Dr Rugo on the Evolving Role of SERDs/Targeted Therapies in Advanced HR+ Breast Cancer

“These drugs are revolutionizing our approach to the [management] of metastatic disease, offering new treatment options that will prolong the duration of oral therapy.”

Hope S. Rugo, MD, a professor in the Department of Medical Oncology & Therapeutics Research, division chief of Breast Medical Oncology, and the director of the Women’s Cancers Program at City of Hope, discussed how targeted therapies and novel oral selective estrogen receptor degraders (SERDs) are positioned to alter the treatment paradigm for patients with advanced hormone receptor (HR)–positive breast cancer.

One significant focus of ongoing research is triplet regimens such as inavolisib (Itovebi), palbociclib (Ibrance), and fulvestrant (Faslodex), which is being evaluated in the phase 2/3 INAVO120 trial (NCT04191499) for patients with PIK3CA-mutated, advanced, HR-positive breast cancer, Rugo began. This study enrolled patients with early relapsed or metastatic disease who had progressed during or shortly after adjuvant endocrine therapy. Results demonstrated both a progression-free survival (PFS) and overall survival benefit with the regimen compared with fulvestrant plus palbociclib, according to Rugo.

However, Rugo noted a critique of the study: patients in the control arm rarely received a PIK3CA inhibitor upon progression. Because data are lacking regarding the efficacy of adding agents such as inavolisib or alpelisib (Piqray) for patients already progressing on endocrine therapy partners, this triplet provides a strengthened clinical option, she said. A primary concern for the future application of this regimen is hyperglycemia management, as patients with abnormal glucose control were excluded from the trial, Rugo noted. She emphasized that education and proactive treatment strategies are essential to manage PIK3CA inhibition–related metabolic toxicities.

Another key area of investigation involves the integration of oral SERDs with targeted agents, Rugo continued. The phase 3 evERA Breast Cancer trial (NCT05306340) evaluated giredestrant (GDC-9545) plus everolimus (Afinitor) in the second line for patients with endocrine-sensitive metastatic breast cancer enriched for ESR1 mutations. Although PFS improvements were most notable in the cohort of patients harboring ESR1 mutations, overall response rates improved regardless of mutation status, suggesting that the use of targeted agents may overcome ESR1 wild-type resistance, Rugo explained. She highlighted the necessity of managing treatment-emergent toxicities, such as stomatitis, through steroid mouthwashes and patient education. Finally, Rugo proposed a shift in toxicity reporting, suggesting that the duration of high-grade toxicities, rather than just the rate, is critical for oncologists to accurately balance treatment options and maintain patient quality of life.