Dr Goetz on the Development of Novel Approaches in Endocrine-Resistant HR+ Breast Cancer

ADCs are exciting. We’re all excited about ADCs, but at the end of the day, ADCs are chemotherapy. The consideration for new and better targeted approaches for treating patients with ER-positive [breast cancer] that will allow us to delay chemotherapy is going to be a major focus over the next 10 to 15 years.

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 unmet needs in endocrine-resistant, hormone receptor (HR)–positive, HER2-negative advanced breast cancer, emphasizing the development of agents such as gedatolisib (Revtorpyk), treatment sequencing considerations, and the potential for targeting multiple resistance pathways as approaches to improving outcomes for this patient population.

Goetz contrasted this endocrine-resistant population with patients with endocrine-sensitive disease, including de novo presentations or recurrence after a prolonged treatment-free interval. These patients often respond well to a CDK4/6 inhibitor plus endocrine therapy, whereas endocrine resistance creates a need for additional targeted approaches.

Gedatolisib is an intravenous inhibitor targeting all class I PI3K isoforms and the mTORC1 and mTORC2 complexes, providing broad blockade of the PI3K/AKT/mTOR pathway, and in July 2026, the FDA approved gedatolisib with fulvestrant (Faslodex), with or without palbociclib (Ibrance), for the treatment of adult patients with HR-positive, HER2-negative advanced breast cancer without a PIK3CA mutation following progression on or after treatment with 1 or more lines of endocrine therapy in the metastatic setting.

Goetz identified sequencing as a major unresolved question after resistance to standard CDK4/6 treatment. He asked whether gedatolisib should be used earlier or reserved until after progression on an investigational oral allosteric PI3K inhibitor, considering the potential tolerability advantages of these emerging agents.

A separate consideration involves tumors harboring both ESR1 and PIK3CA mutations. Goetz questioned whether therapies should be administered sequentially or whether both pathways should be targeted together. He favored the investigation of combined targeting in this setting, citing imlunestrant alongside a PI3K-targeted agent as a potential approach requiring further evaluation.

Despite enthusiasm for targeted drugs, Goetz emphasized that the duration of benefit remains limited for many patients. More effective endocrine-based strategies could help postpone chemotherapy and address the ongoing need for durable disease control after resistance develops to standard endocrine treatment regimens.

He also acknowledged interest in antibody-drug conjugates while emphasizing that these agents essentially deliver chemotherapy. Developing better targeted approaches that delay chemotherapy remains, in his view, a major research priority for HR-positive breast cancer over the next 10 to 15 years.