancer, factors that complicate the decision to use CDK4/6 inhibitors in the second-line setting after disease progression on frontline CDK4/6 inhibitors, and considerations for using targeted therapies in this patient population.

OncLive: What was the rationale for your presentation on the management of HR-positive, HER2-negative metastatic breast cancer beyond CDK4/6 inhibitors?

Cobain: The treatment options in the second line for patients with HR-positive, HER2-negative metastatic breast cancer have expanded rapidly in the past several years. That’s due to the FDA approvals of some targeted inhibitors. We had [the FDA approval of] the PI3K inhibitor alpelisib [(Vijoice) for patients with HR-positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer]. More recently, we’ve had an FDA approval for capivasertib [Truqap], an AKT inhibitor, [for patients with locally advanced or metastatic HR-positive, HER2-negative disease harboring at least 1 PIK3CA, AKT1, or PTEN alteration], as well as the first FDA approval of an oral SERD, elacestrant, [for patients with ESR1-mutated estrogen receptor-positive, HER2-negative advanced or metastatic disease].

All those therapies, [which are] most often considered in the second-line treatment setting and beyond for patients with HR-positive metastatic disease, are administered on the basis of the presence or absence of somatic molecular alterations in the patient’s tumor. [This IPC was] a good opportunity to highlight the drugs themselves and where and how they should be used, as well as discuss the strategies for molecular testing that we should be employing in the clinic to best identify patients who can benefit from these therapies.

What are the optimal endocrine therapy–based treatment strategies in the second- and third-line settings after disease progression on first-line endocrine therapy plus a CDK4/6 inhibitor?

Once patients progress on endocrine therapy and CDK4/6 inhibitors in the first-line setting, one of the important questions [to ask] right away is: Did we use an AI or fulvestrant in that first-line setting? Whether a patient has PD on an AI vs fulvestrant has implications for which endocrine therapy backbone we may wish to use in the subsequent lines of therapy.

The second most important questions are: What are the molecular features of the tumor? What are the targetable genomic alterations that can be identified? This gets into a question of the timing of that testing. Mutations, such as activating alterations in PI3K, tend to be present at diagnosis of metastatic disease and are often identifiable from a primary tumor. In other words, they tend to be tumor-initiating events that are present early on and are often detectable from multiple samples collected throughout the course of a patient’s disease and treatment. In contrast to that, we believe that [alterations such as] ESR1 mutations principally develop or emerge as a mechanism of resistance to AI therapy.

If I’m considering whether a patient could be a candidate for elacestrant and I did molecular testing at diagnosis of metastatic disease before [the patient] had prolonged exposure to an AI, I may not identify an activating ESR1 mutation from that sample. That is why if a patient has had multiple years of AI therapy, before I consider what treatment to give them in the second-line setting, it may be important to repeat that molecular testing and understand whether an ESR1 mutation or any other actionable molecular targets may have emerged in that time. Because doing serial tissue sampling is sometimes a challenge, we’re all glad we now have liquid biopsies or circulating tumor DNA assays readily available that we can use when repeat tissue sampling may be more complicated or cumbersome for a patient. I consider that in my practice.

In that second-line treatment setting, the questions I’m asking myself are: Do [the patients] have an activating PI3K mutation? Do they have evidence of an AKT1 molecular alteration or PTEN loss that may make them a candidate for capivasertib? Do they have an ESR1 mutation? If the patients have wild type [disease] for all those [mutations], if we’re still using endocrine therapy in the second-line treatment setting, we are often using combinations such as fulvestrant and everolimus [Afinitor], an mTOR inhibitor which can be administered regardless of the molecular profile of the tumor. However, if [a patient has] a targetable molecular alteration, for instance a PI3K mutation, I consider combining endocrine therapy, usually fulvestrant, with either alpelisib or capivasertib and I always think about the possibility of a clinical trial. If there are novel PI3K or AKT inhibitors and we have a trial available based on those molecular alterations, that’s the other consideration.

What are the notable safety concerns associated with PI3K inhibitors and AKT inhibitors and how do they impact clinical decision-making?

With both PI3K inhibitors and AKT inhibitors we have seen patients experience a fair amount of toxicity. Most notably, especially with the PI3K inhibitors which we have the most familiarity with because they’ve been FDA approved for some time, is a concern about hyperglycemia. Patients [may develop] elevated blood sugars or type 2 diabetes because of [receiving] these medications, and [oncologists need] to stay vigilant in monitoring glucose [levels] so patients are promptly started on medication that can lower their blood sugar if that becomes an issue throughout treatment.

With that same class of inhibitors, we’ve also seen a fair amount of dermatologic reactions that patients experience [including] rashes and stomatitis. Particularly with everolimus which we use if patients do not have a targetable alteration identified by next-generation sequencing [NGS] analysis, we’ve gained a lot of familiarity with managing stomatitis; use of a steroid mouth rinse has helped us manage that adverse effect [and we should use the mouth rinse] prophylactically so we’re not we’re not trying to play catch up after the fact if patients develop stomatitis. These drugs are challenging to tolerate. As we use them more, I am hoping we also get better at managing their toxicities.

What data support the use of CDK4/6 inhibitors in the second-line HR-positive, HER2-negative metastatic breast cancer setting?

A couple trials have investigated continuing a CDK4/6 inhibitor in the second-line setting after receipt of a CDK4/6 inhibitor for first-line treatment of metastatic disease. The MAINTAIN clinical trial primarily evaluated a patient population that received palbociclib [Ibrance] as an initial CDK4/6 inhibitor and then in the second-line treatment setting, when they were switching endocrine therapy, switched to ribociclib. That [regimen] was compared with endocrine therapy alone.

[MAINTAIN] demonstrated that using an alternative CDK4/6 inhibitor such as ribociclib [in the second-line setting] appeared to have a benefit over endocrine therapy alone. Some data support that this may be a useful treatment strategy. However, I’m not doing this routinely as something standard in the vast majority of my patients.

I am thinking about whether it may be appropriate to continue a CDK4/6 inhibitor after a prior CDK4/6 inhibitor. I’m considering this in the patients who tolerated a CDK4/6 inhibitor well and in those [for whom] I have significant concern that they will not be able to handle the toxicities of some of these other targeted inhibitors due to comorbid medical conditions or maybe being more advanced in age or frail. [I would also consider this treatment strategy] for patients who try those other targeted inhibitors and [for whom the treatment] doesn’t go well because of the toxicity.

What novel and emerging endocrine therapy-based treatments are on the horizon for patients with HR-positive, HER2-negative metastatic disease?

We’ve started to see [results with] novel endocrine therapies presented at meetings such as the San Antonio Breast Cancer Symposium and the American Society of Clinical Oncology Annual Meeting. A compound we’ve used in clinical trials at the University of Michigan, as well as at many other places across the country, is ARV-471 a proteolysis targeting chimera [PROTAC] protein degrader. This is a novel mechanism of anti-estrogen therapy.

The early results we have seen from the study [with ARV-471] as a single agent were promising, even in patients who were heavily pretreated. Now we are starting to see ARV-471 used in combination with other standard targeted inhibitors such as CDK4/6 inhibitors and PI3K inhibitors. We’re awaiting trial data to see where [PROTACs] may be appropriately used in the treatment algorithm.

We will also continue to see more oral SERDs. We’ve already seen data for several [SERD] compounds beyond elacestrant, which has an FDA approval. Seeing these drugs in combination [regimens] is critically important for understanding how we can best use them because it is now rare that we are using single-agent endocrine therapy. We are awaiting more trial data with the combination therapies.

How does molecular testing factor into treatment decisions beyond the frontline setting?

In the second- and third-line endocrine therapy settings, using molecular profiling wisely has now become critically important for selecting the therapy for patients that would be most likely to result in clinical benefit. Sometimes now we have to consider the timing of when we pursue that molecular testing. We often have data from initial diagnosis of metastatic disease. However, if patients do incredibly well on AIs and CDK4/6 inhibitors in the first-line treatment setting, and many years elapse by the time we’re selecting appropriate second- and third-line therapies, it may be worthwhile to consider repeating molecular testing and NGS to best understand the features of the tumor at present so we can select appropriate therapy.


  1. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed April 26, 2024.
  2. Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: MAINTAIN trial. J Clin Oncol. 2023;41(24):4004-4013. doi:10.1200/JCO.22.02392
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