Dr Brufsky on Unmet Needs and Unanswered Questions in HR+/HER2– Breast Cancer

Adam M. Brufsky, MD, PhD, FACP, professor, medicine, associate division chief, Division of Hematology/Oncology, Department of Medicine, the University of Pittsburgh School of Medicine; medical director, the Magee-Women's Cancer Program, associate director, clinical investigation, codirector, the Comprehensive Breast Cancer Center, UPMC Hillman Cancer Center, discusses remaining questions and unmet needs following the FDA approval of capivasertib (Truqap) in combination with fulvestrant (Faslodex) in hormone receptor–positive, HER2-negative breast cancer.

On November 16, 2023, the FDA approved this treatment combination for patients with locally advanced or metastatic hormone receptor–positive, HER2-negative breast cancer harboring 1 or more PIK3CA, AKT1, or PTEN alterations based on data from the phase 3 CAPItello-291 trial (NCT04305496). With this approval, new unmet needs have surfaced. Investigators continue to question the rationale behind not initiating treatment in the first line and waiting until disease progression. Patients with poor prognostic features, such as recurrence on aromatase inhibitor or within 12 months of stopping adjuvant hormone therapy, or those with PI3K mutations, may have a worse prognosis with this approach, Brufsky begins. In response, investigators assessed these patients in a phase 3 study, he states.

Notably, the major adverse effect (AE) observed with the combination was hyperglycemia, which was expected. Although these initial data are intriguing, updates are highly anticipated, he emphasizes. Nevertheless, this could potentially offer an advanced upfront PI3K inhibitor–containing regimen for challenging, primarily endocrine-resistant patients—a population with notable unmet need, Brufsky explains.

Looking to other unmet needs, the sequencing of ADCs also remains a significant concern in breast cancer, particular for patients who develop drug resistance, Brufsky expands. The current sequence of therapy involves hormone therapy, CDK4/6 inhibitors, and an oral selective estrogen receptor degrader, he explains. However, the there is a lack of consensus on what regimens should be administered next after these options are exhausted.

Many oncologists turn to chemotherapy with capecitabine (Xeloda), but the challenge lies in deciding the appropriate sequence thereafter, he continues. For HER2-low patients, fam-trastuzumab deruxtecan-nxki (Enhertu) is an option, and HER2-zero patients may consider sacituzumab govitecan-hziy (Trodelvy), Brufsky imparts. Both are distinct ADCs with different toxicity profiles. One is a 3-week drug with notable AEs, including nausea, hair loss, and potential interstitial lung disease (ILD), he emphasizes. The other is a day 1/ day 8 drug with different AEs like neutropenia, mild nausea, alopecia, and diarrhea. Although managing these toxicities is feasible, uncertainties persist regarding the optimal approach in this setting, he concludes.