The treatment landscape for estrogen receptor (ER)-positive advanced breast cancer is evolving with the emergence of novel anti-estrogen therapies, offering new hope for patients who have progressed on CDK4/6 inhibitor-based treatments. These advancements aim to address the limitations of current standard-of-care approaches and provide more personalized treatment strategies. Seth Wander, MD, PhD, highlighted the potential of these agents, stating, "There are amazing opportunities, both in clinical trials right now and soon in standard practice, across the spectrum with these agents."
INAVO120 Trial: A Promising Triplet Combination
The phase 3 INAVO120 trial (NCT04191499) investigated the PI3K pathway inhibitor inavolisib (GDC-0077) in combination with palbociclib (Ibrance) and fulvestrant (Faslodex) for patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer who had progressed on adjuvant endocrine therapy. The primary data revealed a significant improvement in median progression-free survival, with 15.0 months for the triplet combination compared to 7.3 months for palbociclib and fulvestrant alone (HR, 0.43; 95% CI, 0.32-0.59; P < .0001).
Updated findings presented at the 2024 ASCO Annual Meeting further underscored the benefit of the inavolisib combination. The median time from randomization to the end of next-line treatment was 24.0 months in the inavolisib arm versus 15.1 months in the palbociclib/fulvestrant arm (HR, 0.54; 95% CI, 0.38-0.77).
Addressing Unmet Needs in ER-Positive Breast Cancer
Wander emphasized the need for better strategies for patients with higher-risk disease who progress on adjuvant anti-estrogen-based therapy. He noted that the INAVO120 study demonstrated the benefit of the triplet combination in patients with PIK3CA mutations who progressed on adjuvant anti-estrogen therapy. Conversely, he also pointed out that some patients with slower-growing, indolent disease might benefit from avoiding CDK4/6 inhibitors in the first-line metastatic setting.
"One of the key unmet needs here is understanding how this population is spreading out across this spectrum," Wander explained. "Who may be able to get away with endocrine therapy alone? Who needs more aggressive up-front therapy, even with a triplet combination?"
Novel Anti-Estrogen Therapies: A Spectrum of Approaches
The landscape of novel anti-estrogen therapies includes oral selective estrogen receptor degraders (SERDs), selective estrogen receptor modulators (SERMs), proteolysis-targeting chimeras (PROTACs), and covalent ER antagonists. Elacestrant (Orserdu) was the first oral SERD to receive FDA approval, based on the phase 3 EMERALD trial (NCT03778931).
Wander highlighted the importance of genomic sequencing to identify patients who may benefit from specific targeted therapies, such as alpelisib (Vijoice) or capivasertib (Truqap) for patients with PI3K pathway alterations, or novel next-generation anti-estrogen agents for patients with ESR1 alterations.
The Future of Personalized Treatment
As these novel agents continue to advance through clinical development, the challenge will be to determine which patients will benefit most from each category of agent. Researchers are exploring clinical parameters and genomic and molecular features to guide treatment decisions, aiming to personalize therapy based on individual patient characteristics. The ultimate goal is to optimize treatment strategies by identifying the most effective agents and combinations for each patient subgroup.
