Decoding Treatment Sequencing in Metastatic Breast Cancer: A Patient's Guide

Table of Contents

• Introduction: The Challenge of Sequencing Treatments
• CDK4/6 Inhibitor Timing: First-Line vs. Second-Line Strategies
• The SONIA Trial: A Closer Look at Sequencing CDK4/6 Inhibitors
• Sequencing Therapy After CDK4/6 Inhibition
• Oral SERDs and New Endocrine Options
• Optimizing Antibody-Drug Conjugate (ADC) Sequencing
• What This Means for Patients: Clinical Implications
• Understanding the Limitations of Current Research
• Actionable Recommendations for Patients
• Source Information

Introduction: The Challenge of Sequencing Treatments

Deciding the best order of treatments for metastatic breast cancer (MBC) is one of the most complex challenges in oncology today. This process requires carefully combining evidence from clinical trials, real-world patient experiences, and individual patient factors to create personalized treatment plans.

As new drugs and treatment combinations rapidly become available, doctors face critical decisions about how to sequence therapies to maximize benefits, minimize side effects, and preserve future treatment options. This comprehensive review translates recent research findings into practical insights that can help patients understand their treatment options.

The article focuses on three key areas: sequencing challenges after using cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), which are commonly used for estrogen receptor-positive (ER+) disease; the strategic placement of powerful new drugs called antibody-drug conjugates (ADCs) across all breast cancer subtypes; and evolving treatment approaches for HER2-positive disease.

CDK4/6 Inhibitor Timing: First-Line vs. Second-Line Strategies

For patients with estrogen receptor-positive, HER2-negative (ER+ HER2-) metastatic breast cancer, a major question is when to start CDK4/6 inhibitors in combination with endocrine therapy. Three CDK4/6 inhibitors are available: palbociclib, ribociclib, and abemaciclib.

Large phase III clinical trials have demonstrated that these drugs improve progression-free survival (PFS - the time until cancer worsens) when used in both first-line and second-line settings. However, the overall survival (OS) benefits have varied between drugs:

• Ribociclib showed significant overall survival improvement when combined with either an aromatase inhibitor (AI) or selective estrogen receptor modulators (MONALEESA-2, MONALEESA-7 trials) and with fulvestrant (MONALEESA-3 trial)
• Abemaciclib showed overall survival benefit when combined with fulvestrant (MONARCH-2 trial)
• No overall survival benefit was seen with abemaciclib plus AI (MONARCH-3 trial) or with palbociclib combined with either letrozole (PALOMA-2 trial) or fulvestrant (PALOMA-3 trial)

These differing survival outcomes raise questions about whether the three CDK4/6 inhibitors are equally effective. A large US-based real-world study of 9,146 patients with ER+ HER2- MBC receiving first-line AI plus CDK4/6 inhibitor found no significant differences in overall survival among the three drugs.

While most treatment guidelines recommend first-line use of CDK4/6 inhibitors combined with endocrine therapy, some patients may experience durable disease control with endocrine therapy alone initially. This has led to important questions about whether saving CDK4/6 inhibitors for later use might be a reasonable strategy for some patients.

The SONIA Trial: A Closer Look at Sequencing CDK4/6 Inhibitors

The SONIA trial (phase III, 1,050 patients) directly addressed whether immediate CDK4/6 inhibitor initiation is necessary for all patients. This study included pre- and postmenopausal women with ER+ HER2- metastatic breast cancer who had not received previous systemic therapy for MBC and had no visceral crisis.

Patients were randomly assigned to one of two strategies:

1. CDK4/6 inhibitor plus aromatase inhibitor in the first line, followed by fulvestrant at progression
2. Aromatase inhibitor alone first, followed by CDK4/6 inhibitor plus fulvestrant in the second line

The primary endpoint was progression-free survival 2 (PFS2), which measures the time from starting first-line therapy until progression on second-line treatment.

After a median follow-up of 37.3 months, the results showed:

• Median PFS2 was 31.0 months in the CDK4/6i-first group
• Median PFS2 was 26.8 months in the second-line group
• The hazard ratio was 0.87 (95% CI, 0.74 to 1.03) with a p-value of 0.10

The study did not establish that starting with the CDK4/6 inhibitor first was superior. However, the second-line strategy was found to be noninferior (not worse than), with the upper limit of the 95% confidence interval (1.35) within the noninferiority margin (1.54).

Important additional findings from SONIA:

• Quality of life was comparable between both groups
• Fewer adverse events occurred with the CDK4/6i-second strategy
• Lower treatment costs were associated with the second-line approach

While palbociclib was the dominant CDK4/6 inhibitor used (91% in both strategies), the similar PFS across CDK4/6 inhibitors in first- and second-line landmark trials suggests that a different distribution of drugs would unlikely alter the progression rates.

The SONIA trial hasn't significantly changed global standard practice, especially in private payer-based systems like the United States, as it doesn't support up-front endocrine therapy monotherapy for all patients while reserving CDK4/6 inhibitors for second-line treatment. However, these results may help prioritize and allocate expensive treatments in national healthcare systems and may provide justification for using endocrine therapy alone in selected frail patients where CDK4/6 inhibitors could pose a concern.

Sequencing Therapy After CDK4/6 Inhibition

For patients whose cancer progresses after first-line endocrine therapy with a CDK4/6 inhibitor, the optimal treatment sequence remains unclear. Several trials have investigated whether continuing CDK4/6 inhibition beyond progression is beneficial:

MAINTAIN trial (phase II, 120 patients): Patients progressing on previous CDK4/6i and endocrine therapy were randomly assigned to ribociclib or placebo, with an endocrine therapy switch. The ribociclib group showed significant improvement in median progression-free survival (5.29 vs. 2.76 months, HR 0.57, 95% CI 0.39 to 0.95, p=0.006). At 12 months, the PFS rate was 24.6% with ribociclib compared with 7.4% with placebo.

PACE trial (phase II, 220 patients): This study found no benefit to continuing palbociclib after progression on a CDK4/6 inhibitor. Median PFS was 4.6 months in the experimental arm compared with 4.8 months in the control arm (HR 1.11, 95% CI 0.79 to 1.55, p=0.62).

PALMIRA trial (phase II, 198 patients): Continuing palbociclib with a different endocrine therapy after progression on first-line palbociclib plus endocrine therapy did not improve PFS compared with endocrine therapy alone.

postMONARCH trial (phase III, 368 patients): Patients received fulvestrant plus either abemaciclib or placebo after progression on a CDK4/6 inhibitor plus AI for MBC or recurrence on/after adjuvant CDK4/6i plus endocrine therapy. The 6-month investigator-assessed PFS was 50% versus 37%, and median PFS was 6.0 months in the experimental arm versus 5.3 in the control arm (HR 0.73, 95% CI 0.57 to 0.95, p=0.02).

Exploratory biomarker analyses showed that ESR1 and PIK3CA mutations were linked to reduced benefit from CDK4/6 inhibitor combinations in some trials but improved outcomes in others, highlighting the complexity of treatment decisions after progression.

Oral SERDs and New Endocrine Options

For patients who progress after CDK4/6 inhibitor treatment, therapy is largely guided by genomic testing. The selective estrogen receptor degrader (SERD) elacestrant is approved for ESR1-mutated ER+ HER2- metastatic breast cancer after at least one previous endocrine therapy, based on the EMERALD trial (phase III, 477 patients).

Key findings from EMERALD:

• Improved 6-month PFS: 41% vs. 19% compared with investigator's endocrine therapy choice
• Improved 12-month PFS: 26.8% vs. 8.2%
• Median PFS: 3.8 vs. 1.9 months (HR 0.55, 95% CI 0.39 to 0.77, p=0.0005)
• No superior PFS benefit in patients without circulating tumor DNA-detectable ESR1 mutations

However, the modest median PFS improvement (less than 2 months), lack of overall survival benefit in the final analysis, and suboptimal control arm choices raised some questions about the magnitude of benefit.

Several other oral SERDs are being investigated in clinical trials:

• EMBER-3 trial (phase III, 874 patients): Evaluating imlunestrant, standard endocrine therapy, or imlunestrant plus abemaciclib
• SERENA-2 trial (phase II, 240 patients): Testing camizestrant against fulvestrant
• AMEERA-3 trial (phase II, 290 patients): Studying amcenestrant compared with fulvestrant or AI
• acelERA trial (phase II, 303 patients): Investigating giredestrant versus fulvestrant or AI

These developments could mark a future shift from combining CDK4/6 inhibitors with traditional endocrine therapy to combining them with oral SERDs in first-line therapy or after progression on previous CDK4/6 inhibitors.

Optimizing Antibody-Drug Conjugate (ADC) Sequencing

Antibody-drug conjugates (ADCs) have revolutionized treatment for metastatic breast cancer across all subtypes. These powerful drugs combine targeted antibodies with potent chemotherapy payloads, allowing precise delivery of cancer-killing agents to tumor cells while sparing healthy tissues.

Current ADC options include:

• For metastatic triple-negative breast cancer (mTNBC): Sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd) for HER2-low disease
• For ER+ MBC with nonoverexpressed HER2: Datopotamab deruxtecan (Dato-DXd) in addition to the above options

In patients with pretreated mTNBC (HER2-0 or HER2-low), the TROP2-directed ADC sacituzumab govitecan showed significant improvement in both progression-free survival and overall survival compared with treatment of physician's choice (HR 0.41 and 0.51, respectively, in the final analysis).

An exploratory analysis of 58 patients with ER-HER2-low MBC included in the DESTINY-Breast04 trial showed a numerical improvement in both PFS and OS with the HER2-targeted ADC trastuzumab deruxtecan compared with treatment of physician's choice.

The growing number of ADC options creates both opportunities and challenges for optimal sequencing. Understanding which ADC to use when, and in what order, requires careful consideration of tumor characteristics, previous treatments, and individual patient factors.

What This Means for Patients: Clinical Implications

The research reviewed has several important implications for patients living with metastatic breast cancer:

Treatment sequencing is highly personalized: There is no one-size-fits-all approach to managing metastatic breast cancer. Decisions must integrate clinical trial data, real-world evidence, and individual patient factors including age, overall health, specific tumor characteristics, and personal preferences.

CDK4/6 inhibitor timing may be flexible: The SONIA trial suggests that for some patients, starting with endocrine therapy alone and reserving CDK4/6 inhibitors for later may be a reasonable strategy that offers similar long-term disease control with fewer side effects and lower costs.

Biomarker testing is crucial: Genomic testing, particularly for ESR1 mutations, can guide treatment selection after progression on CDK4/6 inhibitors. Patients with ESR1 mutations may benefit from specific targeted therapies like elacestrant.

Multiple options exist after progression: Research continues to expand the treatment landscape after CDK4/6 inhibitor progression, with several new drugs and combinations showing promise in clinical trials.

ADCs have transformed treatment: These powerful drugs have improved outcomes across breast cancer subtypes, but their optimal sequencing requires careful consideration by multidisciplinary teams.

Understanding the Limitations of Current Research

While the studies reviewed provide valuable insights, several limitations should be considered:

Trial design challenges: Many studies face biases from control arm selection, crossover design, and heterogeneous post-progression treatments, all of which may complicate the interpretation of endpoints like overall survival and progression-free survival 2.

Changing treatment landscape: Since the start of trials like SONIA, new targeted therapies including capivasertib, alpelisib, and most recently inavolisib have entered clinical practice, potentially changing the optimal sequencing strategies.

Biomarker limitations: The lack of robust biomarkers to identify which patients could benefit equally well from endocrine therapy monotherapy versus combination therapy remains a significant challenge.

Generalizability concerns: Outcome interpretation may be complicated by differences in pre- and post-treatment access across international study sites and healthcare systems.

Long-term data needed: For many newer approaches, longer follow-up is needed to fully understand overall survival benefits and long-term side effects.

Actionable Recommendations for Patients

Based on the current evidence, patients with metastatic breast cancer and their healthcare teams should consider the following:

1. Discuss all sequencing options: Have detailed conversations with your oncology team about the pros and cons of different treatment sequences, including the possibility of starting with endocrine therapy alone for selected patients.
2. Request comprehensive biomarker testing: Ensure your tumor undergoes appropriate genomic testing, including ESR1 mutation status, to guide treatment decisions after progression on CDK4/6 inhibitors.
3. Consider clinical trials: Explore participation in sequencing-specific trials that may offer access to novel treatment approaches and contribute to advancing knowledge.
4. Balance efficacy and quality of life: Discuss not only treatment effectiveness but also side effect profiles and impacts on daily life when making sequencing decisions.
5. Seek second opinions: Consider consulting with specialized centers that have extensive experience with complex sequencing decisions and access to the latest treatment options.
6. Stay informed about new developments: The metastatic breast cancer treatment landscape evolves rapidly, so maintain open communication with your healthcare team about emerging options.

Source Information

Original Article Title: Decoding Clinical Trials in Metastatic Breast Cancer: Practical Insights for Optimal Therapy Sequencing

Authors: Chiara Corti, MD; Hope S. Rugo, MD, FASCO; Sara M. Tolaney, MD, MPH, FASCO

Publication: American Society of Clinical Oncology Educational Book, Volume 45, Issue 3

DOI: https://doi.org/10.1200/EDBK-25-100053

Published: May 14, 2025

This patient-friendly article is based on peer-reviewed research and aims to translate complex scientific information into accessible content for educated patients and caregivers. Always consult with your healthcare team for personalized medical advice.