Now, we will switch focus to MBC, specifically to explore how we go about selecting treatments for patients with HR‑positive/HER2‑negative disease.

There are many things to consider about the disease (brain or bone metastases, visceral crisis, and endocrine resistance) and the patient (premenopausal, postmenopausal, and frailty status) in the metastatic setting. We often think about deciding what to recommend in the first‑line setting and then about subsequent therapies for these patients.

In addition to what patients will receive as their first‑line therapy, we also think about treatment of bone metastases with antiresorptive agents such as denosumab or zoledronic acid.

In patients with immediately life‑threatening visceral crisis, we may consider chemotherapy. In patients who do not have visceral crisis and who are premenopausal, we would recommend ET with an AI plus a CDK4/6 inhibitor and LHRH agonist, and an AI plus a CDK4/6 inhibitor if postmenopausal, because this combination is expected to yield improvement in survival.

In patients with confirmed CNS disease, local CNS‑directed therapy (eg, radiation) followed by ET and abemaciclib may be one consideration.

Once a patient’s disease becomes refractory to sequential ET in the metastatic setting, we then proceed with targeted agents (eg, PARP inhibitor if BRCA1/2 mutation or PALB2 mutation)¹⁵ or systemic chemotherapy, often as part of an antibody drug conjugate.

To help summarize current guidelines¹ and expert recommendations for recommending therapy to patients with high-risk MBC, we have put together an algorithm to consider what to do with some common scenarios.

The algorithm shown here has been put together by breast cancer experts who collaborated on this program. In the minority of patients with metastatic or local regional recurrence who are very frail and have multiple comorbidities, we may proceed with single‑agent ET. In patients with metastatic or local regional recurrence and severe end‑organ dysfunction (eg, rising bilirubin, lymphangitic spread, borderline need for intubation), I would consider systemic chemotherapy.

For all other patients with metastatic or local regional recurrence, we want to know if the patient has a germline BRCA mutation to help determine whether a PARP inhibitor might be an option. However, even in patients with a germline BRCA mutation in the metastatic setting, we often prefer a CDK4/6 inhibitor plus ET first because of the documented improvement in OS with CDK4/6 inhibitors in the metastatic setting.^16-23

If we look at the data from phase III trials of abemaciclib, palbociclib, and ribociclib, we see improvement in median PFS across all of these trials with the addition of a CDK4/6 inhibitor.^16-23 The hazard ratio for PFS with the addition of a CDK4/6 inhibitor is 0.52-0.66 for all of the phase III trials shown in the table.

Where we see some differences between the first-line clinical trials for MBC is in regard to improving OS. No improvement in OS was reported with the addition of palbociclib to letrozole in the PALOMA-2 trial (53.9 months vs 51.2 months; hazard ratio: 0.96; P = .3378).^16,17 There are 3 first‑line trials with ribociclib: MONALEESA‑2, evaluating letrozole with or without ribociclib in postmenopausal patients with no previous systemic therapy; MONALEESA‑3, not shown here, evaluating fulvestrant plus ribociclib in HR-positive/HER2-negative advanced breast cancer (ABC) in the first‑line or second‑line setting; and MONALEESA‑7, evaluating tamoxifen, anastrozole, or letrozole with or without ribociclib in pre/perimenopausal patients with no previous ET for advanced disease.^18-21,24,25 All 3 of these trials showed a statistically significant improvement in OS (hazard ratio range: 0.71-0.76). However, the phase II RIGHT Choice trial with ribociclib plus anastrozole plus goserelin or letrozole vs investigator’s choice of chemotherapy did not have power to show improvement in OS, but showed a major improvement in PFS with first-line ribociclib plus ET vs combination chemotherapy.²⁶

I would like to look a little closer at the update from the phase III MONARCH 3 study presented SABCS 2023 by Dr Matthew Goetz, which included the final OS data.²⁷

As you may recall, patients enrolled on this trial had HR-positive/HER2-negative ABC (eg, metastatic or locoregional recurrence), had no prior systemic therapy, were postmenopausal, and had to have completed ET or had a disease-free interval of >12 months from receiving (neo)adjuvant ET (N = 493). They could not have had disease recurrence on adjuvant ET. In this study, patients received an NSAI (anastrozole or letrozole) plus either abemaciclib 150 mg orally or placebo twice daily until disease progression. The primary endpoint was investigator-assessed PFS. Secondary endpoints were OS, overall response rate (ORR), and safety.

Looking at the PFS and OS data presented for MONARCH 3 at SABCS 2023, we saw a 13.1‑month improvement in median OS for the overall population—from 53.7 months with NSAI alone to 66.8 months with abemaciclib plus NSAI (hazard ratio: 0.804; P = .0664). This was a substantial improvement similar to what we have previously seen in MONALEESA‑2 and MONALEESA‑7.^18-21 However, the improvement in OS did not meet statistical significance per the prespecified P value boundaries in the protocol.

In patients with visceral disease, there was a 14.9‑month improvement in median OS for the overall population—from 48.8 months with NSAI alone to 63.7 months with abemaciclib plus NSAI (hazard ratio: 0.758; P = .0757).

The PFS benefit—the primary endpoint of the study—was maintained in this final analysis (29.0 vs 14.8 months; hazard ratio: 0.535; 95% CI: 0.429-0.668; nominal P <.0001), with a substantial difference in 6-year PFS rates (23.3% vs 4.3%) seen for abemaciclib plus NSAI compared with NSAI alone. 

A forest plot also was presented, not shown, and we saw in the subset analyses that, essentially, for all of the prognostic variables in the first-line setting, there was a benefit from the addition of abemaciclib to NSAI.²⁷ 

The consensus opinion for why this trial did not reach statistically significant results with a 13.1-month to 14.9-month improvement in OS is the smaller sample size compared with was used in other first‑line trials. It took 8 years for enough events to accrue for OS analysis. With 8 years of follow-up, there are many variables that can potentially influence those final OS results.

The global, multicenter, randomized, double-blind, placebo-controlled phase III postMONARCH trial is evaluating fulvestrant plus abemaciclib or placebo in patients with HR-positive/HER2-negative locally advanced or metastatic breast cancer with evidence of disease progression either while receiving treatment with a different CDK4/6 inhibitor (palbociclib or ribociclib) and an AI as initial therapy for advanced disease or on/after therapy with a CDK4/6 inhibitor plus ET as adjuvant therapy for early-stage breast cancer (N = 350; NCT05169567).²⁸ The question this trial is attempting to answer is whether CDK4/6 inhibitor rechallenge with abemaciclib in combination with fulvestrant after progression on a first‑line CDK4/6 inhibitor will be more effective than fulvestrant alone. We are looking forward to seeing the results of the postMONARCH trial in the near future.

I also would like to cover data for the randomized, open-label, multinational phase II RIGHT Choice trial of ET (letrozole or anastrozole plus goserelin) plus ribociclib 600 mg vs investigator’s choice of combination chemotherapy (eg, docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine) in pre/perimenopausal women with HR-positive/HER2-negative ABC.²⁶ Patients enrolled on this trial had not received previous systemic therapy for metastatic disease and had aggressive disease defined as symptomatic visceral metastases, rapid disease progression, impending visceral compromise, or markedly symptomatic nonvisceral disease (N = 222). Patients had bilirubin ≤1.5‑fold the upper limit of normal. Patients were not in absolute frank hepatic failure but were deemed to be very close to visceral crisis. The primary endpoint of the study was PFS assessed locally per Response Evaluation Criteria in Solid Tumors version 1.1.

I think this trial highlights the importance of prioritizing ET plus a CDK4/6 inhibitor as first-line therapy over chemotherapy.

In the figure shown on the right, we can see a significant improvement in median PFS in favor of ribociclib plus ET vs investigator’s choice of combination chemotherapy (24.0 months vs 12.3 months; hazard ratio: 0.54; P = .0007). Similarly, time to treatment failure was prolonged with ribociclib plus ET vs investigator’s choice of combination chemotherapy (median: 18.6 months vs 8.5 months; hazard ratio: 0.45).

The ORR and clinical benefit rate (CBR) in the RIGHT Choice study were very similar with ribociclib plus ET vs investigator’s choice of chemotherapy.

Median time to response was 4.9 months with ribociclib plus ET vs 3.2 months with chemotherapy.

Although the total number of AEs was similar between arms, treatment-related serious AEs were noticeably lower with ribociclib plus ET (all-grade AEs: 1.8% vs 8.0%; grade 3/4 AEs: 0.9% vs 7.0%). Treatment-related AEs of any grade leading to treatment discontinuation were lower with ribociclib plus ET vs chemotherapy (7.1% vs 23.0%).

With regard to dose modifications, 72.3% vs 54.0% of patients did not require a dose reduction with ribociclib plus ET vs chemotherapy, and approximately 27% vs 46% had 1-2 dose‑level reductions with ribociclib plus ET vs 1 to ≥3 dose‑level reductions with chemotherapy.

These data demonstrates that these patients with aggressive and symptomatic, and often viscera disease, do not benefit from first‑line chemotherapy nearly as much as they do from first‑line ET plus a CDK4/6 inhibitor. I think ET plus a CDK4/6 inhibitor now should be our go‑to-therapy even if patients have symptomatic visceral disease and/or nonvisceral disease.

Support for use of the oral PI3K inhibitor alpelisib in patients with PIK3CA mutations comes from the randomized phase III SOLAR-1 study.^29,30 Patients with disease progression on or after AI therapy were randomized to receive alpelisib plus fulvestrant or placebo plus fulvestrant. It is important to note that the SOLAR-1 trial participants had not previously received a CDK4/6 inhibitor, as that was not yet a standard of care at the time this trial was conducted. The data showed a significant improvement in median PFS with the addition of alpelisib to fulvestrant (11.0 vs 5.7 months; P = .00065) in patients with a PI3KCA mutation.²⁹ There was also a trend toward improved OS, although this was not statistically significant (median OS: 39.3 vs 31.4 months; P = .15).³⁰

PIK3CA mutations, which occur in approximately 35% to 40% of cases, can be detected in the primary breast cancer, metastatic tissue, and ctDNA to identify individuals who may be candidates for alpelisib.³¹ However, suitable patients need to have good glycemic control, with an A1C of <6.5%, given the potential for hyperglycemia associated with alpelisib.^30,32

BYLieve was a large phase II trial that enrolled patients whose HR-positive/HER2-negative, PIK3CA-mutated breast cancer was progressing through first- or second-line treatment.^33,34 Cohort A included patients progressing on an AI plus CDK4/6 inhibitor, and these individuals received treatment with alpelisib plus fulvestrant.

After a median follow-up of 21.8 months, median PFS and OS were 8.0 and 27.3 months, respectively. On the bottom right, we can see the primary analysis response data showing that the CBR was 45% and the ORR was 17% in patients with confirmed PI3KCA mutation. Of note, median PFS is not as good as that reported in SOLAR-1 (11.0 months). However, post CDK4/6 inhibitor, a median PFS of 8.0 months with fulvestrant and alpelisib is clinically meaningful for patients.

Recently, the combination of capivasertib and fulvestrant received FDA approval for patients with HR-positive/HER2-negative ABC and a mutation in PI3KCA, AKT1, and/or PTEN after progression on ≥1 ET regimen for metastatic disease or recurrence within ≤12 months of completing adjuvant therapy based on data from the CAPItello‑291 trial.³⁵ 

The global, randomized phase III CAPItello-291 trial was conducted in men and postmenopausal women with HR-positive/HER2-negative MBC who had progressed on first-line AI therapy, and they could have previously received up to 2 previous lines of ET and 1 previous line of chemotherapy in the context of advanced disease.³⁶ In fact, ≥51% of patients were required to have a CDK4/6 inhibitor before trial entry. Eligible individuals were randomized to receive either fulvestrant with placebo or fulvestrant with capivasertib 400 mg orally twice daily administered at a schedule of 4 days on and 3 days off. The 3 days off allows patients to recover from toxicity, particularly diarrhea, and this strategy appears to have worked well as few patients discontinued therapy due to toxicity.

There were dual primary endpoints: PFS in the overall population unselected for any mutations in the PI3K/AKT pathway and PFS in the cohort of approximately 40% of patients who had a PIK3CA mutation, AKT mutation, or PTEN loss-of-function alteration.

In the AKT pathway‒altered population (figure on the right), the median PFS went from 3.1 months with placebo plus fulvestrant  to 7.3 months with capivasertib plus fulvestrant (hazard ratio: 0.50; 2-sided P <.001). Approximately 70% of patients on the CAPItello-291 trial had a prior treatment with a CDK4/6 inhibitor, so these data are relevant to our patients progressing on a CDK4/6 inhibitor, as well.  

The main safety concerns with capivasertib are diarrhea, nausea, and rash, which can be prevented or mitigated in the clinic. Patients also may take loperamide to help with diarrhea.

In patients with recurrent disease and an ESR1 mutation, elacestrant is a relatively new treatment option. As a reminder, ESR1 mutations develop as a resistance mechanism to ET, particularly AIs, especially in the metastatic setting.³⁷ Approximately 40% of patients will develop an ESR1 mutation over time under the selective pressure of ET.^37,38 Because of this, we must assess ctDNA for an ESR1 mutation upon progression on first-line ET and upon progression on second-line therapy.¹ Testing ctDNA is the best way to find ESR1 mutations.

In the randomized, open-label phase III EMERALD trial, eligible patients with ER-positive/HER2-negative MBC had received 1 line of treatment with a CDK4/6 inhibitor and ≤1 line of chemotherapy for advanced disease (N = 478).³⁹ Upon progression, they were randomized to receive either elacestrant 400 mg once daily or investigator’s choice of single-agent fulvestrant, anastrozole, letrozole, and exemestane. The coprimary endpoints were PFS in the all-comers population and PFS in the ESR1-mutated population, which comprised approximately 48% of the total population.

The tables show median PFS for all patients and for patients with an ESR1 mutation. In all patients, median PFS was 2.8 months with elacestrant vs 1.9 months with standard of care (hazard ratio: 0.70; P = .002), and in patients with an ESR1 mutation, median PFS was 3.8 months with elacestrant vs 1.9 months with standard of care (hazard ratio: 0.55; P = .0005). 

Shown here are data that can help inform how HCPs in the clinic can best choose which patients should receive elacestrant. The table on the bottom shows PFS outcomes in the population with ESR1-mutated disease based on previous duration of treatment with a CDK4/6 inhibitor of ≥6, ≥12, and ≥18 months, which helps illustrate the likelihood of ET sensitivity given that elacestrant is administered as a single agent.

Patients who had received a prior CDK4/6 inhibitor for ≥12 months (middle of bottom table) or ≥18 months (on right in bottom table) had a median PFS with single-agent elacestrant of 8.6 months vs approximately 2 months with single-agent ET.³⁹ So, that is the “sweet spot”—patients with ESR1-mutated disease who had received a previous CDK4/6 inhibitor for ≥1 year—as this increases the likelihood that they still have ET-sensitive disease.

Here as well, if we look at the table on the bottom for patients with ESR1-mutated disease, those individuals who had a shorter duration of previous treatment with a CDK4/6 inhibitor did not benefit from treatment with elacestrant. Patients who had received a CDK4/6 inhibitor for <6 months had a median PFS of 1.9 months with elacestrant, which was the same as with standard therapy.³⁹

Similar PFS durations were seen for both elacestrant and standard-of-care therapy for individuals who had been receiving a previous CDK4/6 inhibitor for 6-12 months. Thus, these data provide a good rationale for offering elacestrant to patients who attained ≥1 year of benefit from their previous CDK4/6 inhibitor—which is the vast majority of patients, as the median PFS with first-line CDK4/6 inhibitor use is 2+ years.⁴⁰

The safety profile of elacestrant is excellent. Patients can expect low-grade nausea (grade 3 in 2.5%), which can be prevented by taking the medication with food.⁴¹ If patients have dyspepsia, they can take a proton pump inhibitor, because elacestrant does not need an acidic environment to be absorbed. Approximately 35% of patients on the EMERALD trial had any nausea; however, patients on the trial were not instructed to take the medication with food.^38,39 Only 8% of patients on the elacestrant arm required use of an antiemetic, and only 3.4% of patients discontinued elacestrant because of AEs, which reaffirms that it was a very well-tolerated therapy.

Elacestrant is an important agent for our patients. I choose it for patients who have disease with a confirmed ESR1 mutation that I think is ET sensitive and who had received their previous CDK4/6 inhibitor for ≥12 months. For those patients with more indolent disease, I have a window of opportunity where I have 3-4 months to see if their disease responds to elacestrant. I do not use single-agent elacestrant in patients with disease that is rapidly progressing in the liver or with highly symptomatic disease.

Other promising oral SERDs are currently in development. One such agent is the investigational SERD camizestrant. The phase II SERENA-2 trial is evaluating 3 doses of camizestrant in patients who experienced disease progression with recurrence or progression on ≥1 line of ET with no more than 1 line of ET for advanced disease and no more than 1 line of chemotherapy for advanced disease (N = 240).⁴² Patients were randomized to receive camizestrant 75 mg, 150 mg, or 300 mg once daily vs fulvestrant 500 mg IM. The 300 mg was stopped early with a clinical study protocol amendment, and efficacy is being evaluated only with the 75-mg and 150-mg doses. The primary endpoint of this trial was investigator-assessed PFS. Secondary endpoints included CBR at 24 months, ORR, OS, and safety.

The data shown here depict PFS improvements for both the 75-mg and 150-mg doses of camizestrant vs fulvestrant (median PFS: 7.2 to 7.7 months vs 3.7 months; P <.02 for both doses). This PFS benefit was consistent in patients who had received a prior CDK4/6 inhibitor, who comprised more than 50% of the population. Moreover, the secondary endpoints of ORR and CBR at 24 months also were improved. Thus, camizestrant is clearly superior compared with fulvestrant, although they are both SERDs. Data analyses are ongoing to look at efficacy in patients with ESR1-mutated disease vs the all-comers population, so we will stay tuned for those results.

We also are keeping an eye out for imlunestrant, another promising investigational oral SERD. In the phase Ia/b EMBER study, imlunestrant was combined with abemaciclib. Patients with ER-positive/HER2-negative ABC were randomized to receive imlunestrant (either 400 mg or 800 mg orally once daily) plus abemaciclib with or without an AI (N = 85).⁴³ Patients on this trial were stratified based on menopausal status and the presence of visceral metastases and had not previously received a CDK4/6 inhibitor, but they did have up to 1 prior line of ET. The primary endpoint of this study is determining the recommended phase II dose.

Pooled PFS, on the right, was favorable with imlunestrant plus abemaciclib, and the addition of an AI did not appear to make much difference in terms of further improving PFS. In both arms, 80% of patients were progression-free at 1 year. The CBR was also very good at approximately 75% among all patients on the trial and was roughly similar between the 2 arms.

Unfortunately, there comes a time when HR-positive/HER2-negative disease becomes resistant to ET, and we have to go on to cytotoxic therapy. Many times we will use capecitabine first in the HR-positive/HER2-negative population, but then we have to go on to IV cytotoxic therapy, with 2 main ADC options available. When considering ADC therapy, T-DXd is preferred for the HER2-low population, and sacituzumab govitecan is preferred for the HER2-zero population.¹

The phase III TROPiCS-02 trial led to FDA approval of sacituzumab govitecan, an ADC with the irinotecan-derivative payload SN-38 that is targeted toward an ubiquitously expressed tumor-associated antigen called TROP-2, for patients with locally advanced or metastatic HR-positive/HER2-negative breast cancer after ET and ≥2 additional lines of treatment in the metastatic setting.⁴⁴ The patients on TROPiCS-02 were heavily pretreated, having received 2-4 lines of prior chemotherapy. Participants were randomized to receive sacituzumab govitecan 10 mg/kg on Day 1 and Day 8 of a 21-day cycle or to receive single-agent chemotherapy. The primary endpoint was PFS.

Results from the TROPICS-02 clinical trial show that median PFS was improved with sacituzumab govitecan vs chemotherapy (5.5 vs 4.0 months; P = .0001). Of greatest importance, we also saw a significant improvement in median OS (14.5 vs 11.2 months; P = .0133).⁴⁵ There was a 3.3-month improvement in median OS with sacituzumab govitecan vs chemotherapy, and we see a greater percentage of patients alive at 12 months (60.9% vs 47.1%) and 18 months (39.2% vs 31.7%). Survival trumps everything, so these data show that sacituzumab govitecan is more effective in previously treated patients with HR-positive/HER2-negative MBC compared with single-agent chemotherapy.

Although the definition of HER2 positivity is in flux, we know that having HER2-low disease is not the same as having HER2-positive disease. “HER2 positive” currently is defined as HER2 IHC 3+ or IHC 2+ and FISH positive, whereas “HER2 low” currently includes patients with IHC 1+ or IHC 2+ and FISH-negative tumors.¹ T-DXd is a great option for our patients with HER2-low disease, and it is approved by the FDA for patients with HER2-low metastatic breast cancer after previous chemotherapy in the metastatic setting or disease recurrence during or within 6 months of completing adjuvant chemotherapy based on data from the phase III DESTINY-Breast04 trial.⁴⁶

In DESTINY-Breast04, T-DXd was compared with single-agent chemotherapy in patients with unresectable or metastatic HER2-low disease and 1-2 previous lines of chemotherapy or recurrence ≤6 months after adjuvant chemotherapy. The primary endpoint of the study was PFS in HR-positive disease by blinded independent central review.⁴⁷

When looking at the PFS data shown here, we see that regardless of whether we look at patients with HR-positive disease on the left or all-comers on the right, we see approximately a doubling of PFS with use of T-DXd compared with single-agent chemotherapy, which is statistically significant (P <.001).

Putting it all together, how do we plan and sequence treatment for our patients with HR‑positive/HER2‑negative MBC? 

This table shows a summary to navigate the various treatment options available for us depending on the line of treatment. Starting on the left, the vast majority of patients should be treated with ET plus a CDK4/6 inhibitor in the first‑line setting. In the second- and third‑line settings, we await with great interest phase III level 1 evidence to see whether treating patients with abemaciclib plus fulvestrant after progression on an AI plus a different CDK4/6 inhibitor in the first line will be beneficial to patients. Data from the small, randomized, phase II MAINTAIN trial combining fulvestrant with ribociclib after progression on AI plus palbociclib show a 5.5‑month median PFS, which is quite interesting.⁴⁸ So, that is a potential option for patients.

In the second- or third-line setting, we need to know patients’ PIK3CA, AKT1, and PTEN mutation status to determine if capivasertib plus fulvestrant is an option. We also can offer patients alpelisib if they have a PIK3CA mutation.

For patients with germline BRCA mutations, once their disease becomes resistant to ET, I certainly want to prioritize olaparib or talazoparib.

Other options in patients with an ESR1 mutation after first‑line progression include elacestrant, with camizestrant or imlunestrant being an option in the context of a clinical trial. ET plus everolimus is also a consideration in patients who lack PI3KCA/AKT1/PTEN, BRCA1/2, or ESR1 mutations. 

If upon recurrence patients with HR-positive/HER2-negative status are found to have an acquired HER2 mutation, then we may consider neratinib, fulvestrant, and trastuzumab based on the SUMMIT trial data.^1,49

Eventually, patients’ breast cancer becomes ET resistant. We need to know HER2‑low status because we would prioritize therapy with T‑DXd for this subset of patients.¹ DESTINY‑Breast06 is evaluating T-DXd vs investigator’s choice of chemotherapy as first-line in patients with HR-positive/HER2-low and ultralow breast cancer (NCT04494425), with data eagerly anticipated. Currently, however, we give capecitabine in this that setting. By contrast, if patient’s breast cancer is HER2 IHC 0, we would prioritize sacituzumab govitecan.

We also want to ascertain microsatellite instability status and tumor mutational burden status to consider whether checkpoint inhibitor therapy might be an option. After we have considered all other biomarkers and available treatment options, including a clinical trial, we may go on to various cytotoxic agents (eg, taxane, eribulin).¹

I wanted to bring to your attention another helpful interactive decision support tool developed by Clinical Care Options with assistance from 5 breast oncology experts for selecting therapy in patients with advanced, recurrent, or metastatic breast cancer. This tool is available online; you also can access it via the link at the bottom left of the slide, the QR code, or the AliCEA app in your app store.

To use the tool, we enter key patient characteristics by answering a few questions, such as HR status, triple-negative status, and HER2 status, as well as germline BRCA1/2 status. The tool asks you to select the therapy you are planning or considering for your patient with MBC and then shows you the recommendations from 5 experts, including caveats and commentary for context on their treatment of choice. I find these tools to be very interesting and helpful and would encourage HCPs to explore them.