What’s Next? A Guide to Second-Line and Emerging Treatments for HR+/HER2- Metastatic Breast Cancer 
CancerBreast Cancer

What's Next? A Guide to Second-Line and Emerging Treatments for HR+/HER2- Metastatic Breast Cancer

What's Next? A Guide to Second-Line and Emerging Treatments for HR+/HER2- Metastatic Breast Cancer
Everyday Health
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Published on January 30, 2026
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Treatment for hormone receptor–positive (HR-positive)/HER2-negative metastatic breast cancer often starts with hormone therapy (tamoxifen or an aromatase inhibitor) and a CDK 4/6 inhibitor.

 But it doesn't always end there. At some point, you may need to switch treatments.

The growing number of options to manage HR-positive/HER2-negative metastatic breast cancer can offer reassurance and hope for the future. Learn which treatments are available now and which treatments are on the horizon, and find out how to determine whether a clinical trial is the right next step for you.

Looking Ahead to the Next Step

When to take the next step depends on your response to the first treatment. "The general rule is to stay on each therapy for as long as possible, as long as the disease is under control and quality of life is maintained," says Akshjot Puri, MD, a breast medical oncologist at Houston Methodist in Texas.

Doctors consider making a change when symptoms return, imaging tests like a computed tomography (CT) scan or positive emission tomography (PET) scan show that the cancer is progressing, or there are new areas of cancer, says Dr. Puri.

Another reason to switch is if you test positive for a gene mutation like ESR1 or PIK3CA. An ESR1 mutation makes breast cancer resistant to hormone therapy and CDK4/6 inhibitors.

 A PIK3CA mutation causes cancer cells to grow uncontrollably, which makes it more difficult to treat.

Genomic testing with a liquid or tissue biopsy can find the most effective targeted therapy for your cancer and its gene mutations.

 A liquid biopsy uses a simple blood test to look for signs of cancer cells or DNA in your blood, whereas a tissue biopsy involves taking a sample of tissue from the tumor, which will likely involve local anesthetic.

 Both of these tests give your doctor information that can help decide which therapy might work best for you.

Your goals and preferences are also considered in the decision. "There are several oral therapy options, and even the IV drugs have different schedules. Different drugs have different side effect profiles," Puri says. "Picking an option that is best suited for the patient is prudent."

Second-Line Options

There are a few options when hormone therapy and CDK4/6 inhibitors stop working. Which treatment comes next depends on how sensitive the cancer is to hormone therapy, and whether it has any gene mutations.

Selective Estrogen Receptor Degraders (SERDs)

In HR-positive breast cancer, estrogen attaches to receptors on the surface of cancer cells and helps them grow. SERDs block those receptors, which slows or stops cancer cell growth.

Fulvestrant (Faslodex) is a SERD that can be taken alone or in combination with other therapies, and can be used either as a primary or second-line treatment. It’s received as two injections, biweekly for the first month, and once a month after the first round of injections.

If you have an ESR1 mutation, you’ll likely hear about two specific SERD drugs. Up to 40 percent of people with HR-positive/HER2-negative metastatic breast cancer develop this mutation after receiving hormone therapy.

 The ESR1 gene makes estrogen receptors, and mutations in this gene allow breast cancer cells to grow without estrogen binding to the receptor. Blocking this receptor with a SERD weakens or destroys the receptor to stop or slow cell growth.

Two SERDs are approved to treat HR-positive/HER2-negative breast cancers with an ESR1 mutation:

  • elacestrant (Orserdu)
  • imlunestrant (Inluriyo)
These medicines are for people who have already taken at least one type of hormone therapy.

 They come as once-daily pills.
Giredestrant is a new SERD that isn't yet approved by the U.S. Food and Drug Administration (FDA), but it has shown promising results in studies for HR-positive/HER2-negative metastatic breast cancer, says Puri. Compared with people who took tamoxifen or aromatase inhibitors, people who took giredestrant were less likely to have cancer return.

 Giredestrant is taken orally.

PIK3CA Inhibitors

About 40 percent of HR-positive/HER2-negative breast cancers have a PIK3CA gene mutation.

 The PIK3CA gene holds the instructions for making a protein that helps cancer cells grow, divide, and survive. PIK3CA inhibitors block this protein.

Three PIK3CA inhibitors are approved for HR-positive/HER2-negative metastatic breast cancer:

  • alpelisib (Vijoice)
  • capivasertib (Truqap)
  • inavolisib (Itovebi)

These medicines come as once-daily pills.

Capivasertib also treats breast cancers with an AKT1 or PTEN gene mutation or both.

PIK3CA inhibitors are not recommended for people with diabetes, because high blood sugar is a possible side effect.

mTor Inhibitors

"If you don't have an ESR1 or PIK3CA mutation, you are going to use a drug that we've been using for ages, called everolimus," says Michelina Cairo, MD, a breast oncologist with Texas Oncology, Memorial City in Houston, and Gulf Coast Breast Research Coordinator.

Everolimus (Afinitor) belongs to a class of drugs called mTOR inhibitors.

 The mTOR protein helps control cell division. Blocking this protein prevents breast cancer cells from multiplying.
You might get this medicine after an aromatase inhibitor like letrozole (Femara) or anastrozole (Arimidex).

 Everolimus is usually given with an injectable SERD like fulvestrant.

PARP Inhibitors

Olaparib (Lynparza) and talazoparib (Talzenna) are PARP inhibitors used to treat HR-positive/HER2-negative metastatic breast cancers with a BRCA1 or BRCA2 gene mutation.

 BRCA mutations prevent cancer cells from repairing their damaged DNA. Breast cancer cells with this mutation instead use the PARP protein to fix DNA damage. PARP inhibitors prevent the cancer cells from repairing themselves, which causes them to die. They are taken by mouth as a pill.

Chemotherapy

This medicine kills fast-growing cells, including cancer cells, all over the body. Chemotherapy can be an option when hormone therapy and targeted drugs like CDK4/6 inhibitors stop working. While early-stage breast cancer is often treated with combinations of chemotherapy drugs, for metastatic breast cancer usually one drug is given at a time.

Chemotherapy drugs that treat HR-positive/HER2-negative metastatic breast cancer include:

  • capecitabine (Xeloda)
  • gemcitabine (Gemzar)
  • ixabepilone (Ixempra)
  • vinorelbine (Navelbine)
  • anthracyclines such as doxorubicin (Adriamycin) and epirubicin (Ellence)
  • platinum drugs (cisplatin, carboplatin)
  • taxanes like paclitaxel (Taxol) and docetaxel (Taxotere)

Immunotherapy

Immunotherapy boosts the immune system response to make it a more effective cancer fighter.

Antibody-Drug Conjugates

Antibody-drug conjugates contain a monoclonal antibody (a lab-made antibody that recognizes a specific target) linked to a chemotherapy drug.

 The monoclonal antibody locks onto a protein on the surface of the cancer cell and delivers the chemotherapy directly to the cell. This treatment is so precise at targeting cancer cells that it's sometimes called a "biological missile."
Examples of antibody-drug conjugates are:

  • fam-trastuzumab deruxtecan (Enhertu)
  • sacituzumab govitecan (Trodelvy)
  • datopotamab deruxtecan (Datroway)
Fam-trastuzumab deruxtecan treats HR-positive metastatic breast cancers that are HER2-low or HER2-ultralow.

 HER2-low and HER2-ultralow breast cancer cells contain much less HER2 protein than HER2-positive breast cancer cells. But they still have enough of this protein on their surface for the drug to latch onto.

Sacituzumab govitecan is for people with HR-positive/HER2-negative metastatic breast cancer who have taken hormone therapy, plus at least two other medicines (such as targeted therapy or chemotherapy).

Datopotamab deruxtecan is given after hormone therapy and chemotherapy stop working.

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors are a type of immunotherapy being investigated for HR-positive/HER2-negative metastatic breast cancer. These medications basically act like switches, turning on the immune system so that it can fight the cancer.

In early studies, immunotherapy wasn't very effective against HR-positive/HER2-negative metastatic breast cancer. In recent years, researchers have tried combining it with other medicines, such as chemotherapy, hormone therapy, and targeted treatments like AKT inhibitors and CDK 4/6 inhibitors, to see whether it might improve the outcome. Some of these combinations were somewhat successful, but adding another drug also increased side effects.

PD-1/PD-L1 inhibitors are one type of immune checkpoint inhibitor that has shown promise in recent studies for HR-positive/HER2-negative metastatic breast cancer.

 PD-1 is a protein on the outside of immune cells. When PD-1 binds to another protein, PD-L1, on the surface of cancer cells, it switches off the immune cell's attack on the cancer cell. PD-1/PD-L1 inhibitors block these proteins to help the immune system kill cancer cells.

Pembrolizumab (Keytruda) and nivolumab (Opdivo) are examples of PD-1/PD-L1 inhibitors.

Researchers still need to learn which tumors might respond best to which type of immunotherapy, and how to minimize side effect risks before this treatment can be approved for HR-positive/HER2-negative metastatic breast cancer.

 Many studies of immunotherapy drugs alone, and in combination with other medicines, are happening now. If you're interested in joining one of these trials, you can search ClinicalTrials.gov, or ask your oncologist to recommend a study.

Clinical Trials

Researchers study emerging treatments for HR-positive/HER2-negative metastatic breast cancer in clinical trials. Joining one of these studies could give you the chance to try a new treatment that isn't available to the public, says Puri.

Another benefit to joining a clinical trial is the opportunity to contribute to medical advancements and help future breast cancer patients. "Science moves forward quickly only because of our patients who are willing to try something new and different," Cairo says.

Understanding Clinical Trial Phases

Researchers conduct clinical trials in steps called phases. The study phase affects which drug you get.

 The investigational drugs used in phase 1 trials are in the early stage of development. Researchers don't have much information yet on their safety or effectiveness. "A phase 1 trial is generally reserved for patients who have tried multiple [treatments] before, and do not have many remaining options," Puri says.

Phase 2 trials show whether the new drug works. Usually all the participants get the study drug, says Puri.

Phase 3 trials include a few thousand people and compare the experimental drug with standard treatments. You'll either get the new drug or an FDA-approved treatment if you join.

Common Eligibility Criteria

In the past, clinical trials were one-size-fits-all. They enrolled very large groups of people with breast cancer. "Now the trials are becoming much more precise," Cairo says. Each study has specific criteria to determine who is and who isn't eligible to join. These criteria include:

  • Age
  • Gender
  • Cancer type and stage
  • Past treatments
  • Other medical conditions
Before you can join a study, the research team will ask you a series of questions to determine whether it is safe and appropriate for you.

 You may need to undergo additional testing to make sure you don’t have any other medical conditions that might interfere with the trial treatment. If one clinical trial isn't a good fit, you can try to enroll in another one.

Questions to Ask Your Doctor

Have a discussion with your oncologist and the clinical trial team so you can be a more informed participant. Here are some questions to ask.

  • What is the purpose of the study?
  • Why is it a good fit for me?
  • Has this treatment been tested before? What do you know about its safety and effectiveness?
  • What are the possible risks and side effects?
  • How long will the study take? How much time will I have to commit?
  • Who will pay for the treatments I receive during the trial?
  • Are there any other studies that might help me?

The Takeaway

  • The first treatment for HR-positive/HER2-negatie metastatic breast cancer is often hormone therapy plus a CDK 4/6 inhibitor.
  • A second-line treatment may be considered if the cancer starts to grow again or you test positive for a gene mutation like ESR1 or PIK3CA.
  • Second-line treatments include SERDs, PIK3CA inhibitors, everolimus, PARP inhibitors, and antibody-drug conjugates.
  • Joining a clinical trial is a way to try a new breast cancer treatment before it is approved.

Resources We Trust

EDITORIAL SOURCES
Everyday Health follows strict sourcing guidelines to ensure the accuracy of its content, outlined in our editorial policy. We use only trustworthy sources, including peer-reviewed studies, board-certified medical experts, patients with lived experience, and information from top institutions.
Resources
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Lisa Curcio, MD, is a board-certified general surgeon and a fellowship-trained surgical oncologist. She is currently the medical director of breast surgery at Northern Dutchess Hospital in Rhinebeck, New York. Dr. Curcio attended George Washington University Medical School in Washington, D.C., where she also completed a residency in general surgery. She was invited to fellowship training in cancer surgery at City of Hope National Medical Center in Duarte, California. She was the recipient of the competitive U.S. Air Force Health Professions Scholarship Program. During her military commitment, Dr. Curcio served in the military as chief surgical oncologist at Keesler Medical Center in Biloxi, Mississippi. 

From 2003 to 2004, she served as program director for Susan G. Komen in Orange County and remains involved with Komen outreach efforts. She was on the board of Kids Konnected, a nonprofit that helps children of cancer patients deal with the emotional fallout of a cancer diagnosis. Currently, she is on the board at Miles of Hope Breast Cancer Foundation, an organization dedicated to providing support services for people affected by breast cancer in New York's Hudson Valley. Dr. Curcio also has a strong background in breast cancer research, having contributed to dozens of peer-reviewed articles. She is currently a member of the Alpha Investigational Review Board.

Her practice includes benign and malignant breast diagnoses. Dr. Curcio was diagnosed with breast cancer at the age of 37. Although her fellowship training was in surgical oncology, this experience motivated her to provide compassionate, high level breast care and to focus on breast surgery.

Dr. Curcio is passionate about treating the patient and individualizing the care plan to their specific needs. Dr. Curcio strongly believes that cancer care must include lifestyle changes to focus on healthier habits to reduce future events. Her practice also focuses on breast cancer risk reduction, education, and access to genetic testing for patients with a family history of breast cancer.
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