The treatment landscape for endocrine therapy (ET) in hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer has been remarkably changed over the past 10 years. In addition to the development of increasingly effective ET drugs, we have the benefit of a portfolio of “helper” drugs that augment effectiveness of ET in both the metastatic and nonmetastatic settings, particularly the CDK4/6 inhibitors. There are three FDA-approved drugs for breast cancer in this class – palbociclib, ribociclib, and abemaciclib, which have been added to first- and second-line ET over the past 5-10 years in metastatic breast cancer, and more recently have entered the curative intent arena. These drugs are expensive but increase progression-free survival (PFS) by two-fold compared with ET alone in either first- or second-line setting; this benefit translates to an approximate 2-year progression-free interval on first-line therapy with ET plus CDK4/6 inhibition and has resulted in the combination of ET plus CDK4/6 inhibition as the recommended first-line therapy for metastatic HR+/HER2-disease. Although the benefits are unquestioned, these are expensive and relatively toxic drugs; an unanswered question has been whether (and in whom) use of the CDK4/6 inhibitor can be delayed to second- or later-line, reserving the less toxic ET alone option for the first-line setting. At ASCO 2023, the SONIA trial (BOOG 2017-03, NCT03425838) was reported. This pragmatic trial compared CDK4/6 inhibition (> 90% used palbociclib) added to first-line ET versus reserving it for second-line, finding a nonsignificant 4-month difference in PFS after the second line of therapy, nor a difference in overall survival.
Other drugs added to ET for metastatic disease in the second- or later-line setting include those that interfere with the PI3K-AKT-mTOR signaling cascade that is implicated in ET resistance. Several drugs in this class have demonstrated effectiveness when added to ET in later-line metastatic disease, including the PI3K inhibitor alpelisib in patients with PIK3CA mutation-containing tumors, the mTOR1/2 inhibitor everolimus, and, more recently, the AKT inhibitor capivasertib, which demonstrated doubling of PFS from 3.6m to 7.2m when added to second-line ET with fulvestrant.
In 2021, the CDK4/6 inhibitor abemaciclib was FDA-approved in the early, nonmetastatic setting added to ET for curative intent in high-risk node-positive HR+ disease on the basis of the MonarchE trial testing ET plus abemaciclib given for the first two years of adjuvant ET. Abemaciclib improved 3-year invasive disease-free survival (iDFS) by 4.8% (from 84.4% to 89.2%), a difference that had broadened to 6.4% by the year 4 analysis. This is a costly drug, in the U.S. ET alone typically costs less than $1000 per year, whereas abemaciclib wholesale acquisition costs for a 24-month course is approximately $350,000 (although actual costs vary substantially by payer). In addition to cost, these drugs are far more toxic than ET alone and require far more active monitoring. In addition to neutropenia and fatigue, abemaciclib causes significant diarrhea in 8% of patients; in the MonarchE trial 44% required dose reductions on the basis of side effects.
At ASCO 2023 was the first presentation of NATALEE (NCT 03701334), an adjuvant trial incorporating ribociclib into the first three years of adjuvant ET in HR+/HER2- breast cancer that was either node-positive, or high-risk node-negative. While patients with node-negative disease were allowed in NATALEE (unlike MonarchE), these patients comprised fewer than 30% of the study population, which was mostly stage III disease, so NATALEE, like MonarchE, mostly included those at high clinical risk. In NATALEE, the 3y iDFS benefit was a statistically significant 3.3% (from 87.1% to 90.4%); notable side effects included neutropenia, fatigue, and liver function abnormalities, with less diarrhea than is seen with abemaciclib. A particular concern with ribociclib is QTc prolongation; the lower dose used in the adjuvant trial succeeded in reducing this risk to < 5%, almost all of which were minimal and without clinical consequence. Approximately 19% prematurely stopped ribociclib, mostly due to toxicity. Thus, ribociclib may provide an alternative to abemaciclib in the adjuvant setting, one that has less symptomatic toxicities although almost certainly similar financial toxicities, and a longer duration of therapy that has greater patient burden.
Among the biggest challenges for rationally treating HR+ HER2- disease in either metastatic or early settings is the reliance on clinical variables to drive therapeutic decision-making; beyond PIK3CA mutations for use of alpelisib and acquired ESR1 mutations for the selective estrogen receptor down regulator (SERD) elacestrant we lack predictive biomarkers for the majority of decisions we and our patients face. Promising directions include on treatment biopsies for ET sensitivity and the use of circulating biomarkers such as circulating tumor DNA (ctDNA) to help tailor therapy. A ctDNA analysis from the adjuvant palbociclib trial PENELOPE-B demonstrated that of 129 ET-naïve patients, 9% had measurable ctDNA at initial evaluation and another 4% over the next 12 months. Patients with positive ctDNA had exceptionally poor outcomes; although too small for interpretation there was a suggestion that the CDK4/6 inhibitor impact was largely in the ctDNA-positive population. It should be noted that both treatment and biology of HR+ HER2- disease is evolving; for example, we do not know what the impact of adjuvant CDK 4/6 inhibitors will have on sensitivity to the same class of drugs in the metastatic setting (although we assume there will be an impact).
In the meantime, current treatment for HR+ HER2- early breast cancer remains ET of various types (aromatase inhibitor (AI) or tamoxifen, ovarian function suppression in premenopause) for 5-10 years. We consider adding abemaciclib for the first two years in node-positive breast cancer either on the basis of 4 or more involved lymph nodes or 1-3 lymph nodes with other negative prognostic features such as high grade or large size. Ribociclib for the first three years may soon be a different CDK 4/6 inhibitor option for these patients as well as those with high-risk node-negative tumors such as grade 3 or grade 2 with poor risk biology by Ki67 or genomic profiling.
For metastatic disease, the ET options are more varied with a nonsteroidal AI as the usual first-line treatment, followed by the intramuscular SERD fulvestrant or, if an ESR1 mutation is present, the oral SERD elacestrant, but multiple other ET options exist including tamoxifen, the steroidal AI exemestane, and others. These drugs, which depend on estrogen signaling to be a dominant driver of tumor growth, are often accompanied by CDK 4/6 inhibitors in first- or second-line, although usually first-line. If PIK3CA mutations are detected in blood or tumor, the PI3K inhibitor alpelisib can be added to fulvestrant as can everolimus to fulvestrant or exemestane, and now the AKT inhibitor capivasertib appears to provide similar benefits added to fulvestrant in the pretreated setting.
With the incorporation of CDK 4/6 inhibitors, disease-free survival has improved by over 6% in the early nonmetastatic setting, and overall survival in the metastatic setting has similarly improved. We anticipate that additionally nuanced approaches to tailoring therapy will continue to improve outcomes as well as quality of life.
Dr. Carey has no conflicts of interest to report.
Illustration by Jennifer Bogartz
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