Back Back
Optimizing Outcomes for HRpos HER2neg MBC
Evolving Standards in HR+/HER2- Metastatic Breast Cancer: Optimizing Outcomes Through Precision Medicine and Real-world Insight

Released: May 12, 2025

Expiration: November 11, 2025

Sara A. Hurvitz
Sara A. Hurvitz, MD, FACP
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • CDK4/6 inhibitors combined with endocrine therapy (ET) are the gold standard in the front-line setting and after first-line single-agent ET for HR-positive/HER2-negative advanced breast cancer.
  • Next-generation sequencing is essential to guide therapy selection after disease progression on ET, enabling use of targeted agents such as inavolisib, alpelisib, capivasertib, or elacestrant in patients with actionable mutations like PIK3CA or ESR1.
  • Effective use of CDK4/6 inhibitors requires careful monitoring for adverse events like neutropenia, QTc prolongation, and diarrhea, as well as evaluation of drug–drug interactions and patient-specific comorbidities to ensure safety and adherence.

Brief Overview
In the past decade, we have seen the approval of 3 CDK 4/6 inhibitors, 3 PI3-kinase pathway inhibitors, an oral SERD and 3 antibody–drug conjugates for the treatment of HR-positive/HER2-negative metastatic breast cancer (MBC). The availability of these novel therapeutics has been associated with significant improvements in long-term outcomes for patients. Understanding the indications for each of these therapies as well as their associated risks is critical as we begin to incorporate their use in standard practice. 

First-line Trials of ET ± CDK4/6 Inhibitor vs ET for Patients With HR-Positive/HER2-Negative MBC Without Actionable Mutations
Four large randomized, phase III clinical trials investigated the use of a CDK4/6 inhibitor plus endocrine therapy (ET) as first-line therapy for patients with HR-positive/HER2-negative MBC (PALOMA-2, MONALEESA-2, MONALEESA-7, and MONARCH 3). PALOMA-2 investigated palbociclib, MONALEESA-2 and MONALEESA-7 assessed ribociclib, and MONARCH 3 evaluated abemaciclib. All 4 trials showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with the addition of a CDK4/6 inhibitor to ET with a strikingly similar HR of approximately 0.50. Overall survival (OS) was significantly improved with the addition of ribociclib to ET in MONALEESA-2 and MONALEESA-7 whereas there was a strong trend toward statistical significance in OS in MONARCH 3. In PALOMA-2, there was no statistical significance in OS with the addition of palbociclib to ET. All 3 CDK4/6 inhibitors have also shown significant PFS benefits when added to fulvestrant in the second-line setting after first-line single-agent ET based on results from PALOMA-3, MONARCH 2, and MONALEESA-3. Abemaciclib and ribociclib have been shown to also improve OS in this setting.

First-line Trials of CDK4/6 Inhibitor + ET vs Chemotherapy for Patients With HR-Positive/HER2-Negative MBC Without Actionable Mutations
Multiple studies including the phase III PADMA trial and the phase II RIGHT Choice trial have interrogated whether patients should preferentially receive chemotherapy for symptomatic or high-risk HR-positive/HER2-negative MBC as first-line therapy. RIGHT Choice evaluated ribociclib plus ET and ovarian suppression vs physician’s choice of combination chemotherapy for aggressive advanced or MBC among young patients and demonstrated a statistically significant improvement in PFS with the addition of ribociclib to ET and ovarian suppression. PADMA evaluated induction therapy with palbociclib plus ET vs physician’s choice of chemotherapy with or without maintenance ET for patients with higher-risk advanced breast cancer (ABC). This study demonstrated that the use of palbociclib plus ET significantly prolonged time to treatment failure and PFS compared with chemotherapy. Data from PADMA and Right Choice indicate that even for patients who are newly diagnosed with aggressive, high-risk HR-positive/HER2-negative MBC, the use of a CDK4/6 inhibitor–based treatment strategy leads to improved outcomes compared with chemotherapy.

Trials for Patients With HR-Positive/HER2-Negative ABC Harboring Actionable Alterations
For patients who experience disease recurrence while on or within 12 months of taking an adjuvant aromatase inhibitor (AI), it is now standard practice to perform next-generation sequencing (NGS) on a tumor sample or circulating-tumor DNA. In addition, once a patient has experienced disease progression on first-line therapy, tumor genomic profiling to detect the presence of an actionable tumor genomic alteration should be performed. If no such alteration is detected by liquid circulating-tumor DNA testing initially, reflex-to-tissue analysis using NGS is recommended. The results from such testing should guide the selection of the next line of therapy for patients.

The phase III INAVO120 study evaluated the use of the PI3-kinase inhibitor inavolisib in combination with palbociclib and fulvestrant for patients with PIK3CA-mutated, HR-positive/HER2-negative locally advanced or MBC with disease recurrence during or within 12 months of completing adjuvant ET. The addition of inavolisib to palbociclib and fulvestrant demonstrated a statistically significant improvement in PFS vs placebo plus palbociclib and fulvestrant. Overall, the combination was well tolerated. Based on these results, inavolisib in combination with palbociclib and fulvestrant received FDA approval for adults with endocrine-resistant, PIK3CA-mutated, HR-positive/HER2-negative, locally advanced or MBC. Of note, patients on INAVO120 were required to have a glycated hemoglobin less than 6.0% and a fasting glucose level less than 126 mg/dL to be eligible.

Two other PI3-kinase-pathway inhibitors are approved for patients with PIK3CA-mutated disease after first-line endocrine-based therapy. The phase III SOLAR-1 trial demonstrated significantly prolonged PFS by adding alpelisib to fulvestrant in men and postmenopausal women with HR-positive/HER2-negative, PIK3CA-mutated ABC after disease progression during or after AI therapy (NCT02437318). Capivasertib combined with fulvestrant is available for patients with disease harboring a PI3-kinase pathway alteration (PIKC3A, AKT1 or PTEN alterations) based on the results of the phase III CAPItello-291 trial, which demonstrated a statistically significant improvement in PFS with capivasertib plus fulvestrant vs fulvestrant alone. Patients without an actionable PI3-kinase pathway alteration are candidates for ET alone or in combination with everolimus. If the disease is rapidly progressing after first-line therapy, chemotherapy-based options may be considered.

Patients with ESR1-mutant disease are eligible to receive elacestrant, an oral selective ER degrader. This is based on the results of the phase III EMERALD trial which showed a statistically significant improvement in PFS with elacestrant vs ET for patients with ER-positive/HER2-negative advanced breast cancer after receiving at least 1, but no more than 2 previous lines of ET for advanced breast cancer (NCT03778931).

Key Data From Real-world Studies, Adverse Event Management and Potential Drug–Drug Interactions
As with all medications, cancer treatments come with side effects. All 3 CDK4/6 inhibitors are associated with neutropenia, but it is most commonly seen with ribociclib and palbociclib. Patients should be monitored for neutropenia, especially during the first several months of therapy. Diarrhea is another adverse event (AE) associated with all 3 CDK4/6 inhibitors, but it is most commonly reported with abemaciclib. Patients should be warned about this potential AE and prepared to have antidiarrheals at home for immediate use when needed. Other significant but less common AEs are interstitial lung disease with any CDK4/6 inhibitor, venous thromboembolism with abemaciclib, and QTc prolongation with ribociclib.

A retrospective, real-world, cross-sectional cohort study of 24,340 women aged 18 years or older at initial diagnosis of HR-positive/HER2-negative MBC demonstrated that approximately 16% of patients with HR-positive/HER2-negative MBC have a congenital long QT syndrome, cardiovascular disease, or an electrolyte abnormality that could place them at higher risk of QTc prolongation with ribociclib. The risk of QTc prolongation increases with increasing age. Therefore, it is important for healthcare professionals to be mindful of this when prescribing drugs like ribociclib and be aware of concomitant medications that may also increase the risk of QTc prolongation such as antiemetics, analgesics, antibiotics, antidepressants, antipsychotics, diuretics, and proton pump inhibitors.

Data from real-world studies are important as they provide evidence regarding the safety and effectiveness of new therapies in patients being treated outside of the tightly controlled context of a clinical trial. As we begin to prescribe newly approved agents, it is important to be cognizant of a patient's comorbid conditions and concomitant medications in addition to their laboratory and ECG results. Proactive monitoring and management of patients receiving CDK4/6 inhibitors will optimize treatment adherence and improve patient safety.

Conclusions
In summary, we have seen profound improvements in patient outcomes with the use of CDK4/6 inhibitor–based therapies for patients with HR-positive/HER2-negative ABC. CDK4/6 inhibitors are currently the gold standard of care in the first- or second-line setting. Individualized treatment decisions should be made after a nuanced discussion with the patient about the safety, AEs, and potential for drug–drug interactions with each of these CDK4/6 inhibitors. Of great importance, the patient’s treatment goals should be considered before choosing among these 3 CDK4/6 inhibitors, in particular, because some patients will remain on these agents for several years. Healthcare professionals should not hesitate to involve the expertise of a multidisciplinary team, including pharmacists, palliative care providers, and relevant subspecialty colleagues to optimally manage patients with HR-positive/HER2-negative MBC who often have preexisting medical conditions for which they are already receiving treatment.

Your Thoughts
What questions do you have about CDK4/6 inhibitor–based treatment options for your patients with HR-positive/HER2-negative ABC? Answer the polling question and join the conversation in the discussion box below.

Continue

Poll

1.

Approximately what percentage of your patients with HR-positive/HER2-negative MBC have significant comorbidities that affect your treatment recommendation with CDK4/6 inhibitor–based therapies?

Submit