CDK4/6 Inhibitors, SERDs, and More in NCCN Talk on Breast Cancer Updates

Describing the latest updates from the National Comprehensive Cancer Network (NCCN) as tales of “escalation and de-escalation,” William J. Gradishar, MD, of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, on Thursday offered an overview of guidelines for treatment of HER2-negative breast cancer, with some updates in triple-negative breast cancer (TNBC).

NCCN guidelines are no longer “a group of monotherapy choices,” but selections that feature partners for endocrine therapy, he highlighted.

“What is dominant in this partnership is CD4/6 inhibitors, at least at the outset,” said Gradishar, who discussed the importance of the MONALEESA trials for ribociclib, especially the overall survival (OS) benefit seen in the MONALEESA-7 trial. MONALEESA-7, he said, was unique because it included premenopausal patients.

He also reviewed results for PALOMA 3, which found that OS was favorable for palbociclib and fulvestrant compared with fulvestrant plus placebo, regardless of a patient’s mutational status.

Among the questions to be addressed at this year’s meeting of the American Society of Clinical Oncology is how long patients should stay on CDK4/6 inhibitors. Gradishar said the MAINTAIN trial, as well as the PACE and TRINITY trials, will ask the question, “Whether or not after disease progression, is there merit in continuing a CDK4/6 inhibitor, either the same one or a different one?”

SERDs. Gradishar reviewed trials involving oral selective estrogen receptor degraders (SERDs). While fulvestrant is approved, newer-generation therapies are in development to offer a solution for treating patients after CDK4/6 inhibitors. He spent time reviewing results from the phase 3 EMERALD study comparing elacestrant vs stand of care; elacestrant demonstrated superior progression-free survival (PFS) in all patients but especially among those with mutated ESR1.

PARP inhibitors. In understanding the role of PARP inhibitors, Gradishar said,it helps to understand the numbers: Although the percentage of patients in HER2-negative breast cancer with germline BRCA is smaller (5%), the universe is so much larger that the resulting population ends up being about 10,000 patients per year. By contrast, a higher share of patients with TNBC harbor a BRCA mutation (14%), but this ends up being about 4800 patients per year.

Gradishar keyed in on findings from the OlympiAD (olaparib) and EMBRACA (talazoparib) phase 3 trials, both of which resulted in significant improvement in PFS and quality of life, but not OS compared with chemotherapy. “One thing I would just point out is that there is a suggestion, at least based on the OlympiAD data, that if you've not [received] prior therapy, you're more likely to benefit—so no prior chemotherapy for metastatic disease; that group clearly had about a 7-month advantage in terms of overall survival.”

Immunotherapy. Gradishar covered the major development of the year: Genetech’s voluntary withdrawal of the indication for atezolizumab after the IMPassion131 trial did not meet its primary end point in TNBC. However, he said, there was a lot of knowledge gained from these trials, including an understanding of adverse effects and the role of testing in determining who should have checkpoint inhibitors.

Antibody drug conjugates. The mechanism of ADCs involves attaching a small molecule agent to an antibody with a linker to target a specific antigen on the tumor. Gradishar discussed the phase 3 ASCENT study involving sacituzumab govitecan (SG), which is now a preferred regimen for metastatic TNBC. Patients in ASCENT had at least 2 prior lines of therapy. SG targets TROP2, a cell surface protein that is associated with aggressive tumor behavior but is hardly seen in normal tissue.

Results from ASCENT presented at the San Antonio Breast Cancer Symposium in December 2021 showed significant improvement in overall survival, with a near doubling among patients at least 65 years of age (6.7 vs 12.1 months). The trial was halted early due to these responses.

Asked to summarize the latest NCCN updates, Grandishar said there are some recommendations to intensify therapy where patients are higher risk, and other cases where therapy can be eased. “We may not be giving endocrine therapy to everybody forever,” he said. “I think it is an issue that is really summarized by saying, ‘We're getting better at tailoring our therapy, enhancing it for high-risk patients, and perhaps de-escalating it for those with lower risk of recurrence.’”