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Optimizing Tx of HRpos HER2neg MBC

CME

Optimizing Treatment for Patients With HR-Positive/HER2-Negative MBC

Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™

Released: March 24, 2025

Expiration: September 23, 2025

Sara A. Hurvitz
Sara A. Hurvitz, MD, FACP
CME/CE Information

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Current Treatment Algorithm for Patients With HR+/HER2- MBC

Patients who are newly diagnosed with HR-positive/HER2-negative MBC and have experienced disease recurrence more than 12 months after completing adjuvant AI therapy, or those without prior AI exposure should initiate treatment with a nonsteroidal aromatase inhibitor (NSAI) in combination with a CDK4/6 inhibitor.1,2 Ribociclib is the CDK4/6 inhibitor associated with the highest level 1 evidence for PFS and OS benefits in this setting based on the results of the MONALEESA-2 and MONALEESA-7 clinical trials.3-7 For select patients, however, the use of abemaciclib or palbociclib in this setting may also be appropriate as both CDK4/6 inhibitors have been shown to significantly improve the PFS when added to an NSAI in the MONARCH 3 and PALOMA-2 trials, respectively.8,9 

For those patients who experience disease recurrence while on adjuvant AI or within 12 months of completing adjuvant AI therapy, the addition of ribociclib or abemaciclib to fulvestrant has been associated with significant improvements in PFS and OS  based on data from the MONALEESA-3 study and MONARCH 2 trial, respectively vs fulvestrant alone.10-12 For select patients who are not candidates for ribociclib or abemaciclib in combination with fulvestrant, the use of palbociclib plus fulvestrant would be appropriate based on improved PFS and a trend toward an improvement in OS associated with this combination vs fulvestrant alone in the PALOMA-3 trial.13,14

Recently, it has become standard of care to perform NGS on patient’s tumor samples or circulating-tumor DNA at the time of disease recurrence while on an adjuvant AI or within 12 months of completing adjuvant AI.1,2 This is because the INAVO120 study indicated that the use of inavolisib in combination with palbociclib and fulvestrant is beneficial for patients whose tumors harbor a PIK3CA mutation.15

Once a patient has experienced disease progression on first-line therapy, tumor genomic profiling should be done to detect the presence of an actionable tumor genomic alteration. If no such alteration is detected by liquid circulating-tumor DNA testing initially, reflex-to-tissue analysis using NGS should be performed.16 The results may guide the selection of the next line of therapy.

Patients with disease harboring an ESR1 mutation are eligible to receive a selective ER degrader such as elacestrant.17 This is based on the results of the phase III EMERALD trial, which compared single-agent elacestrant with standard of care ET for patients with ER-positive, HER2-negative advanced breast cancer who have received at least 1, but no more than 2 previous lines of ET for advanced breast cancer (NCT03778931). This trial demonstrated a statistically significant improvement with elacestrant vs ET. The benefits were primarily seen in those patients with a tumor ESR1 mutation (HR: 0.55; 95% CI: 0.39-0.77; P = .0005).18

Patients with a tumor PIK3CA mutation who have not received prior fulvestrant are eligible to receive fulvestrant plus either alpelisib or capivasertib.19,20 The phase III SOLAR-1 trial evaluated the addition of alpelisib to fulvestrant vs fulvestrant alone for men and postmenopausal women with HR-positive, HER2-negative advanced breast cancer after disease progression during or after AI therapy (NCT02437318). In the cohort of patients with PIK3CA-mutated disease, the median PFS was significantly prolonged with the combination of alpelisib and fulvestrant vs fulvestrant alone (HR: 0.65; 95% CI: 0.50 to 0.85; P <.001).21

Patients with disease harboring a PI3 kinase pathway alteration based on the detection of 1 or more of PIKC3A, AKT1 or PTEN alterations are eligible to receive a PI3 kinase pathway inhibitor–based treatment (fulvestrant plus capivasertib).19 This is based on the results of the phase III CAPItello-291 trial of capivasertib plus fulvestrant vs placebo plus fulvestrant for patients with HR-positive, HER2-negative advanced breast cancer after recurrence or progression during or after treatment with an AI with or without prior CDK4/6 inhibitor–based therapy (NCT04305496). This trial demonstrated a statistically significant improvement in PFS with capivasertib plus fulvestrant vs fulvestrant alone in the population of patients with disease harboring an AKT pathway alteration (HR: 0.50; 95% CI: 0.38-0.65; P <.001).22

Patients without an actionable mutation in the PI3 kinase pathway should be considered for either single-agent ET or ET in combination with everolimus. If the disease is rapidly progressing after first-line therapy, chemotherapy-based options may also be considered.

Next, we will focus on the randomized studies that evaluated the use of CDK4/6 inhibitor–based therapy in the first-line setting for patients with advanced HR-positive/HER2-negative breast cancer. These include PALOMA-2, MONALEESA-2, MONALEESA-3, MONALEESA-7, MONARCH 3, Right Choice, PADMA and INAVO120.

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