Dr Goetz on Post-CDK4/6 Inhibitor Treatment Options in HR-Positive Breast Cancer

Matthew P. Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses the available treatment options for patients with metastatic hormone receptor (HR)–positive breast cancer in the post-CDK inhibitor setting.

The treatment armamentarium for patients with HR-positive breast cancer whose disease has progressed following prior treatment with a CDK4/6 inhibitor has greatly expanded in recent years, Goetz begins. In order to guide treatment navigation and optimize outcomes for these patients, it is necessary to define their molecular subtype and identify any actionable mutations, Goetz says. For example, BRCA1/2 and PALB2 mutations indicate that a patient may respond favorably to PARP inhibitors. Other actionable biomarkers include PIK3CA, which is targeted by alpelisib (Vijoice), and ESR1 mutations, which is targeted by elacestrant (Orserdu), Goetz lists.

In addition to these targeted therapies, several therapeutic options in this space may not require the identification of specific biomarkers, Goetz adds. One emerging option is the orally bioavailable, small-molecule AKT inhibitor capivasertib. The agent has been granted priority review by the FDA when administered alongside fulvestrant (Faslodex) for patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer who experienced recurrence or progression on or after endocrine-based therapy. Capivasertib was also granted fast track designation for use in this population in January 2023.

Data supporting the use of this agent indicate that it provides benefit regardless of whether patients' tumors harbor PIK3CA, AKT1 or PTEN alterations in the AKT pathway, indicating that there may not be a need to select patients based on the presence or absence of these mutations, Goetz details. Future investigations of capivasertib may continue to explore its efficacy in combination with other approved drugs in the HR-positive space, he notes.

Lastly, antibody-drug conjugates (ADCs), such as fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd), provide another effective option for patients in the post-CDK4/6 inhibitor space, Goetz states. T-DXd is currently approved by the FDA for the treatment of patients with unresectable or metastatic HER2-low breast cancer, as well as HER2-positive disease, he says. Another well-established ADC is sacituzumab govitecan-hziy (Trodelvy), which is effective for patients with estrogen receptor–positive disease that is refractory to standard therapies, but is not associated with other biomarkers, Goetz concludes.