Navigating Post-Progression Therapy in HR-Positive Metastatic Breast Cancer: What Pharmacists Need to Know Now

As CDK4/6 inhibitors have become the foundational first-line therapy for hormone receptor–positive metastatic breast cancer, oncology pharmacists are increasingly tasked with guiding patients and providers through a rapidly expanding and complex postprogression landscape. From the rise of ESR1-directed therapies and PI3K/AKT/mTOR pathway inhibitors to the growing role of antibody-drug conjugates, treatment decisions now hinge on molecular testing, prior therapeutic exposures, and patient-centered considerations. In this conversation at the Hematology/Oncology Pharmacy Association 2026 Annual Conference, Annalise Labatut, PharmD, BCOP, breaks down the latest evidence and offers practical insights to help pharmacists support thoughtful, individualized sequencing strategies.

Q: CDK4/6 inhibitors have become the standard first-line backbone for hormone receptor (HR)–positive metastatic breast cancer, which means the postprogression space is now one of the most common and consequential decision points oncology pharmacists encounter. How has the treatment landscape in this setting shifted most meaningfully in the past couple of years, and what’s driving the complexity in sequencing decisions today?

Annalise Labatut, PharmD, BCOP: This space is continuously evolving, which ultimately is a good thing. We have more options that we can offer our patients. That being said, we have many options to choose from, so there is a bit of a challenge in selecting what is best for the patient in the next-line setting. In recent years, we have had the introduction of 2 ESR1 inhibitors—imlunestrant [Inluriyo; Eli Lilly and Company] and elacestrant [Orserdu; Stemline Therapeutics, Inc]—and other medications that target the PIK3CA pathway, like alpelisib (Piqray; Novartis Pharmaceuticals Corporation), capivasertib (Truqap; AstraZeneca), and everolimus (Afinitor; Novartis Pharmaceuticals Corporation), which is reserved for the first-line setting.

Q: The question of whether to continue CDK4/6 inhibition beyond progression is one of the more heavily debated topics in this space. What does the current evidence tell us about which patients are most likely to benefit from a subsequent CDK4/6 inhibitor, and how should pharmacists be framing that conversation with the oncology team?

Labatut: This is a great question and something that comes up often. I agree that it is debated, and it may not be right for every patient. I think the first thing to keep in mind is that, regardless of which way you are doing this, retrying a CDK4/6 inhibitor after progression on initial CDK4/6 inhibition and endocrine therapy is off-label use.

There are 2 trials: MAINTAIN [NCT02632045], which evaluates ribociclib [Kisqali; Novartis Pharmaceuticals Corporation] and changing endocrine therapy, and postMONARCH [NCT05169567], which evaluates changing endocrine therapy to fulvestrant [Faslodex; AstraZeneca] and continuing or changing the CDK4/6 inhibitor to abemaciclib [Verzenio; Eli Lilly and Company]. Both postMONARCH and MAINTAIN have significant progression-free survival, but note that it is short durations, and compared [with] placebo, it is not a whole lot of extra time. Time is still time, and it might be right for a certain subset of patients—patients with bone-only metastases, patients who previously were on palbociclib (Ibrance; Pfizer Inc). Those patients tend to do a little better on those trial series or have slightly more meaningful progression-free survival.

That being said, there is also combination therapy, and I really think we are headed that way with imlunestrant in combination with abemaciclib. When a subgroup of patients on EMBER-3 (NCT04975308) were evaluated, many of those patients who had a previous CDK4/6 inhibitor, regardless of whether they had an ESR1 mutation, had a significant progression-free survival—around 9 months—compared with imlunestrant monotherapy. So now, when I am thinking about retrying a CDK4/6 inhibitor, I am most comfortable doing that in combination with an oral selective estrogen receptor degrader like imlunestrant because of the more robust data. That being said, all of this is off-label.

Q: With multiple targeted options available—including PI3K/AKT/mTOR pathway inhibitors and ESR1-directed therapies—how do you approach helping a team prioritize among them, particularly when molecular testing results are pending or unavailable?

Labatut: Ultimately, if you decide between a PI3K inhibitor, an AKT inhibitor, or an ESR1 inhibitor, you have to have that next-generation sequencing testing. You have to know what you are going to target to target it. But if nothing is available, there are options for no targetable mutation.

That is a situation where you could consider retrying a CDK4/6 inhibitor because also in the EMBER-3 approach, not all patients had an ESR1 mutation and still benefited. Patients without an ESR1 mutation still benefited from the combination of abemaciclib and imlunestrant. And on-label, we also have everolimus in combination with endocrine therapy, which is a great option if no targetable mutation is present.

Q: For the antibody-drug conjugate (ADC) being highlighted in your session, what key efficacy data should pharmacists be familiar with, and are there particular patient characteristics or treatment histories that make someone a stronger or weaker candidate for this agent?

Labatut: My session highlighted the use of trastuzumab deruxtecan (Enhertu; Daiichi Sankyo/AstraZeneca), or T-DXd, after progression on an initial CDK4/6 inhibitor and endocrine therapy. This is per the results of the DESTINY-Breast06 clinical trial, which evaluated patients who either had 2 or more lines of therapy or those who progressed on their initial CDK4/6 inhibitor in less than 6 months. Those are the patients who I really would consider this approach for, whether they are low or ultralow, which is more than 0% membrane staining up to 10%.

Q: ADCs carry distinct toxicity considerations that differ meaningfully from traditional chemotherapy and targeted agents. What are the most clinically significant adverse effects pharmacists need to anticipate, and how does proactive monitoring or dose modification support better patient outcomes?

Labatut: Things to consider are that it is a transition to intravenous [IV] therapy. It is highly emetogenic, so both of those are important counseling points, and patients may not be ready for that step from endocrine therapy. But who I am thinking of for it in my practice are patients with more aggressive disease who likely have primary endocrine therapy resistance, who were on their CDK4/6 inhibitor for a short amount of time, and have more aggressive disease.

I will talk about the 3 ADCs that we use in breast cancer after a CDK4/6 inhibitor. Right after that, we have T-DXd available to us, but later down the line, we also have sacituzumab govitecan (Trodelvy; Gilead Sciences, Inc) and datopotamab deruxtecan.

As far as [adverse]-effect profiles, keep in mind that for T-DXd, you have to monitor for interstitial lung disease [ILD], which we can do when a patient gets scans. But it is also important that a patient is educated on what to look out for—signs and symptoms of ILD, such as shortness of breath while resting and dry cough—and involve a multidisciplinary approach if the patient does end up developing ILD and initiate steroids, if appropriate, for symptom management and treatment.

Additionally, all these ADCs in this space are considered highly emetogenic, so [it’s important to make] sure the patient understands the appropriate antiemetic regimen they need to take to best manage their nausea and [escalate] that further if needed.

With sacituzumab govitecan, we do see more significant neutropenia. We might want to consider primary growth factor prophylaxis support if they meet other high-risk criteria, [such as] a history of neutropenia, advanced age, or other comorbidities. I do find [that] often in practice, we do not use it in the primary setting; we might have to add on granulocyte colony-stimulating factor (G-CSF) in the secondary setting after their counts have dropped.

And datopotamab deruxtecan has some unique toxicities as well, specifically ocular toxicity. Patients are supposed to use a preservative-free lubricant eye drop 4 times daily while on treatment and avoid contact lens use. There is also mucositis risk, and good oral hygiene and a prophylactic corticosteroid mouth rinse are vital.

Q: This patient population often lives with metastatic disease for years across multiple lines of therapy, which makes patient preferences, quality of life, and treatment burden especially relevant. What strategies do you find most effective for pharmacists to meaningfully contribute to shared decision-making in this setting, beyond simply reviewing medications?

Labatut: I think one of the most important things is to get to know the patient. What gives them a good quality of life? What do they enjoy? And are any of those things going to change due to the [adverse] effects of the treatment that we start? Of course, also: What are their comorbidities, their previous treatments, and how long were they on their initial CDK4/6 inhibitor? Those are all clinical things that we can contribute.

But I also think it is meaningful to meet the patient where they are, talk to them about options if you have multiple options on the table, and determine whether you are able to target multiple pathways—or whether there is one that you should do first based on the patient’s preference or [adverse]-effect profile.