Endocrine Therapy Plus Targeted Agents in MBC: Balancing Toxicity, Cost, and Efficacy

Medscape recently interviewed Erica L. Mayer, MD, MPH, director of clinical research in the Breast Oncology Center at the Dana-Farber Cancer Institute, an institute physician at Dana-Farber, and an associate professor of medicine at Harvard Medical School, Boston, Massachusetts, to gain her insight on adding targeted agents to endocrine therapy (ET) for hormone receptor–positive, human epidermal growth factor 2–negative (HR+/HER2-) metastatic breast cancer (MBC).

Endocrine therapy remains the mainstay of treatment for patients with HR+/HER2- MBC. What targeted agents can be added to ET in this patient population?

Historically, the backbone of treatment for patients with metastatic HR+/HER2-disease is to give an ET-based therapy designed to block the body's hormones from potentially stimulating cancer cells. Increasingly over the past decades, we have seen the expansion of targeted partners for the endocrine agents that, through a number of randomized trials, have demonstrated improved disease control and patient outcomes. The targeted medicines that we primarily use as a first approach are the cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including ribociclib, abemaciclib, and palbociclib. We know from multiple randomized studies that the addition of a CDK4/6 inhibitor to ET improves not only progression-free survival but also overall survival.

Right now, a multitude of options can be used following cancer progression while receiving a CDK4/6 inhibitor combined with ET. One approach includes targeting a signaling pathway in cancer cells that includes protein kinase B (AKT), phosphatidylinositol 3-kinase (PI3K), and mammalian target of rapamycin (mTOR). This cascade of signals becomes especially important when cancers become resistant to hormone therapies. We have several agents designed to target that pathway. The first agent approved was everolimus, which targets mTOR, followed by the approval of alpelisib, which targets a mutated PI3 kinase enzyme which is found in about 40% of tumors.

The newest agent inhibiting this pathway is capivasertib, which targets AKT. The randomized CAPitello-291 trial enrolled patients with metastatic HR+/HER2- breast cancer after progression on an aromatase inhibitor (AI), with the majority having prior CDK4/6 inhibitor exposure. Findings from the trial, presented at the December 2022 San Antonio Breast Cancer Symposium, showed that when added to the selective estrogen receptor degrader (SERD) fulvestrant, capivasertib improved outcomes compared with the fulvestrant alone — independent of whether there was an alteration in the signaling pathway. We might see regulatory approval of capivasertib in combination with fulvestrant later this year. So, we have several approaches that can be used after disease progression on a CDK4/6 inhibitor.

Another area of great interest is the development of oral SERDs. One type of SERD, fulvestrant, has been available for many years but has limited bioavailability and therefore needs to be given intramuscularly. Novel oral SERDs are the next-generation version of this type of drug. We have now seen the first of these drugs approved, elacestrant, an oral SERD that shows its greatest benefits in tumors with an estrogen receptor 1 (ESR1) mutation — a dynamic mutation that forms over time and is associated with resistance to some forms of ET. ESR1 mutations are less common when a patient is first diagnosed with breast cancer but become more common during ET. A number of other oral SERDs with a variety of mechanisms of action are currently in clinical trials, both as monotherapy and in combination with a targeted agent. There really is a rich pipeline of different drugs in development for the treatment of metastatic HR+ disease.

Are CDK4/6 inhibitors added to ET only after disease progression?

Technically, in the advanced disease setting, CDK4/6 inhibitors are approved in the first-line or pretreated setting in combination with an endocrine partner. However, in practice, and according to international guideline recommendations, the majority of patients will receive a CDK4/6 inhibitor as part of the initial regimen for metastatic disease. A CDK4/6 inhibitor is also available in the adjuvant setting for patients with higher-risk early HR+/HER2- breast cancer, with a second CDK4/6 inhibitor already showing positive results as treatment for early-stage disease.

Can alpelisib and everolimus be given in the first-line setting?

These agents were studied as strategies to use in the setting of endocrine resistance and are generally used as second-line or later-line therapy for patients with pretreated disease. Sequencing considerations (in what order to give therapy) are driven by relative effectiveness as well as side-effect considerations. The usual approach for patients with newly diagnosed HR+ MBC is to treat with an endocrine agent and CDK4/6 inhibitor. If the disease progresses, patients would go on to receive one of the other combination regimens previously mentioned.

How do you balance toxicity, cost, and efficacy of CDK4/6 inhibitors?

Decisions about which therapies to recommend to patients with breast cancer are typically built around efficacy and tolerability goals. For patients with MBC, we always want to maximize the efficacy of the recommended regimen while maintaining and hopefully improving quality of life (QOL). So, the selection and administration of a treatment regimen should attempt to minimize any side effects that could be introduced with the medications offered. The majority of hormone medicines given to breast cancer patients are well tolerated, and there is great interest in developing targeted agents in a way that minimizes toxicity and preserves or improves QOL.

There are a range of side effects associated with targeted agents. However, these effects can often be anticipated and prevented with prophylactic medicines and close monitoring, especially at the initiation of treatment, as some patients may need dose adjustments to make treatment more tolerable. But the overall goal is to reach a dose and schedule of these medicines that maintains their effectiveness with the least amount of side effects possible to maximize QOL.

Can you go into more detail about the adverse effects and events associated with adjuvant treatments, particularly with CDK4/6 inhibitors?

Side effects of palbociclib and ribociclib include neutropenia, and blood counts should be monitored at baseline and during treatment. Patients receiving ribociclib also require a series of ECGs at the time of initiation to monitor cardiac function. Abemaciclib is less likely to cause neutropenia but is more likely to cause diarrhea, particularly when the drug is started. For the first few weeks of treatment, patients are encouraged to monitor closely for any diarrhea and treat it aggressively with antidiarrheal agents. After the first few weeks of treatment, diarrhea is generally easier to control due to dose reduction or use of preventive antidiarrheal therapies. All CDK4/6 inhibitors can cause small mouth sores and thinning of hair, as well as fatigue.

Side effects of alpelisib include rash, hyperglycemia, and diarrhea. Prophylactic treatment with antihistamines and antihyperglycemics can prevent significant toxicity with this agent.

Another example of how knowledge of common side effects may be employed to use prophylactic therapies for prevention is seen with everolimus. Some patients taking everolimus develop stomatitis; however, treatment with a prophylactic steroid mouthwash, particularly when starting the drug, can substantially reduce this side effect. Similarly, nonsedating antihistamines may reduce rash seen with several targeted agents, such as alpelisib.

Fatigue is a side effect common to all CDK4/6 inhibitors. If any side effect becomes too impactful, a modest dose reduction can reduce toxicity while maintaining efficacy.

As a hormone medicine, the new oral SERD elacestrant tends to be very well tolerated. Common side effects include nausea, vomiting, diarrhea, constipation, muscle and joint pain, headaches, and hot flushes. Albeit rare, serious side effects include hypercholesterolemia (Grade 3) and hypertriglyceridemia (Grade 4). Capivasertib, while not yet approved, was associated with rash and diarrhea but with less hyperglycemia than has been seen with PI3K inhibitors in the CAPitello-291 trial. Other studies found capivasertib to have a safe and tolerable profile with no adverse events associated with its use (eg, sudden death, torsades de pointes, seizures, ECG changes). Experiences with this agent in larger populations of patients will help better define the side-effect profile with precision.

Regardless of the systemic therapy selected, patients should be encouraged to communicate closely with the provider team, report any symptoms, and follow directions regarding dose changes or use of prophylactic medicines. Doing so is extremely helpful in early identification of side effects and helps to prevent them from becoming a more significant issue.

How do you choose between abemaciclib and ribociclib for a particular patient? Do you discuss the side effects of each drug to determine patient preference?

Selection of agents should be an open conversation between patient and provider. Part of the discussion should include a review of the available supportive data, drug schedule, and side-effect profile for each agent. For some patients, one or another side effect may be particularly worrisome or bothersome or perhaps something that they have had trouble with before. For example, if a patient tends to have diarrhea, an agent like abemaciclib may be less preferable. There are also situations where a patient may have had exposure to one of these medicines earlier on in their breast cancer treatment and, in those situations, we may not want to repeat the medicine. Drug selection is very personalized, considering a patient's breast cancer treatment course, tolerance of any prior medicines, and of course, patient preference.

What is the efficacy of alpelisib and everolimus? Are there differences in efficacy?

Regarding efficacy, alpelisib and everolimus are both highly active. Established clinical trial data support the use of both agents in the appropriate clinical settings. Since alpelisib showed activity only in patients whose tumors had activating mutations in PIK3CA, this drug should only be given if tumors are found to have this mutation. Based on clinical trial data, everolimus appears to be effective independent of the PIK3CA status.

Is the efficacy of capivasertib similar to that of alpelisib and everolimus?

These agents have not been compared head-to-head, and the trials for each agent enrolled patients at different time periods and practice patterns. We do know that the recent phase 3 CAPitello-291 study of patients previously treated with CDK4/6 inhibitors found that capivasertib plus fulvestrant significantly improved progression-free survival compared with fulvestrant monotherapy. That positive data support offering capivasertib to patients when the drug becomes available through regulatory approval. But we do not have direct comparison data, and it would be inappropriate to compare the registration trials for the three agents.

What other emerging agents are on the horizon as an add-on to ET for patients with MBC?

In addition to the AKT inhibitor capivasertib, many other agents are under investigation. The next-generation PI3 kinase inhibitors in development have shown greater precision targeting against PI3K alterations with possibly fewer side effects. As previously mentioned, elacestrant is the first of the oral SERDs approved. Other oral SERDs and other agents targeting the estrogen receptor are in development to treat metastatic disease or as adjuvant therapy. We anticipate data from all of those efforts in the next few years that potentially will result in other new drugs that will move toward approval and availability for our patients, with the goal of improving therapeutic options and efficacy.

Disclosures: Erica L. Mayer, MD, MPH, has disclosed that she is a consultant for Novartis, Lilly, Gilead, AstraZeneca, and Diaccurate.

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Image 1: Erica L. Mayer, MD, MPH

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Cite this: Endocrine Therapy Plus Targeted Agents in MBC: Balancing Toxicity, Cost, and Efficacy - Medscape - Jun 28, 2023.