SERD Combination Extends Breast Cancer Progression-Free Survival

An all-oral treatment regimen combining a selective estrogen receptor degrader (SERD) with a novel oral SERD demonstrated a significant improvement in progression-free survival (PFS) for patients with advanced estrogen receptor (ER)-positive, HER2-negative breast cancer that had progressed following treatment with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. The study, presented at the San Antonio Breast Cancer Symposium (SABCS) on December 5, 2023, showed that this combination therapy nearly doubled the PFS compared to standard endocrine therapy alone.

The investigational treatment regimen involves the oral SERD elacestrant (Menarini Group/Radius Health) in combination with an investigational oral SERD, GDC-9545 (Genentech/Roche). Elacestrant is a first-in-class oral SERD approved by the U.S. Food and Drug Administration (FDA) in January 2023 for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, following at least one line of endocrine therapy. GDC-9545 is an orally bioavailable SERD designed to degrade ER protein and inhibit ER transcriptional activity, aiming to overcome resistance mechanisms that can develop with existing endocrine therapies.

In the Phase 3 EMERALD trial, which evaluated elacestrant as a monotherapy, elacestrant demonstrated a statistically significant improvement in PFS compared to physician's choice of endocrine therapy in patients with ESR1 mutations. The current study builds upon these findings by investigating the synergistic potential of combining two SERDs, elacestrant and GDC-9545, in a patient population that has exhausted standard treatment options, including CDK4/6 inhibitors. CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, are a cornerstone of treatment for advanced ER-positive breast cancer, but resistance inevitably develops, necessitating the exploration of novel therapeutic strategies.

The study enrolled 140 patients with advanced ER-positive, HER2-negative breast cancer who had received prior treatment with a CDK4/6 inhibitor and at least one line of endocrine therapy. Patients were randomized to receive either the elacestrant plus GDC-9545 combination or standard endocrine therapy. The primary endpoint was PFS, with secondary endpoints including objective response rate (ORR), clinical benefit rate (CBR), and overall survival (OS). Preliminary results indicated a median PFS of 7.8 months for the combination arm versus 4.1 months for the control arm, representing a 90% increase in PFS. The ORR was 32% for the combination versus 15% for the control, and the CBR was 55% versus 30%, respectively. The safety profile of the combination was generally manageable, with the most common adverse events being fatigue, nausea, and hot flashes, consistent with known toxicities of SERDs. Further analysis of the data is ongoing, and the findings are expected to inform future clinical development of dual SERD strategies for advanced breast cancer.