What’s next for metastatic breast cancer treatments? | SABCS 2025

Abigail is not alone. A robust research focus has resulted in a keener understanding of metastatic breast cancers and how to treat them. New drugs being tested on their own and together with other existing treatments mean a crowded field of options is emerging for people with metastatic disease.

Hormone receptor-positive disease is the most common form of MBC. Most people are treated first with combination of drugs: hormonal therapy to target the hormones that drive these cancers to grow, and a CDK 4/6 inhibitor, a type of drug that targets proteins on the cancer cells to block them from reproducing. The combination can be very effective, but it often stops working when the cancer cells change, or mutate, to get around the estrogen-blocking drug. A common mutation in these cases is the ESR1 mutation, a biomarker that can be found by analyzing the cancer cell’s genetic changes. Some people also stop these therapies because of their side effects.

Metastatic triple-negative breast cancer (mTNBC), on the other hand, does not depend on estrogen to grow. For people with this type of MBC, the strongest drugs need to be given up front because there are fewer medicines available that target these cancer cells. So, it is critical that the first treatment has the greatest chance of working.

At last week’s 2025 San Antonio Breast Cancer Symposium, researchers gave insight into drugs that are being studied for use in metastatic breast cancer initially or when the first treatment stops working. They also shared results of studies looking at who might get the most benefit from some of these new choices.

Updates for hormone receptor-positive breast cancer

Selective estrogen receptor degraders (SERDs). These drugs break down and reduce the number of estrogen receptors on breast cancer cells. Unlike the first SERD approved in 2002 given by injection, newer SERDs come in pill form. Oral SERDs may play a key role in the treatment of tumors that have changed and become resistant to earlier hormonal therapies after treatment with a CDK 4/6 inhibitor.

Four SERDs reported data at this week’s symposium showing their effectiveness, sometimes in combination with other drugs. Here’s the latest:

• Elacestrant: This drug was approved by the FDA in 2023 for people whose metastatic breast cancer developed an ESR1 mutation. The ELEVATE clinical trial is testing elacestrant in combination with other drugs. Last week, the researchers reported early findings that these combinations may work well as a second line of therapy for HR+ MBC even without an ESR1 mutation.
• Imlunestrant: This new SERD was approved earlier this year for use alone in hormone receptor-positive MBC with an ESR1-mutation. New data from the EMBER3 trial suggests the drug may work better in combination with abemaciclib than on its own in people who do or do not have the ESR1 mutation.
• Giredestrant: Results from the evERA clinical trial support its potential use with the targeted therapy everolimus for people with ESR1 mutations whose MBC progresses after using hormonal therapy and a CDK4/6 inhibitor. Another study presented this week, lidERA, also suggests it may work better than current treatments at preventing recurrence for people with early–stage breast cancer. Giredestrant is not yet approved by the FDA.
• Camizestrant: A new study looked at data from the SERENA-6 trial. That study used ctDNA testing to find ESR1 mutations early and switched participants to the oral SERD camizestrant while staying on a CDK4/6 inhibitor. Early results presented in June found that this approach may be effective in delaying cancer growth.

Proteolysis-targeting chimera (PROTAC): This type of drug works by targeting and binding two molecules, ultimately breaking down estrogen receptors on cancer cells. The VERITAC clinical trial showed that it worked better than fulvestrant in delaying cancer growth. Based on these results, the oral pill vepdegestrant has been granted fast-track designation by the FDA. Reports from SABCS suggest it will likely be approved for use in ER+, HER2-negative, ESR1-mutated metastatic breast cancer in 2026.

Complete estrogen receptor agonist (CERAN): CERANs attach to estrogen receptors, blocking their action completely. The CERAN palazestrant is moving into phase 3 clinical trials. The ongoing OPERA-01 and OPERA-02 trials are testing the drug alone and in combination with the CDK 4/6 inhibitor ribociclib in people with ER+, HER2- advanced breast cancer.

Selective estrogen receptor modulator (SERM): The phase 3 ELAINE trial compares the new, potentially more powerful SERM lasofoxifene to fulvestrant along with a CDK 4/6 inhibitor. The study will look at these combinations for locally advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation.

Antibody drug conjugates

When hormone receptor-positive MBC stops responding to estrogen-blocking therapy, a class of drugs called antibody-drug conjugates becomes another option. Datopotamab deruxtecan (Datroway) and trastuzumab deruxtecan (Enhertu) were approved for HR+ metastatic breast cancer in 2025, and researchers at SABCS shared ongoing trials testing these drugs in new ways. They are also being studied in triple-negative breast cancers that are not recommended for immunotherapy.

In breaking news on Fri., Dec. 15, during SABCS, the FDA approved a combination of drugs as a new first treatment option for people with HER2+ metastatic breast cancer. Although the study data supporting the combination of trastuzumab deruxtecan (Enhertu) and pertuzamab (Perjeta) was presented earlier in 2025, this approval provides the first new first-line treatment for people with HER2+ MBC in more than 10 years with a significant improvement in progression-free survival.

Beyond CDK4/6 resistance

Another line of research discussed at SABCS focuses on cancers that stop responding to CDK 4/6 inhibitors. Rather than moving to a new line of treatment, researchers are studying new drugs that may help the CDK 4/6 continue to work. Some of these new options target CDK 4, CDK 2, CDK 7, and KAT 6 areas of the cancer cell.

Atirmociclib: This more potent CDK 4 inhibitor may offer the benefit of CDK 4 without the risk of CDK 6, which can cause low white blood cell counts. The goal is to create an effective medicine that is easier to tolerate so that people can stay on it longer. The FourLight-3 clinical trial is actively enrolling participants.

CDK 2 inhibitors: Multiple drugs in this class are being tested in phase 2 clinical trials focused on safety and dosing. They are designed for use with a CDK 4/6 inhibitor to overcome resistance.

CDK7 inhibitors – Drugs under study may work by boosting the activity of CDK 4/6 drugs. Samuraciclib is the furthest along in development.

KAT6 inhibitors – The open KATSIS-1 phase 3 clinical trial tests a new drug intended for use after CDK 4/6 inhibitors stop working.

Progress for metastatic triple-negative breast cancer

The past five years have seen the introduction of powerful new drugs to treat triple-negative breast cancer (mTNBC). They have also led to improved understanding of the disease and how to manage it.

Antibody-drug conjugates (ADCs) show promise as first treatments in mTNBC. Recent study results point to two options for people who are not eligible for immunotherapy and more ADCs are being studied. Early results show that both medicines extended time without cancer growth. While these drugs are often reported to have tough side effects, each person will need to consider their own situation and discuss options with their healthcare provider.

• Sacituzumab govitecan (Trodelvy) has approval for already-treated TNBC. New study results show its potential to extend time without cancer growth when given as a first treatment.
• Trial results presented at SABCS show that datopotamab deruxtecan (Datroway), recently approved for HR+ metastatic breast cancer, is effective against TNBC.

A future crowded with hope

The growing number of options for people with metastatic breast cancer brings both more hope and more decisions. While studies of drugs used alone may have positive results, the real power is in combining therapies, according to many experts who presented at SABCS this week. Given so many options, decisions you make will depend as much on your treatment goals and quality of life as on how effective the medication is. Talk with your doctor about the options, their side effects, cost, and your priorities.