Dr Goetz on the Navigation of Oral SERDs and Targeted Therapy in Advanced Breast Cancer

Here with the PROTACs, this is the first drug, BTX-9341, that is targeting 4 and 6 for degradation, whereas all other drugs are kinase inhibitors. So we’re very excited to see what happens when you degrade 4 and 6, especially 6, especially since CDK6 appears to be an escape mechanism.

Matthew P. Goetz, MD, the Erivan K. Haub Family Professor of Cancer Research Honoring Richard F. Emslander and deputy director of Mayo Clinic Comprehensive Cancer Center, discussed evolving targeted approaches for hormone receptor (HR)–positive, HER2-negative advanced breast cancer, including oral selective estrogen receptor degraders (SERDs), PI3K-targeted therapies, and next-generation CDK-directed treatments.

Goetz examined research aiming to determine if replacing an aromatase inhibitor with an oral SERD improves outcomes when combined with a CDK4/6 inhibitor in the up-front setting. He highlighted the phase 3 persevERA Breast Cancer trial (NCT04546009) evaluating giredestrant and the SERENA-4 trial (NCT04711252) evaluating camizestrant (Etcamah); neither demonstrated a statistically significant progression-free survival advantage over an aromatase inhibitor plus palbociclib (Ibrance). He notes that tolerability or quality-of-life differences may still warrant consideration, although these trials did not establish superior disease control with the oral SERD–based combinations.

Turning to PIK3CA-mutated disease, Goetz explained that agents targeting the PIK3 pathway have been approved in later lines of treatment for select patients with HR-positive disease. He highlighted inavolisib (Itovebi) plus palbociclib and fulvestrant (Faslodex), as evaluated in the phase 3 INAVO120 trial (NCT04191499) that supported the combination’s 2024 FDA approval for patients with endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer following recurrence on or after completing adjuvant endocrine therapy. The triplet improved outcomes compared with palbociclib and fulvestrant alone. However, he raised questions about how this strategy compares with other available PI3K-, AKT-, or mTOR-directed approaches, since those were not utilized in the control arm of INAVO120, Goetz explained tolerability challenges with alpelisib (Piqray), which some patients will not be candidates for due to its adverse effect profile. He described investigational allosteric PI3K inhibitors as promising candidates that may reduce adverse effects such as hyperglycemia, with ongoing phase 3 studies evaluating their activity in patients with PIK3CA-mutated tumors.

Beyond PI3K targeting, Goetz discussed selective CDK4 inhibitors, including atirmociclib (PF-07220060), and the investigational CDK4/6 degrader BTX-9341. Unlike conventional CDK4/6 inhibitors, which inhibit kinase activity, BTX-9341 is designed to remove the CDK4 and CDK6 proteins through targeted degradation.

He emphasized interest in determining whether this different mechanism can address resistance, particularly because CDK6 may serve as an escape pathway. Goetz identified ongoing clinical trials as essential to clarifying their therapeutic roles and whether their potential advantages translate into meaningful benefits for patients in the advanced disease setting.