Secondary (Metastatic) HR+ Breast Cancer: Your Treatment Options

Two women holding hands

If you have been diagnosed with secondary (metastatic, advanced) hormone receptor positive (HR+), HER2 negative breast cancer, this blog explains the treatments used today, how genomic testing can guide your options, and the newer treatments and clinical trials shaping what comes next. It is written for people already living with advanced HR+ breast cancer and anyone supporting them, and it focuses on what each treatment is for and where it fits, rather than on jargon.

Nearly a third of people diagnosed with earlier stages of breast cancer will eventually develop advanced disease1. Many people are living well with secondary breast cancer for a long time, yet it can feel left out of breast cancer awareness. Research has shown that people with advanced breast cancer often feel isolated, and 67% feel that no one understands what they are going through2. Understanding your options can help you feel more in control and have clearer conversations with your care team.

Key takeaways

  • Secondary (metastatic, stage IV) HR+, HER2 negative breast cancer is usually treated first with hormone (endocrine) therapy combined with a CDK4/6 inhibitor.
  • If the cancer stops responding, genomic testing looks for changes such as ESR1, PIK3CA, AKT1, PTEN and BRCA that can open up more targeted treatments.
  • On the NHS in England, options after hormone therapy include elacestrant for an ESR1 mutation, and capivasertib or alpelisib with fulvestrant for a PIK3CA, AKT1 or PTEN change.
  • Several newer options (such as imlunestrant, vepdegestrant, inavolisib and gedatolisib) are approved in the US and are being reviewed by regulators elsewhere, so what is available depends on where you live.
  • Antibody-drug conjugates (ADCs) are expanding the choices after hormone-based treatment, and clinical trials continue to change the picture.
  • Keeping a record of your symptoms and treatments in the OWise app can help you notice changes early and make the most of every appointment.

In this article

  • What is secondary HR+, HER2 negative breast cancer?
  • First-line treatment: hormone therapy plus a CDK4/6 inhibitor
  • Why do some cancers stop responding to hormone therapy?
  • Genomic testing: looking for changes in the cancer
  • Treatment if an ESR1 mutation is found
  • Treatment if a PIK3CA, AKT1, PTEN or BRCA change is found
  • Treatment if no targetable mutation is found
  • Antibody-drug conjugates (ADCs)
  • Chemotherapy
  • When breast cancer spreads to the bones or brain
  • Clinical trials shaping what comes next
  • Questions to ask your care team

What is secondary HR+, HER2 negative breast cancer?

Secondary breast cancer (also called advanced, metastatic or stage IV)  is a breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body.

Hormone receptor positive (ER positive), HER2 negative means the cancer cells grow in response to the hormones oestrogen and progesterone, but not in response to the HER2 protein. If your cancer is HER2 positive, read our guide to HER2 positive breast cancer instead.

Although it is possible to be diagnosed with secondary breast cancer from the outset (called de novo metastasis), it is more common to develop it after previously being treated for a localised breast cancer. One study that followed around 60,000 women with ER positive localised breast cancer found that even some people with lower risk disease (tumours under 2 cm, lymph node negative) can develop secondary cancer, and that a risk of recurrence remains even after five years of hormone therapy3. This is why understanding drug resistance, managing side effects so treatment can continue, and responding well to therapy all matter so much.

“Something to look forward to is what everyone does. You might have to scale it back from not looking forward to something that is in five years time, but if you can look forward to something that is in three weeks and something that is in three months, and dare to plan it and dare to believe you be able to enjoy it and you will, you will be able to”6 Diane, secondary breast cancer patient

First-line treatment: hormone therapy plus a CDK4/6 inhibitor

For most people with secondary HR+, HER2 negative breast cancer, treatment usually starts with hormone (endocrine) therapy combined with a CDK4/6 inhibitor. The aim of hormone therapy is to lower oestrogen levels or block oestrogen from reaching the cancer cells, since oestrogen is the main signal driving HR+ cancer to grow. These treatments can control secondary breast cancer for long periods and are usually offered first.

First line therapy refers to the first treatment given for a disease. If this doesn’t cure the disease or causes severe side effects, then second line therapy would be given, and so forth.

Hormone (endocrine) therapy

Hormone therapy for secondary HR+ breast cancer may include:

  • Aromatase inhibitors such as anastrozole (Arimidex®), letrozole (Femara®) or exemestane (Aromasin®). Aromatase is a protein that converts androgens into oestrogen in fat, liver, muscle and other cells. Blocking it lowers oestrogen levels. Aromatase inhibitors are used in people who are postmenopausal and improve progression-free survival compared with tamoxifen5.
  • Ovarian suppression for people who are premenopausal, using drugs such as goserelin (Zoladex®) or by surgically removing the ovaries, which lowers the oestrogen made by the ovaries.
  • Tamoxifen, which binds directly to the oestrogen receptor on cancer cells and reduces oestrogen activity. It is recommended alongside ovarian suppression for men and premenopausal women6. Read more in our guide to tamoxifen and aromatase inhibitors.

Diagram explaining aromatase inhibitors

Diagram showing how tamoxifen works

CDK4/6 inhibitors

CDK4/6 inhibitors are oral drugs that block two proteins, CDK4 and CDK6, which help cancer cells divide. Blocking them can slow or stop cancer growth. Abemaciclib (Verzenios® in UK/EU or Verzenio® in the US), palbociclib (Ibrance®) or ribociclib (Kisqali®), given alongside an aromatase inhibitor, are recommended as a first-line treatment for previously untreated secondary breast cancer7. Clinical trials have shown that adding a CDK4/6 inhibitor improves survival compared with an aromatase inhibitor alone8.

Palbociclib and ribociclib are usually given with a seven-day break each cycle to let white blood cell levels recover, as they can lower these immune cells. Abemaciclib can be given continuously, but fatigue and diarrhoea are common. Your team may also check your liver and heart function9. Monitoring often happens around every three months to check how well treatment is working and to manage side effects.

iPhoneXS Trends - FatigueStarting a CDK4/6 inhibitor and not sure which side effects to expect, or whether they are settling? Track fatigue, diarrhoea and more than 30 other symptoms day by day in the free OWise app, so you can show your care team exactly what you are experiencing and when it started. Clearer information helps them adjust your treatment and keep you on it.

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Why do some cancers stop responding to hormone therapy?

Most HR+ breast cancers respond well to hormone therapy at first, but some become resistant over time. Cancer cells can change and find alternative ways to grow, so they may no longer depend on oestrogen. One well-understood mechanism involves the oestrogen receptor itself: mutations in the ESR1 gene (which carries the instructions for the oestrogen receptor) can develop after treatment with an aromatase inhibitor and make that treatment stop working10. Our guide to hormone therapy resistance explains this in more detail. When resistance develops, genomic testing can help find out what is driving it.


Diagram showing drug resistance

Genomic testing: looking for changes in the cancer

Genomic testing looks for changes in the cancer that may affect how it grows, responds to treatment or develops resistance. It is worth being clear about two different kinds of test. Tumour (somatic) genomic testing looks at changes that have appeared in the cancer itself, sometimes using a tissue sample and sometimes using a blood test that detects cancer DNA (a liquid biopsy). Genetic (germline) testing looks for inherited changes you were born with, such as BRCA1 or BRCA2. Some of the key changes your team may look for are:

Which tests are offered, and when, varies between hospitals and countries, and testing on the NHS continues to evolve. If your current treatment stops working, it is worth asking your oncologist what genomic or molecular testing might be suitable for you and what it could mean for your options. Our hormone therapy resistance guide covers testing for ESR1 and other changes in more depth.

Want to understand what your test results mean for your own treatment? Answer a few questions in the OWise app to get personalised, reliable information about your diagnosis, and keep your results, appointments and notes together in one place so nothing gets lost between visits. Get the free OWise app

Treatment if an ESR1 mutation is found

If an ESR1 mutation is found, treatments that target and break down the oestrogen receptor may be considered. These are known as selective oestrogen receptor degraders (SERDs).

  • Elacestrant (Orserdu® in the US, Korserdu® in the UK and EU) is an oral SERD for advanced HR+, HER2 negative, ESR1-mutated breast cancer that has already been treated with hormone therapy. In England it is available on the NHS for an ESR1 mutation11. A test is used to identify the ESR1 mutation.
  • Imlunestrant (Inluriyo®) is an oral SERD for ESR1-mutated disease after at least one line of hormone therapy. In the EMBER-3 trial, people with an ESR1 mutation on imlunestrant went a median of 5.5 months without the cancer growing, compared with 3.8 months on standard hormone therapy12. It is approved in the US and is being reviewed by NICE.
  • Vepdegestrant (Veppanu®) is a newer type of oral treatment (a PROTAC oestrogen receptor degrader) for ESR1-mutated advanced HR+, HER2 negative breast cancer after previous hormone therapy. It is approved in the US.
  • Camizestrant is a next-generation oral SERD studied in the SERENA-6 trial, where blood tests were used to spot an emerging ESR1 mutation early while on an aromatase inhibitor and a CDK4/6 inhibitor. Switching to camizestrant (with the same CDK4/6 inhibitor) delayed progression to 16.6 months, compared with 9.2 months for staying on the aromatase inhibitor combination13. A European regulator committee (the CHMP) recommended it for approval in May 2026, so European availability was following, while the US decision was still under review.

Treatment if a PIK3CA, AKT1, PTEN or BRCA change is found

Different changes point to different targeted treatments, usually given alongside the SERD fulvestrant.

  • Alpelisib (Piqray®) with fulvestrant is for cancers with a PIK3CA mutation after progression on hormone therapy. It targets the PI3K protein, which around 40% of HR+, HER2 negative cancers rely on14. In England it is available on the NHS through the Cancer Drugs Fund for a PIK3CA mutation15.
  • Capivasertib (Truqap®) with fulvestrant is for cancers with a PIK3CA, AKT1 or PTEN change after progression on hormone therapy. It blocks the AKT pathway. In the CAPItello-291 trial, people with these changes went a median of 7.3 months without progression on capivasertib and fulvestrant, compared with 3.1 months on fulvestrant alone16. It is available on the NHS in England for a PIK3CA, AKT1 or PTEN change17.
  • Inavolisib (Itovebi®) with palbociclib and fulvestrant is for certain hormone-resistant cancers with a PIK3CA mutation. In the INAVO120 trial, people on this combination went a median of 15 months without progression, compared with 7.3 months for palbociclib and fulvestrant with a placebo18. It is approved in the US and is currently being reviewed by NICE.
  • Olaparib (Lynparza®) or talazoparib (Talzenna®), known as PARP inhibitors, can be offered to people with an inherited BRCA1 or BRCA2 mutation. Read more in our guide to BRCA gene mutations.

Treatment if no targetable mutation is found

If no targetable change is found, hormone-based treatment continues with fulvestrant, often alongside a targeted treatment.

  • Fulvestrant (Faslodex®) is an injectable SERD that attaches to oestrogen receptors and breaks them down, reducing the signals driving HR+ cancer growth. It is often used as a second-line or later treatment, usually combined with a targeted treatment such as a CDK4/6 inhibitor, alpelisib, capivasertib, inavolisib with palbociclib, everolimus or gedatolisib.
  • Everolimus (Afinitor®) blocks the mTOR protein, which affects how cells grow and divide. It can be used after earlier hormone-based treatments stop working, combined with hormone therapy such as exemestane or fulvestrant19.
  • Imlunestrant (Inluriyo®) with abemaciclib (Verzenios® for UK/EU and Verzenio® for US) is an oral SERD and CDK4/6 inhibitor combination listed in US guidelines as an option after progression, including for some cancers without an ESR1 mutation.
  • Gedatolisib (Revtorpyk®) with fulvestrant, with or without palbociclib, is a combined PI3K and mTOR inhibitor for HR+, HER2 negative secondary breast cancer without a detected PIK3CA mutation, after progression on hormone therapy. It was approved in the US in July 202620. In the VIKTORIA-1 trial, people on gedatolisib, palbociclib and fulvestrant went a median of 9.3 months without progression, compared with about 2 months on fulvestrant alone21.

Antibody-drug conjugates (ADCs)

Antibody-drug conjugates are a highly targeted class of treatment made of a monoclonal antibody linked to a chemotherapy drug, a little like a smart chemotherapy. The antibody homes in on a target on the cancer cell so the chemotherapy is delivered directly to it, reducing the effect on healthy cells.

  • Datopotamab deruxtecan (Datroway®) targets the TROP-2 protein and can be a second-line option for secondary HR+, HER2 negative breast cancer. In the TROPION-Breast01 trial, people on it went a median of 6.9 months without progression, compared with 4.9 months on chemotherapy22. It is approved in the US and EU.
  • Trastuzumab deruxtecan (Enhertu®) links the antibody trastuzumab to chemotherapy and can be an option for HR+, HER2-low breast cancer. In DESTINY-Breast06, people on it went a median of 13.2 months without progression, compared with 8.1 months on standard treatment23. It is approved in the US and EU (an earlier HER2-low use, after chemotherapy, is also approved). Read our guide to trastuzumab deruxtecan.
  • Sacituzumab govitecan (Trodelvy®) links the antibody sacituzumab to the chemotherapy drug SN-38 and also targets TROP-2. It can be a later-line option for secondary HR+, HER2 negative breast cancer, based on the TROPiCS-02 trial24. It is approved in the US and EU.

A newer TROP-2 ADC, sacituzumab tirumotecan (Sac-TMT), is being studied in heavily pre-treated patients in the OptiTROP-02 trial, where it delayed progression compared with chemotherapy. It is not yet approved for this use, and it is not yet clear where a further ADC will fit in the treatment sequence.

Chemotherapy

Chemotherapy may be used when hormone-based treatments are no longer controlling the cancer, or when a faster response is needed. Common regimens recommended in the UK include a taxane (paclitaxel, nab-paclitaxel or docetaxel) and, in some situations, an anthracycline (such as doxorubicin or epirubicin). For people who cannot have anthracyclines, docetaxel is often offered first, followed by vinorelbine or capecitabine7. After two or more chemotherapy regimens, the chemotherapy drug eribulin may be recommended; its most common side effects include hair loss, nausea, low white cell counts, fatigue and numbness or tingling7.

When breast cancer spreads to the bones or brain

Bone metastases

If breast cancer spreads to the bones, treatments can help prevent fractures and other bone problems and manage pain. Bisphosphonates such as zoledronic acid (Zometa®) and ibandronate (Bondronat®) act on the cells that break down old bone, making bones denser and less likely to fracture2526. Denosumab is a monoclonal antibody that can be offered instead. It targets a protein that controls the bone-breakdown cells, is given as an injection under the skin, and has been found to delay skeletal problems for longer than bisphosphonates with fewer kidney side effects25.

Brain metastases

Whole-brain radiotherapy may be offered to people with a single or a small number of brain metastases where surgery is not suitable27.

Pain relief

Effective pain relief is available and is usually built up in steps, from milder to stronger as needed. Morphine-based pain relief can be taken as tablets, patches or injections under the skin, and works for many types of pain28. Common side effects include sleepiness, constipation and nausea, and it is not legal to drive while taking it (though the rules differ in Scotland)29. Other medicines, including anti-inflammatory drugs and some antidepressant or anti-epilepsy drugs, are also used to help manage particular kinds of pain.

Clinical trials shaping what comes next

Treatment for secondary HR+ breast cancer is changing quickly, and clinical trials are a big part of why. A few recent trials give a sense of where treatment is heading:

  • VIKTORIA-1 tested gedatolisib with fulvestrant, with or without palbociclib, in cancers that stopped responding to an aromatase inhibitor and a CDK4/6 inhibitor. It supported the US approval of gedatolisib for cancers without a PIK3CA mutation.
  • EVeRa tested giredestrant (a SERD) with everolimus. People with an ESR1 mutation went a median of 9.99 months without progression, compared with 5.45 months on standard treatment. The FDA is reviewing giredestrant with everolimus for ESR1-mutated ER+ breast cancer, with a decision expected in December 2026.
  • SERENA-6 tested switching to camizestrant when a blood test picked up an emerging ESR1 mutation, before the cancer had visibly progressed (see above).
  • ELEVATE tested elacestrant combined with everolimus or with abemaciclib. People went a median of 8.3 months (with everolimus) or 14.3 months (with abemaciclib) without progression, in tumours with and without an ESR1 mutation, suggesting potential non-chemotherapy options after CDK4/6 inhibitors.
  • OptiTROP-02 tested the TROP-2 ADC sacituzumab tirumotecan against chemotherapy in heavily pre-treated patients (see above).

Whether any of these becomes available to you depends on approvals and funding where you live, and on your individual situation. If you are interested in a trial, your oncologist can tell you what might be suitable.

Questions to ask your care team

Use the OWise app to create your own question lists and add the questions below to make sure you cover everything you need:

  • Which subtype of breast cancer do I have, and is it hormone receptor positive and HER2 negative?
  • What is my first-line treatment, and would a CDK4/6 inhibitor be part of it?
  • If my current treatment stops working, would genomic or molecular testing (including a blood test) be useful for me?
  • Have I been tested for ESR1, PIK3CA, AKT1, PTEN or a BRCA change, and would any of these change my options?
  • Are there treatments I could have on the NHS that we have not tried yet, and are any only available privately or in a trial?
  • Could a clinical trial be suitable for me, and how would I find out about one?

Related OWise blogs

You may also find these blogs helpful:

Staying in control between appointments

With so many treatments, tests and possible side effects, keeping track of what is happening can feel like a full-time job, and the details you share with your team can shape your next treatment decision. The free OWise app lets you record your symptoms, save what your doctor says, keep your appointments and results in one place, and prepare questions for your next visit, so you can focus on living your life rather than remembering everything.

Editorial Information 

Written by: OWise editorial team  |  Clinically reviewed by: A. Bruinvels, MSc PhD  |  Last reviewed: July 2026 

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References

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